The Design, Preparation, and Use of Chiral Organoaluminum Dibromide Lewis Acids in Asymetric Reactions

University of Calgary PRISM: University of Calgary's Digital Repository

Graduate Studies The Vault: Electronic Theses and Dissertations

2015-09-02 The Design, Preparation, and Use of Chiral Organoaluminum dibromide Lewis Acids in Asymetric Reactions

Warner, Thomas

Warner, T. (2015). The Design, Preparation, and Use of Chiral Organoaluminum dibromide Lewis Acids in Asymetric Reactions (Unpublished doctoral thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/28049 http://hdl.handle.net/11023/2425 doctoral thesis

University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. Downloaded from PRISM: https://prism.ucalgary.ca UNIVERSITY OF CALGARY

The Design, Preparation, and Use of Chiral Organoaluminum dibromide

Lewis Acids in Asymmetric Reactions

Thomas G. Warner

A THESIS

SUBMITTED TO THE FACULTY OF GRADUATE STUDIES

IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE

DEGREE OF DOCTOR OF PHILOSOPHY

GRADUATE PROGRAM IN CHEMISTRY

CALGARY, ALBERTA

AUGUST, 2015

This dissertation adds to the current knowledge of aluminum-based Lewis acids for use in asymmetric catalysis. A highly regioselective and diastereoselective hydroalumination of olefins was used to generate novel achiral and chiral organoaluminum dibromide compounds in situ. Low-temperature proton NMR binding studies were conducted with several different Lewis bases to prove that the Lewis acids coordinate reversibly to Lewis bases. These Lewis acids were investigated for their ability to promote and catalyze organic reactions including Diels-Alder, intramolecular

Diels-Alder, epoxide-opening and Strecker reactions.

Allylic O-benzylated dienophiles substituted with chiral oxazolidin-2-one auxiliaries were reacted with the sterically hindered diene 1,3,3-trimethyl-2-vinylcyclohexene to access a substituted drimane skeleton for natural product synthesis. The exo adduct was obtained as the major diastereomer in up to 60 % yield. Similar crotonic acid-derivatized dienophiles that were reacted with the same diene produced the endo adduct as the major product in up to 96 % yield.

The very first example of a chiral organoaluminum dibromide Lewis acid catalyzing a reaction asymmetrically is also described. The Diels-Alder reaction between methacrolein and cyclopentadiene was catalyzed in 80 % yield and 13.3 % ee, with an exo:endo ratio of 25:1. Additionally, the first example of an R*AlBr(OR*)-type Lewis acid catalyzing a reaction asymmetrically is described. These Lewis acids were shown to undergo a dehydroalumination under the conditions of their formation, but nevertheless generated the Diels-Alder adduct in the reaction between methacrolein and cyclopentadiene in 68 % yield and 16 % ee, with a 29:1 exo:endo ratio.

ii Finally, a novel class of 3,3’-disubstituted BINOL-aluminum bromide Lewis acids is also described, generating the same Diels-Alder adduct in up to 77 % yield and

37.5 % ee, with an exo:endo ratio of 14:1. Asymmetric Strecker and epoxide-opening reactions are also described making use of this novel class of BINOL-aluminum bromide

Lewis acids. Chiral Strecker adduct was obtained in up to 72 % yield and up to 9.1 % ee with chiral bromohydrins being obtained from the opening of meso-epoxides in up to 65

% yield and 16.8 % ee.

iii Preface

Aluminum-based Lewis acids are widely used as catalysts, and with numerous chiral ligands commercially available, chiral aluminum-based Lewis acids are very popular for asymmetric synthesis. Three classes of novel aluminum-based Lewis acids are described within this dissertation. The first class includes achiral RAlBr2 and chiral

R*AlBr2-type Lewis acids that are used to both promote and catalyze organic reactions.

The second class includes R*AlBr(OR*)-type Lewis acids, which unfortunately appear to be prone to dehydroalumination. The final class includes BINOL-aluminum bromide complexes. All three classes of novel aluminum-based Lewis acid are easy to prepare, and are highly efficient Lewis acids for promoting and catalyzing asymmetric reactions.

All three classes are shown to be capable of catalyzing several different organic reactions enantioselectively.

Chapter one is divided into five sections. The first section provides a brief overview of asymmetric synthesis, including what it is and why it is an important topic to advance through continued research and development. The second section outlines a number of different synthetic philosophies toward the goal of asymmetric synthesis, including the use of chiral templates, classical resolution, chiral auxillaries, and finally chiral catalysts. The third section provides a thorough review of chiral aluminum-based

Lewis acids used to asymmetrically catalyze several different organic reactions. The organic reactions reviewed in this section include the asymmetric Diels-Alder, Strecker, epoxide opening, sulfide oxidation, and hydrophosphonylation reactions, along with asymmetric aluminum-catalyzed rearrangements. The fourth section includes an introduction of the hydroalumination reaction, along with an introduction of the specific

iv hydroalumination reaction proposed as a basis for the chemistry described in this dissertation. The fifth section outlines the tendency of aluminum complexes to form dimers through bridging substituents. Finally, the sixth section outlines several of the project goals.

Chapter two is divided into four sections. The first is an overview of the hydroalumination reaction that forms the entire basis for this chemistry, along with in situ

1 13 H and C NMR spectra for several simple hydroaluminated RAlBr2-type Lewis acids.

1 The second section includes low temperature H NMR binding studies wherein RAlBr2- type Lewis acids are investigated for their ability to coordinate and activate simple Lewis base crotonaldehyde reversibly. The third section of this chapter outlines a number of experiments using RAlBr2-type Lewis acid (R = dodecyl) being used to promote the

Diels-Alder reaction between chiral oxazolidin-2-one substituted allylic O-benzylated dienophiles and diene 1,3,3-trimethyl-2-vinyl-cyclohexene. Several reaction conditions were tested in an attempt to optimize both the reaction yield as well as the formation of the major exo-adduct. A debenzylation reaction is also described, which pushed this research toward simplified dienophile structures. Finally, the fourth section will highlight the important conclusions from the research conducted in chapter two.

Chapter three is divided into six sections. Section one is a brief introduction to the chapter. Section two describes the simplification of the chiral dienophiles into chiral crotonic acid derivatized oxazolidin-2-one substituted dienophiles, along with their use in the Diels-Alder reaction with 1,3,3-trimethyl-2-vinyl-cyclohexene. Each diastereomer is assigned using 1H NMR spectroscopy in conjunction with X-ray crystallography. An elaborate optimization of reaction conditions is described, including optimization of the

v amount of Lewis acid, the temperature of the reaction mixture, the reaction time, the solvent, the structure of the dienophile, the R group in the RAlBr2 Lewis acid, among other variables. The optimization of this reaction included the insight that 3.5 equivalents of RAlBr2-type Lewis acid provided the best results. Section three therefore describes numerous efforts to reduce the amount of Lewis acid delivered to the reaction mixture.

Section four outlines a proposed binding mechanism to explain the results obtained in sections two and three. Section five introduces two new chemical reactions to study, including a Strecker reaction using TMSCN, an intramolecular Diels-Alder furan reaction, and efforts to catalyze a Diels-Alder reaction using a 1,2-diketone as a dienophile in conjunction with the previously described diene 1,3,3-trimethyl-2-vinylcyclohexene. Conclusions for this chapter’s chemistry are presented in section six.

Chapter four is divided into seven sections, the first of which simply introduces the chapter. The second section describes the use of simple chiral olefins (+)-camphene and (1R)-(+)--pinene to generate chiral R*AlBr2 Lewis acids to promote and catalyze the three reactions that were successfully optimized in chapter three. The third section describes the synthesis and hydroalumination of several novel chiral olefin derivatives of

(1R)-(+)-camphor. The fourth section describes the use of these previously generated novel chiral R*AlBr2 to promote and catalyze the three reactions that were optimized in chapter three. The firth section describes a number of Lewis acid binding studies proving that RAlBr2-type Lewis acids do not disproportionate in solution, and that these Lewis acids are indeed suitable for asymmetric catalysis. The sixth section describes efforts to synthesize dimers of (1R)-(+)-camphor and (+)-camphene with an internal double bond.

Conclusions for this chapter’s chemistry are presented in section seven.

vi Chapter five is divided into five sections. The first section reiterates the important conclusions from chapter four and introduces the fifth chapter. The second section introduces the novel classes of Lewis acid R*AlBr(OR*) along with R*AlBr(NOR*) by adding either lithiated chiral alcohols or lithiated chiral tertiary amino alcohols to chiral

R*AlBr2 Lewis acids. It describes their use in catalyzing the asymmetric Diels-Alder reaction between methacrolein and cyclopentadiene. It also describes a dehydroalumination process that limits their effectiveness as catalysts. The third section describes the in situ preparation of a novel class of BINOL-aluminum bromide Lewis acid complexes and their use in catalyzing the asymmetric Diels-Alder reaction between methacrolein and cyclopentadiene, along with asymmetric Strecker reactions and asymmetric epoxide opening reactions. The fourth section highlights the original

R*AlBr2-type Lewis acid promoting the asymmetric Diels-Alder reaction between methacrolein and cyclopentadiene. Conclusions for this chemistry are presented in the fifth section.

Chapter six presents all of the experimental details for the chemical reactions described in this dissertation, along with relevant characterization data and references to literature procedures.

vii Acknowledgements

First of all, thanks to my supervisor, Professor Brian A. Keay for bringing me into his research group, inspiring a great interest in building molecules asymmetrically, challenging me to expand both as a student and as a scientist, and giving me the independence which enabled me to do so. I wish to thank him especially for his patience, particularly over the final year and a half. Thanks also to Dr. Evgueni Gorobets, a highly skilled and knowledgeable chemist, with whom it was a pleasure and a great privilege to work these past several years.

Thanks also to my supervisory committee, Professor Todd. C. Sutherland and

Professor Thomas G. Back both for their wisdom, encouragement, and advice, and for two very enjoyable graduate courses in chemistry. My thanks to the late Ms. Bonnie King for her exemplary efforts and her unfailingly pleasant demeanor, as well as for first putting me in contact with Professor Keay during my search for a research group. Thanks also to Ms. Janice Crawford for all her administrative help, and some enjoyable Star

Trek-related discussions. My thanks extend also to Mrs. Dorothy Fox, Mrs. Qiao Wu,

Mr. Wade White, Mr. Jian Jun Li, and Dr. Michelle Forgeron for their technical assistance and expertise.

Thanks to Professor Darren Derksen for his friendliness, encouragement, and advice as he inherited the lab from Professor Keay. I wish to thank him for inviting me to his group meetings and for treating me as an honorary member of his research group.

Thanks to the many graduate students and post doctoral fellows I have known for their advice and friendship, including Dr. Danica Rankic, Dr. Daniela Lucciola, Dr. Phil Edler,

viii Dr. David Press, Christina LeGay, and Jin Lee. Thanks also to Joel Viccars, Norman

Wong, and Jordan Wilson for being great friends.

Last, but certainly not least, I am greatly indebted to and thankful for the help and support of my family. Thanks to my wonderful girlfriend Analise Brett for her love, support, and encouragement, and thanks to her family for helping to keep me both focused and relaxed. Thanks to my friend and mentor Joseph Zepedeo for helping me through a difficult period of my life, and for advice which only grows more relevant as each new challenge presents itself. Thanks to my brother John for his love and his advice, and for conversations which can proceed without end. Thanks to my grandfather John

Thomson for his quiet, stoic confidence in me, and for being such an important influence on me, along with my late grandmother Francis Thomson. Most importantly, thanks to my father Trevor Warner and my mother Sharon Thomson, for their tireless support, encouragement, and patience. Without their help and support I could not have completed this project.

ix Dedication

Dedicated to my mom and to my dad.

x Table of Contents

Abstract ...... ii Preface...... iii Acknowledgements ...... viii Table of Contents ...... xi List of Tables ...... xviii List of Figures and Illustrations ...... xxii List of Symbols, Abbreviations and Nomenclature ...... xxiv Epigraph ...... xxvii

CHAPTER ONE: CHIRAL ALUMINUM-BASED LEWIS ACID CATALYSIS IN ASYMMETRIC ORGANIC SYNTHESIS ...... 1 1.1 Introduction ...... 1 1.2 Strategies for Chiral Induction ...... 3 1.2.1 Chiral Template ...... 3 1.2.2 Classical Resolution ...... 3 1.2.3 Chiral Auxilliaries ...... 3 1.2.4 Chiral Catalysts ...... 4 1.3 Chiral Aluminum-Based Lewis Acids in The Chemical Literature ...... 4 1.3.1 Aluminum-Catalyzed Asymmetric Diels-Alder Reactions ...... 6 1.3.2 Aluminum-Catalyzed Asymmetric Rearrangements ...... 8 1.3.3 Aluminum-Catalyzed Asymmetric Sulfide Oxidation ...... 14 1.3.4 Aluminum-Catalyzed Asymmetric Strecker Reaction ...... 19 1.3.5 Aluminum-Catalyzed Asymmetric Hydrophosphonylation ...... 24 1.3.6 Aluminum-Catalyzed Asymmetric Epoxide Opening ...... 37 1.3.7 Summary of Asymmetric Aluminum-Based Catalysis ...... 39 1.4 Hydroalumination Reactions ...... 40 1.5: Dimerization of Aluminum Complexes ...... 43 1.6: Project Goals ...... 44

CHAPTER TWO: 3ALBR3·LIALH4-MEDIATED HYDROALUMINATION OF SIMPLE OLEFINS AND THE ACTIVATION OF OBN-PROTECTED OXAZOLIDINONE-BASED DIENOPHILES ...... 47 2.1 Hydroalumination of Simple Olefins ...... 47 2.2 Low Temperature Lewis Acid Binding Studies ...... 53 2.3 Diels-Alder Reactions using OBn-Protected Oxazolidinone-based Dienophiles to access the Drimane Skeleton ...... 58 2.3.1 Introduction to Drimane Sesquiterpene Natural Products ...... 58 2.3.2 Previous Synthesis of Drimane Natural Products Reported by the Keay Group ...... 60 2.3.3 Repeating Previously Reported Diels-Alder Reaction between 95a and 96 using a new RAlBr2-type Lewis acid as catalyst ...... 62 2.3.4 Time Studies to Optimize Diels-Alder Reaction between 95a and 96 in Toluene ...... 69 2.3.5 Optimizing Delivery of Lewis Acid to Diels-Alder Reaction between 95a and 96 in Toluene...... 72 xi 2.3.6 Optimizing the Structure of the Chiral Auxilliary to Determine the Optimal Dienophile ...... 74 2.3.7 Discovery of a Debenzylation Reaction ...... 76 2.4 Conclusions ...... 77

CHAPTER THREE: SIMPLER OXAZOLIDINONE-BASED DIENOPHILES FOR THE DIELS-ALDER REACTION AND EXPLORATION OF OTHER ORGANIC REACTIONS ...... 79 3.1 Introduction ...... 79 3.2 Simplification of Chiral Oxazolidinone-Based Dienophiles for the Diels-Alder Reaction ...... 79 3.2.1 Synthesis of chiral crotonic acid-derivatized oxazolidinone-based dienophile 134a ...... 80 3.2.2 Separation and Characterization of the three Diastereomers ...... 82 3.2.3 Optimization of Quantity of Lewis Acid Delivered to the Diels-Alder Reaction Between 134a and 96 ...... 89 3.2.4 Synthetic Targets for this Methodology ...... 94 3.2.5 Time Study of the Diels-Alder Reaction between 134a and 96 at 3.5 equivalents 125...... 95 3.2.6 Optimization of the Diels-Alder Reaction by Changing Solvent and Temperature at 3.5 equivalents of Lewis Acid 125 ...... 96 3.2.7 Optimization of the Diels-Alder Reaction by Varying the R group on RAlBr2-type Lewis acids ...... 97 3.2.8 Optimization of the Diels-Alder Reaction by Pre-equilibrating the Mixture Prior to the addition of diene 96 ...... 99 3.2.9 Optimization of the Diels-Alder Reaction by Employing Alternative Chiral Oxazolidinone-based Auxilliaries ...... 100 3.2.10 Optimization of the Diels-Alder Reaction between Achiral Oxazolidinone-Substituted Dienophile 153a and Diene 96...... 103 3.2.11 Attempts at Diels-Alder Reaction Between Other Achiral Oxazolidinone-based Dienophiles and diene 96 ...... 105 3.3 Efforts to Reduce Catalyst Loading in the Diels-Alder Reaction from 3.5 equivalents ...... 107 3.3.1 Reducing Catalyst Loading through Concentrating the Reaction Mixture ...108 3.3.2 Attempts to reduce catalyst loading by adding silver salts to the reaction mixture ...... 110 3.4 Proposed mechanism for binding of RAlBr2 Lewis acids to oxazolidinone dienophiles ...... 112 3.5 Developing new organic reactions requiring the addition of less RAlBr2 ...... 117 3.5.1 Using ,β-unsaturatred esters and ketones as dienophiles for the Diels- Alder reaction with several common dienes ...... 118 3.5.4 The RAlBr2-Promoted Strecker Reaction ...... 128 3.6 Conclusions ...... 130

CHAPTER FOUR: SYNTHESIS OF NOVEL CAMPHOR-BASED OLEFINS FOR THE HYDROALUMINATION OF NOVEL CHIRAL RALBR2-TYPE LEWIS ACIDS...... 132

xii 4.1 Introduction ...... 132 4.2 The use of simple commercially available chiral olefins ...... 133 4.2.1 Synthesis of chiral R*AlBr2 Lewis acids from simple commercially available chiral olefins ...... 133 4.2.2 Diels-Alder Reactions between chiral oxazolidinone dienophiles 134a-d and chiral R*AlBr2 Lewis acids 87, 88, 196...... 134 4.2.3 Using simple chiral R*AlBr2 Lewis acids 87 and 88 to promote organic reactions reactions enantioselectively ...... 138 4.3 Synthesis of more complex chiral olefin derivatives using camphor as a chiral template ...... 142 4.3.1 Synthesis of (1R)-1,7,7-Trimethyl-2-methylene-bicyclo[2.2.1]heptane (200) and its corresponding hydroalumination product 201 ...... 143 4.3.2 Synthesis of (1R)-1-Benzyl-7,7-dimethyl-2-methylene- bicyclo[2.2.1]heptane (203) and its corresponding hydroalumination product 204 ...... 145 4.3.3 Synthesis of (1R)-7-Benzyl-1,7-dimethyl-2-methylene- bicyclo[2.2.1]heptane (217) and its corresponding hydroalumination product 218 ...... 152 4.3.4 Synthesis of (1R)-1,7,7-Trimethyl-2-phenyl-bicyclo[2.2.1]hept-2-ene (225) and its corresponding hydroalumination product 226 ...... 158 4.3.5 Synthesis of (1R)-2-Benzyl-1,7,7-trimethyl-bicyclo[2.2.1]hept-2-ene (229) and its corresponding hydroalumination product 230 ...... 160 4.3.6 Synthesis of (1R)-1,7,7-trimethyl-2-phenethylidene-bicyclo[2.2.1]heptane (234) and its corresponding hydroalumination product 235 ...... 162 4.3.7 Synthesis of (1R)- 9-(1,7,7-Trimethyl-bicyclo[2.2.1]hept-2-en-2-yl)- anthracene (242) and its corresponding hydroalumination product 243 ...... 164 4.3.8 Synthesis of (1R)-3-Benzyl-1,7,7-trimethyl-2-methylene- bicyclo[2.2.1]heptane (247a) and its corresponding hydroalumination product 248 ...... 165 4.4 Using the previously obtained synthetic chiral R*AlBr2 Lewis acids to promote all three reactions described above ...... 170 4.4.1 Performance of each novel chiral R*AlBr2 Lewis acid in the Diels-Alder reaction between oxazolidinone-based dienophile 153a and diene 96 ...... 170 4.4.2 Performance of each novel chiral R*AlBr2 Lewis acid in the IMDAF reaction of 182g ...... 172 4.4.3 Performance of each novel chiral R*AlBr2 Lewis acid in the Strecker reaction of 192 with TMSCN ...... 173 4.5 Lewis acid studies to confirm the formation of only a single R*AlBr2 Lewis acid in solution ...... 174 4.6 Efforts to Synthesize dicamphor-derivatized olefins 255 and 257 ...... 179 4.6.1 Efforts to Synthesize dicamphor derivative 255 with Grignard chemistry ...179 4.6.2 Efforts to synthesize dicamphor derivative 257 with Grignard chemistry ....181 4.6.3 Efforts to Synthesize dicamphene derivative 257 with Wittig chemistry .....183 4.6.4 Efforts to Synthesize dicamphene derivative 257 with R*AlBr2 as the nucleophilic agent in solution ...... 183 4.7 Conclusion ...... 184

xiii CHAPTER FIVE: SUBSITUTION REACTIONS USING O-LITHIATED ALCOHOLS TO REPLACE BROMINE ATOMS ON R*ALBR2-BASED LEWIS ACIDS WITH SECOND AND THIRD CHIRAL GROUPS ...... 186 5.1: Introduction ...... 186 5.2: Synthesis of R*AlBr(OR*)-type Lewis acids and their use to promote organic reactions ...... 189 5.2.1: Developing a Diels-Alder model system for R*AlBr(OR*) Lewis acid Lewis acids...... 190 5.2.2: Monitoring the hydroalumination reaction and the subsequent substitution reaction with chiral lithiated alcohols with 1H NMR spectroscopy ...... 194 5.2.3: Novel R*Al(R*NO) derivatives using chiral tertiary amines ...... 206 5.3: Using RAlBr2 Lewis acids as both an electrophile and a base in conjuction with monolithiated enantiopure BINOL-based compounds ...... 212 5.3.1: The Diels-Alder reaction between methacrolein and cyclopentadiene catalyzed by novel BINOL-aluminum bromide complex 293 ...... 214 5.3.2: The Epoxide Opening reaction of meso-epoxides promoted by novel BINOL-aluminum bromide complex 293 ...... 227 5.3.3: The BINOL-aluminum bromide complex 293 promoted Strecker reaction 229 5.3.4: Using the original chiral R*AlBr2 Lewis acids to catalyze the Diels-Alder reaction between methacrolein and cyclopentadiene in DCM ...... 232 5.4: Conclusions ...... 235 5.5 Future Work ...... 236

CHAPTER SIX: EXPERIMENTAL METHODS ...... 240 5.1: Experimental Conditions ...... 240 5.2 Chromatographic techniques ...... 240 5.3 Compound Identification and Characterization ...... 241 5.4 Naming Standards ...... 242 5.5 Resolution of enantiomers using chiral HPLC ...... 242 5.6 General Experimental Procedures ...... 243 5.6.1 General Procedure for Hydroalumination Reactions ...... 243 5.6.2 General Procedure for Mixed Anhydride Coupling Methodology ...... 244 5.6.3 General Procedure for Diels-Alder Reactions in Chapters 2+3 ...... 244 5.6.4 General Procedure for IMDAF Reactions in Chapters 3+4 ...... 245 5.6.5 General Procedure for Strecker Reactions in Chapters 3-5 ...... 246 5.6.6 General Procedure for Preparing RAlBr(OR) Lewis acids described in Chapter 5 ...... 246 5.6.7 General Procedure for Preparing BINOL-aluminum bromide complexes described in chapter 5 ...... 247 5.7 Experimental Procedures Pertaining to Chapter 2 ...... 248 5.7.1 Synthesis of RAlBr2 Lewis acid 99 ...... 248 5.7.2 Synthesis of RAlBr2 Lewis acid 86 ...... 248 5.7.3 Synthesis of RAlBr2 Lewis acid 87 ...... 249 5.7.4 Synthesis of RAlBr2 Lewis acid 125 ...... 250 5.7.5 Characterization of 2,2,3-Trimethyl-bicyclo[2.2.1]heptane ...... 251 5.7.6 Synthesis of 3-Bromomethyl-2,2-dimethyl-bicyclo[2.2.1]heptane ...... 251 xiv 5.7.7 Synthesis of 1,3,3-trimethyl-2-vinylcyclohexene ...... 252 5.7.8 Synthesis of 4-Benzyloxy-but-2-enoic acid ethyl ester ...... 253 5.7.9 Synthesis of 4-Benzyloxy-but-2-enoic acid ...... 254 5.7.10 Synthesis of (3aS-cis)-3-(4-benzyloxy-but-2-enoyl)-3,3a,8,8a-tetrahydro- indeno[1,2-d]oxazol-2-one ((+)-95a) ...... 254 5.7.11 Synthesis of (4S)-4-benzyl-3-(4-benzyloxy-but-2-enoyl)-oxazolidin-2- one ((+)-95b) ...... 255 5.7.12 Synthesis of (4S)-3-(4-benzyloxy-but-2-enoyl)-4-phenyl-oxazolidin-2- one ((+)-95c) ...... 256 5.7.13 Synthesis of (4S)-3-(4-benzyloxy-but-2-enoyl)-4-isopropyl-oxazolidin-2- one ((+)-95d) ...... 257 5.7.14 Synthesis of (1S,2S,8aS)-3-(2-benzyloxymethyl-5,5,8a-trimethyl- 1,2,3,5,6,7,8,8a-octahydro-naphthalene-1-carbonyl)-(3aS)-3,3a,8,8a- tetrahydro-indeno[1,2-d]oxazolidin-2-one (exo-(+)-97a)...... 258 5.7.15 Synthesis of (1S,2S,8aS)-(4S)-benzyl-3-(2-benzyloxymethyl-5,5,8a- trimethyl-1,2,3,5,6,7,8,8a-octahydro-naphthalene-1-carbonyl)-oxazolidin- 2-one (exo-(+)-97b) ...... 259 5.7.16 Synthesis of (1S,2S,8aS)-3-(2-benzyloxymethyl-5,5,8a-trimethyl- 1,2,3,5,6,7,8,8a-octahydro-naphthalene-1-carbonyl)-(4S)-phenyl- oxazolidin-2-one (exo-(+)-97c) ...... 260 5.7.17 Synthesis of (1S,2S,8aS)-3-(2-benzyloxymethyl-5,5,8a-trimethyl- 1,2,3,5,6,7,8,8a-octahydro-naphthalene-1-carbonyl)-(4S)-isopropyl- oxazolidin-2-one (exo-(+)-97d) ...... 261 5.7.18 Characterization of (3aS-cis)-3-(4-Hydroxy-but-2-enoyl)-3,3a,8,8a- tetrahydro-indeno[1,2-d]oxazol-2-one (131) ...... 262 5.8 Experimental Procedures Pertaining to Chapter 3 ...... 263 5.8.1 Synthesis of (3aS-cis)-3-But-2-enoyl-3,3a,8,8a-tetrahydro-indeno[1,2- d]oxazol-2-one (134a) ...... 263 5.8.2 Synthesis of 4-Benzyl-3-but-2-enoyl-oxazolidin-2-one (134b) ...... 264 5.8.3 Synthesis of 3-But-2-enoyl-4-phenyl-oxazolidin-2-one (134c) ...... 265 5.8.4 Synthesis of 3-But-2-enoyl-4-isopropyl-oxazolidin-2-one (134d) ...... 266 5.8.5 Synthesis of 3-But-2-enoyl-oxazolidin-2-one (153a) ...... 267 5.8.6 Synthesis of 3-Acryloyl-oxazolidin-2-one (153b) ...... 267 5.8.7 Synthesis of 3-(2-Methyl-acryloyl)-oxazolidin-2-one (153c) ...... 268 5.8.8 Synthesis of 3-(3-Phenyl-acryloyl)-oxazolidin-2-one (153d) ...... 269 5.8.9 Synthesis of (3aS-cis)-3-(2,5,5,8a-Tetramethyl-1,2,3,5,6,7,8,8a-octahydro- naphthalene-1-carbonyl)-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazol-2-one (135a endo I) ...... 270 5.8.10 1H-NMR Characterization of minor diastereomers of (3aS-cis)-3- (2,5,5,8a-Tetramethyl-1,2,3,5,6,7,8,8a-octahydro-naphthalene-1- carbonyl)-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazol-2-one (135a endo II and exo) ...... 271 5.8.11 Synthesis of 4-Benzyl-3-(2,5,5,8a-tetramethyl-1,2,3,5,6,7,8,8a- octahydro-naphthalene-1-carbonyl)-oxazolidin-2-one (135b endo I) ...... 272

xv 5.8.12 1H-NMR Characterization of minor diastereomers of 4-Benzyl-3- (2,5,5,8a-tetramethyl-1,2,3,5,6,7,8,8a-octahydro-naphthalene-1-carbonyl)- oxazolidin-2-one (135b endo II and exo)...... 274 5.8.13 Synthesis of 4-phenyl-3-(2,5,5,8a-tetramethyl-1,2,3,5,6,7,8,8a- octahydro-naphthalene-1-carbonyl)-oxazolidin-2-one (135c endo I) ...... 275 5.8.14 1H-NMR Characterization of minor diastereomers of 4-phenyl-3- (2,5,5,8a-tetramethyl-1,2,3,5,6,7,8,8a-octahydro-naphthalene-1-carbonyl)- oxazolidin-2-one (135c endo II and exo) ...... 276 5.8.15 Synthesis of 4-Isopropyl-3-(2,5,5,8a-tetramethyl-1,2,3,5,6,7,8,8a- octahydro-naphthalene-1-carbonyl)-oxazolidin-2-one (135d endo I) ...... 277 5.8.16 1H-NMR Characterization of minor diastereomers of 4-Isopropyl-3- (2,5,5,8a-tetramethyl-1,2,3,5,6,7,8,8a-octahydro-naphthalene-1-carbonyl)- oxazolidin-2-one (135d endo II and exo) ...... 278 5.8.17 Synthesis of 3-(2,5,5,8a-Tetramethyl-1,2,3,5,6,7,8,8a-octahydro- naphthalene-1-carbonyl)-oxazolidin-2-one (154 endo and exo) ...... 278 5.8.18 Synthesis of 3-(5,5,8a-Trimethyl-1,2,3,5,6,7,8,8a-octahydro- naphthalene-1-carbonyl)-oxazolidin-2-one (154b endo and exo) ...... 281 5.8.19 Characterization of but-2-enoic acid (2-bromoethyl)-amide (155) ...... 282 5.8.20 Synthesis of 1-(2-Phenyl-[1,3]dithian-2-yl)-but-2-en-1-ol (177) ...... 282 5.8.21 Synthesis of 2-Hydroxy-1-phenyl-pent-3-en-1-one (178) ...... 283 5.8.22 Synthesis of 1-Phenyl-pent-3-ene-1,2-dione (179) ...... 284 5.8.23 Synthesis of 2-(3-chloro-propyl)-5-methyl furan (185) ...... 285 5.8.24 Synthesis of 2-(3-iodo-propyl)-5-methyl-furan (186) ...... 286 5.8.25 Synthesis of 6-(5-Methyl-furan-2-yl)-hex-1-en-3-ol (188a) ...... 287 5.8.26 Synthesis of 2-Methyl-6-(5-methyl-furan-2-yl)-hex-1-en-3-ol (188b) ...... 288 5.8.27 Synthesis of 7-(5-Methyl-furan-2-yl)-hept-2-en-4-ol (188c) ...... 288 5.8.28 Synthesis of 6-(5-Methyl-furan-2-yl)-hex-1-en-3-one (182e) ...... 289 5.8.29 Synthesis of 2-Methyl-6-(5-methyl-furan-2-yl)-hex-1-en-3-one (182f) .....290 5.8.30 Synthesis of 7-(5-Methyl-furan-2-yl)-hept-2-en-4-one (182g) ...... 291 5.8.31 Synthesis of 8-Methyl-11-oxa-tricyclo[6.2.1.01,6]undec-9-en-5-one (183e) ...... 292 5.8.32 Synthesis of 6,8-Dimethyl-11-oxa-tricyclo[6.2.1.01,6]undec-9-en-5-one (183f)...... 293 5.8.33 Synthesis of 7,8-Dimethyl-11-oxa-tricyclo[6.2.1.01,6]undec-9-en-5-one (183g) ...... 294 5.8.34 Synthesis of Benzylidene-phenyl-amine (192) ...... 294 5.8.35 Synthesis of Phenyl-phenylamino-acetonitrile (193) ...... 295 5.9 Experimental Procedures Pertaining to Chapter 4 ...... 296 5.9.1 Synthesis of RAlBr2 Lewis acid 88 ...... 296 5.9.2 Synthesis of 1,7,7-Trimethyl-2-methylene-bicyclo[2.2.1]heptanes (200) ....297 5.9.3 Synthesis of RAlBr2 Lewis acid 201 ...... 298 5.9.4 Characterization of 1,2,7,7-Tetramethyl-bicyclo[2.2.1]heptanes (202) ...... 299 5.9.5 Synthesis of 1-Iodomethyl-7,7-dimethyl-bicyclo[2.2.1]heptan-2-one (206) 299 5.9.6 Synthesis of 1-Benzyl-7,7-dimethyl-bicyclo[2.2.1]heptan-2-one (213) ...... 300 5.9.7 Synthesis of 1-Benzyl-7,7-dimethyl-2-methylene-bicyclo[2.2.1]heptanes (203) ...... 301

xvi 5.9.8 Characterization of 1-(2,2-Dimethyl-3-methylene-cyclopentyl)-propan-2- one (210) ...... 302 5.9.9 Synthesis of RAlBr2 Lewis acid (204) ...... 303 5.9.10 Characterization of 1-Benzyl-2,7,7-trimethyl-bicyclo[2.2.1]heptanes (216) ...... 304 5.9.11 Synthesis of 7-Iodomethyl-1,7-dimethyl-2-methylene- bicyclo[2.2.1]heptanes (220) ...... 304 5.9.12 Synthesis of 7-Benzyl-1,2,7-trimethyl-bicyclo[2.2.1]heptanes (217) ...... 305 5.9.13 Synthesis of R*AlBr2 Lewis acid (218) ...... 306 5.9.14 Characterization of 7-Benzyl-1,2,7-trimethyl-bicyclo[2.2.1]heptane (221) ...... 307 5.9.15 Synthesis of 1,7,7-Trimethyl-2-phenyl-bicyclo[2.2.1]heptan-2-ol (224) ....308 5.9.16 Synthesis of 1,7,7-Trimethyl-2-phenyl-bicyclo[2.2.1]hept-2-ene (225) .....309 5.9.17 Synthesis of R*AlBr2 Lewis acid 218 ...... 310 5.9.18 Characterization of 1,7,7-Trimethyl-2-phenyl-bicyclo[2.2.1]heptanes (227) ...... 310 5.9.19 Synthesis of 2-Benzyl-1,7,7-trimethyl-bicyclo[2.2.1]heptan-2-ol (228) .....311 5.9.20 2-Benzylidene-1,7,7-trimethyl-bicyclo[2.2.1]heptanes (229) ...... 312 5.9.21 Synthesis of endo-3-Benzyl-1,7,7-trimethyl-bicyclo[2.2.1]heptan-2-one (245a) ...... 313 5.9.22 Synthesis of endo-3-Benzyl-1,7,7-trimethyl-2-methylene- bicyclo[2.2.1]heptanes (247a) ...... 315 5.9.23 Characterization of 3-Benzyl-1,2,7,7-tetramethyl-bicyclo[2.2.1]hept-2- ene (247e)...... 316 5.9.24 Synthesis of R*AlBr2 Lewis acid 248a ...... 317 5.9.25 Synthesis of 2-Bromomethyl-1,7,7-trimethyl-bicyclo[2.2.1]heptanes (259) ...... 318 5.9.26 Synthesis of 3,3-Dimethyl-bicyclo[2.2.1]heptan-2-one (265) ...... 319 5.10.9 Experimental Procedures Pertaining to Chapter 5 ...... 320 5.10.1 Synthesis of 2-Methyl-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (exo- 11c) ...... 320 5.10.2 Synthesis of 1,7,7-Trimethyl-bicyclo[2.2.1]heptan-2-ol (279) ...... 321 5.10.3 Synthesis of 1-Methyl-pyrrolidine-2-carboxylic acid (283) ...... 322 5.10.4 Synthesis of (1-Methyl-pyrrolidin-2-yl)-methanol (284) ...... 322 5.10.5 Synthesis of (R)-BINAM derivative 286 ...... 323 5.10.6 Synthesis of 2-Bromo-cyclohexanol (273b) ...... 324 5.10.7 Synthesis of 2-Bromo-1,2-diphenyl-ethanol (301) ...... 325 5.10.8 Synthesis of (4-Methyl-benzylidene)-phenyl-amine (192b) ...... 326 5.10.9 Synthesis of Allyl-benzylidene-amine (192c) ...... 327 5.10.10 Synthesis of Phenylamino-p-tolyl-acetonitrile (307b) ...... 328 5.10.11 Synthesis of Allylamino-phenyl-acetonitrile (307c) ...... 329

REFERENCES ...... 330

xvii List of Tables

Table 1.1 Original chiral aluminum catalyzed asymmetric Diels-Alder published by Koga ...... 6

Table 1.2 Chiral aluminum Lewis acid catalyzed Diels Alder reaction on tropones ...... 7

Table 1.3: Catalytic asymmetric rearrangement of ,-dialkyl--siloxy aldehydes ...... 9

Table 1.4: Kinetic resolution using Maruoka’s catalytic asymmetric rearrangement ...... 10

Table 1.5 Maruoka’s Desymmetrizing Ring Expansion ...... 12

Table 1.6: Scope of Maruoka’s Desymmetrizing Ring Expansion...... 13

Table 1.7: Katsuki’s aluminum catalyzed asymmetric sulfide oxidation ...... 15

Table 1.8: Scope of Katsuki’s methodology on various aryl-substituted methyl sulfides ...... 16

Table 1.9: Katsuki’s solvent-free conditions for asymmetric sulfide oxidation ...... 17

Table 1.10: Scope of Katsuki’s methodology for solvent-free asymmetric sulfide oxidation ...... 18

Table 1.12: Scope of Yamamoto’s aluminum catalyzed asymmetric Strecker reaction .. 22

Table 1.13: Catalytic asymmetric Strecker reaction reported by Li and coworkers ...... 23

Table 1.14: Effect of inorganic salts, temperature, and catalyst structure on hydrophosphonylation ...... 27

Table 1.15: Hydrophosphonylation of different aldehydes using optimized reaction conditions ...... 29

Table 1.16: Optimization of Yamamoto’s aluminum-catalyzed hydrophosphonylation system ...... 30

Table 1.17: Results from Yamamoto’s methodology to hydrophosphorylate aldehydes . 31

Table 1.18: Optimization of catalyst structure for hydrophosphonylation of trifluoromethylketones ...... 33

Table 1.19: Optimized asymmetric hydrophosphonylation of various trifluoromethyl ketones ...... 34

Table 1.20: The effect of an inorganic base on the reaction time for He’s methodology ...... 36

xviii Table 1.21: Hydrophosphonylation of aldehydes and ketones using He’s optimized methodolgy ...... 37

Table 1.22: Asymmetric Epoxide Opening Reported in 1988 by Yamamoto and Co- Workers ...... 38

Table 1.23: Kinetic Resolution of a keto-epoxide using Chiral Aluminum Complexes .. 39

Table 2.1: 1H chemical shift differences (Δδ) of crotonaldehyde (103) upon a complexation with different Lewis acids at -20 ºC in CD2Cl2 ...... 54

Table 2.2: 1H chemical shift differences (Δδ) of crotonaldehyde (103) upon a complexation with Lewis acids 99 and 86 at -60 ºC in CD2Cl2 ...... 55

Table 2.3: MeAlCl2-catalyzed Diels-Alder Reaction Previously Reported by the Keay Group ...... 61

Table 2.4: Initial Trials on Diels-Alder Reaction between 95a and 96 ...... 65

Table 2.5: Repeating Diels-Alder Reaction between 95a and 119 using toluene instead of DCM ...... 68

Table 2.6: Time Study for Diels-Alder Reaction in Toluene...... 70

Table 2.7: Time Study for Diels Alder Reaction in Toluene ...... 71

Table 2.8: Henderson’s MeAlCl2 Equivalent Study on Diels Alder Reaction Between 95a and 96 ...... 72

Table 2.9 Optimizing the Delivery of Lewis Acid to the Reaction between 95a and 96 in toluene ...... 73

Table 2.10: All Diels-Alder Reactions Conducted Between Dienophiles 95a-e and 96 .. 76

Table 3.1: Time Study for the Diels-Alder Reactions Between 134a and 96 ...... 81

Table 3.2: Evans Asymmetric Diels Alder Reaction Lewis Acid Study ...... 90

Table 3.3: Lewis acid study on 125 promoting the Diels Alder reaction between 134a and 96 ...... 92

Table 3.4: Time study of Diels-Alder Reaction at 3.5 equivalents of Lewis acid 125 ..... 95

Table 3.5: Effect of Solvent and Temperature on Diels-Alder Reaction between 134a and 96 ...... 96

Table 3.6: Effect of Different RAlBr2 Lewis acids on the Diels-Alder Reaction between 134a and 96 ...... 98

xix Table 3.7 Preequilibration Study for Diels Alder Reaction between 134a and 96 ...... 100

Table 3.8 Results of Diels-Alder Reaction using Dienophiles 134b-d and diene 96 with RAlBr2 Lewis acids 86 and 99 ...... 102

Table 3.9: Temperature Study for Diels Alder Reaction between 153a and 96 ...... 104

Table 3.10 Diels-Alder reaction between achiral dienophiles 153b-d and diene 96 ...... 107

Table 3.11 Efforts to reduce RAlBr2 loading through concentration effects ...... 109

Table 3.12 Addition of silver triflate to the reaction mixture to reduce catalyst loading 111

Table 3.13 Diels Alder Reaction using various alternative dienophiles and dienes ...... 119

Table 3.14 RAlBr2-promoted Diels Alder reactions between 1,2-diketone 178 and various dienes ...... 122

Table 3.15 Lewis Acid study on the IMDAF of 182b reported by Rogers and Keay .... 124

Table 3.16: IMDAF reactions of 182c-g using 0.1 and 1.1 equivalents of MeAlCl2 ..... 125

Table 3.17 RAlBr2-promoted IMDAF reaction using precursors 182e-g ...... 127

Table 3.18 RAlBr2-promoted Strecker reaction of imine 192 ...... 129

Table 4.1 Double diastereoselection using chiral dienophiles 134a-d and chiral R*AlBr2 Lewis acids ...... 135

Table 4.2 Diels-Alder reaction between 134a and 96 using chiral R*AlBr2 Lewis acids ...... 137

Table 4.3: The Diels-Alder reaction of 153a and 96 using simple chiral R*AlBr2-type Lewis acids ...... 139

Table 4.4: IMDAF reaction using chiral R*AlBr2 Lewis acid 87 as catalyst ...... 141

Table 4.6: Diels-Alder reaction between 153a and 96 promoted by novel chiral R*AlBr2 Lewis acids ...... 171

Table 4.7: IMDAF reaction of 182f promoted by novel chiral R*AlBr2 Lewis acids .... 173

Table 4.8: Strecker reaction of 192 and TMSCN promoted by novel chiral R*AlBr2 Lewis acids ...... 174

Table 4.9: Lewis acid binding studies of Lewis acids 87 and AlBr3 with Lewis bases 103 and 252 ...... 177

Table 5.1: Koga’s Al(OR*)Cl2- and RAl(OR*)Cl-promoted Diels-Alder reactions ...... 192

xx Table 5.2: Diels-Alder reactions promoted by R*AlBr(OR*) LAs ...... 193

Table 5.3: Diels-Alder reactions promoted by R*AlBr(OR*) LAs kept at low temperature ...... 205

Table 5.4: Diels-Alder reactions using catalyst 274d ...... 209

Table 5.5: Diels-Alder reactions promoted by tertiary amine-based aluminum Lewis acids ...... 211

Table 5.6: Diels-Alder reaction between 9 and 10c in toluene at low temperature ...... 214

Table 5.7: Literature precedents for BINOL-aluminum complex catalysis of Diels- Alder reaction ...... 215

Table 5.8: Diels-Alder reaction catalyzed by 293 in DCM ...... 217

Table 5.9: Diels-Alder reaction catalyzed by 293 over 3 hours, and concentration effects ...... 220

Table 5.10: Diels-Alder reaction between 9 and 10c catalyzed by 299a-e ...... 221

Table 5.11: Diels-Alder reactions over 3 hours comparing LA 99 and EtAlCl2 ...... 223

Table 5.12: Time study of the Diels-Alder reaction using 299b as catalyst ...... 226

Table 5.13: Complex 293 and the opening of meso epoxides ...... 228

Table 5.14: Complex 293 and the enantioselective Strecker reaction using TMSCN .... 231

Table 5.15: Enantioselective Diels-Alder reaction catalyzed by R*AlBr2 LA 201 ...... 233

Table 5.16: Diels-Alder reaction in DCM using various R*AlBr2 Lewis acids ...... 234

Table 5.17: Summary of best results obtained in the Diels-Alder reaction ...... 236

xxi List of Figures and Illustrations

Figure 1.1 Enantiomers of Thalidomide ...... 2

Figure 2.1: In situ spectra of 98 and 99 in benzene-d6 ...... 49

Figure 2.2: In situ spectra of 81 and 86 in benzene-d6 ...... 50

Figure 2.3: In situ spectra of 82, 87, and 92 in benzene-d6 ...... 52

Figure 2.4: 1H NMR spectra of Lewis Acid Binding Experiment between 103 and Lewis acid 99 in d2-DCM ...... 56

Figure 3.3: 1H NMR spectra of major endo diastereomer of 135b ...... 86

Figure 3.4: X-ray crystal structure of major endo diastereomer of 135b ...... 87

Figure 3.5: XRD of dihedral angle of C1 and C2 for major endo diastereomer of 135b . 88

Figure 3.6 Lewis Acid Binding Study of Dienophile 135a, toluene, room temperature .. 93

1 Figure 4.1: H NMR spectra of olefin 200, and RAlBr2 Lewis acid 201 ...... 145

1 Figure 4.2: H NMR spectra of olefin 203, and R*AlBr2 Lewis acid 204 ...... 151

1 Figure 4.3 H NMR spectra of olefin 217 and RAlBr2 Lewis acid 218 ...... 154

Figure 4.4: NMR experiments to confirm the structure of olefin 217 ...... 157

1 Figure 4.5: H NMR spectra of olefin 225 and hydrocarbon 227 in benzene-d6 ...... 159

Figure 4.6: 1H NMR spectra of the mixture of the isomers of olefin 247a and 248a (benzene-d6) ...... 169

Figure 4.7: Binding study of Lewis base 252 with 86 with AlBr3 and with LA 87 (-65 oC) ...... 178

Figure 5.1: Monitoring the hydroalumination of olefin 200 to R*AlBr2 Lewis acid 201 and after the addition of lithiated alcohol 3 in C6D6...... 195

Figure 5.2: Monitoring the hydroalumination of olefin 82 and the addition of alcohol 3 in C6D6...... 198

Figure 5.3: Monitoring the effect of temperature on the results of the addition of lithiated alcohol 3 in C6D6...... 202

Figure 5.4: Low temperature 1H NMR monitoring 274a at -78 ºC ...... 203

Figure 5.5: Lewis acid 99 reacting with TMEDA in toluene over time ...... 210

xxii 1 + Figure 5.6: H NMR spectra of 294a, 293, and H quenched product BINOL (d5- pyridine) ...... 219

xxiii List of Symbols, Abbreviations and Nomenclature

Symbol Definition 1H Proton 13C Carbon-13 27Al Aluminum-27  Chemical Shift * Chiral ABq AB quartet Ac Acetyl AcCN Acetonitrile AcOH Acetic acid Anal. Elemantal analysis Ar Aromatic BINAM 1,1’-binaphthyl-2,2’-diamine BINOL 1,1’-bi-2-naphthol Bn Benzyl BnOH Benzyl alcohol br Broad c Cyclo CDN Canadian d Doublet DA Diels-Alder DCM Dichloromethane dd Doublet of doublets dt Doublet of triplets ddd Doublet of doubet of doublets ddm Doublet of doublet of multiplets ddt Doublet of doublet of triplets ddq Doublet of doublet of quartets DEPT Distortionless enhancement by polarization transfer DIBAL Diisobutylaluminum hydride DMA Dimethylacetamide DMSO Dimethylsulfoxide dr Diastereomeric ratio dppf 1,1’-bis(diphenylphosphino)ferrocene dq Doublet of Quartets ee Enantiomeric excess Et Ethyl Et2O Diethyl ether EtOAc Ethyl Acetate EtOH Ethanol Eq. Equivalent/Equivalents FT-IR Fourier-transform infrared g Gram/Grams GC Gas chromatography

xxiv gem Geminal Hex Hexanes HMBC Heteronuclear multiple-bond correlation HMQC Heteronuclear multiple quantum coherence HPLC High performance liquid chromatography HRMS High resolution mass spectrometry Hz Hertz iBu Isobutyl IMDAF Intramolecular Diels-Alder Furan Ind Indene/Indeno iPr Isopropyl iPrOH Isopropyl alcohol IR Infrared IUPAC International Union of Pure and Applied Chemistry J Coupling constant LA Lewis acid LDA Lithium diisopropylamide LRMS Low-Resolution Mass Spectrometry M Molar [M+] Molecular ion m Multiplet Me Methyl MeOH Methanol mg Milligram/Milligrams MHz Megahertz mL Milliliter/Milliliters mmol Millimole/Millimoles mp Melting Point MS Mass Spectrometry/Mass Spectrum m/z Mass/charge ratio NA Not applicable Nath Naphthyl NBS N-bromosuccinimide nBuLi n-butyl lithium NCS N-chlorosuccinimide NEt3 Triethylamine NMR Nuclear Magnetic Resonance NOESY Nuclear overhauser effect spectroscopy NR No Reaction OBn O-benzyl On-Bu O-n-butoxide Ph Phenyl Piv Pivaloyl ppm Parts per million PTSA Para-toluenesulfonic acid q Quartet

xxv R General alkyl group rt Room Temperature s Singlet s-BuLi s-butyl lithium SALEN 2,2’-ethylenebis(nitrilomethylidene)diphenol SALAN N,N’-bis(o-hydroxybenzyl)1,2-diaminobenzene SM Starting Material t Triplet tBu t-butyl tBuLi t-butyl lithium Temp. Temperature THF Tetrahydrofuran TLC Thin Layer Chromatography TMAC Trimethylacetyl chloride TMEDA Tetramethylethylenediamine TMSCN Trimethylsilyl cyanide Ts p-toluenesulfonyl tt Triplet of triplets VAPOL 2,2’-diphenyl-(4-biphenanthrol) X Halogen XRD X-Ray Diffraction

xxvi Epigraph

If you’re going through hell, keep going.

–Sir Winston Churchill

xxvii

CHAPTER ONE: CHIRAL ALUMINUM-BASED LEWIS ACID CATALYSIS IN ASYMMETRIC ORGANIC SYNTHESIS

1.1 Introduction

Asymmetric synthesis in the laboratory traces its humble beginnings to the year

1815 when Jean-Baptiste Biot first passed polarized light through sugar solutions, and noted that they rotated the plane of the incident light. This phenomenon would not be explained until 1848 when Louis Pasteur physically separated enantiomorphic crystals of tartaric acid, confirmed that each rotated polarized light in opposite directions, and proposed the two isomeric forms were optically active mirror images of each other. Such chiral enantiomers have identical physical properties, and differ only with respect to the arrangement of atoms or groups around a stereogenic center, plane, or axis.

For the modern organic chemist, synthesis of a chiral compound favoring one enantiomer over the other presents a uniquely difficult challenge; merely achieving proper bond connectivity of atoms in a compound is no longer sufficient, those atoms must also be suitably arranged relative to each other in space. This is not merely an interesting theoretical puzzle, but a very practical problem with important consequences.

In 1957, thalidomide was first introduced to the market in West Germany as an over-the-counter sedative which was also claimed to alleviate anxiety, insomnia, and tension. Before long, it was being used by pregnant women to ease nausea and morning sickness. Unfortunately, thalidomide was sold as a racemic mixture containing both enantiomers of the compound (Figure 1.1). Although (+)-(R)-thalidomide (1) functioned as advertized, (-)-(S)-thalidomide (2) turned out to be a potent teratogen, resulting in limb

deformities in newborns.1 Before it was finally discontinued, thalidomide had caused more than 10,000 cases of birth deformities worldwide.

These tragic events reveal an important reality for academia and the pharmaceutical industry; nature is an enantiopure chiral system. Although two enantiomers of a compound may have identical physical properties in a lab, they nevertheless behave very differently in the chiral environment that is life. In the living organism, the enantiomeric relationship between these two compounds is transformed into a diastereomeric relationship as each enantiomer of the chiral compound interacts differently with the enantiopure chiral substrates in the body.

(+)-(R)-thalidomide, 1 (+)-(S)-thalidomide, 2 O O O O NH HN N O O N

O O sedative teratogen

mirror plane Figure 1.1 Enantiomers of Thalidomide

It has been almost 200 years since Biot’s landmark experiment, and almost 60 years since the thalidomide disaster. In that time Organic Chemistry has matured as a science and the burgeoning field of asymmetric organic synthesis has become increasingly successful in developing strategies for generating enantiopure samples of a target compound on a preparative scale.

1.2 Strategies for Chiral Induction2

1.2.1 Chiral Template

Many syntheses of chiral organic compounds begin with a template molecule, often a chiral natural product with either the desired chirality or with usable chirality built in. The chiral product is then obtained through a series of transformations with its chirality derived from the ancestral template molecule. Although useful, this method is not per se an enantioselective transformation, as nature carried out the enantiodetermining chemistry. This dissertation will make use of several chiral templates for the synthesis of target olefins in chapter 4.

1.2.2 Classical Resolution

Racemic syntheses producing equal quantities of each enantiomer can be resolved using chiral resolving agents. A reversible reaction with an enantiopure chiral resolving agent is carried out on the racemic mixture, changing the pair of enantiomers into a pair of diastereomers. These diastereomers have different physical properties and can, in principle, be separated by any number of techniques including chromatography. Removal of the resolving agent from each diastereomer affords purified enantiomer.

1.2.3 Chiral Auxilliaries

A removable chiral auxiliary can be attached to a prochiral substrate making that substrate chiral, and allowing for chiral induction in a subsequent step. Following purification, removal of the auxiliary affords enantioenriched product. The fact that the chiral auxiliary can be recovered and recycled makes this an attractive methodology. This

technique, however, is also not truly enantioselective, but rather diastereoselective, since the enantiodetermining step is in the preparation of the auxiliary. This dissertation will make use of several chiral auxiliaries, particularly in chapters two and three.

1.2.4 Chiral Catalysts

This is perhaps the only truly enantioselective mechanism among the presently mentioned strategies for asymmetric synthesis. A catalyst with chiral ligands or chiral substituents is prepared and used to effect a catalytic transformation of a prochiral substrate. With biological enzymes falling into this category, the power of this strategy is obvious. This work will predominantly concern itself with chiral catalysts, and in particular those based on the Lewis acidity of aluminum compounds. The evolution and application of this type of chiral aluminum-based Lewis acid catalyst in the chemical literature will be discussed in the next section.

1.3 Chiral Aluminum-Based Lewis Acids in The Chemical Literature

Chiral aluminum-based Lewis-acid catalyzed reactions have been reported extensively in the chemical literature for decades. One of the first examples of a chiral aluminum complex catalyzing an asymmetric reaction was reported over 30 years ago in

1979 by Koga and co-workers.3 In this study, chiral aluminum Lewis acids were prepared by reacting chiral alcohols 3-5 and ethyl aluminum dichloride (Scheme 1.1).3

EtAlCl2 EtAlCl2

OH OAlCl2 OH OAlCl2

3 6 4 7

EtAlCl2

OH OAlCl2 5 8 Scheme 1.1

The chiral catalysts so generated were then used to promote the Diels Alder reaction between cyclopentadiene (9) and three different achiral dienophiles 10a-c (Table

1.1).3 The best enantioselection was obtained with dienophile 10c in conjunction with catalyst 6, generating product 12c in 56% yield and 57% ee (entry 7). This result is reasonably good, and though the other reported results were not as impressive, this paper stands as an important entry into the field of asymmetric aluminum-based catalysis, as it demonstrated convincingly that aluminum complexes could be made chiral and used to promote chemical reactions enantioselectively.

Since this landmark paper was reported, the field of aluminum-catalyzed asymmetric reactions has exploded with hundreds of papers reporting hundreds of different chiral aluminum structures promoting a wide array of different organic reactions. Several books and reviews have been written to compile these results, demonstrating the efficacy and popularity of chiral aluminum-based catalysis.4 The following sections of this chapter will focus on the most recent examples of chiral aluminum Lewis acid catalysis reported in the chemical literature. 5

Table 1.1 Original chiral aluminum catalyzed asymmetric Diels-Alder published by Koga

toluene a: X = CO2Me, Y = H + Y Y b: X = CHO, Y = H X Y 3 hours X X c: X = Me, Y = CHO 9 10a-c 6-8 11a-c 12a-c

OAlCl2 OAlCl2 OAlCl2

6 7 8 Entry Dienophile Catalyst Cat. Temperature Product Yield ee (%) ratio (ºC) (%) 1 10a 6 0.26 -23 11a 65 6 2 10a 7 0.15 -45 to -23 11a 82 0 3 10a 8 0.16 -45 to -23 12a 78 9 4 10b 6 0.11 -78 11b 40 0 5 10b 7 0.11 -78 11b 73 3 6 10b 8 0.16 -78 11b 55 27 7 10c 6 0.15 -78 12c 56 57 8 10c 7 0.16 -78 11c 69 56 9 10c 8 0.16 -78 12c 84 25

1.3.1 Aluminum-Catalyzed Asymmetric Diels-Alder Reactions

A survey of the chemical literature reveals the Diels-Alder reaction to be among the most common reactions promoted by aluminum Lewis acids. In recent years, however, there have been comparatively few papers on aluminum-catalyzed asymmetric

Diels-Alder chemistry. Though there are indeed several papers on asymmetric Diels-

Alder reactions employing a chiral catalyst, there has been a greater focus primarily on methodologies employing chiral organocatalysts,5 phosphoric acids,6 oxazaborolidines,7 and ruthenium-based catalysts.8 Nevertheless, one excellent paper on chiral aluminum-

catalyzed Diels-Alder chemistry was reported by Yamamoto and Li in 2009, for an inverse-demand Diels Alder reaction of tropones (Table 1.2).9

Table 1.2 Chiral aluminum Lewis acid catalyzed Diels Alder reaction on tropones

Si(m-xylyl)3 Si(m-xylyl)3

OH DIBAL (2 eq.) O Al(iBu)2 OH O CH2Cl2, rt, 30 min Al(iBu)2

Si(m-xylyl)3 Si(m-xylyl)3

(S)-13 (S)-14

O R O R OEt 10 mol % (S)-14 OEt o CH2Cl2, 0 C OEt EtO 15 16 17 4 eq. Entry R Product Yield (%) ee (%) 1 H 17a 82 46 2 OAc 17b 67 94 3 OPiv 17c 81 97 4 2,4,6-trimethylBz 17d 98 93 5 3-BrBz 17e 98 94 6 p-TsO 17f 96 96 7 Cl 17g 81 86 8 Br 17h 92 90 9 I 17i 85 90 10 n-Bu 17j 36 78

Aluminum complex (S)-14 was prepared quite simply from BINOL derivative

(S)-13 and 2 equivalents of DIBAL-H. This aluminum complex was then used to catalyze a [4+2] Diels Alder reaction between substituted tropone 15 and ketene diethyl acetal

(16). Interestingly, many of the other initial achiral Lewis acid structures used to optimize this methodology (including AlMe3 and Me2AlCl) promoted a competing [8+2]

cycloaddition.9 As shown above, this methodology furnished products 17a-j in excellent yield and ee (Table 1.2). The poorest enantioselectivity was obtained with unsubstituted tropone, producing 17a in 46% ee (entry 1). This excellent methodology provides simple access to substituted bicyclo[2.2.3] ring structures with yields up to 98% and ee values up to 97%.

1.3.2 Aluminum-Catalyzed Asymmetric Rearrangements

While asymmetric rearrangements represent a minority of examples of chiral aluminum catalysis, there have nevertheless been recently published a small number of highly interesting papers on the subject. One excellent paper on the subject was published by Maruoka and co-workers in 2007, when they reported a catalytic asymmetric rearrangement of ,-disubstituted -siloxy aldehydes to -siloxy ketones (Scheme

1.2).10 This type of reaction works as shown below (Scheme 1.2); a chiral Lewis acid binds to the carbonyl group of 18, activating it for the enantiodetermining 1,2-alkyl shift shown in 20. The silyl group migrates, thus forming the chiral -siloxy ketone 19.

R O R R R OSiEt chiral Lewis acid Et3SiO R R 3 H R R O CHO SiEt O OSiEt3 O 3 Al* 18 Al* 19 20 21

Scheme 1.2

As shown below (Table 1.3), 5-10 mol % (S,S)-22, a catalyst made from (S)-

BINOL in 7 steps, was effective in promoting the rearrangement of 18 to 19. Recovered product yields ranged from 81% (entry 7) to 99% (entry 1), with the majority being in the

high 90s. Enantioselectivity was also quite good, with ee values ranging from 74%

(entries 9 and 10) to 90% (entry 4). Enantioselectivity was improved using bulkier R groups.

Table 1.3: Catalytic asymmetric rearrangement of ,-dialkyl--siloxy aldehydes

O Me R (S,S)-22 (5-10 mol %) Ar R OSiEt3 R R O Al toluene, -20oC, 12 h CHO OSiEt3 N SO2Ar 18 19

(S,S)-22 [Ar = 3,5-(CF3)2-C6H3]

Entry R Product Yield (%) ee (%) 1 PhCH2 (S)-19a 99 87 2 PhCH2 (S)-19a 96 87 3 p-MeO–C6H4CH2 (S)-19b 98 85 4 p-F–C6H4CH2 (S)-19c 97 90 5 p-Cl–C6H4CH2 (S)-19d 94 86 6 2-NaphCH2 (S)-19e 95 85 7 trans-PhCH=CHCH2 (S)-19f 81 83 8 (CH3)2C=CHCH2 (S)-19g 84 80 9 (CH3)2CHCH2 (S)-19h 94 74 10 c-Hex (S)-19i 97 74 [a]Reaction carried out with 10 mol % (entries 1-3) or 5 mol % (entries 4-12) of (S,S)-22

Interestingly, Maruoka and co-workers reported a kinetic resolution with this methodology using two different R groups (each with different migratory aptitudes).10

Their results are outlined below (Table 1.4). The kinetically resolved products 19j-n could be obtained in very high yield, and in excellent ee. In addition, unreacted 18j-n could be recovered in excellent yield and ee, demonstrating the catalyst’s ability to discriminate the enantiomers of racemic 18j-n. More interestingly, the regioselectivity

was excellent, with 19j-n all being obtained in greater than 20:1 excess over their respective regioisomeric rearrangement adducts.10 Thus Maruoka and co-workers have developed an excellent aluminum-based Lewis acid that is capable of a very efficient, highly enantioselective, highly regioselective rearrangement of ,-disubstituted - siloxy aldehydes to -siloxy ketones with catalyst loading of only 5-10 mol %.

Table 1.4: Kinetic resolution using Maruoka’s catalytic asymmetric rearrangement O R2 18j: (R1 = PhCH2, R2 =Ph) (S,S)-22 (5 mol %) R1 OSiEt3 R1 18k: (R1 = PhCH2, R2 = p-F-C6H4) R2 18l: (R = PhCH , R = p-Me-C H ) toluene, -20oC CHO 1 2 2 6 4 OSiEt3 18m: (R = trans-PhCH=CHCH , R = Ph) 18 1 2 2 19j-n 18n: (R1 = PhCH2, R2 = c-Hex)

Entry 18 Time (h) Yield of 19 (%)[a] ee (%) Recovery of 18 (%) 1 18j 12 49 (19j) 86 51 2 18j 15 55 (19j) 79 45 3 18k 11 49 (19k) 86 51 4 18l 12 51 (19l) 85 49 5 18m 3 57 (19m) 63 43 6 18n 0.5 55 (19n) 77 44 [a]The ratios of 19j-n to their respective products formed via alternate migration was 20:1.

Maruoka and co-workers also published a second paper on the subject of aluminum-catalyzed asymmetric rearrangements in 2011.11 This study highlights an aluminum-catalyzed asymmetric ring expansion that desymmetrizes cyclohexanone using substituted -diazoacetates to produce -substituted cycloheptanones. The basic reaction and the way it works are outlined below (Scheme 1.3).11 The chiral Lewis acid binds to

23a, activating it for nucleophilic attack by -diazo ester 24. The chirality of the Lewis acid directs the enantiofacial selectivity of the addition to 26, producing chiral intermediate 27, which rearranges stereospecifically to furnish (S)-25.

O O CO2R Bn CO2R (S)-Lewis acid Bn + N2 24 23a (S)-25

LA* O LA* Bn CO2R O N2 N2 CO2R Bn 26 27 chiral intermediate

Scheme 1.3

This methodology was optimized by testing 3 different chiral catalyst structures

11 prepared by adding silylated BINOL derivatives (S)-28a-c to AlMe3 (Table 1.5). The resulting aluminum complex, generated in situ, was then used to catalyze the asymmetric ring expansion between 23a and 24. The three BINOL derivatives (S)-28a-c were tested in conjunction with AlMe3, and a number of different R groups on 24 were tested as well.

Finally, reaction conditions were optimized by altering reaction temperature and time.11

BINOL-derivative (S)-28a was determined to give the best results, with the reaction between 23a and 24a furnishing (S)-25a in 97% yield and 76% ee (entry 1). Interestingly, this same reaction did not work at all when 20 mol % of both (S)-28a and AlMe3 was delivered (entry 4). When 24b and 24c were used in place of 24a under the same reaction conditions, the enantioselectivity fell to 58% and 54% respectively (entries 5 and 6).

Thus the methyl ester 24a was determined to be the optimal structure tested. Finally, as the temperature was decreased, the enantioselectivity increased, with the reaction between 23a and 24a going to 72% yield and 90% ee at -78ºC (entry 8). Because of the

decreased temperature, the reaction time was increased to 48 hours for all subsequent reactions carried out under these conditions.

Table 1.5 Maruoka’s Desymmetrizing Ring Expansion O O CO2R Bn CO R (S)-28 (20 mol %) 2 Bn + AlMe3 (40 mol %) N2 toluene 23a 24 (S)-25

(S)-28a: X = TMS OH (S)-28b: X = TBS OH (S)-28c: X = TPS

X (S)-28

Entry R Catalyst Product Temp Yield (%) ee (%) (ºC), Time (h) 1 Me (24a) (S)-28a (S)-25a -40, 24 97 76 2 Me (24a) (S)-28b (S)-25a -40, 24 91 58 3 Me (24a) (S)-28c (S)-25a -40, 24 99 40 4[a] Me (24a) (S)-28a (S)-25a -40, 24 NR NR 5 Bn (24b) (S)-28a (S)-25b -40, 15 76 58 6 t-Bu (24c) (S)-28a (S)-25c -40, 15 90 54 7 Me (24a) (S)-28a (S)-25a -60, 24 84 86 8 Me (24a) (S)-28a (S)-25a -78, 48 72 90 [a] Performed using 20 mol % (S)-28a and 20 mol % AlMe3

With this optimized methodology, Maruoka and co-workers expanded the scope of this reaction by screening several different substituted -diazo methyl esters 24a-m, in addition to the three different ketones 23a-c using (S)-28a and AlMe3 as the catalytic system (Table 1.6).11 As shown below, the scope of this reaction is quite impressive.

Methyl-substituted derivative 24j gave the poorest ee at 14% (entry 8), and iBu-

substituted derivative 24k was also mediocre at only 43% ee (entry 9). In fact, the reaction with 24k was very sluggish and required a 66 hour reaction time. Interestingly, all other derivatives had bulkier R groups and provided much more enantioselective results, with ee values ranging from 71 to 90%. Ketones 23b and 23c (entries 10 and 11) also provide an interesting result, demonstrating that the rearrangement can proceed with an O or an S heteroatom at the 4 position of cyclohexanone. Thus, Maruoka and co- workers have demonstrated an efficient enantioselective rearrangement for the construction of seven-membered rings, one that is catalyzed by a chiral silylated (S)-

BINOL derivative in conjunction with AlMe3.

Table 1.6: Scope of Maruoka’s Desymmetrizing Ring Expansion O CO2Me O (S)-28a (20 mol %) R CO2Me + AlMe3 (40 mol %) R N2 o X toluene, -78 C, 48 h X 23 24a (S)-25

Entry R X Product Yield (%) ee (%) 1 Bn (24a) CH2 (23a) (S)-25a 72 90 2 2-MeC6H4CH2 (24d) CH2 (23a) (S)-25d 24 71 3 3-MeC6H4CH2 (24e) CH2 (23a) (S)-25e 72 81 4 4-MeC6H4CH2 (24f) CH2 (23a) (S)-25f 94 84 5 4-MeOC6H4CH2 (24g) CH2 (23a) (S)-25g 93 84 6 4-BrC6H4CH2 (24h) CH2 (23a) (S)-25h 50 89 7 2-NathCH2 (24i) CH2 (23a) (S)-25i 58 80 8 Me (24j) CH2 (23a) (S)-25j 92 14 [a] 9 i-Bu (24k) CH2 (23a) (S)-25k 69 43 10 Bn (24a) O (23b) (S)-25l 67 80 11[b] Bn (24a) S (23c) (S)-25m 74 77 [a]Performed for 66 h. [b]Performed at -60ºC for 24 h.

1.3.3 Aluminum-Catalyzed Asymmetric Sulfide Oxidation

At a first glance, this may seem a less important reaction than the others. Chiral sulfoxides, however, are of great interest as chiral reagents due to their configurational stability.12 Enantiopure sulfoxides are used as chiral auxiliaries, organocatalysts, and ligands for catalytic transition metals used in synthetic applications.13 The most straightforward method for obtaining sulfoxides is the oxidation of sulfides, a topic that has been discussed in the chemical literature for decades.14 Although arguably the most underdeveloped field with respect to aluminum-based catalysis is asymmetric oxidation,15 catalytic asymmetric sulfide oxidation to chiral sulfoxides has made numerous advances in recent years.12

The first highly enantioselective aluminum-catalyzed asymmetric sulfide oxidation using aqueous H2O2 as the oxidant was reported as recently as 2007 by Katsuki and co-workers using chiral aluminum(salalen) complexes (Table 1.7).15 One of the advantages of H2O2 is that, along with O2, it is the greenest oxidant available for this reaction.16 Five different aluminum(salalen) based chiral catalysts were tested, along with a number of different solvents to optimize this reaction. One challenge associated with this reaction is limiting the formation of the sulfone, which forms as the desired sulfoxide is oxidized further. The first solvent tested was methanol, and the optimum catalyst was determined to be 33d, which promoted the oxidation of 29a to 30a in 99% conversion to products (entry 5). Of these products, the desired sulfoxide (S)-30a was formed in 90% yield and 98% ee, with the undesired sulfone 31a forming only 9%. The other solvents tested (entries 6-10), were not as selective for the formation of sulfoxide 30a, instead

forming the undesired sulfone 31a in much greater quantity. The addition of the phosphate buffer improved the catalytic activity and reproducibility of the reaction.

Table 1.7: Katsuki’s aluminum catalyzed asymmetric sulfide oxidation Al(salalen) (2 mol %) 30% H2O2 (1.1 equiv.) O phosphate buffer (pH 7.4) O O S S + S Ph Me RT, 24 h Ph Me Ph Me 29a 30a 31a 33a: (aR,R,R), R = H 33b: (aR,R,R), R = Me R 33c: (aR,S,S), R = H N N N N 33d: (aR,S,S), R = Me Al Al O O O Cl O Cl PhPh

Entry Catalyst Solvent Conv. (%) Yield Yield ee (%) Sulfoxide (%) Sulfone (%) 1 32 MeOH 40 40 2 20 (S) 2 33a MeOH 70 64 6 46 (S) 3 33b MeOH 55 51 4 10 (R) 4 33c MeOH 86 78 8 89 (S) 5 33d MeOH 99 90 9 98 (S) 6 33d EtOH 92 78 14 98 (S) 7 33d AcOEt 85 68 17 97 (S) 8 33d THF 85 66 18 98 (S) 9 33d CH2Cl2 81 78 13 99 (S) 10 33d toluene 84 59 25 99 (S) 11[a] 33d MeOH 33 32 <1 94 (S) [a]1 hour reaction time.

The scope of this optimized methodology was subsequently expanded on aryl- substituted methyl sulfides 29a-g (Table 1.8).15 Chiral sulfoxides 30a-g were all obtained in good yield with outstanding enantioselectivity. In addition, the formation of sulfones was kept to a minimum, with the highest being 31g, formed in only 10% (entry 7). The 15

best result was obtained through the oxidation of 29e (entry 5), which selectively yielded sulfoxide (S)-30e in 82% (sulfone 31e was formed in only 1%), and in 99% ee.

Table 1.8: Scope of Katsuki’s methodology on various aryl-substituted methyl sulfides Al(salalen) 33d (2 mol %) 30% H2O2 (1.1 equiv.) O phosphate buffer (pH 7.4) O O S S + S Ar Me MeOH, RT, 24 h Ar Me Ar Me 29 (S)-30 31

Entry Ar Yield sulfoxide (%) Yield sulfone (%) ee (%) 1 C6H5 (29a) 86 (30a) 9 (31a) 98 2 p-ClC6H4 (29b) 83 (30b) 9 (31b) 97 3 p-MeC6H4 (29c) 82 (30c) 9 (31c) 98 4 p-MeOC6H4 (29d) 82 (30d) 8 (31d) 97 5 o-MeOC6H4 (29e) 82 (30e) 1 (31e) 99 6 o-NO2C6H4 (29f) 84 (30f) 2 (31f) 99 7 m-BrC6H4 (29g) 81 (30g) 10 (31g) 99

The following year, in 2008, Katsuki and co-workers expanded on their work by describing a method for conducting this same oxidation in solvent-free conditions (Table

1.9).17 This was an interesting combination of their previously reported work from 2007 and a paper published by Noyori and co-workers in 2001 outlining a method for solvent-

18 free oxidation of sulfides to sulfoxides using 30% H2O2. For these experiments, the previously optimized catalyst 33d was used once again. The solvent free conditions were first optimized by concentrating the reaction in methanol, and varying both temperature and catalyst loading. The results are very interesting. As the quantity of solvent decreases, the increase in concentration necessitates orders of magnitude less catalyst loading. At 0.1 M concentration of 29a, for example (entries 1 and 2), 2 mol % 33d oxidizes 29a to (S)-30a in 90% yield and 98% ee, whereas 0.2 mol % does so in only

52% yield and 87% ee. By concentrating 29a all the way to 5 M (entries 5-7), however,

the same reaction proceeds using 0.2 mol % 33d in 95% yield and 97% ee, and diminishing this catalyst loading all the way to 0.002 mol % still produces (S)-30a in

87% yield and 90% ee. Under solvent-free conditions, 0.002 mol % 33d furnishes (S)-

30a in 92% yield and 96% ee (entry 8), a phenomenal result.

Katsuki and co-workers also demonstrated the scope of this chemistry by conducting the optimized solvent free reaction on a number of different sulfides (Table

1.10).17 The results were all excellent, with the best result yielding (S)-30h (entry 3) in

85% yield and greater than 99% ee. Interestingly, the highly activated o-methoxyphenyl methyl sulfide required less catalyst loading at only 0.004 mol % at 0ºC to yield (S)-30e in 88% yield and 96% ee (entry 2).

Table 1.9: Katsuki’s solvent-free conditions for asymmetric sulfide oxidation Al(salalen) 33d (x mol %) 30% H2O2 (1.1 equiv.) O phosphate buffer (pH 7.4) O O S S + S Ph Me MeOH, 24 h Ph Me Ph Me 29a (S)-30a 31a

Entry Concentration (M) x (mol %) Temperature (ºC) Yield (%) ee (%) 1 0.1 2 RT 90 98 2 0.1 0.2 RT 52 87 3 1 0.2 RT 88 93 4 1 0.2 0 91 98 5 5 0.2 0 95 97 6 5 0.02 0 92 95 7 5 0.002 0 87 90 8 Solvent free 0.002 0 92 96

Table 1.10: Scope of Katsuki’s methodology for solvent-free asymmetric sulfide oxidation Al(salalen) 33d (x mol %) 30% H2O2 (1.1 equiv.) O phosphate buffer (pH 7.4) S S R Me 24 h R Me 29 (S)-30 Entry R x (mol Temperature (ºC) Product Yield ee (%) %) (%) 1 p-MeC6H4 0.01 -10 (S)-30c 86 98 2 o-MeOC6H4 0.004 0 (S)-30e 88 96 3 o-ClC6H4 0.01 -10 (S)-30h 85 >99 4 m-ClC6H4 0.01 -10 (S)-30i 78 98 5 PhCH2 0.01 -10 (S)-30j 88 69

Katsuki and co-workers’ most recent publication on the subject was in 2011, when they reported an asymmetric oxidation of cyclic 1,3-dithiane derivatives using the same catalyst (aR,S,S)-33d (Table 1.11).13 For this study, ethyl acetate proved to be a more effective solvent than methanol, which had previously been the optimum solvent. In ethyl acetate at 10ºC, the majority of the reactions were complete in less than 7 hours.

Starting 1,3-dithianes 34a-l are all achiral molecules, hence both stereogenic centers are established during the reaction. This implies the potential formation of two diastereomers, each forming a pair of enantiomers. Despite this, the reactions were all highly stereoselective, with diastereoselectivity greater than 20:1 for all but (1S,2S)-35c, which was 19:1 diastereoselective (entry 3). The enantioselectivity for this reaction was absolutely outstanding, in all cases going to at least 99% ee, and in many cases producing product in greater than 99% ee. Significantly, with two methyl groups, (S)-35k has a single stereogenic center, and thus does not have a diastereoisomer. Finally, yields for this reaction were excellent with many reactions going to greater than 90% in 12 hours or less at 2 mol % catalyst loading. Considering Kagan’s original report on the subject of

catalytic asymmetric sulfide oxidation in 1984 called for stoichiometric delivery of

19 Ti(OiPr)4, the enormous progression of this field becomes clear. Katsuki and coworkers have thus considerably developed the field of aluminum-catalyzed asymmetric sulfide oxidation in recent years, demonstrating the great scope and power of aluminum-based

Lewis acids.

Table 1.11: Katsuki’s asymmetric oxidation of cyclic 1,3-dithianes

Al(salalen) 33d (2 mol %) 30% H O (1.1 equiv.) 2 2 N N S S phosphate buffer (pH 7.4) S S Al O R1 R2 EtOAc, 10oC R1 R2 O Cl O PhPh 34 35

(aR,S,S)-33d [a] Entry R1 R2 Time (h) Product dr Yield (%) ee (%) 1 Ph H 4.5 35a >20:1 93 99 2 PhCH=CH H 4 35b >20:1 94 99 3 PhC C H 4 (1S,2S)-35c 19:1 72 >99 4 PhCH2 H 3 35d >20:1 92 99 5 PhCH2CH2 H 4 (1S,2S)-35e >20:1 94 99 6 (CH3)2CH H 5 35f >20:1 98 >99 7 cC3H5 H 11 35g >20:1 95 >99 8 cC6H11 H 12 35h >20:1 98 99 9 (CH3)3C H 12 (1S,2S)-35i >20:1 73 >99 10 (CH3)3Si H 3 (1S,2S)-35j >20:1 91 99 11 CH3 CH3 24 (S)-35k 68 99 12 Ph CH3 48 35l >20:1 79 >99 [a]Absolute configuration not reported for all compounds.

1.3.4 Aluminum-Catalyzed Asymmetric Strecker Reaction

The Strecker reaction is one of the oldest and most widely documented organic reactions. First reported by Adolph Strecker in 1850,20 it was among the earliest atom-

economical, multi-component one-pot reactions reported.21 With enantiopure amino acids of such importance in both biology and chemistry, asymmetric Strecker reactions have already been extensively reported over the last four decades.21 The first example of an asymmetric Strecker reaction was reported in 1963 by Harada (Scheme 1.4).22 This was done by substituting the ammonia used in the classic Strecker reaction with enantiopure

(S)--phenylethylammonium hydrochloride (37). As shown below, the addition of the amine to acetaldehyde (36) forms chiral imine 38 in situ, the chirality of which controls the diastereofacial selectivity of the attack by sodium cyanide to form 39. Fundamentally,

Harada was preparing an imine substituted with a chiral auxiliary in situ, which was later removed via hydrogenolysis to furnish L-alanine (40) in 17% yield and 90% ee. While the yield of this reaction was very poor, the enantioselectivity was excellent, proving the important principle that enantioselective Strecker reactions were possible, and opening the door to subsequent research in this area.

H H NH3Cl H N H N O O NaCN NaCN + CN OH H H2O/MeOH NH 5 days 2 36 37 38 39 40

Scheme 1.4

As mentioned above, the classic Strecker reaction generates an imine in situ.

Thus, many of the recent Strecker reactions that have been reported in the literature merely use an imine as a starting material. Since 2007, there have been two excellent reports of chiral aluminum-catalyzed asymmetric Strecker reactions. The first was reported in 2009 by Yamamoto and Abell.23 Alternative cyanide sources have recently

been of great interest for carbonyl compounds in asymmetric cyanohydrin synthesis, due to the toxicity, expense, and volatility of TMSCN.23-24 This same research, however, has been extremely limited for imines.23 Thus, this study was also aimed at testing four different cyanide sources, 41a-d (Scheme 1.5). Compounds 41a and 41c worked extremely well at promoting the reaction in Table 1.12, while 41b and 41d were much less effective. Interestingly, the Strecker reactions reported in this paper are dual activated, and require both 10 mol % of the chiral Lewis acid, as well as 10 mol % of the

23 achiral Lewis base NEt3. Ethyl cyanoformate (41a) was chosen as the cyanide source, as it provided the best results in preliminary studies.

O O O P NC OH EtO CN EtO CN Et CN OEt 41a 41b 41c 41d

Scheme 1.5

As shown below, the scope of the reaction between 41a and 42 was excellent, with both aldimines and ketimines reacting to furnish products 43a-n in good yield and excellent enantioselectivity (Table 1.12).23 The two heteroaromatic-substituted imines that were tested also furnished product in good yield and excellent enantioselectivity despite these compounds normally being problematic (entries 3 and 4).23 As expected, the ketimines, which provide access to quaternary stereogenic centers, were slightly less reactive, due to the greater steric bulk during the formation of the carbon-carbon bond.23

The ketimines were thus reacted for 12 hours instead of the 6 hours required for the aldimines.

Table 1.12: Scope of Yamamoto’s aluminum catalyzed asymmetric Strecker reaction Br

O i-PrOH (1.5 equiv.) O P NEt3 (10 mol %) P O N Ar HN Ar N Me Ar 44 (10 mol %) Ar + O EtO CN R1 R2 toluene, rt, 6 h R1 CN Cl Al R2 O 1.5 equiv. Ar = 2,6-Me2-C6H3 N Me 41a 42 43

Br 44 Entry R1 R2 Product Yield (%) ee (%) 1 Ph H 43a 96 97 2 p-Br-C6H4 H 43b 92 94 3 2-furyl H 43c 99 96 4 2-thienyl H 43d 93 96 5 m-MeO-C6H4 H 43e 99 98 6 o-Me-C6H4 H 43f 99 98 7 p-MeO-C6H4 H 43g 88 95 8 p-Me-C6H4 H 43h 93 97 9[a] Ph Me 43i 82 96 [a] 10 p-Br-C6H4 Me 43j 91 94 11[a] Ph Et 43k 75 94 12[a] Ph n-Pr 43l 71 96 13[a] 2-furyl Me 43m 83 92 14[a] t-Bu Me 43n 95 82 [a]Reaction used 2.5 equiv. i-PrOH, 2.5 equiv. 41a, solvent was toluene:hexanes (1:1), 12 hours

The results were all excellent, with yields ranging from 71% to 99%, and enantioselectivity ranging between 82% and 98% ee. These efficient reactions require only 10 mol % of chiral aluminum Lewis acid 44, go to completion in between 6-12 hours, furnishing product enantioselectively in high yield, and perhaps most impressively, make use of alternative cyanide sources that are less expensive, safer, and much easier to handle.

The other recent aluminum-catalyzed asymmetric Strecker reaction was reported by Li and co-workers in 2010 (Table 1.13).25 This interesting methodology also sought a

less toxic and volatile alternative to TMSCN as a source of cyanide, and found that ligating the aluminum catalyst with a CN group was an excellent solution. Chiral additive

(R)-48 was added in only 10 mol % to stoichiometric Et2AlCN, activating the cyanide group for transfer, and generating a chiral aluminum catalyst. The aluminum reagent itself thus becomes the source of cyanide, and transfers the cyano group to imine 45 enantioselectively. The drawback to this approach is that the aluminum species must be administered stoichiometrically, although this isn’t much of a drawback considering the ease with which Et2AlCN can be handled, and that the more expensive chiral additive

(R)-48 is only delivered in 10 mol %.

Table 1.13: Catalytic asymmetric Strecker reaction reported by Li and coworkers Et AlCN (47) Naphth Naphth 2 Naphth Naphth N N toluene, i-PrOH N N Ph Ph P P Ph N O HN O 48 (10 mol %) H N OH o 2 R -78 C, 5 hours R CN 45 46 (R)-48 Entry R Product Yield (%) ee (%) 1 Phenyl 46a 94 98 2 p-nitrophenyl 46b 96 93 3 p-dimethylaminophenyl 46c 97 96 4 p-fluorophenyl 46d 95 94 5 p-biphenyl 46e 94 99 6 o-methylphenyl 46f 93 96 7 o-furylphenyl 46g 94 95 8 o-bromophenyl 46h 92 97 9 3,4,5-trimethyoxyphenyl 46i 90 95 10 m-bromophenyl 46j 92 97 11 m-nitrophenyl 46k 89 96

Interestingly, the naphthalen-1-ylmethyl substitution on the N-phosphonyl imine

45 was chosen not only for its ability to improve reaction yield and enantioselectivity, but also because it enabled complete purification of crude 46 with a simple hexane wash.25 In

fact, several chiral additives were tested, and (R)-48 was found to be the most enantioselective reagent when used in conjunction with Et2AlCN. Several derivatives of naphthalene-1-ylmethyl-N-phosphonyl imine 45 were reacted under these conditions

(Table 1.13). Products 46a-k were all obtained in excellent yield with outstanding enantioselectivity, demonstrating the enormous power of this method.

1.3.5 Aluminum-Catalyzed Asymmetric Hydrophosphonylation

The most prominent application of asymmetric aluminum-based Lewis acid catalysis reported in the chemical literature in recent years has been asymmetric hydrophosphonylation. This reaction is important because numerous different biologically active organic compounds containing phosphorus are known,26 and compounds such as -hydroxy and -amino phosphonic acids have been reported as antibiotics,27 anti-tumor agents,28 and enzyme inhibitors.29

Asymmetric carbon-phosphorus bond formation via Lewis acid catalysis was first reported in 1993 by Shibuya and co-workers using a titanium-based Sharpless catalyst.30

The first aluminum-catalyzed asymmetric hydrophosphonylation was reported 6 years later in 1999 by Kee and co-workers who reacted various aldehydes with dimethyl phosphonate.31 Salen-based aluminum Lewis acid (R)-52 affording the best results. Such salen-based catalysts are advantageous because not only are they quite H2O and O2 stable,31-32 but they are also cheaply prepared, easily structurally tuned, and reusable without reprocessing.31 These reactions reported by Kee and co-workers all proceeded in quantitative yield, but the enantioselectivites varied widely. The best result reported in this study is shown below (Scheme 1.6). Benzaldehyde (49) was reacted with dimethyl

phosphonate (50) in the presence of 5 mol % (R)-52 to yield -hydroxyphosphonate (R)-

51a quantitatively in 49% ee.31

O OH HP(O)(OMe)2 (50)

H P(OMe)2 N N THF, 20 oC, 48 h O Al (R)-52 (5 mol %) O Me O

49 (R)-51a (R)-52 100 % yield 49 % ee

Scheme 1.6

The way this aluminum-catalyzed hydrophosphonylation works is outlined below

(Scheme 1.7). Dimethyl phosphonate (50a) is in equilibrium with its tautomer, dimethyl phosphite (50b). Although the equilibrium favors the phosphonate tautomer, the phosphite, along with benzaldehyde, binds the aluminum Lewis acid, facilitates the nucleophilic attack of 50b on 49, and produces adduct 51a. Naturally, with a chirally- substituted aluminum atom, the reaction proceeds asymmetrically, producing adduct 51a enantioselectively.

O H O O O H+ P : P Ph MeO H MeO P MeO MeO Ph H MeO MeO OH 50a 50b 49 51a

Scheme 1.7

Thus, by 1999, aluminum-catalyzed asymmetric hydrophosphonylation was known, and the door had been opened to new research. As mentioned above, there have been several papers published in more recent years, and the scope and results have both greatly improved since it was first moved to aluminum in 1999. In 2010, Katsuki and co- workers published a paper outlining a method to decrease the reaction time and improve the yield of a landmark aluminum-catalyzed asymmetric hydrophosphonylation they had previously reported in 2007.33 Originally, the reaction previously reported in 200733a used

Al(III)-salalen complex (R)-53 as the Lewis acid to transform compounds 49 and 50 into

(S)-51a in 90% yield and 87% ee (Scheme 1.8). While this method was highly effective, producing (S)-51a in excellent yield and enantioselectivity, the 10% catalyst loading and

48 hour reaction time both left room for improvement.

O OH HP(O)(OMe)2 (50) N N H P(OMe) THF, -15 oC, 48 h 2 Al O (R)-53 (10 mol %) O Cl O

49 (S)-51a

(R)-53 Scheme 1.8

As mentioned above, the tautomerization between dimethyl phosphonate and dimethyl phosphite favors dimethyl phosphonate, which has the effect of decreasing its reactivity for hydrophosphonylation. Thus, in their 2010 paper, Katsuki and co-workers outlined a method using inorganic bases to accelerate the tautomerization in order to improve upon their 2007 results.33b This was a reasonable approach, since the original

Pudovik hydrophosphonylation reaction is promoted by base.34 Several inorganic bases were used in conjunction with aluminum Lewis acid (R)-53 to promote the reaction shown in Scheme 1.8, including lithium, sodium, potassium, and cesium carbonates

(Table 1.14).33b

Table 1.14: Effect of inorganic salts, temperature, and catalyst structure on hydrophosphonylation O OH HP(O)(OMe)2 (50) H (R)-53 or (R)-54 P(OMe)2 O base (1 equivalent) THF, 24 h 49 (S)-51a

N N N N Al Al O Cl O O Cl O

(R)-53 (R)-54 Entry Catalyst mol % Base T (ºC) Yield (%) ee (%) 1[a] (R)-53 10 – -15 87 90 2 (R)-53 10 Li2CO3 -15 >99 90 3 (R)-53 10 Na2CO3 -15 >99 90 4 (R)-53 10 K2CO3 -15 >99 90 5 (R)-53 10 Cs2CO3 -15 84 11 6 (R)-53 10 Li2CO3 -30 53 93 7 (R)-53 10 Na2CO3 -30 65 91 8 (R)-53 10 K2CO3 -30 91 92 [b] 9 (R)-53 10 K2CO3 -30 >99 92 [b] 10 (R)-54 10 K2CO3 -30 >99 97 [b] 11 (R)-54 1 K2CO3 -30 >99 97 [a] [b] Reaction time: 48 hours. Et2O was used as solvent instead of THF.

Carbonates of earth alkali metals were also tested, but showed no positive effect.33b At -15ºC, lithium, sodium, and potassium carbonates all show a positive result

on the reaction rate, and improve the yield to over 99%. In an attempt to utilize this new found reactivity to improve the enantioselectivity of the reaction, the temperature was decreased to -30ºC.33b Although this did indeed positively influence the enantioselectivity of the reaction, the reaction yield dropped markedly for both lithium and sodium carbonates. Potassium carbonate, however, still promoted the reaction to 91% yield in

92% ee at -30ºC (entry 8). Carrying out the reaction in diethyl ether using postassium carbonate maintained the enantioselectivity at 92% ee, but improved the yield to >99%

(entry 9). With the reaction optimized so well, the slightly bulkier aluminum-based Lewis acid (R)-54 was also tested in diethyl ether with potassium carbonate as an additive.

These conditions furnished product (S)-51a in >99% yield and 97% ee (entry 10).

Incredibly, this same result could be obtained under these conditions by decreasing the catalyst loading to only 1 mol % (entry 11).

This optimized reaction was subsequently used to transform several different aldehydes to their corresponding -hydroxy phosphonates (Table 1.15).33b As shown below, the scope of this methodology is excellent, with products (S)-51b-h all forming in excellent yield with excellent enantioselectivity at only 2 mol % catalyst loading. In addition, the reaction now proceeds in only 24 hours as opposed to the 48 hours originally reported. Thus, addition of inorganic base accelerated the tautomerization to dimethyl phosphite, improving the reactivity sufficiently for the reaction to proceed at lower temperatures, which improved the enantioselectivity. Importantly, the Al(III)- salalen system was flexible enough to allow for the inorganic base additive without inhibiting substrate binding or affecting ee.33b

Table 1.15: Hydrophosphonylation of different aldehydes using optimized reaction conditions O HP(O)(OMe)2 (50) OH (R)-54 (2 mol %) R H R P(OMe)2 K2CO3 (1 equiv) o O Et2O, -30 C, 24 h 49 (S)-51 Entry Product R Yield (%) ee (%) 1 (S)-51b p-MeOC6H4 98 93 2 (S)-51c p-O2NC6H4 98 98 3 (S)-51d o-ClC6H4 94 97 4 (S)-51e (E)-PhCH=CH 97 95 [a] 5 (S)-51f PhCH2CH2 93 97 6 (S)-51g nC7H15 90 96 7[b] (S)-51h iPr 96 96 [a] [b] Reaction time was 48 hours. 0.1 equiv. of K2CO3.

Aluminum-catalyzed asymmetric hydrophosphonylation has expanded beyond salen, salan, and salalen derivatives and has evolved to make use of other ligand systems as well. In 2008, Yamamoto and Abell reported an interesting study optimizing a novel aluminum Lewis acid catalyst for hydrophosphonylation (Table 1.16).35 Unfortunately, the initial results were poor, with ee values as high as only 24% (entries 1-4). Boosting the phosphonate up to 5 equivalents (entry 3) greatly improved the yield, but did not improve the enantioselectivity. To improve both the reactivity and selectivity of this reaction, the phosphonate was substituted with fluorine-containing electron-withdrawing alkyl chains. The electron-deficient phosphonates were hypothesized to more rapidly equilibrate to the active phosphite tautomer under the reaction conditions, and were thus predicted to be more reactive. The optimization of this methodology is shown below

(Table 1.16).35

Table 1.16: Optimization of Yamamoto’s aluminum-catalyzed hydrophosphonylation system R'

O OH O 56 (10 mol %) OR N H + P P OR O H OR THF, 24 h O Cl Al OR O 49 55 N

R' 56a: R' = H 56b: R' = mesityl Entry Product R T (ºC) Yield (%) ee (%) 1 (S)-55a Me RT 20 24 2 (S)-55b Et RT 18 23 3[a] (S)-55c Me RT 94 20 4 (S)-55d Ph RT 48 <5 [b] 5 (S)-55e CH2CF3 RT 94 48 6 (S)-55f CH(CF3)2 RT 30 <5 7 (S)-55e CH2CF3 -15 27 50 [b][c] 8 (S)-55e CH2CF3 RT 93 65 [b][d] 9 (S)-55e CH2CF3 RT 94 78 [b][e] 10 (S)-55e CH2CF3 RT 95 96 [a]5 equiv. phosphonate. [b]reaction complete after 1 hour. [c]1 mol % catalyst. [d]hexanes used as solvent. [e]1 mol % catalyst 56b used, hexanes used as solvent.

The initial attempt using trifluoroethyl groups greatly improved the yield to 94%, and improved the ee to 48% in only 1 hour (entry 5), proving the viability of this approach. Increasing the steric bulk of the alkyl chains was also tested (entry 6), but significantly decreased both yield and ee. In an attempt to improve the enantioselectivity, the temperature was decreased to -15ºC (entry 7), and although this did improve the enantioselectivity to 50% ee, the reaction did not go to completion, yielding product in only 27%. Interestingly, decreasing the catalyst loading of 56a to only 1 mol % (entry 8) improved both the yield and enantioselectivity to 93% and 65% respectively. Changing

the solvent to hexanes (entry 9) significantly improved the enantioselectivity to 78%.

Finally, the catalyst structure itself was modified to 56b, which yielded product (S)-55e in 95% and improved the enantioselectivity all the way to 96% ee (entry 10).

Yamamoto and Abell subsequently used this optimized methodology to transform a series of aldehydes to their corresponding -hydroxy phosphonates (Table 1.17),35 which could then be hydrolyzed to -hydroxy phosphonic acids in concentrated HCl and methanol.

Table 1.17: Results from Yamamoto’s methodology to hydrophosphorylate aldehydes O O 56b (1 mol %) OH + (OCH CF ) P hexanes 2 3 2 R H H (OCH2CF3)2 R P O 57 (S)-58 Entry Product R Time (min) Yield (%) ee (%) 1 (S)-55e Ph 10 95 96 2 (S)-58a 2-naphthyl 15 98 95 3 (S)-58b 4-ClC6H4 15 94 95 4 (S)-58c 4-BrC6H4 15 96 95 5 (S)-58d 4-NO2C6H4 10 93 92 6 (S)-58e 4-MeOC6H4 10 93 97 7 (S)-58f 4-MeC6H4 5 94 94 8 (S)-58g 3-MeOC6H4 20 93 95 9 (S)-58h 2-MeOC6H4 10 93 93 10 (S)-58i 2-MeC6H4 5 95 95 11 (S)-58j c-hexyl 25 95 82 12 (S)-58k n-hexyl 20 91 82

The results shown above really demonstrate the power of this chemistry, with products (S)-55e and (S)-58a-k all forming in excellent yield and enantioselectivity. In fact, the lowest reaction yield was an impressive 91%. Interestingly, the lowest enantioselectivity was observed for aliphatic R groups (entries 11 and 12) suggesting that the steric bulk of the R group plays an important role in determining ee. Thus Yamamoto and Abell expanded the scope and versatility of aluminum-based Lewis acids for 31

asymmetric hydrophosphonylation by tuning the structure of the Lewis acid, as well as the structure and electronic properties of the phosphonate. Their efforts resulted in a very impressive reaction that proceeds almost quantitatively and in high ee at 1 mol % catalyst loading in only minutes.

A closely related strategy was published 2 years later in 2010 by Feng and co- workers for the asymmetric hydrophosphonylation of fluorinated ketones using dimethyl phosphonate.36 The synthesis of -trifluoromethyl alcohols is an interesting topic, since many such compounds have been reported to have interesting biological activities.36 With

-hydroxy phosphonates already possessing biological activity, Feng and co-workers were interested in constructing both moieties in a single step. This paper also screened novel ligands 59-64 as potential agents for complexation to Et2AlCl (Scheme 1.9).

NH OH NH OH NH OH

OH OH OH

59 60 61

NH OH NH OH N OH

OH OH OH

R R

62 63 64 R = adamantyl R = adamantyl

Scheme 1.9

Trifluoromethylphenyl ketone (65a) and dimethyl phosphonate (50) were used to determine the optimal catalyst structure, as shown below (Table 1.18).36 Under the conditions tested, adamantyl-substituted ligand 63 proved by far the most effective, promoting the formation of 66a in 90% yield and 85% ee in conjuction with Et2AlCl

(entry 5). This result was further improved to 99% yield and 89% ee by conducting the reaction at -15ºC for 40 hours (entry 7).

Table 1.18: Optimization of catalyst structure for hydrophosphonylation of trifluoromethylketones O HP(O)(OMe) (50) 2 HO CF3 (OCH3)2 CF3 59-64 (10 mol %) P Et2AlCl (10 mol %) O THF, 0 oC, 12 h 65a 66a Entry Ligand Yield (%) ee (%)[a] 1 59 80 0 2 60 83 0 3 61 86 24 4 62 89 41 5 63 90 85 6 64 78 14 7[b] 63 99 89 [a]Absolute configuration not reported. [b]Reaction carried out at -15ºC for 40 hours.

This optimized methodology was used to transform a number of trifluoromethyl ketones to their corresponding -hydroxy trifluoromethyl phosphonates (Table 1.19).36

Although the reaction time is high at 40 hours, the results are quite excellent, with adducts 66a-h being obtained in yields up to 99%, and enantiomeric excesses as high as

90% ee. Enantiomeric excess was determined using chiral HPLC, but the absolute stereochemical configuration of the products was not reported in this publication. Thus,

Feng and co-workers were able to expand the scope and versatility of aluminum-based

Lewis acid catalyzed hydrophosphonylation with a high yielding and highly enantioselective procedure for trifluoromethyl ketones.

Table 1.19: Optimized asymmetric hydrophosphonylation of various trifluoromethyl ketones O HP(O)(OMe)2 (50) HO CF3 (OCH ) R P 3 2 R CF3 63 (10 mol %) O Et2AlCl (10 mol %) 65 o 66a THF, -15 C, 40 h Entry Product R Yield (%) ee (%)[a] 1 66a Ph 99 89 2 66b 4-CH3C6H4 82 87 3 66c 4-CH3OC6H4 85 90 4 66d 4-BrC6H4 87 85 5 66e 4-ClC6H4 96 85 6 66f 4-FC6H4 93 86 7 66g 3-FC6H4 95 74 8 66h 2-C4H3S 86 85 [a]Absolute configuration not reported.

The most recent study of aluminum-catalyzed asymmetric hydrophosphonylation was published in 2012 by He and co-workers,37 and it includes several elements described in each of the abovementioned studies. This study used cyclic phosphonates to hydrophosphonylate both aldehydes and ketones to their corresponding -hydroxy phosphonates, and just as described above, this study was optimized using an adamantyl- substituted catalyst structure, and using an inorganic base as an additive. Tridentate

Schiff base 67 was reacted with Et2AlBr to produce dimeric Lewis acid complex (S)-68, which was stable enough to be structurally characterized with X-ray crystallography

(Scheme 1.10).37

tBu

OH R' R N OH Et2AlBr O N R R = isobutyl Al R' = adamantyl R' O O Al R N Br O tBu R'

67 tBu (S)-68

Scheme 1.10

Numerous derivatives of (S)-68 were screened, varying the R and R’ groups. The best results were obtained with (S)-68 itself, which promoted the hydrophosphonylation between benzaldehyde (49) and cyclic phosphonate 69, to afford (S)-70a in 82% yield and 99% ee in 25 hours at -15ºC (Table 1.20, entry 1).37 This reaction was subsequently optimized through the addition of an inorganic base, which considerably improved the reaction time to only 2 hours. Interestingly, in this case K2CO3 was not the most effective inorganic base for promoting the reaction, and in fact Ag2CO3 was determined to be much better. In order for the reaction to proceed in only 2 hours to yield (S)-70a in 75%,

40 mol % K2CO3 was required (entry 5). By contrast, the same 2 hour reaction using

Ag2CO3 required only 4 mol % (entry 9) to match the 82% yield obtained over 25 hours without any additive (entry 1). Thus, the optimum catalyst structure was determined to be

(S)-68, and the reaction time was decreased from 25 hours to 2 hours by using 4 mol %

Ag2CO3.

Table 1.20: The effect of an inorganic base on the reaction time for He’s methodology O O OH H O P (S)-68 (10 mol %) O H + O O P o THF/CH2Cl2, -15 C O 2 hours 49 69 (S)-70a Entry Inorganic base Mol % Yield (%) ee (%) 1[a] none N/A 82 99 2 K2CO3 10 40 99 3 K2CO3 20 45 99 4 K2CO3 30 67 99 5 K2CO3 40 75 99 6 Ag2CO3 1 30 99 7 Ag2CO3 2 44 99 8 Ag2CO3 3 71 99 9 Ag2CO3 4 82 99 [a]Reaction conditions without inorganic base additive were -15ºC for 25 hours.

As mentioned above, this methodology was subsequently used to transform a number of aldehydes and ketones to their corresponding -hydroxy phosphonates. The best results are outlined below (Table 1.21). The enantiomeric excesses are outstanding using this methodology, with % ee values ranging between 92% and 99%. The reaction yields are good, with product yields ranging between and 67% and 84%. Another outstanding aspect of this methodology is the fact that reactions go to completion in only

2 hours.

Table 1.21: Hydrophosphonylation of aldehydes and ketones using He’s optimized methodolgy O O OH H R O P (S)-68 (10 mol %) 2 O R R + O O R P 1 2 AgCO3 (4 mol %) 1 O o THF/CH2Cl2, -15 C 2 hours 69 (S)-70 Entry Product R1 R2 Yield (%) ee (%) 1 (S)-70a Ph H 82 99 2 (S)-70b 4-MeC6H4 H 84 99 3 (S)-70c 3-MeC6H4 H 83 99 4 (S)-70d 4-BrC6H4 H 82 96 5 (S)-70e 4-MeOC6H4 H 79 92 6 (S)-70f 4-ClC6H4 Me 68 98 7 (S)-70g 3-ClC6H4 Me 70 97 8 (S)-70h 4-BrC6H4 Me 70 95 9 (S)-70i 3-BrC6H4 Me 71 95 10 (S)-70j 4-MeOC6H4 Me 67 98

1.3.6 Aluminum-Catalyzed Asymmetric Epoxide Opening

Although there have not been any recent papers on the topic of aluminum- catalyzed asymmetric epoxide opening, it is nevertheless a reaction that is worthy of brief comment herein. Ring opening of meso epoxides to their corresponding chiral β- chloroalcohols is a known reaction that has been previously reported in the chemical literature. Yamamoto and co-workers reported such a procedure in 1988 on cyclohexene oxide.38 As shown in Table 1.22, menthol-derived complex 6 promotes the epoxide opening of meso epoxide 71 at -20 ºC in 37 % yield and 10 % ee (entry 1). Increasing the steric bulk at the Lewis acidic aluminum center in complex 73 resulted in a 24 % boost in ee (entry 2). Interestingly, BINOL-derived complex 76 improved the ee further to 40 %, but owing to the diminished Lewis acidity of this complex, the yield was reduced to 26 % even at higher temperature (entry 3). Although these are modest results by today’s

standards, they demonstrate clearly that chiral Lewis acids can open meso epoxides to obtain enantioenriched β-chloroalcohols.

Table 1.22: Asymmetric Epoxide Opening Reported in 1988 by Yamamoto and Co- Workers 110 mol % catalyst OH O CH2Cl2 Cl 71 72

EtAlCl2 s-BuLi

OH OAlCl2 OAl(s-Bu)Cl2

3 6 73

OH EtAlCl O LiOn-Bu O OnBu 2 AlCl Al OH O O Cl

74 75 76 Entry Catalyst Temperature (ºC) Yield (%) ee (%) 1 6 -20 37 10 2 73 -20 40 34 3 76 40 26 40

Kinetic resolution of racemic epoxides is also a known reaction. As reported by

Yamamoto and co-workers, epoxide 77 was resolved using complex 76.38 This process is shown below in Scheme 1.11.

Me Me 100 mol % 76 15 % recovery O o O 27 % ee CH2Cl2, 0 C, 16 h 77 77 Scheme 1.11

Similarly, the resolution of racemic keto-epoxide 78 was carried out using both complexes 73 and 76 (Table 1.23). Unfortunately side product ketal 79 was formed in the majority under the various conditions tested. Although enentioenriched keto-epoxide 78 could not be recovered in higher yield than 20%, it could be enantioenriched in greater than 95 % ee. This excellent enantioenrichment demonstrates the potential of chiral aluminum complexes to resolve certain racemic epoxides. These results also highlight the potential of chiral aluminum complexes to enantioselectively open certain meso- epoxides.

Table 1.23: Kinetic Resolution of a keto-epoxide using Chiral Aluminum Complexes O 75 mol % catalyst O O + O O CH2Cl2, 5 h O racemic 78 enantioenriched 78 79 Entry Catalyst Temperature (ºC) Yield of 78 (%) ee (%) 1 73 -20 6 71 (S) 2 76 -30 20 >95 (R)

1.3.7 Summary of Asymmetric Aluminum-Based Catalysis

Throughout all of the examples of asymmetric aluminum-based catalysis reported above, numerous advantages and drawbacks are made clear. Some reactions proceed catalytically; some require stoichiometric delivery of aluminum complex to promote the reaction in reasonable yield. Numerous side reactions are possible, owing to the reactivity of these aluminum complexes. Temperature is therefore an important factor in carrying out these reactions, and can be used to optimize chemoselectivity and stereoselectivity.

Although the library of chiral aluminum-based Lewis acid structures reported in the

literature is quite extensive, they all share one commonality; the chirally-tuned substituents are built around the catalytically-active aluminum center through heteroatom bonds. All of the chiral aluminum complexes reported above feature some chiral substituent bonded to aluminum through either a nitrogen-aluminum or an oxygen- aluminum bond. Although this method has advantages, it is not without drawbacks.

For example, having to bond chiral substituents through nitrogen and oxygen reduces the practical scope of prospective chiral structures. If bonding the aluminum directly to a carbon atom were possible, it would allow the active catalytic center to be closer to the stereocenter in some cases, potentially improving chiral induction. Using carbon-aluminum bonds would also increase the Lewis acidity of the catalyst, since carbon contains no lone pairs which can back donate into aluminum’s empty p orbital as both nitrogen and oxygen do.

1.4 Hydroalumination Reactions

One of the reasons heteroatom-bound chiral aluminum-based Lewis acids are common is due to their relative ease of preparation. Hydroalumination – and to a lesser extent carboalumination – are known reactions that generate carbon aluminum bonds, but are each limited in their scope and usefulness with respect to generating chiral aluminum compounds for catalysis. First reported in 1956,39 the simplest hydroalumination reactions are shown below (Scheme 1.12).40

AlH3 + 3 RCH=CH2 Al(CH2CH2R)3

LiAlH4 + 4 RCH=CH2 LiAl(CH2CH2R)4

Scheme 1.12

Several key problems with hydroalumination have limited its usefulness over the past decades. For one thing, it is considerably less reactive than hydroboration.41 Without a catalyst, hydroalumination only proceeds at high temperatures, where competitive dehydroalumination, carboalumination, and metallation compete.41 As such, hydroalumination reactions have been catalyzed by various transition metal compounds based on Ti, Ni, Zr, and even U.42 Despite the limitations, hydroalumination has nevertheless been a topic of great interest; the anti-Markovnikov regioselectivity is synthetically useful, as is the high reactivity of intermediate organoaluminum species with numerous electrophiles. Hydroalumination is synthetically interesting for one additional reason; it has the potential to generate novel aluminum-based catalyst structures for Lewis acid catalysis.

In 1986, Yamamoto and co-workers described a novel method for generating

43 HAlCl2 in situ by reacting R2AlH (R = Et, iBu) with AlCl3. This reagent hydroaluminates di- or tri-substituted alkenes, but like previous hydroaluminating agents, also requires boron or titanium catalysts. While a significant step forward, the methodology nevertheless presents two critical problems with respect to targeting chiral

R*AlX2 type catalysts. The first is that using transition metal catalysts often reduces the regioselectivity of the hydroalumination reaction, creating a problem wherein multiple aluminum species are being generated.41a The second problem is that residual

hydroaluminating catalyst could compete with the R*AlX2 catalyst in promoting organic reactions, leading to a reduction in ee.

In 1993, Gorobets and co-workers reported a hydroaluminating reagent that could smoothly hydroaluminate olefins at room temperature in excellent yield without any additional catalyst.44 This method built upon the previous work of Yamamoto and co- workers, and generated the more reactive species HAlBr2 in situ (Scheme 1.13).

Importantly, this reaction is highly selective for the anti-Markovnikov adduct. More importantly still, the product of this hydroaluminating reaction, RAlBr2 is highly amendable for use as a catalyst in organic reactions, comparing closely to the widely used

MeAlCl2. Gorobets and coworkers reported hydroaluminuation of several mono-, di-, and tri-substituted olefins. Tetrasubstituted olefins did not undergo hydroalumination, with side reactions predominating.44

4 eq. olefin 3AlBr3 + LiAlH4 4HAlBr2 + LiBr 4RAlBr2 + LiBr

Scheme 1.13

Some of the selected olefins that were hydroaluminated in Gorobets’ original paper are shown below (Scheme 1.14). Compounds 80-84 were all hydroaluminated with very high conversion, and intermediate RAlBr2 species 85-89 were converted to various products that were all isolated in excellent yield. These experiments demonstrate the efficiency of this methodology and highlight its potential applicability for the purposes of catalysis.

AlBr3 H2O AlBr2 (100) (95) LiAlH4 80 85 90

AlBr OH AlBr3 2 O2 (95) (86) LiAlH4 81 86 91

H O AlBr3 2 (96) (95) LiAlH4 AlBr2 82 87 92

AlBr3 H2O (95) LiAlH4 (89) AlBr2 83 88 93

AlBr3 CuBr (95) (87) LiAlH4 AlBr2 Br 84 89 94

a Scheme 1.14: Examples of Hydroalumination using HAlBr2 Agent aReaction yields shown in parentheses

1.5: Dimerization of Aluminum Complexes

It is well known in the chemical literature that most aluminum compounds exist in solution as dimers.45 Trimethylaluminum, for example, exists as a dimer through bridging methyl groups via 3-center-2-electron bonding, while aluminum halides have dimeric bridges through 2-center-2-electron bonds (Scheme 1.15).45a The relative ability of substituents to form bridges decreases in the following order: R2N > RO > Cl > Br > Ph >

Me > Et > iPr > iBu.45a Thus, many of the aluminum-based catalysts with nitrogen and oxygen atoms previously discussed in this chapter likely exist as dimeric species if even they have been reported as monomers.

CH3

H3C CH3 Cl Cl Cl R Br Br Al Al Al Al Al Al Cl Cl Br R H3C CH3 Cl Br CH 3 94c 94d 94b Scheme 1.15

Similarly, the RAlBr2-type Lewis acids discussed in this dissertation likely exist as dimers as well, particularly in the non-coordinating aromatic solvents used for the

Hydroalumination reaction. With bromine being less capable of forming bridges than chlorine,45a however, and with some of the larger bulky R groups in 94d-type structures,

RAlBr2-type Lewis acids may demonstrate a lesser tendency to dimerize than other aluminum-based Lewis acids, particularly with LiBr in solution. Despite the fact that

RAlBr2-type Lewis acids likely exist in solution as dimers, they will be drawn as monomers in this dissertation.

1.6: Project Goals

As shown above (Scheme 1.14), Lewis acids 87 and 88 were both derived from chiral olefins. In the case of Lewis acid 88, the aluminum atom is even directly bonded to a stereogenic center. As analogues of MeAlCl2, adducts 85-89 should be expected to 44

promote organic reactions, and in fact chiral induction would be a reasonable expectation were Lewis acids 87 and 88 used as catalysts. Due to the scope and efficacy of this hydroalumination reaction, building a library of chiral olefins and hydroaluminating them to generate novel aluminum-based catalyst structures was the ultimate goal.

As a starting point, the hydroalumination reaction was repeated with simple olefins, and the respective Lewis acids were characterized. Due to their reactivity, characterization of organoaluminum compounds was limited to 1H NMR and 13C NMR spectroscopy. Once generated, these compounds were also quenched and further characterized. Once this chemistry was repeated, the reactivity of simple achiral RAlBr2 compounds was tested through a series of binding studies at low temperature. The relative Lewis acidity of RAlBr2 compounds compared to RAlCl2 compounds was assessed by monitoring coordination to simple carbonyl-containing reagents with NMR spectroscopy.

Once this was complete, simple achiral RAlBr2 compounds were used to promote a known reaction. The Keay group previously reported a novel MeAlCl2-promoted asymmetric Diels-Alder reaction using oxazolidinone-based chiral auxiliaries to access the drimane skeleton via intermediate 97a (Scheme 1.16). This skeleton was appropriately substituted to generate (+)-albicanol, (+)-albicanyl acetate, (+)- dihydrodrimenin, and (-)-dihydroisodrimeninol through a series of additional transformations.46 The best result was obtained using (S-3a-cis)-(-)-3,3a,8,8a-tetrahydro-

2H-indeno[1,2-d]-oxazolidin-2-one substituted dienophile 95a shown below (Scheme

1.16).

O O O O 1.4 eq. MeAlCl2 O N + O N >99:1 dr CH2Cl2, rt, 8h 75% yield

OBn 96 OBn

95a 97a exo

Scheme 1.16

Due to its ability to access the drimane skeleton with high selectivity, this Diels-

Alder chemistry has proven synthetically useful. As stated above, MeAlCl2 has an analogous structure to the RAlBr2 compounds proposed above. As such, a logical starting point for this chemistry was to repeat the Diels-Alder chemistry previously reported by the Keay group. Achiral RAlBr2 compounds were used in an effort to promote this reaction, with the idea being that various chiral R*AlBr2-type compounds could also be prepared and used to promote this Diels-Alder reaction without using the expensive chiral auxiliary. This chemistry was ultimately expanded to include other known reactions as have been reported in this chapter.

CHAPTER TWO: 3ALBR3·LIALH4-MEDIATED HYDROALUMINATION OF SIMPLE OLEFINS AND THE ACTIVATION OF OBN-PROTECTED OXAZOLIDINONE-BASED DIENOPHILES

2.1 Hydroalumination of Simple Olefins

Among the first experiments performed was a thorough repetition of the hydroalumination procedure reported by Gorobets on several simple olefins including 1- hexene, cyclohexene, 1-dodecene, and (+)-camphene. This section will highlight 1- hexene, cyclohexene, and (+)-camphene to demonstrate the efficacy and reliability of this method. Hydroaluminated Lewis acids proved extremely reactive with both H2O and with

O2, and would react rapidly if exposed to atmosphere. As such, hydroaluminated Lewis acids were stored carefully under N2 atmosphere as a solution in benzene, and characterization of all hydroaluminated Lewis acids was limited to in situ 1H NMR and

13C NMR spectroscopy. Hydroalumination of 98 is shown below in scheme 2.1.

AlBr3, LiAlH4

AlBr2 benzene, 1h 98 99 Scheme 2.1

Hydroalumination of 98 was carried out in benzene as per the experimental procedure outlined by Gorobets. AlBr3 and LiAlH4 were combined in benzene and stirred to generate the hydroaluminating agent in situ. Following 30 minutes of stirring, olefin 98 was slowly added dropwise over 5 minutes. After 1 hour, the olefin peaks had completely

1 disappeared from the H NMR spectrum, and a very clean spectrum of 99 in benzene-d6 was obtained, demonstrating how smoothly this methodology is capable of

1 hydroaluminating olefins to their corresponding RAlBr2-type Lewis acids. The in situ H

NMR spectrum of 99 after 1 hour reaction time is shown below in Figure 2.1 (spectrum

2). As can be seen by comparison to the 1H NMR spectrum of olefin 98 (spectrum 1), conversion is complete. In order to confirm the quantitative conversion from olefin 98 to

RAlBr2 Lewis acid 99, 1 molar equivalent of freshly distilled toluene was introduced to the reaction mixture prior to NMR analysis, allowing for product peaks to be integrated against an internal standard. As revealed below, integration revealed that the in situ conversion to Lewis acid 99 was quantitative with protons a integrating against the methyl peak in toluene at 2.11 ppm in a 2.00:3.08 ratio (spectrum 3). A 13C NMR spectrum for Lewis acid 99 was also obtained, revealing 6 peaks (spectrum 5). Carbon a, bonded to the quadrupolar aluminum atom, is very broad and requires numerous scans to visualize.

Proton a, which is on carbon a, directly bonded to the aluminum atom, is found upfield shifted at 0.50 ppm, with the remaining proton resonances where they might be expected, a result consistent with what Gorobets previously observed. Compound 99 could then be rapidly oxidized to the corresponding alcohol 100 in 60 % yield by bubbling pressurized oxygen through the reaction mixture for 1 minute (Scheme 2.2).

The 1H NMR spectrum of isolated 100 exactly matched that reported in the literature,47 and GC-LRMS analysis also revealed the major product in the crude mixture was 1- hexanol. Thus Lewis acid 99 was confirmed to form quantitiatively in situ by its 1H NMR and 13C NMR spectra, as well as by isolating and characterizing its oxidation product, alcohol 100.

Spectrum 1: 1H NMR of 98

Spectrum 2: 1H NMR of 99 a b AlBr2

1 Spectrum 3: H NMR of 99 using toluene-d8 to compute yield

Spectrum 4: 13C NMR of 98

Spectrum 5: 13C NMR of 99

Figure 2.1: In situ spectra of 98 and 99 in benzene-d6

O2, 1 min

AlBr2 OH Et2O 99 100 Scheme 2.2

In addition to 1-hexene, cyclohexene was also hydroaluminated in benzene using the 3AlBr3·LiAlH4 hydroalumination system (Scheme 2.3) as per Gorobets’ experimental procedure. Conversion of 81 to 86 was complete in 1 hour, and again with complete disappearance of the olefin peaks. The peaks in the 1H NMR spectrum integrated as expected (spectrum 2), and there were four distinct peaks in an otherwise clean 13C NMR spectrum (spectrum 4).

Spectrum 1: 1H NMR of 81

Spectrum 2: 1H NMR of 86

Spectrum 3: 13C NMR of 81

Spectrum 4: 13C NMR of 86

Figure 2.2: In situ spectra of 81 and 86 in benzene-d6

Just like with Lewis acid 99, Lewis acid 86 could be rapidly oxidized to the corresponding alcohol 101. The 1H NMR spectrum of crude 101 revealed major product peaks that matched those reported in the literature. In addition, GC-LRMS analysis confirmed the formation of cyclohexanol.

AlBr3, LiAlH4 O2 AlBr2 OH

benzene, 1h 81 86 101 Scheme 2.3

A more complex olefin, (+)-camphene, was also hydroaluminated in benzene using the 3AlBr3·LiAlH4 hydroalumination system (Scheme 2.4) as per Gorobets’ original experimental procedure. Conversion of 82 to 87 was complete in 1 hour, again with complete disappearance of the olefin peaks, and only a single diastereomer visible in

1 a clean H NMR spectrum (Figure 2.3). Lewis acid 87 was quenched with H2O to afford product 92 quantitatively (Scheme 2.4). In addition, Lewis acid 87 could also be brominated as reported by Gorobets using CuBr2 in THF to obtain adduct 102 in 57 % yield (Scheme 2.4).

AlBr3, LiAlH4 X

benzene, 1h

AlBr2 Y 82 87 92: X = H2O, Y = H 102: X = CuBr2, Y = Br Scheme 2.4

Spectrum 1: 1H NMR of 82

1 c Spectrum 2: H NMR of 87

c Ha AlBr Hb 2

Spectrum 3: 1H NMR of crude 92

Spectrum 4: 13C NMR of 82

Spectrum 5: 13C NMR of 87

Spectrum 6: 13C NMR of crude 92

Figure 2.3: In situ spectra of 82, 87, and 92 in benzene-d6

As demonstrated above (Figure 2.3), the overall change from olefin to RAlBr2

Lewis acid to hydrocarbon can be monitored easily with both 1H NMR and 13C NMR spectroscopy. On the 1H NMR spectrum for Lewis acid 87, the two diastereotopic protons a and b on the carbon directly bonded to the aluminum atom are upfield shifted and show up as two doublets of doublets at 0.59 and 0.54 ppm. The two most obvious peaks, those of the two methyl groups c, show up at 0.91 and 0.72 ppm, both shifted from their original positions of 1.04 and 1.02 ppm in the 1H NMR spectrum of olefin 82. The

13C NMR spectrum of 87 reveals the carbon signal for the carbon directly bonded to the aluminum atom to be very broad, requiring numerous scans to visualize. Finally, the stereochemical configuration of 87 was determined to be endo by comparing the 13C

44 NMR peaks of worked-up adduct 92 in CDCl3 to known peaks for endo-isocamphane.

2.2 Low Temperature Lewis Acid Binding Studies

Childs and co-workers have done a series of low-temperature binding studies in

CD2Cl2 to compare and contrast the Lewis acidity of numerous different Lewis acids through complexation with 6 different Lewis bases.48 This is a useful technique for three important reasons. The first reason is that it demonstrates conclusively that binding is occurring; the peaks of the uncoordinated Lewis base disappear and are shifted either up or down field on the 1H NMR spectrum. The second reason is that the Lewis acidity of various Lewis acids can be compared; the relative charge induced on the base by complexation can be assessed by measuring the magnitude of the shifts of the base’s peaks on the 1H NMR spectrum. The third reason is that reversible binding can be demonstrated; if the base can be recovered after quenching the reaction mixture, it proves

that binding does not polymerize or otherwise transform the base into other compounds.

One of the bases used in Childs’ original study was crotonaldehyde (103). Shown below are the relative chemical shifts of crotonaldehyde upon binding various different Lewis

48 acids (Table 2.1). Table 2.1 is organized in decending order of Lewis acidity, with BBr3 at the top, and Et3Al at the bottom.

Complexation of the various alkylaluminum species to crotonaldehyde was carried out at -60 ºC, to limit side reactions.48 Childs’ study concluded that the charge induced by complexation with Lewis acid had different effects on the four different protons of crotonaldehyde, with the effects being more pronounced on H2 and H3 than on H1 and H4. This Lewis acid binding experiment was repeated to investigate the binding strength of RAlBr2-type Lewis acids using crotonaldehyde as base.

Table 2.1: 1H chemical shift differences (Δδ) of crotonaldehyde (103) upon complexation a with different Lewis acids at -20 ºC in CD2Cl2 LA O O H2 1 eq. LA H2 H1 H1 H4 CD Cl H4 H3 2 2 H3 103 104 Proton Δδ (ppm) Lewis Acid H1 H2 H3 H4 BBr3 0.11 0.93 1.49 0.51 BCl3 -0.65 0.85 1.35 0.49 SbCl5 0.17 0.78 1.32 0.48 AlCl3 -0.20 0.76 1.23 0.47 b EtAlCl2 -0.20 0.77 1.25 0.47 BF3 -0.27 0.74 1.17 0.44 b Et3Al2Cl3 -0.15 0.69 1.14 0.39 TiCl4 0.03 0.60 1.03 0.36 b Et2AlCl -0.15 0.55 0.91 0.30 SnCl4 0.02 0.50 0.87 0.29 b Et3Al -0.34 0.42 0.63 0.23 aChemical shifts of uncomplexed base are: δ = 9.47 (d, 1H, H1), 6.10 (ddq, 1H , H2), 6.93 (m, 1H, 3H), 2.02 (dd, 3H, H4). bConducted at -60 ºC

Complexation of RAlBr2 Lewis acids 99 (R = hexyl) and 86 (R = cyclohexyl) with crotonaldehyde was monitored in freshly distilled CD2Cl2 at -60 ºC. The resulting proton shifts are outlined below in Table 2.2. In addition, the 1H NMR spectra for the experiment with Lewis acid 99 is shown below in figure 2.4.

Table 2.2: 1H chemical shift differences (Δδ) of crotonaldehyde (103) upon complexation a with Lewis acids 99 and 86 at -60 ºC in CD2Cl2 Br Br Al O O R H2 1 eq. LA H2 H1 H1 H 4 CD Cl H4 H3 2 2 H3 103 104a: R = Hex (LA = 99) 104b: R = cyclohex (LA = 86) Proton Δδ (ppm) Lewis Acid Complex H1 H2 H3 H4 104a -0.13 0.68 1.13 0.38 104b -0.24 0.72 1.20 0.44 aChemical shifts of uncomplexed base are: δ = 9.47 (d, 1H, H1), 6.10 (ddq, 1H , H2), 6.93 (m, 1H, 3H), 2.02 (dd, 3H, H4).

At room temperature, mixtures of any RAlBr2 Lewis acid in CH2Cl2 produce a violent exothermic reaction. No such reaction, however, occurs at low temperature.

Extreme caution should be observed when mixing these chemicals to keep the reaction mixture at low temperature. This is an observation that will be elaborated on in more detail later in this chapter.

Based on the data, complexation of RAlBr2 Lewis acids to crotonaldehyde causes chemical shifts that compare very closely with BF3 and EtAlCl2. These results suggest that RAlBr2 Lewis acids are only slightly less Lewis acidic than EtAlCl2. Although the bromine atoms are less capable of stabilizing the aluminum atom via overlap of the lone pair electrons with the vacant p orbital on aluminum than chlorine atoms are, which

would increase the Lewis acidity of RAlBr2 relative to EtAlCl2, the bromine atoms are also less electronegative than the chlorine atoms are, which reduces the relative Lewis acidity of RAlBr2 compared to EtAlCl2. The data therefore suggests that chlorine’s greater electronegativity more than compensates for its greater ability to back donate electron density into the empty p orbital of aluminum via resonance.

Spectrum 1: 1H NMR of 104a

Spectrum 2: 1H NMR of crotonaldehyde

Spectrum 3: crude 1H NMR of quenched 104a

33a104a104b

Figure 2.4: 1H NMR spectra of Lewis Acid Binding Experiment between 103 and Lewis acid 99 in d2-DCM

What must be kept in mind is that LiBr is generated in situ during the hydroalumination process, and LiBr was not present for any of the Lewis acids tested by

Childs. It is quite possible that the presence of LiBr may stabilize the RAlBr2 Lewis acid

+ - due to the formation of Li RAlBr3 , decreasing its observed Lewis acidity under the

conditions tested, while its acidity may prove to be greater under other experimental conditions.

Interestingly, the signal for protons a in the crotonaldehyde-complex 104a

(Scheme 2.5) is upfield shifted to 0.25 ppm, up from 0.50 ppm in uncomplexed Lewis acid 99 (Figure 2.4, spectrum 1). This is to be expected, as complexation with crotonaldehyde fills the empty p-orbital of aluminum with electron density, and puts a formal negative charge on the aluminum atom. The resulting increase in electron density around the aluminum atom has a shielding effect on proton a of complex 104a (Scheme

2.5).

Br Br Al O O a H2 1 eq. 99 H2 H1 H1 H 4 CD Cl H4 H3 2 2 H3 103 104a Scheme 2.5

Importantly, unreacted crotonaldehyde could be recovered after the cold reaction mixtures were quenched in H2O. RAlBr2 Lewis acids 99 (R = hexyl) and 86 (R = cyclohexyl) were thus confirmed capable of binding reversibly to crotonaldehyde, and were demonstrated to be slightly less acidic than EtAlCl2. Having completed a Lewis- acid binding study, the next step was to test their ability to promote a known reaction.

2.3 Diels-Alder Reactions using OBn-Protected Oxazolidinone-based Dienophiles to access the Drimane Skeleton

2.3.1 Introduction to Drimane Sesquiterpene Natural Products

Drimanes are a common and diverse class of bioactive sesquiterpene natural products. Biological activities include antibacterial, antifungal, antifeedant, plant-growth regulatory, cytotoxic, phytotoxic, and piscicidal properties.49 The parent drimane skeleton

(105) is shown below in scheme 2.6, along with related compounds labdane (106) and abietane (107). Compound 105 is a sesquiterpene, meaning it is composed of three isoprene units which have a chemical formula of C15H24. Compounds 106 and 107 are diterpenes, meaning they are composed of four isoprene units which have a chemical formula of C20H32. To the synthetic chemist, these distinctions are semantic, as these compounds share numerous structural features including a trans-fused decalin system, geminal dimethyl groups at C1, and similar substitution around the decalin system

(Scheme 2.6). Compounds 106 and 107 are therefore included in this analysis as a synthetic strategy providing access to 105 would be useful for accessing 106 and 107 as well.

H 1 1 1 H H H drimane (105) labdane (106) abietane (107) Scheme 2.6

The biosynthesis of drimane is shown below, along with the reason for its sesquiterpene classification (Scheme 2.7). Farnesyl pyrophosphate (108) is the biological precursor that cyclizes to form carbocation 110, and it has been drawn to clearly show the three isoprene units of which it is comprised. Each isoprene unit is in a square bracket.

Compound 108 is also redrawn to show its chair-chair conformation (109), which accounts for the trans ring fusion observed in the product. Carbocation intermediate 110 is the reactive intermediate used to produce a variety of drimane natural products.50

OPP OPP

H+ H H H 108 109 110 3- PP = P2O6 Scheme 2.7

Substitution of these parent compounds is quite diverse and several papers reporting novel natural products of this type have been published recently.51 Interestingly, natural products are known where one of the gem-dimethyl groups is substituted, as in recently isolated and reported compounds 111-113 (Scheme 2.8).51b Maximization of other carbons on the drimane parent skeleton yields hundreds more structures on

SciFinder, indicating a very diverse library of bioactive natural products.

O O O SO H SO3H OH N 3 N H H

H H OH H

OH Clathric Acid (111) Clathrimide A (112) Clathrimide B (113) Scheme 2.8

2.3.2 Previous Synthesis of Drimane Natural Products Reported by the Keay Group

The Keay group has previously reported an efficient, high yielding route to the drimane skeleton using a MeAlCl2-catalyzed Diels-Alder reaction between 1,3,3- trimethyl-2-vinylcyclohexene (96) and the various different chirally-substituted oxazolidinone based dienophiles 95a-95g outlined below (Table 2.3).46 Comparing benzyl-substituted oxazolidinones (R1 = benzyl), the data demonstrates that OBn- protected dienophiles (R2 = OBn) provide much better diastereoselectivity than bromine in the allylic position (R2 = Br) or hydrogen in that same position (R2 = H). In fact, the latter two result in extremely poor diastereoselectivity, up to only 1.5:1 (entry 9). The

OBn-protected, indene-substituted oxazolidinone dienophile 95a (Scheme 2.9), provided the best result, with a diastereoselectivity of 15:1, which could be improved to >99:1 following recrystallization (Table 2.3, entry 1).

Table 2.3: MeAlCl2-catalyzed Diels-Alder Reaction Previously Reported by the Keay Group O O O O O O O N O N O N 1.4 eq. MeAlCl2 R1 R1 R1 + DCM R2 R2 R2

96 95a 97a exo 97a endo a b entry compound R1 R2 temp time % yield exo:endo (oC) (h) 1 95a Indc OBn 23 8 75 15:1 [99:1] 2 95b Bn OBn 0 12 62 10:1 3 95b Bn OBn 23 5 65 12:1 4 95c Ph OBn 0 12 52 3:1 5 95c Ph OBn 23 5 52 3:1 6 95d iPr OBn 0 12 60 12:1 7 95d iPr OBn 23 5 60 20:1 8 95e Bn H 23 5 87 1:1 9 95e Bn H 23 24 75 1.5:1 10 95f Bn Br 23 5 40 1:1 11 95g Bn OTBS 23 5 nr na aIsolated yields. bDetermined by 400 MHz NMR. cR = (S-3a-cis)-(–)-3,3a,8,8a- tetrahydro-2H-indeno[1,2-d]-oxazolidin-2-one. dRecrystallized to give >99:1.

O O O O O N O N 1.4 eq. MeAlCl2 + DCM OBn OBn

96 95a 97a exo R OR 2 R1 O

114: R = H 116: R1 + R2 =O 115: R = Ac 117: R1 = H, R2 =OH Scheme 2.9

The exo adduct of 97a, obtained using the optimized methodology (Table 2.3, entry 1) was subsequently carried forward as a synthetic intermediate to synthesize four drimane natural products, including (+)-albicanol (114), (+)-albicanyl acetate (115), (+)- dihydrodrimenin (116), and (-)-dihydroisodrimeninol (117), shown above (Scheme 2.9).

It is with these results in mind that the initial goal of this project was to repeat these

Diels-Alder reactions using the conditions optimized by Henderson and Keay, but using

RAlBr2-type Lewis acids instead of MeAlCl2. If these reactions could be shown to work, enantioselective synthesis might be possible without resorting to the use of expensive chiral auxiliaries, as chiral R* groups on R*AlBr2-type Lewis acids could be derived from inexpensive chiral olefins. In this way, more elaborate drimane and labdane natural products could potentially be synthesized at a reduced cost.

2.3.3 Repeating Previously Reported Diels-Alder Reaction between 95a and 96 using a new RAlBr2-type Lewis acid as catalyst

In order to repeat the Diels-Alder reaction shown above in Scheme 2.9 using

RAlBr2-type Lewis acids, starting materials were synthesized according to the procedures that Henderson had previously used. To begin, diene 96 was synthesized according to the procedure reported by Ley et. al. (Scheme 2.10).52

1) (CH3)3SiCH2Cl O Mg, I2, Et2O

2) p-TsOH, H2SO4 118 82 % 96 Scheme 2.10

Dienophile 95a was also synthesized using a three-step process outlined below

(Scheme 2.11). In the first step of the synthesis, 4-benzyloxy-but-2-enoic acid ethyl ester

(120) was synthesized by refluxing ethyl-2-butynoate (119), benzyl alcohol, acetic acid, and triphenyl phosphine in toluene for 18 hours. This procedure was outlined by Han et al.53

O BnOH, PPh3, AcOH O O O O toluene, 110 oC, 18 h 71 % 119 120

O LiOH O O O O THF/H2O HO 18 h 120 59 % 121

LiCl, TEA, TMAC O O O THF, 0oC, 1 h O O HO

121 OBn 122

O O O O O 123a soln. (THF) O THF, rt, 18 h O N O NH

88 % OBn OBn 122 95a 123a

Scheme 2.11

The product ester 120 was saponified according to the procedure outlined by

Henderson using LiOH in a THF/H2O solution over 18 hours to afford the corresponding

unsaturated carboxylic acid 121. Carboxylic acid 121 was then transformed into its trimethylacetic anhydride derivative 122 in situ using trimethylacetyl chloride and triethylamine over 1 hour in THF. Chiral oxazolidinone derivative 123a was obtained commercially from Aldrich, and was added to anhydride 122. The target product dienophile 95a is generated as the carbamate nitrogen slowly reacts with anhydride 122 at its less sterically hindered carbonyl group over 18 hours at room temperature. The final two steps of the synthesis were carried out according to procedures outlined by

Henderson.54 With both diene 96 and dienophile 95a in hand, their corresponding Diels-

Alder reaction was conducted with RAlBr2 Lewis acid 125 (R = dodecyl). It was decided at this point in the project that 1-dodecene was the most appropriate olefin for hydroalumination, as its non volatility ensured that side products could be evaluated; all side products related to the RAlBr2 Lewis acid would remain in the reaction’s crude products, even in vacuo. Hydroalumination of 1-dodecene was thus carried out as before

(Scheme 2.12) to obtain the required organoaluminum compound 125.

AlBr3, LiAlH4

AlBr2 benzene, 1h 124 125 Scheme 2.12

A solution of 95a was prepared in freshly distilled DCM, and the mixture was cooled to -78 ºC. A freshly prepared 1.0 M solution of 125 in toluene (1.4 equivalents) was added dropwise down the side of the cold flask, and the mixture equilibrated for 5 minutes. DCM along with 1.4 eq. of Lewis acid was chosen as it had been previously

used by Henderson and Keay. Diene 96 (2 equivalents) was added down the side of the cold flask, and the mixture was warmed and stirred. Henderson had previously included two sets of conditions in the initial investigation with MeAlCl2, 5 hours at room temperature, and 12 hours at 0 ºC (Table 2.3). Both of these conditions were tested using

Lewis acid 125 and the results are shown below (Table 2.4).

Table 2.4: Initial Trials on Diels-Alder Reaction between 95a and 96 O O O O O O

O N DCM/toluene O N O N + 1.4 eq. 125 OBn 96 OBn OBn

95a exo-97a endo-97a Entry Conditions Conversiona Isolated exo:endoa Yieldb 1 5 h, 25 ºC 82 % 54% 5.5:1 2 12 h, 0º C 66 % 41% 2.8:1 aConversion to products and exo:endo ratios measured by NMR spectroscopy. bIsolated Yield off column

The crude 1H NMR spectra for both product mixtures were very complex, with a number of side reactions evident. By 1H NMR analysis, conversion to products was 82% complete after 5 hours at 25 ºC, while conversion to products was only 66% complete after 12 hours at 0 ºC. The isolated yield at 25 ºC, 54 %, was also better than it was at 0

ºC, which was 41 %. Additionally, the diastereoselectivity was also improved at the higher temperature, with exo-97a being favored by a 5.5:1 margin (entry 1), in comparison to a 2.8:1 margin at 0 ºC (entry 2).

The reason these reactions were conducted in a mixture of DCM and toluene is that the hydroaluminated RAlBr2 Lewis acids were found to react violently when stored in DCM, but were stable as solutions in benzene and toluene. Thus the Lewis acid was delivered as a solution in toluene. One interesting side reaction that was apparently occurring as a result of mixing these two solvents was a Friedel-Crafts alkylation reaction in which activated DCM was attacked by toluene. This process is shown below in

Scheme 2.13.

a H H R Br Cl Al Br Cl Cl Al Br Br R b b 126 127 Scheme 2.13

The resulting chloromethyl toluene adduct 126 is activated in the same way and finally forms adduct 127. Compound 127 could not be purified completely, but could be isolated as a mixture of other non-polar compounds at the solvent front. The 1H NMR signal for protons a, between two ring systems, is found downfield shifted at 3.9 ppm.

Protons b, next to only a single ring system are found upfield relative to a, at 2.3 ppm.

Due to the methyl groups on toluene, numerous product isomers of 127 are possible and multiple singlets can be observed at both 3.9 and 2.3 ppm. The peaks at 3.9 and 2.3 integrate in a 2:6 ratio, consistent with the chemical structure of compound 127. In addition, multiple isomer peaks were confirmed on a GC trace, with the corresponding

LRMS showing a molecular ion of 196.

This Friedel-Crafts reaction even occurs by mixing benzene with DCM. The crude GC-LRMS trace is simpler by mixing benzene with DCM instead of toluene, as multiple isomers do not form. Most interestingly, two Friedel-Crafts product peaks are observed on the GC trace, and LRMS data confirm the two products are 128 and 129

(Scheme 2.14).

128 129 Scheme 2.14

For the Diels-Alder reactions shown above in Table 2.4, the numerous isomers of adduct 127 were noted as prominent side products on the crude product spectra for both sets of reaction conditions. More of the Friedel-Crafts product was formed over 12 hours at 0 ºC than was formed over 5 hours at 25 ºC. This indicates that it forms at both temperatures, but that over time it forms in greater quantities. As a result of these initial set of experiments, two conclusions were drawn. The first was that 5 hours at 25 ºC is a superior set of reaction conditions for the Diels-Alder reaction than 12 hours at 0 ºC. The second was that DCM should be avoided for reactions at 25 ºC and at 0 ºC. Thus, the

Diels-Alder reaction shown above in Table 2.4 was conducted in toluene instead of

DCM. Both conditions tested above were repeated using only toluene as solvent. The results of those tests are shown below in Table 2.5.

Table 2.5: Repeating Diels-Alder Reaction between 95a and 119 using toluene instead of DCM O O O O O O

O N 1.4 eq. 125 O N O N + toluene OBn 96 OBn OBn

95a exo-97a endo-97a Entry Conditions Conversiona Isolated Yieldb exo:endoa 1 5 h, 25 ºC 64 % 35% 3.3:1 2 12 h, 0º C 58 % 34% 3:1 aConversion to products and exo:endo ratios measured by NMR spectroscopy. bIsolated Yield off column

Additionally, a second side product was isolated in the crude mixture, an oxidation product of Lewis acid 125, 1-dodecanol (scheme 2.15). Over the course of the reaction Lewis acid 125 is likely exposed to small quantities of O2. Due to its very high reactivity with O2, the alcohol is formed in situ, and is present in the crude mixture. The reaction mixture had been kept under light flow of commercial argon. The gas was subsequently upgraded to ultra-high purity nitrogen, and the oxidation product disappeared from the crude mixture.

O2 AlBr2 OH 125 130 Scheme 2.15

The 1H NMR spectra for the Diels-Alder reaction in toluene were considerably less complex than those obtained from the same reaction in DCM, with fewer side products being obvious on the crude 1H NMR spectra. Nevertheless, analysis of these

crude spectra still made evident the fact that other side products were still forming. The most obvious difference between the reactions carried out in DCM (Table 2.4) and in toluene (Table 2.5) is that conversion to products is slower in toluene. After 5 hours at room temperature in DCM (Table 2.4, entry 1), conversion of starting materials to products had proceeded to 82 %. After 5 hours at room temperature in toluene (Table 2.5, entry 1), the same conversion had only proceeded to 64%. Isolated yields off a column were consequently slightly less in toluene than they were in DCM. The exo:endo ratio in toluene was also poorer, at 3.3:1 after 5 hours at room temperature (Table 2.5, entry 1), having been 5.5:1 after 5 hours at room temperature in DCM.

2.3.4 Time Studies to Optimize Diels-Alder Reaction between 95a and 96 in Toluene

Having obtained the initial results described above, a time study was carried out in order to determine the optimal reaction time at room temperature in toluene. It was hoped that conversion to products and isolated yields could be maximized by allowing the mixture to react longer, and that exo:endo ratios might also improve over time. Thus, the Diels-Alder reaction was set up exactly as before in toluene, except on a much larger scale, warmed to room temperature, and aliquots taken to the NMR at 2.5 hours, 5 hours,

7.5 hours, 10 hours, 12.5 hours, and 15 hours. The data are shown below in Table 2.6.

Table 2.6: Time Study for Diels-Alder Reaction in Toluene O O O O O O

O N 1.4 eq. 125 O N O N + toluene OBn 96 OBn OBn 2 equiv. 95a exo-97a endo-97a Entry Time (hours) Conversion (%)a exo:endoa 1 2.5 71 2.7:1 2 5 75 2.9:1 3 7.5 83 3.3:1 4 10 84 3.5:1 5 12.5 84 3.0:1 6 15 93 2.9:1 aConversion to products and exo:endo ratios measured by NMR spectroscopy.

Conducting the reaction on a larger scale seemed to improve the results slightly.

As can be seen above in Table 2.6 the conversion to products had already reached 71 % after only 2.5 hours, and rose steadily up to 93 % after 15 hours. The diastereomeric ratio also steadily improved, favoring the exo adduct, and reaching a maximum diastereoselectivity of 3.5:1 after 10 hours, and declining slightly thereafter, perhaps as a function of diastereoselective product degradation. Although the reaction proceeded more cleanly in toluene than it did in a mixture of DCM/toluene, the diastereoselectivity was clearly superior in DCM, with a 5.5:1 ratio after 5 hours (Table 2.4, entry 1), comparing to a 2.9:1 ratio after 5 hours in toluene (Table 2.6, entry 2).

At this point, the most obvious problem with this reaction was the formation of numerous side products, even though toluene diminished this problem. It was thought that by increasing the amount of diene delivered to the reaction mixture, the Diels-Alder reaction could be sped up relative to other competing side reactions, conversion to

products would proceed in a shorter time period, and yields off the column might be significantly improved. The exact same time study conducted above was therefore carried out on the exact same scale, the only variable being changed was the amount of diene, being doubled from 2 equivlents to 4 equivalents. The results from this second time study are outlined below in Table 2.7.

Table 2.7: Time Study for Diels Alder Reaction in Toluene O O O O O O

O N 1.4 eq. 125 O N O N + toluene OBn 96 OBn OBn 4 equiv. 95a exo-97a endo-97a Entry Time (hours) Conversion (%)a exo:endoa 1 2.5 59 2.5:1 2 5 75 2.8:1 3 7.5 80 3.1:1 4 10 82 3.4:1 5 12.5 85 3.5:1 6 15 86 3.4:1 aConversion to products and exo:endo ratios measured by 1H NMR spectroscopy.

Interestingly, the conversion after only 2.5 hours had fallen to 59 % (Table 2.7, entry 1), down from 71 % in the previous time study (Table 2.6, entry 2). This unexpected result was the only significant difference from the two studies, with other conversions being almost identical in magnitude. Just like in the time study with 2 equivalents of diene, in the time study with 4 equivalents of diene, the exo:endo ratios increase with time, going through a maximum at about the same time, and then begin to fall, although the diminishment in the exo:endo ratios was smaller in the second study. In

any case, with the conversion to products being almost identical, the slight improvement in diastereoselectivity was not enough to justify the cost of 2 extra equivalents of diene, and the reaction was thus optimized to be carried out for 15 hours at room temperature using 2 equivalents of diene.

2.3.5 Optimizing Delivery of Lewis Acid to Diels-Alder Reaction between 95a and 96 in Toluene

Henderson had previously reported that the Diels-Alder reaction between dienophile 95a and diene 96 proceeded optimally at 1.4 equivalents of Lewis acid.

Henderson tested 0.7, 1.0, 1.4, and 2.1 equivalents of MeAlCl2 in promoting the reaction between 95a and 96 (Table 2.8).54 It was discovered that the reaction conversion proceeds minimally at 0.7 equivalents and goes through a maxium at about 1.4 equivalents, before declining again as it is increased beyond that. The other observation was that the exo:endo selectivity was very poor at low Lewis acid loading, and improved as more Lewis acid was delivered (Table 2.8).

Table 2.8: Henderson’s MeAlCl2 Equivalent Study on Diels Alder Reaction Between 95a and 96 O O O O O O

O N MeAlCl2 O N O N + 8 h, DCM OBn 96 OBn OBn

95a exo-97a endo-97a Entry Equiv. MeAlCl2 Conversion (%) exo:endo 1 0.7 16 2:1 2 1.0 47 5:1 3 1.4 81 10:1 4 2.1 62 10:1

The same studies were carried out using Lewis acid 125 on the Diels-Alder reaction between 95a and 96 (Table 2.9). Henderson had carried out his equivalent study over 8 hours,54 but the equivalent study used for Lewis acid 125 was done at the previously optimized 15 hours. Although Henderson observed conversion to products at

0.7 and 2.1 equivalents of MeAlCl2, no Diels-Alder products were formed using 0.7, 2.0, or 2.6 equivalents of 125. Because all starting materials were consumed, forming a complex product mixture, it was not possible to assess the conversion to products using

NMR. Thus yields were measured by isolating product mixtures off a column for all equivalents of Lewis acid tested.

Table 2.9 Optimizing the Delivery of Lewis Acid to the Reaction between 95a and 96 in toluene O O O O O O

O N 125 O N O N + 15 h, toluene OBn 96 OBn OBn 2 equiv. 95a exo-97a endo-97a Entry Equivalents of Lewis Acid Yield (%)a exo:endob 1 0.7 0 NA 2 1.0 26 1.9:1 3 1.4 60 3.8:1 4 1.6 28 3.2:1 5 2.0 0 NA 6 2.6 0 NA aIsolated Yield off column b exo:endo ratios measured by NMR spectroscopy.

Interestingly, the same trends in exo:endo ratios were observed using Lewis acid

125 that were observed using MeAlCl2. The exo:endo ratio was only 1.9:1 at 1.0 equivalent of catalyst, and increased to a maximum at 1.4 equivalents. The equivalent

study conducted using Lewis acid 125 confirms exactly what Henderson had previously observed, that the Diels-Alder reaction between 95a and 96 proceeds optimally at 1.4 equivalents of Lewis acid, and that the yield falls off if the amount of Lewis acid is either increased or decreased. Thus the optimal amount of Lewis acid for this Diels-Alder reaction was determined to be 1.4 equivalents, consistent with what was previously observed by Henderson and Keay.46,54 The Diels-Alder reaction had thus been determined unsuitable in DCM, and the reaction time, the amount of diene, and the amount of catalyst had all been optimized. The best result obtained was a 60 % yield with a 3.8:1 exo:endo (Table 2.9, entry 3).

2.3.6 Optimizing the Structure of the Chiral Auxilliary to Determine the Optimal Dienophile

The only variable left to optimize was the structure of the dienophile, specifically the chiral oxazolidinone-based auxiliary that would be used. Henderson had used 3 other chiral oxazolidinone-based auxiliaries to synthesize dienophiles for the Diels-Alder reaction. Thus, these would also be synthesized in order to determine if they could be used to improve the exo:endo ratio. The syntheses were carried out exactly as described above, and are outlined below in scheme 2.16. The three new dienophiles synthesized were the phenyl, benzyl, and isopropyl-based oxazolidinones.

LiCl, TEA, TMAC O O O THF, 0oC, 1 h O O HO

121 OBn 122

O O O O O 123b-d soln. (THF) O THF, rt, 18 h O N O NH

R R OBn OBn 122 95b: R = Bn (79 %) 123b: R = Bn 95c: R = Ph (76 %) 123c: R = Ph 95d: R = iPr (62 %) 123d: R = iPr

Scheme 2.16

As a result of the fact that some of these reactions were being carried out while the reaction between 95g and 96 was still being optimized, the reaction conditions used to test all Diels-Alder reactions between newly-synthesized dienophiles were the same reported by Henderson. Dienophiles 95b-d were synthesized and reacted with diene 96.

All results from these investigations are outlined below in Table 2.10. Included are the initial results between dienophile 95a and 96 already outlined above for the purposes of comparison. What these studies demonstrate is that the exo:endo selectivities obtained are generally poor using Lewis acid 125, with the best ratio being only 5.5:1. These studies confirm that toluene is the superior solvent, as the isolated yield per amount of starting material converted to products is higher in toluene than it is in DCM/toluene. As the yields and exo:endo ratios were poor for this reaction, however, it was increasingly becoming clear that different dienophiles would need to be synthesized and tested in order for higher yielding, more selective RAlBr2-promoted Diels-Alder reactions to provide access to other drimane natural products.

Table 2.10: All Diels-Alder Reactions Conducted Between Dienophiles 95a-e and 96 O O O O O O

O N 1.4 eq. 125 O N O N + conditions R R R OBn 96 OBn OBn 95b-d exo-97b-d endo-97b-d Entry Dienophile Conditions Conversiona Yieldb exo:endoa 1 95a Toluene, 25 ºC, 5h 64 % 35% 3.3:1 2 95b Toluene, 25 ºC, 5h 68 % 45 % 2:1 3 95c Toluene, 25 ºC, 5h 99 % 42 % 2:1 4 95d Toluene, 25 ºC, 5h 65 % 47 % 5:1 5 95a Toluene, 0 ºC, 12 h 58 % 34% 3:1 6 95b Toluene, 0 ºC, 12 h 50 % 29 % 2:1 7 95c Toluene, 0 ºC, 12 h 66 % 36 % 2:1 8 95d Toluene, 0 ºC, 12 h 50 % 23 % 4:1 9 95a DCM/tol, 25 ºC, 5h 82 % 54% 5.5:1 10 95b DCM/tol, 25 ºC, 5h 70 % 30 % 2:1 11 95c DCM/tol, 25 ºC, 5h 85 % 51 % 2:1 12 95d DCM/tol, 25 ºC, 5h 90 % 46 % 4:1 13 95a DCM/tol, 0 ºC, 12h 66 % 41% 2.8:1 14 95b DCM/tol, 0 ºC, 12h 58 % 40 % 2:1 15 95c DCM/tol, 0 ºC, 12h 70 % 24 % 2:1 16 95d DCM/tol, 0 ºC, 12h 93 % 45 % 4:1 aConversion to products and exo:endo ratios measured by NMR spectroscopy. bIsolated Yield off column

2.3.7 Discovery of a Debenzylation Reaction

At this point in the research project, considerable time was being dedicated to attempting to isolate and analyze some of the numerous side products that were showing up both on 1H NMR and on TLC. Small amounts of side product 131 were isolated, purified, and characterized (Scheme 2.17). The confirmation that Lewis acid 125 was capable of debenzylating dienophile 95a, resulting in side product 131, naturally makes it likely that Lewis acid 125 would be similarly capable of removing the benzyl group from

Diels-Alder adduct 97a as well. Unfortunately, all efforts to isolate this debenzylated

adduct were met with failure. Ultimately, the identification of this side reaction meant that allylic OBn-protected dienophiles were not optimal for RAlBr2-promoted Diels-

Alder reactions. It is possible that the debenzylation reaction is not due to the different

Lewis acidity, but rather to the LiBr in solution. In either case, the development of a second generation of simpler dienophiles became the next goal of the project, and oxazolidinone-based dienophiles without an allylic OBn group would be synthesized to further develop this chemistry and access a new group of drimane natural products.

O O O O

O N toluene O N + 1.4 eq. 125 OBn 96 OH

95a 131 side product debenzylation Scheme 2.17

2.4 Conclusions

Several novel RAlBr2-type Lewis acids were prepared by hydroaluminating their corresponding olefins. These compounds were characterized in situ using 1H NMR and

13C NMR spectroscopy, in addition to quenching these compounds and fully characterizing the resulting derivatives. Lewis acid binding studies were carried out, and these new RAlBr2 Lewis acids were determined to be slightly less Lewis acidic than

EtAlCl2, and capable of binding reversibly to crotonaldehyde, a common Lewis base. 1-

Dodecene was hydroaluminated to form Lewis acid 125 for the purposes of promoting

Diels-Alder reactions between oxazolidinone-based dienophiles 95a-e and diene 96 so that potential side products related to 125 would remain in crude mixtures even after being placed in vacuo. Ultimately, Lewis acid 125 yielded poorer results than MeAlCl2, with poorer exo:endo ratios, poorer conversion to products, and poorer isolated yields.

Several side reactions were identified, including a Friedel-Crafts alkylation between toluene and DCM, and a debenzylation process wherein Lewis acid 125 was found to cleave the benzyl group from dienophile 95a. Despite these drawbacks, however, these modest results stand as the very first organic reactions promoted by RAlBr2-type Lewis acids. In order to improve these results, a second generation of simpler oxazolidinone- substituted dienophiles without allylic OBn groups were synthesized and reacted with diene 96. The goals were to improve both the yield and the diastereoselectivity to develop a practical methodology for the development of synthetic strategies toward drimane natural products.

CHAPTER THREE: SIMPLER OXAZOLIDINONE-BASED DIENOPHILES FOR THE DIELS-ALDER REACTION AND EXPLORATION OF OTHER ORGANIC REACTIONS

3.1 Introduction

RAlBr2-type Lewis acid 125 was prepared and used to promote the Diels-Alder reactions previously reported by Henderson, and was determined to be problematic for several reasons. Firstly, Lewis acid 125 was found to debenzylate dienophile 95a, and although a Diels-Alder adduct could be obtained, it was often obtained in low yield as part of a complex mixture of products. Secondly, DCM was found to be an unsuitable solvent above 0 ºC due to a Friedel-Crafts side reaction that complicated the reaction mixture. The next step was therefore to find suitable organic reactions RAlBr2-type

Lewis acids could promote or catalyze, and use these reactions as model systems. Thus several starting materials were synthesized for study in Diels-Alder, Intramolecular

Diels-Alder Furan (IMDAF), and Strecker reactions.

3.2 Simplification of Chiral Oxazolidinone-Based Dienophiles for the Diels-Alder Reaction

With RAlBr2-type Lewis acid 125 promoting Diels-Alder reactions between oxazolidinone-substituted dienophiles 95a-d and diene 96, it made sense to study this type of Diels-Alder reaction further, but on simplified dienophiles lacking allylic OBn protecting groups.

3.2.1 Synthesis of chiral crotonic acid-derivatized oxazolidinone-based dienophile 134a

The OBn-protected dienophiles used in chapter 2 turned out to be inappropriate.

Both the reaction yields and the exo:endo ratios were poor, likely due in part to competing debenzylation. In order to improve these results, a second generation of simplified chiral oxazolidinone-based dienophiles lacking allylic OBn protecting groups was targeted. Because indene-based chiral auxiliary 123a provided the best results among the auxiliaries tested in chapter 2, it was chosen for the synthesis of simplified crotonic acid-derivatized dienophile 134a shown below (scheme 3.1).

LiCl, TEA, TMAC O O O o THF, 0 C, 1 h O HO

132 133

O O O O O 123a soln. (THF) THF, rt, 18 h O N O NH O 68 % 133

134a 123a Scheme 3.1

Crotonic acid-derivatized chiral dienophile 134a was subsequently tested in the

Diels-Alder reaction with diene 96, promoted by Lewis acid 125. In this reaction, three diastereomers formed, two of which were subsequently determined to be endo adducts, and a third which was determined to be an exo adduct. Endo adduct I forms preferably over endo adduct II, although this selectivity appears to decline over time (Table 3.1).

The reaction is also selective for the combined endo adducts over the exo adduct, and the

Σendo/Σexo ratios obtained at -20 ºC were all 3 (Table 3.1).

Unfortunately, the reaction proceeds slowly with very low conversion at -20 ºC. It was thus determined that this reaction likely required higher temperatures in order to proceed more fully to completion. The reaction was therefore also conducted over 24 hours at 25 ºC (Table 3.1, entry 6).

Table 3.1: Time Study for the Diels-Alder Reactions Between 134a and 96 O O O O O O O O

O N 1.4 eq. O N O N O N + 125 toluene 96 -20 oC

134a 135a endo I 135a endo II 135a exo I (absolute configuration unknown) Entry Time Conversion (%)a Σendo/Σexoa endo I/endo IIa 1 1 hour 27 3 8 2 2 hours 33 3 7.7 3 5 hours 36 3 7.7 4 8 hours 38 3 7.7 5 24 hours 41 3 5.9 6c 24 hours 50 0.66 4 aConversion to products and endo:exo ratios measured by 1H NMR spectroscopy. bAbsolute configuration of exo adduct unknown. cReaction conducted at room temperature.

After 24 hours at room temperature, the reaction between 134a and 96 had proceeded to 50 % conversion. At this temperature, both the Σendo/Σexo and the endo

I/endo II ratios were significantly poorer, with the first actually favoring the exo adduct by a factor of 1.5, and the second only favoring endo adduct I by a factor of 4.

Nevertheless, because the crude 1H NMR spectra were very clean, with few side products forming, and with all three diastereomers adequately resolved, the reaction between 134a and 96 was determined to be a suitable model system to further optimize the use of Lewis acid 125.

3.2.2 Separation and Characterization of the three Diastereomers

The next step in developing the Diels-Alder reaction between 134a and 96 was to isolate each diastereomer mentioned above, and to confirm the absolute stereochemical configuration of each. Although the identity of each diastereomer has been reported in the table above, at this point in the project the exact structure of the diastereomers was actually uncertain. Indeed at this point in the project, it was believed that there were only two diastereomers in the crude mixture due to endo adduct II forming in very small quantities. Thus in order to proceed, confirmation of the exact stereochemistry of each adduct was necessary. The mixture of diastereomers above was purified via column chromatography. Unfortunately, with three diastereomers eluting so close to each other, this separation was very difficult, and could not be done perfectly. Nevertheless, separation was carried out sufficiently to identify conclusively that there were three diastereomers in the mixture, rather than two. The 1H NMR spectrum of each of the purified diastereomers is shown on the following page (Figure 3.1).

Spectrum 1 shows the 1H NMR of the crude mixture, containing all three diastereomers. Spectrum 2 shows the major endo diastereomer, along with small amounts of the exo diastereomer that could not be completely separated. Spectrum 3 shows the minor endo diastereomer, and spectrum 4 shows the exo diastereomer.

Spectrum 1: crude mixture

Spectrum 2: endo I adduct He1 Hc1 = 10.1 Hz Ha1 Hd1 Hb1

Spectrum 3: endo II adduct He2 Ha2 Hc2 = 4.1 Hz Hd2 Hb2

Spectrum 4: exo adduct He3

Ha3 Hd3 Hb3 Hc3 = 11.3 Hz

Figure 3.1: 1H NMR spectra for each diastereomer of 135a

The coupling of proton Hc (Figure 3.2), which is found between 3.9-4.1 ppm in the 1H NMR spectra for all three diastereomers (Figure 3.1), is vital for determining the relative stereochemical configuration of each Diels-Alder adduct. The reason for this is depicted below in Figure 3.2. In endo diastereomers, when both rings are in a chair conformation, the chiral auxiliary and the neighboring methyl group are axially substituted, meaning that the coupling of Hc with its neighboring proton is diequatorial.

3 Diequatorial JH-H coupling constants for fused cyclohexane systems are typically between 1-7 Hz.55 In the more thermodynamically favored exo diastereomer, however, the chiral auxiliary and the neighboring methyl group are equatorially substituted, meaning that Hc and its neighbor proton are both axial. This type of coupling is called

3 trans-diaxial coupling, with JH-H coupling constants for fused cyclohexane systems typically being between 8-14 Hz.55

O O O O O O O O Hc1 Hc2 Hc3 Hc4 O N O N O N O N Hb1 Ha1 Hb2 Ha2 Hb3 Ha3 Hb4 Ha4 Hd1 Hd2 Hd3 Hd4 He1 He2 He3 He4

H Aux Hc3 Hc1 Aux Hc2 Aux H H Aux Hc4 H 135a endo I 135a endo II 135a exo I 135a exo II not formed Figure 3.2: Diagram of each of the three labeled diastereomers

The coupling constant for the exo diastereomer (spectrum 4) was determined to be

11.3 Hz, as might be expected for an exo adduct. At first it was thought that the major endo diastereomer shown in spectrum 2 was one of two exo diastereomers forming in the

Diels-Alder reaction due to its relatively large coupling constant of 10.1 Hz. This was an

especially tempting conclusion upon isolation of the minor endo diastereomer, with its much smaller coupling constant of 4.1 Hz (spectrum 3); it was thought that if one endo diastereomer was coupling at 4.1 Hz, as might be expected, it would be unlikely to find the other coupling at 10.1 Hz. X-ray crystallography, however, ultimately proved that the major Diels-Alder adduct shown in spectrum 2 had an endo stereochemical configuration.

Unfortunately, despite numerous attempts to crystallize 135a under a variety of conditions, all three diastereomers of Diels-Alder adduct 135a were colourless foams, and did not crystallize. In order to verify the exact stereochemical configuration of the three diastereomers that were forming, a second commercially available chiral oxazolidinone was purchased and used to prepare 134b (Scheme 3.2).

LiCl, TEA, TMAC O O O o THF, 0 C, 1 h O HO

121d 122d O O O O O 123b soln. (THF) O N O NH THF, rt, 18 h O 89 % 122d

134b 123b O O O O O O O O

O N 1.4 eq. O N O N O N + 125

96 toluene 24 h

134b 135b endo I 135b endo II 135b exo I (absolute configuration unknown) Scheme 3.2

The Diels-Alder reaction between 134b and 96 was then performed using Lewis acid 125 (Scheme 3.2). The 1H NMR spectrum of the major diastereomer is shown below

(Figure 3.3). Spectrum 2 is zoomed in from 3.0 to 6.5 ppm for clarity. Both protons Hc and Ha are partially overlapping even on the 400 MHz 1H NMR spectrum shown below.

Nevertheless, the coupling of the doublet at 4.09 ppm was determined to be 10.2 Hz, extremely close to what was previously determined for the major diastereomer of 135a.

The major diastereomer of 135b was subsequently purified and successfully crystallized. An X-ray crystal structure for this compound was obtained (Figure 3.4). The

X-ray crystal structure confirmed the major diastereomer of 135b to be an endo diastereomer, despite the large coupling constant of 10.2 Hz. With this revelation, the absolute stereochemical configuration of the major endo diastereomer was confirmed, along with the absolute stereochemical configuration of the minor endo diastereomer.

Spectrum 1: pure endo I adduct of 135b

Spectrum 2: pure endo I adduct of 135b Hc He Hd Hb Ha

Figure 3.3: 1H NMR spectra of major endo diastereomer of 135b

O O Hc O N Ha Hb Hd He

135b endo I

Figure 3.4: X-ray crystal structure of major endo diastereomer of 135b

With the absolute stereochemical configuration of both endo adducts of 135b having been confirmed, the absolute stereochemical configurations of the endo adducts of

135a were also confirmed (figure 3.2). The peak at 4.09 ppm with a 10.1 Hz coupling is the major endo I adduct. The peak at 4.13 with a 4.1 Hz coupling is the minor endo II adduct, as an exo adduct could not have such a small coupling constant. With both endo adducts accounted for, the peak at 3.9 ppm with 11.3 Hz coupling was determined to be one of the two possible exo adducts. Unfortunately a crystal structure could not be obtained for the exo adduct of any of 135a-d, and thus the absolute configuration of this exo adduct could not be confirmed with certainty.

One observation remained to be explained, that being the coupling constant for the major endo I adduct. At 10.1 Hz, the coupling is considerably larger than what is

3 expected for diequatorial JH-H coupling. A 10.1 Hz coupling is more consistent with the trans-diaxial coupling in an exo adduct. The crystal structure for 135b was able to explain this observation by rotating the ring system to more closely examine the proton substitution at C1 and C2. As can be seen, the ring system sits in a half-chair conformation, resulting in a very large dihedral angle between these two protons (Figure

3.5). It is unclear why the ring system is sitting in this particular conformation, but a reasonable proposition is that the Diels-Alder adduct is a highly substituted system with considerable strain that twists into an unexpected conformation to relieve some of the strain. It is also important to remember the decalin system contains a double bond, which ultimately distorts the conformation away from the proposed chair-chair conformation.

Figure 3.5: XRD of dihedral angle of C1 and C2 for major endo diastereomer of 135b

The coupling of Hc (Figure 3.2) is also important for a second reason, as it rules out the opposite regioisomeric Diels-Alder adducts. The Diels-Alder reaction between

134a and 96 can yield numerous diastereomers, but it can also produce regioisomers.

This process is shown below (Scheme 3.3). Regioisomeric Diels-Alder adduct 136 results from diene 96 approaching dienophile 134a in a conformation rotated exactly 180º around axis a relative to the approach required to produce the desired Diels-Alder adduct

135a. Proton Hc in adduct 136 has three proton neighbours, however, and would therefore show up on the 1H NMR spectrum as a doublet of doublet of doublets. As can be seen above, no such peaks are observable on any of the 1H NMR spectra (figure 3.1), confirming the desired regiochemistry of the Diels-Alder adducts.

O O O O H Hc H O N + O N a H

96 134a 136 Scheme 3.3

3.2.3 Optimization of Quantity of Lewis Acid Delivered to the Diels-Alder Reaction Between 134a and 96

Evans and co-workers have studied Diels-Alder reactions between chiral oxazolidinone dienophiles that are derivatives of crotonic acid.56 Reactions were studied using a variety of dienes as well as different Lewis acids 138-143. As expected, the different Lewis acids produced different results, with some being more selective than

others. This Lewis acid study used dienophile 137 and diene 9 as a model system (Table

3.2). As can be seen below, 2.0 equivalents of Et2AlCl gave the best diastereoselectivity at -78 ºC, with an Σendo/Σexo ratio of 60 and an endo I/endo II ratio of 20.

Table 3.2: Evans Asymmetric Diels Alder Reaction Lewis Acid Study O O

O N 138-143 + Aux Aux Me Aux Aux 9 Me 144 145 146 147 137 (exo) (exo) (endo) (endo) Lewis acids 138-143 Temp Time Conversion Σendo/Σexoa endo I/endo (ºC) (h) (%) IIa 1.1 eq. SnCl4 (138) -78 3 70 14.9 3.1 0.9 eq. TiCl4 (139) 25 3 100 7.1 2.3 1.1 eq. TiCl4 (139) -78 3 100 9.9 2.7 1.4 eq. ZrCl4 (140) -78 3 100 99 7.2 1.0 eq. AlCl3 (141) -78 3 60 4.2 1.5 1.1 eq. EtAlCl2 (142) -78 3 50 11 1.7 0.3 eq. Et2AlCl (143) 0 6 30 3.1 1.3 0.8 eq. Et2AlCl (143) 0 6 100 15 6.5 1.4 eq. Et2AlCl (143) 0 0.5 100 42 7.6 1.4 eq. Et2AlCl (143) -78 2.5 100 50 17.0 2.0 eq. Et2AlCl (143) -78 2.5 100 60 20 aRatios determined by capillary gas chromatography.

In addition, a number of different chiral oxazolidinone-based dienophiles were tested by Evans in the same Diels-Alder reaction, and were demonstrated to show marked differences in diastereoselectivities, as well as reaction yields.56 Interestingly, the most highly diastereoselective dienophile tested by Evans was dienophile 148, which was

100% selective for the endo adducts 149 and 150 (no exo adduct was detectable by 500

MHz NMR), and favored endo adduct I over endo adduct II by a ratio of 93:7 (Scheme

3.4).

O O

O N 1.4 eq. Et2AlCl + Ph Ph -20 oC, 2.5 h Aux Aux 9 DCM 149 (endo I) 150 (endo II) 148 Scheme 3.4

One interesting result observed by Evans was that the diastereoselectivity varied with Lewis acid stoichiometry (Table 3.2). Both the Σendo/Σexo ratio as well as the endo

I/endo II ratio improved significantly with greater amounts of Lewis acid. Using Et2AlCl as the Lewis acid, the relative reaction rate also increased by a factor of approximately

100 between 1.0 eq. and 2.0 eq. of added Lewis acid.56

With this information in mind, a study was conducted comparing the stoichiometric delivery of Lewis acid 125 to the reaction between 134a and 96 (Table

3.3). Interestingly, the selectivity of endo adduct I over endo adduct II was best at 1.1 equivalents of 125 and below. Unfortunately, the conversion proceeded only to 12 % at

1.1 equivalents of 125 (entry 3). The reaction proceeded to quantitative conversion with a very clean 1H NMR spectrum at 3.5 equivalents of 125. The Σendo/Σexo ratio was also optimized at higher amounts of 125, and did not appear to change appreciably above 2.5 equivalents. Unfortunately, the endo I/endo II ratio peaked at 1.6 equivalents of 125

(entry 5), and declined thereafter. With all of these factors taken into consideration, 3.5 equivalents of Lewis acid 125 was judged to be the optimum amount for promoting this

Diels-Alder reaction. Naturally, this very high delivery of Lewis acid was undesirable.

Nevertheless, as it offered the best results for this reaction, further optimization of this reaction was conducted employing 3.5 equivalents of Lewis acid.

Table 3.3: Lewis acid study on 125 promoting the Diels Alder reaction between 134a and 96 O O O O O O O O 125 O N toluene O N O N O N + 25 oC 96 24 h

134a 135a endo I 135a endo II 135a exo I (absolute configuration unknown) Entry Eq. 125 Conversion (%)a Σendo/Σexoa endo I/endo IIa 1 0.4 NR NA NA 2 0.7 6 0.38 99 3 1.1 12 0.38 99 4 1.4 50 0.65 4.8 5 1.6 55 0.71 5.4 6 1.8 62 1.36 4.9 7 2.0 65 2.0 4.6 8 2.5 80 2.2 4.2 9 3.5 Quantitative 2.1 3.5 10 5.0 79 2.2 3.3 aConversion to products and endo:exo ratios measured by NMR spectroscopy. bAbsolute configuration of exo adduct unknown

An NMR binding study was conducted to determine if the 1H NMR spectrum of the bound dienophile was different at 1.4 equivalents and at 3.5 equivalents of Lewis acid

125 (Figure 3.6). The results are shown below. As can be seen, the 1H NMR spectra for both 1.4 eq. of 125 (spectrum 2) and 3.5 eq. of 125 (spectrum 3) are incomprehensible.

The important point, however, is that they are very different from one another, indicating that different species predominate in solution. Additionally, dienophile 134a is not being consumed in the process, in spite of the complex spectra, and can be recovered following

H+ work up (spectrum 4). It was thus concluded that different Lewis acid-dienophile complexes form as a function of Lewis acid stoichiometry, and that this explains the different results at different amounts of Lewis acid for the Diels-Alder reaction between

134a and 96. This is also consistent with what Evans has previously proposed.56 Evans’ exact postulate for Lewis acid binding of crotonic acid-based oxazolidinone dienophiles, along with that proposed for RAlBr2-type Lewis acids will be elaborated on further in section 3.4.

Spectrum 1: Dienophile 134a (t = 0)

Spectrum 2: 134a +1.4 eq. 125

Spectrum 3: 134a + 3.5 eq. 125

Spectrum 4: H+ worked up (t = 30 minutes)

Figure 3.6 Lewis Acid Binding Study of Dienophile 135a, toluene, room temperature

3.2.4 Synthetic Targets for this Methodology

The methodology described above, having been not yet fully optimized, was nevertheless proceeding in very high conversion and with reasonable diastereoselectivity.

The simplified dienophiles without allylic-OBn protecting groups were yielding a less versatile Diels-Alder adduct, however, and as such different drimanes were identified as ultimate synthetic targets. Additionally, if the diastereoselectivity of the Diels-Alder reaction could not be further optimized, a synthetic strategy would be desired to make use of both endo and exo diastereomers. Two interesting synthetic targets were chosen, which would enable the use of both endo and exo diastereomers if diastereoselectivity could not be fully optimized. These targets are polygodial and isotadeonal, both shown below in

Scheme 3.5.

O O O O

H H 151 152 polygodial isotadeonal Scheme 3.5 Natural product drimanes polygodial and isotadeonal

Polygodial and isotadeonal are two candidate drimane natural products that fit the requirements listed above. Polygodial is the natural product derived from the exo diastereomer of the Diels-Alder adducts discussed above, while isotadeonal is the natural product derived from the endo diastereomer of the same Diels-Alder adducts. More interestingly, due to the structural similarity between 151 and 152, the two Diels-Alder

adducts can potentially be carried through the exact same synthetic steps to reach the final products.

3.2.5 Time Study of the Diels-Alder Reaction between 134a and 96 at 3.5 equivalents 125.

In order to determine how quickly the Diels-Alder reaction proceeds between

134a and 96 at 3.5 equivalents of Lewis acid 125, a time study was conducted. The reaction was set up on a 0.4 g scale in toluene at room temperature, and aliquots were taken to the NMR spectrometer at various times. It was hoped that it could be determined how quickly the reaction proceeded to completion, and whether or not the diastereoselectivity changed due to equilibration over time. The results from this time study are outlined below in Table 3.4.

Table 3.4: Time study of Diels-Alder Reaction at 3.5 equivalents of Lewis acid 125 O O O O O O O O

O N 3.5 eq. O N O N O N + 125 toluene 96 25 oC

134a 135a endo I 135a endo II 135a exo I (absolute configuration unknown) Entry Time Conversion (%)a Σendo/Σexoa endo I/endo IIa 1 30 minutes 80 3 4 2 1 hour 82 3 4 3 2.5 hours 82 3 4 4 5 hours 83 3 4 5 8 hours 83 3 4 6 11 hours 82 3 4 7 24 hours 82 3 4 aConversion to products and endo:exo ratios measured by NMR spectroscopy. bAbsolute configuration of exo adduct unknown

The time study shown above proves three things conclusively. The first is that the reaction proceeds to completion within 30 minutes. The second is that the reaction can be allowed to proceed overnight for 24 hours without any degradation of products. The third is that the diastereoselectivity after 30 minutes does not change; it stays exactly the same over a 24-hour time period.

3.2.6 Optimization of the Diels-Alder Reaction by Changing Solvent and Temperature at 3.5 equivalents of Lewis Acid 125

It was thought that the reaction might be further optimized by changing the solvent or the temperature of the reaction. The solvents were limited to benzene and toluene, because Lewis acid 125 was previously shown to react violently with DCM. It was thought that chlorinated solvents should therefore be avoided, as should ethers and other Lewis basic solvents. The results are shown below in Table 3.5.

Table 3.5: Effect of Solvent and Temperature on Diels-Alder Reaction between 134a and 96 O O O O O O O O

O N 3.5 eq. O N O N O N + 125

96 24 h

134a 135a endo I 135a endo II 135a exo I (absolute configuration unknown) Entry Conditions Conversion (%)a Σendo/Σexoa endo I/endo IIa 1 toluene, 25 ºC 82 3 4 2 toluene, -5 ºC 63 4 4 3 toluene, -25 ºC 55 5 4 4 toluene, -78 ºC NR NA NA 5 benzene, 25 ºC 83 3 4 aConversion to products and endo:exo ratios measured by 1H NMR spectroscopy. bAbsolute configuration of exo adduct unknown

As can be seen above, the conversion by 1H NMR spectroscopy decreases as the temperature decreases, as the reaction proceeds to only 55 % at -25 ºC. Interestingly, the

Σendo/Σexo ratio improves as temperature decreases, consistent with expecting more of the kinetic endo product at lower temperatures. The optimal diastereoselectivity was found in toluene at -25 ºC, with an Σendo/Σexo ratio of 5, comparing to 3 at room temperature. Unfortunately, the endo I/endo II ratio does not change with temperature.

Additionally, the reaction proceeds exactly the same in benzene as it does in toluene at 25

ºC, with 83 % and 82 % conversions and Σendo/Σexo and endo I/endo II ratios of 3 and 4 respectively. The insight that the diastereoselectivity improves at lower temperature is an important one, but as the conversion goes only to 55 % after 24 hours at -25 ºC, it isn’t a very practical one.

3.2.7 Optimization of the Diels-Alder Reaction by Varying the R group on RAlBr2-type Lewis acids

With numerous attempts to optimize the Diels-Alder reaction between 134a and

96 already having been completed, the focal point became the R group on the RAlBr2

Lewis acids. Having already synthesized both RAlBr2 Lewis acids 86 and 99, the Diels-

Alder reaction between 134a and 96 was tested with these. As shown below, the two new

Lewis acids 86 and 99 are slightly more diastereoselective than the corresponding reactions with Lewis acid 125 (Table 3.6). Consistent with LA 125, the conversion to products using LAs 86 and 99 goes most completely at room temperature, where it proceeds almost fully. Another interesting observation is that LA 99 appreciably improves the endo I/endo II ratio as the reaction temperature is decreased.

Table 3.6: Effect of Different RAlBr2 Lewis acids on the Diels-Alder Reaction between 134a and 96 AlBr2

AlBr2 86 99

O O O O O O O O

O N LA O N O N O N + (3.5 eq.)

96 toluene 24 h

134a 135a endo I 135a endo II 135a exo I (absolute configuration unknown) Entry LA Conditions Conversion (%)a Σendo/Σexoa endo I/endo IIa 1 86 25 ºC 89 4 4 2 86 -5 ºC 59 5 4 3 86 -25 ºC 53 5 4 4 86 -78 ºC 3.4 no exo detected only endo I 5 99 25 ºC 96 4 4 6 99 -5 ºC 78 4 6 7 99 -25 ºC 61 4 7 8 99 -78 ºC NR NA NA 9 125 25 ºC 82 3 4 10 125 -5 ºC 63 4 4 11 125 -25 ºC 55 5 4 12 125 -78 ºC NR NA NA aConversion to products and endo:exo ratios measured by 1H NMR spectroscopy. bAbsolute configuration of exo adduct unknown

Perhaps most interestingly, the reaction proceeds to 3.4 % conversion at -78 ºC using LA 86, while it does not proceed at all under the same conditions using LA 99 or

125. This confirms the previously reported Lewis acid binding study where LA 86 was determined to be slightly more Lewis acidic than LA 99. Additionally, at this low temperature, the only diastereomer that forms is endo I. It also appears that LA 86 is capable of greater Σendo/Σexo selectivity when compared with LA 99, although the difference is small. Interestingly, for each of the various temperatures tested, LA 99

appears to promote the reaction in higher conversion than LA 86. Overall, between the three different Lewis acids tested, 99 appears to provide the superior conversions and diastereoselectivities.

3.2.8 Optimization of the Diels-Alder Reaction by Pre-equilibrating the Mixture Prior to the addition of diene 96

Reactions had been set up previously by dissolving the dienophile in solvent, cooling the mixture to -78 ºC, adding the RAlBr2 Lewis acid, then the diene immediately thereafter, and then warming to room temperature. As hypothesized above in section

3.2.3, the binding of RAlBr2-type Lewis acids is likely complex, and may form numerous species in solution, depending on the amount of Lewis acid delivered to the reaction. It may also be that certain species form preferentially given time. Thus a study was conducted by setting up the reaction as before, but allowing the mixture of 134a and 99 to preequilibrate at low temperature for a number of different time periods prior to the addition of the diene which would then start the Diels-Alder reaction. The results of this study are outlined below in Table 3.7. As LA 99 had previously been determined to provide the optimum results, it was chosen as the Lewis acid for the preequilibration study. As can be seen below, the preequilibration of LA 99 and dienophile 134a at -78 ºC has absolutely no effect whatsoever on the results of the reaction.

Table 3.7 Preequilibration Study for Diels Alder Reaction between 134a and 96 O O O O O O O O

O N 3.5 eq. O N O N O N + 99

96 toluene 25 oC 1 hours 134a 135a endo I 135a endo II 135a exo I (absolute configuration unknown) Entry Equilibration time at -78 Conversion (%)a Σendo/Σexoa endo ºC (minutes) I/endo IIa 1 0 76 3.3 5 2 15 75 3.3 5 3 25 75 3.3 5 4 45 75 3.2 5.2 5 75 76 3.3 5 aConversion to products and endo:exo ratios measured by NMR spectroscopy. bAbsolute configuration of exo adduct unknown

3.2.9 Optimization of the Diels-Alder Reaction by Employing Alternative Chiral Oxazolidinone-based Auxilliaries

The final means of optimizing the Diels-Alder reaction described above was to test multiple different oxazolidinone-based auxiliaries. Having already synthesized the 4- benzyl-substituted oxazolidinone dienophile, the 4-phenyl and the 4-isopropyl-substituted oxazolidinone dienophiles were also synthesized as well as the achiral unsubstituted dienophile. The synthesis of these three new dienophiles was carried out in exactly the same way as the previous dienophiles, and the process is shown below in Scheme 3.6.

100

O LiCl, TEA, TMAC O O THF, 0oC, 1 h HO O

132 133

O O 123b-e soln. (THF) O O O THF, rt, 18 h O O N O NH

133 R R 134b: R = Bn (89 %) 123b: R = Bn 134c: R = Ph (72 %) 123c: R = Ph 134d: R = iPr (76 %) 123d: R = iPr 153a: R = H (91 %) 123e: R = H Scheme 3.6

The Diels-Alder reaction with diene 96 was conducted exactly as it was previously, in toluene at 25 ºC for 24 hours. The new dienophiles 134b-d were used in the Diels-Alder reaction to determine which auxiliary provided the best results. These results are shown below in Table 3.8. Because RAlBr2-type Lewis acids 86 and 99 provided better results than Lewis acid 125, both Lewis acids 86 and 99 were included in the study with the new dienophiles.

Lewis acid 99 generally provided the best results; conversions, Σendo/Σexo ratios, and endo I/endo II ratios were all better for Lewis acid 99 than they were for Lewis acid

86 with the exception of the conversion to products for the isopropyl adducts. The best

Σendo/Σexo ratio obtained was 7.1 in the case of the Diels-Alder reaction using 4-benzyl oxazolidinone-substituted dienophile 134b and Lewis acid 99. Unfortunately, the endo

I/endo II ratio for benzyl-substituted dienophile 134b could not be determined due to overlap of proton signals even on a 400 MHz 1H NMR spectrum. The most diastereoselective dienophile was therefore determined to be the iPr-substituted

101

oxazolidinone dienophile 134d. The Σendo/Σexo ratio using Lewis acid 99 to promote the reaction was 5.6, with an endo I/endo II ratio of 4.9. This selectivity is certainly not exceptional, but was nevertheless the best selectivity that had yet been determined.

Table 3.8 Results of Diels-Alder Reaction using Dienophiles 134b-d and diene 96 with RAlBr2 Lewis acids 86 and 99 AlBr2

AlBr2 86 99 O O O O O O O O

O N 3.5 eq. O N O N O N + LA

R1 toluene R1 R1 R1 134b-d 96 135b-d endo I 25 oC 135b-d endo II 135b-d exo I (absolute configuration 24 h unknown) a a a Entry R1 LA Conversion (%) Σendo/Σexo endo I/endo II 1 Bn 86 73 5.9 Unclearc 2 Bn 99 79 7.1 Unclearc 3 Ph 86 80 5.0 1.0 4 Ph 99 88 6.7 1.3 5 iPr 86 88 4.0 3.8 6 iPr 99 84 5.6 4.9 aConversion to products and endo:exo ratios measured by NMR spectroscopy. bAbsolute configuration of exo adduct unknown. cDetermination not possible on 400 MHz 1H NMR spectrum.

With the diastereoselectivity and conversion of the Diels-Alder reaction improved as previously described, two approaches were made clear. The first was to employ chiral

R*AlBr2-type Lewis acids to promote the Diels-Alder reaction in conjunction with the aforementioned chiral dienophiles 134a-d. It was believed that the synergistic effect of the chiral R*AlBr2 Lewis acid promoting the Diels-Alder reaction along with the chiral oxazolidinone auxiliary might result in a significant double-diastereodifferentiative effect on the reaction, which would even further improve the diastereoselectivity. It should be

102

noted that upon cleavage of the chiral auxiliary, the endo I and endo II adducts become enantiomers. Thus, this important ratio reflects what might alternatively be considered the enantioselectivity of the endo diastereomer.

The second approach was to test the unsubstituted achiral oxazolidinone- substituted dienophile 153a (Scheme 3.6) in the Diels-Alder reaction using chiral

R*AlBr2 Lewis acids to promote the reaction enantioselectively. As both of these approaches call for the use of chiral R*AlBr2 Lewis acids in an organic reaction, and thus reflect the next generation of this research project, these efforts will be addressed in chapter 4. For now, the Diels-Alder reaction between dienophile 153a and diene 96 would need to be optimized, and conditions found to maximize the endo/exo ratio.

3.2.10 Optimization of the Diels-Alder Reaction between Achiral Oxazolidinone- Substituted Dienophile 153a and Diene 96

In order to determine if dienophile 153a would be a suitable candidate to use as a prochiral starting material in conjuction with a chiral R*AlBr2 Lewis acid for enantioselective transformation, it was first necessary to determine if the reaction between 153a and 96 could be conducted diastereoselectively. It was hoped that conditions could be found such that reasonably good endo:exo ratios could be obtained.

These efforts were focused mostly around altering the temperature of the reaction. Due to the reduced steric hindrance surrounding the unsubstituted oxazolidinone in 153a relative to the previously discussed chiral oxazolidinones, it was thought the reaction might proceed at lower temperatures than before, with less of a reduction in conversion. Thus

103

an experiment was set up to determine what effect temperature had on the results of this

Diels-Alder reaction. These results are shown below in table 3.9.

Table 3.9: Temperature Study for Diels Alder Reaction between 153a and 96 O O O O O O 1.4 eq. 99 O N O N O N + toluene 24 h 153a 96 154 endo 154 exo Entry Temperature Conversion (%)a endo/exoa 1 40 ºC 98 2 2 25 ºC 99.9 3.7 3 0 ºC 99.8 4.4 4 -20 ºC 99.6 5.3 5 -40 ºCb 13 6.7 6 -60 ºCb 4 no exo detected 7 -78 ºCb NR NA aConversion to products and endo:exo ratios measured by 1H NMR spectroscopy. bReaction time 8 hours.

As shown above, the endo/exo ratios steadily improved as the temperature decreased, down to an endo/exo ratio of 6.7 at -40 ºC. Although no exo adduct could be detected by 400 MHz 1H NMR spectroscopy after 8 hours at -60 ºC, the formation of exo adduct at this temperature cannot be ruled out due to the very small quantities of product formed. At -40 ºC, the reaction proceeded in only 13 % conversion after 8 hours, but proceeded to 99.6 % conversion after 24 hours at -20 ºC with an endo/exo ratio of 5.3.

This ratio is not exceptional, but is adequate considering especially that it may be possible to improve these ratios with chiral R*AlBr2-type Lewis acids.

Finally, two control reactions were set up between dienophile 153a and diene 96, one using AlBr3 and one using the HAlBr2 hydroaluminating species generated in situ to promote the Diels-Alder reaction. These reactions were conducted in order to

104

demonstrate conclusively that neither of these aluminum species is capable of promoting the Diels-Alder reaction. Indeed, these studies revealed that AlBr3 consumed both dienophile and diene and produced a complex mixture with large quantities of polymer, and HAlBr2 resulted in a complex mixture with no Diels-Alder adduct, suggesting that neither of these species are present in the reaction mixtures under study.

3.2.11 Attempts at Diels-Alder Reaction Between Other Achiral Oxazolidinone-based Dienophiles and diene 96

With achiral oxazolidinone-based dienophile 153a having produced outstanding conversion and reasonable endo/exo ratios, three other achiral oxazolidinone-based dienophiles 153b-d were synthesized and tested in the Diels-Alder reaction with 96. The synthesis of these three dienophiles was carried out in exactly the same manner as previously synthesized dienophiles (Scheme 3.7).

O O O LiCl, TEA, TMAC R THF, 0oC, 1 h 1 HO R2 O R1 R2

132b: R1 = R2 = H 133b: R1 = R2 = H 132c: R1 = Me, R2 = H 133c: R1 = Me, R2 = H 132d: R1 = H, R2 = Ph 133d: R1 = H, R2 = Ph

O O O O 123e soln. (THF) O R1 THF, rt, 18 h R O O N 1 O NH

R2 R2

133b: R1 = R2 = H 153b: R1 = R2 = H (63 %) 123e 133c: R1 = Me, R2 = H 153c: R1 = Me, R2 = H (83 %) 133d: R1 = H, R2 = Ph 153d: R1 = H, R2 = Ph (61 %) Scheme 3.7

105

Dienophile 153d was of particular interest due to the fact that Evans had previously determined that the 4-isopropyl oxazolidinone derivative of cinnamic acid yielded product extremely diastereoselectively, with exo adducts being entirely undetectable by 500 MHz 1H NMR (Scheme 3.4).56

The Diels-Alder reaction between each of dienophiles 153b-d and diene 96 was tested under several different reaction conditions. As RAlBr2 Lewis acid 99 had previously been determined to provide the optimum results, it was the Lewis acid selected for this series of experiments. The results from this study are outlined below in

Table 3.10. As outlined below, the reaction between dienophile 153b and diene 96 proceeds much more smoothly in DCM than it does in toluene. The reaction goes to completion within a single hour at -25 ºC, but with an endo:exo ratio of only 1:1 (entry

4). This ratio could be improved to 4:1 by cooling the reaction mixture to -78 ºC, but the conversion under those conditions proceeded to only 25 % (entry 5).

Unfortunately, neither dienophiles 153c nor 153d yielded Diels-Alder adduct under the conditions tested. The reaction between 153c and 96 produced a complex product mixture under the conditions tested, while the reaction between 153d and 96 did not proceed at all under the conditions tested with only starting materials being observed by 1H NMR spectroscopy. The most likely explanation for this is that cinnamic acid derivative 153d is a very sterically hindered dienophile, and along with the sterically hindered diene 96, the reaction cannot proceed. In any case, dienophiles 153b-d were determined to provide poorer results than the previously tested dienophile 153, and thus no further optimization was conducted on prochiral oxazolidinone-substituted dienophiles.

106

Table 3.10 Diels-Alder reaction between achiral dienophiles 153b-d and diene 96

O O O O O O R O N 1 3.5 eq. 99 O N O N + R1 R1 R2 R2 R2

153b: R1 = R2 = H 96 endo-154b: R1 = R2 = H exo-154b: R1 = R2 = H 153c: R1 = Me, R2 = H endo-154c: R1 = Me, R2 = H exo-154c: R1 = Me, R2 = H 153d: R1 = H, R2 = Ph endo-154d: R1 = H, R2 = Ph exo-154d: R1 = H, R2 = Ph Entry Dienophile Conditions Conversion (%)a endo/exoa 1 153b toluene, -25 ºC, 24 h 22 1 2 153b toluene, -78 ºC, 24 h 30 1 3 153b DCM, -25 ºC, 24 h 94 1 4 153b DCM, -25 ºC, 1 h 91 1 5 153b DCM, -78 ºC, 24 h 25 4 6 153c toluene, -25 ºC, 24 h complex mixture NA 7 153c DCM, -25 ºC, 24 h complex mixture NA 8 153c DCM, -25 ºC, 5 h complex mixture NA 9 153d toluene, -25 ºC, 24 h NR NA 10 153d toluene, 25 ºC, 24 h NR NA 11 153d DCM, 25 ºC, 5 h NR NA aConversion to products and endo:exo ratios measured by NMR spectroscopy.

3.3 Efforts to Reduce Catalyst Loading in the Diels-Alder Reaction from 3.5 equivalents

Although the results of the Diels-Alder reaction described above had been optimized to the point of being synthetically useful, the fact that this reaction required 3.5 equivalents of Lewis acid made this methodology unattractive. This is particularly true given the fact that synthesis of complex chiral olefin precursors for hydroalumination may be difficult and costly, and delivery of such large amounts of Lewis acid to promote a simple reaction is impractical, and may prove more costly than the chiral auxiliaries themselves.

107

3.3.1 Reducing Catalyst Loading through Concentrating the Reaction Mixture

An hypothesis for the mechanism of RAlBr2 binding to the oxazolidinone dienophiles is proposed below in section 3.4. Although the exact mechanism of binding is unknown, what is fairly clear is that the RAlBr2-type Lewis acid behaves more as a reagent than as a catalyst since a load > 1.0 equivalents is required for the Diels-Alder reaction to proceed. If the Lewis acid was behaving as a reagent and not as a catalyst, it was thought that concentrating the reaction mixture might increase the rate of the Diels-

Alder reaction due to an increase in molecular collisions, and that it may improve the diastereoselectivity as well. An experiment was thus devised to vary the concentration of the reaction mixture to determine if conversion and diastereoselectivity could be improved at 1.4 equivalents of Lewis acid. The results are outlined below in Table 3.11.

The effects of concentration on the Diels-Alder reaction are highly significant.

Even at 1.4 equivalents of Lewis acid, the Σendo/Σexo ratios vary from 0.5 at a 0.085 M dienophile concentration all the way to 3.3 at a 0.75 M dienophile concentration.

Furthermore, at a 0.75 M dienophile concentration, the endo I/endo II ratio is 5.0, which is one of the best results obtained even at 3.5 equivalents of Lewis acid with dienophile

135a. This interesting result meant that concentration could potentially provide the answer to improve the Diels-Alder reaction without having to use a heavy loading of

Lewis acid.

The one puzzling result was that conversion improved up to 66 % at a dienophile concentration of 0.48 M, and then began to decline, falling to only 60 % at a dienophile concentration of 0.75 M. It was therefore presumed a side reaction was occurring in more

108

concentrated reaction conditions. Interestingly, closer examination of the 1H NMR spectra for these reactions demonstrated that the chiral auxiliary was actually being removed under the reaction conditions, resulting in small amounts of chiral auxiliary

123a being observable on the crude 1H NMR spectrum (Scheme 3.8).

Table 3.11 Efforts to reduce RAlBr2 loading through concentration effects O O O O O O O O

O N 1.4 eq. O N O N O N + 125

96 toluene 25 oC 24 hours 134a 135a endo I 135a endo II 135a exo I (absolute configuration unknown) Entry Concentration of Conversion (%)a Σendo/Σexoa endo dienophile I/endo IIa 1 0.085 M 32 0.5 6.6 2 0.22 M 61 0.8 4.6 3 0.30 M 68 1.7 4.0 4 0.48 M 66 2.0 4.0 5 0.63 M 61 2.2 4.0 6 0.75 M 60 3.3 5.0 aConversion to products and endo:exo ratios measured by 1H NMR spectroscopy. bAbsolute configuration of exo adduct unknown.

O O O

O N 1.4 eq. RAlBr2 O NH

toluene concetrated

135a 123a Scheme 3.8

It is unclear exactly how this process is occurring, but the return of small amounts of chiral auxiliary 123a is quite clear by 1H NMR spectroscopy. It is possible that under

109

concentrated reaction conditions the R group on RAlBr2 is sufficiently nucleophilic to cleave the amide bond. Whatever the explanation, it became quite clear that simply concentrating the reaction mixture would not be the answer, as the side reaction described above would reduce the conversion of the desired Diels-Alder adduct.

3.3.2 Attempts to reduce catalyst loading by adding silver salts to the reaction mixture

One hypothesis that was advanced due to the numerous observations outlined above was that LiBr might be competing as a Lewis base with the target carbonyl groups of the dienophile, inhibiting the Diels-Alder reaction from proceeding, and thus requiring the addition of more RAlBr2-type Lewis acid to the reaction mixture to get the same result. This hypothesis is further clarified below in the proposed binding model in section

3.4. It was thus hypothesized that the addition of AgOClO3, a silver salt that is soluble in toluene, would remove the Lewis basic Br- anions in solution, and that AgBr and

LiOClO3 would be insoluble under the conditions tested, thereby making the targeted carbonyl groups the only Lewis bases in solution the RAlBr2 Lewis acid could bind

(Scheme 3.9).

1) LiAlH4 + AlBr3 4HAlBr2 + LiBr + RAlBr2 + LiBr RAlBr3Li

AgOClO3 2) RAlBr2 + LiBr RAlBr2 + AgBr(s) + LiOClO3(s) Scheme 3.9

It was hoped that the availability of the RAlBr2 Lewis acid would improve, thereby promoting the Diels-Alder reaction without any LiBr available either to bind

110

RAlBr2 or take part in any other potential side reactions. A number of different attempts were made to develop this methodology using dienophile 153a. The data so generated is outlined below in Table 3.12.

Table 3.12 Addition of silver triflate to the reaction mixture to reduce catalyst loading O O 99 O O O AgOClO3 O N O N HN + toluene 12 h Br 153a 96 154a 155 mixture of diastereomers Entry Eq. Eq. AgOClO3 Conditions Conversion to 154a Conversion to 155 99 (%)a (%)a 1 0.5 0.5 -25 ºC 0 0 2 1.0 1.0 -25 ºC 0 0 3 1.4 1.4 -25 ºC 0 0 4 1.4 2.8 -25 ºC 0 0 5 1.0 1.0 25 ºC 0 0 6 1.4 1.4 25 ºC 0 0 7 0.5 0 -25 ºC 0 17 8 1.0 0 -25 ºC 0 50 9 1.4 0 -25 ºC 19 7 aConversion to products measured by 1H NMR spectroscopy.

As can be seen AgOClO3 did not improve the conversion to 154a; in fact under every condition wherein AgOClO3 was employed, the Diels-Alder reaction did not proceed at detectable levels by 400 MHz 1H NMR spectroscopy. What was discovered while conducting these experiments, however, was that a side product was forming following a Lewis-acid catalyzed bromination-decarboxylation process resulting in adduct 155.

More interestingly still is that two factors inhibit this side reaction. Firstly, the addition of AgOClO3 inhibits the side reaction, likely by ridding the reaction mixture of

111

the LiBr as previously hypothesized. Where AgOClO3 is added to the reaction mixture, adduct 155 does not form in any quantities. Under the same conditions, however, where

AgOClO3 is not added, adduct 155 forms, and indeed can form in significant quantities.

Lewis acid 99 (1.0 equivalent) over 12 hours at -25 ºC forms adduct 155 in 50 % conversion (Entry 8). Interestingly, further addition of 0.4 equivalents of Lewis acid, for a total addition of 1.4 equivalents results in adduct 155 forming in only 7 % conversion.

The explanation for this phenomenon is reasonably clear. In much the same way that AgOClO3 reacts with and removes LiBr from solution, RAlBr2 Lewis acid added beyond 1.0 equivalents helps to sequester it, thereby reducing its reactivity. Although this series of experiments did not turn out to be synthetically useful, it provided sufficient insight into the mechanism of RAlBr2 binding to oxazolidinone-based dienophiles to formally propose a mechanism.

3.4 Proposed mechanism for binding of RAlBr2 Lewis acids to oxazolidinone dienophiles

The Evans paper described above proposed a binding mechanism to explain the varying diastereoselectivity as a function of Lewis acid stoichiometry. The way Evans explained the changing diastereoselectivity is outlined below in Scheme 3.10.56

112

R R O O R2ClAl O Al R2AlCl R2AlCl O O O N N + R2AlCl2 1.0 eq. O N O O

138 156 157

endo : exo ~ 20:1 endo : exo ~ 60:1 endo I : endo II ~ 4:1 endo I : endo II ~ 20:1 relative rate ~ 1 relative rate ~ 100

Scheme 3.10

A single equivalent of Lewis acid or less binds to the carbonyl group shown in

156. Delivery of greater quantitites of Lewis acid above and beyond 1.0 equivalent results in chelate 157. The chelate forms because the second equivalent of Lewis acid added absorbs the chloride anion previously bound to the first equivalent of Lewis acid.

Naturally, with these two very different intermediate structures, the diastereoselectivity changes considerably, and the relative reaction rate is also very different, with intermediate 157 apparently being far more active for the Diels-Alder reaction than intermediate 156.

Although this explanation seems reasonable, a slightly different binding model is proposed herein. Having completed the series of experiments described above, 5 points have been clarified which enable speculation on the binding mechanism of RAlBr2-type

Lewis acids to oxazolidinone-based dienophiles. The 5 points that have been clarified are listed below.

1) The carbonyl group in the carbamate moiety in the oxazolidinone is bound first.

2) LiBr binds RAlBr2 Lewis acids, tying them up.

113

3) Delivery of RAlBr2 Lewis acid beyond 1.4 equivalents speeds up the reaction and

changes the diastereoselectivity.

4) Concentrating the reaction mixture using 1.4 equivalents of Lewis acid speeds up

the reaction and changes the diastereoselectivity.

5) The 1H NMR spectrum of 125-bound dienophile 134a is different at 1.4

equivalents of Lewis acid than it is at 3.5 equivalents of Lewis acid.

Point number 1 is confirmed for two reasons. The first is that the reaction proceeds to only 6 % conversion at 0.7 equivalents of 125 (Table 3.3, entry 2). If the

RAlBr2 Lewis acid bound the other carbonyl group first, it would be reasonable to expect the dienophile to be activated sufficiently for the Diels-Alder reaction to proceed at this quantity of Lewis acid delivery. Point number 1 is also confirmed due to the formation of side product 155 (Table 3.12), which would not form at 1.0 equivalents of RAlBr2 were the carbamate moiety not the first carbonyl bound to the Lewis acid.

Point number 2 is reasonable having completed the AgOClO3 studies conducted above. Addition of RAlBr2 beyond 1.0 equivalents inhibits the production of adduct 155 in much the same way that AgOClO3 does: by helping to tie up LiBr in solution. Point number 3 is clear having completed the Lewis acid equivalent studies shown in Table 3.3, and having found that adding 3.5 equivalents of Lewis acid to be optimal. Point number 4 is clear having completed the concentration studies shown in Table 3.11, and having determined that the Diels-Alder reaction speeds up and becomes more diastereoselective upon concentrating the reaction mixture at 1.4 eq. Lewis acid loading. Finally, point number 5 was determined from the NMR binding studies shown above in Figure 3.6. As

114

a result of these 5 points, the following binding model for RAlBr2-type Lewis acids with oxazolidinone-based dienophiles is proposed (Scheme 3.11).

LiAlH4 + AlBr3 4HAlBr2 + LiBr + RAlBr2 + LiBr RAlBr3 + Li 158 O O

O N O 158 N 1st eq. O Br2RAl O + LiBr 159 134a 158 2nd eq.

O O Br2RAl O

N N N O O O Br2RAl O Br2RAl O Br2RAl O + RAlBr3Li + RAlBr2 + LiBr + LiBr 161 160 162

R Br Al O O RAlBr3

N O

163 Scheme 3.11

Intermediate 159 forms as the first equivalent of Lewis acid is tied up by the carbamate moiety of the oxazolidinone. This binding does not activate the dienophile sufficiently to promote the Diels-Alder reaction. Thus conversion to products at 1.0

115

equivalent of Lewis acid and below is very low. Further, it must be remembered that LiBr is present in solution as a byproduct of the hydroalumination process. Thus, the second equivalent of RAlBr2 delivered may be tied up by the LiBr that accompanies it (161), preventing the dynamic previously described by Evans, that being the absorption of a halide anion by the second equivalent of Lewis acid, to form chelate 163. It may nevertheless bind the second carbonyl group reversibly, in equilibrium with the LiBr in solution, to form intermediate 162. This intermediate is sufficiently activated to promote the Diels-Alder reaction, and conversion to products is observed at 1.4 equivalents of

Lewis acid favoring the exo adduct. If chelate 163 was the dominant species formed at

1.4 equivalents, no major inversion of diastereoselectivity would likely be observed with further delivery of Lewis acid.

As more Lewis acid is added to solution beyond 2.0 equivalents, the equilibria are slowly pushed toward the formation of chelate 163, and concentrating the mixture has the same effect. As sufficient Lewis acid is added to solution or as sufficient molecular collisions occur, the formation of chelate 163 becomes possible. The chelate intermediate is highly activated, as previously described by Evans, and the relative rate of the Diels-

Alder reaction increases. Due to the changing conformation of the Lewis acid-bound dienophile as the equilibria shift, the exo selectivity previously observed disappears and the Diels-Alder reaction starts to favor the endo adduct.

This hypothesis is supported by the NMR binding study shown above in Figure

3.4, because the dominant species that is formed at 1.4 equivalents is different than that formed at 3.5 equivalents, despite the 1H NMR spectra for both mixtures being incomprehensible.

116

Finally, the diastereoselectivity varying as a function of dienophile concentration at 1.4 equivalents of Lewis acid suggests that chelate 161 may have a mechanism for forming through increased molecular collisions, consistent with what has been proposed.

In concentrated enough conditions, it therefore seems likely that the bound first equivalent of RAlBr2 starts to compete with both LiBr and the second carbonyl group to donate a bromide to the second equivalent of RAlBr2 as it is added. As postulated, this is likely due to increased molecular collisions between the second equivalent of Lewis acid and the bound first equivalent. In dilute conditions, the second equivalent simply alternates between absorbing the LiBr in solution and binding the second carbonyl group as shown in 162. This proposed binding mechanism is very similar to that previously proposed by Evans, but with some minor additions to account for 5 key experimental observations.

3.5 Developing new organic reactions requiring the addition of less RAlBr2

Several attempts were made to promote other organic reactions that would allow for the delivery of less Lewis acid. The first reactions tested for this purpose included using simple ,β-unsaturatred esters and ketones as well as 1,2-diketones as dienophiles for the Diels-Alder reaction. In addition to that, an intramolecular Diels-Alder furan

(IMDAF) reaction was tested, as well as a Strecker reaction.

117

3.5.1 Using ,β-unsaturatred esters and ketones as dienophiles for the Diels-Alder reaction with several common dienes

Simple ,β-unsaturatred esters and ketones 164-166 were distilled and tested as dienophiles in the RAlBr2-promoted Diels-Alder reaction with two common dienes, 167 and 168, as well as diene 96 used previously (scheme 3.12). Lewis acid was added in 0.5 and of 1.4 molar equivalents under a number of different reaction conditions. Although these efforts were met with failure, they are outlined below in Table 3.13.

O O O

O MeO

164 165 166 167 168 96 9 Scheme 3.12

Dienophiles 164-166 were tested with dienes 167-168 and diene 96 using both

RAlBr2-type Lewis acids 99 and 125. No reactions were observed under the conditions tested, with only starting materials left on the 1H NMR spectra. Under some conditions tested, small amounts of tar formed in the reaction vessel, but starting materials still remained on crude 1H NMR spectra. Interestingly, dienophile 164 was susceptible to small amounts of 1,4-bromination via Michael addition to form adduct 170 under all conditions tested in toluene, with the exception being the reaction set up by adding 0.5 eq. of AgOClO3 along with the 0.5 eq. of Lewis acid 99 (entry 8). This observation is consistent with previously observed results, as AgOClO3 reduces or eliminates the reactivity of Br- anions in solution. Due to the fact that no Diels-Alder adducts were

118

observed to form among any of the conditions tested, efforts to promote reactions using simple ,β-unsaturatred esters and ketones as dienophiles were discontinued.

Table 3.13 Diels Alder Reaction using various alternative dienophiles and dienes O O R3 O

R R LA R 1 + 3 1 R4 conditions R2 R2 Br R4 170 164-166 167-168, 96 169 Entry D.phile Diene LA Temperature Solvent Result [time] 1 164 167 0.5 eq. 99 -78 ºC [5 h] toluene NR, only SM 2 164 167 0.5 eq. 99 -20 ºC [5 h] toluene SM, some 170 3 164 167 0.5 eq. 99 0 ºC [5 h] toluene SM, some 170 4 164 167 1.0 eq. 99 0 ºC [5 h] toluene SM, some 170 5 164 167 0.5 eq. 99 25 ºC [24 h] toluene SM, some 170 6 164 167 0.5 eq. 99 -20 ºC [24 h] DCM SM, polymer 7 164 96 0.5 eq. 99 -20 ºC [24 h] toluene SM, some 170 8 164 96 0.5 eq. 99 + -20 ºC [24 h] toluene Only SM AgOClO3 9 165 168 1.4 eq. 125 -78 ºC [6 h] toluene NR 10 165 168 1.4 eq. 125 -25 ºC [6 h] toluene NR 11 166 168 1.4 eq. 125 -78 ºC [6 h] toluene NR, only SM 12 166 168 1.4 eq. 125 -25 ºC [6 h] toluene NR, only SM

3.5.2 Testing a 1,2-diketone as dienophile in the RAlBr2-promoted Diels-Alder reaction

As stated previously, although the Diels-Alder reaction with oxazolidinones was working acceptably, it required large amounts of Lewis acid to proceed efficiently, whether 1.4 or 3.5 equivalents was used. The most likely explanation, as stated above, is that the first equivalent of Lewis acid is tied up by the carbamate moiety of the

119

oxazolidinone auxiliaries, and a complex equilibrium involving LiBr follows as greater quantities of Lewis acid are added. Nevertheless, due to the fact that simple ,β- unsaturatred esters and ketones were not sufficiently electron-withdrawing for RAlBr2- promoted Diels-Alder reactions, it was thought that 1,2-diketones might provide a simple and elegant solution.

The first advantage provided by 1,2-diketones is that the -keto group in 171 provides an electron-withdrawing group that might activate the dienophile moiety sufficiently for RAlBr2-promoted reactions (Scheme 3.13). The second, perhaps more important advantage 1,2-diketones might provide is that the carbonyl group a may be more Lewis basic than carbonyl group b due to resonance, meaning that the first equivalent of Lewis acid will not be tied up by a remote Lewis basic moiety. The Lewis acid will instead bind carbonyl group a, as intermediate 172 illustrates. It should therefore be possible for a Diels-Alder reaction to access the drimane skeleton to proceed using catalytic quantities of RAlBr2 Lewis acids. The third advantage is that the second carbonyl group b in Diels-Alder adduct 173 can later be cleaved off via periodate cleavage to reveal the desired functionalized Diels-Alder adduct 174. One limitation of this chemistry is that the R1 group on 1,2-diketone 171 should not contain an -proton, as it might be acidic enough for the basic R group of RAlBr2 to deprotonate. A phenyl group was therefore chosen as R1, with R2 being a methyl group, as previous experiments demonstrated crotonic acid-derivatized dienophiles yield acceptable diastereoselectivity.

120

AlRBr2 O O O periodate O R1 b RAlBr2 R b Diels Alder R b cleavage a 1 a 1 a a O O O R2 R2 R2 R2 EWG dienophile moiety 171 172 173 174 Scheme 3.13

The synthesis of 1,2-diketone 178 was conducted in a 4-step sequence from commercially available starting materials. The exact procedure, based on a procedure reported by Page et al.57 is outlined below in scheme 3.14. The concept behind the synthesis is that a 1,3-dithiane group provides an acidic proton along with being a carbonyl surrogate. Diketone 178 was then tested under a number of conditions with several different dienes, shown above in scheme 3.12. The results of these series of experiments are outlined below in Table 3.14.

S o 1) nBuLi, -78 C S S S 2) crotonaldehyde OH 42 % 175 176

SO -pyridine NCS, AgNO O 3 O S S 3 Hunig's base AcCN OH OH DMSO O 98 % 69 % 176 177 178 Scheme 3.14

Unfortunately, under most conditions tested, very complex crude product spectra were obtained. While crude product 1H NMR spectra contained tiny peaks that could

121

conceivably have represented a Diels-Alder adduct, the quantities formed were too small to isolate off a column. In addition, other products were clearly forming, and in most cases the major product was still starting material 178. Interestingly, for the two reactions carried out at room temperature (entries 5 and 6) with Lewis acids 86 and 99, 1,4- bromination side product 181 was observed to form in an approximately 4:1 ratio with unreacted starting materials. This is an interesting observation given that the catalyst was present in 20 mol %.

Table 3.14 RAlBr2-promoted Diels Alder reactions between 1,2-diketone 178 and various dienes R1 X O O O diene O RAlBr O 2 O R2 180: X = Cl 178 179 181: X = Br Entry Diene LA Temperature [time] Solvent Result 1 96 0.2 eq. 125 -20 ºC [24 hours] toluene SM 2 96 0.5 eq. 125 -20 ºC [24 hours] toluene complex mixture with SM 3 96 0.5 eq. 99 -20 ºC [24 hours] toluene complex mixture with SM 4 96 0.5 eq. 99 -78 ºC [5 hours] toluene SM 5 96 0.2 eq. 99 25 ºC [24 hours] toluene ~4:1 ratio SM:181 6 96 0.2 eq. 86 25 ºC [24 hours] toluene ~4:1 ratio SM:181 7 96 0.2 eq. BCl3 -78 ºC [5 hours] toluene mostly SM 8 96 0.2 eq. BCl3 -20 ºC [5 hours] DCM 5:1 ratio SM:180 9 168 0.2 eq. 99 0 ºC [8 hours] toluene SM 10 168 1.0 eq. 99 0 ºC [8 hours] toluene Mostly SM 11 9 0.2 eq. 99 0 ºC [8 hours] toluene SM 12 9 1.0 eq. 99 0 ºC [8 hours] toluene polymer

This observation was also made at -20 ºC while attempting to find out whether

BCl3 would promote this Diels-Alder reaction. In the case of BCl3, however, chlorination

122

side product 180 was formed in small amounts. Apart from this side product, no other side product in the mixture was confirmed apart from unreacted starting materials. While the side reactions taking place were numerous based on the complex 1H NMR crude product spectra, each individual product was formed in very small quantites, making isolation extremely difficult and time consuming. As no significant quantities of Diels-

Alder adduct were apparent under the conditions tested, further attempts to develop 1,2- diketones as dienophiles in RAlBr2-catalyzed Diels-Adler reactions were abandoned.

3.5.3 The RAlBr2-promoted Intramolecular Diels-Alder Furan reaction

The Keay group has previously reported a series of Lewis acid-catalyzed IMDAF reactions.58 A number of IMDAF precursors 182a-g were previously synthesized by

Rogers and Keay for use in the Lewis acid-catalyzed IMDAF reaction. These precursors are shown below in Scheme 3.15, along with their corresponding IMDAF adducts 183a- g. The first series of experiments tested used 1.1 equivalents of a number of different

Lewis acids to promote the IMDAF reaction of 182b to 183b. The progress of the reaction was monitored by taking aliquots to the NMR. The reaction was stirred until no further progress in the reaction was observed via 1H NMR. Interestingly, at 1.1 equivalents of Lewis acid, the ratio of starting material to Diels-Alder adduct favored the starting materials, although to different degrees depending on the Lewis acid used. These results are outlined below in Table 3.15.

123

R 2 LA R1 O R3 O R1 O R2 R3 O

182a: R1 = R2 = R3 = H 183a: R1 = R2 = R3 = H 182b: R1 = R3 = H, R2 = Me 183b: R1 = R3 = H, R2 = Me 182c: R1 = R2 = H, R3 = Me 183c: R1 = R2 = H, R3 = Me 182d: R1 = H, R2 = R3 =Me 183d: R1 = H, R2 = R3 =Me 182e: R2 = R3 = H, R1 = Me 183e: R2 = R3 = H, R1 = Me 182f: R3 = H, R1 = R2 = Me 183f: R3 = H, R1 = R2 = Me 182g: R2 = H, R1 = R3 = Me 183g: R2 = H, R1 = R3 = Me Scheme 3.15

Table 3.15 Lewis Acid study on the IMDAF of 182b reported by Rogers and Keay Lewis acid O O (1.1 eq.) O O 182b 183b Entry Lewis acid Conditions 183b:182b ratio 1 ZnI3 1 h, -78ºC 0:100 2 SnCl4 1 h, -78ºC 24:76 3 BF3·Et2O 2.5 h, -78ºC 28:72 4 TiCl4:Ti(OiPr)4 4.5 h, -78ºC 32:68 5 EtAlCl2 2.5 h, -78ºC 35:65 6 MeAlCl2 2.5 h, -78ºC 35:65 7 Et2AlCl 2.5 h, -50ºC 35:65 8 Me2AlCl 2.5 h, -50ºC 32:68 9 Florisil/CH2Cl2 14 days, 25ºC 100:0 10 2.0 M CaCl2 4 days, 25 ºC 50:50

The strength of the Lewis acid has pronounced effects on the final ratio between

182b and 183b, with decreasing Lewis acid strength providing the greatest conversion to products. Interestingly, florisil in DCM provided the best results, with 100 % conversion to 182b, but it took 14 days at room temperature for the reaction to proceed. Rogers and

Keay later discovered that the reaction proceeds more fully at lower catalyst loading, with optimum results being obtained at 0.1 equivalents of Lewis acid.58 An experiment was set

124

up to test the difference between 1.1 and 0.1 equivalents of MeAlCl2 in the IMDAF reactions of 182a-g. The best results were obtained using IMDAF precursors 182c-g, and these results are outlined below in Table 3.16.

Table 3.16: IMDAF reactions of 182c-g using 0.1 and 1.1 equivalents of MeAlCl2 R 2 MeAlCl2 R1 O R3 O R1 O DCM R2 R3 O

182c: R1 = R2 = H, R3 = Me 183c: R1 = R2 = H, R3 = Me 182d: R1 = H, R2 = R3 =Me 183d: R1 = H, R2 = R3 =Me 182e: R2 = R3 = H, R1 = Me 183e: R2 = R3 = H, R1 = Me 182f: R3 = H, R1 = R2 = Me 183f: R3 = H, R1 = R2 = Me 182g: R2 = H, R1 = R3 = Me 183g: R2 = H, R1 = R3 = Me Entry SM Conditions Time (h) 182:183 ratio Yield (%) Adduct 1 182c 0.1 eq. MeAlCl2 2 31:69 69 183c 2 182c 1.1 eq. MeAlCl2 8 78:22 11 183c 3 182d 0.1 eq. MeAlCl2 2 95:5 4 183d 4 182d 1.1 eq. MeAlCl2 2 100:0 0 183d 5 182e 1.1 eq. MeAlCl2 1 0:100 99 183e 6 182f 0.1 eq. MeAlCl2 2 0:100 99 183f 7 182f 1.1 eq. MeAlCl2 8 19:81 80 183f 8 182g 0.1 eq. MeAlCl2 2 24:76 74 183g 9 182g 1.1 eq. MeAlCl2 8 82:18 18 183g

As is evident from the data, the results using 0.1 equivalents of MeAlCl2 are vastly superior to the results using 1.1 equivalents of MeAlCl2. The best results are obtained using IMDAF precursors 182e-g. Yields of up to 99 % were obtained with both

182e and 182f. Both 182e and 182f go to completion in 1 hour and 2 hours respectively, indicating that the reaction requires little time. Due to the fact that 182e-g provided the best results of all IMDAF precursors tested by Rogers and Keay, these were synthesized as precursors to study in the RAlBr2-promoted IMDAF reaction at 0.1 eq. of Lewis acid

125

99. The synthesis of these starting materials was each carried out in a 4-step sequence exactly as previously described by Rogers and Keay. These syntheses are outlined below in Scheme 3.16.

o O 1) nBuLi, THF, -78 C O NaI, acetone O Cl I 2) 1-bromo-3-chloropropane 24 h, 25 oC 184 87 % 185 19 % 186

R2 o O 1) t-BuLi, Et2O, -78 C I O R2 R1 2) 187a-c, 78 % OH H 186 188a-c R1 O R2 R2 187a: R = R = H Swern oxidation 1 2 O O 187b: R1 = Me, R2 = H R1 R1 73 % 187c: R1 = H, R2 = Me OH O 188a-c 182e-g Scheme 3.16

With IMDAF precursors 182e-g synthesized, the IMDAF reaction was conducted using RAlBr2 Lewis acid 99 (R = hexyl). The first reactions were tested using IMDAF precursor 182g, and then expanded to include IMDAF precursors 182e and 182f. These results are outlined below in Table 3.17. The first efforts to repeat the results reported by

Rogers and Keay were in toluene, for the reasons previously described. Unfortunately, in toluene the reaction did not proceed, with 182:183 ratios of 100:0 (entries 1 and 2).

Interestingly, at room temperature in toluene, the only reaction that took place was a 1,4- addition which produced adduct 189 in a 1:9 ratio with starting material 182g.

126

Table 3.17 RAlBr2-promoted IMDAF reaction using precursors 182e-g R 2 LA R1 O R3 O O R1 O R2 O Br R3 O 189 182e: R2 = R3 = H, R1 = Me 183e: R2 = R3 = H, R1 = Me 182f: R3 = H, R1 = R2 = Me 183f: R3 = H, R1 = R2 = Me 182g: R2 = H, R1 = R3 = Me 183g: R2 = H, R1 = R3 = Me Entry IMDAF precursor LA Conditions 182:183 ratioa 1 182g 0.1 eq. 99 toluene, -65 ºC, 2h 100:0 2 182g 0.1 eq. 99 toluene, 25 ºC, 24 h 100:0 3 182g 0.1 eq. MeAlCl2 DCM, -65 ºC, 2h 69:31 4 182g 0.1 eq. 99 DCM, -65 ºC, 2h 36:64 5 182g 0.3 eq. 99 DCM, -65 ºC, 2h 73:27 6 182e 0.1 eq. 99 DCM, -78 ºC, 1h 0:100 7 182f 0.1 eq. 99 DCM, -65 ºC, 1h 24:76 8 182f 0.1 eq. 99 DCM, -78 ºC, 2h 11:89 aRatios determined by 300 MHz 1H NMR spectroscopy.

The IMDAF reaction with 182g worked in DCM at -65 ºC using both MeAlCl2 and RAlBr2 LA 99. Interestingly, when tested, the reaction actually proceeded in greater conversion using LA 99 as catalyst (entry 4) than it did using MeAlCl2 as catalyst (entry

3). When 0.3 equivalents of 99 was used to promote the reaction with 182g the conversion to products was significantly worse than it was with 0.1 equivalents (entry 5), consistent with what Rogers and Keay had previously observed.58 The reaction with 182g proved to be the most sluggish, proceeding only to 64 % over 2 hours at -65 ºC. The

IMDAF reactions with both 182e and 182f proceeded much more rapidly; 182e proceeded to 100 % conversion over 1 hour at -78 ºC, while 182f proceeded to 89 % conversion over 2 hours at -78 ºC.

Having repeated the results previously observed by Rogers and Keay, and having found conditions to repeat the reaction in good conversion, the IMDAF reaction was

127

ready to be studied using chiral R*AlBr2 Lewis acids. Significantly, this reaction proceeded at catalytic delivery of RAlBr2. As stated above, the investigations using chiral

R*AlBr2 Lewis acids will be outlined in chapter 4.

3.5.4 The RAlBr2-Promoted Strecker Reaction

Having developed a Diels-Alder reaction proceeding in high conversion at 3.5 equivalents of RAlBr2, and an IMDAF reaction proceeding in high conversion at 0.1 equivalents of RAlBr2, an additional organic reaction was desired that could proceed at about 1.0 equivalent of RAlBr2, and possibly be amenable to proceeding catalytically.

Having covered several interesting Strecker reactions in chapter 1, a simple Strecker reaction was chosen as a model system.

Having observed RAlBr2 Lewis acids promote numerous bromination reactions along with a debenzylation reaction, however, the imine chosen to model the RAlBr2- promoted Strecker reaction was a simple one without acidic protons that could be deprotonated or protecting groups that could be removed. The model system chosen along with its synthesis is highlighted below in Scheme 3.17. A Strecker reaction

59 between TMSCN and imine 192 has been reported in the literature, catalyzed by RhI3.

O NH2 toluene H N + reflux, 5h 190 191 81 % 192 Scheme 3.17

128

Imine 192 was dissolved along with TMSCN in DCM and RAlBr2 Lewis acid 99

(R = hexyl) was used to promote the reaction. A number of reaction conditions were tested to find the optimal reactivity at the lowest possible temperature, with the results shown below in Table 3.18. Just as with the IMDAF reaction, the Strecker reaction was initially tested in toluene. Interestingly, the Strecker reaction did not proceed at all using this solvent, and benzaldehyde peaks reappeared in toluene but did not reappear in DCM.

Thus, with DCM already being used as a low temperature solvent for the IMDAF reaction, it was chosen as the solvent to study the Strecker reaction as well. As this reaction would eventually be promoted with chiral R*AlBr2 Lewis acids, the lowest possible temperature was desired. It was thus tested over 24 hours at -25 ºC, and was found to proceed to 99 % conversion under those conditions (entry 3). The temperature was decreased to -78 ºC, and went to 94 % conversion within 2 hours (entry 4).

Additionally, the reaction was conducted without Lewis acid at room temperature to determine whether it would proceed, and was found not to proceed (entry 5).

Table 3.18 RAlBr2-promoted Strecker reaction of imine 192 99, TMSCN CN N N H

192 193 Entry Eq. 99 Conditions Conversion (%)a 1 2 toluene, -25 ºC, 24 hours NR 2 1 toluene, -25 ºC, 24 hours NR 3 1 DCM, -25 ºC, 24 hours 99 4 1 DCM, -78 ºC, 2 hours 94 5 0 DCM, 25 ºC, 2 hours 0 aConversion to products determined by NMR spectroscopy.

129

Thus, having discovered conditions for an RAlBr2-promoted Strecker reaction using 1.0 eq. of Lewis acid, the possibility of an enantioselective R*AlBr2-promoted

Strecker reaction using chiral R*AlBr2 Lewis acids was on the horizon. As stated previously, these experiments will be described in chapter 4.

3.6 Conclusions

Numerous reactions were tested using a variety of conditions, and results were optimized sufficiently among three successful organic reactions to justify using them as model systems for enantioselective reactions using chiral R*AlBr2 Lewis acids. The first reaction optimized was the Diels-Alder reaction between achiral oxazolidinone- substituted dienophile 153a and diene 96, obtaining complete conversion to Diels-Alder adduct in toluene at -20 ºC, with a 5.3 endo:exo ratio.

In addition, a binding mechanism was proposed for the binding of RAlBr2-type

Lewis acids to this type of dienophile. The proposed binding model was consistent with the binding model previously proposed by Evans, but with some minor variations accounting for a number of experimental observations using RAlBr2-type Lewis acids.

The second reaction optimized was the IMDAF reaction previously reported by

Rogers and Keay, and this reaction required only 0.1 equivalents of Lewis acid, allowing the study of RAlBr2 as a catalyst in a true catalytic reaction. IMDAF adducts 183e-g could be obtained with up to 100 % conversion in DCM at -78 ºC. Finally, the third reaction optimized was the Strecker reaction using TMSCN and simple imine 192. This

130

reaction was optimized at 1.0 equivalent of RAlBr2 Lewis acid in DCM at -78 ºC, and could generate Strecker adduct 193 in up to 94 % conversion.

131

CHAPTER FOUR: SYNTHESIS OF NOVEL CAMPHOR-BASED OLEFINS FOR THE HYDROALUMINATION OF NOVEL CHIRAL RALBR2-TYPE LEWIS ACIDS

4.1 Introduction

Three model reactions had been optimized to this point, including a Diels-Alder reaction between oxazolidinone-substituted crotonyl dienophiles, an IMDAF reaction, and a Strecker reaction. The optimum quantitiy of Lewis acid used to promote these reactions included 3.5, 0.1, and 1.0 equivalents respectively. Having completed a thorough survey of the performance of three achiral RAlBr2-type Lewis acids, 86, 99, and

125, several additional chiral R*AlBr2-type Lewis acids were synthesized and tested.

These investigations started with inexpensive commercially available olefins including

(+)-camphene, (1R)-(+)--pinene, and (1S)-(-)--pinene, as well as (1R)-(+)-β-pinene. A thorough investigation of double diastereoselectivity is reported herein using chiral oxazolidinone-substituted dienophiles 134a-d in conjunction with these chiral R*AlBr2- type Lewis acids.

Several novel chiral camphor-based olefin derivatives were synthesized using multi-step synthetic procedures, and these were hydroaluminated to their corresponding chiral R*AlBr2-type Lewis acid structures. These chiral Lewis acids were used to investigate the possibility of enantioselective reactions using the three optimized organic reactions noted above.

132

4.2 The use of simple commercially available chiral olefins

The most desirable outcome of this chemistry was that the elimination of heteroatoms bound to the aluminum atom would improve chiral induction, since the asymmetric center(s) would be closer to the aluminum atom in some cases. It was therefore reasonable to believe that even simple commercially available olefins may be capable of effecting such chiral induction in organic reactions following hydroalumination. The most attractive possibility was that inexpensive chiral olefins such as -pinene or camphene could be hydroaluminated, with the resulting Lewis acids being capable of promoting organic reactions asymmetrically.

4.2.1 Synthesis of chiral R*AlBr2 Lewis acids from simple commercially available chiral olefins

The synthesis of chiral R*AlBr2 Lewis acid 87 based on chiral olefin 82 was described previously (Scheme 2.4). The additional synthesis of three new chiral R*AlBr2- type Lewis acids was attempted, based on the hydroalumination of commercially available olefins 83, 194, and 195 (Scheme 4.1).

LiAlH4 LiAlH4 AlBr2 AlBr3 AlBr3 benzene benzene 1h, rt 1h, rt AlBr2 194 82 87 196 LiAlH Br Al LiAlH4 4 2 AlBr AlBr3 3

benzene benzene Br2Al 1h, rt 1h, rt 83 88 195 197 Scheme 4.1

133

Unfortunately, the hydroalumination of (1R)-β-pinene (195) did not proceed satisfactorily. The reason for this is unclear, but as satisfactory 1H NMR spectra for the hydroaluminated Lewis acid were not obtained, efforts to produce Lewis acid 197 were discontinued, and this particular Lewis acid was not tested in any asymmetric reactions.

Both enantiomers of -pinene were successfully hydroaluminated to produce chiral

R*AlBr2 Lewis acids 88 and 196 in addition to Lewis acid 87, that had previously been synthesized (Scheme 2.4). The successful synthesis of these simple Lewis acids illustrated that chiral R*AlBr2 Lewis acids could be obtained with the same ease as achiral ones. Adducts 87, 88, and 196 were the first chiral R*AlBr2 Lewis acids tested.

4.2.2 Diels-Alder Reactions between chiral oxazolidinone dienophiles 134a-d and chiral R*AlBr2 Lewis acids 87, 88, 196.

The Diels-Alder reaction between chiral oxazolidinone dienophiles 134a-d and diene 96 had previously been promoted by achiral RAlBr2 Lewis acids under a variety of conditions. One element of these reactions that left room for improvement was the diastereoselectivity between two different endo adducts, as well as an exo adduct.

Additionally, as previously mentioned, the ratio between adducts endo I and endo II reflect the enantioselectivity of the Diels-Alder reaction once the chiral auxiliaries are removed. Thus, optimizing the diastereoselectivity between these three adducts was of great interest.

It was thought that this diastereoselection could be augmented by the use of chiral

R*AlBr2-type Lewis acids, as there may be a synergistic effect between the chiral

134

oxazolidinone auxiliary and the chiral Lewis acid. Thus a series of experiments were set up to determine whether this would indeed be the case. The first studies conducted in this manner explored the Diels-Alder reaction between 134a and 96 as a model system, promoted by chiral R*AlBr2 Lewis acid 196. The results of this initial survey are outlined below in Table 4.1.

Table 4.1 Double diastereoselection using chiral dienophiles 134a-d and chiral R*AlBr2 Lewis acids O O O O O O O O

O N 196 O N O N O N + toluene o 96 25 C 2.5 hours

134a 135a endo I 135a endo II 135a exo I (absolute configuration unknown) Entry Eq. LA Conversion (%)a ddd (%)a Σendo/Σexoa endo I/endo IIa 1c 3.5 46 18 4 3.3 2 3.5 67 7 4 3.3 3 1.4 24 0 0.2 only endo I 4d 1.4 21 0 0.6 4 5e 1.4 25 0 0.5 3.3 aConversion to products and endo:exo ratios measured by 1H NMR spectroscopy. bAbsolute configuration of exo adduct unknown. c24 h reaction time. dDCM. echlorobenzene.

The conversion to products was very poor over 24 hours at 25 ºC (entry 1), but it was determined that the conversion could be improved significantly if the reaction was conducted over 2.5 hours (entry 2). Disappointingly, both Σendo/Σexo and endo I/endo II ratios were very similar to the results obtained using achiral RAlBr2 Lewis acids 86 (R =

135

cyclohexyl) and 99 (R = hexyl) to promote the same Diels-Alder reaction, with only minor changes in the overall diastereoselectivity.

Interestingly, a very clear doublet of doublet of doublets was observed at exactly

4.3 ppm forming in 7 % over 2.5 hours (Table 4.1, entry 2), and increasing to 18 % over

24 hours (entry 2). It is likely that this peak represents the opposite regioisomer 136 described previously in chapter 3.2.2 (scheme 3.3), although the small quantities formed could not be isolated for characterization. It is possible this peak is forming in small amounts due to the fact that Lewis acid 196 is considerably bulkier than those previously tested. The data above indicates a degradation of products over time, indicating that 2.5 hours is a more suitable reaction time than 24 hours. The results also clearly indicate that

3.5 equivalents of LA 196 results in superior performance to 1.4 equivalents.

Additionally, the same inversion of diastereoselectivity between 1.4 and 3.5 equivalents of Lewis acid previously observed with achiral Lewis acids was also observed with

Lewis acid 196.

Chiral R*AlBr2 Lewis acids 87, 88, and 196 were all hydroaluminated and tested in the Diels-Alder reaction between chiral oxazolidinone-based dienophiles 134a-d.

Hydroalumination of both enantiomers of -pinene was crucial, as double diastereoselection would imply that each enantiomer of -pinene might yield different results in conjuction with chiral dienophiles of a single enantiosense. The results of this complete survey on double diastereoselection are outlined below in Table 4.2.

Secondary R*AlBr2 -pinene-based Lewis acids 88 and 196 performed the worst under the conditions tested, although they demonstrated a marked improvement in conversion in comparison to the trials previously conducted over 24 hours. What is 136

immediately apparent is that the diastereoselectivity for these two R*AlBr2 Lewis acids among all four dienophiles is poorer than those results previously obtained using any of the achiral RAlBr2 Lewis acids 86, 99, and 125 (Tables 3.6 and 3.8). Interestingly, the difference in conversion between the two -pinene-based Lewis acids is minimal, but there are some significant differences in Σendo/Σexo ratios between these two Lewis acids; Lewis acid 196, based on the S enantiomer of -pinene, produced superior

Σendo/Σexo ratios for all four dienophiles 134a-d tested in comparison to Lewis acid 88, which is based on the R enantiomer of -pinene. This is a very promising result, because it is consistent with double diastereoselectivity and asymmetric induction.

Table 4.2 Diels-Alder reaction between 134a and 96 using chiral R*AlBr2 Lewis acids O O O O O O O O 1.4 eq. O N O N O N O N + LA R toluene R R R o 134a-d 96 25 C 135a-d endo I 135a-d endo II 135a-d exo I (absolute 2.5 hours configuration unknown) Entry Dienophile LA Conversion (%)a Σendo/Σexoa endo I/endo IIa 1 134a 87 85 2.6 4 2 134a 88 58 1.7 4 3 134a 196 50 2 4 4 134b 87 91 4 unknownc 5 134b 88 76 1.8 unknownc 6 134b 196 66 2 unknownc 7 134c 87 85 5 1.1 8 134c 88 64 2 1 9 134c 196 61 4 1 10 134d 87 92 3 3 11 134d 88 65 1.7 3 12 134d 196 68 2.8 3 aConversion to products and endo:exo ratios measured by 1H NMR spectroscopy. bAbsolute configuration of exo adduct unknown.

137

Lewis acid 87 provided the best results for all four of the dienophiles tested, with superior conversions, as well as superior Σendo/Σexo ratios. Interestingly, chiral Lewis acid 87 showed no improvement on the endo I/endo II ratios for any of the four dienophiles when compared with Lewis acids 88 or 196, with each dienophile yielding identical endo I/endo II ratios for each of the three Lewis acids tested. It is not clear why primary Lewis acid 87 provides superior diastereoselection when compared to secondary

Lewis acids 88 or 196, or why these two secondary Lewis acids yield such poor diastereoselection in general, but it is consistent with previous observations that the chiral

R group attached to the aluminum atom plays a role in the stereochemical outcome of the reaction.

The double diastereoselection observed is interesting, but as the ultimate goal of this chemistry was enantioselective synthesis, efforts to combine chiral auxiliaries with chiral catalysts were henceforth terminated. From this point onward, only prochiral starting materials were tested in conjuction with chiral Lewis acids.

4.2.3 Using simple chiral R*AlBr2 Lewis acids 87 and 88 to promote organic reactions reactions enantioselectively

Simple chiral R*AlBr2 Lewis acids 87 and 88 were prepared and used to promote the enantioselective Diels-Alder reaction between prochiral 153a and 96. It should be pointed out that hydroaluminating both enantiomers of -pinene was no longer necessary, as both enantiomers would perform identically in promoting the Diels-Alder reaction using prochiral reagents. Enantioselectivity was determined with the use of a chiral HPLC. Numerous conditions were tested but the two enantiomers of the major

138

endo adduct were eventually separated using a chiralcel AD column, with a 0.04 mL/minute flow rate of a 50 % mixture of hexanes and iPrOH. The two enantiomers were found to elute at 121.2 and 128.0 minutes. One challenge with this method of determining enantioselectivity was that not only do the two enantiomers of the endo adduct elute very close to one another, but the minor exo adduct overlaps with one of the enantiomers of the endo adduct. It is therefore necessary to separate the endo diastereomer from the exo diastereomer via column chromatography prior to HPLC analysis. The results of the Diels-Alder reaction described above are outlined below in

Table 4.3.

Table 4.3: The Diels-Alder reaction of 153a and 96 using simple chiral R*AlBr2-type Lewis acids

Br2Al

AlBr2 87 88

O O O O O O LA O N + O N O N toluene, -25 oC 24 hours 153a 96 154a endo I 154a exo I Entry LA Conversion (%)a endo/exoa eeb 1 1.4 eq. 87 56 2.3 racemic 2 3.5 eq. 87 83 5 racemic 3 1.4 eq. 88 13 1.6 NA 4 3.5 eq. 88 85 3 racemic 5c 3.5 eq. 87 84 5 racemic 6c 3.5 eq. 88 75 3 racemic 7 5.0 eq. 87 95 5.6 racemic 8d 3.5 eq. 87 87 3 racemic aConversion to products and endo:exo ratios measured by 1H NMR spectroscopy. bMeasured using chiralcel AD column on HPLC. cReaction conducted over 24 hours at 0 ºC. dReaction conducted in DCM.

139

The most obvious result is that Lewis acids 87 and 88 did not promote the Diels-

Alder reaction between 153a and 96 enantioselectively, as HPLC analysis revealed both enantiomers forming in equal quantities. Lewis acid 87 nevertheless provided better results than 88, exactly as it did in the survey using chiral dienophiles. The Diels-Alder reaction was also attempted at 1.4 equivalents of chiral R*AlBr2, but the results obtained were poorer, with less endo adduct being formed with no enantioselection. Interestingly,

5.0 equivalents of Lewis acid 87 was attempted in this reaction, and provided not only the best conversion, but also the best endo/exo selectivity. Unfortunately, the products were formed as racemic mixtures.

The IMDAF reaction described previously was also used to test the efficacy of

Lewis acid 87 to promote reactions enantioselectively. Unfortunately, all efforts to resolve the enantiomers 183e and 183g failed despite numerous conditions being tested on two chiral HPLC columns, chiralcel OD and chiralcel AD, as well as on a chiral GC.

The two enantiomers of IMDAF adduct 183f, however, were ultimately resolved using a chiralcel OD column, with a 0.17 mL/minute flow rate of a 1:16 iPrOH:hexanes solvent mixture. The two enantiomers of 183f eluted at 37.69 and 39.72 minutes. The results from the reactions of IMDAF precursors 182e-g with R*AlBr2 Lewis acid 87 are shown below in Table 4.4.

Due to the fact that only 183f could be resolved by chiral HPLC, this was the

IMDAF adduct chosen to model the asymmetric R*AlBr2-promoted IMDAF reaction hereafter. Unfortunately, although Lewis acid 87 promoted the IMDAF reaction of 182f to 100 % completion, with a 79 % yield isolated off a column, the product was completely racemic, with exactly 50 % of each enantiomer by chiral HPLC.

140

Table 4.4: IMDAF reaction using chiral R*AlBr2 Lewis acid 87 as catalyst

R2 0.1 eq. 87 R O R O 1 3 o 2h, -78 C R1 O R2 DCM R3 O AlBr2 87 182e: R2 = R3 = H, R1 = Me 183e: R2 = R3 = H, R1 = Me 182f: R3 = H, R1 = R2 = Me 183f: R3 = H, R1 = R2 = Me 182g: R2 = H, R1 = R3 = Me 183g: R2 = H, R1 = R3 = Me Entry IMDAF precursor Conversion (%)a Yieldb ee (%)c 1 182e 100 83 Not determined 2 182f 100 79 0 3 128g 46 39 Not determined aConversion to products measured by 1H NMR spectroscopy. bIsolated yields. cMeasured using chiralcel OD column on HPLC.

Finally, the asymmetric Strecker reaction described in chapter 3 was tested with

Lewis acid 87. It was possible to resolve the enantiomers of Strecker adduct 193 very easily via chiral HPLC, using a chiralcel OD column with a 0.2 mL/min flow rate of a 50

% solvent mixture of iPrOH and hexanes. This method yielded exceptional resolution of the enantiomers of 193. A number of different reaction conditions were tested in order to obtain enantioenriched Strecker adduct from the reaction with Lewis acid 87, unfortunately the best result obtained was only a 4 % ee (table 4.5).

Table 4.5: Strecker reaction using chiral RAlBr2 Lewis acid 87 87, TMSCN CN N N DCM H

192 193 Entry Conditions Yield (%)a ee (%)b 1 25 ºC, 2 hours 44 % racemic 2 -25 ºC, 24 hours 88 % racemic 3 -78 ºC, 2 hours 94 % 4 % aIsolated yields. bMeasured using chiralcel OD column on HPLC.

141

In summary, between the three reactions optimized in chapter 3, the simple chiral

Lewis acid 87, based on (+)-camphene, was found to promote the Strecker reaction between 192 and TMSCN in only 4 % ee over 2 hours at -78 ºC (entry 3). Lewis acid 87 promoted the IMDAF reaction of 182f in good yield, but did not effect any measurable amount of enantioselection. Finally, the Diels-Alder reaction between 153a and 96 was promoted by both Lewis acids 87 and 88 in good yield, but all product mixtures were found to be racemic. Thus, a second generation of more sterically encumbered chiral

R*AlBr2 structures was targeted.

4.3 Synthesis of more complex chiral olefin derivatives using camphor as a chiral template

Several chiral olefin derivatives of camphor were proposed, with the rationale behind this concept demonstrated below in scheme 4.2.

R 3 R3 4

O 2 R2 R1 1 198 199a 199b 199c 199d Scheme 4.2

The use of (1R)-(+)-camphor (198) as a chiral template to develop this chemistry is attractive for several reasons. For one thing it is abundant and inexpensive, costing

0.47 cents per gram (CDN) at the time of this writing. Secondly, the ketone can easily be converted into an exocyclic double bond, via Wittig-type chemistry. The third reason is

142

that the two bridgehead methyl groups can be relied on to help direct the diastereoselectivity of the hydroalumination reaction, so that multiple diastereomeric

R*AlBr2 species are not active in solution. Finally, camphor offers multiple positions to substitute with bulky groups. Positions 1-4 are of particular interest due to their proximity to the carbonyl group (scheme 4.2). The type of adducts that were thus targeted are 199a-

199d where the first R group targeted for these structures was a phenyl group. It may even be possible to add multiple groups to the camphor skeleton at different locations, to create a highly chiral environment.

4.3.1 Synthesis of (1R)-1,7,7-Trimethyl-2-methylene-bicyclo[2.2.1]heptane (200) and its corresponding hydroalumination product 201

The simplest chiral olefin derivative of (1R)-(+)-camphor (198), is simply olefin

200, which is the compound obtained via a Wittig reaction. This was a very simple procedure, conducted over 24 hours at room temperature, and olefin 200 could be very simply isolated from the crude mixture simply by using neat hexanes as the chromatography solvent. The synthesis of olefin 200, along with its hydroalumination to form Lewis acid 201 is shown below in scheme 4.3.

1) PPh3MeBr LiAlH o 4 nBuLi, 0 C, 1h AlBr3 H+ + benzene O 2) 24 hours o o AlBr 25 C, 75 % 0 C, 2h 2 endo-202 exo-202 198 200 201 Scheme 4.3

143

Olefin 200 was hydroaluminated to Lewis acid 201 over 1 hour at room temperature, as previously described. The diastereoselectivity of this reaction was determined by H+ quenching Lewis acid 201 and integrating the peaks for the two diastereomers by GC-LRMS. At room temperature, the diastereoselectivity of the hydroalumination was determined to be a problem, proceeding in only a 3.3:1 ratio in favor of the endo hydroalumination product (202). The diastereofacial selectivity yields the endo isomer in the majority, confirmed by comparing the 13C NMR peaks of 202 to

60 known literature values. Approach of the HAlBr2 hydroalumination reagent from the exo face pushes the methylene group downwards, producing the endo Lewis acid as the dominant species in solution.

In order to improve the diastereoselectivity of this hydroalumination reaction, it was conducted at 0 ºC. Even at 0 ºC, the hydroalumination reaction was complete within

2 hours, likely due to the fact that the olefin contains a highly strained ring system.

Whatever the explanation for the rapidity of this particular hydroalumination reaction, at

0 ºC the diastereoselectivity was found to have improved to 10:1. The 1H NMR spectrum for olefin 200 and the in situ 1H NMR spectrum for Lewis acid 201 are both shown below in figure 4.1. As can be seen, the hydroalumination reaction goes to completion within 2 hours, with complete consumption of the olefin, along with the appearance of two doublet of doublets at 0.5 ppm. The in situ spectrum of 201 has some toluene peaks, because the Lewis acid was redissolved in toluene before being used. Nevertheless, spectrum 2 reveals a single product forming in the majority. The H+ quenched product

202 was also isolated and characterized. With the formation of 201 confirmed, the synthesis of other chiral olefins was continued.

144

1 Spectrum 1: H NMR spectrum of 200 in d6-benzene

1 Spectrum 2: H NMR spectrum of 201 in d6-benzene

1 Figure 4.1: H NMR spectra of olefin 200, and RAlBr2 Lewis acid 201

4.3.2 Synthesis of (1R)-1-Benzyl-7,7-dimethyl-2-methylene-bicyclo[2.2.1]heptane (203) and its corresponding hydroalumination product 204

The next chiral olefin targeted for synthesis was 203, as Lewis acid 204 has an interesting chiral structure that may provide improved chiral induction in organic reactions due to the presence of an adjacent benzyl group (scheme 4.4). The synthetic strategy was to purchase commercially available (1R)-(+)-camphor derivative, (1S)-(+)- camphorsulfonic acid (207), and transform it to the target compound 203. The initial strategy was to first transform the sulfonic acid moiety into the corresponding alkyl iodide, transform the ketone to the exocyclic double bond using the Wittig procedure described above, and then install the phenyl group using commercial phenylmagnesium bromide (Scheme 4.4).

145

LiAlH4, AlBr3 H

benzene, 1h AlBr2 0 oC

203 204 retrosynthetic analysis

O O I I SO3H 205 206 207 203 Scheme 4.4

The first step in this sequence was an iodination conducted by refluxing triphenyl

61 phosphine and I2 in toluene along with sulfonic acid 207 for 18 hours. This reaction worked exceptionally well, in almost quantitative yield (Scheme 4.5). The second step in the sequence was to transform the carbonyl group into the exocyclic double bond. Both a

Wittig olefination as well as a Peterson olefination were attempted, and neither resulted in the desired product (Scheme 4.5). Both produced a complex mixture of products as indicated in their 1H NMR spectra. It was not immediately clear why these reactions did not work, as the Wittig reaction of unsubstituted camphor proceeded readily. It was thought that the answer must lie with the iodine atom as it was the only difference between 206 and 198. The iodine atom is very large, but steric effects of the iodine atom preventing these reactions from proceeding seemed unlikely, so these failures were initially puzzling.

146

PPh3, I2, toluene toluene, 18 hours O 90 % O SO3H I 207 206

MePPh3Br o nBuLi, 0 C Mg, ClCH2Si(CH3)3

O 24 hours, 25 o C O diethyl ether I I I I 206 205 206 205 Scheme 4.5

β-keto halides have long been known to undergo Grob fragmentation, and a Grob fragmentation is known on β-keto halide 206.61 If a Grob fragmentation was occurring in this case with the Wittig reaction, it meant that intermediate 208, forming in situ, was fragmenting to form β-keto phosphine 209. Due to the β-keto group, this intermediate

209 is unstable and appears to have collapsed under workup conditions to form 210.

Ketone 210 was isolated following column purification of the crude mixture (Scheme

4.6).

O PPh3Br I O O PPh3Br 208 209 210 Scheme 4.6

Although this process is not synthetically useful, it confirmed the reason for the failure of Wittig chemistry, and likely that of Peterson olefination chemistry as well. It

147

indicated that it would likely not be possible to carry out the olefination step of the synthesis with the iodine atom present. Thus the next efforts to synthesize olefin 203 were to carry out substitution of the iodine atom. In order to use a Grignard reagent, however, the ketone would require protection. Due to the Grob fragmentation described above, it was thought that a protection sequence carried out in acidic conditions would inhibit any Grob fragmentation taking place. An appropriate procedure was found using ethylene glycol and PTSA in benzene.62 This process is shown below in scheme 4.7.

OH(CH2)2OH

PTSA O + O benzene O O I reflux I I 206 211 206 Scheme 4.7

Although 1H NMR spectroscopy confirmed the formation of 211, this reaction did not go to completion within 6 hours, going only to 20 % completion by NMR analysis. In addition, attempts to purify the protected adduct were met with failure, because the ketal collapsed to reform the ketone upon coming in contact with the silica gel. Ultimately, the failure to obtain a completely pure adduct 211 was due to the reaction not going to completion. An analogue of this reaction was conducted using trimethylorthoformate as well, but the results of this reaction were even poorer, with only starting materials remaining. Substitution of the iodine was therefore attempted by simply reacting phenylmagnesium bromide with a mixture of 211 and 206. It was thought that both 212 and 214 would form, and upon workup 212 would collapse to form 213, which would be

148

easy to separate from 214 (scheme 4.8). These attempts resulted in failure, with no apparent formation of either 212 or 214.

+ PhMgBr H3O + O O Et O, reflux O + O O 2 O OH I I I 206 211 214

212 213 Scheme 4.8

With all efforts to protect ketone 206 having been met by failure, another strategy was considered to access olefin 203. Alkyl iodide 206 is an extremely hindered neopentyl iodide, and substitution may not even be possible. Thus a procedure for a nickel- catalyzed coupling of Grignard reagents with neopentyl iodides was found and attempted.63 Although this paper reported high product yields, it did not test systems with carbonyl groups present. Thus, the coupling reaction was conducted by adding PhMgBr via syringe pump into a mixture of 206 and Ni(dppf)2Cl2 in refluxing diethyl ether over 1 hour. The syringe pump was employed to keep the concentration of PhMgBr relative to

206 low over the course of the reaction. Interestingly, ketone 213 was obtained as desired in 90 % yield (scheme 4.9) without the need to protect the ketone. With intermediate 213 in hand, the final step was olefination of 213.

A Wittig reaction was attempted on 213, but failed, yielding only unreacted starting materials. Ketone 213 was therefore considered too sterically hindered for a

Wittig reaction to be carried out. In order to circumvent this problem, a smaller reagent was chosen. A paper was found outlining a procedure to create a tertiary alcohol on

149

camphor derivatives by adding Grignard reagents and then eliminating them.64 Thus a solution of MeMgBr was obtained commercially and added to a refluxing mixture of 213 in Et2O. This reaction worked, although due to the steric hindrance around the ketone, it went only to 50 % completion using 5 equivalents of MeMgBr after refluxing for a full week (Scheme 4.9). Although this may seem like an undesirable result, it was actually very promising. The steric bulk around the carbonyl group meant that it would be reasonable to expect Lewis acid 204 to effect some degree of chiral induction. The final result was a simple elimination, using catalytic SOCl2 in pyridine over 30 minutes. By

NMR analysis, adduct 203 was formed in good yield, but due to its lack of any polar groups, purification was very difficult. Pure 203 was finally obtained in only 10 % yield off a column, but in sufficient quantities to provide plenty of chiral R*AlBr2 Lewis acid for promoting the three reactions under study.

Ni(dppf) Cl 2 2 MeMgBr SOCl2 OH o PhMgBr Et2O, reflux pyridine, 0 C O Et2O, reflux O 1 week 30 minutes I 24 hours 50 % 10 % 206 90 %

213 215 203 Scheme 4.9

Hydroalumination of olefin 203 was conducted at 0 ºC, and the olefin was completely consumed within 2 hours (Figure 4.2). The consumption of olefin 203 and the formation of Lewis acid 204 could be monitored by 1H NMR spectroscopy, as shown below (figure 4.2). The loss of olefin peaks was accompanied by the appearance of an

ABq at 2.5 ppm corresponding to the methylene group next to the phenyl ring. In addition, the appearance of two upfield doublet of doublets was observed, confirming the 150

formation of 204 in situ. Prominent toluene peaks appear on the 1H NMR spectrum due to the Lewis acid being dissolved in toluene prior to use. In addition, Lewis acid 204 was quenched with H+ to reveal a remarkably pure 1H NMR spectrum containing two diastereomers of hydrocarbon 216, in a 6:1 ratio, further confirming the formation of 204 in situ.

LiAlH4 + AlBr3 H H H benzene H AlBr 0 oC, 2h 2

203 204 endo-216 exo-216 Spectrum 1: 1H NMR of olefin 203

1 Spectrum 2: H NMR of R*AlBr2 adduct 204

Spectrum 3: 1H NMR of H+ worked up 216

1 Figure 4.2: H NMR spectra of olefin 203, and R*AlBr2 Lewis acid 204

151

Thus, having successfully completed a synthesis of olefin 203 and successfully hydroaluminating that olefin to the corresponding Lewis acid 204, the synthesis of other chiral olefins was continued.

4.3.3 Synthesis of (1R)-7-Benzyl-1,7-dimethyl-2-methylene-bicyclo[2.2.1]heptane (217) and its corresponding hydroalumination product 218

The next chiral olefin synthesized was 217 for the corresponding Lewis acid 218

(Scheme 4.10), but it was not actually the original target molecule. A paper was found outlining a procedure to iodinate alpha to a double bond.65 This procedure seemed attractive as there is only one such position on olefin 200. It was hoped that an iodine atom could be installed alpha to the double bond, to generate 219 (scheme 4.10). The goal was actually to provide a leaving group for substitution at that position.

Unexpectedly, the only iodination product following iodination using I2 in DMA on the crude 1H NMR spectrum was actually determined to be olefin 220 (scheme 4.10).

I I2, DMA I I2, DMA 15 minutes 15 minutes 25 oC 25 oC 200 219 200 63 % 220

I LiAlH4 Ni(dppf)2Cl2 AlBr3 H3O

PhMgBr, Et2O benzene o AlBr2 30 C, 24 hours 0 oC 220 30 % 217 218 221 Scheme 4.10

152

Compound 219 was not found in any quantities. Compound 220 was the dominant product, and although the crude product spectrum was reasonably pure, perfect purification was very difficult due to the non-polar nature of the crude mixture.

Separation of these compounds resulted in some loss of product, with only 63 % isolated following column chromatography. With compound 220, the same nickel-catalyzed coupling based on the methodology previously discussed was an obvious choice. Thus a solution of PhMgBr was added to a mixture of refluxing 220 and Ni(dppf)2Cl2 in diethyl ether over 24 hours (Scheme 4.10). Target olefin 217 was obtained as the dominant product formed, but here again purification was difficult for the same reason as before, with only 30 % of pure compound being isolated following column chromatography in neat hexanes.

This olefin was of great interest, as due to the bulky benzyl group on the bridgehead above the olefin, the diastereoselection was presumed to favor the exo Lewis acid, rather than the previously obtained endo Lewis acid. The hydroalumination process was carried out at 0 ºC, just as before, in order to maximize the diastereoselectivity of the hydroalumination reaction. Olefin 217 was hydroaluminated as shown above in scheme

4.10 to afford a single diastereomer of 218. The reaction was monitored by 1H NMR spectroscopy, and had gone to completion within 2 hours, as before. The 1H NMR spectra of both olefin 217 as well as Lewis acid 218 are shown below in Figure 4.3. The disappearance of the olefin peaks was accompanied by the appearance of two doublets of doublets at 0.6 ppm. Lewis acid 218 was redissolved in toluene for use in promoting low temperature organic reactions, and thus was taken to the 1H NMR spectrometer as a solution in benzene-d6 containing small quantities of toluene. A single diastereomer of

153

hydrocarbon 221 could also be obtained following H+ work up of Lewis acid 218, confirming the formation of 218 in situ. The proposed exo stereochemistry of the product

Lewis acid 218 and hydrocarbon 221 are due to the phenyl group being positioned above the double bond in 217, preventing an exo face approach.

Spectrum 1: 1H NMR of olefin 217

1 Spectrum 2: H NMR of RAlBr2 adduct 218

1 Figure 4.3 H NMR spectra of olefin 217 and RAlBr2 Lewis acid 218

An interesting problem arose based on the 1H NMR spectrum for olefin 217. Due to the structure of olefin 200 containing three neopentyl methyl groups in close proximity, it was not possible to determine conclusively which methyl group was substituted with the phenyl group (scheme 4.11). Simple 1H NMR or 13C NMR analysis was not sufficient to differentiate olefin 217 from olefin 222. For that matter, the only reason the possibility of the unknown olefin being 203 was ruled out is that it was previously synthesized as described above, and both the 1H NMR and the 13C NMR spectra were thus known. The only effort remaining was therefore to confirm the product

154

olefin was 217 and not 222. This was important, as hydroaluminated R*AlBr2 Lewis acid

218 would have the installed phenyl group above the active Lewis acidic aluminum atom, in a position appropriate for chiral induction (scheme 4.11). Hydroaluminated R*AlBr2

Lewis acid 223, however, contains the phenyl group substituted on the opposite side of the molecule from the Lewis acidic aluminum atom, which would likely result in the endo diastereomer of Lewis acid forming upon hydroalumination of the olefin, and would make it unlikely that the phenyl group would significantly impact the chiral induction.

Hf 7 He He 6 3 Hd Hc 4 2 5 Hb 1 Ha 217 222 203

H AlBr2 218 AlBr2 223 Scheme 4.11

Thus, in order to confirm olefin 217 was formed and not olefin 222, a series of

2D-NMR experiments were conducted. The strategy was to determine which carbon signal in the 13C NMR spectrum corresponded to carbon 3, then to conclusively determine via 2D-HMQC, which proton signals in the 1H NMR spectrum corresponded

155

to protons Hc and Hd. The final step was to confirm a through-space interaction between one of these two protons and either of protons He and Hf.

A 2D-HMBC confirmed correlations between the vinyl Ha/Hb pair of protons and carbons 1, 2, 3, 4, 5, and 6. The next step was to determine which among these signals corresponded to carbon 3. In conjuction with 13C NMR and 135-Dept 13C NMR, carbons

4 and 6 were ruled out as quaternary carbons, while carbon 5 was clearly one of the methyl groups due to its chemical shift. With carbons 1 and 2 being vinyl carbons at

100.4 and 171.6 ppm, only carbon 3 at 43.4 ppm was left among those correlating to vinyl protons Ha and Hb. 135-Dept 13C NMR confirmed this carbon to be a methylene group (figure 4.4).

A 2-D HMQC confirmed that the carbon signal for C3 at 43.4 ppm correlated to the proton signals at 1.51 and 1.57 ppm. The proton signal at 1.51 was a doublet of doublets, as expected, while the proton signal at 1.57 was a doublet of doublet of doublets, with the smallest coupling constant being 1.7 Hz, consistent with 4J coupling to

Hb. Although 1H NMR, 13C NMR, and 135-DEPT 13C NMR, in conjunction with 2D-

HMBC and 2-D-HMQC was sufficient to label most carbons and protons in olefin 217, only the determination of Hc/Hd was desired, as a subsequent 2D-NOESY would likely confirm a through-space correlation either between He and Hd/Hc, or between Hf and

Hd/Hc, or between both. Through space proton-proton interactions were investigated by acquiring a 2D-NOESY spectrum. Both protons He were found to have through-space interactions with proton Hd but not proton Hc, consistent with the structure proposed above. In addition, protons He also correlated to protons Hf, Ha, and Hb, also consistent with the proposed olefin structure 217.

156

Hf 7 He He 6 3 Hd Hc 4 2 5 Hb 1 Ha 217 Spectrum 1: 1H NMR of 217

Spectrum 2: 1H NMR of 217, 0.5-2.0 ppm

Spectrum 3: 13C NMR of 217

Spectrum 4: 135-DEPT 13C NMR of 217

Figure 4.4: NMR experiments to confirm the structure of olefin 217

157

The possibility of the newly synthesized compound being undesired olefin 222 was thus ruled out. Having confirmed the desired olefin structure 217, along with confirming it could be hydroaluminated to affored a single diastereomer of Lewis acid in situ, efforts were directed to completing the synthesis of other chiral olefins.

4.3.4 Synthesis of (1R)-1,7,7-Trimethyl-2-phenyl-bicyclo[2.2.1]hept-2-ene (225) and its corresponding hydroalumination product 226

The next site targeted for substitution was the ketone of 198 itself. A procedure was obtained for the addition of phenyl MgBr to ketone 198, followed by elimination to afford the endocyclic double bond.64 The stereochemistry in alcohol 224 was confirmed by comparing NMR data to known values reported by Ruedi et. al., who conducted NOE experiments on this compound.66 This process is described below, along with the hydroalumination of olefin 225 to afford Lewis acid 226. Unfortunately, Lewis acid 226

1 13 was too reactive to obtain H NMR or C NMR spectra, as it was extremely O2 sensitive, and reacted with oxygen by the time it arrived at the NMR spectrometer.

Thus Lewis acid 226 was characterized indirectly. N2 gas was bubbled through a small amount of H2O, and this was poured into a solution of 226 in benzene and allowed to stir. As the only products on the crude 1H NMR spectrum were hydrocarbon 227 and small amounts of olefin 225, Lewis acid 226 was confirmed to form in situ. The stereochemistry of 227 is uncertain, but if the phenyl Grignard approached ketone 198 from the endo face, opposite the dimethyl bridgehead, it is reasonable to propose that the hydroaluminating reagent would approach the endocyclic double bond from this face as well.

158

PhMgBr SOCl2 LiAlH4, AlBr3 pyridine Et2O OH benzene o O reflux 0 C, 0.5 h 0 oC, 2h 24 h 52 % AlBr2 198 56 % 226

224 225

H+ Hb Hb Ph Ha Hc Hc AlBr2 Ha Ph 226 227 227b Scheme 4.12

Spectrum 1: 1H NMR of 225

Spectrum 2: 1H NMR of 227

1 Figure 4.5: H NMR spectra of olefin 225 and hydrocarbon 227 in benzene-d6

Hydrocarbon 227 was also purified and characterized to help support this stereochemical hypothesis. The 1H NMR spectra are shown above in figure 4.5. Proton

Ha in 227 (scheme 4.12) is a doublet of doublet of doublets, with coupling constants of

159

11.6 Hz, 5.4 Hz, and 2.5 Hz. The 11.6 Hz and 5.4 Hz coupling constants are consistent with the exo diastereomer proposed above, since Ha and Hb have a large dihedral angle in 227. In 227b, Ha should have small coupling constants to both Hb and Hc. The 2.5 Hz

4 coupling constant is likely due to JH-H coupling; the phenyl ring likely has a locked

4 conformation, resulting in JH-H coupling to one Ph proton, but not the other. With the formation of Lewis acid 226 confirmed, however, no more time was spent addressing this problem, as the in situ mixture would be used to promote the three reactions described above, whatever the stereoconfiguration of the in situ Lewis acid.

4.3.5 Synthesis of (1R)-2-Benzyl-1,7,7-trimethyl-bicyclo[2.2.1]hept-2-ene (229) and its corresponding hydroalumination product 230

The next olefin targeted was 229 (Scheme 4.13). This olefin was of great interest, as the hydroaluminated Lewis acid structure 230 has two contiguous stereogenic centers, with the AlBr2 moiety being directly bonded to one of them. Although an endocyclic double bond was possible, as with previously synthesized olefin 225, it was considered far more likely that the exocyclic double bond would form, as it was in conjugation with the phenyl group. With the proposed structure, two geometric isomers are possible, with olefin 231 being a possible result of the elimination step as well as the desired olefin 229

(scheme 4.13). It was hypothesized that 231 would not form due to the steric strain that would likely result between the phenyl group and the neighbouring methyl group, as shown below.

160

The synthesis of olefin 229 was conducted in exactly the same manner as that of

225, with the exception that benzyl MgBr was prepared in situ before being added into a mixture of 198 refluxing in Et2O. The intermediate alcohol 228 was eliminated in the same manner previously described, with catalytic SOCl2 in pyridine, to afford olefin 229.

Unfortunately, the isolated yield off of a column over these two steps was only 16.3 %.

Conversion by NMR spectroscopy was higher, but complete purification of the non polar olefin was very challenging. The synthesis of 229 and its anticipated hydroalumination product 230 is shown below in scheme 4.13.

BnMgBr SOCl2 pyridine Et2O OH o O reflux 0 C, 0.5 h 24 h 16.3 % 198 77 % 228 229 231

LiAlH4, AlBr3 H rt, 24 h Br Al 2 H 229 230 Scheme 4.13

Unfortunately, hydroalumination of olefin 229 did not proceed. The in situ 1H

NMR spectrum of 230 revealed the unexpected fact that the olefin was completely unreactive in the presence of hydroaluminating agent, with no reaction proceeding whatsoever even at 25 ºC over 24 hours. There are two likely reasons for this

161

observation. The first explanation for the lack of hydroalumination reaction is likely the steric bulk around the olefin. Gorobets’ original paper had reported that tri-substituted olefins would hydroaluminate,44 but no olefins as sterically hindered as 229 had been tested. The second explanation for the lack of hydroalumination in this case is the fact that the double bond in olefin 229 is conjugated with the neighbouring phenyl group, which likely stabilizes the double bond, thereby reducing its reactivity. It is likely a combination of these two factors which prevented the hydroalumination reaction from proceeding as anticipated.

4.3.6 Synthesis of (1R)-1,7,7-trimethyl-2-phenethylidene-bicyclo[2.2.1]heptane (234) and its corresponding hydroalumination product 235

The fact that olefin 229 did not hydroaluminate did not reduce the interest in having the aluminum atom directly bonded to a chiral carbon atom. Thus the next chiral olefin targeted was 234 (Scheme 4.14). The proposed synthesis of this compound was the same as that previously described. Olefin 234 would then be hydroaluminated to form

235 as shown below. Unfortunately, the Grignard procedure did not work, and the crude

1H NMR spectrum for the crude products of this reaction revealed only unreacted 198, as well as large quantities of styrene (236).

162

SOCl 232, Mg 2 Br OH pyridine Et2O o O reflux 0 C, 0.5 h 24 h 198 233 234 232

LiAlH4, AlBr3 benzene H 0o C Br Al 2 H 234 235 236 Scheme 4.14

Although the Grignard reaction did not work, Wittig chemistry had worked previously on ketone 198 in high yield. The synthesis of alkylphosphonium bromide 237 was thus attempted, as it was thought a simple Wittig procedure might yield olefin 234 in a single step (scheme 4.15). The proposed chemistry is a well known process in the chemical literature.67 Unfortunately, the first step to form 237 did not work, with unreacted PPh3 along with tar being recovered. Having failed to produce olefin 234, another compound was targeted for synthesis.

1) nBuLi PPh 0 oC, THF Br 3 PPh3Br toluene 2) 198 reflux THF, 25 oC 232 237 234 24 hours Scheme 4.15 Proposed Wittig procedure to form olefin 234

163

4.3.7 Synthesis of (1R)- 9-(1,7,7-Trimethyl-bicyclo[2.2.1]hept-2-en-2-yl)-anthracene (242) and its corresponding hydroalumination product 243

The next olefin targeted for synthesis was 242 (scheme 4.16). Unfortunately, this strategy failed due to the failure to transform 9-bromoanthracene (239) into anthracenyl magnesium bromide (240). Attempts were also made to lithiate 239 using t-BuLi via a halogen-metal exchange, but these efforts failed as well. The likely reason neither of these efforts worked is due to the steric effect with the two neighbouring protons on anthracene. Interestingly, a simple experiment was set up to confirm this hypothesis.

Lithiation of 239 was attempted using t-BuLi at -78 ºC, and after 1 hour, 198 was added to the solution at low temperature (Scheme 4.16). The reaction was allowed to warm to room temperature over 24 hours and worked up with D2O. The compounds recovered were unreacted 9-bromoanthracene, as well as deuterocamphor (244), confirmed by GC-

LRMS analysis. This proves that the t-BuLi could not halogen-metal exchange 9- bromoanthracene, but rather deprotonated the proton  to the carbonyl group of ketone

198, which upon work up with D2O was deuterated. With this failure, one last such olefin derivative of camphor was attempted.

164

Mg, I2

Et2O Br reflux MgBr 239 240

240 LiAlH , AlBr SOCl2 4 3 Et O pyridine 2 OH benzene, 0 oC anth reflux 0 oC, 0.5 h O 24 h anth anth AlBr2 198 241 242 anth = anthracenyl 243

1) tBuLi, THF D -78 oC + o Br 2) 198, 25 C Br O 239 24 hours 240 244 3) D2O Scheme 4.16

4.3.8 Synthesis of (1R)-3-Benzyl-1,7,7-trimethyl-2-methylene-bicyclo[2.2.1]heptane (247a) and its corresponding hydroalumination product 248

As the iodination described above did not work, enolate chemistry was employed in order to access olefin 247a. The synthetic strategy for accessing this compound is outlined below in scheme 4.17. The first problem with this synthetic strategy was encountered in step one. The diastereoselectivity of the enolate chemistry at room temperature was very poor, favoring the endo adduct by only a factor of 2:1. This ratio was improved to 4:1 in favor of the endo adduct at 0 ºC, with the reaction proceeding in

88 % overall. For the purposes of generating a chiral olefin, either the exo or the endo diastereomer could be used as precursors for either diastereomer of olefin 247a, but a mixture of both diastereomers could not be used. Solving this problem proved simple,

165

however, as refluxing the mixture of diastereomers of 245b in THF with catalytic KOtBu equilibrated the mixture to form the desired endo adduct 245a as the major product, confirmed by comparing 1H and 13C NMR signals to known literature values (Scheme

4.18).68

1) LiN(iPr) SOCl2 2 MeMgBr pyridine 2) benzyl bromide Et2O 0 oC, 0.5 h OH reflux 18 % over O 3) KOtBu O 24 h 67 % over two steps 198 two steps 245a 246 247a

LiAlH , AlBr 4 3 Ph benzene, 0 oC

247a AlBr2 248a Scheme 4.17

5 % KOtBu

THF, reflux O 24 hours O 245b 245a Scheme 4.18

This equilibration improved the diastereomeric ratio of 245b to greater than 22:1 in favor of 245a, which was carried forward to the next step. Both Wittig olefination and

Peterson olefination were attempted to transform 245a to 247a, as either of these 166

reactions would have been convenient had they worked (Scheme 4.19). Unfortunately, neither reaction worked, with only starting materials remaining in the crude 1H NMR spectra. Thus MeMgBr and SOCl2 were used as described previously in Scheme 4.12.

This synthetic strategy required an extra step but was nevertheless found to produce the desired product. MeMgBr was refluxed with ketone 245a in Et2O for 24 hours to generate alcohol 246 (Scheme 4.17). Over 24 hours, the reaction only went 25 % to completion, with 22 % being isolated off a column. Prior to attempting to increase the conversion of this reaction over longer reaction time, elimination was attempted using

SOCl2 to find out if this step would work on the small quantities so generated.

Unfortunately, this elimination step resulted in an extremely complex mixture of isomeric olefins. This mixture was characterized, and small quantities of certain isomers could be either isolated or their purity amplified via column chromatography. The 1H NMR spectra are shown below in figure 4.6. Thus olefin 247 was generated in 18 % yield over the final two steps (Scheme 4.17), but as a complex mixture of isomeric olefins.

MePPh3Br nBuLi, THF ClCH2(CH3)3 0 oC, 1 h Mg, E2tO O 24 h, 25 oC O 245a 247a 245a 247a Scheme 4.19

167

The explanation for this phenomenon is reasonably clear, as there is a thermodynamic driving force for the double bond to migrate across the molecule to be in conjugation with the phenyl group as shown in compounds 247c and 247d (Figure 4.6). It is possible that given more time the mixture would have equilibrated to yield a mixture of only 247c and 247d, but these two compounds were undesirable, as a previous attempt to hydroaluminate the exocyclic phenyl-substituted tertiary olefin 229 had already failed.

Compound 247e could be completely isolated from the mixture of isomers, but the other isomers could not be fully separated. The 1H NMR spectrum of 247e is shown below in spectrum 1 (Figure 4.6). The remaining purified mixture of isomers is shown below in spectrum 2 (Figure 4.6), specifically with a zoomed-in view of the vinyl region.

The possibility of hydroaluminating the mixture was initially dismissed, but having spent so much time synthesizing and purifying the mixture to that shown in spectrum 2 (figure 4.6), this mixture of olefins was hydroaluminated to attempt obtaining

1 a H NMR spectrum of R*AlBr2 for the mixture of 247. Hydroalumination was carried out at 0 ºC over 2 hours, and surprisingly, only a single isomer of olefin 247 was hydroaluminated, confirmed by the disappearance of only one of the two doublet of doublets (spectrum 3). Examination of the region of the 1H NMR spectrum between 0-1.0 ppm also confirms the two doublet of doublets expected from a single hydroaluminated

R*AlBr2 Lewis acid (spectrum 4). As hydroalumination was not originally intended, a spectrum of the mixture of isomers was not obtained in benzene-d6.

168

247a 247b 247c 247d 247e 1 Spectrum 1: H NMR of 247e (benzene-d6)

1 Spectrum 2: H NMR of further purified mixture (benzene-d6)

1 Spectrum 3: H NMR of 248a, 4.0-5.0 ppm (CDCl3)

1 Spectrum 4: H NMR of 248a, 0.0-1.0 ppm (benzene-d6)

Figure 4.6: 1H NMR spectra of the mixture of the isomers of olefin 247a and 248a (benzene-d6)

169

Many questions remain, including the absolute stereochemical configuration of each of the isomers formed, and exactly which isomer among the mixture of isomers was hydroaluminated. These matters, however, are the subject of future research. Overall, the strategy to access olefin 247a was not entirely successful. Nevertheless, having obtained a single isomer of R*AlBr2 Lewis acid from the mixture of isomers of olefin 247a, the three organic reactions described above were carried out using the Lewis acid obtained from the mixture of isomers of 247.

4.4 Using the previously obtained synthetic chiral R*AlBr2 Lewis acids to promote all three reactions described above

The synthesis of eight chiral olefin derivatives of (1R)-(+)-camphor was attempted, and six were successfully obtained. Among these olefins, only five novel chiral R*AlBr2 Lewis acids were generated in situ. Each of these five novel R*AlBr2

Lewis acids were tested one at a time by using them to promote the three organic reactions optimized above in chapter 3.

4.4.1 Performance of each novel chiral R*AlBr2 Lewis acid in the Diels-Alder reaction between oxazolidinone-based dienophile 153a and diene 96

Each of the five novel chiral R*AlBr2-type Lewis acids successfully prepared in situ are outlined below in Table 4.6, along with the results generated from using them to promote the Diels-Alder reaction between oxazolidinone-based dienophile 153a and diene 96.

170

Table 4.6: Diels-Alder reaction between 153a and 96 promoted by novel chiral R*AlBr2 Lewis acids

Ph H H AlBr AlBr2 2 AlBr2 AlBr 2 AlBr2 218 226 248a 201

204 O O O O O O LA O N + O N O N toluene, -25 oC 24 hours 153a 96 154a endo 154a exo Entry Lewis acid Conversion (%)a Σendo/Σexoa ee (%)b 1 201 90 3.3 racemic 2 204 61 3 racemic 3 218 52 3 racemic 4 226 43 2.8 racemic 5 248a 37 2.5 3.4 aConversion to products and endo:exo ratios measured by 1H NMR spectroscopy. bMeasured using chiralcel AD column on HPLC.

The five different chiral R*AlBr2 Lewis acids are generally organized from least sterically hindered to most sterically hindered. LA 201 is reasonably unhindered, while

204 is slightly more hindered. LA 218 is considerably more hindered, with the phenyl group and the AlBr2 group oriented closely. LA 226 is still more hindered, with the AlBr2 group on a secondary carbon  to the phenyl-substituted tertiary carbon. Finally, 248a is likely the most sterically hindered LA, with the bridgehead methyl group, the AlBr2 group, and a neighboring -benzyl group possibly converging into a single area.

Predictably, the percent conversion of the Diels-Alder reaction between 153a and

96 decreases with the increased steric bulk around the Lewis acidic aluminum atom, with a 90 % conversion by NMR spectroscopy using Lewis acid 201, and only a 37 %

171

conversion using LA 248a. Not only that, but the Σendo/Σexo ratio drops as well, from

3.3 down to only 2.5. It seems that the greater the steric bulk of the Lewis acid, the more the exo diastereomer is favored. Unfortunately, this reaction did not proceed enantioselectively, with the best selectivity obtained in only 3.4 % ee using R*AlBr2

Lewis acid 248a.

4.4.2 Performance of each novel chiral R*AlBr2 Lewis acid in the IMDAF reaction of 182g

The IMDAF reaction of 182f was also used as a model system to test the five chiral R*AlBr2 Lewis acids previously synthesized. The same trend observed for the

Diels-Alder reaction of 153a and 96 was observed. The less sterically hindered Lewis acids catalyzed the reaction with a greater conversion, while the more sterically hindered

Lewis acids did so with less conversion. In fact, the difference was quite pronounced, going from 79 % conversion in the case of LA 201 to only 20 % conversion in the case of

LA 248a (Table 4.7). Unfortunately, the only enantioselection observed using chiral

HPLC was for the simplest Lewis acid, 201, which catalyzed the reaction in only 4.9 % ee. Interestingly, Lewis acid 226 was unable to catalyze the IMDAF reaction, for reasons that are not clear. It is reasonable to assume the greater steric bulk of the secondary carbon atom being bound to the aluminum atom results in a more sterically strained transition state in the IMDAF reaction, preventing it from proceeding at the temperature tested.

172

Table 4.7: IMDAF reaction of 182f promoted by novel chiral R*AlBr2 Lewis acids

Ph H H AlBr AlBr2 2 AlBr2 AlBr 2 AlBr2 218 226 248a 201

204 0.1 eq. LA O O 2h, -78oC O DCM O 182f 183f Entry Lewis acid Conversion (%)a ee (%)b 1 201 79 4.9 2 204 63 racemic 3 218 59 racemic 4 226 NR NA 5 248a 20 racemic aConversion to products and endo:exo ratios measured by 1H NMR spectroscopy. bMeasured using chiralcel AD column on HPLC.

4.4.3 Performance of each novel chiral R*AlBr2 Lewis acid in the Strecker reaction of 192 with TMSCN

Finally, the five novel chiral R*AlBr2 Lewis acids were used to promote the

Strecker reaction between imine 192 and TMSCN (Table 4.8). The trend observed for the previous two reactions basically holds true for this reaction as well, except for Lewis acid

204, which promoted the Strecker reaction in 94 % yield. Apart from that, Lewis acid 201 promoted the reaction in 61 %, with a decline thereafter, down to only 30 % for Lewis acid 248a. Lewis acid 226 promoted the reaction with only minor enantioselection, yielding Strecker adduct 193 in only 4.7 % ee. Thus adduct 204 unquestionably was the superior R*AlBr2 Lewis acid for promoting this particular Strecker reaction to completion, and the overall ees obtained were very disappointing.

173

Table 4.8: Strecker reaction of 192 and TMSCN promoted by novel chiral R*AlBr2 Lewis acids

Ph H H AlBr AlBr2 2 AlBr2 AlBr 2 AlBr2 218 226 248a 201

204 LA, TMSCN CN

N o N -78 C, 2 h H DCM 192 193 Entry Lewis acid Conversion (%)a ee (%)b 1 201 61 racemic 2 204 94 racemic 3 218 60 racemic 4 226 55 4.7 5 248a 30 racemic aConversion to products and endo:exo ratios measured by NMR spectroscopy. bMeasured using chiralcel AD column on HPLC.

4.5 Lewis acid studies to confirm the formation of only a single R*AlBr2 Lewis acid in solution

Several different chiral R*AlBr2 Lewis acids were used to promote three different organic reactions, and products generated were for the most part racemic mixtures in all three reactions. One concern was that products could be racemizing on silica gel. This concern was dismissed, however, as crude product mixtures taken to the chiral HPLC did not improve results. It was thought that either during the hydroalumination reaction or during the process of binding a Lewis basic atom to the aluminum atom during one of the reactions, a disproportionation reaction might have been occurring, resulting in the formation of achiral AlBr3 and a different chiral Lewis acidic species. This achiral

174

species AlBr3 could then catalyze these reactions racemically. This hypothesis is shown below in Scheme 4.20.

Br Br R* Br Al + Al Al + Al Br R* Br R* Br R* Br Br 249 249 250 251 Scheme 4.20

It was thought that the desired R*AlBr2 Lewis acid 249 may form as postulated, but that either during the hydroalumination process, moments afterwards, or during the binding of a Lewis base, disproportionation occurs to form R2*AlBr 250 and aluminum tribromide, or perhaps some other achiral aluminum species. This process would potentially be disasterous, as even if a chiral R*AlBr2 or R2*AlBr compound was in solution, a more Lewis acidic and less hindered achiral Lewis acid may be present, promoting the reaction to yield racemic adduct. If the process shown above was taking place, the hydroalumination procedure would be only useful for generating reactive intermediates for synthetic operations, as Gorobets had initially described for the generation of alcohols, alkyl halides, and hydrocarbons. Unfortunately, if this were the case, this hydroalumination procedure would not be useful for generating a chiral Lewis acid to promote asymmetric organic reactions, unless a procedure could be developed for purifying the R*AlBr2 or R2*AlBr Lewis acids so formed.

1 13 Although the H NMR and C NMR spectra collected for all RAlBr2 Lewis acids synthesized displayed only a single product being formed, they could not confirm that it was species 249 and not 250. In addition, integration of the protons  to the aluminum

175

atom against an external standard such as toluene, previously carried out, could not solve this problem, as either 249 or 250 would yield the same integrals on the NMR. Thus the only way to confirm conclusively that this process was not taking place was via low temperature 1H NMR binding study with a variety of different Lewis bases and Lewis acids.

If the process shown in scheme 4.20 were taking place, two sets of product peaks would be apparent in the 1H NMR spectrum, corresponding to both 250- and 251-bound

Lewis base. In addition, one of these sets of product peaks would be for AlBr3-bound

Lewis base, meaning spectra for AlBr3-bound Lewis base could be obtained for comparison. Both cyclohexenone (252) and crotonaldehyde (103) were selected as simple and appropriate Lewis bases to study binding. They were each added to chiral R*AlBr2

1 Lewis acid 87 as well as AlBr3, and the respective H NMR spectra were compared, along with their 27Al NMR spectra.

Solutions of crotonaldehyde and cyclohexenone were prepared in toluene-d8, and cooled to -65 ºC. A solution of R*AlBr2-type Lewis acid 87 was delivered to the mixture at low temperature, and 1H NMR spectra were collected immediately. The results of this binding study are tabulated below (Table 4.9), and the spectra for 87- and AlBr3-bound

Lewis base 252 are also shown below (Figure 4.7). Importantly, in all cases unreacted

Lewis base could be recovered following H+ work up.

176

Table 4.9: Lewis acid binding studies of Lewis acids 87 and AlBr3 with Lewis bases 103 and 252 LA LA O O O O LA LA H H H H 1 1 H 1 H 1 toluene 3 toluene 3 o o H2 -78 C H2 H2 -78 C H2 AlBr2 252 253 103 254 87 Entry Lewis base Lewis acid H1 H2 H3 1 252 87 6.19 6.62 NA 2 252 AlBr3 5.85 6.21 NA 3 103 87 5.98 6.50 9.40 4 103 AlBr3 4.62 5.33 7.85

Just like with the binding study previously conducted in DCM, this binding study conducted in toluene-d8 suggested that only a single Lewis acid-Lewis base complex was forming. Additionally, these studies confirmed that no Lewis base-AlBr3 complex was forming in any quantities with either Lewis base 103 or 252. This was demonstrated both with 1H NMR as well as 27Al NMR. A representative set of spectra are shown below in

Figure 4.7. These studies conclusively ruled out the hypothesis described above in scheme 4.20, and with that, efforts to generate more complex chiral olefins were revisited.

177

1 Spectrum 1: H NMR for 87-bound 252 in toluene-d8

1 + Spectrum 2: H NMR after H work up in toluene-d8

1 Spectrum 3: H NMR of AlBr3-bound 252 in toluene-d8

27 Spectrum 4: Al NMR of 87-bound 252 in toluene-d8

27 Spectrum 5: Al NMR of AlBr3-bound 252 in toluene-d8

o Figure 4.7: Binding study of Lewis base 252 with 86 with AlBr3 and with LA 87 (-65 C)

178

4.6 Efforts to Synthesize dicamphor-derivatized olefins 255 and 257

With the possibility of numerous species forming in solution upon binding of a

Lewis base ruled out, the only other explanations for the lack of enantioselection previously observed were that 1) the chirality of the R*AlBr2 LAs was too remote from the aluminum atom, with the activated organic groups too distant from the chiral groups for chiral induction to occur, and that 2) the R*AlBr2 LAs were too Lewis acidic, thereby reducing the activation energies of both diastereomeric transition states to the extent there is sufficient energy to readily proceed along both pathways at the temperatures tested.

Addressing the first problem without changing the philosophy of this chemistry will be addressed in the present discussion. In order to improve the chiral environment of camphor-derivatized olefins, compounds 255 and 257 were targeted as precursors for

R*AlBr2 Lewis acids 256 and 258 (scheme 4.21).

LiAlH4 LiAlH4 AlBr AlBr3 H 3 H benzene benzene H o o 0 C H 0 C Br2Al Br2Al H H

255 256 257 258 Scheme 4.21

4.6.1 Efforts to Synthesize dicamphor derivative 255 with Grignard chemistry

Several attempts to make 3rd generation chiral derivative of camphor 255 were attempted. These structures were targeted as it was thought the synthesis would be trivial.

179

Unfortunately, all attempts to produce these target compounds were met with failure. The first synthetic strategy to access these compounds is described below in scheme 4.22.

Mg SOCl2 pyridine Et2O 198 H H H H OH o reflux 0 C Br MgBr 30 mins 259 260

261 255 Scheme 4.22

The first attempts toward olefin 255 required the synthesis of alkyl bromide 259.

A procedure was found to transform olefins to alkyl bromides via hydroboration using

69 Br2 as the oxidation agent directly instead of using H2O2 to go through the alcohol.

Unfortunately, both attempts to carry this reaction out were met with failure, with only complex mixtures being obtained. Interestingly, the hydroalumination procedure outlined

44 by Gorobets to transform olefins to alkyl bromides using CuBr2 in THF via the corresponding intermediate R*AlBr2 Lewis acid was found to work quite well. This reaction was carried out and alkyl bromide 259 was obtained as a mixture of diastereomers in 62 % overall yield isolated off a column.

With alkyl bromide 259 in hand, the formation of the Grignard reagent 260 was attempted numerous times. All attempts failed, resulting in a very complex crude spectrum consisting of a mixture of inseparable hydrocarbons. Interestingly, the major products formed turned out to be 262 and 264, confirmed by GC-LRMS analysis

180

(Scheme 4.23). This process was confirmed by attempting the Grignard reaction as described below, then working it up with D2O. Small amounts of unreacted alkyl bromide

259 and large amounts of unreacted camphor (198) along with hydrocarbon 264 were confirmed by GC-LRMS analysis, along with deuterated hydrocarbon 263 (Scheme

4.23).

Mg, Et O 1) 198 2 H reflux Et2O, reflux H H H 2) H2O/ D2O Br MgBr R

259 260 262: R = H 264 263: R = D Scheme 4.23

4.6.2 Efforts to synthesize dicamphor derivative 257 with Grignard chemistry

These same efforts were also conducted on olefin 82, as it was thought it was a slightly less hindered system. Camphene-derivatized olefin 257 was targeted to access its slightly less-hindered hydroaluminated R*AlBr2 Lewis acid 258 (scheme 4.24). In order to synthesize olefin 257, Olefin 82 was both ozonized with a reductive workup to form ketone 265, and was also hydroaluminated to form R*AlBr2 Lewis acid 87, which was subsequently reacted with CuBr2 in THF to form alkyl bromide 102 (scheme 4.24). As with previous efforts to synthesize 255, the Grignard reaction to access 257 yielded only deuterated hydrocarbon 266, along with hydrocarbon 267, large amounts of unreacted ketone 265, and small amounts of unreacted alkyl bromide 102. No NMR spectra could

181

be obtained for these compounds, as they were part of a very complex mixture of non polar hydrocarbons, but the formation of these adducts was confirmed using GC-LRMS, indicating the Grignard reagent was not forming effectively, and upon forming it reacted more rapidly with 102 than with 265 to form dimer 267.

As a result, one final effort to make this chemistry work was attempted, a Barbier- type reaction with the formation of the Grignard reagent of alkyl bromide 102 set up with ketone 263 predissolved in the ether solution. Unfortunately, this did not yield product either. Thus, efforts to synthesize dicamphene olefin derivative 257 to access R*AlBr2

Lewis acid 258 using Grignard chemistry were also abandoned. With efforts to access olefins 255 and 257 having failed, another strategy was attempted to form both.

1) O /O 2 3 LiAlH4 MeOH AlBr3 2) Zn, AcOH O benzene H 52 % 0 oC Br2Al 82 265 H

257 258

LiAlH4 CuBr2 1) Mg, Et2O AlBr3 benzene THF 2) 265 o 0 C 52 % 3) D2O AlBr2 Br D 266 82 87 102 267 Scheme 4.24

182

4.6.3 Efforts to Synthesize dicamphene derivative 257 with Wittig chemistry

Having already synthesized alkyl bromide 102 along with ketone 265, it made sense to attempt to investigate more Wittig chemistry. Attempts to transform alkyl halide

102 into its corresponding alkyltriphenylphosphonium bromide 268 were conducted. The alkyl halide was refluxed with PPh3 in toluene over 24 hours (scheme 4.25). The product mixture for the reaction between 102 and PPh3 contained only those two compounds, with absolutely no reaction having taken place. With this reaction failing, it made little sense to attempt it on alkyl halide 259, which is an even more sterically hindered compound than 102. Thus further attempts to develop this chemistry using a Wittig approach were abandoned.

PPh3

toluene, reflux Br PPh3Br 102 268 Scheme 4.25

4.6.4 Efforts to Synthesize dicamphene derivative 257 with R*AlBr2 as the nucleophilic agent in solution

One final attempt was made to access olefin 257, by adding sublimed ketone 265 to the in situ solution of Lewis acid 87 in toluene and refluxing the mixture. It was thought that Lewis acid 87 already contained the nucleophilic group desired for addition

183

to the ketone, and that prior efforts to form the corresponding Grignard reagents might have been redundant. The concept for this reaction is shown below in scheme 4.26.

SOCl2 toluene pyridine + reflux, 2 hours OH 0 oC O 30 minutes AlBr2 87 265

269 257 Scheme 4.26

This reaction was conducted several times, including at room temperature as well as at 110 ºC, as it was thought it offered a very good chance of forming the desired alcohol 269, and that under the conditions the tertiary alcohol might even dehydrate into the desired olefin 257 in a one-pot reaction. Unfortunately, these efforts resulted in failure, producing a complex product mixture including plenty of unreacted ketone 265.

4.7 Conclusion

Simple chiral R*AlBr2-type Lewis acids derived from simple, inexpensive chiral olefins (+)-camphene, (1R)-(+)--pinene, and (1S)-(-)--pinene were used to promote the

Diels-Alder reaction between chiral dienophiles 134a-d and diene 96. Small amounts of double diastereoselectivity were observed, with product mixtures generally forming in poorer yields and diastereoselectivities than had previously been obtained in chapter 3.

184

These simple R*AlBr2-type Lewis acids, along with a number of more complex chiral R*AlBr2 Lewis acids were used to promote the three reactions previously optimized in chapter 3. The in situ formation of more complex R*AlBr2-type Lewis acids required the synthesis of more complex chiral olefins, and these synthetic strategies were based on derivatizing (1R)-(+)-camphor, (1S)-(+)-camphorsulfonic acid, and (+)- camphene. Some targeted chiral olefins remained unaccessed, but several of these novel chiral olefins were successfully synthesized and hydroaluminated to their corresponding chiral R*AlBr2 Lewis acid structures. Unfortunately, it was determined that these

R*AlBr2 Lewis acids were not capable of promoting any of the three organic reactions previously optimized with enantioselectivities above 5 %. In addition it was determined that greater steric bulk of the RAlBr2 Lewis acid generally resulted in diminished product yields.

The possibility of the chiral R*AlBr2 Lewis acids disproportionating in solution to form multiple aluminum species including achiral Lewis acidic species such as AlBr3 was ruled out based on multiple 1H NMR and 27Al NMR binding studies with both Lewis bases cyclohexenone and crotonaldehyde. This left two possible explanations. Either the chiral environment surrounding the Lewis acidic aluminum atom was insufficient for chiral induction, or the high Lewis acidity of R*AlBr2 Lewis acids reduce both diastereomeric transition states for catalyst-bound Lewis-base too far for enantioselection to occur. With all efforts to synthesize dicamphor and dicamphene olefin derivatives 255 and 257 having failed, a brand new approach to this chemistry was pursued, one which substituted one of the bromine atoms on chiral R*AlBr2 with a chiral lithiated alcohol

LiOR*. This strategy addressed both of these potential problems at the same time.

185

CHAPTER FIVE: SUBSITUTION REACTIONS USING O-LITHIATED ALCOHOLS TO REPLACE BROMINE ATOMS ON R*ALBR2-BASED LEWIS ACIDS WITH SECOND AND THIRD CHIRAL GROUPS

5.1: Introduction

Enantioselection was predicted using novel chiral R*AlBr2-based Lewis acids, and yet no ee was observed above 5 % for any of the reactions outlined in chapter 4.

Having completed a series of NMR binding studies and having ruled out disproportionation of the Lewis acid, the two most likely explanations became clear. The first possible explanation for the lack of enantioselection was insufficient chiral environment around the aluminum atom for the desired chiral induction to take place.

The second explanation was that R*AlBr2-type Lewis acids may be too reactive for enantioselection to occur. Fortunately, both of these issues can be addressed with a single synthetic operation, outlined below in Scheme 5.1.

LiAlH4 LiBr 2 LiBr * * AlBr3 LiOR LiOR H H H benzene 1 eq. 2 eq. O O 0 oC Al R* Al R* AlBr2 Br O 200 201 R* 270a 270b Scheme 5.1

The hydroalumination of olefin 200 is used as an example. A lithiated chiral alcohol is added to Lewis acid 201, resulting in the targeted substitution reaction to yield

186

270a and LiBr. This is a promising strategy for a number of reasons. The first is that

R*AlBr2-type Lewis acids are promising candidates for substitution reactions, due to the bromine atoms being excellent leaving groups. The second is that such a substitution reaction using a lithiated alcohol would yield LiBr as a side product of the substitution, which is already in the solution as a side product of the hydroalumination reaction. Thus nothing new is added to the solution. Along this same line of reasoning, a logical lithiating agent to be used is nBuLi, as the butane generated in the lithiation step can be removed in vacuo. Thus no new chemical species are added to the in situ mixture of

Lewis acid as a result of the substitution.

More importantly, this process would address the two problems proposed above; it would significantly improve the chiral environment around the aluminum atom, making chiral induction more likely, and with the second chiral group being bonded through an oxygen atom, it would significantly reduce the Lewis acidity via back donation of the oxygen lone pairs into the empty p-orbital on the aluminum atom.

There are still other advantages of this approach, including an immense tunability of Lewis acid structure; there are numerous chiral olefins that can be diastereoselectively hydroaluminated, and in conjuction with the myriad chiral alcohols available, an enormous library of novel chiral aluminum-based Lewis acids becomes accessible. The chirality of the alcohols will also reduce the necessity for complex olefin synthesis, as there will be two chiral groups rather than just the one. This is highly desirable, as the non-polar hydrocarbon nature of the targeted chiral olefins makes purification difficult.

Finally, highly complex chiral structures become accessible at very low cost.

Olefin 200 can be accessed in a single step from (1R)-(+)-camphor (198), which is very

187

inexpensive, and many natural chiral alcohols are also very inexpensive. For example, at the time of this writing, (-)-menthol is commercially available at approximately 18 cents per gram (CAD). If this chemistry were to yield good enantioselection, it would therefore be a highly attractive methodology, as the enantioselection per cost may prove to be very high.

Although the proposed chemistry is novel, a somewhat related literature precedent could be found for chiral boron-based Lewis acids reported by H.C. Brown in 1988.70

The strategy is outlined below in Scheme 5.2. β-Halodiisopinocamphenylboranes 272a-c were prepared by passing HCl, HBr, or HI through a suspension of optically pure 271 in pentane at 0 ºC. These three compounds were then used in 1.1 equivalents to promote the asymmetric epoxide opening of 71, shown below. The epoxide opening was conducted using different reaction conditions for each of the three different permutations of 272.

The reaction using 272a was conducted at -78 ºC over 3 hours, while 272b and 272c were conducted at -100 ºC over 3 hours and at -100 ºC over 30 minutes respectively. The best result was obtained in generating β-halo alcohol 273c in 89 % yield and 91 % ee.

OH HX O BH BX 272a-c X 2 pentane 2 0 oC

271 272a: X = Cl 71 273a: X = Cl (70 %, 22 % ee) 272b: X = Br 273b: X = Br (82 %, 84 % ee) 272c: X = I 273c: X = I (89 %, 91 % ee) Scheme 5.2

188

Obviously, there are two key differences between 272a-c, and the structures proposed above, the first being in the group 13 element used, and the second being the heteroatom-bound group in the proposed chemistry. Nevertheless, the overall success of

Brown’s method provided sufficient precedent to justify attempting the proposed experimentation.

5.2: Synthesis of R*AlBr(OR*)-type Lewis acids and their use to promote organic reactions

Simple chiral olefins 82 and 200 were hydroaluminated to produce the precursors for the first two R*AlBr(OR*)-type Lewis acids, 274a and 275a, shown below (Scheme

5.3). Simple chiral alcohol 3 was chosen as the alcohol precursor for these two structures.

The R*AlBr2-type Lewis acid was prepared in benzene as previously described, before a solution of lithiated alcohol in benzene was added dropwise at room temperature. This strategy was predicted to work very efficiently, as the R*AlBr(OR*) Lewis acids so formed would be less reactive and have a superior chiral environment than their R*AlBr2 counterparts; each equivalent of LiOR* delivered to the reaction mixture would therefore likely only react with R*AlBr2, and not with previously formed R*AlBr(OR*), thus preventing double addition and multiple speciation. Were these initial R*AlBr(OR*)-type

Lewis acids found to promote reactions enantioselectively, the library of chiral olefins described in chapter 4 could also be used as precursors to generate an expanded library of novel Lewis acids.

189

LiBr LiAlH4 H AlBr3 nBuLi H benzene 3 Al O OH 0 oC Br AlBr2 3 200 201 274a

LiAlH4 LiBr AlBr3 nBuLi benzene 3 O 0 oC Al AlBr2 82 Br 87 275a Scheme 5.3

5.2.1: Developing a Diels-Alder model system for R*AlBr(OR*) Lewis acid Lewis acids

The first R*AlBr(OR*)-type Lewis acids synthesized were 274a and 275a, derived from R*AlBr2 LAs 87 and 201 and alcohol 3 (scheme 5.3). The first reactions attempted with these new Lewis acids were the three reactions described previously.

Unsurprisingly, these R*AlBr(OR*) LAs were not Lewis acidic enough to promote either the Diels-Alder reaction between 153a and 96 or the IMDAF reaction of 182f at the temperatures previously used (Table 4.6 and 4.7). They were, however, acidic enough to promote the Strecker reaction previously described between 192 and TMSCN (Table

4.8), with Lewis acid 274a doing so in 61 % yield, although the Strecker adduct so generated was determined to be racemic by HPLC analysis.

As previously described in chapter 1, the first asymmetric Diels-Alder reaction reported in the chemical literature was reported in 1979 by Koga and co-workers.3 This

190

methodology made use of a number of chiral alcohols, including chiral alcohol 3, in conjunction with EtAlCl2 to promote the Diels-Alder reaction between 9 and 10c (Table

5.1). Although numerous other chiral alcohols were tested in this manner, catalyst 6, derived from EtAlCl2 and alcohol 3, provided the best result, promoting the Diels-Alder reaction in 56 % yield and 57 % ee (entry 1). Interestingly, Koga and co-workers also prepared a Lewis acid out of Et2AlCl and (-)-menthol to generate catalyst 276, an

RAlCl(OR*) LA, similar to those being proposed herein, which promoted the same reaction in 67 % yield and 23 % ee (entry 2). The product strongly favored the exo adduct for the Diels-Alder reaction catalyzed by 6, with an exo:endo ratio of 49:1. The exo:endo ratio for the Diels-Alder reaction catalyzed by 276 was not reported.

Before R*AlBr(OR*) LAs were tested to catalyze this Diels-Alder reaction, the results reported by Koga were repeated exactly, to determine their reproducibility (entry

3). The ee obtained was 58 %, identical to that reported by Koga within experimental error, as was the reaction yield, determined to be 57 %. Interestingly, the exo:endo ratio obtained was only 20:1, very different from the 49:1 ratio originally reported by Koga.

Under further examination, the exo:endo ratios reported by Koga in 1979 were those isolated off a column, and it is unlikely that both diastereomers formed in the reaction were quantitatively recovered off the column. The exo:endo ratios determined in the

Keay lab were determined using the crude product mixture on a 400 MHz NMR spectrometer.

191

Table 5.1: Koga’s Al(OR*)Cl2- and RAl(OR*)Cl-promoted Diels-Alder reactions

EtAlCl2 Et2AlCl

toluene OH toluene OAlCl2 OH OAlEtCl

3 6 3 276

O O O toluene, -78 oC + H 3 hours

9 10c exo-11c endo-11c Entry Catalyst Yield (%) exo:endo ee (%)a 1 6 56 49:1 57 2 276 67 not reported 23 3b 6 57 20:1 58 aDetermined by optical rotation. bReaction repeated in the Keay lab under conditions identical to those reported by Koga.

Having repeated the reaction carried out by Koga, and having reproduced the

Diels-Alder adduct enantioselectively, the Diels-Alder reaction was tested using several simple R*AlBr(OR*)-type structures, all of which were synthesized from simple chiral olefins and commercially available chiral alcohols (Table 5.2). The R*AlBr(OR*)-type

Lewis acids were generated as described previously and added to a toluene solution of

10c at -78 ºC, followed by dropwise addition of 9. The results from these experiments are shown below in Table 5.2.

In addition to the use of R*AlBr(OR*)-type Lewis acids, R*AlBr2-type Lewis acids 201 and 87 were also used to catalyze the Diels-Alder reaction between methacrolein and cyclopentadiene. Neither catalyzed the reaction enantioselectively, with no rotation whatsoever being observed on the polarimeter. Interestingly, the exo:endo selectivity was also quite poor relative to the other results obtained in this experiment,

192

consistent with the hypothesis that the high reactivity of R*AlBr2 LAs reduces selectivity. Interestingly, exo:endo ratios of up to 100:1 were obtained (entry 4), with this selectivity coming from the R*AlBr(OR*) LA obtained by combining Lewis acid 201 with lithiated (+)-isopinocampheol (278).

Table 5.2: Diels-Alder reactions promoted by R*AlBr(OR*) LAs Br a: R1 = 3 R1O Al b: R1 = 277 OR1 Al c: R1 = 278 H Al OR1 Br Br 274a-c 275a 276c

OH OH OH AlBr2 H AlBr2 3 277 278 201 87

O O O toluene, -78 oC + H 3 hours catalyst 9 10c exo-11c endo-11c Entry Catalyst Yield (%)a exo:endob ee (%)c 1 201 >99 10:1 racemic 2 274a 68 27:1 5.1 3 274b 63 27:1 2.2 4 274c 63 100:1 racemic 5 87 >99% 10:1 racemic 6 275a 74 25:1 3.2 7 276c 46 99:1 4.8 aYields determined by integrating product peaks against 1-dodecene. bexo:endo ratios determined by 400 MHz 1H NMR. cDetermined by optical rotation.

In terms of enantioselection, the results are very disappointing, with the highest ee being obtained in only 5.1 %, using LA 274a (entry 2). This was a very surprising result,

193

because a 58 % ee was previously obtained with (-)-menthol and EtAlCl2 under the same conditions (Table 5.1, entry 3). Not only did the addition of the chiral R group reduce the enantioselection by a factor of 10 (Table 5.2, entry 2), but this observation could not be accounted for by the possibility of 201 and 3 being a mismatched diastereomeric pair, as the opposite enantiomer of menthol was also used, with ever poorer results (entry 3).

5.2.2: Monitoring the hydroalumination reaction and the subsequent substitution reaction with chiral lithiated alcohols with 1H NMR spectroscopy

In order to attempt to explain what appeared to be a failure that made no sense, a series of 1H NMR experiments were conducted to monitor the in situ formation of

R*AlBr2 from the olefin, and to further monitor the R*AlBr(OR*) complex as it formed in situ following the addition of lithiated alcohol. These first studies were carried out using the hydroalumination reaction of olefin 200, followed by the substitution reaction using lithiated 3 to form 274a. The 1H NMR spectra obtained for this reaction are shown below in Figure 5.1.

These experiments reveal a fascinating process taking place. Spectrum 1 reveals

1 the H NMR spectrum of olefin 200 in benzene-d6. Spectrum 2 reveals the corresponding hydroaluminated R*AlBr2-type LA 201 in benzene-d6 after one hour. Even after numerous scans, no trace of olefin remained, indicating it had been completely consumed by the hydroalumination reaction, just as previously observed. Spectrum 4 is the 1H NMR spectrum immediately following rapid addition of lithiated alcohol 3 (spectrum 3) to the mixture at room temperature, and even in dilute solution it reveals the return of peaks corresponding to olefin 200 in large quantities.

194

LiAlH4 benzene AlBr3 + benzene OLi rt O Al 0 oC, 2h AlBr2 200 201 3 274a Spectrum 1: 1H NMR of 200 (olefin)

1 Spectrum 2: H NMR of 201 (R*AlBr2)

Spectrum 3: 1H NMR of 3

Spectrum 4: 1H NMR of 274a [R*AlBr(OR*)]

Figure 5.1: Monitoring the hydroalumination of olefin 200 to R*AlBr2 Lewis acid 201 and after the addition of lithiated alcohol 3 in C6D6.

195

At first the explanation for this unexpected observation was elusive, but in fact it is quite reasonable. β-Hydride eliminations are well-known reactions in organometallic chemistry, and are common in organometallic systems containing sp3 β hydrides. Lewis acid 201 contains a metal-bonded sp3 carbon atom with a β hydride. The most likely explanation for the reappearance of the olefin peaks in Figure 5.1 is that a specific kind of

β hydride elimination, β dehydroalumination, is taking place. The proposed process is outlined below in scheme 5.4.

The obvious question to ask is why Lewis acid 201 does not similarly dehydroaluminate. It is tempting to propose an equilibrium process wherein 201 is in equilibrium with HAlBr2 and olefin, yet if this were the case olefin should be visible in the 1H and 13C NMR spectra, and olefin peaks are not apparent. In addition, no such process was observed when various Lewis bases were bound to various RAlBr2-type

Lewis acids as described previously; olefin peaks did not return on the 1H NMR, and unreacted Lewis base could be recovered following acid work up.

Thus this phenomenon appears unique to R*AlBr(OR*)-type Lewis acid structures. The most likely explanation is therefore that steric repulsion between large chiral R* and OR* groups is driving the dehydroalumination process forward. The large alkyl groups could possibly be forcing the β hydride in closer proximity to the empty p- orbital on the aluminum atom, reducing the activation energy for dehydroalumination to occur (scheme 5.4).

196

LiBr LiAlH4 AlBr3 nBuLi H H O benzene 3 Al o 0 C AlBr Br 200 2 201 274a

H HO Al O + Br

3 200 280 Scheme 5.4

Additionally, this process is irreversible. Gorobets previously observed that the hydroalumination does not occur in ethers or in the presence of other Lewis bases that deactivate the hydroaluminating agent. In other words, after lithiated alcohol 3 binds

Lewis acid 201, any dehydroalumination process leaves olefin 200 and LA 280, an aluminum hydride deactivated by a heteroatom bond, which is subsequently no longer a strong enough hydraoluminating agent to rehydroaluminate 200 (Scheme 5.4).

It was thought that this process may simply be peculiar to R*AlBr2 Lewis acid

201; that the structure made dehydroalumination a unique feature of this particular system, one not shared by other R*AlBr2-type Lewis acids. Olefin 82 was therefore hydroaluminated to 87, and lithiated alcohol 3 was added to generate 275a. The resulting

1H NMR spectra were collected exactly as before with spectrum 1 corresponding to

197

olefin 82, spectrum 2 to Lewis acid 87, and spectrum 3 corresponding to 275a (figure

5.2).

H O 2 HO Al O + + Br 92 3 82 275a Spectrum 1: 1H NMR of 82 (olefin)

1 Spectrum 2: H NMR of 87 (R*AlBr2)

Spectrum 3: 1H NMR of 275a [R*AlBr(OR*)]

Figure 5.2: Monitoring the hydroalumination of olefin 82 and the addition of alcohol 3 in C6D6.

198

The 1H NMR study proves the exact same dehydroalumination process is taking place at room temperature, with the olefin peaks reappearing immediately following the addition of the lithiated alcohol. Spectrum 3 contains some large peaks for hexanes, which could not be completely removed, as the nBuLi was added as a solution in hexanes. With this second NMR study, it seems more likely that this process may simply be a characteristic feature of this particular chemistry. It may therefore not be possible to obtain a stable R*AlBr(OR*)-type Lewis acid that does not immediately dehydroaluminate. It was also unclear what percentage of R*AlBr(OR*) in solution was dehydroaluminating, or exactly what proportion of the original olefin was returning.

Therefore, in addition to the 1H-NMR studies so described, both LAs 274a and

275a were quenched with H2O and the crude mixtures characterized using LR-GCMS.

These analyses revealed a complex mixture of products, containing mostly the starting olefins and (-)-menthol (3), suggesting dehydroalumination predominates. Small quantities of the corresponding hydrocarbons expected following a H+ work up of an

R*AlBr2-type Lewis acid were also present (Figure 5.2).

These 1H NMR studies help explain the lack of enantioselection previously observed in Table 5.2. Using LA 274a as an example, the dehydroalumination process likely leaves a mixture of aluminum hydride 280 and leftover 274a (scheme 5.4). It may be that at -78 ºC, the Diels-Alder reaction is faster than the reduction of methacrolein, as no reduced methacrolein, either 1,2 or 1,4, could be isolated. It may also be that for primarily steric reasons, Lewis acid 280 is more active than Lewis acid 274a. If so, the expected enantioselection of Diels-Alder reactions using R*AlBr(OR*)-type Lewis acids

199

would only equal the enantioselection of their corresponding dehydroaluminated

HAlBr(OR*)-type Lewis acids, thus explaining the low % ee in Table 5.2.

Since all previous substitution reactions were conducted at room temperature with rapid addition of the chiral lithiated alcohol to the R*AlBr2-type Lewis acid, it was hypothesized that the dehydroalumination process may actually be a function of either the rapid addition of LiOR* or the temperature of addition. A series of experiments were therefore conducted adding benzene solutions of lithiated 3 to Lewis acid 201 at a number of different temperatures. The mixtures were then slowly warmed to room temperature over 30 minutes, and immediately taken to the 1H NMR spectrometer to collect a spectrum. These spectra are outlined below over the following two pages

(Figure 5.3).

As demonstrated below, addition of lithiated alcohol by syringe pump over 1 hour has no effect on the result, with rapid addition (spectrum 3) and addition via syringe pump over 1 hour (spectrum 4) being identical. Nor does decreasing the temperature of addition prevent the reapperance of olefin. Addition at -30 ºC (spectrum 5) and at -60 ºC

(spectrum 6) also both result in prominent olefin peaks being formed. All spectra were collected in benzene-d6, but in order for the lithiated alcohol 3 to be added at -30 ºC and at -60 ºC, toluene was required as a solvent, which is why large toluene peaks are present in spectra 5 and 6. In addition, peaks for hexanes are also present due to the addition of nBuLi as a solution in hexanes. Removing these solvents by concentrating the mixture in vacuo was avoided, as it was thought that doing so might impact the result, and as close an approximation as possible was desired for what was occurring in solution at the solvent composition and concentration at which 274a was forming.

200

Spectrum 1: 1H NMR of 200 (olefin)

1 Spectrum 2: H NMR of 201 (R*AlBr2)

Spectrum 3: Rapid addition of 3 at 25 ºC

Spectrum 4: Addition of 3 over 1 hour at 25 ºC

Spectrum 5: Addition of 3 over 1 hour at -30 ºC

201

Spectrum 6: Addition of 3 over 1 hour at -60 ºC

Figure 5.3: Monitoring the effect of temperature on the results of the addition of lithiated alcohol 3 in C6D6.

Interestingly, a second set of olefin peaks were observed at room temperature at both rapid addition (spectrum 3) and addition over an hour by syringe pump (spectrum

4). This second set of olefin peaks may suggest a rearrangement is occurring prior to elimination to form a second olefin, but this requires future study to confirm. Perhaps more interestingly still, the second set of olefin peaks entirely disappears when lithiated alcohol 3 is added to Lewis acid 201 at low temperature, supporting the hypothesis that a rearrangement may be occurring. The exact structure of this product, however, is the subject of future research.

Having completed this set of experiments, one question remained. Was the dehydroalumination occurring as the lithiated alcohol was added at low temperature or as the reaction mixture was warmed and taken to the NMR spectrometer? Thus a final NMR analysis was conducted by transferring a small quantity of a solution of 274a in toluene- d8 formed at -78 ºC to an NMR tube under N2 containing toluene-d8 at -78 ºC and collecting NMR spectra at -78 ºC. The results are shown below (Figure 5.4). A prominent benzene peak remains as the hydroalumination itself was conducted in benzene, not toluene, and the benzene could not be fully removed. As before, small amounts of

202

hexanes are present, contributing to large alkyl peaks in the upfield region of the 1H

NMR spectra.

Spectrum 1: 1H NMR of 200 (olefin)

1 Spectrum 2: H NMR of 201 (R*AlBr2)

Spectrum 3: 1H NMR of 274a [R*AlBr(OR*)] after 10 minutes at -78 ºC

Spectrum 4: 1H NMR of 274a [R*AlBr(OR*)] after 1 hour at -78 ºC

Figure 5.4: Low temperature 1H NMR monitoring 274a at -78 ºC

The 1H NMR spectra shown above prove that even at -78 ºC, small amounts of olefin have returned, although the peaks do not appear to grow over time at this

203

temperature. It is possible that these peaks are a result of transferring the solution to the

NMR tube, although unlikely, as the syringe was precooled by washing with toluene-d8 at

-78 ºC, and the NMR tube was precooled under N2 at -78 ºC. Nevertheless, it appears that there may be less olefin returning at low temperature than had returned previously.

As a result, the Diels-Alder reactions previously conducted were redesigned. The

R*AlBr(OR*)-type Lewis acids had previously been prepared on a large scale to mitigate against any O2 contamination, and small amounts were transferred via syringe to a toluene solution of pre-cooled methacrolein at -78 ºC. This method made warming the

Lewis acid solution difficult to avoid. In line with the results from the low temperature

NMR study, however, only that amount of R*AlBr(OR*) required was prepared in situ and kept in a toluene solution at -78 ºC. This preparation was conducted by removing benzene from the R*AlBr2-type Lewis acid in vacuo, redissolving it in toluene or DCM, cooling the mixture to -78 ºC, and adding a pre-cooled dilute solution of lithated alcohol in toluene or DCM to the R*AlBr2-type Lewis acid solution down the side of the flask to keep it cold. Methacrolein and cyclopentadiene were then added to the mixture at low temperature, and were allowed to react over 3 hours at low temperature as before.

Prior to conducting this study, another chiral alcohol of interest was synthesized

71 in a single step via a modified procedure for LiAlH4 reduction (Scheme 5.5). The stereochemistry was confirmed by comparing 1H NMR values to known values.72

LiAlH4

THF OH o O 2 h, 0 C 89 % 198 279 Scheme 5.5

204

The results from the new series of Diels-Alder studies using R*AlBr(OR*) Lewis acids kept at low temperature are outlined below (Table 5.3). These Diels-Alder reactions were conducted in both DCM and toluene, as it was thought the more polar DCM might further inhibit the dehydroalumination process along with the low temperature. As described in chapter 2, mixing DCM with RAlBr2-type Lewis acids results in a vigorous exothermic reaction. It may be that the chlorine atoms are coordinating to the Lewis acidic aluminum atom. If so, this solvent was a logical choice to mitigate against any dehydroalumination taking place.

Table 5.3: Diels-Alder reactions promoted by R*AlBr(OR*) LAs kept at low temperature O O 10c, 9 H OR Al 1 H DCM + Br O -78 oC Al R 280 1 3 h exo-11c endo-11c Br 274a-c

a: R1 = 3 OH b: R1 = 278 OH c: R1 = 279 OH

278 279 3 Entry Catalyst Yield (%)a exo:endob ee (%)c 1 274a 69 17:1 3.2 (+) 2 274ad 22 50:1 8.4 (+) 3 274b 76 20:1 4.2 (-) 4 274c 72 13:1 1.3 (+) 5e 274a 68 29:1 16 (+) aYields determined by integrating product peaks against 1-dodecene. bexo:endo ratios determined by 400 MHz 1H NMR. cDetermined by optical rotation. d2.0 eq. lithiated alcohol 3. eReaction conducted in toluene.

Comparing the Diels-Alder reaction catalyzed by 274a in DCM (Table 5.3, entry

1) and in toluene (entry 5), however, revealed toluene to be the superior solvent.

205

Diastereoselectivity was far better in toluene, favoring the exo adduct in a 29:1 ratio, compared to only 17:1 in DCM. Most importantly, the ee jumped from only 3.2 % in

DCM to 16 % in toluene. Although this is a significant improvement from what had previously been obtained using R*AlBr(OR*)-type Lewis acids that had been allowed to warm to room temperature, it was still a considerable reduction in enantioselection from that previously obtained using Koga’s original methodology.

Interestingly, both the diastereoselectivity and the enantioselectivity improved significantly by using 2.0 equivalents of lithiated 3 to generate the corresponding

R*Al(OR*)2-type Lewis acid, but at great cost to the reaction yield (entry 2).

It may be, as previously hypothesized, that multiple catalytic species exist in solution, but by not allowing the R*AlBr(OR*) mixture to ever warm above -78 ºC, there may simply be less of the dehydroaluminated HAlBr(OR*) Lewis acid 280 relative to the amount of R*AlBr(OR*)-type Lewis acid remaining, and the ee consequently improves slightly. Although the fact that a dehydroalumination appeared to be taking place was discouraging, the slight improvement in ee obtained by keeping the mixture cold was promising, and a subsequent generation of R*AlBr(OR*)-type Lewis acid structures was therefore targeted and designed.

5.2.3: Novel R*Al(R*NO) derivatives using chiral tertiary amines

It was hypothesized that by adding a tertiary amine to the chiral alcohol, the dehydroalumination process could be inhibited. After all, the p-orbital on the aluminum atom needs to be available to accept the hydride for the dehydroalumination process to

206

proceed. The inspiration for this concept came from a paper published by Corey in 2003, although the proposed strategy is also somewhat different.73 As reported by Corey, boron-based Lewis acid 281 was synthesized by combining a tertiary amino alcohol ligand with BBr3 and used to promote the same Diels-Alder reaction described above in

96 % yield, with greater than 99:1 exo:endo selectivity, and in 96 % ee, an absolutely outstanding result (scheme 5.6).

Ph O O O o N Br DCM, -94 C Ph B + H 281, 1 hour O

9 10c exo-11c endo-11c Br

96 % yield 281 99:1 exo:endo 96 % ee Scheme 5.6

It was hypothesized that a bromine substitution from the lithiated alcohol would proceed more quickly than that from the tertiary amine, to rapidly yield aluminum complex 274d (Scheme 5.7). As soon as this substitution took place, the free lone pair on the nitrogen atom would donate into the empty p-orbital of the aluminum atom, as shown in 274e, preventing the dehydroalumination from taking place. It was also supposed that a third structure, that of 274f, might be in equilibrium with the other two structures. This third structure is formed after the tertiary amine has displaced the second bromine atom and formed a salt. Either 274d or 274f would be the active catalytic species, with 274e existing in equilibrium simply to slow down the competing dehydroalumination reaction.

207

LiBr LiBr LiBr 1) nBuLi N Br Br OH Al N N N 2) 201 Al Al O O O Br 284 274d 274e 274f Scheme 5.7

Thus, an N-methylated amino-alcohol derivative of (S)-proline (284) was synthesized in a two-step sequence from (S)-proline. Amino alcohol 284 was deprotonated with a single equivalent of nBuLi and added dropwise to R*AlBr2-type

Lewis acid 201 at -78 ºC. Unfortunately, the species that formed was completely insoluble in both DCM and toluene. It was soluble in THF, however, and the Diels-Alder reaction was conducted in THF. At -78 ºC over 3 hours, the Diels-Alder reaction went to less than 5 % completion (Table 5.4, entry 3), but over 18 hours at -25 ºC, product was formed in 44 % yield, with 24:1 exo:endo selectivity and 5.3 % ee (entry 4). Examination of the Lewis acid so formed as a solution in THF-d8 revealed the reappearance of olefin peaks corresponding to olefin 200, indicating the undesired dehydroalumination reaction was still occurring.

Another tertiary amine-based Lewis acid was investigated as a possibility, that being 287, formed from a double susbstitution reaction using ditertiary amine 286, which could be synthesized from (R)-BINAM (285) in a single step (scheme 5.8). The trouble with this method was that the formation of multiple Lewis acid species might form in solution, with simple coordination competing with the desired disubstitution, as previously proposed in scheme 5.7. Both because adduct 286 was expensive and because it contained multiple peaks in its 1H NMR spectrum, TMEDA (288) was chosen instead

208

to study the binding process. TMEDA was bound to Lewis acid 99 and the 1H NMR spectrum monitored over time (figure 5.5).

Table 5.4: Diels-Alder reactions using catalyst 274d Pd/C LiAlH4 N H CO N THF N H COOH 2 MeOH COOH reflux, 24 h OH H2 282 283 284

1) nBuLi H N 2) 201 Br OH N Al 284 O 274d O O O 0.25 eq. 274d + H

9 10c exo-11c endo-11c Entry Solvent Yield (%)a exo:endob ee (%)c 1 toluene, -78 ºC, 3 h NR NA NA 2 DCM, -78 ºC, 3 h NR NA NA 3 THF, -78 ºC, 3 h <5 NA NA 4 THF, -25 ºC, 18 h 44 24:1 5.3 aYields determined by integrating product peaks against 1-dodecene. bexo:endo ratios determined by 400 MHz 1H NMR. cDetermined by optical rotation. dReaction conducted in THF.

1,4-dibromobutane Br N RAlBr N NH hunig's base 2 2 Al R NH toluene R = hexane 2 N N reflux, 24 hours Br

285 286 287 Scheme 5.8

209

As can be seen on the first NMR spectrum obtained immediately after the two compounds were mixed, three peaks between -0.5 and 0.5 ppm can be observed. The two upfield peaks are kinetic products that form quickly, and then disappear over time, likely corresponding to coordination complexes 289a and 289b wherein the aluminum atom has a formal negative charge. This negative charge explains the upfield shift relative to the third peak at 0.3 ppm. This third peak is very broad and grows over time, with the peak at

18 hours being considerably larger. Thus it may be that the desired Lewis acid 289c forms slowly over time.

N Br Br Br RAlBr2 99 N N N N N N N R = hexane Al Al Br Al Br Br 288 R Hb Hc Ha R R Ha Hb Hc 289a 289b 289c

Spectrum 1: 1H NMR after 5 minutes

Spectrum 2: 1H NMR after 18 hours

Figure 5.5: Lewis acid 99 reacting with TMEDA in toluene over time

210

The Diels-Alder reaction using the mixture of catalyst isomers 289a-c that had been aged for 18 hours was also used to determine the optimum conditions for this type of catalyst system (Table 5.5). The reaction did not proceed over 3 hours at -78 ºC, but did so at -25 ºC.

As a result, Lewis acid 287 was prepared by mixing 286 with RAlBr2-type Lewis acid 99 (R = hexyl) and allowing the mixture to stir over a full day before using it to promote the Diels-Alder reaction over 3 hours at -25 ºC. Unfortunately, the enantioselection using this method was limited to only a 5.2 % ee (Table 5.5). This is not completely surprising, as the NMR study (Figure 5.5) demonstrated there were likely multiple aluminum complexes existing in solution. It is therefore possible that an unexpected Lewis acidic catalyst complex catalyzes the Diels-Alder reaction, with the anticipated structure being inactive or absent. With this failure, the next generation of catalyst structure derived from RAlBr2-type Lewis acids was sought.

Table 5.5: Diels-Alder reactions promoted by tertiary amine-based aluminum Lewis acids O O O toluene, 3 h + H 25 % catalyst

9 10c exo-11c endo-11c Entry Catalyst, conditions Yield (%)a exo:endob ee (%)c 1 289a-c, -78 ºC 5 NA NA 2 289a-c, -25 ºC 51 20:1 NA 3 289a-c, 0 ºC 59 20:1 NA 4 287, -25 ºC 60 25:1 5.2 aYields determined by integrating product peaks against 1-dodecene. bexo:endo ratios determined by 400 MHz 1H NMR spectroscopy. cDetermined by optical rotation.

211

5.3: Using RAlBr2 Lewis acids as both an electrophile and a base in conjuction with monolithiated enantiopure BINOL-based compounds

With the dehydroalumination process proposed herein being supported by the body of data in section 5.2, the next generation of aluminum-based catalyst complex structures was investigated. Initial efforts to design a catalyst had been with the goal of reducing or eliminating the dehydroalumination from occurring. The next generation of catalyst structure was designed to allow it to happen.

Br +LiBr OH nBuLi OLi RAlBr2 99 O Al OH toluene OH R = hexane OH H

290 291 292a dehydroalumination sequence:

Br Br H O Al O Al O R H Al Br OH OH O

+ hexene + hexene 292a 292b 293 deprotonation sequence:

Br O Al O R Al Br OH O + hexane 292a 293 Scheme 5.9

If adding lithiated alcohols at any temperature resulted in a dehydroalumination, it meant that RAlBr2-type Lewis acids provided excellent precursors for a strategy to 212

generate novel aluminum-BINOL complexes with a bromine atom attached to the aluminum atom. The proposed process is shown above in scheme 5.9. A single equivalent of n-BuLi as a solution in hexane was used to monolithiate one of the hydroxyl groups on

(R)-BINOL. Lewis acid 99 (R = hexyl) is then added to 291 to generate 292a in situ.

Following the formation of 292a, there are two possibilities proposed above. The simplest is for the basic hexyl R group to deprotonate the second hydroxyl group to generate the targeted BINOL-aluminum bromide complex 293. If the dehydroalumination reaction occurs more quickly than the deprotonation reaction, dehydroalumination will predominate, generating aluminum hydride 292b in situ. Even in this case, however, the basic hydride can still deprotonate the second hydroxyl group in 292b to form the target

BINOL-aluminum bromide complex 293. In either proposed scenario, the desired aluminum complex 293 is likely to form in situ. Thus BINOL-based Lewis acid 293 seemed like the perfect Lewis acid target to compensate for the dehydroalumination reaction that was occurring.

LA 99 is the most appropriate RAlBr2 compound to use, since whether the R group in 292a or the hydride in 292b acts as the base to deprotonate the second phenol group, the resulting side products are both volatile and can be are removed in vacuo if desired. Hexane is generated if the R group deprotonates the second hydroxyl group, as shown in the deprotonation sequence (Scheme 5.9). Since hexane was already present in solution based on the addition of a hexane solution of nBuLi, this process adds no new chemical species to solution. Hexene is generated if the hydride deprotonates the second phenol group following dehydroalumination (Scheme 5.9). The only other side product generated in this process is a second equivalent of LiBr, due to the substitution reaction to

213

generate 292a, which was also already present in solution from the hydroalumination reaction to generate LA 99 as described above.

5.3.1: The Diels-Alder reaction between methacrolein and cyclopentadiene catalyzed by novel BINOL-aluminum bromide complex 293

Lewis acid 293 was used to catalyze the Diels-Alder reaction between 9 and 10c in toluene at both -25 ºC and -78 ºC, as it was uncertain whether this new BINOL- aluminum derivative would promote the Diels-Alder reaction at all. The results of these reactions are shown below in Table 5.6. At -25 ºC, the reaction proceeded in 60.2 % yield over 3 hours, with a 20:1 exo:endo ratio and a 4.8 % ee. At -78 ºC, however, the exo:endo ratio is much better, at 33:1, with a 20.4 % ee. This is a good result, but improvements were desired, and thus the chemical literature was surveyed.

Table 5.6: Diels-Alder reaction between 9 and 10c in toluene at low temperature O O O toluene + H 24 hours 0.25 eq. 293 9 10c exo-11c endo-11c Entry Temperature Yield (%)a exo:endob eec 1 -25 ºC 60.2 20:1 4.8 2 -78 ºC 41.6 33:1 20.4 aYields determined by integrating product peaks against 1-dodecene. bexo:endo ratios determined by 400 MHz 1H NMR spectroscopy. cDetermined by optical rotation.

BINOL-aluminum complexes catalyzing the Diels-Alder reaction between 9 and

10c have been reported in the chemical literature. Yamamoto and Rheingold have both

74 reported procedures to generate catalyst 294a in situ from (R)-BINOL and Et2AlCl.

This process is shown below in Table 5.7. As originally described by Yamamoto, (R)-

214

BINOL ligands 290a-d were reacted at 25 ºC over 30 minutes with Et2AlCl to produce

Lewis acids 294a-d in situ. Interestingly, the Diels-Alder adduct from the reaction using

294a as catalyst could only be obtained in 5 % overall yield and in 19:1 exo:endo. The ee, from this reaction, however, was 41 % (entry 1). Yamamoto’s best result, that obtained using catalyst 294d, generated Diels-Alder adduct quantitatively in 98 % ee, with a 98:2 exo:endo ratio (entry 4). A better result than this could not be found in the chemical literature.

Table 5.7: Literature precedents for BINOL-aluminum complex catalysis of Diels-Alder reaction O O O DCM + H 3 hours 5 % 294 9 10c exo-11c endo-11c

Et2AlCl (1 eq.) Ligand 290a-d Catalysts 294a-d CH2Cl2 25 oC, 30 min

SiAr3

OH OH Ph OH Ph OH OH OH Ph OH Ph OH

SiAr3

290a 290b 290c 290d Entry Catalyst Yield (%) exo:endoa eeb 1 294a 5 % 19:1 41 % (+) 2 294b 100 % 13:1 17 % (-) 3 294c 100 % 24:1 29 % (+) 4 294d 100 % 98:2 98 % (-) 5c 294a 10 % 11:1 Not conducted aexo:endo ratios determined by 400 MHz 1H NMR. bDetermined by optical rotation. cResults obtained in the Keay lab repeating Yamamoto’s original procedure.

215

The same Diels-Alder reaction using catalyst 293 generated in the Keay lab from

(R)-BINOL (Table 5.6, entry 2) already provided superior yield (41.6 %) and diastereoselectivity (33:1 exo:endo) to that obtained by Yamamoto using 294a, also derived from unsubstituted (R)-BINOL, although the enantioselection obtained with 293 was worse, yielding adduct in only 20.4 % ee. In addition, the result above was repeated exactly as originally described by Yamamoto to verify it was reproducible (Table 5.7, entry 5).74b Repeating Yamamoto’s procedure using 294a in the Keay lab resulted in product forming in only 10 % yield and 11:1 exo:endo. Unfortunately, the product mixture was very complex, and it was not possible to isolate sufficient pure adduct to get a reliable optical rotation reading at the polarimeter.

Inspired by Yamamoto’s results using DCM as solvent, and having previously conducted the Diels-Alder reaction using LA 293 in toluene, DCM was chosen as the solvent to determine if the results already obtained with 293 could be improved with such a simple change in the experimental procedure. These results are outlined below in Table

5.8.

Although Yamamoto reported 3 hour reaction times, the first reactions conducted using catalyst 293 in toluene (Table 5.6) were carried out over 24 hours. Thus the initial reactions in DCM using catalyst 293 were also conducted over 24 hours for the purposes of comparison to earlier results. The first amount of LA 293 delivered to the reaction mixture was 0.25 equivalents, as this is also what had been done previously in toluene.

As can be seen below, the reaction worked much better in DCM, proceeding to 73 % yield with a 32 % ee (entry 1).

216

Table 5.8: Diels-Alder reaction catalyzed by 293 in DCM O O O LA DCM + H 24 hours -78 oC 9 10c exo-11c endo-11c

Me2AlCl (1 eq.) Ligand 290a Catalyst 294a CH2Cl2 -78 oC, 30 min

O OH Al R OH O

290a 293: R = Br 294a: R = Cl Entry Equivalents LA Yield (%)a exo:endob eec 1 0.25 293 73.3 20:1 32 (+) 2 0.25 294a 60.9 12.5 4.2 (+) 3 0.10 293 62.5 25:1 32 (+) 4 0.10 294a 60.2 12.5:1 1.2 (+) aYields determined by integrating product peaks against 1-dodecene. bexo:endo ratios determined by 400 MHz 1H NMR. cDetermined by optical rotation.

Interestingly, a new bottle of Me2AlCl was ordered and used instead of the nBuLi/RAlBr2 combination without changing any of the reaction conditions, and yield, exo:endo, and enantioselection all fell considerably, with the latter going only to 4.2 % ee. This is a very interesting result, as it indicates that the nBuLi/RAlBr2 system results in different BINOL-aluminum speciation than does simply adding Me2AlCl to (R)-BINOL under the same experimental conditions.

The most likely explanation for this is that the deprotonation of BINOL using

Me2AlCl is likely very fast, and not very selective, with two very fast deprotonation steps occurring, meaning that the difference in rate between intramolecular deprotonation and

217

intermolecular deprotonation is small. This most likely leads to dimeric, monomeric, and likely even polymeric BINOL-aluminum speciation (scheme 5.10).

It was hypothesized that under the same conditions using lithiated BINOL and

RAlBr2, the deprotonation of the phenol moiety may occur quickly, but that the substitution reaction of the lithium phenoxide moiety may occur comparatively slowly.

The slower rate of substitution would favor intramolecular substitution over intermolecular substitution, favoring the targeted BINOL-aluminum complex structure

293 over related dimeric and oligomeric structures.

Cl O Al Me OH Me2AlCl O H H O OH Me Al O Cl

290a 295

Cl Cl O Al O O Al O

O Al O * O O Al * Cl Cl n 296 297 Scheme 5.10

This process is detailed above in scheme 5.10. The untargted deprotonation that can occur is displayed above in 295. The dimer so formed is shown above in 297, with polymer being shown in 296. Trimers, tetramers, and so forth are all likely to form as well, resulting in multiple species in solution. If only a monomeric BINOL-aluminum

218

complex formed as expected, the 1H NMR spectrum would be simple, yet the in situ 1H

NMR spectrum for 294a was complex (Figure 5.6, spectrum 1). It was thought that since

Lewis acid 293 was resulting in enantioselection in the Diels-Alder reaction between 9 and 10c, the 1H NMR spectrum would be simpler, and that peaks for 293 could be identified and assigned. Unfortunately, the 1H NMR spectrum for 293 (spectrum 2) was just as complex and incomprehensible as that for 294a. Unreacted BINOL could be recovered following dilute H+ workup (spectrum 3), indicating that the complex spectra were due to complex speciation, rather than the BINOL reacting irreversibly.

Spectrum 1: 1H NMR of 294a

Spectrum 2: 1H NMR of 293

Spectrum 3: H+ worked up 293

1 + Figure 5.6: H NMR spectra of 294a, 293, and H quenched product BINOL (d5- pyridine)

219

In a similar fashion to the 1H NMR binding study to oxazolidinone-based dienophiles reported in chapter 3, the 1H NMR spectra show nothing except that the speciation is different between 294a and 293. At this point is not possible to explain what is happening in solution, and this is therefore a topic for future research. It is sufficient that LA 294a was not generating enantioselection in the Diels-Alder reaction between 9 and 10c while LA 293 was doing so under identical conditions. With these revelations in mind, Diels-Alder experiments in DCM using LA 293 as a catalyst in 10 % loading were continued, in order to reduce the catalyst loading.

Table 5.9: Diels-Alder reaction catalyzed by 293 over 3 hours, and concentration effects O O O DCM + H 24 hours 0.10 eq. 293 9 10c exo-11c endo-11c Entry Concentration of methacrolein Yield (%)a exo:endob eec 1 0.6 M 64.1 17:1 30.1 (+) 2 0.24 M 66.6 20:1 31.9 (+) 3 0.08 M 65.7 25:1 9.6 (+) aYields determined by integrating product peaks against 1-dodecene. bexo:endo ratios determined by 400 MHz 1H NMR. cDetermined by optical rotation.

The next step was to determine if concentration played a significant effect on the enantioselection of this reaction. A number of different concentrations were tested in the

Diels-Alder reaction over 24 hours. The results of these experiments are shown above in

Table 5.9. As can be seen from these experiments, the concentration of the dienophile does play an important role. In concentrated conditions, the results are very comparable.

When the conditions become dilute however, the enantioselectivity drops considerably

220

from 31.9 % to 9.6 %. This observation will be elaborated on later in the chapter, but for the moment the 0.24 M concentration of dienophile previously used was determined to be optimal, and was therefore used as the concentration of dienophile for all subsequent

Diels-Alder reactions.

The most obvious thing to test next was 3,3’-disubstituted derivatives of (R)-

BINOL. Five of these were purchased from Aldrich, and used in exactly the same way as described above. The results of these reactions are outlined below in Table 5.10.

Table 5.10: Diels-Alder reaction between 9 and 10c catalyzed by 299a-e R R O O methacrolein (10c) O OH 1) nBuLi cyclopentadiene (9) Al Br OH 2) LA 99 o O DCM, -78 C 24 hours exo-11c endo-11c R R 298a-e 299a-e 293: R = H c: R = 2,4,6-triisopropylphenyl a: R = 9-anthracene d: R = 3,5-trifluoromethylphenyl b: R = 9-phenanthrene e: R = 2,4,6-triisopropylphenyl Entry Catalyst Yield (%)a exo:endob eec 1 293 66.6 20:1 31.9 (+) 2 299a 79.2 14:1 27.3 (-) 3 299b 76.9 14:1 37.5 (-) 4 299c 76.8 17:1 36.1 (-) 5 299d 71.8 14:1 11.0 (+) 6 299e 76.9 17:1 36.7 (-) aYields determined by integrating product peaks against 1-dodecene. bexo:endo ratios determined by 400 MHz 1H NMR spectroscopy. cDetermined by optical rotation.

Interestingly, a reversal of product enantiosense was observed for catalysts 299a,

299b, 299c, and 299e. A significant increase in enantioselection was also observed for

299b, 299c, and 299e, with exo-11c being obtained in 37.5, 36.1, 36.7 % ee respectively with these three catalysts. The exo:endo ratio was poorer for the 3,3’-disubstituted

221

BINOL derivatives tested, dropping from an exo:endo ratio of 20:1 with 293 to a 14:1 ratio for catalysts 299a and 299b, and a 17:1 ratio for catalyst 299e. Better enantioselection than what was obtained was expected, but an ee of just under 40 % was also not unreasonable, as these were only the very first efforts to develop these novel catalytic systems.

These reactions had been conducted over 24 hours, due to having initiated this chemistry in toluene over 24 hours, but as previously mentioned, Yamamoto reported

LAs 294a-d catalyzing the Diels-Alder reaction described herein over 3 hours, not 24 hours (Table 5.7). Thus, the Diels-Alder reaction was repeated over 3 hours in DCM just to rule out the different reaction time making a difference. It was hypothesized that there would be no difference between a 3 hour and a 24 reaction time, and that in fact the yield would be higher over 24 hours than it would be over 3 hours, as the highest yield obtained over 24 hours was only 76.9. The result of this experiment is outlined below in

Table 5.11, along with one additional control reaction.

It was presumed that the nBuLi/RAlBr2 system worked based on the superior ability of bromine as a leaving group. If the substitution of the bromine was a significant factor in the observed enantioselection as previously described, it was hypothesized that the use of nBuLi in conjuction with EtAlCl2 would result in a significant decrease in the performance in the Diels-Alder reaction. This would also make for a very good control reaction, as the only other difference was the length of the alkyl chain in the aluminum compound, presumed to be completely insignificant. Thus the reactions using nBuLi/EtAlCl2 and nBuLi/LA 99 with (R)-BINOL over 3 hours in DCM were set up in exactly the same way, with the results outlined below in table 5.11.

222

Table 5.11: Diels-Alder reactions over 3 hours comparing LA 99 and EtAlCl2

O O methacrolein O OH 1 cyclopentadiene (9) Al X OH 2 o O DCM, -78 C 3 hours exo-11c endo-11c

290a procedure 1: 293, X = Br procedure 2: 294a, X = Cl

1: nBuLi, LA 99 AlBr2 2: nBuLi, EtAlCl2 99 Entry Conditions Yield (%)a exo:endob eec 1 1 79.3 20:1 32.5 2 2 19.7 20:1 4.0 aYields determined by integrating product peaks against 1-dodecene. bexo:endo ratios determined by 400 MHz 1H NMR spectroscopy. cDetermined by optical rotation.

These two reactions revealed three things conclusively. For the reaction with 293, the first is that neither the exo:endo ratio nor the enantioselectivity changed appreciably between 3 hour and 24 hour reaction times. The second is that the yield was 13 % higher when the reaction was carried out over 3 hours relative to 24 hours. This observation indicates that the reaction likely proceeds to completion more quickly than previously hypothesized, and that over time product degradation occurs. The third and final observation is that the bromine atoms play a crucial role in this novel chemistry, as when the identical reaction was carried out using EtAlCl2 instead of LA 99, the reaction proceeded in only 19.7 % yield with a 4.0 % ee, although the exo:endo ratio was actually found to be exactly the same.

One final test that was carried out was the use of (R)-VAPOL (290d) as the ligand. As previously discussed, Yamamoto had determined this ligand in conjuction with Et2AlCl produced catalyst 294d, which catalyzed the Diels-Alder reaction in 100 %

223

yield, with an 98:2 exo:endo ratio and in 98 % ee (Table 5.7, entry 4). It was thought that repeating these results by generating a novel VAPOL-aluminum bromide catalyst complex would be a fitting way to finish these investigations. When this reaction was set up using nBuLi/LA 99, however, the reaction proceeded in only 60 % yield and 6.8 % ee, with a 17:1 exo:endo ratio (scheme 5.11).

O O methacrolein O Ph OH 1) nBuLi Ph cpd Al Br Ph OH Ph DCM, -78 oC 2) LA 99 O 3 hours exo-11c endo-11c 60 % yield 17:1 exo:endo 290d 294d 6.8 % ee Scheme 5.11

This was an unexpected result, and the explanation was not immediately obvious.

It is likely that the enantioselective catalyst complex does not form rapidly, that but as a mixture of species that changes over time to form the desired complex. The enantioselective reactions using other 3,3’-derivatized BINOL compounds were carried out over 24 hours (Table 5.10), giving this process plenty of time to occur. Unsubstituted

(R)-BINOL proceeds in much the same way, but due to a lack of steric hindrance, this proposed equilibration process proceeds much more quickly, resulting in identical results between 3 hour and 24 hour trials in all respects except yield. Due to the very high steric hindrance of 290d, this proposed transformation process does not proceed quickly, and the enantioselection reaches only 6.8 % over the 3 hours the reaction was carried out.

224

There is one additional piece of evidence previously determined that is consistent with this hypothesis. The enantioselection was previously determined to be significantly poorer in dilute solution, proceeding to only 9.6 % ee at a dienophile concentration of

0.08 M (Table 5.9, entry 3), compared to 31.9 % ee at a dienophile concentration of 0.24

M (entry 2). If an transformation process requiring molecular collisions was taking place to generate an enantioselective catalyst complex over time, it would likely proceed more slowly in dilute conditions than it would in concentrated conditions, and thus the enantioselection would be poorer in dilute conditions. Using larger ligands in concentrated solution may result in more molecular collisions, but due to the increased steric bulk of the ligands, the collisions may not immediately result in the necessary chemical transformation taking place, instead requiring several hours.

This hypothesis needed to be tested, and it was a very easy hypothesis to test. If it was correct, one of the previously used sterically hindered chiral 3,3’-disubstituted

BINOL compounds could be used in the Diels-Alder reaction over 3 hours instead of 24 hours, and a reduction in enantioselectivity would be observed. Phenanthrene-substituted

BINOL derivative 298b was chosen for this experiment as it was previously determined to generate the best enantioselection out of all the BINOL ligands tested in the previous series of experiments. The results from carrying out this reaction over 3 hours instead of

24 hours are outlined below in Table 5.12.

225

Table 5.12: Time study of the Diels-Alder reaction using 299b as catalyst R R O O methacrolein O OH 1) nBuLi cyclopentadiene (9) Al Br OH 2) LA 99 O DCM, -78 oC exo-11c endo-11c R R 298b 299b R = 9-phenanthrene Entry Time Yield (%)a exo:endob eec 1 3 hours 82.3 25:1 7.2 (-) 2 24 hours 76.9 14:1 37.5 (-) aYields determined by integrating product peaks against 1-dodecene. bexo:endo ratios determined by 400 MHz 1H NMR spectroscopy. cDetermined by optical rotation.

The results above clearly support the postulated hypothesis, with the ee dropping to only 7.2 % over 3 hours (entry 1), down from 37.5 % over 24 hours. Interestingly, the yield increased to 82.3 % over 3 hours, consistent with what was previously observed over 3 hours. Also interestingly, the exo:endo selectively almost doubled over 3 hours, strongly supporting the contention that the dominant catalytic complex in solution changes over time.

It is not immediately clear that conducting the Diels-Alder reaction over 24 hours would be the answer to improve this chemistry, as the highest yields are obtained over shorter reaction periods. It may therefore be that the catalyst would need to sit over several days before the desired complex was formed in the majority. The Diels-Alder reaction would only then be carried out over 3 hours. It may also be that the binding of methacrolein speeds up the transformation process of the catalyst, meaning that that cyclopentadiene should not be added immediately, but that the transformation process should be given sufficient time before the Diels-Alder reaction begins. It may also be that

226

the lithium bromide is involved in the aluminum complexation, and it changes the reactivity significantly. Regardless, these are questions best left for future study.

5.3.2: The Epoxide Opening reaction of meso-epoxides promoted by novel BINOL- aluminum bromide complex 293

The asymmetric epoxide opening of meso-epoxides to generate -chlorohydrins was described previously in chapter 1 (Table 1.22). The methodology being developed using nBuLi/RAlBr2 to generate BINOL-aluminum bromide complexes was perfect for an epoxide ring opening, because LiBr is generated during the hydroalumination of 1- hexene to afford Lewis acid 99, and another equivalent of LiBr is generated during the substitution reaction to generate BINOL-aluminum bromide complex 293. This lithium bromide could be put to great use by opening meso-epoxides in the presence of chiral

BINOL-aluminum complex 293 to yield -bromohydrins. As the majority of focus was devoted to the asymmetric Diels-Alder reaction between methacrolein and cyclopentadiene, the asymmetric epoxide opening reaction was given comparatively less attention, and expanding this chemistry beyond what is reported herein will therefore be the subject of future research. Nevertheless, the results from the opening of simple meso- epoxides using this novel BINOL-aluminum bromide complex are shown below in Table

5.13.

227

Table 5.13: Complex 293 and the opening of meso epoxides OH OH O O 293 Br 293 Br R R O OnBu DCM R DCM R Al -78 oC -78 oC O Cl 71 273b 300: R = Ph 301: R = Ph

76 Entry Time (hours) Meso-epoxide Yield (%)a ee (%)b 1c 3 71 6 Not measured 2 3 71 14 13.2 3 24 71 55 16.8 4 24 300 65 10.6 aYields determined by integrating product peaks against 1-dodecene. bDetermined by optical rotation. cReaction conducted in toluene.

Opening 71 using 293 proceeded in only 6 % yield in toluene over 3 hours at -78

ºC (entry 1). Due to the very small conversion, no pure product could be isolated to measure the % ee. When the solvent was changed to DCM, however, the yield improved to 14 % and pure 273b was obtained in 13.2 % ee (entry 2). Obviously the reaction required more time to go to completion at this temperature, and it was thus conducted over 24 hours instead of 3 hours (entry 3). Over 24 hours, the same reaction proceeded to

55 % yield, and pure 273b was obtained in 16.8 % ee. While this yield is not very good, it is nevertheless significantly better than the best yield obtained by Yamamoto over this same time period. Yamamoto’s best results included a 40 % yield and a 40 % ee, after considerable optimization. In fact the catalyst used by Yamamoto to generate the 40 % ee was 76, the n-butoxide derivative of 294a. It is quite likely that BINOL-aluminum bromide complexes could promote the epoxide opening of cyclohexene oxide with comparable enantioselection, but as with the Diels-Alder reaction, further optimization and study will be necessary.

228

Apart from cyclohexene oxide, epoxide 300 was also opened with product being obtained in 65 %. The enantioselection of the opening of this meso-epoxide was slightly poorer, with adduct being obtained in only 10.6 % ee. It was hypothesized that the more bulky phenyl substituted meso-epoxide would provide the higher ee, but unfortunately the results were just the opposite, with 300 providing the poorest enantioselection of the two epoxides tested. It would be interesting to repeat this chemistry by adding nBuOLi to the solution of 293, just as Yamamoto had originally reported to transform 294a to 76 (Table

5.13).

5.3.3: The BINOL-aluminum bromide complex 293 promoted Strecker reaction

In addition to prochiral imine 192 previously synthesized (Scheme 3.17), two new prochiral imines were synthesized. One of them was allyl protected imine 192c, which has been used by Sigman and Jacobsen.75 These syntheses, carried out exactly as before, are shown below in scheme 5.12.

O NH toluene H 2 + reflux N 24 hours 302 190 91 % 192b O toluene N H + reflux NH 2 24 hours 191 303 80 % 192c Scheme 5.12

229

Sigman and Jacobsen used imine 192c in a Strecker reaction with TMSCN, catalyzed by SALEN derivative aluminum complex 305 (scheme 5.13). In fact the bulk of the reactions they reported used HCN as the cyano-containing reagent. Nevertheless, they did use TMSCN for several reactions, although the experimental procedure they reported for the reaction was only for HCN. The best result of the experiments conducted by Sigman and Jacobsen between 192c and TMSCN is shown below in scheme 5.13.

Et2AlCl N N N N

CH2CH2 Al OH HO 25 oC, 2h O Cl O

304 305 O 1) 305 N F3C N TMSCN 23 oC, 15h CN

2) CF3COOCOCF3 192c 306 100 % conv. 45 % ee Scheme 5.13

These Strecker reactions were repeated using BINOL-aluminum bromide complex 293, although they were conducted at -78ºC, because complex 293 was sufficiently Lewis acidic to promote the Strecker reaction at this temperature. The results from these Strecker reactions are shown below in Table 5.14. Significantly, Sigman and

Jacobsen had prepared the trifluoromethylacetate amide derivative 306 by working the reaction mixture up in trifluoracetic anhydride. They had done this because they found

230

some racemization during the purification step on silica gel. Despite this fact, crude mixtures produced in the Keay lab that were subsequently taken to the HPLC did not yield superior results to those that were first purified.

Table 5.14: Complex 293 and the enantioselective Strecker reaction using TMSCN

R R N 2 LA HN 2 O Al R TMSCN 3 CN O -78 oC, 24h R1 R1 192a-c 307a-c 293: R3 = Br 192a: R = Ph, R = Ph 307a: R = Ph, R = Ph 1 2 1 2 294a: R3 = Cl 192b: R1 = p-tol, R2 = Ph 307b: R1 = p-tol, R2 = Ph 192c: R1 = Ph, R2 = Allyl 307c: R1 = Ph, R2 = Allyl Entry Imine Catalyst Yield (%)a eeb 1 192a 293 72 4.0 2 192b 293 58 3.4 3 192c 293 50 9.1 4c 192c 294a 96 racemic aYields determined by integrating product peaks against 1-dodecene. bDetermined by c chilral HPLC using chiralcel OD column. Prepared by mixing (R)-BINOL with Me2AlCl at -78 ºC

Amine 307c was obtained in up to 9.1 % ee using this method, with amines 307a and 307b being obtained in 4.0 % ee and 3.4 % ee, respectively. Interestingly, the same reaction using catalyst 294a, prepared by adding Me2AlCl to (+)-BINOL, produced 307c as a racemate (entry 4). The enantioselection obtained in these experiments is slightly lower than anticipated, but nevertheless demonstrates a proof of principle that this chemistry can be further developed for the purposes of promoting the asymmetric

Strecker reaction. As described above, the majority of focus was devoted to the asymmetric Diels-Alder reaction. As the interest in the Strecker reaction was only insofar

231

as it could be demonstrated to proceed enantioselectively and approximately to what extent, further investigations into this reaction were discontinued.

5.3.4: Using the original chiral R*AlBr2 Lewis acids to catalyze the Diels-Alder reaction between methacrolein and cyclopentadiene in DCM

One of the interesting observations made above for both the Diels-Alder reaction and the epoxide-opening reaction was that DCM was a better solvent than was toluene.

Two of the first reactions conducted in the Diels-Alder reaction between 9 and 10c that was initially being explored as a model system were the Diels-Alder reactions promoted by Lewis acids 87 and 201 (Table 5.2). They both produced Diels-Alder adduct in 99 % yield in toluene, with approximately 10:1 exo:endo selectivity. These reactions were determined to be racemic, with absolutely no rotation on the polarimeter whatsoever. It was hypothesized that since DCM had provided better enantioselection for several of the reactions tested above, it may do the same for the Diels-Alder reaction between 9 and 10c catalyzed by R*AlBr2 Lewis acid 201. Thus a series of experiments were set up to determine if the original R*AlBr2 Lewis acids could finally be proven capable of promoting or catalyzing a reaction with significant enantioselection. Pleasingly, the reaction did produce Diels-Alder adduct enantioselectively, with exo-11c being isolated in 80 % yield and 13.3 % ee when conducted at -78 ºC over 3 hours in DCM (Table

5.15). With this success, several experiments were conducted for the purposes of improving these original results. A simple study was carried out to determine the optimal time and temperature for this reaction.

232

Table 5.15: Enantioselective Diels-Alder reaction catalyzed by R*AlBr2 LA 201

methacrolein O O LiAlH , AlBr cyclopentadiene 4 3 H benzene 0 oC DCM AlBr2 10 % catalyst exo-11c endo-11c 200 201 Entry Time (hours) Temperature (ºC) Yield (%)a exo:endob eec 1 1 -78 87 14:1 6.6 2 3 -78 80 25:1 13.3 3 5 -78 33 14:1 9.6 4d 3 -100 64 17:1 13.3 aYields determined by integrating product peaks against 1-dodecene. bexo:endo ratios determined by 400 MHz 1H NMR spectroscopy. cDetermined by optical rotation. dReaction mixture was a icy slurry

Interestingly, the reaction appears to go to completion very quickly, followed by a rapid degradation of products. After a single hour, the reaction had proceeded in 87 % yield (entry 1). After 3 hours, the yield had dropped to 80 % (entry 2), and by the time 5 hours had elapsed, the yield had dropped all the way to 33 % (entry 3). Interestingly, the same could be said for both the exo:endo ratios and the ee, which peaked at 3 hours and were both lower at 1 hour and at 5 hours. The reaction was also conducted at -100 ºC

(entry 4). This temperature was obtained using a MeOH/CO2 ice bath. Interestingly, at this temperature the reaction mixture was a slurry, but it nevertheless proceeded to 64 % yield and 13.3 % ee. Although higher enantioselection was desired, with these results the original goal of the project was accomplished, demonstrating that a chiral R*AlBr2-type

Lewis acid obtained via hydroalumination can successfully be used as an asymmetric catalyst.

The immediate question was whether some of the chiral olefins previously synthesized in chapter 4 might improve the enantioselectivity demonstrated by R*AlBr2

233

Lewis acid 201. With this goal in mind, several of the chiral olefins previously synthesized were synthesized once again, and tested in the asymmetric Diels-Alder reaction between methacrolein and cyclopentadiene. The results of these experiments are outlined below in Table 5.16.

Unfortunately, Lewis acid 201 provided the optimal results, with the enantioselection of Lewis acids 87 and 88 being non-existent, and that of 218 and 226 both yielding adduct in 4.0 % ee. Although these results may not be very high, they nevertheless comprise the first definite example of an R*AlBr2-type Lewis acid promoting or catalyzing an organic reaction enantioselectively.

Table 5.16: Diels-Alder reaction in DCM using various R*AlBr2 Lewis acids O O O 10 % RAlBr2 + H DCM, -78 oC 3 hours exo-11c endo-11c

Br2Al

AlBr2 AlBr2 AlBr2 87 88 218 226 Entry LA Yield (%)a exo:endob eec 1 87 87 11:1 racemic 2 88 78 11:1 racemic 3 218 81 13:1 4.0 4 226 86 8:1 4.0 aYields determined by integrating product peaks against 1-dodecene. bexo:endo ratios determined by 400 MHz 1H NMR. cDetermined by optical rotation.

234

5.4: Conclusions

A new class of BINOL-aluminum bromide complexes have been developed and used as catalysts in the asymmetric Diels-Alder reaction between methacrolein and cyclopentadiene with enantioselection up to 37.5 % ee when catalyst 299b was used

(Table 5.17, entry 1). Additionaly, these BINOL-aluminum bromide complexes were also shown to promote both asymmetric epoxide ring opening of meso-epoxides and asymmetric Strecker reactions using TMSCN, albeit with lower ee values obtained for both of these reactions. These are the first examples of a BINOL-aluminum bromide complex catalyzing a reaction enantioselectively.

Additionally, a series of R*AlBr(OR*)-type compounds were synthesized by lithiating chiral alcohols and adding them to the R*AlBr2 Lewis acids generated by hydroaluminating chiral olefins. A dehydroalumination sequence was shown to take place via NMR studies, with varying amounts of olefin returning on the 1H NMR spectra depending on the temperature of the mixture. Nevertheless, this methodology was also shown to promote the Diels-Alder reaction between methacrolein and cyclopentadiene enantioselectively, with an ee of 16 % being obtained for Diels-Alder adduct when catalyst 274a was used in toluene at -78 ºC (entry 2). This is the first example of an

R*AlBr(OR*)-type Lewis acid catalyzing a reaction enantioselectively.

Finally, and most significantly, R*AlBr2 Lewis acid 201 was shown to promote the same Diels-Alder reaction enantioselectively, with a 13.3 % ee being obtained for exo-adduct 11c (entry 3). This enantioselection is modest, but it is nevertheless an important result, as it was the original goal of the project. This is the first example of an

235

R*AlBr2-type Lewis acid catalyzing a reaction enantioselectively, and although further optimization is required, it demonstrates that the 3AlBr3·LiAlH4 hydroalumination system is a viable strategy for generating chiral aluminum-based Lewis acids for asymmetric catalysis.

Table 5.17: Summary of best results obtained in the Diels-Alder reaction O O O DCM, 3 h + H 10 % catalyst

9 10c exo-11c endo-11c

O H Al Br H O O Al Br AlBr R 2 201 299b 274a R = 9-phenanthrene Entry LA Yield (%)a exo:endob eec 1 299b 76.9 14:1 37.5 (-) 2d 274a 68 29:1 16 (+) 3 201 80 25:1 13.3 (+) aYields determined by integrating product peaks against 1-dodecene. bexo:endo ratios determined by 400 MHz 1H NMR. cDetermined by optical rotation. dConducted in toluene.

5.5 Future Work

As previously mentioned, there remains a number of interesting experiments that could be carried out to expand this chemistry. The most obvious is to expand the chemistry involving the novel BINOL-aluminum bromide complexes described in this chapter. Numerous studies are required, including how the catalyst transforms over time

236

in solution, and what the optimum reaction times are. This chemistry could prove very promising in a number of different reactions, including asymmetric opening of meso- epoxides due to the LiBr generated in situ. It would be interesting to synthesize novel

3,3’-derivatives of (R)-BINOL to find a balance between the steric bulk of the complex and its ability to direct enantioselection.

Another interesting approach to take would be to alter the approach originally used by Yamamoto to generate catalysts out of Et2AlCl, (R)-BINOL, and lithium alkoxides. One such proposed catalyst structure is outlined below in scheme 5.14. The reason this approach is desirable is that it could maximize the enantioselection obtained using simple (R)-BINOL, without the need for synthesizing or purchasing more expensive 3,3’-derivatized (R)-BINOL structures.

O LiOnBu O OH 1) nBuLi OnBu Al Br Al OH 2) LA 99 Br O O

290 293 308

Scheme 5.14

Another interesting project would be to test chiral secondary amines along with chiral R*AlBr2-type Lewis acids (scheme 5.15). This would be a very interesting set of experiments to conduct, as the lone pair on the nitrogen atom would back-donate into the empty p-orbital on the aluminum, and it may be sufficient back-donation to prevent the dehydroalumination reaction from proceeding at low temperature.

237

1) nBuLi H Al N N 2) 201 Br

309

310

Scheme 5.15

Chiral catalyst structure 310, were it formed in solution would almost certainly offer excellent enantioselection, and chiral amines such as 309 are available commercially. Were this chemistry to work, other chiral secondary amines could easily be synthesized to improve enantioselection in such reactions as the Diels-Alder reaction between methacrolein and cyclopentadiene, and the epoxide opening of meso-epoxides as well.

Finally, having proven that R*AlBr2 Lewis acids are capable of promoting the

Diels-Alder reaction between 9 and 10c enantioselectively, it would be interesting to synthesize still more chiral olefins with the goal of improving enantioselection in the

Diels-Alder reaction. One proposed structure is outlined below in scheme 5.16. Olefin

312 in particular is of interest, as quaternary carbon center a means that the previously described migration of the double bond would not be possible, and that the targeted structure would be obtained as a single isomer. This would also be a desirable synthetic sequence, as with 2 equivalents of MeI being used, no mixture of exo and endo isomers would be formed in generating 311. It is unclear which diastereomer of 313 would form

238

in the majority following hydroalumination, but with the additional methyl group on the exo face, it is presumed the exo diastereomer will form preferentially following an approach of the hydroaluminating agent from the endo face.

1) LiN(iPr)2 nBuLi a LiAlH4, AlBr3

o 2) MeI (2 eq.) MePPh3 benzene, 0 C AlBr O O 2 198 311 312 313

Scheme 5.16

239

CHAPTER SIX: EXPERIMENTAL METHODS

5.1: Experimental Conditions

Unless otherwise specified, all chemicals and reagents were obtained from

Aldrich. All anhydrous and anoxic reactions were conducted using flame dried glassware, and all syringes were stored in an oven (overnight at 120 ºC). All solvents were distilled under N2 atmosphere over CaH2, except for THF, which was distilled under N2 atmosphere over sodium benzophenone ketyl. Cyclopentadiene was slowly cracked under

N2 gas at atmospheric pressure immediately prior to use, while methacrolein was distilled under N2 after stirring over CaSO4 for several hours. Other common reagents such as triethylamine and pyridine were dried over CaH2 and stored in sure-seal bottles. All olefins and dienes were distilled over CaH2 or sublimed prior to use. All aqueous solutions used were saturated unless otherwise specified. The following methods were used to obtain sub-ambient temperatures: ice-water (0 ºC), dry ice-acetonitrile (-40 ºC), dry ice-chloroform (-60 ºC), dry ice-acetone (-78 ºC). For temperatures between -10 and

-30 ºC, a VWR HF-5015 freezer was used. All reaction mixtures were set up in dry glass ware evacuated in vacuo and back purged with ultra-high purity N2.

5.2 Chromatographic techniques

Aluminum-backed silica plates with a uniform 0.2 mm Merck silica gel 60 F254 were used for TLC. The plates were most often visualized using an ultraviolet lamp at

254 nm, but were also visualized by using one of the following three methods: 1)

240

immersion in a p-anisaldehyde developing solution (0.56 g p-anisaldehyde, 180 mL 95 %

EtOH, 4 mL concentrated H2SO4, 0.2 mL glacial acetic acid) followed by heating with a hot air gun, 2) immersion in a phosphomolybdic acid developing solution (10 % phosphomolybdic acid in EtOH) followed by heating with a hot air gun, or 3) immersion in a potassium permanganate staining solution (5 % KMnO4 in H2O) followed by thorough rinsing with plenty of H2O. Product mixtures were purified by flash column chromatography with silica gel (Aldrich, 230-400 mesh).

5.3 Compound Identification and Characterization

All melting points were obtained via electrothermal melting point apparatus in sealed capilliary tubes. All boiling points reported are uncorrected and refer to measured air-bath temperatures using a Kugelrohr short-path distillation apparatus.

Optical rotations were measured as individually specified using a 10 cm path length cell on a Rudolph Research Autopol IV Polarimeter. Only HPLC-grade solvents were used to prepare samples for optical rotation. Infrared spectra were recorded using a

FT-IR spectrometer, by fusing samples on a KBr plate from CHCl3 solutions.

NMR spectra were recorded on 300 MHz and 400 MHz spectrometers, and unless otherwise specified made use of CDCl3 as NMR solvent, with chemical shifts reported

1 relative to the internal reference peak of CDCl3 (7.27 ppm for H NMR, 77.16 ppm for

13 C NMR). For NMR spectroscopy analysis of the RAlBr2 Lewis acids, benzene-d6 was used as solvent, with chemical shifts reported relative to the internal reference peak of

1 13 1 C6D6 (7.16 ppm for H NMR, 128.06 ppm for C NMR). All H NMR data reported

241

herein are listed in the following format: chemical shift (multiplicity, number of protons, coupling constant). Low-resolution mass spectra and high-resolution mass spectra were obtained at the University of Calgary by Mrs. D. Fox using a Kratos MS80 mass spectrometer with 70 eV ionization direct probe sample introduction. An Agilent HP5973 capillary GC-MS was used as reported in the body of this work. Elemental analyses were obtained by Mr. J. Li on a Perkin Elmer Model 2400 series II CHN analyzer.

X-ray structure determination was carried out by Dr. Masood Parvez using a

Bruker APEX2 CCD installed on a Nonius Kappa Goniometer diffractometer with graphite monochromated Mo-K radiation.

5.4 Naming Standards

The names of structures presented within this chapter were obtained using the

Beilstein AutoNom Standard feature built into ChemDraw Ultra 7.0, and thus do not necessarily exactly follow IUPAC rules. Atom numbering is only for convenience and clarity of assignment, and thus does not necessarily reflect IUPAC numbering.

5.5 Resolution of enantiomers using chiral HPLC

Mixtures of enantiomers were resolved using a Waters 1525 Binary HPLC pump, equipped with a Waters 717 plus autosampler and a Waters 2487 Duel  absorbance detector. Dilute solutions (10 L) were injected into either Chiralcel OD or Chiralpak AD chiral columns and resolved using mixtures of HPLC grade hexanes and HPLC grade

EtOAc.

242

5.6 General Experimental Procedures

5.6.1 General Procedure for Hydroalumination Reactions Br AlBr3/LiAlH4 Al R R Br benzene

A flask was flame dried using a Bunsen burner and sealed under ultra-pure nitrogen atmosphere. Benzene (3 mL per mmol of LiAlH4) was added to the flask once it had reached room temperature and a 1.0 M solution of LiAlH4 (1 eq.) in diethyl ether was added. All solvent was removed in vacuo (10-1 torr), and the flask was back purged with ultra high purity nitrogen. The solid LiAlH4 was suspended in benzene (3 mL per mmol of LiAlH4), and a solution of commercially available 99.99% AlBr3 (3 eq.) in benzene (1 mL per mmol of AlBr3) was added to it to generate the hydroaluminating agent

HAlBr2·LiBr in situ. The resulting slurry was stirred for 30 minutes under nitrogen atmosphere. Freshly distilled olefin (4 eq.) was added dropwise to the hydroaluminating agent, and the reaction mixture was stirred for 24 hours. The benzene was removed under high vacuum to concentrate the organoaluminum compound, which was redissolved in toluene to produce a 1.0 M Lewis acid solution. This solution was then used as the catalyst without further purification for all required reactions. Characterization was

1 13 limited to H NMR and C NMR spectra due to extreme reactivity with O2 and H2O. All

NMR samples were prepared using benzene-d6 freshly distilled over CaH2.

243

5.6.2 General Procedure for Mixed Anhydride Coupling Methodology R OH O 1) LiCl, NEt3 O O O o + CH2Cl2, 0 C N* O Cl R O *N R 2) N* N* = chiral oxazolidione

Dry LiCl (15.6 mmol) was suspended in dry THF (30 mL). To this suspension was added both triethylamine (31.2 mmol) and trimethylacetylchloride (12.5 mmol). The reaction mixture was cooled to 0 ºC and a THF solution (10 mL) of carboxylic acid was added dropwise. The reaction slurry was allowed to stir for 1 hour at 0 ºC before the appropriate commercially available oxazolidinone (10.4 mmol) was added all at once as a solid. The reaction mixture was warmed to 25 ºC and allowed to stir for 18 hours before being quenched with distilled water (50 mL) and extracted with CH2Cl2 (25 x 3). The organic layers were combined and dried over MgSO4 before being concentrated in vacuo.

Flash column chromatography was used to purify the crude mixture (Hex:EtOAc) to yield the desired oxazolidione (60-80%) for use in the Diels-Alder reaction.

5.6.3 General Procedure for Diels-Alder Reactions in Chapters 2+3 O O O O

R1 1.4 eq. LA *N *N *N *N + R1 R1 R1 toluene or DCM R R R2 R 2 96 2 2 exo endo I endo II R1 = H, Me; R2 = CH2OBn, Ph, Me, H N* = chiral oxazolidinone

The Diels-Alder reactions conducted in chapter 2 were carried using either a mixture of CH2Cl2/toluene or neat toluene as the solvent. The appropriate dienophile

(0.286 mmol) was dissolved in either CH2Cl2 or toluene (1.6 mL). The mixture was

244

cooled to -78 ºC. Lewis acid 125 (1.0 M, 0.4 mmol) was added dropwise and the reaction mixture was stirred for 10 minutes. Freshly distilled 1,3,3-trimethyl-2-vinylcyclohexene

(0.572 mmol) was added slowly down the side of the cold reaction flask. The mixture was then warmed to the specified temperature and allowed to react for the specified duration. The reaction was then quenched with a 5 % solution of aqueous HCl and extracted with CH2Cl2 (3 x 5 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified via flash column chromatography

(Hex:EtOAc) to yield the desired Diels-Alder adducts (30-95 %).

5.6.4 General Procedure for IMDAF Reactions in Chapters 3+4 O R O 2 0.1 eq. LA R2 R1

DCM, 2h, -78 oC R1 O O

R1 = H, Me; R2 = H, Me

Into freshly distilled CH2Cl2 (30 mL) was dissolved the appropriate IMDAF precursor (0.662 mmol), also freshly distilled. The reaction mixture was cooled to -78 ºC and freshly prepared Lewis acid (0.066 mL, 0.066 mmol) was added. The reaction was stirred at -78 ºC for 2 hours before being quenched at low temperature with 10%

NaHCO3 (50 mL). The mixture was extracted with CH2Cl2 (3 x 25 mL) and the combined organic layers were washed with H2O and dried over Na2SO4. Concentration in vacuo followed by purification via flash column chromatography (10:1 Hex:EtOAc) to afford the desired IMDAF adduct.

245

5.6.5 General Procedure for Strecker Reactions in Chapters 3-5 R R N 2 1.0 eq. LA HN 2

TMSCN, DCM CN -78 oC R1 R1

R1 = H, Me; R2 = Ph, allyl

Into freshly distilled solvent (1 mL) was dissolved the appropriate imine for the

Strecker reaction (0.552 mmol). The solution was cooled to -78 ºC and freshly prepared

Lewis acid (0.52 mL, 0.52 mmol) was added dropwise. The reaction mixture was stirred for 10 minutes before neat TMSCN (0.1 mL, 0.80 mmol) was added dropwise over 1 minute. The solution was stirred at -78 ºC for 2 hours before being quenched at low temperature with concentrated NH4Cl (1 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were dried over MgSO4. Concentration in vacuo followed by purification via flash column chromatography (10:1 Hex:EtOAc) afforded the target Strecker adducts.

5.6.6 General Procedure for Preparing RAlBr(OR) Lewis acids described in Chapter 5 Br Br nBuLi/ROH AlBr3/LiAlH4 Al Al R* + LiBr *R *R *R O benzene Br benzene

Into freshly distilled CH2Cl2 (5 mL) was dissolved the appropriate chiral alcohol

(0.604 mmol), and the mixture was cooled to -78 ºC. A 1.6 M solution of n-BuLi in hexanes (0.604 mmol) was added dropwise to the reaction mixture, which was subsequently allowed to stir for 10 minutes. A second flask was prepared by flame drying 246

and back purging with ultra high purity N2 gas. Into this flask under N2 was added a stir bar and CH2Cl2 (18 mL). This CH2Cl2 was cooled to -78 ºC before a 0.4 M solution in benzene of the appropriate RAlBr2 Lewis acid was added to it. The lithiated alcohol solution was then added to the RAlBr2 solution by adding the solution down the side of the cold flask. The reaction mixture was then stirred for several minutes and kept at -78

ºC until ready for use.

5.6.7 General Procedure for Preparing BINOL-aluminum bromide complexes described in chapter 5 R R

1) nBuLi, -78 oC O OH Al Br OH 2) RAlBr 99 2 O R = hexane R R

R = H, anthracene, phenanthrene, 3,4,6-triisopropylphenyl, 3,5-trifluoromethylphenyl

Into freshly distilled DCM (25 mL) was added (R)-BINOL or the appropriate

3,3’-disubstituted (R)-BINOL derivative (0.604 mmol). The mixture was cooled to -78

ºC, and a 1.6 M solution of nBuLi in hexanes (0.604 mmol) was added dropwise. The reaction mixture was stirred for 15 minutes, before the RAlBr2 Lewis acid 99 (R = hexyl) was added dropwise to the mixture. The mixture was stirred for several minutes and kept at -78 ºC until ready for use.

247

5.7 Experimental Procedures Pertaining to Chapter 2

5.7.1 Synthesis of RAlBr2 Lewis acid 99 5 3 1 6 4 2 AlBr2 99

A 1.0 M solution of LiAlH4 in diethyl ether (3 mL, 3 mmol) was dissolved in freshly distilled benzene (9 mL) in a flame dried reaction flask. The solvents were all removed in vacuo over 15 minutes. The solid LiAlH4 was suspended in benzene (9 mL).

A solution of 99.99 % AlBr3 (2.4 g, 9 mmol) in benzene (9 mL) was slowly added to the

LiAlH4 suspension to generate the hydroaluminating agent in situ. This mixture was stirred for 30 minutes before 1-hexene (1.5 mL, 12 mmol) was added dropwise as a solution in benzene (2 mL) over 5 minutes. The reaction was stirred for an hour before all solvent was removed in vacuo. Lewis acid 99 was obtained as a clear, colourless, viscous oil, which was kept under N2 pressure at all times. This oil was redissolved in 10.5 mL

1 toluene to make a 1.0 M solution of Lewis acid 99. H NMR (400 MHz, C6D6): δ 1.55-

1.45 (m, 2H), 1.37-1.18 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H, H-6), 0.56 (t, J = 8.0, 2H, H-1);

13 C NMR (400 MHz, CDCl3): δ 33.99, 31.53, 24.18, 22.63, 15.42 (br, C-1), 14.03 ppm.

5.7.2 Synthesis of RAlBr2 Lewis acid 86 2 3 1 AlBr2

4 86

A 1.0 M solution of LiAlH4 in diethyl ether (3 mL, 3 mmol) was dissolved in freshly distilled benzene (9 mL) in a flame dried reaction flask. The solvents were all

248

removed in vacuo over 15 minutes. The solid LiAlH4 was suspended in benzene (9 mL).

A solution of 99.99 % AlBr3 (2.4 g, 9 mmol) in benzene (9 mL) was slowly added to the

LiAlH4 suspension to generate the hydroaluminating agent in situ. This mixture was stirred for 30 minutes before cyclohexene (1.2 mL, 12 mmol) was added dropwise as a solution in benzene (2 mL) over 5 minutes. The reaction was stirred for an hour before all solvent was removed in vacuo. Lewis acid 86 was obtained as a clear, colourless, viscous oil, which was kept under N2 pressure at all times. This oil was redissolved in 10.8 mL

1 toluene to make a 1.0 M solution of Lewis acid 86. H NMR (400 MHz, C6D6): δ 1.84-

1.76 (m, 2H), 1.68-1.56 (m, 3H), 1.47-1.36 (m, 2H), 1.29-1.18 (m, 3H), 0.73 (tt, J = 12.1,

13 3.3 Hz, 1H, H-1); C NMR (400 MHz, C6D6): δ 28.32, 28.06, 26.94 (C-1), 24.68 ppm.

5.7.3 Synthesis of RAlBr2 Lewis acid 87 3

3 2 1 AlBr2 87

A solution of 99.99 % AlBr3 (2.4 g, 9 mmol) in benzene (9 mL) was slowly added to the

LiAlH4 suspension to generate the hydroaluminating agent in situ. This mixture was stirred for 30 minutes before freshly sublimed (+)-camphene (1.63 g, 12 mmol) was added dropwise as a solution in benzene (2 mL) over 5 minutes. The reaction was stirred for an hour before all solvent was removed in vacuo. Lewis acid 87 was obtained as a

249

clear, colourless, viscous oil, which was kept under N2 pressure at all times. This oil was redissolved in 10.0 mL toluene to make a 1.0 M solution of Lewis acid 87. 1H NMR (400

MHz, C6D6): δ 2.15 (br s, 1H), 1.79-1.73 (m, 1H), 1.67 (br s, 1H), 1.63-1.59 (m, 1H),

1.54-1.48 (m, 1H), 1.38-1.33 (m, 1H), 1.26-1.18 (m, 2H), 1.10 (ddd, 1H, J = 9.7, 1.6, 1.6

Hz), 0.92 (s, 3H, H-3)), 0.73 (s, 3H, H-3), 0.60 (dd, 1H, J = 11.3, 7.9 Hz, H-1), 0.55 (dd,

13 1H, 11.3, 3.3 Hz, H-1); C NMR (400 MHz, C6D6): δ 49.18, 46.82, 45.03, 38.16, 37.39,

32.18, 25.07, 22.19, 20.33, 13.66 (br, C-1) ppm.

5.7.4 Synthesis of RAlBr2 Lewis acid 125 1 AlBr 2 2 125

A solution of 99.99 % AlBr3 (2.4 g, 9 mmol) in benzene (9 mL) was slowly added to the

LiAlH4 suspension to generate the hydroaluminating agent in situ. This mixture was stirred for 30 minutes before freshly distilled 1-dodecene (2.02 g, 12 mmol) was added dropwise as a solution in benzene (2 mL) over 5 minutes. The reaction was stirred for an hour before all solvent was removed in vacuo. Lewis acid 125 was obtained as a clear, colourless, viscous oil, which was kept under N2 pressure at all times. This oil was redissolved in 9.3 mL toluene to make a 1.0 M solution of Lewis acid 125. 1H NMR (400

MHz, C6D6): δ 1.52 (m, 2H), 1.42-1.18 (m, 18H), 0.92 (t, 3H, H-2), 0.58 (m, 2H, H-1);

250

13 C NMR (400 MHz, C6D6): 34.67, 32.38, 30.32, 30.20, 30.16, 30.04, 29.86, 29.75,

24.51, 23.16, 15.72 (br, H-1), 14.41.

5.7.5 Characterization of 2,2,3-Trimethyl-bicyclo[2.2.1]heptane 2

1 92

Compound 92 was formed by working up Lewis acid 87 in H2O, and was obtained as a clear colourless oil. See Gorobets et. al. for further characterization data.44

1 H NMR (400 MHz, CDCl3): δ 1.99 (br s, 1H), 1.73 (br s, 1H), 1.63 (m, 1H), 1.57-1.50

(m, 2H), 1.44-1.39 (m, 1H), 1.27-1.20 (m, 2H), 1.16-1.12 (m, 1H), 0.93 (s, 3H, H-2), 0.81

13 (d, 3H, J = 7.2 Hz, H-1), 0.79 (s, 3H, H-2); C NMR (400 MHz, C6D6): δ 49.20, 44.80,

44.08, 37.26, 36.85, 32.34, 24.89, 21.55, 20.03, 11.49 ppm. MS: m/z 138 [M+], 123, 109,

95, 81, 70, 67, 55, 41; HRMS calculated for C10H18 138.1409, found 138.1414.

5.7.6 Synthesis of 3-Bromomethyl-2,2-dimethyl-bicyclo[2.2.1]heptane 2

1 Br 102

Compound 102 was obtained via Lewis acid 87 in a single step as described by

Gorobets.44 Lewis acid 87 was prepared exactly as previously described. All solvents were removed from the in situ mixture of 87, before the mixture was redissolved in THF

(50 mL) at -78 ºC and CuBr2 (5.3 g, 24 mmol) was added. The reaction mixture was

251

allowed to warm to room temperature over 24 hours. The reaction mixture was concentrated in vacuo before being poured into H2O (100 mL) and extracted with CH2Cl2

(3 x 30). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude oil was purified via flash column chromatography (50:1 Hex:EtOAc) to yield 102 as a clear colour less oil (57 %). This compound has been previously reported

44,76 20 and characterized in the chemical literature. []D 3.4 (c 3.0, CHCl3); IR (film) vmax

-1 1 2957, 2879, 1463, 1386, 1365, 1225, 956, 875, 640 cm ; H NMR (400 MHz, CDCl3): δ

3.45 (dd, 1H, J = 10.0, 6.5 Hz, H-1), 3.39 (dd, 1H, J = 10.0, 10.0 Hz, H-1), 2.39 (br s,

1H), 1.92-1.82 (m, 2H), 1.72-1.52 (m, 2H), 1.31 (m, 3H), 1.20 (dd, J = 7.8 Hz, 1H), 1.02

13 (s, 3H, H-2), 0.87 (s, 3H, H-2); C NMR (400 MHz, CDCl3): δ 52.76, 49.68, 41.72,

38.43, 36.60, 33.46, 32.15, 24.48, 20.39, 19.70 ppm. MS: m/z 218 [M+], 201, 137, 95, 81,

67, 55, 41.

5.7.7 Synthesis of 1,3,3-trimethyl-2-vinylcyclohexene 6 1 5 8 H11

2 3 4 9 H10 7 7 96

Diene 96 was prepared using a general Wittig procedure. Into THF (250 mL) was suspended PPh3MeBr (12.91 g, 36.1 mmol). The solution was cooled to 0 ºC and a 2.5 M solution of n-BuLi (15.1 mL, 38 mmol) in hexanes was added dropwise. The resulting orange solution was stirred 1 hour at 0 ºC. A solution of β-cyclocitral (5.0 g, 33 mmol) in

THF (25 mL) was added dropwise over 15 minutes, and the reaction mixture was allowed to come to room temperature overnight. The reaction was quenched with concentrated

NH4Cl (100 mL), and the mixture was extracted with EtOAc (3 x 75 mL). The combined

252

organic layer was dried over MgSO4 and concentrated in vacuo. Purification via flash column chromatography (neat hexanes) yielded 96 as a clear colourless liquid (4.06 g,

27.03 mmol, 82.4%). See Ley et. al.52 for characterization data. 1H NMR (300 MHz,

CDCl3): δ 6.21 (ddm, J = 17.7, 11.3 Hz, 1H, H-9), 5.23 (dd, J = 11.3, 2.7 Hz, 1H, H-10),

4.97 (dd, J = 17.7, 2.7 Hz, 1H, H-11), 1.99 (m, 2H, H-6), 1.70 (m, 3H, H-8), 1.68-1.57

(m, 2H), 1.48-1.43 (m, 2H), 1.01 (s, 6H, H-7) ppm.

5.7.8 Synthesis of 4-Benzyloxy-but-2-enoic acid ethyl ester 5 4 2 1 O 7 O 3 6 10 8 O 9 120

Compound 120 was prepared according to the procedure outlined by Han et. al.53

Ethyl-2-butynoate (5.18 g, 44.6 mmol), benzyl alcohol (4.61 mL, 44.6 mmol), triphenyl phosphine (0.59 g, 2.27 mmol), and conc. AcOH (0.50 mL, 8.76 mmol) were combined in toluene (45 mL) and heated at 110 ºC for 18 hours. After cooling to room temperature,

H2O (100 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over MgSO4. Concentration in vacuo followed by purification via flash column chromatography yielded 120 as a clear colourless oil (7.0 g,

31.8 mmol, 71.3%). See Han et. al. for characterization data.53 1H NMR (300 MHz,

CDCl3): δ 7.34 (m, 5H), 6.97 (dt, J = 15.7, 4.3, 1H), 6.13 (dt, J = 15.7, 2.0 Hz, 1H), 4.55

(s, 2H), 4.24-4.14 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H) ppm.

253

5.7.9 Synthesis of 4-Benzyloxy-but-2-enoic acid 5 4 2 OH 1 O 3 8 6 O 7 121

Carboxylic acid 121 was prepared as described by Henderson.54 Ester 120 was dissolved in THF and H2O. Lithium Hydroxide was added as a solid and the reaction was stirred for 18 hours at room temperature. The solution was diluted with H2O and then concentrated in vacuo. The aqueous layer was acidified dropwise with conc. HCl and extracted with diethyl ether. The combined organic layers were dried over Na2SO4 and concentrated to a white crystalline solid (3.63 g, 18.9 mmol, 59.4%) that was purified by recrystalization from hexanes. See Ito et. al. for characterization data.77 1H NMR (300

MHz, CDCl3): δ 11.32 (br s, 1H, H-1), 7.40-7.26 (m, 5H, H-6,7,8), 7.10 (dt, J = 15.7, 4.1

Hz, 1H, H-3), 6.18 (dt, J = 15.7, 1.9 Hz, 1H, H-2), 4.59 (s, 2H, H-5), 4.22 (dd, J = 4.1,

1.9 Hz, 2H, H-4) ppm.

5.7.10 Synthesis of (3aS-cis)-3-(4-benzyloxy-but-2-enoyl)-3,3a,8,8a-tetrahydro- indeno[1,2-d]oxazol-2-one ((+)-95a) O O 8 O N 7 6 9 10 5 2 11 2 4 2 2 O 2 2 3 1 2 2 2 95a

Compound 95a was prepared according to a general procedure outlined by

Henderson.46,54 Into dry THF (30 mL) was suspended flame dried LiCl (0.65 g, 15.6 mmol). To this solution was added triethylamine (4.35 mL, 31.2 mmol) and

254

trimethylacetyl chloride (1.54 mL, 12.5 mmol). The reaction mixture was cooled to 0 ºC and a solution of acid 121 (2.0 g, 10.4 mmol) in THF (10 mL) was added dropwise. The resulting slurry was stirred for 1 hour at 0 ºC before (3aS-cis)-(–)-3,3a,8,8a-tetrahydro-

2H-indeno[1,2-d]oxazol-2-one (1.82 g, 10.4 mmol) was added as a solid. The reaction mixture was warmed to room temperature over 18 hours. The reaction was quenched with

H2O (50 mL), the mixture was extracted with DCM (3 x 75 mL), and the combined organic layers were dried over MgSO4. Concentration in vacuo followed by purification via flash column chromatography (4:1 Hex:EtOAc) afforded 95a as a viscous clear colourless oil (2.11 g, 6.04 mmol, 88.1%). See Henderson for characterization data.46,54

1 H NMR (300 MHz, CDCl3): δ 7.68 (d, J = 7.3 Hz, 1H, H-5), 7.54 (dt, J = 15.5, 1.9 Hz,

1H, H-6), 7.40-7.20 (m, 9H, H-2), 5.95 (d, J = 6.9 Hz, 1H, H-10), 5.35-5.29 (m, 1H, H-

9), 4.59 (s, 2H, H-3), 4.25 (dd, J = 4.6, 1.9 Hz, 1H, H-4), 3.41 (d, J = 3.5 Hz, 1H, H-11) ppm.

5.7.11 Synthesis of (4S)-4-benzyl-3-(4-benzyloxy-but-2-enoyl)-oxazolidin-2-one ((+)-95b) O O 8 O N 7 6 10 9 5 2 2 11 4 2 2 2 O 2 3 1 2 2 2 2 95b

Compound 95b was prepared according to a general procedure outlined by

Henderson.46,54 Into dry THF (25 mL) was suspended flame dried LiCl (0.70 g, 13.7 mmol). To this solution was added triethylamine (3.81 mL, 27.3 mmol) and

255

trimethylacetyl chloride (1.34 mL, 10.9 mmol). The reaction mixture was cooled to 0 ºC and a solution of acid 121 (1.75 g, 9.10 mmol) in THF (12 mL) was added dropwise. The resulting slurry was stirred for 1 hour at 0 ºC before (S)-4-benzyl-2-oxazolidinone (1.61 g, 9.10 mmol) was added as a solid. The reaction mixture was warmed to room temperature over 18 hours. The reaction was quenched with H2O (50 mL), the mixture was extracted with DCM (3 x 75 mL), and the combined organic layers were dried over

MgSO4. Concentration in vacuo followed by purification via flash column chromatography (4:1 Hex:EtOAc) afforded 95b as a colourless crystalline solid (2.52 g,

7.17 mmol, 78.8%). See Henderson for characterization data.46,54 1H NMR (300 MHz,

CDCl3): δ 7.55 (dt, J = 15.5, 1.8 Hz, 1H, H-5), 7.40-7.17 (m, 11H, H-2,6), 4.74 (m, 1H,

H-10), 4.61 (s, 2H, H-3), 4.26 (dd, J = 4.5, 1.9 Hz, 2H, H-4), 4.21 (m, 2H, H-9), 3.36 (dd,

J = 13.4, 3.2 Hz, 1H, H-11), 2.81 (dd, J = 13.4, 9.6 Hz, 1H, H-11) ppm.

5.7.12 Synthesis of (4S)-3-(4-benzyloxy-but-2-enoyl)-4-phenyl-oxazolidin-2-one ((+)-95c) O O 8 O N 7 6 10 9 5 2 2 4 2 2 2 2 O 2 2 3 1 2 2 95c

Compound 95c was prepared according to a general procedure outlined by

Henderson.46,54 Into dry THF (23 mL) was suspended flame dried LiCl (0.55 g, 12.9 mmol). To this solution was added triethylamine (3.59 mL, 25.7 mmol) and trimethylacetyl chloride (1.27 mL, 10.3 mmol). The reaction mixture was cooled to 0 ºC

256

and a solution of acid 121 (1.65 g, 8.58 mmol) in THF (10 mL) was added dropwise. The resulting slurry was stirred for 1 hour at 0 ºC before (S)-4-phenyl-2-oxazolidinone (1.40 g, 8.58 mmol) was added as a solid. The reaction mixture was warmed to room temperature over 18 hours. The reaction was quenched with H2O (50 mL), the mixture was extracted with DCM (3 x 75 mL), and the combined organic layers were dried over

MgSO4. Concentration in vacuo followed by purification via flash column chromatography (4:1 Hex:EtOAc) afforded 95c as a white powder (2.21 g, 6.55 mmol,

46,54 1 76.3%). See Henderson for characterization data. H NMR (300 MHz, CDCl3): δ 7.56

(dt, J = 15.5, 1.9 Hz, 1H, H-5), 7.41-7.26 (m, 10H, H-2), 7.09 (dt, J = 15.5, 4.4 Hz, 1H,

H-6), 5.50 (dd, J = 8.8, 3.9 Hz, 1H, H-10), 4.63 (t, J = 8.8 Hz, 1H, H-9), 4.58 (s, 2H, H-

3), 4.31-2.21 (m, 3H, H-9,4) ppm.

5.7.13 Synthesis of (4S)-3-(4-benzyloxy-but-2-enoyl)-4-isopropyl-oxazolidin-2-one ((+)- 95d) O O 8 O N 7 6 10 9 5 4 2 11 2 12 12 2 O 3 1 2 2 95d

Compound 95d was prepared according to a general procedure outlined by

Henderson.46,54 Into dry THF (45 mL) was suspended flame dried LiCl (1.00 g, 23.5 mmol). To this solution was added triethylamine (6.55 mL, 47.0 mmol) and trimethylacetyl chloride (2.32 mL, 18.8 mmol). The reaction mixture was cooled to 0 ºC and a solution of acid 121 (3.01 g, 15.7 mmol) in THF (20 mL) was added dropwise. The

257

resulting slurry was stirred for 1 hour at 0 ºC before (S)-4-isopropyl-2-oxazolidinone

(2.02 g, 15.7 mmol) was added as a solid. The reaction mixture was warmed to room temperature over 18 hours. The reaction was quenched with H2O (50 mL), the mixture was extracted with DCM (3 x 75 mL), and the combined organic layers were dried over

MgSO4. Concentration in vacuo followed by purification via flash column chromatography (4:1 Hex:EtOAc) afforded 95d as a viscous clear colourless oil (2.91 g,

9.59 mmol, 61.5%). See Henderson et. al. for characterization data.46,54 1H NMR (300

MHz, CDCl3): δ 7.56 (dt, J = 15.5, 1.9 Hz, 1H, H-5), 7.42-7.26 (m, 5H, H-2), 7.11 (dt, J

= 15.5, 4.5 Hz, 1H, H-6), 4.58 (s, 2H, H-3), 4.45 (m, 1H, H-10), 4.09-4.20 (m, 4H, H-

9,4), 2.36 (m, 1H, H-11), 0.86 (dd, J = 12.9, 7.1 Hz, 6H, H-12) ppm.

5.7.14 Synthesis of (1S,2S,8aS)-3-(2-benzyloxymethyl-5,5,8a-trimethyl-1,2,3,5,6,7,8,8a- octahydro-naphthalene-1-carbonyl)-(3aS)-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazolidin- 2-one (exo-(+)-97a) O O 7 7 11 10 O N 6 1 13 4 7 12 2 14 5 3 9 O 8 9 9 9 9 9 9 9 9 97a

Dienophile 95a (0.10 g, 0.286 mmol) was dissolved in dry toluene (0.8 mL), and the solution was cooled to -78 ºC. Freshly prepared 125 (0.40 mL, 0.40 mmol) was added dropwise over 5 minutes and the solution was stirred at -78 ºC for 10 minutes. Freshly distilled 96 (0.086g, 0.572 mmol) in toluene (0.8 mL) was added dropwise to the reaction mixture, which was then allowed to come to room temperature and stir for 5 hours. The

258

reaction was quenched with 10% HCl (5 mL) and extracted with DCM (3 x 10 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo. Purification via flash column chromatography (10:1 Hex, EtOAc) afforded 97a as a mixture of diastereomers that was a clear colourless oil (76.5 mg, 0.153 mmol, 53.5%, 5:1 exo:endo). See Henderson et. al. for characterization data.46,54 1H NMR (300 MHz,

CDCl3): δ 7.57 (d, J = 7.0 Hz, 1H, H-9), 7.41-7.20 (m, 8H, H-9), 5.66 (d, J = 7.1 Hz, 1H,

H-13), 5.47 (t, J = 3.8 Hz, 1H, H-2), 4.60 (m, 1H, H-12), 4.47 (ABq, J = 13.4 Hz, 2H, H-

8), 4.07 (d, J = 11.5 Hz, 1H, H-6), 3.57-3.47 (m, 1H), 3.44-3.37 (m, 1H), 3.27-3.21 (m,

2H), 2.69 (m, 1H, H-4), 2.34-2.19 (m, 1H, H-3), 2.01-1.91 (m, 1H, H-3), 1.73-1.53 (m,

1H), 1.51-1.17 (m, 6H), 1.41 (s, 3H, H-7), 1.13 (s, 3H, H-7), 1.07 (s, 3H, H-7) ppm.

5.7.15 Synthesis of (1S,2S,8aS)-(4S)-benzyl-3-(2-benzyloxymethyl-5,5,8a-trimethyl- 1,2,3,5,6,7,8,8a-octahydro-naphthalene-1-carbonyl)-oxazolidin-2-one (exo-(+)-97b) O O 7 7 11 10 O N 6 1 13 4 7 12 2 14 3 9 5 O 8 9 9 9 9 9 9 9 9 9 97b

Dienophile 95b (0.10 g, 0.285 mmol) was dissolved in dry toluene (0.8 mL), and the solution was cooled to -78 ºC. Freshly prepared 125 (0.40 mL, 0.40 mmol) was added dropwise over 5 minutes and the solution was stirred at -78 ºC for 10 minutes. Freshly distilled 96 (0.086 g, 0.569 mmol) in toluene (0.8 mL) was added dropwise to the reaction mixture, which was then allowed to come to room temperature and stir for 5

259

hours. The reaction was quenched with 10% HCl (5 mL) and extracted with DCM (3 x 10 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo.

Purification via flash column chromatography (10:1 Hex, EtOAc) afforded 97b as a mixture of diastereomers that was a clear colourless oil (54.2 mg, 0.108 mmol, 38.0%,

5:1 exo:endo). See Henderson et. al. for characterization data.46,54 1H NMR (300 MHz,

CDCl3): δ 7.43-7.07 (m, 10H, H-9), 5.46 (t, J = 3.6 Hz, 1H, H-2), 4.38 (q, J = 9 Hz, 2H,

H-8), 4.00 (d, J = 11.8 Hz, 1H, H-6), 3.80 (dd, J = 9.0, 3.3 Hz, 1H), 3.58-3.29 (m, 4H),

2.62 (m, 1H), 2.47 (dd, 13.0, 10.8 Hz, 1H), 2.30-2.18 (m, 1H, H-4), 2.00-1.86 (m, 1H),

1.80-1.55 (m, 2H), 1.53-1.31 (m, 4H), 1.34 (s, 3H, H-7), 1.12 (s, 3H, H-7), 1.08 (s, 3H,

H-7) ppm.

5.7.16 Synthesis of (1S,2S,8aS)-3-(2-benzyloxymethyl-5,5,8a-trimethyl-1,2,3,5,6,7,8,8a- octahydro-naphthalene-1-carbonyl)-(4S)-phenyl-oxazolidin-2-one (exo-(+)-97c) O O 7 7 11 10 O N 6 1 13 4 7 12 2 9 5 3 9 O 8 9 9 9 9 9 9 9 9 97c

Compound 95c (0.10 g, 0.296 mmol) was dissolved in dry toluene (0.8 mL), and the solution was cooled to -78 ºC. Freshly prepared 125 (0.42 mL, 0.42 mmol) was added dropwise over 5 minutes and the solution was stirred at -78 ºC for 10 minutes. Freshly distilled 96 (0.089 g, 0.563 mmol) in toluene (0.8 mL) was added dropwise to the reaction mixture, which was then allowed to come to room temperature and stir for 5

260

hours. The reaction was quenched with 10% HCl (5 mL) and extracted with DCM (3 x 10 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo.

Purification via flash column chromatography (10:1 Hex, EtOAc) afforded 97c as a mixture of diastereomers that was a clear colourless oil (73.1 mg, 0.154 mmol, 52.0%,

5:1 exo:endo). See Henderson et. al. for characterization data.46,54 1H NMR (300 MHz,

CDCl3): δ 7.39-7.16 (m, 10H, H-9), 5.41 (m, 1H, H-2), 4.88 (t, J = 7.1 Hz, 1H, H-13),

4.40 (q, J = 12.5 Hz, 2H, H-8), 4.00-3.89 (m, 3H, H-6,12), 3.52-3.34 (m, 2H, H-5), 2.56

(m, 1H), 2.27-2.13 (m, 1H), 1.95-1.79 (m, 1H), 1.60-1.20 (m, 5H), 1.15-0.92 (m, 2H),

1.07 (s, 3H), 1.04 (s, 6H) ppm.

5.7.17 Synthesis of (1S,2S,8aS)-3-(2-benzyloxymethyl-5,5,8a-trimethyl-1,2,3,5,6,7,8,8a- octahydro-naphthalene-1-carbonyl)-(4S)-isopropyl-oxazolidin-2-one (exo-(+)-97d) O O 7 7 11 10 O N 6 1 13 4 7 12 2 14 5 3 15 O 8 15 9

9 9 9 9 97d

Compound 95d (0.10 g, 0.330 mmol) was dissolved in dry toluene (0.8 mL), and the solution was cooled to -78 ºC. Freshly prepared 125 (0.46 mL, 0.46 mmol) was added dropwise over 5 minutes and the solution was stirred at -78 ºC for 10 minutes. Freshly distilled 96 (0.10 g, 0.659 mmol) in toluene (0.8 mL) was added dropwise to the reaction mixture, which was then allowed to come to room temperature and stir for 5 hours. The reaction was quenched with 10% HCl (5 mL) and extracted with DCM (3 x 10 mL). The

261

combined organic layer was dried over MgSO4 and concentrated in vacuo. Purification via flash column chromatography (10:1 Hex, EtOAc) afforded 97d as a mixture of diastereomers that was a clear colourless oil (67.4 mg, 0.149 mmol, 45.1%, 5:1 exo:endo). See Henderson et. al. for characterization data.46,54 1H NMR (300 MHz,

CDCl3): δ 7.17-7.32 (m, 5H, H-9), 5.43 (t, J = 3.9 Hz, 1H, H-2), 4.36 (q, J = 10.3Hz, 2H,

H-8), 4.10 (m, 1H, H-13), 4.01 (d, J = 11.4 Hz, 1H, H-6), 3.85 (dd, J = 8.6, 3.4 Hz, 1H),

3.59-3.26 (m, 3H), 2.58 (m, 1H, H-4), 2.28-2.13 (m, 2H), 1.80-1.97 (m, 2H), 1.52-1.79

(m, 2H), 1.48-1.19 (m, 3H), 1.30 (s, 3H, H-7), 1.10 (s, 3H, H-7), 1.06 (s, 3H, H-7), 0.79

(d, J = 2.9 Hz, 3H, H-15), 0.76 (d, J = 2.9 Hz, 3H, H-15) ppm.

5.7.18 Characterization of (3aS-cis)-3-(4-Hydroxy-but-2-enoyl)-3,3a,8,8a-tetrahydro- indeno[1,2-d]oxazol-2-one (131) O O

O 5 N 4 3 6 7 2 1 8 9 OH10 9 9 9 131

Compound 131 was obtained as a side product in the Diels-Alder reactions carried out with 1.4 equivalents of 125 using dienophile 95a, as described in chapter 2.

Compound 131 was obtained as a clear colourless oil. IR (film) vmax 3357, 2914, 2848,

-1 1 1762, 1690, 1648, 1362, 1276, 1190, 1029 cm ; H NMR (400 MHz, CDCl3): δ 7.68 (d,

J = 7.6 Hz, 1H), 7.49 (dt, J = 15.5, 2.0 Hz, 1H), 7.39-7.26 (m, 4H), 6.02 (d, J = 6.9 Hz,

1H), 5.32 (m, 1H), 4.44 (m, 2H), 3.42 (m, 2H), 1.68 (br s, 1H); 13C NMR (400 MHz,

CDCl3): δ 165.10, 148.83, 145.67, 139.44, 139.06, 129.89, 128.17, 127.39, 125.18,

262

119.30, 78.18, 63.22, 62.41, 38.00 ppm; MS: m/z 259 [M+], 228, 207, 184, 176, 158, 146,

132, 115, 103, 85, 77, 69, 55, 44; HRMS calcd for C14H13NO4 259.0845, found 259.0838.

5.8 Experimental Procedures Pertaining to Chapter 3

5.8.1 Synthesis of (3aS-cis)-3-But-2-enoyl-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazol-2- one (134a) O O

O 4 N 3 2 5 6 1 7 9 8

8 8 8 134a

Into dry THF (20 mL) was suspended flame dried LiCl (0.36 g, 8.57 mmol). To this solution was added triethylamine (2.4 mL, 17.1 mmol) and trimethylacetyl chloride

(0.9 mL, 6.85 mmol). The reaction mixture was cooled to 0 ºC and a solution of crotonic acid (0.49 g, 5.71 mmol) in THF (5 mL) was added dropwise. The resulting slurry was stirred for 1 hour at 0 ºC before (3aR,8aS)-3,3a,8,8a-tetrahydro-2H-indeno[1,2- d][1,3]oxazol-2-one (1.0 g, 5.71 mmol) was added as a solid. The reaction mixture was warmed to room temperature over 18 hours. The reaction was quenched with H2O (50 mL), the mixture was extracted with CH2Cl2 (3 x 50 mL), and the combined organic layers were dried over MgSO4. Concentration in vacuo followed by purification via flash column chromatography (4:1 Hex:EtOAc) afforded 134a as a white crystalline solid

20 (0.95 g, 3.89 mmol, 68.1%): []D -277.27 (c 1.00, CHCl3); mp 112.5-113; IR (film) vmax 3024, 2977, 1772, 1679, 1635, 1443, 1363, 1340, 1240, 1187, 1124, 1044, 968, 928,

263

1 749; H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 7.5 Hz, 1H, H-8), 7.38-7.24 (m, 5H, H-

8,1,2), 6.00 (d, J = 6.9 Hz, 1H, H-6), 5.30 (m, 1H, H-5), 3.40 (m, 2H, H-7), 1.98 (dd, J =

13 5.2, 1.2 Hz 3H, H-9); C NMR (400 MHz, CDCl3): δ 165.37, 153.01, 147.03, 139.45,

139.24, 129.82, 128.14, 127.43, 125.16, 121.81; MS: m/z 243 [M+], 199, 184, 157, 131,

115, 103, 89, 69, 51; HRMS calcd for C14H13NO3 243.0895, found 243.0899.

5.8.2 Synthesis of 4-Benzyl-3-but-2-enoyl-oxazolidin-2-one (134b) O O

O 4 N 3 2 6 5 1 7 9 8 8 8

8 8 134b

Into dry THF (25 mL) was suspended flame dried LiCl (0.35 g, 8.46 mmol). To this solution was added triethylamine (2.36 mL, 16.9 mmol) and trimethylacetyl chloride

(0.88 mL, 6.77 mmol). The reaction mixture was cooled to 0 ºC and a solution of crotonic acid (0.61 g, 7.05 mmol) in THF (5 mL) was added dropwise. The resulting slurry was stirred for 1 hour at 0 ºC before (R)-4-benzyl-2-oxazolidinone (1.25 g, 7.05 mmol) was added as a solid. The reaction mixture was warmed to room temperature over

18 hours. The reaction was quenched with H2O (50 mL), the mixture was extracted with

DCM (3 x 50 mL), and the combined organic layers were dried over MgSO4.

Concentration in vacuo followed by purification via flash column chromatography (4:1

Hex:EtOAc) afforded 134b as a white crystalline solid (1.55 g, 6.32 mmol, 89.6%). See

78 1 Tredwell et. al. for characterization data. H NMR (400 MHz, CDCl3): δ 7.37-7.18 (m, 264

7H), 4.77-4.70 (m, 1H), 4.25-4.15 (m, 2H), 3.34 (dd, J = 13.4, 3.3 Hz, 1H), 2.80 (dd, J =

11.4, 9.5 Hz, 1H), 1.99 (d, J= 5.3, 3H) ppm.

5.8.3 Synthesis of 3-But-2-enoyl-4-phenyl-oxazolidin-2-one (134c) O O

O 4 N 3 2 6 1 5 7 8 9

8 8 8 8

134c

Into dry THF (15 mL) was suspended flame dried LiCl (0.38 g, 9.2 mmol). To this solution was added triethylamine (2.56 mL, 18.4 mmol) and trimethylacetyl chloride

(0.96 mL, 7.36 mmol). The reaction mixture was cooled to 0 ºC and a solution of crotonic acid (0.53 g, 6.13 mmol) in THF (8 mL) was added dropwise. The resulting slurry was stirred for 1 hour at 0 ºC before (R)-4-phenyl-2-oxazolidinone (1.0 g, 6.13 mmol) was added as a solid. The reaction mixture was warmed to room temperature over

18 hours. The reaction was quenched with H2O (50 mL), the mixture was extracted with

DCM (3 x 50 mL), and the combined organic layers were dried over MgSO4.

Concentration in vacuo followed by purification via flash column chromatography (4:1

Hex:EtOAc) afforded 134c as a white crystalline solid (1.03 g, 4.44 mmol, 72.4%). See

79 1 Chiarotto et. al. for full characterization data. H NMR (400 MHz, CDCl3): δ 7.42-7.26

(m, 6H), 7.10 (dq, J = 15.3, 6.9 Hz, 1H), 5.49 (dd, J = 8.8, 3.9, 1H), 4.70 (t, J = 8.8 Hz,

1H), 4.28 (dd, J = 8.8, 3.9 Hz, 1H), 1.94 (dd, J = 6.9, 1.6 Hz, 3H) ppm.

265

5.8.4 Synthesis of 3-But-2-enoyl-4-isopropyl-oxazolidin-2-one (134d) O O

O 4 N 3 2 6 1 5 8 9 7 8 134d

Into dry THF (24 mL) was suspended flame dried LiCl (0.53 g, 12.8 mmol). To this solution was added triethylamine (3.6 mL, 25.7 mmol) and trimethylacetyl chloride

(1.27 mL, 10.3 mmol). The reaction mixture was cooled to 0 ºC and a solution of crotonic acid (0.74 g, 8.56 mmol) in THF (8 mL) was added dropwise. The resulting slurry was stirred for 1 hour at 0 ºC before (R)-4-isopropyl-2-oxazolidinone (1.11 g, 8.56 mmol) was added as a solid. The reaction mixture was warmed to room temperature over

18 hours. The reaction was quenched with H2O (50 mL), the mixture was extracted with

DCM (3 x 50 mL), and the combined organic layers were dried over MgSO4.

Concentration in vacuo followed by purification via flash column chromatography (4:1

Hex:EtOAc) afforded 134d as a white crystalline solid (1.30 g, 6.57 mmol, 76.8%). See

56 1 Evans et. al. for characterization data. H NMR (400 MHz, CDCl3): δ 7.29 (dq, J =

15.2, 1.5 Hz, 1H), 7.15 (dq, J = 15.2, 6.7 Hz, 1H), 4.49 (ddd, J = 8.3, 3.2, 0.3 Hz, 1H),

4.28 (dd, J = 8.3, 0.3 Hz, 1H), 4.21 (dd, J = 9.1, 3.2 Hz, 1H), 2.41 (m, 1H), 1.96 (dd, J =

6.7, 1.5 Hz, 3H), 0.93 (d, J = 7.1 Hz, 3H), 0.89 (d, J = 7.1 Hz, 3H) ppm.

266

5.8.5 Synthesis of 3-But-2-enoyl-oxazolidin-2-one (153a) O O

O 4 N 3 2 6 1 5 7 153a

Into dry THF (100 mL) was suspended flame dried LiCl (0.78 g, 18.9 mmol). To this solution was added triethylamine (7.9 mL, 56.7 mmol) and trimethylacetyl chloride

(2.91 mL, 22.7 mmol). The reaction mixture was cooled to 0 ºC and a solution of crotonic acid (1.79 g, 20.8 mmol) in THF (25 mL) was added dropwise. The resulting slurry was stirred for 1 hour at 0 ºC before 2-oxazolidinone (1.65 g, 18.9 mmol) was added as a solid. The reaction mixture was warmed to room temperature over 18 hours.

The reaction was quenched with H2O (100 mL), the mixture was extracted with DCM (3 x 100 mL), and the combined organic layers were dried over MgSO4. Concentration in vacuo followed by purification via flash column chromatography (2:1 Hex:EtOAc) afforded 153a as a white crystalline solid (2.69 g, 17.3 mmol, 91.5%). See Nakamura et.

80 1 al. for characterization data. H NMR (400 MHz, CDCl3): δ 7.25 (dq, J = 15.4, 1.1 Hz,

1H), 7.17 (dq, J = 15.4, 6.5 Hz, 1H), 4.42 (dd, J = 7.8, 0.9 Hz, 2H), 4.06 (dd, J = 7.8, 0.9

Hz, 2H), 1.96 (dd, J = 6.5, 1.1 Hz, 3H) ppm.

5.8.6 Synthesis of 3-Acryloyl-oxazolidin-2-one (153b) O O

O 4 N 3 2 6 1 5

153b

267

Into dry THF (70 mL) was suspended flame dried LiCl (2.13 g, 51.6 mmol). To this solution was added triethylamine (14.4 mL, 103 mmol) and trimethylacetyl chloride

(5.1 mL, 41.3 mmol). The reaction mixture was cooled to 0 ºC and a solution of acrylic acid (2.48 g, 34.4 mmol) in THF (30 mL) was added dropwise. The resulting slurry was stirred for 1 hour at 0 ºC before 2-oxazolidinone (3.0 g, 34.4 mmol) was added as a solid.

The reaction mixture was warmed to room temperature over 18 hours. The reaction was quenched with H2O (100 mL), the mixture was extracted with DCM (3 x 100 mL), and the combined organic layers were dried over MgSO4. Concentration in vacuo followed by purification via flash column chromatography (2:1 Hex:EtOAc) afforded 153b as a white crystalline solid (3.05 g, 21.6 mmol, 62.8%). See Buzas et. al. for characterization data.81

1 H NMR (300 MHz, CDCl3): δ 7.50 (dd, J = 17.0, 10.5 Hz, 1H), 6.56 (dd, J = 17.0, 1.8

Hz, 1H), 5.90 (dd, J = 10.5, 1.8 Hz, 1H), 4.45 (t, J = 9.7 Hz, 2H), 4.09 (t, J = 9.7 Hz, 2H) ppm.

5.8.7 Synthesis of 3-(2-Methyl-acryloyl)-oxazolidin-2-one (153c) O O 7 O 4 N 3 2 6 5 1

153c

Into dry THF (70 mL) was suspended flame dried LiCl (2.13 g, 51.6 mmol). To this solution was added triethylamine (14.4 mL, 103 mmol) and trimethylacetyl chloride

(5.1 mL, 41.3 mmol). The reaction mixture was cooled to 0 ºC and a solution of methylacrylic acid (2.96 g, 34.4 mmol) in THF (30 mL) was added dropwise. The

268

resulting slurry was stirred for 1 hour at 0 ºC before 2-oxazolidinone (3.0 g, 34.4 mmol) was added as a solid. The reaction mixture was warmed to room temperature over 18 hours. The reaction was quenched with H2O (100 mL), the mixture was extracted with

DCM (3 x 100 mL), and the combined organic layers were dried over MgSO4.

Concentration in vacuo followed by purification via flash column chromatography (2:1

Hex:EtOAc) afforded 153c as a white crystalline solid (4.41 g, 28.4 mmol, 82.6%). See

82 1 Sibi et. al. for characterization data. H NMR (300 MHz, CDCl3): δ 5.44 (m, 2H), 4.45

(t, J = 7.6 Hz, 2H), 4.04 (t, J = 7.6 Hz, 2H), 2.05 (s, 3H) ppm.

5.8.8 Synthesis of 3-(3-Phenyl-acryloyl)-oxazolidin-2-one (153d) O O

O 4 N 3 2 6 7 5 1 7

7 7 7 153d

Into dry THF (70 mL) was suspended flame dried LiCl (2.13 g, 51.6 mmol). To this solution was added triethylamine (14.4 mL, 103 mmol) and trimethylacetyl chloride

(5.1 mL, 41.3 mmol). The reaction mixture was cooled to 0 ºC and a solution of cinnamic acid (5.1 g, 34.4 mmol) in THF (30 mL) was added dropwise. The resulting slurry was stirred for 1 hour at 0 ºC before 2-oxazolidinone (3.0 g, 34.4 mmol) was added as a solid.

The reaction mixture was warmed to room temperature over 18 hours. The reaction was quenched with H2O (100 mL), the mixture was extracted with DCM (3 x 100 mL), and the combined organic layers were dried over MgSO4. Concentration in vacuo followed by purification via flash column chromatography (2:1 Hex:EtOAc) afforded 153d as a white crystalline solid (4.58 g, 21.1 mmol, 61.3%). See Sibi et. al.83 and Shibata et. al.84 for

269

1 characterization data. H NMR (300 MHz, CDCl3): δ 7.94 (d, J = 15.8 Hz, 1H), 7.86 (d, J

= 15.8 Hz, 1H), 7.64 (m, 2H), 7.41 (m, 3H), 4.47 (t, J = 7.8 Hz, 2H), 4.15 (t, J = 7.8 Hz,

2H) ppm.

5.8.9 Synthesis of (3aS-cis)-3-(2,5,5,8a-Tetramethyl-1,2,3,5,6,7,8,8a-octahydro- naphthalene-1-carbonyl)-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazol-2-one (135a endo I) 9 9 O O 10 9 2 10 O 4 N 3 9 10 5 6 11 1 7 9 8

8 8 8 135a endo I

Into dry toluene (1 mL) was added 134a (0.05 g, 0.205 mmol) and 96 (0.125 mL,

0.82 mmol). The mixture was sealed under nitrogen atmosphere and cooled to -78 ºC.

Into this solution was added a 1.0 M solution of freshly made Lewis acid (amount and type specified in text) in toluene dropwise over 5 minutes. The reaction was stirred at -78

ºC for 5 minutes before being warmed to -25 ºC and stirred for a further 24 hours. The reaction was quenched at low temperature with 5% HCl (10 mL) and extracted with

DCM (3 x 20 mL). The combined organic layer was dried over MgSO4. Concentration in vacuo followed by purification via flash column chromatography (10:1 Hex:EtOAc) afforded 135a as a mixture of diastereomers that was a clear colourless oil (yields and diastereomeric ratios specified in text, depending on reaction conditions). Small amounts of the major endo I diastereomer could be isolated and characterized. IR (film) vmax 2954,

2924, 2864, 1775, 1689, 1463, 1380, 1353, 1323, 1230, 1174, 1114, 1048, 752 cm-1. 1H

NMR (400 MHz, CDCl3): δ 7.62 (d, J = 7.2 Hz, 1H, H-8), 7.38-7.33 (m, 1H, H-8), 7.31-

270

7.25 (m, 2H, H-8), 6.06 (d, J = 7.2 Hz, 1H, H-6), 5.62 (dd, J = 6.8, 2.1 Hz, 1H, H-1), 5.24

(m, 1H, H-5), 4.09 (d, J = 10.2 Hz, 1H, H-2), 3.42-3.37 (m, 2H, H-7), 2.14 (ddd, J = 16.7,

6.8, 3.7 Hz, 1H, H-9), 2.03-1.93 (m, 1H, H-9), 1.85-1.71 (m, 3H, H-9), 1.55-1.43 (m, 2H,

H-9), 1.38-1.32 (m, 1H, H-9), 1.28-1.22 (m, 1H, H-9), 1.18 (s, 3H, H-10), 1.13 (s, 3H, H-

13 10), 1.09 (s, 3H, H-10), 0.97 (d, J = 6.5 Hz, 3H, H-11); C NMR (400 MHz, CDCl3): δ

175.54, 152. 95, 149.03, 139.52, 139.41, 128.06, 127.13, 127.10, 125.23, 119.40, 77.11,

63.16, 56.26, 41.44, 40.65, 38.14, 37.22, 36.30, 34.08, 33.52, 29.60, 29.09, 28.47, 20.22,

19.17 ppm; MS: m/z 393 [M+], 378, 338, 308, 270, 244, 219, 218, 190, 176, 161, 135,

115, 105, 91, 69; HRMS calcd for C25H31NO3 393.2304, found 393.2295. anal. calcd for

C25H31NO3: C, 76.30; H, 7.94; N, 3.56 found: C, 75.77; H, 8.42; N, 3.53 %.

5.8.10 1H-NMR Characterization of minor diastereomers of (3aS-cis)-3-(2,5,5,8a- Tetramethyl-1,2,3,5,6,7,8,8a-octahydro-naphthalene-1-carbonyl)-3,3a,8,8a-tetrahydro- indeno[1,2-d]oxazol-2-one (135a endo II and exo) 9 9' 9 9 9' 9' O O 10 O O 10' 10 2 2' 10' O 4 N 3 O 4' N 3' 5 6 9 10 5' 6' 9' 10' 11 1 11' 1' 7 9 9' 8 7' 8'

8 8' 8 8' 8 8' 135a endo II 135a exo (absolute config. unknown)

Both endo II and exo diastereomers of 135a also formed during the Diels-Alder

1 reaction between 134a and 96 promoted by RAlBr2 Lewis acid. H NMR (400 MHz,

CDCl3): δ 7.69 (d, J = 7.3 Hz, 1H, H-8), 7.61 (d, J = 7.3 Hz, 1H, H-8’), 7.37-7.24 (m, 3H,

H-8), 7.38-7.25 (m, 3H, H-8’), 6.00 (d, J = 6.8 Hz, 1H, H-6), 6.07 (d, J = 7.1 Hz, 1H, H-

6’), 5.63 (m, 1H, H-1), 5.45 (m, 1H, H-1’), 5.21 (ddd, J = 6.8, 4.3, 2.6 Hz, 1H, H-5), 5.24

(ddd, J = 7.3, 4.5, 3.0 Hz, 1H, H-5’), 4.12 (d, J = 4.1 Hz, 1H, H-2), 3.88 (d, J = 11.3 Hz,

271

1H, H-2’), 3.39 (m, 2H, H-7), 3.39 (m, 2H, H-7’), 2.20-2.06 (m, 3H, H-9), 2.36-1.16 (m,

3H, H-9’), 1.91-1.79 (m, 1H, H-9), 1.89-1.75 (m, 1H, H-9’), 1.60-1.40 (m, 4H, H-9),

1.67-1.61 (m, 1H, H-9’), 1.49-1.44 (m, 1H, H-9’), 1.34-1.19 (m, 3H, H-9’), 1.27-1.23 (m,

1H, H-9), 1.33 (s, 3H, H-10), 1.19 (s, 3H, H-10), 1.10 (s, 3H, H-10), 1.05 (d, J = 6.6 Hz,

3H, H-11), 1.39 (s, 3H, H-10’), 1.12 (s, 3H, H-10’), 1.06 (s, 3H, H-10’), 0.93 (d, J = 6.1

Hz, 3H, H-11’).

5.8.11 Synthesis of 4-Benzyl-3-(2,5,5,8a-tetramethyl-1,2,3,5,6,7,8,8a-octahydro- naphthalene-1-carbonyl)-oxazolidin-2-one (135b endo I) 9 9 O O 10 9 2 10 O 4 N 3 9 10 5 6 11 1 7 9 8

8 8

8 8 135b endo I Into dry toluene (2 mL) was added 134b (0.1 g, 0.408 mmol) and 96 (0.25 mL,

1.63 mmol). The mixture was sealed under nitrogen atmosphere and cooled to -78 ºC.

Into this solution was added a 1.0 M solution of freshly made Lewis acid (amount and type specified in text) dropwise over 5 minutes. The reaction was stirred at -78 ºC for 5 minutes before being warmed to -25 ºC and stirred for a further 24 hours. The reaction was quenched at low temperature with 5% HCl (10 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was dried over MgSO4. Concentration in vacuo followed by purification via flash column chromatography (10:1 Hex:EtOAc) afforded

135b as a mixture of diastereomers that was a clear colourless oil (yields and diastereomeric ratios specified in text, depending on reaction conditions). This endo isomer could be purified from the mixture via column chromatography (10:1

272

Hex:EtOAc) followed by recrystallization from hexanes. mp 99.0-105 ºC; IR (film) vmax

2947, 2921, 1778, 1692, 1386, 1340, 1234, 1207, 1187, 1101, 762, 709 cm-1; 1H NMR

(400 MHz, CDCl3): δ 7.37-7.24 (m, 5H, H-8), 5.63 (dd, J = 6.8, 2.0 Hz, 1H, H-1), 4.80

(m, 1H, H-6), 4.17-4.09 (m, 2H, H-5), 4.07 (d, J = 10.3 Hz, 1H, H-2), 3.44 (dd, J = 13.1,

3.5 Hz, 1H, H-7), 2.64 (dd, J = 13.1, 11.5 Hz, 1H, H-7), 2.12 (ddd, J = 16.6, 6.8, 4.5 Hz,

1H), 2.01-1.89 (m, 1H), 1.85-1.71 (m, 3H), 1.56-1.49 (m, 2H), 1.39-1.14 (m, 2H), 1.37

(s, 3H, H-10), 1.18 (s, 3H, H-10), 1.10 (s, 3H, H-10), 0.92 (d, J = 6.5 Hz, 3H, H-11); 13C

NMR (400 MHz, CDCl3): δ 174.97, 153.39, 148.87, 135.55, 129.33, 128.93, 127.27,

119.47, 65.59, 56.67, 55.54, 41.47, 40.37, 38.80, 37.22, 36.45, 33.94, 33.57, 29.58, 29.06,

28.53, 20.14, 19.16; MS: m/z 395 [M+], 380, 340, 310, 259, 246, 219, 218, 203, 175, 135,

91, 69; HRMS calcd for C25H33NO3 395.2460, found 395.2445. anal. calcd for

C25H33NO3: C, 75.91; H, 8.41; N, 3.54 found: C, 75.93; H, 8.43; N, 3.53 %.

X-Ray crystal structure for 135b endo I

273

Monoclinic P21; a =7.894(3) Ǻ, b = 10.101(4) Ǻ, c = 13.592(6) Ǻ,  = 90º, γ =

90º, β = 91.114(18)º, V = 1077.7(8) Ǻ3; Z = 2; Non hydrogen atoms were refined anisotropically. The H atoms were included at geometrically idealized positions and were not refined. The final cycle of full-matrix least-squares refinement using SHELXL3 converged with unweighted and weighted agreement factors, R = 0.0508 and wR =

0.1135 (all data), respectively, and goodness of fit, S = 1.094. The weighting scheme was based on counting statistics and the final difference Fourier map was essentially featureless. The figure was plotted with the aid of ORTEP-3 for Windows.

5.8.12 1H-NMR Characterization of minor diastereomers of 4-Benzyl-3-(2,5,5,8a- tetramethyl-1,2,3,5,6,7,8,8a-octahydro-naphthalene-1-carbonyl)-oxazolidin-2-one (135b endo II and exo) 9 9 9 9 O O 10 9 O O 10 9 2 10 2' 10 O 4 N 3 O 4 N 3 9 10 9 10 5 6 11 1 5 6' 11 1' 7 9 7 9 8 8

8 8 8 8

8 8 8 8 135b endo II 135b exo (absolute config. unknown)

Both endo II and exo diastereomers of 135b also formed during the Diels-Alder

1 reaction between 134b and 96 promoted by RAlBr2 Lewis acid. H NMR (400 MHz,

CDCl3): δ 7.38-7.24 (m, 5H, H-8), 5.64 (m, 1H, H-1), 5.47 (t, J = 3.5 Hz, 1H, H-1’),

4.84-4.75 (m, 1H, H-6), 4.74-4.67 (m, 1H, H-6’), 4.17-4.06 (m, 3H, H-5, H-2), 3.90 (d, J

= 11.1 Hz, 1H, H-2’), 3.49-3.41 (m, 2H, H-7), 2.69-2.57 (m, 2H), 2.32-2.22 (m, 2H),

274

2.17-2.08 (m, 2H), 1.93-1.28 (m, 6H), 1.56 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H), 1.19 (s,

3H), 1.15 (s, 3H), 1.10 (s, 3H), 1.00 (d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.0 Hz, 3H).

5.8.13 Synthesis of 4-phenyl-3-(2,5,5,8a-tetramethyl-1,2,3,5,6,7,8,8a-octahydro- naphthalene-1-carbonyl)-oxazolidin-2-one (135c endo I) 9 9 O O 10 9 2 10 O 4 N 3 9 10 5 6 11 1 7 9 8 8 8 8 135c endo I

Into dry toluene (1 mL) was added 134c (0.05 g, 0.216 mmol) and 96 (0.132 mL,

0.87 mmol). The mixture was sealed under nitrogen atmosphere and cooled to -78 ºC.

135c as a mixture of diastereomers that was a clear colourless oil (yields and diastereomeric ratios specified in text, depending on reaction conditions). Small amounts of the major endo diastereomer could subsequently be isolated and purified. IR (film)

-1 1 vmax 2951, 2911, 2861, 1772, 1705, 1380, 1317, 1194, 1041, 712 cm ; H NMR (400

MHz, CDCl3): δ 7.40 (m, 5H), 5.59-5.56 (m, 1H, H-1), 5.46 (dd, J = 8.4, 2.7, 1H, H-5),

4.64 (t, J = 8.6, 1H, H-6), 4.26 (dd, J = 8.8, 2.7 Hz, 1H, H-5), 4.10 (d, J = 9.8 Hz, 1H, H-

275

2), 2.00 (dd, J = 12.0, 6.8, 1H), 1.84-1.63 (m, 3H), 1.54-1.45 (m, 2H), 1.32 (s, 3H), 1.30-

1.20 (m, 1H), 1.16 (s, 3H), 1.12-1.01 (m, 2H), 1.06 (s, 3H), 0.65 (d, J = 6.2 Hz, 3H); 13C

NMR (400 MHz, CDCl3): δ 174.37, 153.65, 148.66, 139.59, 129.01, 128.59, 126.05,

119.57, 69.26, 58.32, 56.61, 41.47, 40.12, 37.18, 36.39, 34.06, 33.55, 30.10, 29.08, 28.68,

19.83, 19.13 ppm; MS: m/z 381 [M+], 347, 332, 245, 219, 218, 203, 190, 175, 161, 147,

135, 105, 91, 77, 55; HRMS calcd for C24H31NO3 381.2304, found 381.2303.

5.8.14 1H-NMR Characterization of minor diastereomers of 4-phenyl-3-(2,5,5,8a- tetramethyl-1,2,3,5,6,7,8,8a-octahydro-naphthalene-1-carbonyl)-oxazolidin-2-one (135c endo II and exo) 9 9' 9 9' 9' O O 10 9 O O 10' 10' 2 10 2' O 4 N 3 O 4' N 3' 9 10 6' 9' 10' 5 6 11 1 5' 1' 7 9 7' 11' 9' 8 8' 8 8' 8 8' 8 8' 135c endo II 135c exo (absolute config. unknown) Both endo II and exo diastereomers of 135c also formed during the Diels-Alder

1 reaction between 134c and 96 promoted by RAlBr2 Lewis acid. H NMR (400 MHz,

CDCl3): δ 7.40 (m, 10H, H-8, H-8’), 5.58 (m, 1H, H-1), 5.53-5.50 (m, 2H, H-5, H-5’),

5.42 (m, 1H, H-1’), 4.72-4.61 (m, 2H, H-6, H-6’), 4.33-4.24 (m, 2H, H-5, H-5’), 4.06 (d,

J = 10.2 Hz, 1H, H-2), 3.90 (d, J = 11.3 Hz, 1H, H-2’), 2.1-1.2 (m, 18 H), 1.26 (s, 3H),

1.22 (s, 3H), 1.11 (s, 3H), 1.04 (s, 3H), 1.01 (s, 3H), 1.00 (s, 3H), 0.92 (d, J = 6.2 Hz,

3H), 0.60 (d, J = 6.2 Hz, 3H).

276

5.8.15 Synthesis of 4-Isopropyl-3-(2,5,5,8a-tetramethyl-1,2,3,5,6,7,8,8a-octahydro- naphthalene-1-carbonyl)-oxazolidin-2-one (135d endo I) 9 9 O O 10 9 2 10 O 4 N 3 9 10 5 6 11 1 9 7 8 8 135d endo I

Into dry toluene (1 mL) was added 134d (0.05 g, 0.253 mmol) and 96 (0.15 mL,

1.0 mmol). The mixture was sealed under nitrogen atmosphere and cooled to -78 ºC. Into this solution was added a 1.0 M solution of freshly made Lewis acid (amount and type specified in text) dropwise over 5 minutes. The reaction was stirred at -78 ºC for 5 minutes before being warmed to -25 ºC and stirred for a further 24 hours. The reaction was quenched at low temperature with 5% HCl (10 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was dried over MgSO4. Concentration in vacuo followed by purification via flash column chromatography (10:1 Hex:EtOAc) afforded

135d as a mixture of inseparable diastereomers that was a clear colourless oil (yields and diastereomeric ratios specified in text, depending on reaction conditions). Small amounts of the major endo diastereomer could subsequently be isolated and purified. IR (film)

-1 1 vmax 2961, 2931, 2874, 1782, 1695, 1380, 1297, 1224, 1197, 1061, 775, 712 cm ; H

NMR (400 MHz, CDCl3): δ 5.60 (dd, J = 6.9, 2.2 Hz, 1H), 4.57 (ddd, J = 8.4, 3.5, 1H),

4.26-4.16 (m, 2H), 4.10 (d, J = 10.3 Hz, 1H), 2.35 (m, 1H), 2.09 (ddd, J = 16.4, 6.9, 4.3

Hz, 1H), 1.95-1.86 (m, 1H), 1.82-1.71 (m, 3H), 1.55-1.48 (m, 2H), 1.36 (s, 3H), 1.29-

1.19 (m, 1H), 1.17 (s, 3H), 1.09 (s, 3H), 0.95-0.87 (m, 9H); 13C NMR (400 MHz,

CDCl3): δ 174.75, 153.93, 148.88, 119.42, 62.38, 58.55, 56.54, 41.51, 40.25, 37.23,

277

36.45, 33.99, 33.58, 29.60, 28.97, 28.65, 28.62, 20.03, 19.17, 18.19, 14.67; MS: m/z 347

[M+], 332, 219, 218, 203, 190, 175, 161, 135, 105, 91, 79, 69, 55; HRMS calcd for

C21H33NO3 347.2460, found 347.2471.

5.8.16 1H-NMR Characterization of minor diastereomers of 4-Isopropyl-3-(2,5,5,8a- tetramethyl-1,2,3,5,6,7,8,8a-octahydro-naphthalene-1-carbonyl)-oxazolidin-2-one (135d endo II and exo) 9 9' 9 9' 9' O O 10 9 O O 10' 10' 2 10 2' O 4 N 3 O 4' N 3' 9 10 6' 9' 10' 5 6 11 1 5' 1' 9 11' 9' 7 8 7' 8' 8 8' 135d endo II 135d exo (absolute config. unknown)

Both endo II and exo diastereomers of 135d also formed during the Diels-Alder

1 reaction between 134d and 96 promoted by RAlBr2 Lewis acid. H NMR (400 MHz,

CDCl3): δ 5.62-5.58 (m, 1H, H-1), 5.45 (m, 1H, H-1’), 5.52-5.44 (m, 2H, H-6, H-6’),

4.26-4.12 (m, 4H, H-5, H-5’), 4.09 (d, J = 3.3 Hz, 1H, H-2), 3.91 (d, J = 11.3 Hz, 1H, H-

2’), 2.52-2.32 (m, 2H), 2.14-2.04 (m, 4H), 1.97-1.67 (m, 6H), 1.6-1.2 (m, 8H), 1.34-1.33

(2 singlets, 6H), 1.17-1.16 (2 singlets, 6H), 1.09 (s, 6H), 0.98-0.84 (m, 18H).

5.8.17 Synthesis of 3-(2,5,5,8a-Tetramethyl-1,2,3,5,6,7,8,8a-octahydro-naphthalene-1- carbonyl)-oxazolidin-2-one (154 endo and exo) 6 6' O 6 6 O 6' 6' O 7 O 7' 7 7' O 3 N 2 O 3' N 2' 7 7' 4 5 1 4' 5' 8' 1' 6 6' 8 6 6' 154 endo 154 exo + enant. + enant.

278

Into dry toluene or DCM (8 mL) was added 153a (0.1 g, 0.644 mmol) and 96 (0.4 mL, 2.58 mmol). The mixture was sealed under nitrogen atmosphere and cooled to -78

ºC. Into this solution was added a 1.0 M solution of freshly made Lewis acid (amount and type specified in text) dropwise over 5 minutes. The reaction was stirred at -78 ºC for 5 minutes before being warmed to -25 ºC and stirred for a further 24 hours. The reaction was quenched at low temperature with 5% HCl (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was dried over MgSO4. Concentration in vacuo followed by purification via flash column chromatography (6:1 Hex:EtOAc) afforded 154 as a mixture of diastereomers that was a clear colourless oil (yields and diastereomeric ratios specified in text, depending on reaction conditions). Small amounts of the major endo diastereomer could subsequently be isolated and purified. IR (film) vmax 2914, 1778,

-1 1 1699, 1386, 1250, 1210, 1104, 1034, 765, 709 cm ; H NMR (400 MHz, CDCl3): δ 5.62

(dd, J = 6.9, 2.2 Hz, 1H), 4.43-4.32 (m, 2H), 4.13-3.99 (m, 3H), 2.10 (m, 1H), 1.99-1.87

(m, 1H), 1.84-1.75 (m, 2H), 1.72-1.64 (m, 1H), 1.54-1.47 (m, 2H), 1.30 (s, 3H), 1.28-

13 1.22 (m, 2H), 1.16 (s, 3H), 1.09 (s, 3H), 0.91 (d, J = 6.5); C NMR (400 MHz, CDCl3): δ

175.15, 153.39, 148.78, 119.55, 61.29, 56.77, 42.98, 41.43, 40.07, 37.15, 36.45, 33.90,

33.56, 29.73, 29.15, 28.62, 20.17, 19.12; MS: m/z 305 [M+], 290, 250, 232, 219, 218,

203, 190, 175, 161, 135, 105, 91, 88, 69, 55; HRMS calcd for C18H27NO3 305.1991, found 305.1983. anal. calcd for C18H27NO3: C, 70.79; H, 8.91; N, 4.59 found: C, 70.38;

H, 9.09; N, 4.70 %.

279

X-Ray crystal structure for 154 endo

Orthorhombic Pbca; a =19.6430(5) Ǻ, b = 7.6036(3) Ǻ, c = 21.8917(7) Ǻ,  =

90º, γ = 90º, β = 90º, V = 3269.69(19) Ǻ3; Z = 8; Non hydrogen atoms were refined anisotropically. The H atoms were included at geometrically idealized positions and were not refined. The final cycle of full-matrix least-squares refinement using SHELXL3 converged with unweighted and weighted agreement factors, R = 0.0688 and wR =

0.1009 (all data), respectively, and goodness of fit, S = 1.098. The weighting scheme was based on counting statistics and the final difference Fourier map was essentially featureless. The figure was plotted with the aid of ORTEP-3 for Windows.

280

5.8.18 Synthesis of 3-(5,5,8a-Trimethyl-1,2,3,5,6,7,8,8a-octahydro-naphthalene-1- carbonyl)-oxazolidin-2-one (154b endo and exo) 6 6' O 6 6 O 6' 6' O 7 O 7' 7 7' O 3 N 2 O 3' N 2' 7 7' 4 5 1 4' 5' 1' 6 6' 6 6' 154b endo 154b exo + enant. + enant.

Into dry toluene or DCM (8 mL) was added 153b (0.1 g, 0.701 mmol) and 96

(0.43 mL, 2.83 mmol). The mixture was sealed under nitrogen atmosphere and cooled to

-78 ºC. Into this solution was added a 1.0 M solution of freshly made Lewis acid (amount and type specified in text) dropwise over 5 minutes. The reaction was stirred at -78 ºC for

5 minutes before being warmed to -25 ºC and stirred for a further 24 hours. The reaction was quenched at low temperature with 5% HCl (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was dried over MgSO4. Concentration in vacuo followed by purification via flash column chromatography (6:1 Hex:EtOAc) afforded

154b as an inseparable mixture of diastereomers that was a clear colourless oil (yields and diastereomeric ratios specified in text, depending on reaction conditions). IR (film)

-1 1 vmax 2924, 1772, 1695, 1476, 1383, 1360, 1247, 1220, 1104, 1048, 752, 709 cm ; H

NMR (400 MHz, CDCl3): δ 5.52 (m, 1H, H-8), 5.47 (m, 1H, H-8’), 4.42-4.32 (m, 4H, H-

1,1’), 4.08-3.95 (m, 4H, H-3,3’), 3.92 (dd, J = 12.8, 2.6 Hz, 1H, H-5’), 3.87 (dd, J = 4.1,

2.4 Hz, 1H, H-5), 2.30-1.96 (m, 6H), 1.86-1.58 (m, 6H), 1.55-1.25 (m, 8H), 1.32 (s, 6H),

13 1.13 (s, 3H), 1.12 (s, 6H), 1.08 (s, 3H); C NMR (400 MHz, CDCl3): δ 176.22 (C-4’),

174.15 (C-4), 153.43 (C-2’), 153.32 (C-2), 149.54 (C-9’), 147.09 (C-9), 118.43 (C-8’),

118.13 (C-8), 61.46 (C-1), 61.43 (C-1’), 48.91 (C-5’), 48.74 (C-5), 43.00 (C’), 42.83 (C),

281

40.71 (C’), 40.61 (C), 38.19 (C’), 37.76 (C’), 36.80 (C), 35.71 (C), 35.53 (C’), 35.35 (C),

32.63 (C’), 32.38 (C), 31.03 (C), 31.01 (C’), 30.14 (C), 25.21 (C’), 22.82 (C), 22.16 (C’),

22.09 (C’), 20.98 (C), 18.38 (C), 18.23 (C’) ppm; MS: m/z 291 [M+], 276, 235, 204, 189,

176, 161, 147, 135, 119, 105, 91, 79, 77, 67, 55; HRMS calcd for C17H25NO3 291.1834, found 291.1838.

5.8.19 Characterization of but-2-enoic acid (2-bromoethyl)-amide (155) O 3 Br HN 4 5

1 2 6 7

155

- IR (film) vmax 2914.3, 2847.6, 1761.9, 1690.5, 1647.6, 1361.9, 1190.5, 1028.6 cm

1 1 ; H NMR (400 MHz, CDCl3): δ 6.87 (dq, J = 15.2, 6.9 Hz, 1H), 5.84 (dq, J = 15.2, 1.7

Hz, 1H), 5.90 (br s, 1H), 3.73 (q, 5.8 Hz, 2H), 3.51 (t, 5.8 Hz, 2H), 1.87 (dd, J = 6.9, 1.7

13 Hz, 3H); C NMR (400 MHz, CDCl3): δ 165.88 (C-4), 140.73 (C-6), 124.59 (C-5), 41.05

(C-2), 32.67 (C-1), 17.22 (C-7) ppm; MS: m/z 191 [M+], 193 [M+2], 178, 141, 126, 111,

79 98, 80, 69, 54, 41, 36; HRMS calcd for C6H10NO3 Br 190.9946, found 190.9941; for

81 C6H10NO3 Br 192.9925, found 192.9924.

5.8.20 Synthesis of 1-(2-Phenyl-[1,3]dithian-2-yl)-but-2-en-1-ol (177) 7 6 4 3 S 5 S 2 8 1 11 9 OH 10

177

282

Compound 177 was prepared according to the general procedure reported by Page et. al.57 In freshly distilled THF (300 mL) was added commercial 2-phenyl-1,3-dithiane

(5.0 g, 25.4 mmol). The reaction mixture was cooled to -78 ºC and a 1.6 M solution of n-

BuLi (15.9 mL, 25.4 mmol) in hexanes was added dropwise. The reaction mixture was stirred at -78 ºC for 1 hour before a solution of freshly distilled crotonaldehyde (2.1 mL,

25.4 mmol) in freshly distilled THF (20 mL) was added dropwise. The reaction was warmed to room temperature and stirred for 24 hours, and quenched with 10% HCl (50 mL). The solvent was removed in vacuo and the residue dissolved in DCM (100 mL).

The organic layer was washed with H2O (2 x 30 mL) and dried over MgSO4.

Concentration in vacuo followed by purification via flash column chromatography (4:1

Hex:EtOAc) yielded 177 as a clear viscous oil (2.86 g, 10.8 mmol, 42.6%). See Wartski

85 86 1 et. al. and Chen et. al. for characterization data. H NMR (400 MHz, CDCl3): δ 7.97-

7.93 (m, 2H), 7.42-7.36 (m, 2H), 7.30-7.25 (m, 1H), 5.62 (ddq, J = 15.2, 6.5, 1.0 Hz, 1H),

5.32 (ddq, J = 15.2, 7.2, 1.6 Hz, 1H), 4.28 (dd, J = 5.9 Hz, 1H), 2.73-2.59 (m, 4H), 2.25

(d, J = 5.3 Hz, 1H), 1.94-1.86 (m, 2H), 1.63 (ddd, J = 6.5, 1.6, 0.7 Hz, 3H) ppm.

5.8.21 Synthesis of 2-Hydroxy-1-phenyl-pent-3-en-1-one (178) 5 O 4

6 2 3 1

9 7 OH 8

178

Compound 178 was prepared according to the general procedure outlined by

Kessar et. al.87 Into a 90% aqueous solution of AcCN (150 mL) was added NCS (4.3 g,

283

32.2 mmol) and AgNO3 (6.39 g, 37.6 mmol). This mixture was cooled to 0 ºC and a solution of 177 (2.86 g, 10.7 mmol) in AcCN (15 mL) was added dropwise. The reaction mixture was stirred for 30 minutes at 0 ºC, and diluted with H2O. The mixture was extracted with DCM (5 x 50 mL), and the combined organic layer was washed with 10%

NH4OH (3 x 30 mL), H2O (3 x 30 mL), and saturated NaCl (2 x 30 mL). Concentration in vacuo followed by purification via flash column chromatography (3:1 Hex:EtOAc) afforded 178 as a clear colourless oil (1.89 g, 10.5 mmol, 98.1%). Characterization data

88 was consistent with limited data reported by Lerouge et. al. IR (film) vmax 3448, 3062,

3029, 2976, 2914, 2362, 2329, 1686, 1590, 1452, 1271, 1171, 976, 710; 1H NMR (400

MHz, CDCl3): δ 8.00-7.96 (m, 2H), 7.63-7.58 (m, 1H), 7.51-7.46 (m, 2H), 5.98 (ddq, J =

14.9, 6.5, 0.8 Hz, 1H), 5.52 (ddq, J = 14.9, 6.9, 1.7 Hz, 1H), 5.45 (d, J = 6.9 Hz, 1H),

13 4.01 (s, 1H), 1.68 (ddd, J = 6.7, 1.7, 1.0 Hz, 1H); C NMR (400 MHz, CDCl3): δ 199.29,

133.98, 133.61, 131.04, 129.03, 128.76, 128.44, 74.25, 17.92; MS: m/z 176 [M+], 158,

147, 131, 107, 105, 77, 69, 53, 51; HRMS calcd for C11H12O2 176.0837, found 176.0842. anal. calcd for C11H12O2: C, 74.98; H, 6.86 found: C, 74.13; H, 6.90 %.

5.8.22 Synthesis of 1-Phenyl-pent-3-ene-1,2-dione (179) 5 O 4

6 2 3 1

9 7 O 8 179

Compound 179 was prepared using a modified procedure outlined by Bow et. al.89 Into DCM (250 mL) was dissolved 178 (2.5 g, 14.2 mmol), Hunig’s base (12.4 mL,

284

71.0 mmol), and DMSO (5.0 mL, 71.0 mmol). The reaction mixture was cooled to 0 ºC and sulfur trioxide pyridine complex (6.78 g, 42.6 mmol) was added in one portion. The reaction was warmed to room temperature and stirred overnight. The reaction was quenched with 1M HCl (200 mL), and the organic layer washed with saturated NaCl (3 x

30 mL) and dried over MgSO4. Concentration in vacuo followed by purification via column chromatography (8:1 Hex:EtOAc) afforded 179 as a clear, yellow oil (1.7 g, 9.8 mmol, 69%). IR (film) vmax 3062, 2981, 2905, 1676, 1619, 1595, 1443, 1195, 1176, 971,

1 786, 733, 681, 576; H NMR (400 MHz, CDCl3): δ 7.96-7.93 (m, 2H), 7.66-7.60 (m, 1H),

7.52-7.46 (m, 2H), 7.00 (dq, J = 16.0, 6.9 Hz, 1H), 6.47 (dq, J = 16.0, 1.6 Hz), 1.99 (dd, J

13 = 6.9, 1.6 Hz, 3H); C NMR (400 MHz, CDCl3): δ 193.74, 193.56, 151.00, 134.62,

132.77, 129.96, 128.87, 128.82, 19.16; MS: m/z 174 [M+], 158, 146, 105, 91, 77, 69, 50;

HRMS calcd for C11H10O2 174.0681, found 174.0680.

5.8.23 Synthesis of 2-(3-chloro-propyl)-5-methyl furan (185) 1 6 O 8 2 5 7 Cl 3 4 185

Compound 185 was prepared according to a procedure outlined by Rogers et. al.58

Freshly distilled 2-methyl furan (10.25 mL, 116 mmol) was dissolved in freshly distilled

THF (200 mL). The reaction mixture was cooled to -78 ºC, and a 2.5 M solution of n-

BuLi (46.3 mL, 116 mmol) in hexanes was added dropwise. The reaction mixture was warmed to 0 ºC and stirred 2 hours. Purification of 1-bromo-3-chloropropane was achieved using column chromatography in basic alumina followed by distillation. A solution of 1-bromo-3-chloropropane (15.5 mL, 156 mmol) in freshly distilled THF (20

285

mL) was added dropwise, and the mixture was stirred at room temperature for 24 hours.

Solvent was removed in vacuo and the residue was dissolved in concentrated NH4Cl (100 mL). This mixture was extracted with diethyl ether (3 x 50 mL), and the combined organic extracts were dried over MgSO4. Purification was carried out via flash column chromatography (50:1 Hex:EtOAc) to yield 185 (16.0 g, 101 mmol, 87.1%) as a clear colourless liquid. See Rogers et. al. for characterization data.58 1H NMR (300 MHz,

CDCl3): δ 5.90 (d, J = 3.0, 1H), 5.84 (d, J = 3.0 Hz, 1H), 3.57 (t, J = 6.5 Hz, 2H), 2.75 (t,

J = 7.2 Hz, 2H), 2.25 (s, 3H), 2.09 (q, J = 7.2 Hz, 2H) ppm.

5.8.24 Synthesis of 2-(3-iodo-propyl)-5-methyl-furan (186) 1 6 O 8 2 5 7 I 3 4 186

Compound 186 was prepared according to a procedure outlined by Rogers et. al.58

Into freshly distilled HPLC grade acetone (400 mL) was dissolved 185 (16.0 g, 101 mmol) and NaI (37.7 g, 252 mmol) which had previously been flame dried under vacuum

(10-1 torr). The reaction mixture was heated to 55 ºC under nitrogen atmosphere overnight. The solvent was removed in vacuo and H2O (100 mL) and diethyl ether (100 mL) were added. The organic layer was separated and the aqueous layer was extracted with diethyl ether (2 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification by distillation (bp 100 ºC/20 torr) afforded 186 in

58 1 19.3% yield. See Rogers et. al for characterization data. H NMR (300 MHz, CDCl3): δ

286

5.88 (d, J = 3.0 Hz, 1H), 5.82 (d, J = 3.0 Hz, 1H), 3.21 (t, J = 6.8 Hz, 2H), 2.70 (t, J = 6.8

Hz, 2H), 2.26 (s, 3H), 2.13 (q, J = 6.8 Hz, 2H) ppm.

5.8.25 Synthesis of 6-(5-Methyl-furan-2-yl)-hex-1-en-3-ol (188a) 1 11 O 6 8 2 5 9 7 10 3 4 12HO 188a

Compound 188a was prepared according to the procedure outlined by Keay et. al.58 Into diethyl ether (300 mL) was dissolved 186 (3.1 g, 12.2 mmol). The solution was cooled to -78 ºC and a 1.7 M solution of t-BuLi (15.8 mL) in hexanes was added dropwise. The reaction mixture was stirred 1 hour before neat methacrolein (1.6 mL, 24 mmol) was added dropwise. The reaction was stirred for 30 minutes before being quenched at low temperature with concentrated NH4Cl (50 mL). The resulting mixture was warmed to room temperature and extracted with diethyl ether (3 x 50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification was accomplished via flash column chromatography (5:1 Hex:EtOAc) to afford 188a as a clear colourless oil (1.74 g, 9.67 mmol, 79.3%). See Rogers et. al. for characterization

58 1 data. H NMR (300 MHz, CDCl3): δ 5.87 (ddd, J = 17.2, 10.3, 6.2 Hz, 1H), 5.85 (m,

2H), 5.23 (ddd, J = 17.2, 1.3, 1.3 Hz, 1H), 5.12 (ddd, J = 10.4, 1.3, 1.3 Hz, 1H), 4.13 (m,

1H), 2.61 (t, J = 7.0 Hz, 2H), 2.25 (s, 3H), 1.84-1.54 (m, 4H), 1.52 (s, 1H) ppm.

287

5.8.26 Synthesis of 2-Methyl-6-(5-methyl-furan-2-yl)-hex-1-en-3-ol (188b) 1 11 O 6 8 2 5 9 7 10 3 4 13 12HO 188b

Compound 188b was prepared according to the procedure outlined by Keay et. al.58 Into diethyl ether (300 mL) was dissolved 186 (3.0 g, 12.0 mmol). The solution was cooled to -78 ºC and a 1.7 M solution of t-BuLi (15.5 mL) in hexanes was added dropwise. The reaction mixture was stirred 1 hour before neat methacrolein (2.0 mL, 24 mmol) was added dropwise. The reaction was stirred for 30 minutes before being quenched at low temperature with concentrated NH4Cl (50 mL). The resulting mixture was warmed to room temperature and extracted with diethyl ether (3 x 50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification was accomplished via flash column chromatography (8:1 Hex:EtOAc) to afford 188b as a clear colourless oil (1.84 g, 9.47 mmol, 78.9%). See Rogers et. al. for characterization

58 1 data. H NMR (300 MHz, CDCl3): δ 5.85 (m, 2H), 4.95 (m, 1H), 4.85 (m, 1H), 4.09 (t,

J = 6.2, 1H), 2.61 (t, J = 7.1 Hz, 2H), 2.25 (s, 3H), 1.72 (s, 3H), 1.71-1.56 (m, 4H), 1.49

(s, 1H) ppm.

5.8.27 Synthesis of 7-(5-Methyl-furan-2-yl)-hept-2-en-4-ol (188c) 1 11 13 O 6 8 2 5 9 7 10 3 4 12HO 188c

Compound 188c was prepared according to the procedure outlined by Rogers et. al.58 Into diethyl ether (200 mL) was dissolved 186 (2.22 g, 8.88 mmol). The solution

288

was cooled to -78 ºC and a 1.7 M solution of t-BuLi (11.5 mL, 19.5 mmol) in hexanes was added dropwise. The reaction mixture was stirred for 1 hour before neat crotonaldehyde (1.5 mL, 17.7 mmol) was added dropwise. The reaction was stirred for 30 minutes before being quenched at low temperature with concentrated NH4Cl (50 mL).

The resulting mixture was warmed to room temperature and extracted with diethyl ether

(3 x 50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo.

Purification was accomplished via flash column chromatography (8:1 Hex:EtOAc) to afford 188c as a clear colourless oil (1.40 g, 7.16 mmol, 80.6%). See Rogers et. al. for

58 1 characterization data. H NMR (300 MHz, CDCl3): δ 5.87-5.82 (m, 2H), 5.67 (ddq, J =

15.3, 5.9, 0.9 Hz, 1H), 5.49 (ddq, J = 15.3, 6.9, 1.5 Hz, 1H), 4.06 (m, 1H), 2.60 (t, J = 6.9

Hz, 2H), 2.26 (s, 3H), 1.70 (dd, J = 6.3, 0.9 Hz, 3H), 1.70-1.50 (m, 4H), 1.43 (s, 1H) ppm.

5.8.28 Synthesis of 6-(5-Methyl-furan-2-yl)-hex-1-en-3-one (182e) 1 11 O 6 8 2 5 9 7 10 3 4 O 182e

Compound 182e was prepared according to the procedure outlined by Rogers et. al.58 Into DCM (40 mL) was added oxalyl chloride (0.91 mL, 10.6 mmol). The solution was cooled to -60 ºC and DMSO (1.5 mL, 21.1 mmol) was added dropwise. The reaction mixture was stirred for 2 minutes before a solution of 188a (1.74 g, 9.67 mmol) in DCM

(10 mL) was added dropwise over 5 minutes. The reaction mixture was stirred for 15 minutes and then NEt3 (6.75 mL, 48.4 mmol) was added dropwise. The reaction was

289

stirred for 5 minutes, warmed to room temperature, and quenched with H2O (50 mL). The mixture was extracted with DCM (3 x 25 mL) and the combined organic layers were washed successively with 5 % HCl (2 x 10 mL), 5 % NaHCO3 (2 x 10 mL), and H2O (2 x

10 mL), then dried over Na2SO4. Concentration in vacuo followed by purification via flash column chromatography (20:1 Hex:EtOAc) afforded 182e as a clear colourless oil

(1.10 g, 6.16 mmol, 63.7%). See Rogers et. al. for characterization data.58 1H NMR (300

MHz, CDCl3): δ 6.36 (dd, J = 17.6, 10.4 Hz, 1H), 6.20 (dd, J = 17.6, 1.0 Hz), 5.89-5.79

(m, 3H), 2.63 (t, J = 7.3 Hz, 2H), 2.63 (t, J = 7.3 Hz, 2H), 2.25 (s, 3H), 1.96 (q, J = 7.3

Hz, 2H) ppm.

5.8.29 Synthesis of 2-Methyl-6-(5-methyl-furan-2-yl)-hex-1-en-3-one (182f) 1 11 O 6 8 2 5 9 7 10 3 4 12 O 182f

Compound 182f was prepared according to the procedure outlined by Rogers et. al.58 Into DCM (40 mL) was added oxalyl chloride (0.89 mL, 10.4 mmol). The solution was cooled to -60 ºC and DMSO (1.5 mL, 21.1 mmol) was added dropwise. The reaction mixture was stirred for 2 minutes before a solution of 188b (1.84 g, 9.47 mmol) in DCM

(10 mL) was added dropwise over 5 minutes. The reaction mixture was stirred for 15 minutes and then NEt3 (6.6 mL, 47.0 mmol) was added dropwise. The reaction was stirred for 5 minutes, warmed to room temperature, and quenched with H2O (50 mL). The mixture was extracted with DCM (3 x 25 mL) and the combined organic layers were washed successively with 5 % HCl (2 x 10 mL), 5 % NaHCO3 (2 x 10 mL), and H2O (2 x

290

10 mL), then dried over Na2SO4. Concentration in vacuo followed by purification via flash column chromatography (20:1 Hex:EtOAc) afforded 182f as a clear colourless oil

(1.33 g, 6.92 mmol, 73.1%). See Rogers et. al. for characterization data.58 1H NMR (300

MHz, CDCl3): δ 5.93 (m, 1H), 5.88-5.82 (m, 2H), 5.75 (m, 1H), 2.73 (t, J = 7.3 Hz, 2H),

2.62 (t, J = 7.3 Hz, 2H), 2.25 (s, 3H), 1.95 (q, J = 7.3 Hz, 2H), 1.88 (s, 3H) ppm.

5.8.30 Synthesis of 7-(5-Methyl-furan-2-yl)-hept-2-en-4-one (182g) 1 11 12 O 6 8 2 5 9 7 10 3 4 O 182g

Compound 182g was prepared according to the procedure outlined by Rogers et. al.58 Into DCM (30 mL) was added oxalyl chloride (0.68 mL, 7.87 mmol). The solution was cooled to -60 ºC and DMSO (1.12 mL, 15.7 mmol) was added dropwise. The reaction mixture was stirred for 2 minutes before a solution of 188c (1.4 g, 7.16 mmol) in

DCM (7.5 mL) was added dropwise over 5 minutes. The reaction mixture was stirred for

15 minutes and then NEt3 (5.0 mL, 35.8 mmol) was added dropwise. The reaction was stirred for 5 minutes, warmed to room temperature, and quenched with H2O (50 mL). The mixture was extracted with DCM (3 x 25 mL) and the combined organic layers were washed successively with 5 % HCl (2 x 10 mL), 5 % NaHCO3 (2 x 10 mL), and H2O (2 x

10 mL), then dried over Na2SO4. Concentration in vacuo followed by purification via flash column chromatography (20:1 Hex:EtOAc) afforded 182g as a clear colourless oil

(0.84 g, 4.37 mmol, 61.0%). See Rogers et. al. for characterization data.58 1H NMR (300

MHz, CDCl3): δ 6.83 (dq, J = 15.8, 6.8 Hz, 1H), 6.12 (dq, J = 15.8, 1.6 Hz, 1H), 5.88-

291

5.82 (m, 2H), 2.61 (t, J = 7.4 Hz, 2H), 2.57 (t, J = 7.4 Hz, 2H), 2.25 (s, 3H), 1.94 (q, J =

7.4 Hz, 2H), 1.90 (dd, J = 6.8, 1.6 Hz, 3H) ppm.

5.8.31 Synthesis of 8-Methyl-11-oxa-tricyclo[6.2.1.01,6]undec-9-en-5-one (183e) O 11 9 1 10 8 2 O 7 5 3 6 4

183e

Into DCM (30 mL) was dissolved 182e (0.1 mL, 0.662 mmol), and the reaction mixture was cooled to -78 ºC. Into this solution was added a 1.0 M solution of the appropriate freshly made Lewis acid (0.1 eq.) dropwise over 5 minutes. The reaction was stirred at -78 ºC (reaction times specified) before being quenched at low temperature with

10% NaHCO3 (50 mL). The mixture was extracted with DCM (3 x 25 mL) and the combined organic layers were washed with H2O and dried over Na2SO4. Concentration in vacuo followed by purification via flash column chromatography (10:1 Hex:EtOAc) afforded 183e as a clear colourless oil (yields specified in text, depending on reaction

58 1 conditions). See Rogers et. al. for full characterization. H NMR (300 MHz, CDCl3): δ

6.20 (d, J = 7.6 Hz, 1H), 6.11 (d, J = 7.6 Hz, 1H), 2.51 (m, 1H), 2.44-2.33 (m, 2H), 2.40

(dd, J = 8.2, 3.5 Hz, 1H), 2.22 (m, 1H), 2.20 (dd, J = 11.8, 3.5 Hz, 1H), 2.02-1.89 (m,

2H), 1.60 (dd, J = 11.8, 8.2 Hz, 1H), 1.57 (s, 3H) ppm.

292

5.8.32 Synthesis of 6,8-Dimethyl-11-oxa-tricyclo[6.2.1.01,6]undec-9-en-5-one (183f) 12 O 11 9 1 8 2 O10 7 5 3 6 4

183f

Into DCM (30 mL) was dissolved 182f (0.1 mL, 0.541 mmol), and the reaction mixture was cooled to -78 ºC. Into this solution was added a 1.0 M solution of the appropriate freshly made Lewis acid (0.1 eq.) dropwise over 5 minutes. The reaction was stirred at -78 ºC (reaction times specified) before being quenched at low temperature with

10% NaHCO3 (50 mL). The mixture was extracted with DCM (3 x 25 mL) and the combined organic layers were washed with H2O and dried over Na2SO4. Concentration in vacuo followed by purification via flash column chromatography (10:1 Hex:EtOAc) afforded 183f as a clear colourless oil (yields specified in text, depending on reaction

58 1 1 conditions). See Rogers et. al. for full characterization. H NMR (300 MHz, CDCl3): H

NMR (300 MHz, CDCl3): δ 6.29 (d, J = 5.6 Hz, 1H), 6.14 (d, J = 5.6 Hz, 1H), 2.55 (d, J

= 11.8 Hz, 1H), 2.61-2.54 (m, 1H), 2.40 (m, 1H), 2.25-2.17 (m, 2H), 2.04-1.84 (m, 2H),

1.52 (s, 3H), 1.13 (d, J = 11.8 Hz, 1H), 1.10 (s, 3H) ppm.

293

5.8.33 Synthesis of 7,8-Dimethyl-11-oxa-tricyclo[6.2.1.01,6]undec-9-en-5-one (183g) 12 O 11 1 9 10 8 2 O 7 5 3 6 4

183g

Into DCM (30 mL) was dissolved 182g (0.1 mL, 0.546 mmol), and the reaction mixture was cooled to -78 ºC. Into this solution was added a 1.0 M solution of the appropriate freshly made Lewis acid (0.1 eq.) dropwise over 5 minutes. The reaction was stirred at -78 ºC (reaction times specified) before being quenched at low temperature with

10% NaHCO3 (50 mL). The mixture was extracted with DCM (3 x 25 mL) and the combined organic layers were washed with H2O and dried over Na2SO4. Concentration in vacuo followed by purification via flash column chromatography (10:1 Hex:EtOAc) afforded 183g as a clear colourless oil (yields specified in text, depending on reaction

58 1 1 conditions). See Rogers et. al. for full characterization. H NMR (300 MHz, CDCl3): H

NMR (300 MHz, CDCl3): δ 7.27 (d, J = 5.6 Hz, 1H), 6.22 (d, J = 5.6 Hz, 1H), 2.56 (m,

1H), 2.48-2.11 (m, 4H), 1.99-1.82 (m, 3H), 1.51 (s, 3H), 0.94 (d, J = 7.1 Hz, 3H) ppm.

5.8.34 Synthesis of Benzylidene-phenyl-amine (192) 3 2 3

N 3 2 4 5 1

5 4 5 192

294

Compound 192 was prepared according to a procedure outlined by Keinicke et. al.90 Into toluene (250 mL) was dissolved benzaldehyde (5.10 mL, 50.0 mmol) and aniline (5.45 mL, 50.0 mmol). A Dean-Stark trap was attached and the reaction mixture was refluxed at 110 ºC overnight. Concentration in vacuo followed by purification by recrystalization afforded 192 as colourless crystals (7.34, 40.5 mmol, 81.0%). See

90 1 Keinicke et. al. for characterization data. H NMR (300 MHz, CDCl3): δ 8.36 (s, 1H),

7.84-7.78 (m, 2H), 7.41-7.35 (m, 3H), 7.33-7.25 (m, 2H), 7.16-7.09 (m, 3H) ppm.

5.8.35 Synthesis of Phenyl-phenylamino-acetonitrile (193) 5 4 5 2 HN 6 1 7 CN 3 7

193

Into dry solvent (1 mL) was dissolved 192 (0.1 g, 0.552 mmol) and the solution was cooled to -78 ºC. Into this solution was added a 1.0 M solution of freshly made

Lewis acid (amount and type specified in text) dropwise over 5 minutes. The reaction mixture was stirred for 10 minutes before neat TMSCN (0.1 mL, 0.80 mmol) was added dropwise over 1 minute. The solution was stirred at -78 ºC for 2 hours before being quenched at low temperature with concentrated NH4Cl (1 mL). The mixture was extracted with DCM (3 x 10 mL) and the combined organic layers were dried over

MgSO4. Concentration in vacuo followed by purification via flash column chromatography (10:1 Hex:EtOAc) and recrystallization from hexanes afforded 193 as a

295

white crystalline solid (yields specified in text, depending on reaction conditions). See

59 1 Majhi et. al. for characterization data. H NMR (400 MHz, CDCl3: δ 7.65-7.60 (m, 2H),

7.52-7.45 (m, 3H), 7.32-7.26 (m, 2H), 6.95-6.89 (tt, J = 7.4, 0.8 Hz, 1H), 6.83-6.87 (m,

2H), 5.45 (d, J = 12.4 Hz, 1H), 4.04 (br d, J = 8.2 Hz, 1H) ppm; HRMS calcd for

C14H12N2 208.1000, found 208.1007.

5.9 Experimental Procedures Pertaining to Chapter 4

5.9.1 Synthesis of RAlBr2 Lewis acid 88 7 Br2Al 2 3 1 4 5 6 8 9 9 88

A solution of 99.99 % AlBr3 (2.4 g, 9 mmol) in benzene (9 mL) was slowly added to the

LiAlH4 suspension to generate the hydroaluminating agent in situ. This mixture was stirred for 30 minutes before (1R, 5R)--pinene (1.91 mL, 12 mmol) was added dropwise as a solution in benzene (2 mL) over 5 minutes. The reaction was stirred for an hour before all solvent was removed in vacuo. Lewis acid 88 was obtained as a clear, colourless, viscous oil, which was kept under N2 pressure at all times. This oil was redissolved in 10.1 mL toluene to make a 1.0 M solution of Lewis acid 88. 1H NMR (400

MHz, C6D6): δ 2.43 (m, 1H), 2.14 (m, 1H), 2.00 (m, 1H), 1.86 (m, 1H), 1.73 (m, 1H),

296

1.25 (s, 3H), 1.21 (d, J = 7.0 Hz, 3H), 1.13 (s, 3H), 1.10-0.94 (m, 2H), 0.74 (m, 1H); 13C

NMR (400 MHz, C6D6): δ 48.50, 41.55, 39.29, 37.92, 33.91, 28.63, 28.24, 23.66, 22.61,

7.73 ppm; MS: m/z 138.1 [M+], 123.1, 109.1, 95.1, 84.0, 69.1, 55.1; HRMS calcd for

C10H18 138.1409, found 138.1413.

5.9.2 Synthesis of 1,7,7-Trimethyl-2-methylene-bicyclo[2.2.1]heptanes (200) 6 6

4 7 3 8 5 2 6 1

200

Compound 200 was prepared using a standard Wittig reaction.

Methyltriphenylphosphonium bromide (35.2 g, 98.4 mmol) was suspended in freshly distilled THF (350 mL) and sealed under a nitrogen atmosphere. The reaction mixture was cooled to 0 ºC, and a 2.5 M solution of n-BuLi (38 mL, 95.1 mmol) in hexanes was added dropwise. The resulting orange solution was stirred for 10 minutes before a solution of (1R)-(+)-Camphor (10.0 g, 65.6 mmol) in THF (10 mL) was added dropwise.

The reaction mixture was allowed to reach room temperature over 1 hour, before being quenched with a concentrated NH4Cl solution (30 mL). The solvent was removed under reduced pressure before being dissolved in pentane (50 mL). The organic layer was washed with water (2 x 10 mL) and dried over MgSO4. Concentration in vacuo followed by purification by flash column chromatography (Hexanes) yielded 200 as a clear colourless solid (7.40 g, 49.2 mmol, 75.1%). See Giorgio et. al for characterization

91 20 1 data. []D -38.957 (c 3.75, CHCl3); H NMR (400 MHz, CDCl3): δ 4.72 (m, 1H), 4.66

297

(m, 1H), 2.45-2.37 (m, 1H), 1.94 (ddd, J = 16.2, 2.1, 2.1 Hz, 1H), 1.85-1.73 (m, 2H),

1.70-1.62 (m, 1H), 1.33-1.18 (m, 2H), 0.95 (s, 3H), 0.92 (s, 3H), 0.79 (s, 3H) ppm.

5.9.3 Synthesis of RAlBr2 Lewis acid 201 6 6

4 7 3 8 5 2 6 1 AlBr2 201

A solution of 99.99 % AlBr3 (2.4 g, 9 mmol) in benzene (9 mL) was slowly added to the

LiAlH4 suspension to generate the hydroaluminating agent in situ. This mixture was stirred for 30 minutes before olefin 200 (1.80 g, 12 mmol) was added dropwise as a solution in benzene (2 mL) over 5 minutes. The reaction was stirred for an hour before all solvent was removed in vacuo. Lewis acid 201 was obtained as a clear, colourless, crystalline solid, which was kept under N2 pressure at all times. This oil was redissolved in 10 mL toluene to make a 1.0 M solution of Lewis acid 201. 1H NMR (400 MHz,

C6D6): δ 2.24-2.18 (m, 1H), 1.69-1.56 (m, 2H), 1.55-1.51 (m, 1H), 1.25-1.15 (m, 1H),

1.08-0.99 (m, 1H), 0.94-0.82 (m, 1H), 0.88 (s, 3H), 0.84 (s, 3H), 0.80-0.69 (m, 1H), 0.72

(s, 3H), 0.61 (dd, J = 13.8, 2.8 Hz, 1H), 0.51 (dd, J = 13.8, 12.4 Hz, 1H); 13C NMR (400

MHz, C6D6): δ 49.21, 48.21, 45.65, 39.31, 39.13, 28.63, 27.61, 20.07, 18.32, 16.77 (br s),

13.74 ppm.

298

5.9.4 Characterization of 1,2,7,7-Tetramethyl-bicyclo[2.2.1]heptanes (202) 6 6

4 7 3 8 5 2 6 1 202

The endo diastereomer of hydrocarbon 202 has previously been reported by

60 1 Schmidt and co-workers. H NMR (400 MHz, C6D6): δ 2.01 (ddd, J = 15.7, 4.2, 3.7

Hz), 1.82 (m, 1H), 1.67 (m, 1H), 1.60-1.52 (m, 2H), 1.30-1.21 (m, 2H), 1.06 (m, 1H),

0.92 (d, J = 7.0 Hz, 3H), 0.88 (s, 3H), 0.88 (s, 3H), 0.75 (s, 3H); 13C NMR (400 MHz,

C6D6): 48.51, 47.66, 45.62, 38.01, 37.34, 28.69, 27.99, 19.76, 18.43, 15.46, 13.91. MS:

+ m/z 152 [M ], 137, 109, 95, 82, 67, 55, 41; HRMS calcd for C11H20 152.1565, found

152.1566.

5.9.5 Synthesis of 1-Iodomethyl-7,7-dimethyl-bicyclo[2.2.1]heptan-2-one (206) 6 4 6 3 7 2

8 5 1 9 O I 206

Compound 206 was prepared according to a procedure outlined by Spallek et. al.61 (1S)-(+)-Camphor-10-sulfonic acid (5.0 g, 21.5 mmol), iodine (10.91 g, 43.0 mmol), and triphenylphosphine (22.6 g, 86.0 mmol) were suspended in toluene (40 mL) and heated at 110 ºC for 18 hours. Following reflux, the solvent was removed under reduced pressure, and EtOAc (40 mL) was added. The organic layer was washed with saturated

299

sodium thiosulfate solution (3 x 10 mL), H2O (3 x 5 mL), and brine (2 x 5 mL), and was dried over MgSO4. Concentration followed by purification via flash column chromatography (10:1 Hex:EtOAc) afforded 206 as a white solid (5.38 g, 19.3 mmol,

61 20 1 90%). See Spallek et. al. for characterization data. []D -19.31 (c 3.75, CHCl3); H

NMR (400 MHz, CDCl3): δ 3.31 (d, J = 10.6 Hz, 1H), 3.12 (d, J = 10.6 Hz, 1H), 2.43-

2.37 (m, 1H), 2.16-2.13 (m, 1H), 2.05-1.95 (m, 2H), 1.89 (d, J = 18.3 Hz, 1H), 1.65-1.58

(m, 1H), 1.43-1.36 (m, 1H), 1.06 (s, 3H), 0.89 (s, 3H) ppm.

5.9.6 Synthesis of 1-Benzyl-7,7-dimethyl-bicyclo[2.2.1]heptan-2-one (213) 6 4 6 3 7 2

8 5 1 9 O

10 10 213

Compound 213 was prepared according to a general procedure outlined by Yuan

63 et. al. Into a flame dried flask under nitrogen was added Ni(dppf)2Cl2 (2.22 g, 3.24 mmol). Into this flask was added a solution of 206 (10.0 g, 36.0 mmol) in diethyl ether

(540 mL). The reaction mixture was heated to 34 ºC and a 3.0 M solution of phenyl

Grignard (12.0 mL, 36.0 mmol) was added via syringe pump over 2 hours. The reaction was refluxed a further 24 hours, then cooled to room temperature and quenched with concentrated NH4Cl (50 mL). The solvent was removed in vacuo and the residue was dissolved in pentane (200 mL). The organic layer was washed successively with 1 % HCl

(5 x 50 mL), H2O (3 x 50 mL), and saturated NaCl (2 x 50 mL), and dried over MgSO4.

300

Concentration in vacuo followed by flash column chromatography (50:1 Hex:EtOAc) afforded 213 as a clear, colourless oil (4.24 g, 18.6 mmol, 89.8%). See Vogel et. al for

92 20 1 characterization data. []D 20.97 (c 1.5, CHCl3); H NMR (400 MHz, CDCl3): δ 7.34-

7.15 (m, 5H), 2.99 (d, J = 14.1 Hz, 1H), 2.62 (d, J = 14.1 Hz, 1H), 2.37 (ddd, J = 18.1,

4.5, 3.1 Hz, 1H), 2.03 (ddd, J = 4.5 Hz, 1H), 1.95-1.85 (m, 1H), 1.85 (d, J = 18.2 Hz,

1H), 1.81-1.73 (m, 1H), 1.34-1.18 (m, 2H), 0.94 (s, 3H), 0.86 (s, 3H) ppm.

5.9.7 Synthesis of 1-Benzyl-7,7-dimethyl-2-methylene-bicyclo[2.2.1]heptanes (203) 6 4 6 3 7 2

8 5 1 9 11

10 10 203

Into freshly distilled diethyl ether (200 mL) was added 213 (4.24 g, 18.5 mmol).

A 3.0 M solution of methyl Grignard (31 mL, 93 mmol) was added dropwise and the reaction was heated to 34 ºC for 1 week. The reaction was cooled to room temperature before being quenched with concentrated NH4Cl (30 mL). The solvent was removed in vacuo and the residue was dissolved in pentane (100 mL). The organic layer was washed with H2O (3 x 30 mL) and dried over MgSO4. Concentration in vacuo was followed by flash column chromatography (10:1 Hex:EtOAc) to afford alcohol 215 as a clear colourless oil (1.7 g, 6.96 mmol, 37.6%) that was dissolved in pyridine (10 mL). This mixture was cooled to 0 ºC and SOCl2 (0.5 mL, 6.9 mmol) was added dropwise and the resulting solution was stirred for 1 hour at 0 ºC. The reaction was quenched with water

301

(10 mL), and extracted with pentane (3 x 20 mL). The combined organic layer was washed successively with 10% HCl (10 mL), saturated NaHCO3 (10 mL), and saturated

NaCl (10 mL), and was dried over Na2SO4. Concentration in vacuo followed by purification by flash column chromatography (50:1 Hex:EtOAc) yielded 203 as a clear

20 colourless oil (0.3 g, 1.33 mmol, 10.3%). []D -4.56 (c 1.14, CHCl3); IR (film) vmax

3083, 3060, 3024, 2937, 2874, 1652, 1599, 1496, 1456, 1386, 1366, 868, 755, 702, 735

-1 1 cm ; H NMR (400 MHz, CDCl3): δ 7.30-7.15 (m, 5H), 4.90 (m, 1H), 4.76 (m, 1H), 2.91

(d, J = 14.3 Hz, 1H), 2.77 (d, J = 14.3 Hz, 1H), 2.47-2.38 (m, 1H), 1.99-1.89 (m, 2H),

1.78-1.69 (m, 1H), 1.66-1.62 (ddd, J = 4.4 Hz, 1H), 1.33 (ddd, J = 13.5, 12.3, 4.0 Hz,

1H), 1.20 (ddd, J = 13.5, 12.1, 4.2 Hz, 1H), 0.89 (s, 3H), 0.71 (s, 3H); 13C NMR (400

MHz, CDCl3): δ 159.43, 140.18, 130.65, 127.75, 125.66, 103.15, 54.65, 48.32, 45.39,

37.31, 35.09, 32.20, 27.85, 20.16, 19.79; MS: m/z 226 [M+], 211, 197, 183, 169, 155,

141, 135, 129, 115, 105, 91, 79, 65, 55, 41; HRMS calcd for C17H22 226.1722, found

226.1721. anal. calcd for C17H22: C, 90.20; H, 9.80, found: C, 89.68; H, 10.19 %.

5.9.8 Characterization of 1-(2,2-Dimethyl-3-methylene-cyclopentyl)-propan-2-one (210)

O 210

1 H NMR (400 MHz, CDCl3): δ 4.67 (m, 2H), 2.41 (dd, J = 15.8, 3.5 Hz, 1H),

2.36-2.22 (m, 2H), 2.16 (dd, J = 15.9, 10.2 Hz, 1H), 2.06 (s, 3H), 1.96-1.75 (m, 2H),

13 1.16 (m, 1H), 0.96 (s, 3H), 0.73 (s, 3H); C NMR (400 MHz, CDCl3): δ 208.60, 161.00,

103.44, 45.41, 44.40, 43.68, 30.41, 30.24, 28.26, 26.45, 23.50.

302

5.9.9 Synthesis of RAlBr2 Lewis acid (204)

6 7 6 4 8 3 H 9 5 2 10 1 AlBr 11 2

11 11 204

Dry benzene (1 mL) was added to a flask under nitrogen and a 1.0 M solution of

LiAlH4 (0.33 mL, 0.33 mmol) in diethyl ether was added. The solvent was removed under high vacuum and the flask was back purged with nitrogen. The solid LiAlH4 was redissolved in benzene (1 mL), and a solution of AlBr3 (0.27 g, 1 mmol) in benzene (1 mL) was added dropwise. The resulting slurry was stirred for 30 minutes before a solution of 203 (0.3 g, 1.32 mmol) in benzene (1 mL) was added dropwise over 5 minutes. The reaction was stirred overnight under nitrogen before the benzene was removed under high vacuum. The flask was back purged with nitrogen and the organoaluminum compound dissolved in toluene (2.1 mL) to make a 0.5 M solution that

1 was stored under nitrogen atmosphere. H NMR (400 MHz, C6D6): δ 2.54 (d, J = 13.5

Hz, 1H), 2.46 (d, J = 13.5 Hz, 1H), 2.29-2.19 (m), 1.70-1.56 (m), 1.45-1.41 (m), 1.05-

0.55 (m), 0.88 (s, 3H), 0.84 (s, 3H), 0.26 (dd, J = 13.8, 12.1 Hz, 1H), 0.14 (d, J = 13.8

13 Hz, 1H); C NMR (400 MHz, C6D6): δ 140.28, 130.10, 128.05, 125.87, 52.76, 49.28,

46.18, 40.24, 37.61, 37.09, 28.26, 26.48, 21.01, 20.36, 18.82 ppm.

303

5.9.10 Characterization of 1-Benzyl-2,7,7-trimethyl-bicyclo[2.2.1]heptanes (216) 6 7 6 4 8 3 H 9 5 2 10 1 11

11 11 216

Lewis acid 204 was quenched with 5 % HCl and the corresponding hydrocarbon

1 product 216 was characterized. H NMR (400 MHz, CDCl3): δ 7.25-7.15 (m, 5H), 2.66

(d, J = 3.5 Hz, 1H), 2.56 (d, J = 3.5 Hz, 1H), 2.05 (m, 2H), 1.76-1.62 (m, 2H), 1.54 (m,

1H), 1.48 (m, 1H), 1.08 (m, 2H), 0.91 (s, 3H), 0.89 (s, 3H), 0.67 (d, J = 6.6 Hz, 3H); 13C

NMR (400 MHz, CDCl3): δ 140.92, 130.28, 127.89, 125.69, 51.47, 49.86, 46.23, 38.91,

37.82, 36.10, 28.48, 26.98, 20.48, 19.24, 17.03. MS: m/z 228.1 [M+], 213, 185, 171, 157,

143, 137, 129, 123, 117, 109, 95, 91, 81, 69, 55, 41; HRMS calcd for C17H24 228.1878, found 228.1880.

5.9.11 Synthesis of 7-Iodomethyl-1,7-dimethyl-2-methylene-bicyclo[2.2.1]heptanes (220) 10 6 7 I 4 8 3

9 5 2 6 1 220

Into N,N-dimethylacetamide (300 mL) was dissolved olefin 200 (6.1 g, 40.6 mmol). Crystalline I2 (20.6 g, 81.2 mmol) was added and the reaction was stirred at room temperature for 15 minutes. The reaction mixture was extracted with pentane (3 x 50 mL)

304

and the organic layer was washed with Na2S2O3 (5 x 50 mL) and H2O (2 x 30 mL), and then dried over MgSO4. Concentration in vacuo was followed by flash coloumn chromatography (50:1 Hex:EtOAc) to afford 220 as a clear, colourless oil (7.1 g, 25.7

20 mmol, 63.3%). []D -3.71 (c 0.35, CHCl3); IR (film) vmax 2962, 2919, 2848, 1738,

1 1381, 1262, 1114, 1071, 790; H NMR (400 MHz, CDCl3): δ 4.68 (s, 1H), 4.66 (s, 1H),

3.50 (s, 2H), 1.92-1.83 (m, 2H), 1.79-1.69 (m, 2H), 1.66-1.56 (m, 1H), 1.44-1.39 (dd, J =

9.8, 1.0 Hz, 1H), 1.28-1.20 (m, 1H), 1.09 (s, 3H), 1.04 (s, 3H); 13C NMR (400 MHz,

CDCl3): δ 164.59, 99.38, 53.83, 46.61, 44.02, 43.92, 33.55, 29.26, 26.20, 26.19, 11.83;

MS: m/z 276 [M+], 233, 221, 195, 149, 141, 127, 107. 105, 93, 77, 67, 53; HRMS calcd for C11H17I 276.0375, found 276.0379; anal. calcd for C11H17I: C, 48.24; H, 6.11; found:

C, 47.84, H, 6.20%. anal. calcd for C11H17I: C, 47.84; H, 6.20; found: C, 47.35; H, 6.09

5.9.12 Synthesis of 7-Benzyl-1,2,7-trimethyl-bicyclo[2.2.1]heptanes (217) 11 10 11 6 7 4 11 8 3

9 5 2 6 1 217

Compound 217 was prepared according to a general coupling procedure outlined by Yuan et. al. Into a flame dried flask under nitrogen was added Ni(dppf)2Cl2 (1.57 g,

2.29 mmol). Into this flask was added a solution of 220 (7.1 g, 25.5 mmol) in diethyl ether (300 mL). The reaction mixture was heated to 34 ºC and a 3.0 M solution of phenyl

Grignard (8.5 mL, 25.5 mmol) was added via syringe pump over 2 hours. The reaction

305

was refluxed a further 24 hours, then cooled to room temperature and quenched with concentrated NH4Cl (50 mL). The solvent was removed in vacuo and the residue was dissolved in pentane (200 mL). The organic layer was washed successively with 1 % HCl

(5 x 50 mL), H2O (3 x 50 mL), and saturated NaCl (2 x 50 mL), and dried over MgSO4.

Concentration in vacuo followed by flash column chromatography (50:1 Hex:EtOAc)

20 afforded 217 as a clear, colourless oil (2.16 g, 9.54 mmol, 29.7%). []D 21.80 (c 2.11,

CHCl3); IR (film) vmax 3070, 3024, 2954, 2917, 2864, 1655, 1496, 1453, 1356, 1141,

1 1107, 872, 762, 696, 629; H NMR (400 MHz, CDCl3): δ 7.31-7.26 (m, 2H), 7.23-7.16

(m, 3H), 4.77 (s, 1H), 4.67 (s, 1H), 2.92 (d, J = 13.5 Hz, 1H), 2.86 (d, J = 13.5 Hz, 1H),

1.79 (d, J = 3.8, 1H), 1.73-1.65 (m, 1H), 1.56 (ddd, J = 9.3, 4.2, 2.2 Hz, 1H), 1.51 (dd, J

= 11.9, 3.7 Hz, 1H), 1.35-1.26 (m, 1H), 1.13-1.05 (m, 2H), 1.11 (s, 3H), 1.04 (s, 3H); 13C

NMR (400 MHz, CDCl3): δ 169.09, 139.96, 130.34, 127.79, 125.68, 97.93, 54.15, 46.45,

43.47, 40.86, 38.44, 31.69, 29.53, 26.14, 24.84; MS: m/z 226 [M+], 211, 197, 183, 169,

155, 142, 135, 129, 115, 107, 91, 79, 67, 55, 41; HRMS calcd for C17H22 226.1722, found

226.1717. anal. calcd for C17H22: C, 90.20; H, 9.80; found: C, 90.19; H, 10.50 %.

5.9.13 Synthesis of R*AlBr2 Lewis acid (218) 11 10 11 6 7 4 11 8 3 1 9 5 2 AlBr 6 2 218

306

Dry benzene (6 mL) was added to a flask under nitrogen and a 1.0 M solution of

LiAlH4 (1.9 mL, 1.88 mmol) in diethyl ether was added. The solvent was removed under high vacuum and the flask was back purged with nitrogen. The solid LiAlH4 was redissolved in benzene (6 mL), and a solution of AlBr3 (1.50 g, 5.63 mmol) in benzene (6 mL) was added dropwise. The resulting slurry was stirred for 30 minutes before a solution of 217 (1.72 g, 7.51 mmol) in benzene (3 mL) was added dropwise over 5 minutes. The reaction was stirred overnight under nitrogen before the benzene was removed under high vacuum. The flask was back purged with nitrogen and the organoaluminum compound dissolved in toluene (5.9 mL) to make a 1.0 M solution of

1 218 that was stored under nitrogen atmosphere. H NMR (400 MHz, C6D6): δ 7.22-6.96

(m, 5H), 2.59 (s, 2H), 1.57 (m, 1H), 1.52-1.43 (m, 3H), 1.30 (m, 1H), 1.06-0.97 (m, 3H),

1.02 (s, 3H), 0.89 (s, 3H), 0.62 (dd, J = 14.5, 11.0 Hz, 1H), 0.55 (dd, J = 14.5, 3.9 Hz,

13 1H); C NMR (400 MHz, C6D6): δ 139.71, 130.12, 127.93, 125.82, 54.34, 50.12, 47.90,

40.89, 40.71, 38.58, 32.20, 25.62, 23.53, 23.02, 11.10 ppm.

5.9.14 Characterization of 7-Benzyl-1,2,7-trimethyl-bicyclo[2.2.1]heptane (221) 11 10 11 6 7 4 11 8 3 1 9 5 2 6 221

Lewis acid 218 was quenched with 5 % HCl and the corresponding hydrocarbon

1 product 221 was characterized. H NMR (400 MHz, CDCl3): δ 7.31-7.14 (m, 5H), 2.66

(ABq, J = 17.3, 13.4 Hz), 1.63 (m, 1H), 1.59 (m, 1H), 1.48 (m, 1H), 1.39 (m, 1H), 1.25

(m, 2H), 1.12-1.05 (m, 2H), 0.87 (s, 3H), 0.84 (d, J = 7.6 Hz, 3H), 0.83 (s, 3H); 13C NMR

307

(400 MHz, CDCl3): δ 140.38, 130.17, 127.87, 125.69, 52.85, 47.85, 47.70, 41.17, 40.80,

38.32, 32.28, 25.89, 24.53, 21.85, 8.81; MS: m/z 228 [M+], 213, 185, 157, 143, 137, 129,

117, 109, 91, 81, 67, 55, 41; HRMS calcd for C17H24 228.1878, found 228.1881.

5.9.15 Synthesis of 1,7,7-Trimethyl-2-phenyl-bicyclo[2.2.1]heptan-2-ol (224) 6 7 6 3 4 2 OH 5 8 1 6 9

9 9 224

Compound 224 was prepared by modifying a Grignard procedure outlined by

Chen et. al.64 Into freshly distilled THF (300 mL) was dissolved (1R)-(+)-Camphor (5.0 g, 32.8 mmol). The reaction mixture was cooled to 0 ºC and a 3.0 M solution of phenyl

Grignard (16.4 mL, 49.2 mmol) in diethyl ether was added. The solution was stirred for

30 minutes before being heated to 66 ºC for 12 hours. The reaction mixture was allowed to cool, and was quenched with a concentrated NH4Cl solution (50 mL). The solvent was removed in vacuo, and the remaining residue was dissolved in pentane. The organic layer was washed successively with H2O (2 x 50 mL) and brine (2 x 25 mL), dried over

MgSO4, and concentrated to a clear oil (4.26 g, 18.5 mmol, 56.4%) that was purified by flash column chromatography (9:1 Hex:EtOAc). See Ruedi et. al for characterization

66 1 data. H NMR (400 MHz, CDCl3): δ 7.55-7.51 (m, 2H), 7.36-7.31 (m, 2H), 7.28-7.23

(m, 1H), 2.33 (d, J = 13.9 Hz, 1H), 2.19 (ddd, J = 13.9, 4.2, 3.3 Hz, 1H), 1.91 (ddd, J =

308

4.4, 4.4 Hz, 1H), 1.85 (s, 1H), 1.78-1.68 (m, 1H), 1.28 (s, 3H), 1.27-1.15 (m, 2H), 0.92 (s,

6H), 0.88-0.81 (m, 1H) ppm.

5.9.16 Synthesis of 1,7,7-Trimethyl-2-phenyl-bicyclo[2.2.1]hept-2-ene (225) 6 7 6 3 4 2

5 8 1 6 9 9 9 225

Compound 225 was prepared according to a procedure outlined by Chen et. al.64

Compound 224 (4.26 g, 20.6 mmol) was dissolved in pyridine (20 mL) and the reaction mixture was cooled to 0 ºC. SOCl2 (1 mL, 13.7 mmol) was added dropwise, and the resulting solution was stirred for 1 hour at 0 ºC. The reaction mixture was quenched with water (20 mL), and was extracted with pentane (3 x 20 mL). The combined organic layer was washed successively with 10% HCl (10 mL), saturated NaHCO3 (10 mL), and saturated NaCl (10 mL), and dried over Na2SO4. Concentration in vacuo followed by purification by flash column chromatography (50:1 Hex:EtOAc) yielded 225 as a clear colourless oil (2.05 g, 9.65 mmol, 52.1%). See Chen et. al for full characterization data.64

20 1 []D -152.80 (c 4.19, CHCl3); H NMR (400 MHz, CDCl3): δ 7.41-7.25 (m, 5H), 6.07

(m, 1H), 2.47 (m, 1H), 2.03 (m, 1H), 1.76 (m, 1H), 1.42 (m, 1H), 1.24-1.15 (m, 1H), 1.19

(s, 3H), 0.98 (s, 3H), 0.91 (s, 3H) ppm.

309

5.9.17 Synthesis of R*AlBr2 Lewis acid 218 6 7 6 9 3 9 4 2 9

5 8 1 9 6 AlBr2 226

Dry benzene (7 mL) was added to a flask under nitrogen and a 1.0 M solution of

LiAlH4 (2.41 mL, 2.41 mmol) in diethyl ether was added. The solvent was removed under high vacuum and the flask was back purged with nitrogen. The solid LiAlH4 was redissolved in benzene (7 mL), and a solution of AlBr3 (1.93 g, 7.23 mmol) in benzene (7 mL) was added dropwise. The resulting slurry was stirred for 30 minutes before a solution of 225 (2.05 g, 9.65 mmol) in benzene (7 mL) was added dropwise over 5 minutes. The reaction was stirred overnight under nitrogen before the benzene was removed under high vacuum. The flask was back purged with nitrogen and the organoaluminum compound dissolved in toluene (10.0 mL) to make a 1.0 M solution of

Lewis acid 226 that was stored under nitrogen atmosphere. Lewis acid 226 was too reactive to characterize in situ via 1H and 13C NMR, and was thus worked up in 5% HCl and the corresponding hydrocarbon 227 was fully characterized instead.

5.9.18 Characterization of 1,7,7-Trimethyl-2-phenyl-bicyclo[2.2.1]heptanes (227) 7 3 4 2 9 5 8 9 1 9 6 9 227

310

Lewis acid 226 was quenched with 5 % HCl and the corresponding hydrocarbon

1 product 227 was characterized. H NMR (400 MHz, CDCl3): δ 7.36-7.23 (m, 5H), 3.10

(m, 1H), 2.21 (m, 1H), 1.89-1.79 (m, 2H), 1.58 (dd, J = 13.0, 5.2 Hz, 1H), 1.40 (q, J = 9.7

Hz, 2H), 1.17 (m, 1H), 1.08 (s, 3H), 0.98 (s, 3H), 0.77 (s, 3H); 13C NMR (400 MHz,

CDCl3): δ 142.68, 129.52, 127.79, 125.92, 50.28, 50.11, 49.97, 45.58, 34.40, 28.58,

28.53, 20.07, 18.83, 14.54; MS: m/z 214 [M+], 199, 171, 155, 143, 129, 115, 104, 95, 77,

67, 55, 41; HRMS calcd for C16H22 214.1722, found 214.1719.

5.9.19 Synthesis of 2-Benzyl-1,7,7-trimethyl-bicyclo[2.2.1]heptan-2-ol (228) 6 7 6 3 4 2 OH 5 8 1 6 9 10 10 10 10 228

Compound 228 was prepared according to the general procedure outlined by

Chen et. al.64 Magnesium turnings (1.67g, 68.8 mmol) to a flame dried flask that was then sealed under nitrogen atmosphere. Once the flask had cooled, diethyl ether (20 mL) was added along with a single crystal of I2. Benzyl bromide (7.8 mL, 65.6 mmol) was added dropwise, and the reaction mixture was heated to 34 ºC for 1 hour. To this benzyl

Grignard reagent was added a solution of (1R)-(+)-Camphor (5.0 g, 32.8 mmol) in THF

(250 mL), and the mixture was heated at 66 ºC overnight. The reaction was quenched with a concentrated solution of NH4Cl (10 mL), and the solvent removed in vacuo. The residue was dissolved in pentane (50 mL), and the resulting organic layer was washed

311

with 10 % Na2S2O3 (3 x 10mL) and water (2 x 10 mL), and dried over MgSO4.

Concentration in vacuo was followed by purification via flash column chromatography

(10:1 Hex:EtOAc) to afford 228 as a clear colourless oil (6.2 g, 25.4 mmol, 77.4%). See

93 94 20 Sisti et. al. and Paramahamsan et. al. for characterization data. []D -7.67 (c 2.13,

CHCl3); IR (film) vmax 3572, 3319, 3057, 3024, 2947, 2864, 1496, 1453, 1390, 1074,

1 971, 709; H NMR (400 MHz, CDCl3): δ 7.31-7.19 (m, 5H), 2.81 (ABq, J = 13.1 Hz,

2H), 1.83-1.73 (m, 3H), 1.68-1.61 (m, 2H), 1.51-1.42 (m, 1H), 1.40 (s, 1H), 1.19-1.10

13 (m, 1H), 1.09 (s, 3H), 0.87 (s, 3H), 0.82 (s, 3H); ppm. C NMR (400 MHz, CDCl3): δ

138.31, 130.82, 128.44, 126.62, 80.36, 52.83, 49.47, 46.39, 45.38, 44.88, 30.64, 27.36,

21.72, 21.23, 10.59 ppm; MS: m/z 244.2 [M+], 227.2, 171.1, 153.1, 109.1, 95.1, 91.1,

81.1, 69.2, 55.1; HRMS calcd for C17H24O 244.1827, found 244.1839. anal. calcd for

C17H24O: C, 83.55; H, 9.90; found: C, 83.20; H, 9.85 %.

5.9.20 2-Benzylidene-1,7,7-trimethyl-bicyclo[2.2.1]heptanes (229) 6 7 6 3 4 2 10 5 8 1 10 6 9 10 10

229

Compound 229 is a known compound in the chemical literature.95 Compound 229 was prepared according to the general procedure outlined by Chen et. al.64 Compound

228 (6.2 g, 25.4 mmol) was dissolved in pyridine (20 mL) and the reaction mixture was cooled to 0 ºC. SOCl2 (1 mL, 13.7 mmol) was added dropwise, and the resulting solution was stirred for 1 hour at 0 ºC. The reaction mixture was quenched with water (20 mL),

312

and was extracted with pentane (3 x 20 mL). The combined organic layer was washed successively with 10% HCl (10 mL), saturated NaHCO3 (10 mL), and saturated NaCl (10 mL), and dried over Na2SO4. Concentration in vacuo yielded 229 as the major isomer, which was recovered pure via flash column chromatography (10:1 Hex:EtOAc) as a clear colourless oil (0.94 g, 4.15 mmol, 16.3%). See Momtchev et. al. for limited

95 20 characterization data. []D -76.04 (c 1.85, CHCl3); IR (film) vmax 3024, 2948, 2867,

1 1657, 1595, 1490, 1443, 1386, 910, 748, 690, 514; H NMR (400 MHz, CDCl3): δ 7.47-

7.37 (m, 4H), 7.25-7.20 (m, 1H), 6.17 (m, 1H), 2.84-2.76 (m, 1H), 2.37-2.30 (dd, J =

16.6, 2.2 Hz, 1H), 1.97 (ddd, J = 4.4, 4.3 Hz, 1H), 1.96-1.86 (m, 1H), 1.85-1.76 (ddd, J =

11.9, 11.9, 3.8 Hz, 1H), 1.48-1.41 (ddd, J = 12.2, 9.7, 3.9 Hz, 1H), 1.35-1.28 (ddd, J =

11.7, 9.8, 3.9 Hz, 1H), 1.14 (s, 3H), 1.03 (s, 3H), 0.86 (s, 3H); 13C NMR (400 MHz,

CDCl3): δ 153.46, 139.01, 129.49, 128.06, 127.47, 125.59, 117.09, 52.84, 47.67, 45.29,

37.73, 35.13, 28.05, 19.83, 19.19, 13.37 ppm; MS: m/z 226.3 [M+], 211.3, 183.2, 169.2,

155.2, 141.2, 129.2, 115.2, 105.2, 91.2, 77.2, 55.2; HRMS calcd for C17H22 226.1722, found 226.1718.

5.9.21 Synthesis of endo-3-Benzyl-1,7,7-trimethyl-bicyclo[2.2.1]heptan-2-one (245a) 6 7 6 3 4 2 10

5 8 1 9 10 10 6 O 10 245a

In freshly distilled THF (40 mL) was dissolved diisopropylamine (5.52 mL, 39.4 mmol). The reaction mixture was cooled to 0 ºC, and a 2.5 M solution of n-BuLi (14.4

313

mL, 36.1 mmol) in hexanes was added dropwise. The reaction mixture was stirred at 0 ºC for 30 minutes before a solution of (1R)-(+)-Camphor (5.0 g, 32.8 mmol) in THF (40 mL) was added slowly. This solution was stirred for 30 minutes before benzyl bromide

(3.9 mL, 32.8 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 24 hours before being quenched with concentrated NH4Cl (10 mL). The solvent was removed in vacuo and the residue dissolved in pentane. This organic layer was washed with H2O (3 x 10 mL) and then dried over MgSO4. Concentration in vacuo followed by purification by column chromatography (10:1 Hex:EtOAc) yielded a mixture of endo and exo 245a (7.0 g, 28.9 mmol, 88.1%). This mixture of diastereomers was subsequently dissolved in MeOH (100 mL) and KOMe (0.2 g) and heated for 24 hours at

64 ºC. This reaction mixture was quenched with concentrated NH4Cl (10 mL), and solvent removed in vacuo. The residue was dissolved in pentane and washed with H2O (3 x 10 mL). Concentration in vacuo was followed by further purification using flash column chromatography (10:1 Hex:EtOAc) to afford endo-245a as a clear colorless oil

(5.5 g, 22.7 mmol, 69.2 % over two steps). See Toan et. al for characterization data.68 1H

NMR (400 MHz, CDCl3): δ 7.33-7.28 (m, 2H), 7.24-7.19 (m, 3H), 3.20 (dd, J = 14.3, 4.3

Hz, 1H), 2.77-2.70 (ddd, J = 11.2, 4.3, 4.3 Hz, 1H), 2.57-2.49 (dd, J = 14.3, 11.3 Hz, 1H),

1.97-1.93 (dd, 3.9, 3.6 Hz, 1H), 1.83-1.68 (m, 3H), 1.42-1.34 (ddd, J = 13.6, 7.1, 6.0 Hz,

1H), 0.99 (s, 3H), 0.96 (s, 3H), 0.87 (s, 3H) ppm.

314

5.9.22 Synthesis of endo-3-Benzyl-1,7,7-trimethyl-2-methylene-bicyclo[2.2.1]heptanes (247a) 6 7 6 3 4 2 10 10 5 8 1 9 10 10 6 11 247a

Into freshly distilled diethyl ether (200 mL) was added endo-245a (4.16 g, 17.1 mmol). A 3.0 M solution of methyl Grignard (50 mL, 150 mmol) in diethyl ether was added and the reaction mixture was heated to 34 ºC for 24 hours. The reaction was allowed to cool to room temperature before being quenched with concentrated NH4Cl (10 mL). The solvent was removed in vacuo and the resulting residue was dissolved in pentane. The organic layer was washed with H2O (3 x 10 mL), dried over MgSO4, and concentrated in vacuo. Purification via flash column chromatography (10:1 Hex:EtOAc) yielded a colourless oil (0.95 g, 3.68 mmol, 21.5%), which was dissolved in pyridine (5 mL). SOCl2 (0.25 mL, 3.4 mmol) was added dropwise at 0 ºC, and the resulting solution was stirred for 1 hour at 0 ºC. The reaction mixture was quenched with water (5 mL), and was extracted with pentane (3 x 10 mL). The combined organic layer was washed successively with 10% HCl (10 mL), saturated NaHCO3 (10 mL), and saturated NaCl (10 mL), and dried over Na2SO4. Concentration in vacuo yielded 247a as a mixture of inseparable isomers, which were recovered pure via flash column chromatography (10:1

Hex:EtOAc) as a clear colourless oil (0.73 g, 3.04 mmol, 81.9%). IR (film) vmax 3067,

3030, 2990, 2954, 2861, 1655, 1655, 1599, 1496, 1456, 1383, 1366, 1028, 875, 739, 702

-1 1 cm ; H NMR (400 MHz, CDCl3): δ 7.44-7.26 (m), 4.93-4.83 (m), 4.77 (s), 4.67 (s), 3.59

(d, J = 14.6 Hz), 3.35 (d, J = 14.6 Hz), 3.10 (ddd, J = 13.6, 5.4 Hz), 3.05-2.98 (m), 2.85-

315

2.69 (m), 2.58-2.48 (m), 2.17-2.09 (m), 1.95-1.65 (m), 1.63-1.55 (m), 1.51-1.35 (m), 1.31

(s), 1.26-1.16 (m), 1.20 (s), 1.18 (s), 1.09 (s), 1.08 (s), 1.05 (s), 1.02 (s), 1.00 (s), 0.92 (s),

13 0.82 (s), 0.78 (s); C NMR (400 MHz, CDCl3): δ 170.08, 168.57, 164.57, 163.57,

142.52, 142.33, 141.66, 129.03, 128.91, 128.82, 128.43, 128.38, 125.79, 125.59, 100.71,

100.41, 99.47, 56.47, 54.56, 52.81, 52.56, 51.93, 51.11, 49.50, 48.96, 48.07, 47.37, 47.15,

45.42, 41.43, 41.12, 37.30, 35.80, 35.68, 34.27, 33.90, 32.14, 30.51, 30.14, 29.76, 26.68,

25.86, 25.83, 22.57, 21.92, 20.58, 19.52, 19.33, 16.99, 16.17, 13.15, 12.81, 11.95, 9.93;

MS: m/z 240 [M+], 225, 212, 197, 183, 170, 149, 141, 129, 121, 107, 91, 77, 69, 55, 41;

HRMS calcd for C18H24 240.1878, found 240.1883. anal. calcd for C18H24: C, 89.94; H,

10.06; found: C, 89.65; H, 10.49 %.

5.9.23 Characterization of 3-Benzyl-1,2,7,7-tetramethyl-bicyclo[2.2.1]hept-2-ene (247e) 6 6 7 10 4 3 2 11 5 8 1 12 14 6 9 13 247e

Small amounts of 247e could be isolated from the mixture of isomers of 247, and

1 1 were characterized by H NMR. H NMR (400 MHz, CDCl3): δ 7.27-7.13 (m, 5H), 3.44

(d, J = 14.5 Hz, 1H), 3.20 (d, J = 14.5 Hz, 1H), 1.99 (d, J = 3.5 Hz, 1H), 1.72-1.64 (m,

1H), 1.62 (s, 3H), 1.46 (m, 1H), 1.00-0.93 (m, 1H), 0.92 (s, 3H), 0.85-0.74 (m, 1H), 0.67

(s, 3H), 0.62 (s, 3H) ppm.

316

5.9.24 Synthesis of R*AlBr2 Lewis acid 248a

6 6 7 10 10 9 10 4 3 2 10 5 8 1 6 11 AlBr2 248a

Dry benzene (3 mL) was added to a flask under nitrogen and a 1.0 M solution of

LiAlH4 (0.81 mL, 0.81 mmol) in diethyl ether was added. The solvent was removed under high vacuum and the flask was back purged with nitrogen. The solid LiAlH4 was redissolved in benzene (3 mL), and a solution of AlBr3 (0.65 g, 2.42 mmol) in benzene (3 mL) was added dropwise. The resulting slurry was stirred for 30 minutes before a solution of 247a (0.73 g, 3.22 mmol) in benzene (3 mL) was added dropwise over 5 minutes. The reaction was stirred overnight under nitrogen before the benzene was removed under high vacuum. The flask was back purged with nitrogen and the organoaluminum compound dissolved in toluene (10.0 mL) to make a 1.0 M solution of

Lewis acid 248a that was stored under nitrogen atmosphere. Due to the complex mixture, in situ characterization of the Lewis acid solution was limited to 1H NMR. 1H NMR (400

MHz, C6D6): δ 2.59 (m, 1H), 2.35 (m, 1H), 1.60-1.30 (m, 4H), 1.19-1.09 (m, 1H), 1.03-

0.99 (m, 1H), 0.93-0.77 (m, 1H), 0.90 (s, 3H), 0.81 (s, 3H), 0.72 (s, 3H), 0.58 (dd, J =

14.4, 11.7 Hz, 1H), 0.40 (dd, J = 14.4, 3.8 Hz, 1H).

317

5.9.25 Synthesis of 2-Bromomethyl-1,7,7-trimethyl-bicyclo[2.2.1]heptanes (259) 6 8 6 3 4 2 5 7 1 6 9 Br 259

Alkyl bromide 259 was prepared according to the original procedure reported by

Gorobets and co-workers.44 A freshly prepared solution of Lewis acid 201 (12 mmol) in toluene was concentrated in vacuo, before being redissolved in THF (7 mL) at -78 ºC.

Into this solution was added solid CuBr2 (15.8 g, 70.8 mmol). The mixture was stirred for

1 hour before being warmed to room temperature over 24 hours. The reaction mixture was then concentrated in vacuo on a rotovap, before being suspended in H2O (100 mL) and extracted with pentane (3 x 25 mL). The organic extracts were combined, dried over anhydrous MgSO4, and concentrated in vacuo. The product was obtained as a mixture of diastereomers (10:1 endo:exo) as a clear colourless oil (1.69 g, 7.32 mmol, 61%) which was purified via column chromatography (50:1 Hex:EtOAc). Alkyl bromide 259 is a known compound in the chemical literature, but with very limited characterization data

96 available. IR (film) vmax 2985.0, 2952.3, 2877.4, 1457.7, 1389.1, 1374.1, 1229.3, 664.1,

-1 1 626.0 cm ; H NMR (400 MHz, CDCl3): δ 3.55 (dd, J = 9.2, 3.7 Hz, 1H), 3.34 (dd, J =

10.4, 9.4 Hz, 1H), 2.24-2.07 (m, 1H), 1.80-1.67 (m, 1H), 1.64 (m, 1H), 1.41 (m, 1H),

1.26 (m, 1H), 0.94 (dd, J = 10.0, 3.8 Hz, 1H), 0.89 (s, 3H), 0.86 (s, 6H); 13C NMR (400

MHz, CDCl3): δ 49.55, 49.15, 47.03, 44.90, 38.21, 36.71, 29.71, 28.41, 19.40, 18.47,

14.42; MS: m/z 230 [M+], 232 [M+2], 217, 215, 187, 151, 109, 95, 81, 67, 55, 41; HRMS calcd for C11H19Br 230.0670, found 230.0664.

318

5.9.26 Synthesis of 3,3-Dimethyl-bicyclo[2.2.1]heptan-2-one (265) 7 8 4 3 2 8 5 6 1 O 265

Ketone 265 was prepared by modifying an ozonolysis procedure from the literature.97 Into MeOH (160 mL) was dissolved (+)-camphene (10.0 g, 65.7 mmol) and cooled to -78 ºC. An O3/O2 stream of gas was bubbled into the solution (50 l/h). The reaction was monitored via TLC until completion, which took approximately 3 hours.

Zinc powder (6.4 g, 98.5 mmol) was added to the reaction mixture followed by slow addition of a 50 % aqueous solution of acetic acid (47.2 g, 786 mmol). The reaction mixture was allowed to warm to room temperature before being concentrated in vacuo.

H2O (100 mL) was added to the resulting slurry, and the mixture was extracted with

CH2Cl2 (3 x 25 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude mixture was subsequently purified via column chromatography (30:1 Hex:EtOAc) to afford ketone 265 as a clear colourless oil (4.72 g,

20 34.2 mmol, 52 %). []D 7.63 (c 3.0, CHCl3); IR (film) vmax 2967.7, 1744.1, 1465.0,

-1 1 1153.9, 1057.2 cm ; H NMR (400 MHz, CDCl3): δ 2.55 (m, 1H), 2.21 (br s, 1H), 1.95

(m, 1H), 1.88-1.72 (m, 2H), 1.64-1.53 (m, 1H), 1.48-1.40 (m, 2H), 1.03, (s, 3H), 1.00, (s,

13 3H); C NMR (400 MHz, CDCl3): δ 222.86, 50.11, 46.95, 46.13, 35.01, 24.01, 23.53,

23.18, 21.48; MS: m/z 138 [M+], 123, 110, 95, 81, 72, 69, 66, 55, 41; HRMS calcd for

C9H14O 138.1045, found 138.1045.

319

5.10.9 Experimental Procedures Pertaining to Chapter 5

5.10.1 Synthesis of 2-Methyl-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (exo-11c) 9 O 4 5 2 H 103 1 6 8 7 exo-11c

Diels-Alder adduct exo-11c has been widely reported in the chemical literature.73,98 Two separate procedures for synthesizing exo-11c have been reported in this work. Syntheses using BINOL derivatives prepared catalyst according to the general procedure in section 5.5.7. The second procedure, using RAlBr2-type catalyst, was prepared by slowly adding a benzene solution of Lewis acid into dry DCM (25 mL) precooled at -78 ºC. Into either of these catalyst solutions was added methacrolein (0.42 g, 6.0 mmol) dropwise. The solution was stirred for 5 minutes before cyclopentadiene

(0.5 g, 7.6 mmol) was added dropwise. The reaction mixture was stirred at -78 ºC for 3 hours before being quenched with H2O (50 mL), and extracted with hexanes (3 x 25 mL).

The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude oil was purified via flash column chromatography (600:20:1 Hexanes:Et2O:Et3N) to afford exo-11c as a white crystalline solid (yields and diastereomeric ratios specified in text, depending on reaction conditions). See Corey et. al.98a and Fu et. al.98b for

1 characterization data. H NMR (400 MHz, CDCl3): δ 9.68 (s, 1H, H-1), 6.27 (dd, J = 5.7,

3.0 Hz, 1H, H-5), 6.09 (dd, J = 5.7, 3.0 Hz, 1H, H-6), 2.87 (br s, 1H, H-10), 2.80 (br s,

1H, H-10), 2.23 (dd, J = 12.0, 3.8 Hz, 1H), 1.37 (m, 2H), 0.99 (s, 3H, H-9), 0.75 (m, 1H);

13 C NMR (400 MHz, CDCl3): δ 205.90 (C2), 139.64 (C5/C6), 133.18 (C5/C6), 54.00,

320

48.55, 47.70, 43.32, 34.66, 20,14 ppm; HRMS calcd for C9H12O 136.0888, found

136.0893.

5.10.2 Synthesis of 1,7,7-Trimethyl-bicyclo[2.2.1]heptan-2-ol (279) 6 7 6 3 4 2 5 8 OH9 1 6 279

Alcohol 279 was prepared according to a modified procedure reported in the literature.71 Into dry THF (30 mL) was dissolved (1R)-(+)-camphor (2.0 g, 13.1 mmol).

The solution was cooled to 0 ºC and a 1.0 M solution of LiAlH4 in Et2O (6 mL, 13.1 mmol) was added dropwise over 5 minutes. The reaction mixture was stirred for 1 hour, before being warmed to room temperature and stirred for 1 more hour. The reaction was quenched by adding EtOAc dropwise to the mixture over 5 minutes, before pouring the entire reaction mixture over H2O (100 mL) and extracting with DCM (3 x 25 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude oil was purified using flash column chromatography (10:1 Hex:EtOAc) to obtain alcohol

279 as a white crystalline solid (1.80 g, 11.7 mmol, 89 %). See Roy et. al.99 and Abraham

72 1 et. al. for characterization data. H NMR (400 MHz, CDCl3): δ 3.63 (m, 1H, H-1), 1.79-

1.64 (m, 4H), 1.58 (br s, 1H, H-9), 1.53-1.47 (m, 1H), 1.06-0.94 (m, 2H), 1.03 (s, 3H, H-

13 6), 0.91 (s, 3H, H-6), 0.83 (s, 3H, H-6); C NMR (400 MHz, CDCl3): δ 79.87 (C1),

49.00, 46.39, 45.12, 40.49, 34.01, 27.32, 20.55, 20.19, 11.40 ppm.

321

5.10.3 Synthesis of 1-Methyl-pyrrolidine-2-carboxylic acid (283) 4 3 OH 5 1 7 N 2 O 6

283

Amino acid 283 was prepared according to a procedure reported by Aurelio et. al.100 Into MeOH (20 mL) was dissolved L-proline (2.0 g, 17.4 mmol), along with a 37 % solution of aqueous formaldehyde (2 mL). Catalytic palladium metal over activated charcoal (500 mg) was added carefully as a powder, before the reaction container was sealed and a slow stream of H2 gas was bubbled through the reaction vessel overnight.

The reaction mixture was filtered over celite to remove the charcoal and palladium, and washed with CH2Cl2 (3 x 25 mL). The aqueous layer was concentrated in vacuo. The crude product was purified via flash column chromatography using neat MeOH as a solvent to afford 283 as a colourless solid (2.11 g, 16.4 mmol, 94.8 %). See Aurelio et. al.

100 20 1 for characterization data. []D -75.04 (c 2.0, MeOH); H NMR (400 MHz, D2O): δ

3.93 (m, 1H, H-2), 3.78 (m, 1H, H-5), 3.20 (m, 1H, H-5), 2.97 (s, 3H, H-6), 2.54 (m, 1H),

13 2.26-2.00 (m, 3H); C NMR (400 MHz, D2O): δ 173.72 (C1), 70.76 (C2), 56.40, 40.81,

28.85, 22.89.

5.10.4 Synthesis of (1-Methyl-pyrrolidin-2-yl)-methanol (284) 4 3 OH 5 1 7 N 2 6

284

322

Amino alcohol 284 was prepared according to the procedure reported by Kumada and co-workers.101 Into dry THF (30 mL) was added amino acid 283 (2.0 g, 15.5 mmol).

A 1.0 M solution of LiAlH4 in Et2O (37 mL, 37 mmol) was added dropwise, and the reaction mixture was refluxed for 4 hours. Following the reflux, the reaction mixture was cooled to 0 ºC, and quenched over several minutes via dropwise addition of EtOAc. The reaction mixture was poured over H2O (100 mL) and extracted with CH2Cl2 (3 x 25 mL).

The crude product was purified via flash column chromatography using neat EtOAc as solvent to afford pure 284 as a white crystalline solid (1.1 g, 9.6 mmol, 62%). See

101 102 20 1 Kumada et. al. or Yan et. al. for characterization data. []D -36.6 (c 1.5, EtOH); H

NMR (400 MHz, CDCl3): δ 3.64 (dd, J = 10.8, 3.6 Hz, 1H, H-1), 3.41 (dd, J = 10.8, 2.1

Hz, 1H, H-1), 3.07 (m, 1H, H-2), 2.85 (br s, 1H, H-3), 2.36 (m, 1H, H-5), 2.34 (s, 3H, H-

13 4), 2.31-2.25 (m, 1H, H-5), 1.98-1.67 (m, 4H, H-5); C NMR (400 MHz, CDCl3): δ

66.21, 61.77, 57.65, 40.67, 27.71, 23.36 ppm.

5.10.5 Synthesis of (R)-BINAM derivative 286 7 5 8 6 4 1 2 9 N 11 3 10 12 N

286

(R)-BINAM derivative 286 was prepared according to a procedure outlined by

Johansson et. al.103 (R)-BINAM (1.02 g, 3.58 mmol) was dissolved in toluene (10 mL).

To this solution was added freshly distilled 1,4-dibromobutane (1.70g, 7.87 mmol)

323

followed by freshly distilled hunig’s base (2.73 mL, 15.7 mmol). The reaction mixture was refluxed for 24 hours, before being cooled to room temperature. The toluene was removed in vacuo, and the crude solid product was recrystallized using toluene and diethyl ether to afford 286 as a yellow crystalline solid (0.34 g, 0.87 mmol, 24 %). See

103 20 1 Johnansson et. al. for characterization data. []D -168.49 (c 1.0, CHCl3); H NMR

(400 MHz, CDCl3): δ 7.80 (d, J = 9.1 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 8.3

Hz, 1H), 7.16 (m, 1H), 7.12-7.04 (m, 2H), 3.04 (m, 2H), 2.84 (m, 2H), 1.20 (m, 4H); 13C

NMR (400 MHz, CDCl3): δ 146.57, 137.28, 128.88, 128.35, 128.11, 126.73, 126.46,

122.14, 118.41, 117.59, 49.81, 25.79 ppm.

5.10.6 Synthesis of 2-Bromo-cyclohexanol (273b) 3 OH 1 Br 4 2 4 4 4 273b

Bromohydrin 273b is a well known compound in the chemical literature,104 and was prepared using the general procedure 5.5.7 to generate BINOL based catalyst complex 293. (R)-BINOL (0.7 g, 2.5 mmol) was dissolved in DCM (40 mL). A 1.6 M solution of nBuLi (1.57 mL, 2.5 mmol) was added dropwise to the reaction mixture, followed by a freshly prepared solution of Lewis acid 99 (2.5 mL, 2.5 mmol). The reaction mixture was allowed to stir for 30 minutes, before being cooled to -78 ºC.

Cyclohexene oxide (0.24 g, 2.5 mmol) was added dropwise and the reaction mixture was stirred at -78 ºC for 24 hours. The reaction mixture was quenched by adding H2O (100 mL) and extracted with DCM (3 x 25 mL). The organic extracts were combined and dried

324

over MgSO4 and concentrated in vacuo. The crude extract was purified via flash column chromatography (6:1 Hex:EtAOc) to afford 273b as a clear colourless oil (0.24 g, 1.35

104 20 mmol, 54 %). See Hoenig et. al. for characterization data. []D -5.6 (c 3.0, CH2Cl2);

1 H NMR (400 MHz, CDCl3): δ 3.88 (ddd, J = 12.0, 9.4, 4.4 Hz, 1H, H-1), 3.59 (m, 1H,

H-2), 2.65 (s, 1H, H-3), 2.32 (m, 1H, H-4), 2.12 (m, 1H, H-4), 1.87-1.76 (m, 2H, H-4),

13 1.68 (m, 1H, H-4), 1.41-1.22 (m, 3H, H-4); C NMR (400 MHz, CDCl3): δ 75.36, 61.86,

36.30, 33.65, 26.74, 24.19 ppm; HRMS calcd for C6H11BrO 177.9993, found 177.9998.

5.10.7 Synthesis of 2-Bromo-1,2-diphenyl-ethanol (301) 3 Br 3 3 3 2 3 3 1 3

3 OH 4 301

Bromohydrin 301 is a well-known compound in the chemical literature,105 and was prepared using the general procedure 5.5.7 to generate BINOL based catalyst complex 293. (R)-BINOL (1.0 g, 3.5 mmol) was dissolved in DCM (50 mL). A 1.6 M solution of nBuLi (2.18 mL, 3.5 mmol) was added dropwise to the reaction mixture, followed by a freshly prepared 0.53 M solution of Lewis acid 99 (6.6 mL, 3.5 mmol).

The reaction mixture was allowed to stir for 30 minutes, before being cooled to -78 ºC.

Cis-stilbene oxide (0.68 g, 3.5 mmol) was added dropwise and the reaction mixture was stirred at -78 ºC for 24 hours. The reaction mixture was quenched by adding H2O (100 mL) and extracted with DCM (3 x 25 mL). The organic extracts were combined and dried over MgSO4 and concentrated in vacuo. The crude extract was purified via flash column

325

chromatography (6:1 Hex:EtAOc) to afford 301 as a clear colourless oil (0.63 g, 2.3

105a 20 mmol, 65 %). See Lupattelli, et. al. for characterization data. []D -6.4 (c 2.8,

1 CHCl3); H NMR (400 MHz, CDCl3): δ 7.31-7.17 (m, 10H, H-3), 5.20 (d, J = 8.5 Hz,

1H, H-1), 5.10 (dd, J = 8.5, 2.8 Hz, 1H, H-2), 3.12 (d, J = 2.8 Hzm H-4); 13C NMR (400

MHz, CDCl3): δ 138.84, 138.41, 128.67, 128.53, 128.51, 128.31, 128.28, 126.99, 78.42

(C2), 64.38 ppm (C1); HRMS calcd for C14H13BrO 276.0150, found 276.0150.

5.10.8 Synthesis of (4-Methyl-benzylidene)-phenyl-amine (192b) 2

N 6 2 2 1 5

3 4 2 2 192b

Compound 192b was prepared according to a procedure outlined by Keinicke et. al.90 Into toluene (250 mL) was dissolved benzaldehyde (5.90 mL, 50.0 mmol) and aniline (5.45 mL, 50.0 mmol). A Dean-Stark trap was attached and the reaction mixture was refluxed at 110 ºC overnight. Concentration in vacuo followed by purification by recrystalization afforded 192b as yellow crystals (8.9 g, 45.5 mmol, 91%). mp: 40.5-42;

IR (film) vmax 2876.2, 1590.5, 1495.2, 1438, 1309.5, 1195.2, 1176.2, 971.4, 909.5, 814.3,

-1 1 747.6, 690.5 cm ; H NMR (400 MHz, CDCl3): δ 8.44 (s, 1H, H-2), 7.82 (d, J = 8.7, 1H,

H-2), 7.41 (m, 2H, H-2), 7.30 (d, J = 8.0 Hz, 2H, H-2), 7.26-7.21 (m, 3H, H-2), 2.44 (s,

13 3H, H-3); C NMR (400 MHz, CDCl3): δ 160.46, 152.42, 141.99, 133.84, 129.64,

129.25, 128.94, 125.86, 121.01, 21.77 (C3); MS: m/z 195.2 [M+], 180.1, 165.0, 152.1,

326

119.1, 104.1, 93.2, 91.2, 77.2, 65.2. anal. calcd for C14H13N: C, 85.97; H, 6.82; N, 7.13 found: C, 86.12; H, 6.71; N, 7.17 %.

5.10.9 Synthesis of Allyl-benzylidene-amine (192c) 4 N 5

1 6 2

3 3 3 192c

Compound 192c was prepared according to a procedure outlined by Jacobsen et. al.75,106 Into benzene (125 mL) was dissolved benzaldehyde (1.90 mL, 18.6 mmol) and allyl amine (2.8 mL, 18.6 mmol). A Dean-Stark trap was attached and the reaction mixture was refluxed at 80 ºC overnight. Concentration in vacuo followed by purification by recrystalization afforded 192c as a clear colourless oil (2.2 g, 14.9 mmol, 80%). See

107 1 Seayad et. al. for full characterization. H NMR (400 MHz, CDCl3): δ 8.31 (s, 1H, H-

1), 7.78 (m, 2H, H-3), 7.43 (m, 3H, H-3), 6.09 (m, 1H, H-5), 5.26 (dq, J = 17.2, 1.5 Hz,

1H, H-6), 5.18 (dq, J = 10.3, 1.4 Hz, 1H, H-6), 4.28 (m, 2H, H-4); 13C NMR (400 MHz,

CDCl3): δ 162.09, 136.24, 135.95, 130.78, 128.66, 128.23, 116.15, 63.56 (C4); HRMS calcd for C10H11N 145.0891, found 145.0885.

327

5.10.10 Synthesis of Phenylamino-p-tolyl-acetonitrile (307b) 3 3 3 2 HN 6 3 7 3 1 CN 5 4 8

307b

Compound 307b is well known in the chemical literature.108 Into dry solvent (1 mL) was dissolved 192b (0.1 g, 0.552 mmol) and the solution was cooled to -78 ºC. Into this solution was added a 1.0 M solution of freshly made Lewis acid (amount and type specified in text) dropwise over 5 minutes.. The reaction mixture was stirred for 10 minutes before neat TMSCN (0.1 mL, 0.80 mmol) was added dropwise over 1 minute.

The solution was stirred at -78 ºC for 2 hours before being quenched at low temperature with concentrated NH4Cl (1 mL). The mixture was extracted with DCM (3 x 10 mL) and the combined organic layers were dried over MgSO4. Concentration in vacuo followed by purification via flash column chromatography (4:1 Hex:EtOAc) afforded 307b as a white crystalline solid (yields specified in text, depending on reaction conditions). See Lu et. al.

108a 1 for characterization data. H NMR (400 MHz, CDCl3): δ 7.51 (d, J = 8.1 Hz, 2H, H-

3), 7.30 (m, 4H, H-3), 6.93 (m, 1H, H-3), 6.80 (m, 2H, H-3), 5.41 (d, J = 8.3 Hz, 1H, H-

13 1), 4.00 (d, J = 8.1 Hz, 1H, H-2), 2.42 (s, 3H, H-4); C NMR (400 MHz, CDCl3): δ

144.91, 139.74, 131.23, 130.12, 129.70, 127.31, 120.37, 118.47, 114.30, 50.19 (C1),

21.32 (C-4) ppm; MS: m/z 222.1 [M+], 194.1, 180.1, 152.1, 130.1, 104.1, 77.0, 69.0,

41.0; HRMS calcd for C15H14N2 222.1157, found 222.1151.

328

5.10.11 Synthesis of Allylamino-phenyl-acetonitrile (307c) 2 5 3 HN 4 6 6 6 1 CN 7 6

307c

Compound 307c is well known in the chemical literature.75,106-107,108b Into dry solvent (1 mL) was dissolved 192c (0.1 g, 0.552 mmol) and the solution was cooled to -

78 ºC. Into this solution was added a 1.0 M solution of freshly made Lewis acid (amount and type specified in text) dropwise over 5 minutes. The reaction mixture was stirred for

10 minutes before neat TMSCN (0.1 mL, 0.80 mmol) was added dropwise over 1 minute.

The solution was stirred at -78 ºC for 2 hours before being quenched at low temperature with concentrated NH4Cl (1 mL). The mixture was extracted with DCM (3 x 10 mL) and the combined organic layers were dried over MgSO4. Concentration in vacuo followed by purification via flash column chromatography (4:1 Hex:EtOAc) afforded 307c as a white crystalline solid (yields specified in text, depending on reaction conditions). See Sigman

75,106 1 et. al. for characterization data. H NMR (400 MHz, CDCl3): δ 7.54 (m, 2H, H-6),

7.41 (m, 3H, H-6), 5.91 (m, 1H, H-4), 5.34 (dq, J = 17.2, 1.4 Hz, 1H, H-5), 5.22 (dq, J =

10.2, 1.4 Hz, 1H, H-5), 4.81 (s, 1H, H-1), 3.54 (ddt, J = 13.7, 5.4, 1.2 Hz, 1H, H-3), 3.43

(ddt, J = 13.7, 6.5, 1.2 Hz, 1H, H-3), 1.60 (d, J = 15.3 Hz, 1H, H-2); 13C NMR (400

MHz, CDCl3): δ 134.92, 134.90, 129.19, 129.14, 127.45, 118.90, 118.02, 53.68, 50.06 ppm; HRMS calcd for C11H12N2 172.1000, found 172.0995.

329

REFERENCES

(1) Eliel, E. L. Wilen, S. H. Stereochemistry of Organic Compounds; John Wiley & Sons: Toronto, 1994. (2) (a) Aitken, R. A. Kilenyi, S. N. Asymmetric Synthesis; 1 ed.; Chapman & Hall: London, 1992. (b) Seyden-Penne, J. Chiral Auxilliaries and Ligands in Asymmetric Synthesis; 2 ed.; Wiley-Interscience: New York, 1995. (3) Hashimoto, S.-I. Komeshima, N.; Koga, K. J. Chem. Soc., Chem. Commun. 1979, 437. (4) (a) Christoffers, J. Koripelly, G.; Rosiak, A.; Roessle, M. Synthesis 2007, 9, 1279. (b) Dias, L. C. Journal of the Brazilian Chemical Society 1997, 289. (c) Dias, L. C. Current Organic Chemistry 2000, 4, 305. (d) Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92, 1007. (e) Majumdar, K. C.; Alam, S.; Chattopadhyay, B. Tetrahedron 2008, 64, 602. (f) Santelli, M.; Pons, J.-M. Lewis Acids and Selectivity in Organic Synthesis; CRC Press: London, 1996. (g) Wulff, W. D. In Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-VCH: Weinheim, 2000. (h) Yamamoto, H. Tetrahedron 2008, 84, 134. (i) Zhang, Z.; Wan, B.; Chen. H. Progress in Chemistry 2003, 15, 487. (5) (a) Liu, Y.; Nappi, M.; Arceo, E.; Vera, S.; Melchiorre, P. J. Am. Chem. Soc. 2011, 133, 15212. (b) Singh, R. P.; Bartelson, K.; Wang, Y.; Su, H.; Lu, X.; Deng, L. J. Am. Chem. Soc. 2008, 130, 2422. (6) (a) He, L.; Bekkaye, M.; Retailleau, P.; Masson, G. Org. Lett. 2012, 14, 3158. (b) Momiyama, N. Konno, T.; Furiya, Y.; Iwamoto, T.; Terada, M. J. Am. Chem. Soc. 2011, 133, 19294. (c) Momiyama, N.; Tabuse, H.; Masahiro, T. J. Am. Chem. Soc. 2009, 131, 12882. (7) (a) Jones, S.; Valette, D. Org. Lett. 2009, 11, 5258. (b) Mukkerjee, S.; Corey, E. J. Org. Lett. 2010, 12, 632. (c) Paddon-Row, M. N.; Anderson, C. D.; Houk, K. N. J. Org. Chem. 2009, 74, 861. (d) Payette, J. N.; Yamamoto, H. Angew. Chem. Int. Ed. 2009, 48, 8060. (e) Shibatomi, K.; Futatsugi, K.; Kobayashi, F.; Iwasa, S.; Yamamoto, H. J. Am. Chem. Soc. 2010, 132, 5625. (8) (a) Carmona, D.; Lamata, M. P.; Viguri, F.; Barba, C.; Lahoz, F. J.; Garcia- Orduna, P.; Oro, L. A. Organometallics 2011, 30, 6726. (b) Schotes, C.; Mezzetti, A. J. Am. Chem. Soc. 2010, 132, 3652. (c) Thamapipol, S.; Bernardinelli, G.; Besnard, C.; Kundig, P. Org. Lett. 2010, 12, 5604. (d) Thamapipol, S.; Kundig, E. P. Org. Biomol. Chem. 2011, 9, 7564. (9) Li, P.; Yamamoto, H. J. Am. Chem. Soc. 2009, 131, 16628. (10) Maruoka, K.; Ohmatsu, K.; Ooi, T. J. Am. Chem. Soc. 2007, 129, 2410. (11) Hashimoto, T.; Naganawa, Y.; Maruoka, K. J. Am. Chem. Soc. 2011, 133, 8834. (12) Wojaczynska, E.; Wojaczynska, J. Chem. Rev. 2010, 110, 4303. (13) Fujisaki, J.; Matsumoto, K.; Matsumoto, K.; Katsuki, T. J. Am. Chem. Soc. 2011, 133, 56. (14) Patai, S.; Rappoport, Z. The Synthesis of Sulfones, Sulfoxides, and Cyclic Sulfides; Wiley: New York, 1994. (15) Yamaguchi, T.; Matsumoto, K.; Saito, B.; Katsuki, T. Angew. Chem. Int. Ed. 2007, 46, 4729.

330

(16) Noyori, R.; Aoki, M.; Sato, K. Chem. Commun. 2003, 1977. (17) Matsumoto, K.; Yamaguchi, T.; Katsuki, T. Chem. Commun. 2008, 1704. (18) Sato, K.; Hyodo, M.; Aoki, M.; Zheng, X.-Q.; Noyori, R. Tetrahedron 2001, 57, 2469. (19) Pitchen, P.; Kagan, H. B. Tetrahedron Lett. 1984, 25, 1049. (20) Strecker, A. Ann. Chem. Pharm. 1850, 75, 27. (21) Wang, J.; Xiaohua, L.; Feng, X. Chem. Rev. 2011, 111, 6947. (22) Harada, K. Nature 1963, 200, 1201. (23) Abell, J. P.; Yamamoto, H. J. Am. Chem. Soc. 2009, 131, 15118. (24) (a) Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem. 2002, 41, 3636. (b) Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2003, 5, 3021. (c) Yamagiwa, N.; Tian, J.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 3413. (25) Kaur, P.; Pindi, S.; Wever, W.; Rajale, T.; Li, G. Chem. Commun. 2010, 46, 4330. (26) Hildebrand, R. L. The Role of Phosphonates in Living Systems; CRC Press: Boca Raton, 1983. (27) Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J. Med. Chem. 1986, 29, 29. (28) Lavielle, G.; Hautefaye, P.; Schaeffer, C.; Boutin, A.; Cudennec, C. A.; Pierre, A. J. Med. Chem. 1991, 34, 1998. (29) Hirchmann, R.; Smith III, A. B.; Taylor, C. M.; Benkovic, P. A.; Taylor, S. D.; Yager, K. M.; Sprengler, P. A.; Benkovic, S. J. Science 1994, 265. (30) Yokomatsu, T.; Yamgishi, T.; Shibuya, S. Tetrahedron: Asymmetry 1993, 4, 1779. (31) Duxbury, J. P.; Cawley, A.; Thornton-Pett, M; Wantz, L.; Warne, J. N. D.; Greatrex, R.; Brown, D.; Kee, T. P. Tetrahedron Lett. 1999, 40, 4403. (32) Ward, C. V.; Jiang, M.; Kee, T. P. Tetrahedron Lett. 2000, 41, 6181. (33) (a) Saito, B.; Egami, H.; Katsuki, T. J. Am. Chem. Soc. 2007, 129, 1978. (b) Suyama, K.; Sakai, Y.; Matsumoto, K.; Saito, B.; Katsuki, T. Angew. Chem. Int. Ed. 2010, 122, 809. (34) Pudovik, A. N.; Konovalova, I. V.; Synthesis 1979, 81. (35) Abell, J. P.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 10521. (36) Zhou, X.; Zhang, Q.; Hui, Y.; Chen, W.; Jiang, J.; Lin, L.; Liu, X.; Feng, X. Org. Lett. 2010, 12, 4296. (37) Wang, C.; Xu, C.; Tan, X.; Peng, H.; He, H. Org. Biomol. Chem. 2012, 10, 1680. (38) Naruse, Y.; Esaki, T.; Yamamoto, H. Tetrahedron 1988, 44, 4747. (39) Wilke, G.; Muller, H. Chem. Ber. 1956, 89, 444. (40) Fumie, S. In Fundamental Research in Homogeneous Catalysis; Ishii, Y.; Tsutsui, M., Ed.; Springer US, 1979. (41) (a) Dahlmann, M.; Lautens, M. In Catalytic Heterofunctionalization Togni, A.; Grutzmacher, H., Ed.; Wiley-VCH: London, 2001. (b) Miller, J. A. In Chemistry of Aluminum, Gallium, Indium, and Thallium; Downs, A. J., Ed.; Chapman & Hall: London, 1993. (42) (a) Ashby, E. C.; Noding, S. A. J. Org. Chem. 1979, 44, 4355. (b) Barber, J. J.; Willis, C.; Whitesides, G. M. J. Org. Chem. 1979, 44, 3603. (c) Eisch, J. J.; Foxton, M. W. J. Organomet. Chem. 1968, 12, 33. (d) Folcher, G.; Le Marechal,

331

J. F.; Marquet-Ellis, H. J. Chem. Soc., Chem. Commun. 1982, 323. (e) Gao, F.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 32, 10961. (f) Isagawa, K.; Tatsumi, K.; Otsuji, Y. Chem. Lett. 1976, 1145. (g) Joseph, J.; Jaroschik, F.; Harakat, D.; Radhakrishnan, K. V.; Vasee, J.-L.; Szymoniak, J. Chem. Eur. J. 2014, 20, 5433. (h) Le Marechal, J. F.; Epheritikhine, M.; Folcher, G. J. Organomet. Chem. 1986, 309. (i) Negishi, E.-I.; Yoshida, T. Tetrahedron Lett. 1980, 21, 1501. (j) Sato, F.; Sato, S.; Sato, M. J. Organomet. Chem. 1976, 122. (k) Sato, F.; Sato, S.; Sato, M. J. Organomet. Chem. 1977, 131. (l) Schwartz, J. J. Organomet. Chem. 1976, 1, 461. (43) Nagahara, S.; Maruoka, K.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1993, 66, 3783. (44) Gorobets, E. V.; Shitikova, O. V.; Lomakina, S. I.; Tolstikov, G. A.; Kuchin, A. V. Russian Chemical Bulletin 1993, 42, 1573. (45) (a) Elschenbroich, C. Organometallics; Wiley-VCH: Weinheim, 2006. (b) Mole, T.; Jeffery, E. A. Organoaluminum Compounds; Elsevier: Amsterdam, 1972. (46) Henderson, J. R.; Parvez, M.; Keay, B. A. Org. Lett. 2009, 11, 3178. (47) Kita, Y.; Higuchi, T.; Mashima, K. Chem. Commun. 2014, 50, 11211. (48) Childs, R. F.; Mulholland, D. L.; Nixon, A. Can. J. Chem. 1982, 60, 801. (49) Jansen, B. J. M.; Degroot, A. Nat. Prod. Rep. 1991, 8, 309. (50) Dewick, P. M. In Medicinal Natural Products: A Biosynthetic Approach; 2nd ed.; John Wiley & Sons, Ltd.: New York, 2002. (51) (a) Chakraborty, K.; Lipton, A. P.; Raj, R. P.; Vijayan, K. K. Food Chemistry 2010, 119, 1399. (b) Gupta, P.; Sharma, U.; Schulz, T. C.; McLean, A. B.; Robins, A. J.; West, L. M. J. Nat. Prod. 2012, 75, 1223. (c) Liu, H.-B.; Zhang, H.; Yu, J.H.; Ding, J.; Yue, J.-M. J. Nat. Prod. 2012, 75, 722. (d) Yodsaoue, O.; Karalai, C.; Ponglimanont, C.; Tewtrakul, S.; Chantrapromma, S. Phytochemistry 2010, 71, 1756. (52) Hollinshead, D. M.; Howell, S. C.; Ley, S. V.; Mahon, M.; Ratcliffe, N. M.; Worthington, P. A. J. Chem. Soc., Perkin Trans. 1983, 1, 1579. (53) Han, H. S.; Cho, C. W.; Janda, K. D. Chem. Eur. J. 1999, 5, 1565. (54) Henderson, J. R., Ph.D Thesis, University of Calgary, 2009. (55) Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectrometric Identification of Organic Compounds; 5 ed.; John Wiley & Sons, Inc.: New York, 1991. (56) Evans, D. A.; Chapman, K.T.; Bisaha, J. J. Am. Chem. Soc. 1988, 110, 1238. (57) Page, P.; Graham, A. E.; Park, K. B. Tetrahedron 1992, 48, 7265. (58) Rogers, C.; Keay, B. A. Can. J. Chem. 1992, 70, 2929. (59) Majhi, A.; Kim, S. S.; Kadam, S. T. Tetrahedron 2008, 64, 5509. (60) Schneider, H.-J.; Buchheit, U.; Hoppen, V.; Schmidt, G. Chem. Ber. 1989, 122. (61) Spallek, M. J.; Storch, G.; Trapp, O. Eur. J. Org. Chem. 2012, 3929. (62) Komarov, I. V.; Monsees, A.; Spannenberg, A.; Baumann, W.; Schmidt, U.; Fischer, C.; Boerner, A. Eur. J. Org. Chem. 2003, 1, 138. (63) Yuan, K.; Scott, W. J. Tetrahedron Lett. 1991, 32, 189. (64) Chen, D.; Wang, Y.; Klankermayer, J. Angew. Chem. Int. Ed. 2010, 49, 9475. (65) Yemets, S. V.; Shubina, T. E.; Krasutsky, P. A. Org. Biomol. Chem. 2013, 11, 2891. (66) Ruedi, G.; Hansen, H.-J. Helv. Chem. Acta. 2004, 87, 1968.

332

(67) (a) Buss, A. D.; Warren, S. J. Chem. Soc., Perkin Trans. 1985, 2307. (b) Liu, M.; Mahon, M. F.; Sainsbury, M. J. Chem. Soc., Perkin Trans. 1998, 17, 2943. (c) Porcal, W.; Hernandez, P.; Aguirre, G.; Boiani, L.; Boiani, M.; Merlino, A.; Ferreira, A.; Maio, R. D.; Castro, A.; Gonzalez, M.; Cerecetto, H. Bioorg. Med. Chem. 2007, 15, 2768. (68) Toan, V. V.; Lightner, D. A. Tetrahedron 1987, 43, 5769. (69) Duffield, J. J.; Pettit, G. R. J. Nat. Prod. 2001, 64, 472. (70) Joshi, N. N.; Srebnik, M.; Brown, H. C. J. Am. Chem. Soc. 1988, 110, 6246. (71) Giddings, M. R.; Hudec, J. Can. J. Chem. 1981, 59, 459. (72) Abraham, R. J.; Barlow, A. P.; Rowan, A. E. Magn. Reson. Chem. 1989, 27, 1074. (73) Sprott, K. T.; Corey, E. J. Org. Lett. 2003, 5, 2465. (74) (a) Bao, J.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 1993, 115. (b) Maruoka, K.; Concepcion, A. B.; Yamamoto, H. Bull. Chem. soc. Jpn. 1992, 65. (75) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120. (76) Falorni, M.; Lardicci, L. J. Org. Chem. 1986, 51. (77) Ito, M.; Clark, C. W.; Mortimore, M.; Goh, J. B.; Martin, S. F. J. Am. Chem. Soc. 2001, 123, 8003. (78) Tredwell, M.; Tenza, K.; Pacheco, M. C.; Gouverneur, V. Org. Lett. 2005, 7, 4495. (79) Chiarotto, I.; Feeney, M. M.; Feroci, M.; Inesi, A. Electrochim. Acta. 2009, 54, 1638. (80) Nakamura, T.; Oshida, M.; Nomura, T.; Nakazaki, A.; Kobayashi, S. Org. Lett. 2007, 9, 5533. (81) Buzas, A. K.; Istrate, F. M.; Gagosz, F. Tetrahedron 2009, 65, 1889. (82) Sibi, M. P.; Stanley, L. M.; Soeta, T. Adv. Synth. Catal. 2006, 348, 2371. (83) Sibi, M. P.; Manyem, S. Org. Lett. 2002, 4, 2929. (84) Shibata, I.; Nakamura, K.; Baba, A.; Matsuda, H. Bull. Chem. Soc. Jpn. 1989, 62, 853. (85) Wartski, L.; Bouz, M. E. Tetrahedron 1982, 38, 3285. (86) Chen, M.; Micalizio, G. C. J. Am. Chem. Soc. 2012, 134, 1352. (87) Kessar, S. V.; Singh, T.; Vohra, R. Tetrahedron Lett. 1987, 28, 5323. (88) Lerouge, P.; Paulmier, C. Bull. Soc. Chim. Fr. 1985, 6, 1225. (89) Bow, W. F.; Basak, A. K.; Jolit, A.; Vicic, D. A.; Tius, M. A. Org. Lett. 2010, 12, 440. (90) Keinicke, L.; Fristrup, P.; Norrby, P.-O.; Madsen, R. J. Am. Chem. Soc. 2005, 127, 15756. (91) Giorgio, E.; Viglione, R. G.; Zanasi, R.; Rosini, C. J. Am. Chem. Soc. 2004, 126, 12968. (92) Rao Volla, C. M.; Vogel, P. Angew. Chem. Int. Ed. 2008, 47, 1305. (93) Sisti, A. J.; Rusch, G. M. J. Org. Chem. 1974, 39, 1182. (94) Paramahamsan, H.; Pearson, A. J.; Pinkerton, A. A.; Zhurova, E. A. Organometallics 2008, 27, 900. (95) Momtchev, M.; Vassilev, V.; Blagoev, B. Bull. Soc. Chim. Fr. 1985, 5, 844. (96) Falorni, M.; Lardicci, L.; Giacomelli, G. J. Org. Chem. 1986, 51, 5291.

333

(97) Brecknell, D. J.; Carman, R. M.; Greenfield, K. L. Aust. J. Chem. 1984, 37, 1075. (98) (a) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124, 1498. (b) Fu, F.; Teo, Y.-C.; Loh, T.-P. Org. Lett. 2006, 8, 5999. (99) Roy, S.; Sharma, A.; Mula, S.; Chattopadhyay, S. Chem. Eur. J. 2009, 15, 1713. (100) Aurelio, L.; Box, J. L.; Brownlee, R. T.; Hughes, A. B.; Sleebs, M. M. J. Org. Chem. 2003, 68, 2652. (101) Hayashi, T.; Konishi, M.; Fukushima, M.; Kanehira, K.; Hioki, T.; Kumada, M. J. Org. Chem. 1983, 48, 2195. (102) Yan, W.; Mao, B.; Zhn, S.; Jiang, X.; Liu, Z.; Wang, R. Eur. J. Org. Chem. 2009, 22, 3790. (103) Johansson, M. J.; Schwartz, L.; Amedjkouh, M.; Kann, N. Tetrahedron: Asymmetry 2004, 15, 3531. (104) Hoenig, H.; Seufer-Wasserthal, P. Synthesis 1990, 12, 1137. (105) (a) Lupattelli, P.; Bonini, C.; Caruso, L.; Gambacorta, A. J. Org. Chem. 2003, 68, 3360. (b) MacHarla, A. K.; Chozhiyath Nappunni, R.; Nama, N. Tetrahedron Lett. 2012, 53, 1401. (106) Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2000, 39, 1279. (107) Seayad, A. M.; Ramalingam, B.; Yoshinaga, K.; Nagata, T.; Chai, C. Org. Lett. 2010, 12, 264. (108) (a) Lu, Y.; Wang, Y.; Zhang, X. J. Chem. Res. 2013, 37, 709. (b) Prasad, B. B.; Bisai, A.; Singh, V. K. Tetrahedron Lett. 2004, 45, 9565. (c) Rafiee, E.; Rashidzadeh, S.; Joshaghani, M.; Chalabeh, H.; Afza, K. Synth. Commun. 2008, 38, 2741.

334