PART A. Ni-CATALYZED ASYMMETRIC HYDROVINYLATION AND RELATED REACTIONS

PART B. DEVELOPMENT OF EFFICIENT CYCLIZATION METHODS

DISSERTATION

Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University

By

Hwan Jung Lim, M.S.

Graduate Program in Chemistry

The Ohio State University

2009

Dissertation Committee:

T. V. RajanBabu, Advisor

Jon Parquette

Craig Forsyth

ABSTRACT

In part A, Ni(II)-catalyzed asymmetric hydrovinylation (HV) and related reactions are described. Hydrovinylation has been successfully developed to generate all-carbon chiral quaternary centers. Using this efficient method, neuro-active (-)- desoxyeseroline and related natural products such as non-substituted (-)-physostigmine and key intermediates for the synthesis of its derivatives have been synthesized. The first generation synthesis was initiated by applying linear β-substituted styrenes with functional groups as hydrovinylation substrates. Substrates with a phthalimido functionality at the β-position underwent hydrovinylation reactions successfully, but the enantioselectivities were only modest. The desired hydrovinylation product was converted into the known key intermediate for the target compounds. In order to improve the enantioselectivity and efficiency, cyclic vinylarenes were tested instead of initial linear derivatives. These compounds gave excellent enantioselectivities in the

HV reaction. Using a ring expansion/contraction strategy, the formal synthesis of (-)- desoxyeseroline has been completed in excellent overall selectivities.

ii In a related objective in the development of the asymmetric HV reaction, the mechanism of Ni-phosphoramidite complex catalyzed reaction has been studied. The single crystals of (allyl)Ni(L1)Br (L1 = phosphoramidite) complex were obtained, whose three-dimensional structure confirmed the square planar geometry of the Ni-complex and the binding mode of the phosphoramidite ligand. Moreover, induced atropisomerism of the racemic biaryl by the appended chiral amine was confirmed by the X-ray structure.

31P NMR studies using three (allyl)Ni(L)Br and corresponding BARF complexes provided the first evidence of the hemilabile coordination of a pendant phenyl-group in phosphoramidite ligands. In addition, matched/mismatched ligand effects for hydrovinylation to generate all-carbon chiral quaternary centers were studied.

Isomerization of terminal alkenes have been observed during hydrovinylation or cycloisomerization reactions of α,ω-dienes. Based on this observation, a new Pd(II)- and Ni(II)-catalyzed isomerization of terminal alkenes has been developed. Modified conditions for the generation of metal-hydride complexes were applied for selective isomerizations of terminal alkenes. These conditions gave the desired isomerized products in excellent yields and selectivities. Compared with two representative methods reported recently using Ir- and Ru-catalysts, these reactions appear to be cleaner and more selective. The Pd(II)-catalysts can isomerize even geminal disubstituted alkenes in good yields. Such a reaction is currently not known.

In part B, new cyclization methods are described. Searching for a new method for the preparation of heterocyclic hydrovinylation substrates, seleniranium ion-triggered electrophilic cyclizations have been developed. Generated by AgSbF6 and PhSeBr, seleniranium ion-mediated cyclofunctionalizations give Friedel-Craft cyclization

iii products in good to excellent yields even with substrates carrying non-activated aryl-

groups. Detosylative and debenzylative cyclizations ensue when appropriate N-

substituted derivatives are used.

In pursuit of a biomimetic total synthesis of 7-bromoindolactam V, a key intermediate for all-carbon quaternary center-containing lynbyatoxin A, an unexpected

Cu-mediated tandem cyclization has been discovered. This procedure which uses

CuI/CsOAc is quite mild compared to the more harsh Buchwald-Hartwig amination conditions for macrolactamizations. In a dipeptide substrate an unexpected tetracyclic

2,5-diketopiperazine was formed in a tandem reaction in good yields. Structure of the new compound was confirmed by X-ray crystallography. Mechanism of the tandem reaction was studied in simplified model compounds. The simplified compounds - acyclic benzolactam-V8 - were made by Rh-catalyzed asymmetric hydrogenation.

These substrates were successfully applied to the Cu-mediated tandem cyclization to get tricyclic DKPs, rigid synthetic congeners of benzolactam-V8. Schölkopf reagent, which can be used to prepare unnatural aminoacids, was used as a chiral building-block for the synthesis of DKP-containing heterocycles.

iv

Dedicated to my family, Soyeon and Taewook

v

ACKNOWLEDGEMENTS

I would like to thank Professor T. V. RajanBabu for his guidance and support.

In his role as my advisor, he helped me head in the right direction throughout my entire

PhD course. Especially, his deep knowledge and diverse interests challenged me to enter uncharted areas to find something meaningful and valuable. I would like to thank to Professors David Hart, Jon Parquette, and Craig Forsyth for all their help and showing me how to be an independent chemist. I will remember their classes for a long time.

I really appreciate our past and present group members for their devotion and cooperation for developing our group’s research. I would like to thank Drs. Bin Wu,

Ramakrishna Reddy Singidi, Wang Liu, and other group members for always being good friends and helpful colleagues eager to share their knowledge and resources.

From the day when I decided to come to the US till today, I can not imagine succeeding in my PhD program without my wife’s unselfish support. I really appreciate

Soyeon’s sacrifice and love for my family. I also appreciate my son for being a great kid, and I am proud of him. I also thank my parent for their love and taking good care of themselves.

vi

VITA

August 21, 1973 ...... Born – Seoul, Korea

1997 ...... B.S. Chemistry, Inha University

1999 ...... M.S. Chemistry, Korea University

1999 – 2004 ...... Researcher,

Drug Discovery Lab. Choongwae Pharma Co.

2005 – present ...... Graduate Teaching and Research Associate,

The Ohio State University

PUBLICATIONS

Research Publication

1. Lim, H. J.; RajanBabu, T. V. “Seleniranium Ion-Triggered Reactions: New Aspects of

Friedel-Crafts and N-Detosylative Cyclizations” Org. Lett. 2009, 11(13), 2924.

2. Lim, H. J.; Smith, C. R.; RajanBabu, T. V. “Facile Pd(II)- and Ni(II)-Catalyzed

Isomerization of Terminal Alkenes into 2-Alkenes” J. Org. Chem. 2009, 74, 4565.

(highlighted in Synfacts 2009, 9, 1001.)

vii 3. Smith, C. R.; Lim, H. J.; Zhang, A.; RajanBabu, T. V. “Tunable Phosphoramidite

Ligands for Asymmetric Hydrovinylation: Ligands par excellence for Generation of All-

Carbon Quaternary Centers” Synthesis, 2009, 12, 2089 (invited special topic).

FIELDS OF STUDY

Major Field: Chemistry

viii

TABLE OF CONTENTS

Page

Abstract…………………………………………………………………………………ii

Dedication………………………………………………………………………………v

Acknowledgments………………………………………………………………………vi

Vita……………………………………………………………………………………vii

List of Schemes………………………………………………………………………xiv

List of Tables…………………………………………………………………………xvii

List of Figures…………………………………………………………………………xix

List of Abbreviations…………………………………………………………………xxi

Chapters:

Part A. Ni-catalyzed Asymmetric Hydrovinylation and Related Reactions

1. Introduction 1.1. Hydrofunctionalizations……………………………………………………….1 1.2. Brief History of Hydrovinylation as a Heterodimerization…………………….5 1.3. Pd-catalyzed Hydrovinylation………………………………………………….5 1.4. Ru- and Co-catalyzed Hydrovinylation……………………………………….7 1.5. Ni-catalyzed Non-enantioselective Hydrovinylation……………………….8

ix 1.6. Ni(II)-catalyzed Heterodimerization Using Other Coupling Partners Other than Ethylene………………………………………………………….10 1.7. Ni-Catalyzed Asymmetric Hydrovinylation………………………………….12 1.8. Intramolecular Hydrovinylation Reactions………………………………….19 1.9. Summary…………………………………………………………………….21 1.10. References……………………………………………………………………22

2. Generation of All-carbon Chiral Quaternary Centers and Synthesis of (-)- Physostigmine 2.1. Introduction………………………………………………………………….26 2.1.1. Asymmetric Alkylations……………………………………………….27 2.1.2. Radical Reactions…………………………………………………….28 2.1.3. Diels-Alder Reactions………………………………………………….29 2.1.4. [2+3] Cycloadditions………………………………………………….30 2.1.5. Sigmatropic Rearrangements…………………………………………31 2.1.6. Intramolecular Heck Reactions for Syntheses of (-)-Physogmine and Related Compounds…………………………33 2.1.7. Miscellaneous………………………………………………………….35 2.1.8. Summary……………………………………………………………….36 2.2. Results and Discussion……………………………………………………….37 2.2.1. First Generation Synthesis of (-)-Physostigmine………………………38 2.2.2. Summary of the First Generation Synthesis………………………….45 2.2.3. Second Generation Synthesis of (-)-Physostigmine……………………46 2.2.4. Summary of the Second Generation Synthesis……………………….49 2.2.5. Third Generation Synthesis of (-)-Physostigmine……………………49 2.2.6. Summary of the Third Generation Synthesis……………………….56 2.2.7. Beckman Rearrangement of the Oxime 26a: A New Synthesis of Pyrrolo[1,2-a]indoline………………………….56 2.3. Summary………………………………………………………………………59 2.4. Experimental Procedures………………………………………………………61 2.4. References……………………………………………………………………94

x 3. Structural Studies of Ni(II)-phosphoramidite Complexes 3.1. Introduction…………………………………………………………………...97 3.1.1. General Mechanism of HV…………………………………………….98 3.1.2. Hemilabile Pendant Groups for HV…………………………………..100 3.1.3. Structures of Metal Complexes with Phosphoramidite Ligands…….106 3.2. Results and Discussion……………………………………………………….108 3.2.1. Structure of a Catalyst………………………………………………108 3.2.2. Synergistic Effects of Hemilabile Coordination and a Counter Ion in Ni-Phosphoramidite Complexes…………….111 3.2.3. Induced Atropisomerism of Biphenyl-Phosphoramidite Ligand…...117 3.2.4. Origin of Enantioselectivity and Matched/Mismatched Ligands for Asymmetric HV……………………………………….119 3.3. Summary……………………………………………………………………..121 3.4. Experimental Procedures…………………………………………………….122 3.5. References……………………………………………………………………127

4. Pd(II)- and Ni(II)-Catalyzed Isomerizations of Terminal Alkenes 4.1. Introduction…………………………………………………………………..129 4.1.1. Notable Developments………………………………………………..129 4.1.2. Isomerizations During Hydrovinylation and Cycloisomerization……132 4.2. Results and Discussion……………………………………………………….134 4.3. Summary……………………………………………………………………..144 4.4. Experimental Procedures.…………………………………………………….145 4.5. References……………………………………………………………………157

xi Part B. Development of Efficient Cyclization Methods

5. Introduction 5.1. Cyclization Reactions……………………………………………………….158 5.1.1. General Stoichimetric Cyclizations…………………………………159 5.1.2. Electrophilic Cyclizations for Carbon-Carbon Bond Forming Reactions………………………………………………….160 5.1.3. Electrophilic Cyclizations for Carbon-Heteroatom Bond Forming Reactions Using Selenium Electrophiles……………………162 5.1.4. Catalytic Carbon-Carbon Bond Forming Cyclizations………………165 5.1.5. Catalytic Carbon-Heteroatom Bond Forming Cyclizations…………167 5.2. Summary…………………………………………………………………….172 5.3. References……………………………………………………………………173

6. Seleniranium-ion Triggered Cyclization Reactions 6.1. Introduction…………………………………………………………………..177 6.2. Results and Discussion……………………………………………………….181 6.3. Summary……………………………………………………………………..190 6.4. Experimental Procedures.…………………………………………………….191 6.5. References……………………………………………………………………207

7. Cu-mediated Tandem Diketopiperazine Formation/N-arylation 7.1. Introduction…………………………………………………………………..209 7.1.1. Ni-catalyzed Asymmetric Hydrovinylation to Generate an All-carbon Center: Search for a Synthesis of Lynbyatoxin A……210 7.1.2. Metal-catalyzed Intramolecular N-Arylation…………………………212 7.2. Results and Discussion……………………………………………………….216 7.2.1. Unexpected Formation of Tetracyclic DKPs by Tandem Cyclizations under Copper-Mediated Cyclizations…………………218 7.2.2. Synthesis of Simplified Substrates and Their Cyclizations…………..226 7.2.3. Intermolecular N-Arylations of DKP……………………………….232 7.2.4. Synthesis of Proline-based Tetracyclic DKP………………………….235

xii 7.2.5. Attempted Macro N-arylation Using an Oxazolidinone…………….237 7.3. Summary……………………………………………………………………..239 7.4. Experimental Procedures.…………………………………………………….240 7.5. References……………………………………………………………………272

Bibliography……………………………………………………………………………275

Appendix……………………………………………………………………………290 A. NMR Spectra of Selected Compounds………………………………………290 B. X-ray Crystallography Data……………………………………………………439 C. GC and LC Chromatograms…………………………………………………513

xiii

LIST OF SCHEMES

Scheme Page

1.1. General Mechanism of Hydrocyanation…………………………………………...2

1.2. Proposed Mechanism of Hydrovinylation Based on a Cationic Metal-Hydride

and Role of a Hemilabile Group on a Ligand…………………………………….14

1.3. Hydrovinylation-Based Total Syntheses of Natural Products………………………18

1.4. Hydrovinylation of 1,3-Dienes: Enantioselective Construction

of Exocyclic Sidechains…………………………………………………………19

2.1. Radical Reaction for All-carbon Quaternary Centers………………………………29

2.2. Cu-Box Catalyzed Asymmetric Diels-Alder Reaction……………………………30

2.3. Rhodium-catalyzed Tandem Claisen/Ene Reaction………………………………32

2.4. Thio-Claisen Rearrangement Using a C2-symmetric Chiral Auxiliary……………32

2.5. Overman’s Asymmetric Heck Cyclization and Target Compounds………………33

2.6. Two Representative Syntheses of (-)-Eptazocine……….…….……………………34

2.7. Retrosynthetic Analysis Based on Asymmetric Hydrovinylation…………………39

2.8. Preparation of Vinyltin Compounds…………………………….…….……………40

2.9. Further Synthesis for the Preparation of the Pyrrolidinones 9 and 10……………44

2.10. Linear Versus Cyclic Styrenes for Hydrovinylation………………………………46

2.11. First and Second Generation Approaches to Pyrrolidinoindolines………………..47

xiv 2.12. Second Generation Approach to Pyrrolidinoindolines:

Synthesis and Hydrovinylation of 4-Methylenechroman (14)……………………48

2.13. Third Generation Approach to Pyrrolidinoindolines:

Ring Expansion/Contraction……………………………………………………50

2.14. Third Generation Synthesis……………………………………………………...52

2.15. Beckmann vs Schmidt Ring Exansions…………………………………………...53

2.16. Further Synthesis Toward the Target……………………………………………...55

2.17. Synthesis of Oxime 26a and its Beckman Ring Expansion Reaction…………...56

2.18. Proposed Mechanism of the Unexpected Tandem Reaction……………………...59

3.1. Generation of a Cationic Ni(II)-Hydride Complex from (allyl)NiBr Dimer……..98

3.2. Mechanism of Ni-Hydride Catalyzed Hydrovinylation……………………………99

3.3. Syntheses of (allyl)Ni(L)Br and

Corresponding BARF Derivatives………………………………………………108

3.4. Exchange of an Anion and Corresponding Possible Hemilabile Coordination……113

+ - 3.5. H-H Coupling of [(allyl)Ni(L10)] BARF (29c)…………………………………115

4.1. Ir-catalyzed Isomerization of an Allylic Ether

and Claisen Rearrangement of the Product………………………………………131

4.2. Extensive Isomerizations of Terminal Alkenes Using Ir- or Ru-catalysis………131

4.3. Isomerizations During Asymmetric Hydrovinylation……………………………133

4.4. Proposed Mechanism of Metal-Hydride Catalyzed Isomerization of Alkenes……134

5.1. Zr-catalyst for Asymmetric Hydroamination and its Proposed Mechanism………168

5.2. Pd-catalyzed Intramolecular Amination for Natural Product Syntheses…………169

6.1. Seleniranium-ion Mediated Friedel-Crafts Cyclizations…………………..………176

xv 6.2. Proposed Mechanism of Friedel-Craft Versus Detosylative Cyclizations………186

6.3. Diastereoselective Debenzylative Cyclization Reactions…………………………189

7.1. Fukuyama’s Synthesis of (+)-Yatakemycin………………………………………213

7.2. Hayes Synthesis of SB-214857 via Cu-catalyzed Cyclizations…………………214

7.3. Biosynthesis of Lynbyatoxin A……………………………………………………216

7.4. Retrosynthetic Analysis of the Target Molecule(s)………………………………217

7.5. Syntheses of the Key Intermediates and Horner-Emmons Reaction……………219

7.6. Proposed Steps in the Cu-mediated Tandem Cyclization……....…………………226

7.7. Synthesis of Dipeptide 55b by Rh-cat. Hydrogenations...... …………………227

7.8. Synthesis of Dipeptides 59a-b using Schöllkopf Reagent...... ……………229

7.9. Possible Routes to the Tricyclic Diketopiperazines via Tandem Reactions…..…232

7.10. Synthesis of the trans-isomer 60b Using the Schöllkopf Chiral Auxiliary………234

7.11. Synthesis of Tetracyclic DKP Derivatives Containing L-Proline Residue………236

7.12. Synthesis of the Oxazolidinone Intermediate 66.………………….………….…238

7.13. Synthesis of an Oxazolidinone-based Dipeptide

and its Attempted Cyclization…………………………………………………238

xvi

LIST OF TABLES

Table Page

2.1. Hydrovinylation of Various Substrates……………………………………………42

2.2. Enantioselectvities of Hydrovinylation of 4e...……………………………………43

2.3. Asymmetric HV of 4-Methylene Tetrahydronaphthalenes………...………………51

2.4. Selected Bond Lengths and Angles of the 7-Membered Lactam 23……………54

2.5. Selected Bond Lengths and Angles of Unexpected Cyclization Product 27……58

3.1. Hydrovinylation Using Hemilabile

2-Diphenylphosphino-2’-X-1,1’-binaphthyl Ligands…………………………….102

3.2. (Allyl)Ni(L)X Complexes and Their 31P NMR Spectra……………………….…104

3.3. Synergistic Effects of Hemilabile Coordination in Hydrovinylation of Styrene…105

3.4. Selected Bond Lengths and Angles of Ru- and Ir-complex…………………….…107

3.5. Selected Bond Lengths and Angles of (allyl)Ni(L1)Br Complex (28a)…………110

3.6 (Allyl)Ni(L)X Complexes and Their 31P NMR Spectra……………………………114

3.7. Enantioselectivities of Hydrovinylation of 4-Methylenechroman (14)……..……120

4.1. Isomerization of Disubstituted Exomethylene Double Bonds……………….……136

4.2. Isomerization of HV’s Substrates for All-carbon Quaternary Centers……….……138

4.3. Comparison of Pd, Ru, and Ir Catalysts for Isomerization of Alkenes

with Geminal Disubstituted Double Bonds………………………………………140

4.4. Isomerization of Mono-substituted Terminal Alkenes……………………………141

xvii 4.5. Comparison of Pd, Ru, and Ir Catalysts for Isomerization of Alkenes

with Mono-substituted Terminal Double Bonds…………………………………143

6.1. Seleniranium ion-Induced Friedel-Craft Cyclization Reactions……………..……182

6.2. Results of 6-Endotrig Cyclization Reactions………………………………..……184

6.3. Intramolecular Detosylative Cyclizations…………………………………………187

7.1. Rh-catalyzed Asymmetric Hydrogenations of Z-Dehydroaminoacid 53…………220

7.2. Selective Deprotections of N-Boc Groups in the Dipeptide 53a…………………221

7.3. Pd-catalyzed Intramolecular N-Arylation Reactions……………………………222

7.4. Selected Bond Lengths and Angles of Tetracyclic DKP 54………………………224

7.5. Rh-catalyzed Asymmetric Hydrogenations of Z-Dehydroaminoacid 55…………228

7.6. Selected Results of Cu-mediated Tandem Cyclizations…………………………230

7.7. Intermolecular N-Arylation of the DKP with Arylhalides………………………233

7.8. Results of Ether Cleavage and Cyclization Reactions……………………………235

xviii

LIST OF FIGURES

Figure Page

1.1. Wilke’s Azaphospholene and Other Simplified Ligands…………………………13

1.2. Ligands with Hemilabile Coordination Groups

for Asymmetric Hydrovinylation…………………………………………………15

1.3. Utility of the Ni-Catalyzed Asymmetric Hydrovinylation Reactions………………16

2.1. Target Natural Products Containing an All-carbon Quaternary Center.……………38

2.2. Ortep Plot of 23…………………………………………………..………………54

2.3. Unexpected Ring Expansion Product 27 and its Ortep Plot………………………57

3.1. “Tunable” Hemilabile 2-Diphenylphosphino-2’-X-1,1’–binaphthyl Ligands……101

3.2. Possible Two Diastereomeric Structures of (allyl)Ni(L)X Complexes……………103

3.3. Structures and Their Ortep Plots of Ru- and Ir-phosphoramidite Complexes……106

3.4. Structures of Feringa-type Phosphoramidite Ligands…………………………….109

3.5. Structure of (allyl)Ni(L1)Br Complex (28a) and its Ortep Plot…………….…….110

3.6. Variable Temperature 31P NMR Spectra of

+ - [(allyl)Ni(L3)] BARF Complex (29b)…………………………………………116

3.7. Variable Temperature 31P NMR Spectra of

+ - [(allyl)Ni(L1)] BARF Complex (29a)…………………………………………118

4.1. Unreactive Substrates for Pd-catalyzed Isomerization……………………………139

xix 6.1. Plan of Hydrovinylation-based Synthesis of (-)-Physostigmine…………………179

7.1. 2,5-Diketopiperazine, Pyrazino[1,2-a]indole-1,4-dione, and Gliotoxin…………210

7.2. Structures of Teleocidine Family and Benzolactam-V8…………………………212

7.3. Ortep Plot of Tetracyclic DKP 54………………………………………………224

7.4. Structures of Mycenarubins A and B………………………………………………225

xx

LIST OF ABBREVIATIONS

BINAP 2,2’-Bis(diphenylphosphino)-1,1’-binaphthyl

Binol 2,2’-Bis(hydroxy)-1,1’-binaphthyl

Box Bis(oxazoline)

CNS Central nervous system

COD 1,5-Cyclooctadiene

COE 1,5-Cyclooctene

COSY Correlated Spectroscopy

Cp Cyclopentadienyl

Cy Cyclohexyl

Dba Dibenzylideneacetone

DFT Discrete Fourier transform

DIPAMP Bis[(2-methoxyphenyl)phenylphosphino]ethane

DKP 2,5-Diketopiperazine

DIPEA Diisopropylethylamine (= DIEA)

DMA N,N-Dimethylacetamide

DMAP 4-Dimethylaminopyridine

DMF Dimethylformamide

xxi DOPA 3,4-Dihydroxyphenylalanine

Eq. Equivalent

GABA γ-Aminobutyric acid

HATU O-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium

hexafluorophosphate

Hex. n-Hexane

HRMS High Resolution Mass Spectroscopy

HV Hydrovinylation

LAH Lithium Aluminum Hydride

LHMDS Lithium Hexamethyldisilazide

MeCN Acetonitrile

MOP 2-(Diphenylphosphino)-2’-methoxy-1,1’-binaphthyl

MVK Methylvinylketone

NaBARF Sodium tetrakis-[(3,5-trifluoromethyl)phenyl]borate nbd Norbonadiene

NBS N-Bromosuccimide

NMP N-Methyl Pyrrolidone nOe Nuclear Overhauser effect

OTf Trifluoromethanesulfonate

PMP 4-Methoxyphenyl

Rf Retention coefficient (TLC) rt Room temperature (or RT)

xxii TBS tert-Butyldimethylsilyl (or TBDMS)

TEA Triethylamine

THF Tetrahydrofuran

TLC Thin Layer Chromatography tol. Toluene tr Retention time (GC)

xxiii

PART A. Ni-CATALYZED ASYMMETRIC HYDROVINYLATION AND RELATED

REACTIONS

CHAPTER 1

1. INTRODUCTION

1.1. Hydrofunctionalizations

Regio- and stereo-selective reactions of readily available feed stock materials

represent one of the most important areas for research with huge potential for

improvement of the current level of modern synthetic organic chemistry.1-4 Catalytic

reactions which yield selectively the more branched product in the additions of C-X to a

linear alkene can be used for asymmetric C-C bond formation reactions among others.

In this field, hydrocyanation,4 hydrofomylation,5,6 hydrosilylation,7,8 and hydrovinylation9-11 have been well-studied.

Hydrocyanation is the addition reaction of hydrogen cyanide to a double bond.

This reaction has been used in the industrial process to synthesize polymer intermediates

such as adiponitrile from butadiene. This reaction has been extensively developed by

DuPont scientists.12,13 The mechanism of the reaction, which is typical of many such

1 C-C bond-forming reactions, is based on an oxidative addition of hydrogen cyanide to a metal, usually Ni(0). Migratory insertion of a double bond into a metal-hydride

complex followed by reductive elimination gives a hydrocyanation product (Scheme 1.1).

Most of known catalysts for asymmetric hydrocyanation use Ni or Pd with chiral

bidentate phosphines14 or phosphinites as ligands (Eqs. 1-3)15,16.

Although this reaction is still used in industry, an inherent disadvantage owing to the toxicity of hydrogen cyanide still remains to be unsolved. Also, enantioselectivity does not reach over than 90 % and substrate scope is limited (mostly to vinylarenes).

Hydrocyanated products

R and/or NC ∗ HCN NC R MLn

R H Ln M ∗ Ln M + Ln M R CN CN CN

H

Ln M R R CN Starting alkene

Scheme 1.1. General Mechanism of Hydrocyanation

2 Pd[(R)-BINAP] 2 PPh2 (Eq. 1.1) + HCN CN Benzene, 120 oC PPh2 6%,40%ee

Ni(COD)2, L* +HCN CN (Eq. 1.2) C6F6,rt H3CO H3CO

O 100%,85%ee L* = Ph O O OPh Ar2PO OPAr2

Ar = 3,5-(CF3)2-C6H3 CN Ni(COD)2, L* +HCN (Eq.1.3) C6F6,rt 75 %, 78 %ee

In case of hydroformylation17, Pt18 and Rh19,20 catalysts have been reported.

Due to the high-pressure involved in the activation of carbon monoxide/hydrogen

mixtures, this reaction suffers from side reactions such as hydrogenation, and also is

complicated from undesired regioselectivity (i. e., significant amount of linear achiral product formation). Not only regioselectivity but also chemoselectivity are lower than other hydrofunctionalizations in general. Sugar-based phosphinites were applied for

hydroformylation with good regioselectivities but only moderate enantioselectivities (Eq.

1.4).18

Hydrosilylation is the most well-developed reaction in this area.8 However, the

importance of the reaction is less than that of other hydrofunctionalization, because

further transformation21 of the products such as Tamao-Fleming oxidation22 to get the

corresponding chiral hydroxy-compounds are needed before readily usable intermediates

3 are reached. Besides, this is not a direct C-C bond forming reaction.

Branched Product CHO Rh(COD)BF4, L* Hydrogenated Product (Eq. 1.4) H /CO, Hexane H3CO H CO 2 3 100 % conv. (95 % sel.) 51 %ee H3CO

+ L* = Ph O O O OPh CHO Ar2PO OPAr2

Ar = 3,5-(CF3)2-C6H3 H3CO Linear Product

Finally, use of cheap, neutral, and stable ethylene permits hydrovinylation of alkenes in presence of nickel(II), and this is one of the most efficient carbon-carbon bond forming hydrofunctionalization reactions. Recent achievements of Ni-phosphoramidite complexes enable highly regio- and stereo-selective coupling reactions to yield exclusively hetero-dimerization products with high turnover rate (Eq. 1.5).11,23 This

reaction has even been successfully applied to generate all-carbon chiral quaternary

Hydrovinylation of 1,3-dienes

[(allyl)NiBr]2, L* L* = + (Eq. 1.5) 1atm NaBARF, CH2Cl 2 Ph N Ph >99%,>99%ee P O O Hydrovinylation for all-carbon quaternary centers

[(allyl)NiBr]2, L* + (Eq. 1.6) 1atm NaBARF, CH2Cl2 71 % yield, > 95 %ee

4 centers,24 which is one of the more challenging problems in current organic synthesis (Eq.

1.6).

To sum up, overall hydrovinylation represent a more amenable alternative to

other hydrofunctionalizations, due to mild reaction conditions, use of neutral coupling

partners, and multi-purpose utilities of a vinyl-group in HV products. Further studies

toward the development of more stable, versatile, and selective catalytic systems to solve

the current problems in the area should make this a competitive process for large scale

synthesis.

1.2. Brief History of Hydrovinylation as a Heterodimerization

The initial discovery of the selective dimerization of alkenes was reported by

Ziegler and his coworkers in 1954.25 In this paper, they reported the “nickel effect”

during the polymerization of ethylene. Trace amount of nickel catalyzed the dimerization of ethylene to produce 1-butene in alkylaluminum-catalyzed polymerization reaction. After this initial observation, RhCl3 catalyzed hydrovinylation of styrenes and

1,3-dienes under high pressure of ethylene was first reported by Lindsey et al.26 Wilke developed Ni-phosphane catalyzed propylene homo-coupling reaction independently.27

After these reports, many catalysts based on other metals such as Co,28 Ni,1 Ru,29 and

Pd30 have been developed.

1.3. Pd-catalyzed Hydrovinylation

Initial reports of Pd-catalyzed hydrovinylation showed that Pd-catalyzed reactions gave mostly linear products and extensive isomerization, which prevented the

5 use of this catalysts (Eq. 1.7).31-34 Also, Pd-catalyzed reaction needed elevated pressure of ethylene (Eq. 1.8).

Branched product Linear product Cataly st + + (Eq. 1.7) CH2Cl2

Isomerization

Ph2 P Pd O OEt + + (Eq. 1.8) (30 atm) CH2Cl2

after 1 h (41 % conv.) 92 8 after 3 h (100 % conv.) 9 91

Later, improved reaction conditions using chiral phosphinite ligands with the

- proper counterion (SbF6 ) were developed. These reaction conditions gave branched

products in reasonable yields and excellent selectivities under low conversions (Eq.

1.9).35 However, extensive isomerization was still a problem.

∗ L = [(allyl)PdI]2, L, ethylene (10 atm) (Eq. 1.9) P AgSbF6,CH2Cl 2,EtOAc Conversion 79 % t-Bu O Isomerization 16 % Ph ee 86 % (S)

6 1.4. Ru- and Co-Catalyzed Hydrovinylation

In 2001, Yi and coworkers reported (PCy3)(CO)Ru(Cl)H and HBF4·OEt2 catalyzed hydrovinylation of styrene.36 Later, hydrovinylation using the same metal

catalyst with AgOTf was reported by RajanBabu and his coworkers (Eq. 1.10).37 Still general reaction conditions and scope of the reaction have not been fully determined.

(PCy3)Ru(CO)(Cl)H + + (Eq. 1.10) CH 2Cl2

HBF4 OEt2,6h 99 1 AgOTf(1mol%),1h 83 7

In 2003, Yi and coworkers also disclosed non-asymmetric hydrovinylation of

1,3-dienes using the similar Ru-catalysts.38 Their Ru-catalysts give the 1,4-dienes in

moderate to good yields (Eq. 1.11). Since hydrovinylation of cyclic 1,3-dienes can be

HBF4 OEt2 excess ethylene R 1-2 % Ru catalyst R - H 2 2 Cy3P Cl BF4 Cy3P Cl Ru Ru (Eq. 1.11) + + OC PCy3 OC PCy3 R1 R1 (CH2Cl2) (C6H6) 57 - 90 % AB

used to solve exocyclic stereochemistry problems in many natural products such as

steroids, the development of new efficient catalysts for this reaction is extremely

important. Using Yi’s reaction conditions, the synthesis of a hybrid structure between

Ro 26-9228, a vitamin D3 analogue, and estrone has been demonstrated (Eq. 1.12).

7 B (2 mol%) Et H OH (Eq. 1.12) excess ethylene Et H H H H BnO 88 % 34 % (3 steps) (single diastereomer)

Vogt reported Co-catalyzed hydrovinylation under high pressure of ethylene (30

bar). Co-chelate complexes catalyze the hydrovinylation of simple styrenes in good

yields, but the enantioselectivities are moderate (Eq. 1.13).39 Co-catalyzed asymmetric

HV using various chelating phosphines still does not reach over 50 %ee.40

∗ Cl2CoL,Et2AlCl + (Eq. 1.13) o CH2Cl2,0 C

L = O O NH HN

MeO OMe Ph2P PPh PPh2 PPh2 2 95% 74%,47%ee

1.5. Ni-catalyzed Non-enantioselective Hydrovinylation

Even though a successful asymmetric version of the Ni-catalyzed hydrovinylation was reported in 1972, notable non-asymmetric version of the reaction appeared only after two decades. Ordinas and coworkers developed efficient Ni- catalysts for hydrovinylation of styrene in 1994.41 Under pressurized ethylene (15 bar), their cationic Ni-catalyst gave the desired product in high turnover numbers (up to 1915

h-1) and excellent selectivities (Eq. 1.14).

8 + - [(benzyl)3P]2Ni (mesityl)(CH3CN)BF4 +ethylene (Eq. 1.14) (15 bar) THF, 25 oC 96 % (sel. 97 %)

Dicationic Ni-complexes with bidentate phosphine ligands were reported by

Monteiro and coworkers.42,43 This condition solves the problem of isomerization of the

initial product by applying over 10 bars of ethylene during the reactions (Eq. 1.15).

This is a unique catalytic system where chelating phosphines are used for hydrovinylation.

2+ - [Ni(CH3CN) 6] 2[BF4] , L L = PPh2 + ethylene (Eq. 1.15) o R (10 atm) Et2AlCl, CH2Cl2,25 C, 75 min R PPh2 96 % by GC

RajanBabu and Nomura reported the new Ni-catalyzed conditions for HV, which

clearly improved the level of the technology to the next level.44 Combination of

[(allyl)NiBr]2, PPh3, and AgOTf catalyzes hydrovinylation of various styrenes under

atmospheric ethylene pressure. Typical reaction condition uses 0.007 eq. of the

precatalyst in methylene chloride at – 56 oC. No polymerization of styrene or ethylene

was detected under the reactions using this catalytic system (Eq. 1.16).

[(allyl)NiBr]2/PPh3/AgOTf (cat. 0.007 eq.) + ethylene (Eq. 1.16) o R (1 atm) CH2Cl2,-56 C, 2 h R 90 - 99 % No other sideproducts !!

9 The major breakthroughs made from the early mechanistic studies on hydrovinylation can be summarized as follows: First, as compared to the original Wilke conditions, the use of Ag-salts in place of the strong Lewis acids in the system makes this protocol more broadly applicable to substrates containing Lewis basic functional groups.

Second, only atmospheric pressure of ethylene is needed for the hydrovinylation, so the reactions become operationally simpler. In addition, almost perfect selectivities giving only the branched hydrovinylation product without any isomerization is observed.

Attempts to use chelating phosphines such as BINAP and DIOP for enantioselective reactions do not yield any product. Starting materials were fully recovered.

1.6. Ni(II)-Catalyzed Heterodimerization Using Coupling Partners Other than Ethylene.

Until now, few heterodimerization using olefins other than ethylene has been reported. None of reported condition reaches a practical level. One of the most relevant non-enantioselective examples, the heterodimerization of styrenes with propene was reported by RajanBabu and Jin (Eq. 1.17).45 Using conditions similar to the

[(allyl)NiBr]2 (1.5 mol%) + + (Eq. 1.17) R PPh3,AgOTf,CH2Cl 2 o R R -15to10 C, 10 to 30 min A B R=tBu,OMe,Cl,Br,OAc PhC(O)-, NTs2,... yields 86 to 98 % (A:B: 2:1 to 4:1)

reactions of ethylene, the desired products were obtained in excellent yields as a mixture of regio-isomers. Other heterodimerization or codimerization of styrene with other olefins such as cyclohexene or ethyl vinylether using the same Ni-catalyst at room

10 temperature are unsuccessful and only styrene dimer is seen as the product (Eq. 1.19).37

Styrene itself under several codimerization conditions mainly gave a polymer with small amount of a dimer (Eq. 1.18).

[(allyl)NiBr]2 (0.7 mol%), PPh3 +Polymer (Eq. 1.18) AgOTf, CH2Cl2,rt,2h dimer (14 %)

O +

[(allyl)NiBr]2 (1.5 mol%), PPh3 or dimer + polymer (Eq. 1.19) o AgOTf,CH2Cl2,0 C, 2 h +

Instead of styrene, other olefins have also been tested for heterodimerization with ethylene under similar Ni-catalyzed conditions. Hydrovinylation reaction of 1-t-

butyldimethylsiloxy-5-hexene undergoes to clean isomerization (Eq. 1.20). This result

indicates the potential utility of similar catalysts for the isomerization of terminal olefins,

which will be discussed in Chapter 4.

[(allyl)NiBr]2 (0.7 mol%), PPh3 OTBS + ethylene OTBS (Eq. 1.20) (1 atm) AgOTf,CH Cl ,- 55oC, 4 h 2 2 95 % (E:Z = 3.5:1)

Hydrovinylation of norbonene is a rare example of a mono-alkene that produces the desired hydrovinylation product. Depending on the ligand employed either a 2:1

11 (norbonene:ethylene) adduct or a 1:1 adduct is observed (Eq. 1.21).46,47

[(allyl)NiBr]2,PR3,AgOTf + ethylene + (Eq. 1.21) o (1 atm) CH2Cl 2,-55to-70 C, 2 h

PCy3 - 100 0 PPh3 -1 97

1.7. Ni-catalyzed Asymmetric Hydrovinylation

The major breakthrough in terms of enantioselective hydrovinylation was

initially achieved by Wilke using a catalytic system consisting of [(allyl)NiCl]2, Al2Et3Cl3, and a complex azaphospholene ligand L* (Eq. 1.22).48,49 Although it gave a high yield

L* = P [(allyl)NiCl]2, L*,Al2Et3Cl3 H N (Eq. 1.22) N Ethylene, - 72 oC H P

>90%,95%ee

and enantioselectivity for styrene, this system did not appear to be of general value and was not further developed due to the complex nature of the ligand and the need for strong

Lewis acids in the medium.

12 P P H N N P H P N R H R P R=H,Me,Ph Wilki's azaphospholene R = Me, menthyl

Figure 1.1. Wilke’s Azaphospholene and Other Simplified Ligands

Later, different types of ligands were designed to simplify the original structure

(Figure 1.1) and these were applied for the reaction with no success.9

Chelating phosphines do not show any catalytic activity in most of Ni-catalysts

except in dicationic Ni-complexes.41,50 These results have been rationalized in a number

of reports by suggesting that bidentate phosphines completely block all of coordination

sites of nickel (Scheme 1.2). Therefore, bidentate ligands without complete blockage of

a coordination site were considered for the next generation of ligands. A monodentate

ligand with a ‘hemilabile group’ is expected to stabilize the cationic Ni-complexes during

the reaction, and also help to improve enantioselectivities. Based on these mechanistic

assumptions, various types of hemilabile ligands were designed, synthesized, and applied

for Ni-catalyzed hydrovinylation reactions.

13 P Z + P + P Z M M M Z Y Y- - If Z is phosphine, complex becomes 16e. (No coordination site for further reaction)

- Bidentate ligands for better diastereoselectivities.

Activecatalyst?? P Beta-hydride P M Z P elimination M Z - + Z + Y Y- + M H

Scheme 1.2. Proposed Mechanism of Hydrovinylation Based on a Cationic Metal-

Hydride and Role of a Hemilabile Group on a Ligand

Although there is no definitive evidence for the proposed mechanism, results

from studies using hemilabile ligands51,52,53 clearly suggest advantages of a weak

interaction of the hemilabile atom of these ligands with the metal. It is noteworthy that

monodentate ligands with hemilabile coordination groups such as MOP-types,44,54 tunable phospholanes,54,55 and phosphoramidites23,24,56 clearly elevate the reaction to the

next level in terms of efficiency and selectivity (Figure 1.2). Experimental studies related to hemilabile coordination in hydrovinylation reactions catalyzed by Ni-

phosphoramidites will be discussed in depth in Chapter 3.

14

MOP type Phospholanes Phospholane with acetal

R X O n R O OR O O PPh2 P P P

t R=Alkyl,Bn X = OMe, OBn, SBu n=0-1

Sugar-based phosphinites Phosphoramidites

H Ph Ph O O O O P N NH O Ar2PO OBn Ac Ar Ar = 3,5-Me2-C6H3

Figure 1.2. Ligands with Hemilabile Coordination Groups for Asymmetric

Hydrovinylation

So far, many different types of catalysts have been developed and applied for asymmetric hydrovinylation. Feringa-type phosphoramidite ligands are clearly superior to others.23,24 Not only hydrovinylation of simple styrenes but also 1,3-dienes produce the desired products in good to excellent yields and selectivities with high consistency

(Figure 1.3).

15

∗ ∗

iBu Styenes 1,3-Dienes 97 %, 90 %ee >98%,>99%ee

R + (1 atm)

[AllylNiBr]2, L

NaBARF, CH2Cl 2 ∗

All-carbon Steroidal quaternary centers Dienes ∗ H BnO 95 %, > 95 %ee 83 % (sel. 80 %)

Figure 1.3. Utility of the Ni-Catalyzed Asymmetric Hydrovinylation Reactions

As applications of hydrovinylation of simple styrenes, the syntheses of medicinally important compounds such as enantiopure arylpropionic acids have been demonstrated.57 By hydrovinylation and subsequent oxidative cleavages, ibuprofen, naproxen, and flurbiprofen have been synthesized in the highest enantioselectivities to date (Eq. 1.23).58,59

16 iBu iBu iBu [AllylNiBr]2, L1,ethylene 1. O3,CH2Cl 2 (Eq. 1.23) NaBARF, CH2Cl2 2. NaClO2, HO 95 % (2 steps) O 98 %, 96 %ee (S)-ibuprofen L1 = Ph O P N O Ph

In addition, natural products, such as (-)-(R)-curcumene and (-)-(R)-turmerone, have also been synthesized by the similar strategy. Starting from hydrovinylation of 4- methylstyrene, the synthesis is accomplished by HV and subsequent functionalizations.

The resulting vinyl group in A in Scheme 1.3 is converted into an alkyl-borane, and this product is used for Suzuki coupling with a vinyl bromide unit. This sequence produces

(-)-(R)-curcumene in good yield, and enantioselectivity (Scheme 1.3).60 Hydroboration

/oxidation of the same hydrovinylation product A yields the hydroxy intermediate B.

Oxidation of the alcohol to aldehyde followed by alkylation gives an allylic alcohol,

which is further oxidized to yield the target structure (-)-(R)-turmerone (Scheme 1.3).

17 [allyl)NiBr]2, L, NaBARF 1. 9-BBN, THF

o A 2. Pd(0), cat. K3PO4 Ethylene, CH2Cl 2,-55 C, 2 h > 99% (87 %ee) THF/dioxane Br 55 % 60 oC, 14 h (-)-(R)-curcumene 1. disiamylborane, THF L = 2. NaOH/H O O 2 2

O OH 1. Swern oxidation P 2. MgBr O

B 31 % 3. Swern oxidation (-)-(R)-turmerone .

Scheme 1.3. Hydrovinylation-Based Total syntheses of Natural Products

Hydrovinylation of 1,3-dienes is useful for a potential solution to exocyclic stereochemistry problem.23 The basic idea is shown by the hydrovinylation of a simple

1,3-diene followed by directed hydrogenation (Scheme 1.4). Asymmetric hydrovinylation product (A in Scheme 1.4) of the cyclic 1,3-diene undergoes hydroboration to give an alcohol. Directed hydrogenation using Crabtree’s catalyst

+ - ([Ir(COD)(PCy3)(py)] PF6 ) leads to the stereo-controlled exocyclic model structure B in

Scheme 1.4 in excellent stereoselectivities.61 Since the establishment of exocyclic stereo-centers is the key for the syntheses of many important natural products such as

potent anti-inflammatory pseudopterosins,62 and many steroids, the utility of the reaction

using 1,3-dienes can not be overstated.

18 ∗ OH H ∗ OH X n ∗ n n H

1. 9-BBN HO - Ni-cat, 2. H2O2,HO Pseudopterosin A-F 3. Ir+ cat, H H >98% 2 aglycone ~61% A B dr 30:1

Scheme 1.4. Hydrovinylation of 1,3-Dienes: Enantioselective Construction of Exocyclic

Sidechains

The modified reaction conditions for hydrovinylation is also suitable for the generation of all-carbon chiral quaternary centers in good yields and excellent enantioselectivities (Eq. 1.6).24,63 This aspect will be discussed more thoroughly later in

Chapter 2.

1.8. Intramolecular Hydrovinylation Reactions

Intramolecular version of the dimerization of unsaturated systems can be utilized for the synthesis of various hetero- and carbo-cycles.64 Among them, cyclization of

enynes catalyzed by a presumed Pd-hydride intermediate has been well-studied.65

Cyclization of α,ω-dienes, a type of intramolecular hydrovinylation, has also been studied.66-71 The initial discovery of the cyclization using Ni- and Pd-catalysts was

19 reported by the RajanBabu group.72 Carbo- and hetero-cyclic compounds are easily

made by this protocol using symmetrical dienes, but non-symmetrical substrates do not

give good regioselectivities (Eqs. 1.24-26).

Z [(allyl)NiBr]2 (2.5 mol%), AgOTf Z Z + (Eq. 1.24) Z (p-MeO-Ph)3P, CH2Cl 2,rt,2h Z Z 92 % < 3 % Z=CO2Me

[(allyl)PdBr]2 (5 mol%), L TsN TsN TsN + (Eq. 1.25) AgOTf, CH2Cl 2,rt,2h

L :PPh3 74 % 16 % P(o-tol)3P35% 57%

H [(all yl)Ni Br] 2 (5 mol%), AgOTf O O 64 % (Eq. 1.26) (p-MeO-Ph)3P, CH2Cl2,rt,24h (cis/trans 1:1) Ph Ph

The same catalytic system that is used in Ni-phosphoramidite complex catalyzed hydrovinylation reactions developed by RajanBabu72 is also applicable for the

enantioselective α,ω-diene cyclization. An enantioselective version of the cyclization

was reported by Leitner and Bόing.73,74 However, there are no reports of intramolecular

hydrovinylation of styrenes or 1,3-dienes with another internal olefin in the cyclization

reaction.

20 1.9. Summary

It has been clearly demonstrated that Ni-catalysts are better than other metal- based catalysts for the HV reaction and the synergistic effects of hemilabile coordination

of ligands and counter-ions give promising results in the asymmetric hydrovinylation.

However, there is still a need to develop more robust and versatile hydrovinylation

catalysts for more diverse substrates. Also, there is no solid mechanistic evidence for

the existence of a hemilabile coordination of a pendant group to the metal center, and

unequivocal structural information of a catalyst is still lacking.

As the development of the reaction progressed, applications of the current

methods for biologically important compounds became one of higher priorities.

Applications of this protocol for the synthesis of functionalized molecules will highlight

the strengths of the reaction. Several such applications will be discussed in subsequent

chapters.

21 1.10. REFERENCES (1) RajanBabu, T. V. "Comprehensive Asymmetric Catalysis"; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1996; Vol. 1. (2) Nozaki, K. "Hydrocarbonylation of Carbon-Carbon Double Bonds" In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 1, p 381. (3) Agbossou, F.; Carpentier, J.-F.; Mortreux, A. Chem. Rev. 1995, 95, 2485. (4) RajanBabu, T. V.; Casalnuovo, A. L. "Hydrocyanation of Carbon-Carbon Double Bonds" In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 1, p 367. (5) Cornils, B.; Herrmann, W. A.; Rasch, M. Angew. Chem. Int. Ed. 1994, 33, 2144 and references cited therein. (6) van Leeuwen, P. W. N. M. "Rhodium Catalyzed Hydroformylation"; Claver, C., Ed.; Springer: Berlin, 2002. (7) Hayashi, T.; Yamasaki, K. "C-E Bond Formation through Asymmetric Hydrosilylation of Alkenes" In Comprehensive Organometallic Chemistry III; Crabtree, R. H., Mingos, M. P., Eds.; Elsevier: Amsterdam, 2007. (8) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: New York, 2000. (9) Jolly, P. W.; Wilke, G. In Applied Homogeneous Catalysis with Organometallic Compouns; Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH: New York, 1996; Vol. 2, p 1024. (10) RajanBabu, T. V. Chem. Rev. 2003, 203, 2845. (11) RajanBabu, T. V. Synlett 2008, 21, 853. (12) Arthur Jr., P.; England, D. C.; Pratt, B. C.; Whitman, G. M. J. Am. Chem. Soc. 1954, 76, 5364. (13) Tolman, C. A.; Mckinney, R. J.; Seidel, W. C.; Druliner, J. D.; Stevens, W. R. Adv. Catal. 1985, 33, 1. (14) Hodgson, M.; Parker, D. J. Organomet. Chem. 1987, 325, C27. (15) RajanBabu, T. V.; Casalnuovo, A. J. J. Am. Chem. Soc. 1992, 114, 6265. (16) Saha, B.; RajanBabu, T. V. Org. Lett. 2006, 8, 4567. (17) Hydroformylation and Related Additions of Carbon Monoxide to Alkenes and Alkynes. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 4. (18) Consiglio, G.; Nefkens, S. C. A.; Borer, A. Organometallics 1991, 10, 2046. 22 (19) RajanBabu, T. V.; Ayers, T. A. Tetrahedron Lett. 1994, 35, 4295. (20) Sakai, N.; Mano, S.; Nozaki, K.; Takaya, H. J. Am. Chem. Soc. 1993, 115, 7033. (21) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599. (22) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson, P. E. J. J. Chem. Soc., PT1 1995, 317. (23) Zhang, A.; RajanBabu, T. V. J. Am. Chem. Soc. 2006, 128, 54. (24) Zhang, A.; RajanBabu, T. V. J. Am. Chem. Soc. 2006, 128, 5620. (25) Ziegler, K.; Gellert, H.-G.; Holzkamp, E.; Wilke, G. Brennst. Chem. 1954, 35, 321. (26) Alderson, T.; Jenner, E. L.; Lindsey, R. V. J. Am. Chem. Soc. 1965, 87, 5638. (27) Wilke, G.; Bogdanović, B.; Hardt, P.; Heimbach, P.; Keim, W.; Kröner, M.; Oberkirch, W.; Tanaka, K.; Steinrücke, E.; Walter, D.; Zimmermann, H. Angew. Chem. 1966, 78, 157. (28) Hilt, G.; du Mesnil, F.-X.; Juers, S. Angew.Chem. Int. Ed. 2001, 40, 387. (29) Umezaki, H.; Fujiwara, Y.; Sawara, K.; Teranishi, S. Bull. Chem. Soc. Jpn. 1973, 46, 2230. (30) Englert, U.; Haerter, R.; Vasn, D.; Eggeling, A. S.; Vogt, D. Organometallics 1999, 18, 4390. (31) Barlow, M. G.; Haszeldine, R. N.; Mackie, A. G. J. Organomet. Chem. 1970, 21, 215. (32) Britovsek, G. J. P.; Cavell, K. J.; Keim, W. J. Mol. Catal. A 1996, 110, 77. (33) Eggeling, E. B.; Hovestad, N. J.; H., J. T. B.; Vogt, D.; van Kotten, G. J. Org. Chem. 2000, 65, 8857. (34) Shi, W.-J.; Xie, J.-H.; Zhou, Q., -L. Tetrahedron Asymm. 2005, 16, 705. (35) Bayersdörfer, R.; Ganter, B.; Englert, U.; Keim, W.; Vogt, D. J. Organomet. Chem. 1998, 552, 187. (36) Yi, C. S.; He, Z.; Lee, D. W. Organometallics 2001, 20, 802. (37) RajanBabu, T. V.; Nomura, N.; Jin, J.; Nandi, M.; Park, H.; Sun, X. J. Org. Chem. 2003, 68, 8431. (38) He, Z.; Yi, C. S.; Donaldson, W. A. Org. Lett. 2003, 5, 1567. (39) Grutters, M. M. P.; Müller, C.; Vogt, D. J. Am. Chem. Soc. 2006, 128, 7414. (40) Grutters, M. M. P.; van der Vlugt, J. I.; Pei, Y.; Mills, A. M.; Lutz, M.; Speck, A. L.; Müller, C.; Moberg, C.; Vogt, D. Adv. Synth. Catal. 2009, 351, 2199. (41) Cedar, R.; Muller, G.; Ordinas, J. I. J. Mol. Catal. 1994, 92, 127. (42) Monteiro, A. L.; Seferin, M.; Dupont, J.; Souza, R. F. Tetrahedron Lett. 1996, 37, 1157.

23 (43) Fassina, V.; Ramminger, C.; Seferin, M.; Monteiro, A. L. Tetrahedron 2000, 56, 7403. (44) Nomura, N.; Jin, J.; Park, H.; RajanBabu, T. V. J. Am. Chem. Soc. 1998, 120, 459. (45) Jin, J.; RajanBabu, T. V. Tetrahedron 2000, 56, 2145. (46) Kumareswaran, R.; Nandi, M.; RajanBabu, T. V. Org. Lett. 2003, 5, 4345. (47) Park, H.; Kumareswaran, R.; RajanBabu, T. V. Tetrahedron Symposium-in-Print 2005, 61, 6352. (48) Wilke, G.; Monkiewicz, J. Chem. Abstr. 1988, 109, P6735. (49) Wilke, G.; Monkiewicz, J.; Kuhn, H. "Preparation of optically active azaphospholenes and their use in catalysis for asymmetric codimerization of olefines" US patent, 4912274, 1990. (50) Bogdanović, B. Adv. Organomet. Chem. 1979, 17, 105. (51) Jeffrey, J. C.; Rauchfuss, T. B. Inorg. Chem. 1979, 18, 2658. (52) Bader, A.; Lindner, E. Coord. Chem. Rev. 1991, 108, 27. (53) Slone, C. S.; Weinberger, D. A.; Mirkin, C. A. "The Transition Metal Coordination Chemistry of Hemilabile Ligands" In Progress in Inorganic Chemistry; Karlin, K. D., Ed.; John Wiley: New York, 1999; Vol. 48, p 233. (54) Nandi, M.; Jin, J.; RajanBabu, T. V. J. Am. Chem. Soc. 1999, 121, 9899. (55) Zhang, A.; RajanBabu, T. V. Org. Lett. 2004, 6, 1515. (56) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346. (57) For a review of 2-arylpropionic acid synthesis, see Rieu, J.-P.; Boucherle, A.; Cousse, H.; Mouzin, G. Tetrahedron 1986, 42, 4095. (58) Smith, C. R.; RajanBabu, T. V. Org. Lett. 2008, 10, 1657. (59) Smith, C. R.; RajanBabu, T. V. J. Org. Chem. 2009, 74, 3066. (60) Zhang, A.; RajanBabu, T. V. Org. Lett. 2004, 6, 3159. (61) Saha, B.; Smith, C. R.; RajanBabu, T. V. J. Am. Chem. Soc. 2008, 130, 9000. (62) For a reference about discussion of this problem and citations of earlier works, see Guevel, A.-C.; Hart, D. J. Org. Chem. 1996, 61, 465. (63) Smith, C. R.; Lim, H. J.; Zhang, A.; RajanBabu, T. V. Synthesis 2009, 2089. (64) Lloyd-Jones, G. C. Org. Biomol. Chem. 2003, 215. (65) Trost, B. M. Acc. Chem. Res. 1990, 23, 34 and the references cited therein. (66) For the cyclization using early transition metals, see Nugent, W. A.; Taber, D. F. J. Am. Chem. Soc. 1989, 111, 6435. (67) Piers, W. E.; Shapiro, P. J.; Bunel, E. E.; Bercaw, J. E. Synlett 1990, 74.

24 (68) Knight, K. S.; Waymouth, R. M. J. Am. Chem. Soc. 1991, 113, 6268. (69) Molander, G. A.; Hoberg, J. O. J. Am. Chem. Soc. 1992, 114, 3123. (70) Negishi, E.; Takahashi, T. Acc. Chem. Res. 1994, 27, 124. (71) Yamaura, Y.; Hyakutake, M.; Mori, M. J. Am. Chem. Soc. 1997, 119, 7615 and references cited therein. (72) Radetich, B.; RajanBabu, T. V. J. Am. Chem. Soc. 1998, 120, 8007. (73) Bόing, C.; Leitner, W. Chem. Commun. 2005, 1456. (74) Diez-Holz, C. J.; Boing, C.; Francio, G.; Holscher, M.; Leitner, W. Eur. J. Org. Chem. 2007, 2995.

25

CHAPTER 2

GENERATION OF ALL-CARBON CHIRAL QUATERNARY CENTERS AND

SYNTHESIS OF (-)-PHYSOSTIGMINE

2.1. INTRODUCTION

Generation of all-carbon chiral quaternary centers is one of the most challenging

goals in modern organic synthesis.1,2 At early stages, chiral auxiliaries were used for diastereoselective C-C bond formation. Although this approach needs at least

stoichiometric amounts of a chiral auxiliary and several synthetic steps to attach and

remove them, it is practical and still widely used. This approach has been applied to

reactions of chiral intermediates such as alkylations of enolates, free radical reactions,

Diels-Alder reactions, sigmatropic rearrangements and so forth.2 Recently, these

researches as well as those involving organometallic intermediates have shifted to

catalytic asymmetric approaches using similar reactions to make enantiomerically pure

quaternary all-carbon centers. High efficiency and selectivity have been seen in many

reactions. In this approach, no additional steps are needed for attaching and removing

the chiral auxiliaries.

26 2.1.1. Asymmetric Alkylations

As one of the representative example of stoichiometric approaches, alkylations of enolates have been achieved successfully by many chiral auxiliaries such as chiral cyclic lactams (Eq. 2.1 and Eq. 2.2).3,4

Ph Ph R1 + 1. LDA, R1X H O R1 R2 O O (Eq. 2.1) N N R2 2. LDA, R2X BuOH Ph ∗ CO 2H O O

O O 1. Li/NH ,THF,tBuOH (1 eq.) R N 3 N ∗ (Eq. 2.2) 2. RX O H O H

Michael-type additions and aldol reactions are among the most useful reactions to generate tertiary and quaternary carbon centers.5 In a notable example of a catalytic

asymmetric alkylation, Shibasaki reported a bimetallic lanthanide catalyst for the

enantioselective Michael reactions of stabilized enolates (Eq. 2.3).6 Similarly, Trost

developed Pd-catalyzed allylic alkylations with azalactones for the synthesis of chiral

amino acids containing all-carbon quaternary centers (Eq. 2.4).7

Na O * O O O O O O O Na OMe * La OMe O O (Eq. 2.3) Cat. (10 mol%) O Na O * 85 % yiel d 93 %ee BINOL = *

27 O O O O O N Mo(C7H8)(CO)3,L* K2CO3 Me OH Me N (Eq. 2.4) Me o + LHMDS, THF, 60 C MeOH NH2 Ph Ph Ph OCO2CH3 99 %ee (dr 97:3), 92%

L* = MeO MeO O O Mo(C7H8)(CO)3,LiOtBu O O NH HN (Eq. 2.5) N Allylchloroformate, L* N N N 82 %ee, 98 %

Recently, it was also reported that the Trost catalyst can be used to make an oxindole with an all-carbon quaternary center.8 The product of this reaction was used to synthesize (-)-physostigmine, a natural product isolated from Calabar bean (Eq. 2.5).

The major drawbacks of this reaction are the need to use of a strong base and low catalytic activity (> 10 mol% of catalyst needed for the reaction.).

2.1.2. Radical Reactions

Although asymmetric radical reactions for C-C bond formation have been studied for a long time, the processes that make all-carbon chiral quaternary centers are quite rare.9 In an elegant example, total synthesis of a lycopodium alkaloid was achieved by Zard and coworkers via tandem radical reactions to build multiple quaternary centers (Scheme 2.1).10 However, a truly catalytic enantioselective version of a radical reaction by means of a chiral organometallic complex with an achiral substrate has not been reported yet.

28

OTBS OTBS OTBS OH

Cl H Cl H HSnBu3 H H

CH 3CN BzON N N O N O O O O O O

Scheme 2.1. Radical Reaction for All-carbon Quaternary Centers

2.1.3. Diels-Alder Reactions

Diels-Alder reaction is one of the most versatile tools to build cyclic systems in organic synthesis. The asymmetric reaction of α-substituted enone or enal as a dienophile using chiral Cu-Box complexes, originally developed by Evans,11 gave cyclic

compounds with an all-carbon quaternary center with excellent enantioselectivities. An

example is azaspiro[5,6]dodec-9-ene system that exists in pinnatoxin A (Scheme 2.2).

Also, hetero Diels-Alder reactions were successfully catalyzed by the same type of Cu-

Box complexes (Eq. 2.6).12

O L= O O OMe O Cu(OTf) ,L OEt 2 N N + Me (Eq. 2.6) o CH2Cl2,-78 C O TMSO O CO2Et 62 % yield, 99%ee

29 + O O 2 - OTBS 2AsF6 O N N OTBS cbz O cbz N tBu Cu tBu + N

CH2Cl2,rt,3h OBn BnO OH O O O 82 % yield, 99 %ee endo/exo 1:99 HO O O

- H O2C N H+ Pinnatoxin A

Scheme 2.2. Cu-Box Catalyzed Asymmetric Diels-Alder Reaction

Although, there are many catalysts known for Diels-Alder reactions, catalytic

efficiency is still somewhat low. Most of the known catalysts are needed in 5 to 20

mol% for a full conversion.13-15

2.1.4. [2+3] Cycloadditions

Similar to Diels-Alder reaction, [2+3] asymmetric cycloadditions are divided into two types. In one type, a chirality is induced by a chiral auxiliary such as an

enantiopure oxazolone16, or it is achieved by a chiral organometallic catalyst or a Lewis

acid. Chiral Lewis acid catalyzed asymmetric cycloaddition was first reported by

Kündig using Fe- and Ru-complexes.17 Then, highly selective Co-catalysts for the

30 synthesis of an all-carbon quaternary center-bearing isoxazolidines were developed by

Yamada and his coworkers (Eq. 2.7).18

H Ar Ar + O SbF - Ph + O- Cat.(5 mol%) 6 N H Ph N Ar N N Ar + Co (Eq. 2.7) -40oC, CH Cl H Ar 2 2 Ar O O O O O then NaBH OH 4 99 % endo 83-91 %ee Ar = 1,3,5-trimethylphenyl

2.1.5. Sigmatropic Rearrangements

The significance of sigmatropic rearrangements such as Claisen rearrangement to make C-C bonds is well known.19 Current trend in the area is using diastereoselective

tandem process to build multiple bonds. In 2002, Stoltz and coworkers reported

efficient Rh-catalyzed tandem 1,2-hydride shift/Claisen reaction (Scheme 2.3).20

Various sigmatropic rearrangements involving tandem reactions have been successfully applied for the construction of all-carbon quaternary centers, but almost all of them were diastereoselective reactions. In an example of a highly diastereoselective thio-Claisen rearrangement using a chiral auxiliary, Rawal and coworkers have reported a thio-Claisen

21 rearrangement using a chiral pyrrolidine auxiliary (Scheme 2.4). This C2-symmetric

chiral amine induced good diastereoselectivity (9.8:1).

31

N Ph N H O Rh2(OAc)2 O Claisen O ene Heat H Ph HO

dr >20:1, 63%

DIBAL-H N 2 RhLn O O

HO Ph dr >20:1, 88 %

Scheme 2.3. Rhodium-Catalyzed Tandem Claisen/Ene Reaction

Ph Ph Ph S S 1. n-BuLi, - 78 oC S N N N 2. AllylBr Ph Ph Ph dr 9.8:1, 98 %

Scheme 2.4. Thio-Claisen Rearrangement Using a C2-symmetric Chiral Auxiliary

32 2.1.6. Intramolecular Heck Reactions for Syntheses of (-)-Physostigmine and Related

Compounds

Shibasaki22 and Overman23 reported asymmetric Heck cyclizations independently.

Using this methodology, Overman and coworkers had successfully synthesized many

natural products containing pyrrolidinoindoline core such as (-)-physostigmine24, quadrigmine C, and psycholeine25 (Scheme 2.5). These reactions have been applied

successfully for syntheses of many other natural products with good yields and

enantioselectivities.26

TBDMSO OTBDMS O Pd dba . CHCl N N 2 3 3 O N I (R)-BINAP, DMA N (Z)-alkene o PMP, 100 C pyrrolidinoindoline 92 %ee, 80 %

N N N NH HN NH N H H N N N N O N N H O N HN NH N HN N (-)-quadrigemine C (-)-psycholeine (-)-physostigmine

Scheme 2.5. Overman’s Asymmetric Heck Cyclization and Target Compounds

33 Shibasaki27 and coworker also reported a synthesis based on asymmetric Heck

cyclization. Stereoselective synthesis of analgesic (-)-eptazocine, which was previously

synthesized by Meyers28 using a diastereoselective alkylation, was successfully demonstrated (Scheme 2.6).

Shibasaki's intramolecular Heck reaction

OTBDPS Pd(0) MeO HO N OTBDPS (R)-BINAP MeO OTf (-)-eptazocine 90 % (90 %ee)

Meyer's diastereoselective alkylation

iPr iPr O N O N Ph(Me)2SiLi MeO MeO SiMe2Ph MeO Ether, THF

79 % (dr > 20:1) 18a

Scheme 2.6. Two Representative Syntheses of (-)-Eptazocine

Enantioselective synthesis of (-)-physostigmine and related compounds is one of the most important goal, because of two reasons. One is that these compounds have a potent inhibitory activity to acetylcholine esterase, which is a medicinal target to develop

human brain related diseases such as Alzheimer’s disease.29,30 Another one is that (-)-

34 physostigmine is the simplest natural product which has pyrrolidinoindoline core with an all-carbon chiral quaternary center.

Current catalytic conditions require drastic reaction conditions such as high temperature and use of a large amount of catalysts.22,23 In general, the reaction used more than 10 mol% of catalysts, and the enantiomeric excess was only about 80 %. The most vulnerable aspects of Heck cyclization is that only a Z-alkene gives relatively high enantioselectivity, which means that clean conversion to the Z-alkene is indispensable to obtain a better enantioselectivity. Besides, it needs other appropriately placed groups to control the position of the olefin in a cyclized product. Extensive Pd-catalyzed isomerizations after a cyclization need to be controlled.

2.1.7. Miscellaneous

In addition to the reactions discussed here, there are many other reactions such as organocatalytic Micheal reactions,31 other metal catalyzed C-C bond formations,2,32 and many new approaches that have been developing in these days. Due to the relevance of the compound, reports related to enantioselective syntheses of this compound are plentiful. Among them, syntheses based on intramolecular asymmetric arylcyanation developed by Nakao and coworkers (Eq. 2.8)33 and an organocatalytic Micheal addition using Takamoto’s catalyst (Eq. 2.9)31 are distinctive.

35 O MeO CN Ni(COD)2 (10 mol%) MeO CN L* (20 mol%), DME N Ph P Fe (Eq. 2.8) N AlMe Cl (40 mol %) N 2 Me 2 Me 100 oC, 10 h 88 %, 96 %ee (R,R)-iPr-Foxap

NO2 S MeO NO2 MeO N NHAr O O H (Eq. 2.9) N Cat. (10 mol%) o N Ph(H C) (CH ) Ph Boc THF, - 15 C Boc 2 3 2 3 65 %, 96 %ee Takamoto's catalyst

2.1.8. Summary

Attempts to develop a truly efficient reaction to generate all-carbon chiral

quaternary centers have received a lot of attention recently. Until now, an alkylation of

a chiral enolate still is one of the most facile and efficient ways, albeit it needs additional

steps for adding and cleaving a chiral auxiliary for proper asymmetric induction. Recent

reports related to metal catalyzed approaches clearly show that it should be possible to

find alternative more efficient and economic ways.

Asymmetric hydrovinylation to generate all-carbon quaternary centers using

simple α-alkyl substituted styrenes has been proven to be one of the most efficient

methods.34 However, an application for the synthesis of natural products had not been realized at the outset of this research. Here, we describe our attempts to synthesize (-)- physostigmine and related compounds using Ni(II)-catalyzed asymmetric hydrovinylation of a vinylarene.

36 2.2. RESULTS AND DISSCUSION

In 2006, RajanBabu and Zhang reported Ni-catalyzed asymmetric hydrovinylation to generate all-carbon quaternary centers (Eq. 2.10).35 In this paper, it was reported that cationic Ni-phosphoramidite complexes, stabilized by

[AllylNiBr] , L,ethylene 2 When R is ethyl R R (Eq. 2.10) 96 %, 98 %ee NaBARF, CH 2Cl2

L L1 = L3 = 10 = Ph Ph Ph O O O P N P N P N O O O Ph Ph

BARF-anion when treated with α-alkyl-substituted styrene derivatives under atmospheric ethylene gas, catalyzed hydrovinylation with excellent yields and selectivities. As a logical extension of this work, we decided to explore an enantioselective synthesis of biologically active natural products containing all-carbon chiral quaternary centers such as (-)-physostigmine and its related compounds (Figure 2.1).

37 R R = H, (-)-desoxyeseroline OEt, (-)-eserethole

N N O CNHMe, (-)-physostigmine 2

Figure 2.1. Target Natural Products Containing an All-carbon Quaternary Center

2.2.1. First Generation Synthesis of (-)-Physostigmine

Ni-catalyzed hydrovinylation of a simple α-substituted styrene with a short alkyl group such as ethyl gave a quantitative yield and enantioselectivity to generate an all- carbon quaternary center (Eq. 2.10). A heteroatom-functionalized α-substituted styrene had not been studied for this reaction. In general, polar functional groups such as amines or alcohols in substrates can act as ligands for Ni(II)-complexes to decrease the catalytic reactivity and enantioselectivity of a catalyst. Therefore, appropriate functional groups suitable for further transformations should be selected.

In the first generation synthesis, a well-studied reductive cyclization of a

pyrrolidinone was chosen as an route to build the pyrrolidinoindoline core structure.

The pyrrolidine can be synthesized from a γ-aminobutyric acid (GABA) as shown in

Scheme 2.7. An unnatural GABA can be prepared enantioselectively by asymmetric

hydrovinylation of a functionalized styrene followed by oxidation of the double-bond

formed during hydrovinylation to the corresponding carboxylic acid. Hence, the

success of the first generation strategy will mainly depend on the HV step.

38 O Y Y N R1 OH N Y NR R N O 1 2 NHPG Unnatural GABA

Y I Y HV Y + X NR R R Sn X 1 2 3

Scheme 2.7. Retrosynthetic Analysis Based on Asymmetric Hydrovinylation

For studies of functional-group compatibility of hydrovinylation, it is necessary to prepare α-alkyl-substituted styrenes containing various functional groups such as protected alcohols, amines, and/or other functional groups that can be modified for further synthesis. Stille coupling of aryl iodides with vinyltin compounds is one simple way to prepare the desired styrenes for hydrovinylation. For this synthesis, several vinyltin compounds were prepared by hydroiodination of an acetylene,36 followed by the substitution of iodine in 2 by a tributyltin group to get the compound 3 (Scheme

2.8). The resulting TBS-protected vinyltin compound 3 was used to prepare the phthalimide-protected amine substrate (4b-e) and azide substrate (5d). Using the

39 1. TMSCl, NaI OH tBuLi, Et2O

2. TBSCl, Pyridine I OTBS Bu3SnCl Bu3Sn OTBS 1 3 34 % (2 steps) 2 72 %

HCl EtOH O 1.MsCl,TEA,CH2Cl2 Bu3Sn N 2. Phthalimide potassium salt Bu3Sn OH O 3a 4 91 % (from 3 to 4)

Scheme 2.8. Preparation of Vinyltin Compounds

vinyltin derivatives, desired substituted styrenes were synthesized by Stille reaction.

This gave moderate to good yields (39~70 %) of the products depending on the ortho- substituent of the aryl-group (Eq. 2.11). Ortho-substituted aryliodides gave the desired coupling product 3a, 4b, and 4c in lower yield (39~56 %) than non-substituted substrates

(63~70 %).

Y I 2 X Pd(PPh3)2Cl2,K2CO3 Y2 + X (Eq. 2.11) o Y1 Bu3Sn Et4NCl, DMF, 110 C Y1

MeO I MeO I Ar yliodide Vinyltin ab Bu3Sn NPhthalimide NMeBoc Br 4

MeO I MeO I BnO I Bu Sn OTBS Bu Sn N 3 3 3 3 c d e 5 NO 2

40 With the substrates in hand, asymmetric hydrovinylation was explored.

Substrates bearing a TBS-ether (3d) and an azide (5d) did not react under general

conditions (Table 2.1, entries 1-3). Phthalimide-protected substrates (4d-e) gave consistently good yields of hydrovinylation products with a small amount of isomerized

starting olefin (Table 2.1, entries 4-8). Hydrovinylation of OBn substrate 4e gave 69 % of the desired hydrovinylation product 6 with isomerized starting material 4e’ (Eq. 2.12).

However, ortho-substituted substrates (3a, 4b, and 4c) failed to react (Table 2.1, entries 9-

13).

BnO NPhth 69 % BnO [AllylNiBr]2, L3, NaBARF 6 NPhth + (Eq. 2.12) o CH 2Cl2,35 C 4e BnO NPhth 15 % 4e'

Enantiomeric excess of the product 6 was determined by the derivatization of N-phthalimide as a Mosher’s amide (Eq. 2.13). The enantioselectivity was later confirmed by chiral HPLC separation of another advanced intermediate 9 (Scheme 2.9).

In sharp contrast to the hydrovinylation of simple hydrocarbons, the functionalized substrate 4e just gave only moderate enantioselectivities in reactions using three different ligands (Table 2.2).

O CF3 BnO 1. Hydrazine, EtOH, reflux BnO NPhth N ∗ H OMe (Eq. 2.13) Ph 6 2. MTPA-Cl, TEA, CH2Cl2 6-MTPA MTPA-Cl: alpha-methoxy-alpha-(trifluoromethyl)phenylacetyl chloride 41

Entry Substrates Ligandsd & Conditionsa Isolated yields

b 1 L3, rt, 12 h, 1 atm NR O OTBS o 2 3d L3, 35 C, 12 h, 1 atm NR

O c 3 N3 L3 , rt, 12 h, 1 atm Trace (<5%) 5d

o 4 L3, 35 C, 12 h, 1 atm 47% O NPhth o 5 4d L1, 35 C, 12 h, 1 atm 81%

o 6 L1, 35 C, 12 h, 1 atm 76%

BnO 7 NPhth L3, rt, 12 h, 1 atm 68% 4e o 8 L10, 35 C, 12 h, 1 atm 69%

O OTBS o 9 L1, 35 C, 12 h, 1 atm NR N Boc 3a

10 L , 35 oC, 12 h, 1 atm NR O 1 NPhth

11 Br 4b L1, rt, 30 min, 17 psi NR

o 12 O L1, 35 C, 12 h, 1 atm NR NPhth

13 NO2 4c L1, rt, 30 min, 17 psi NR

a 5 mol% of [(allyl)NiBr]2, 10 mol% of Ligand, and 10 mol% of NaBARF were used. b NR = Starting material was recovered. c 2.5 mol% of [(allyl)NiBr]2, 5 mol% of Ligand, and 5 mol% of NaBARF were used. d See Eq. 2.10 or footnote c in Table 2.2 for the structures of the ligands.

Table 2.1. Hydrovinylation of Various Substrates

42 Ligandsc Hydrovinylation (yields) ee %

b a L1 76 % 55 (53 )

b L3 68 % 61

a L10 69 % 50

a determined by chiral HPLC separation of pyrrolidinone 9. b determined by 19F NMR of N-MTPA derivative of hydrovinylation product 6. c Ph Ph Ph Sc O O O Ra P N Ra P N P N O O O Sc Ph Ph Sc

L (ScSc) L (RaScSc) L (RaSc) 1 3 10

Table 2.2. Enantioselectvities of Hydrovinylation of 4e

The optimized conditions for the HV of phthalimide-protected substrate 4e gave the desired product 6 in consistent yields. The resulting olefin was oxidatively cleaved into carboxylic acid 7 by a Ru-catalyzed reaction (Scheme 2.9). Asymmetric synthesis of unnatural GABA (7) itself could be medicinally valuable. Natural GABA is present in 60 - 70 % all synapses in the central nervous system (CNS) and is the major inhibitory neurotransmitter in CNS.37 So unnatural GABA analogs have been developed for potential therapeutic applications in neurological disorders such as epilepsy.38 Especially, chiral α-substituted GABA analogues have received much attention because of the importance of chirality39 and effects of a phenyl-substituent.40

43 OH Bn NPhth [(allyl)NiBr]2,L3. Bn NPhth Bn O NPhth NaBARF, CH 2Cl2 RuCl3,NaIO4 O O O Ethylene, CH2Cl2 CCl4,H2O,CH3CN 35 oC, 2 d 30 oC, 12 h 4e 7 68 %, 61 %ee 6 76 % MeI, K2CO3 Acetone 80 % reflux, 12 h

Bn Bn OMe N NaH, MeI NH H2NNH2,EtOH Bn O NPhth O O O THF, rt, 1 h 90 oC, 2 d O O 95 % 83 % 10 9 8

Scheme 2.9. Further Synthesis for the Preparation of the Pyrrolidinones 9 and 10 (see

Table 2.2 for structure of L3)

After esterification, the resulting compound 8 was converted into

corresponding pyrrolidinone 9 by one-pot deprotection and cyclization reaction under

high temperature (Scheme 2.9). The pyrrolidinone 9 was easily analyzed by chiral

stationary phase HPLC (Table 2.2) and the enantioselectivities were determined. Aryl-

Bn Bn N NH O NBS, CHCl3 O + Regioisomeric mixture (Eq. 2.14) O rt, 5 d O 25 % 10 Br 75 % 11

R R R NH O N NH Nitration O NaH, MeI O (Eq. 2.15) O O O THF, rt, 1 h NO 2 >99% NO2 9 (R=Bn) 12a (R=Bn) 13a (R=Bn) 12b (R=Me) 13b (R=Me)

44 substituent of the pyrrolidione 9 was derivatized either by regioselective Bromination (Eq.

2.14) or nitration (Eq. 2.15) to get more functionalized cyclic GABAs (11 and 12a). The nitro derivative 13b has been used as a key intermediate for the synthesis of several natural products and their derivatives.41,42 During the nitration, OBn-substrate using

HNO3/Ac2O in CCl4 gave an improved yield (33 % of 12a and 67 % of regioisomeric

mixture) to the desired para-nitrated compound 12a compared to reported OMe-

substituted substrate (19 %).41 The reported absolute configuration of 12b (OMe) was

41,42 matched with the sign of [α]D of the nitrated compound 12a. This still needs further

improvements. Further synthesis of nitro compound to the target had been well-

studied.41

2.2.2. Summary of the First Generation Synthesis

Substituted styrenes with α-functionalized side-chains were synthesized by

Stille coupling in moderate to good yields. These compounds were subjected to

asymmetric hydrovinylation to generate all-carbon chiral quaternary centers.

Phthalimide-protected substrate with no ortho-substituents gave the desired HV-products with good yields and moderate enantioselectivities under slightly elevated temperature.

Using the HV-products, a new class of enantio-enriched 3-phenyl substituted GABA were synthesized. Also, it was shown that an acyclic GABA derivative can be converted into a pyrrolidinone, a cyclic GABA. A 3-methoxyphenyl derivative is a known key intermediate for the synthesis of (-)-physostigmine. Although this study showed that a hydrovinylation-based approach for the total synthesis of the target natural products has potential, further improvements in efficiency and enantioselectivity are needed.

45 2.2.3. Second Generation Synthesis of (-)-Physostigmine

In the first generation synthesis, moderate enantioselectivities of hydrovinylation

and low regioselectivities of the nitration decreased the overall efficiency. Further

studies were undertaken to solve the problems in the first synthetic strategy. In the

second generation, the main idea was to start with a cyclic substrate for the key

hydrovinylation reaction.

In previous studies,35 it was shown that cyclic substrates gave much better

enantioselectivities compared to linear alkyl-chain substituted styrenes (Scheme 2.10).

The synthetic analysis in this approach would suggest starting with bicyclic exomethylene compound with the appropriate functionalities (Scheme 2.11).

C H C5H11 5 11 L = 3 Ph 50 %ee [(allyl)NiBr]2, L3,ethylene O P N NaBARF, CH2Cl 2 O Ph

>95%ee

Scheme 2.10. Linear Versus Cyclic Vinylarenes for Hydrovinylation

46 RO R' NPhth X

st RO nd R' RO 1 generation 2 generation NPhth N N X 50 ~ 60 %ee ?? %ee

Scheme 2.11. First and Second Generation Approaches to Pyrrolidinoindolines

According to these plans, an oxygen-containing cyclic substrate (X = O), 4- methylenechroman (14) was prepared by a reported procedure using iodonium-induced electrophilic cyclization followed by DBU-mediated dehydroiodination (Scheme 2.12).

Alternatively a seleniranium-ion triggered cyclization followed by oxidation that will be discussed in later chapter can be used for the synthesis of this compound. Although there are many other types of reactions that could be used for preparing the 4-methylene- heterocycles, electrophilic cyclization of heteroatom-tethered alkenes followed by a double bond generation is one of the most selective ways to synthesize the desired heterocycles for hydrovinylation.

47 X

OH IP y2BF4,HBF4 DBU o OH DIAD, PPh3 CH2Cl2,-80 C CH 2Cl2 O O THF O 76 % 83 % 83 % 14c 14b 14

[(all yl)Ni Br] 2, L3, NaBARF, CH2Cl2 ethy lene, 30 oC, 2d

OTBDPS 1. TBDPSCl OH Rh(PPh3)3Cl SM + 2. BI ,CHCl Catechol borane (95 %) OH I 3 2 2 O O 5% 15 79 % 14a 16a 77 % TIPSCl Yield = 70 % TEA, CH2Cl2 ee % = 93.8 (GC)

O OTIPS BI3,TEA

CH2Cl2 16 O 15a OH 45 %

Scheme 2.12. Second Generation Approach to Pyrrolidinoindolines: Synthesis and

Hydrovinylation of 4-Methylenechroman (14)

Using freshly prepared 4-methylenechroman (14), asymmetric hydrovinylation was attempted (Scheme 2.12). Hydrovinylation using Feringa ligand (L3) gave the desired product 14a in a good yield and an excellent enantioselectivity with ~ 15 % of dimer (70 %, 93.8 %ee). The enantioselectivity was determined by chiral stationary phase gas chromatography, and configuration of the chiral center was established as R based on the initial hydrovinylation report.35 The next step of the synthesis is ring- opening of the hydrovinylated-heterocycle 14a. However, none of general methods that

48 have been reported for the ring-opening reactions have been successful. Under most of known ether cleavage conditions such as trimethylsilyl iodide or strong acid such as HBr, the vinyl-group does not survive. Therefore, the compound 14a was converted into the alcohol 15 by hydroboration using Wilkinson’s catalyst.28 Simple hydroboration using

9-BBN followed by oxidation did not give the desired alcohol. This was followed by protection of the alcohol as a triisopropylsilyl ether. Typical ring-opening reaction of the

TIPS-ether 15a with BBr3 only gave free alcohol 15 without any opened product.

Boron triiodidie gave 6-membered ether 16 by deprotection, ring-opening, and re-closing in a different direction. So the protecting group was changed to a more robust t-butyldiphenylsilyl (TBDPS) group and the same reagent was tested. The desired ring opening product 16a was obtained in small yield and most of starting ether was recovered

(Scheme 2.12). Hence, a new method for the ring-opening reactions is needed before this strategy can be implemented.

2.2.4. Summary of the Second Generation Synthesis

The problem of moderate enantioselectivity in the first generation synthesis using linear substrates has been solved by applying cyclic substrates. As an oxygen-containing cyclic vinylarene, 4-methylenechroman gave the desired HV-product with a good yield and excellent enantioselectivity, but attempts to open the 6-membered ether-ring were unsuccessful.

2.2.5. Third Generation Synthesis of (-)-Physostigmine

Beckman or Schmidt ring expansions of α-tetralone derivatives for the

49 preparation of diverse benzoazepinones have been a well-established synthetic strategy.43,44 In the third generation synthesis, a ring expansion/contraction strategy will

be applied to insert an amine group at ortho-position of a HV product of a

tetrahydronaphthalene. The plan is to convert the resulting amine containing

intermediate into an oxindole (Scheme 2.13).

MeO CO2Me O N O N N N H O

Scheme 2.13. Third Generation Approach to Pyrrolidinoindolines: Ring

expansion/Contraction

Starting with commercially available α-tetralones, 4-methylenetetrahydro-

naphthalenes were prepared (Eq. 2.16). Following the reported procedure,45 H- (17),

OMe- (17a), and Br-substituted substrate (17b) were synthesized in good yields.

Asymmetric HV of various 4-methylene tetrahydronaphthalenes were attempted, and the results are shown in Table 2.3. Note that HV of a 7-methoxy derivative 17a give essentially a single enantiomer (18a), which is a known key intermediate for asymmetric

50 O 17 (R = H): reported R MePPh3 R 17a (R = OMe): 73 % (18 % of SM) (Eq. 2.16) nBuLi, THF 17b (R = Br): 80 % R = H,Br,OMe

formal synthesis of analgesic (-)-eptazocine shown in Scheme 2.6. Compared to the

previous asymmetric syntheses of this compound 18a, asymmetric hydrovinylation does

not need inherent chirality such as a chiral starting material or a fixed geometry of a double bond for an asymmetric Heck reaction. 7-Bromo derivative 17b gave

isomerized starting material 18b’ as a major product with a small amount of HV product.

[(allyl)NiBr] , L R 2 3 R R + NaBARF, CH2Cl 2 ethylene (1 atm) 17 (R = H) 18 (R = H) 18' (R = H) 17a (R = OMe) 18a (R = OMe) 18a' (R = OMe) 17b (R = Br) 18b (R = Br) 18b' (R = Br) Entry Substrates (R) Conditions Yields (%ee)

1 17 (H) - 70 oC, 6 ha 71 %c (>99)

2 17b (Br) rt, 12 h 9 %d (--)

3 17a (OMe) - 70 oC, 6 hb 82 %e (>99)

a b [(allyl)NiBr]2 (1 mol%), L3 (2 mol%), and NaBARF (2 mol%) were used.; [(allyl)NiBr]2 (2 mol%), c L3 (4 mol%), and NaBARF (4 mol%) were used.; A mixture of isomerized olefin 18’ (28 %), and HV product 18b (71 %).; d A mixture of SM 17b (45 %), isomerized olefin 18b’ (45 %), and HV product 18b (9 %).; e A mixture of SM 17a (3 %), isomerized olefin 18a’ (15 %), and HV product 18a (82 %).

Table 2.3. Asymmetric HV of 4-Methylene Tetrahydronaphthalenes

51 In the third generation approach to pyrrolidinoindolines, we started with Wittig olefination of α-tetralone to get 4-methylenetetrahydronaphthalene (Scheme 2.14).

Asymmetric hydrovinylation of this compound 17 gave the desired hydrovinylation product 18 in 70 % yield and > 99 %ee. The vinyl-group was oxidatively cleaved by

Ru-catalyzed oxidation, and the resulting acid 19a was converted into corresponding methyl-ester 19. The benzylic position was oxidized by CrO3 and the ring was

expanded to a 7-membered lactam ring under either the Beckamn43 or the Schmidt46 reaction conditions (Scheme 2.15).

O MePPh3 [(allyl)NiBr]2, L3, ethylene o nBuLi, THF CH2Cl2,- 78 C, 6 h 70 %, > 99 %ee 17 18

RuCl3,NaIO4 CCl4,AcCN,H2O

MeO MeO O O MeO HO O O H2NOH, Py. CrO3 MeI, NaH

EtOH, Reflux Ac2O, AcOH THF 89 % >99% 88 % 21 NOH 20 O 19 (2 steps) 19a

Scheme 2.14. Third Generation Synthesis

52 Interestingly, Beckman rearrangement procedure using oxime 21 gave only aryl- migration product with an excellent yield (Scheme 2.15). However, Schmidt reaction with ketone 20 gave a mixture of aryl- and alkyl-migration products. Beckman reaction with O-tosyl oxime 21a did not give any rearrangement product.

The desired phenyl-migration product 22 was N-methylated using methyl iodide and sodium hydride. The resulting benzazepinone 23 was purified by recrystallization that gave highly crystalline material analyzed by X-ray crystallography (Figure 2.2 and

Table 2.4). The absolute configuration of all-carbon quaternary center should be R-

configuration to match the reported configuration in the chiral center in (-)-

desoxyeseroline. X-ray crystallography can not be used to determine absolute

configuration due to the absence of a heavy atom in the structure. However, the

absolute configuration was established by conversion of 24 into (S)-(-)-desoxyeseroline

(Scheme 2.16).

MeO MeO MeO O O O Conditions 20 (X = O) + NH 21 (X = NOH) N 21a (X = NOTs) X H O 22O 22a

o Schmidt (X= O,NaN3,PPA,60 C, 24 h) - 51 % 35 % Beckman (X = NOH, PPA, 110 oC) - 88 % (only) o Beckman (X= NOTs, CF3CO2H, 60 C) - No desired product

Scheme 2.15. Beckmann vs Schmidt Ring Exansions

53

C12 C14 C2 C10 C3 C13 C1 C4 MeO C6 C9 O C5 C11

N C8 O C7 23

Figure 2.2. Ortep Plot of 23

Entry Bonds Lengths Entry Bonds Angles

1 C(6)-N 1.4358(17) 1 C(6)-N-C(7) 122.40(11)

2 C(7)-N 1.3714(18) 2 C(1)-C(10)-C(13) 111.03(11)

3 C(7)-O(1) 1.2282(16) 3 C(1)-C(10)-C(9) 109.64(11)

4 C(10)-C(13) 1.5366(19) 4 O(1)-C(7)-N 121.18(13)

5 C(1)-C(10) 1.5194(19) 5 C(13)-C(10)-C(12) 104.37(11)

Table 2.4. Selected Bond Lengths and Angles of the 7-Membered Lactam 23

54 Subsequent transformations of 22 are shown in Scheme 2.16. Acid-mediated

hydrolysis of recrystallized N-methyl compound 23, gave the thermally more stable oxindole 24 in an excellent yield. The terminal carboxylic acid unit was converted into an ethyl carbamate 25 via a Curtius rearrangement using diphenylphosphoryl azide

(DPPA) in refluxing ethanol. The resulting compound was cyclized as well as reduced to the desired (-)-desoxyeseroline by LAH (Scheme. 2.16). The transformation of (-)- desoxyeseroline to (-)-physostigmine has been reported in literatures.41,47

MeO MeO O O O MeI, NaH conc. HCl OH THF, rt AcOH, reflux O N N N 95 % O 95 % 24 H O (82 % after recryst.) 22 23 DPPA 74 % EtOH, reflux

MeHN O NHCO2Et N reported N LAH O N N O THF N 25 (-)-physostigmine (-)-desoxyeseroline 57 %

Scheme 2.16. Further Synthesis Toward the Target

55 2.2.6. Summary of the Third Generation Synthesis

Overall, the ring expansion/contraction strategy that follows an asymmetric

hydrovinylation has been successfully applied for an asymmetric synthesis of (-)-

desoxyeseroline and a formal total synthesis of (-)-physostigmine. The enantioselective

construction of an all-carbon quaternary center proceeds with near perfect asymmetric

induction and subsequent reactions are easy to execute for an efficient synthesis of

several pyrrolidinoindolines.

2.2.7. Beckman Rearrangement of the Oxime 26a: A New Synthesis of Pyrrolo[1,2-

a]indoline

Using the enantiopure HV product 18, oxime 26a was prepared by the same sequence that was used before (Scheme 2.17). The resulting oxime 26a was treated

CrO3,AcOH NH2OH

Ac2O Pyridine, EtOH 68 % O N 18 26 94 % 26a OH

PPA 110 oC

N

27 O N H O

Scheme 2.17. Synthesis of Oxime 26a and its Beckman Ring Expansion Reaction

56 with polyphosphoric acid under 110 oC for Beckman ring expansion. This reaction gave a quite clean unexpected product in moderate yield without any desired product.

The structure of unexpected compound 27 was confirmed by NMR and X-ray crystallography (Figure 2.3 and Table 2.5).

X-ray analysis indicated that the compound was a racemic mixture, even though the starting oxime 26 was enantiopure. Since the space group is P2(1)/n, which contains an inversion center, both enantiomers are present in the crystal. This racemization of the quaternary center indicated that one of C-C bonds connected to the quaternary center was cleaved during the reaction.

C12 C13

C11 C1 C9 C2 C8 C10

C5 C3 C7 N C4 C6 O Racemic mixture

Figure 2.3. Unexpected Ring Expansion Product 27 and its Ortep Plot

57

Entry Bonds Lengths Entry Bonds Angles

1 C(1)-N 1.4874(16) 1 N-C(1)-C(13) 108.78(10)

2 C(4)-O 0.9900 2 O-C(4)-N 125.49(13)

3 C(4)-N 1.3556(16) 3 C(4)-N-C(5) 132.33(11)

4 C(5)-N 1.4110(16) 4 C(10)-C(11)-C(1) 102.15(10)

5 C(1)-C(11) 1.5480(18) 5 C(2)-C(1)-C(11) 118.49(11)

Table 2.5. Selected Bond Lengths and Angles of Unexpected Cyclization Product 27

A potential mechanism for the unexpected tandem reaction sequence is shown in

Scheme 2.18. After Beckman ring expansion, the carbocation in 26c was generated by addition of a proton to the double bond in 26b under the strongly acidic conditions. The phenyl group migrated to form a more stable tertiary carbocation (26d). Further intramolecular amination of 26d and the subsequent deprotonation of 26e led the tricyclic heterocycle. That is, two different ring expansions – Beckman rearrangement and 1,2- aryl migration – occurred, followed by trapping of the resulting tertiary carbocation by an internal nucleophile.

58 H Beckman Rearrangement Protonation

N N N H O H O 26a OH 26b 26c

1,2-aryl migration

Intramolecular Deprotonation Amination N N+ H N H 27 O 26e O 26d O

Scheme 2.18. Proposed Mechanism of the Unexpected Tandem Reaction

2.3. Summary

Asymmetric total synthesis of (-)-desoxyeseroline was achieved using catalytic asymmetric hydrovinylation as a key step to generate the all-carbon chiral quaternary center in this molecule. In the first generation, functionalized styrenes were prepared and tested for hydrovinylation. Phthalimide-protected ethyl amine substituted styrenes were compatible with hydrovinylation. The reaction proceeded in a moderate yield and enantioselectivity. Based on this substrate, formal synthesis of the target compound was performed via a γ-aminobutyric acid (GABA) as a key intermediate. The GABA was converted into a pyrrolidinoindoline, followed by nitration to get a known intermediate for the target compound. In order to improve enantioselectivity and efficiency of further synthesis, cyclic HV substrates were tested. Most of cyclic substrates gave excellent enantioselectivities with good yields. However, chroman-type HV product was not easy

59 to manipulate for the further synthesis. In the third generation synthesis, a ring expansion/contraction strategy was adapted to efficiently convert the simplest cyclic HV product that nearly gave perfect enantioselectivity to the desired target by Beckman ring expansion of 3,3’-dialkyltetralone to a 7-membered benzazepinone. The 7-membered amide was converted into 5-membered oxindole under hydrolysis condition. Those reaction conditions efficiently converted the almost enantiopure simple HV product to

(-)-desoxyeseroline in excellent chemical yields. Also, the same ring-expansion strategy was tested on the vinyl-group containing oxime. During the Beckman rearrangement, an unexpected tandem Beckman ring expansion/1,2-aryl migration/intramolecular amination occurred. Formation of the pyrrolo[1,2-a]indoline structure was confirmed by X-ray crystallography.

60 2.4. EXPERIMENTAL PROCEDURES

General Information.

All solvents were dried by standard methods prior to use. Methylene chloride

was distilled from calcium hydride under nitrogen and stored over molecular sieves.

Tetrahydrofuran was distilled under nitrogen from sodium/benzophenone ketyl.

Reactions requiring air-sensitive manipulations were conducted under an inert

atmosphere of nitrogen by using Schlenk techniques or a Vacuum Atmospheres glovebox.

+ - 48,49 48,50 Reagents such as Na [3,5-(CF3)2C6H3]4B] (NaBARF) and [(allyl)NiBr]2 were prepared according to the literature. Ligands for hydrovinylation, [(allyl)NiBr]2, and

NaBARF were stored in a Vacuum Atomspheres drybox. Ethylene (99.5%) was purchased from Matheson Inc., and passed through Drierite before use. Analytical TLC was performed on E. Merck precoated (0.25 mm) silica gel 60 F254 plates. Flash column chromatography was carried out on silica gel 40 (Scientific Adsorbents

Incorporated, Microns Flash). NMR experiments were performed using CDCl3 with

CHCl3 (δ 7.24) as an internal standard. Enantiomeric excesses of chiral compounds 14a,

18, and 18a were determined by gas chromatographic analyses on chiral stationary phase, which were performed on a Hewlett-Packard 5890 equipped with Cyclodex B (25 m x

0.25 mm, 0.12 mm film thickness) capillary GC column purchased from Chrompack.

Helium was used as the carrier gas. For the determination of the enantiomeric excess of

6, 19F NMR using the corresponding Mosher amide of the amine derived from the

deprotection of 6 was used. For 9, liquid chromatographic analysis on chiral stationary

phase was used, which were performed on Shimadzu SPD-10AV equipped with OJ-H

61 column. Optical rotations were recorded on a Perkin-Elmer Model 241 polarimeter at

the sodium D line in chloroform.

Synthesis of tert-butyl(3-iodobut-3-enyloxy)dimethylsilane (2). OTBS HO I

To a stirred solution of NaI (6.0 g, 40 mmol) in CH3CN (30 mL) was added

TMSCl (5.1 g, 40 mmol), followed by H2O (0.36 ml, 20 mmol). After 10 min, 3-

butyne-1-ol (1.4 g, 20 mmol) in CH3CN (5 ml) was added to the mixture. The resulting reaction mixture was stirred for 1 h, and then the reaction was quenched with water (60

ml) and the product was extracted by ether (3*50 mL). The combined organic layers

were dried over MgSO4 and evaporated. To this crude alcohol in CH2Cl2 (25 ml), pyridine (3.2g, 40 mmol) and TBSCl (5.4 g, 36 mmol) were added at 0 oC successively.

The resulting mixture was stirred at rt for 1 day, and then the reaction was quenched with water (60 mL) and extracted by ether (3*50 mL). The combined organic layers were

dried over MgSO4 and evaporated, and the crude product was purified by column (2.1 g,

1 34 %, colorless oil). H NMR δ (CDCl3): 6.05 (s, 1H, R=CH2), 5.73 (s, 1H, R=CH2),

3.72-3.69 (t, 2H, J = 6.4 Hz, RCH2CH2OTBS), 2.58-2.55 (t, 2H, J = 6.4 Hz,

13 RCH2CH2OTBS), 0.87 (s, 9H, tBu), 0.50 (s, 6H, RSi(CH3)2); C NMR δ (CDCl3): 127.6,

107.8, 61.9, 48.6, 26.1, 18.5, -5.0; IR cm-1 (neat) : 2954, 2928, 2856, 1616, 1471, 1387,

1360, 1257, 1104, 1033, 926, 894.

62 tert-butyldimethyl(3-(tributylstannyl)but-3-enyloxy)silane (3).

OTBS OTBS

I Bu3Sn The vinyliodide 2 (3.0 g, 9.6 mmol) was dissolved in ether (20 ml), and the

solution was cooled to - 78 oC. tBuLi (12.9 mL, 1.5 M in pentane) was slowly added to

the mixture, and the reaction mixture was stirred for additional 10 min. To this lithiated

compound, nBu3SnCl in ether (20 mL) was added dropwise, and the mixture was stirred

at the same temperature for 15 min. After the reaction was quenched with water (10

mL), the crude product was extracted by ether (3*30 mL). The combined organic layers

were dried over MgSO4 and evaporated, and the crude product was purified by column

1 (3.3 g, 72 %, colorless oil). H NMR δ (CDCl3): 5.89-5.55 (dd, 1H, JSn-H = 66.4 Hz, JH-H

= 2.8 Hz, R=CH2), 5.25-5.09 (dd, 1H, JSn-H = 29.6 Hz, JH-H = 2.8 Hz, R=CH2), 3.63-3.59

(t, 2H, J = 7.6 Hz, RCH2CH2OTBS), 2.48-2.45 (t, 2H, J = 7.6 Hz, RCH2CH2OTBS),

1.52-1.44 (m, 6H, RSnBu3), 1.35-1.26 (m, 6H, RSnBu3), 0.91-0.85 (m, 24H, RSnBu3 &

13 tBu), 0.04 (s, 6H, RSiMe3); C NMR δ (CDCl3): 151.2, 127.4, 63.6, 44.8, 29.4, 27.7,

26.2, 18.6, 13.9, 9.8, - 5.0; IR cm-1 (neat) : 2955, 2926, 2855, 1462, 1376, 1255, 1096,

1005, 916.

2-(3-(tributylstannyl)but-3-enyl)isoindoline-1,3-dione (4).

OTBS Bu Sn NPhth Bu3Sn 3 TBS-protected alcohol 3 (0.5 g, 1.05 mmol) in EtOH (5 mL) was treated with 3

N HCl (2 ml). After 10 min stirring, CH2Cl2 (10 mL) and water (10 mL) were added to

the mixture, and organic layer was separated. The aqueous layer was extracted with

63 CH2Cl2 (10 mL*2) additionally, and the combined organics was dried over MgSO4 and

evaporated. The crude alcohol was dissolved in dry THF (10 mL), and then PPh3 (1.11 g,

4.2 mmol) and phthalimide (0.62 g, 4.2 mmol) were added to the solution. After the

mixture was cooled to 0 oC, diisopropyl azodicarboxylate (0.85 g, 4.2 mmol) was slowly

added. The resulting mixture was stirred at rt for 12 h. The solvent was evaporated,

and then the crude product was purified by column chromatography (0.48 g, colorless oil).

1 H NMR δ (CDCl3): 7.82-7.78 (m, 2H, Ar), 7.70-7.67 (m, 2H, Ar), 5.97-5.65 (dd, 1H, JSn-

H = 64.0 Hz, JH-H = 1.2 Hz, R=CH2), 5.37-5.22 (dd, 1H, JSn-H = 29.6 Hz, JH-H = 0.8 Hz,

R=CH2), 3.71-3.68 (t, 2H, J = 7.8 Hz, RCH2CH2NPhth), 2.58-2.54 (t, 2H, J = 7.8 Hz,

RCH2CH2OTBS), 1.58-1.45 (m, 6H, RSnBu3), 1.35-1.26 (m, 6H, RSnBu3), 0.97-0.95 (m,

13 6H, RSnBu3), 0.93-0.91 (t, 9H, J = 4.8 Hz, RSnBu3); C NMR δ (CDCl3): 168.4, 151.1,

134.1, 132.4, 127.9, 123.3, 39.5, 38.0, 29.3, 27.6, 26.5, 13.9, 9.8; IR cm-1 (neat) : 2955,

2927, 2853, 1772, 1714, 1466, 1393, 1357, 1295, 1254, 1187, 1084, 1068, 1000.

General procedure of Stille coupling

A flask was charged with aryliodide (100 mol%), vinyltin (120 mol%),

Pd(PPh3)2Cl2 (5 mol%), K2CO3 (100 mol%) Et4NCl (100 mol%), and deoxygenated DMF,

and the resulting mixture was stirred at 110 oC overnight. After the reaction was

completed, the reaction was cooled to rt, and then the mixture was filtered through celite

pad to remove solid impurities. The crude product was extracted with EtOAc, dried

over MgSO4, and purified by column chromatography.

64 Synthesis of tert-butyl 2-(4-(tert-butyldimethylsilyloxy)but-1-en-2-yl)-4-methoxy- phenyl(methyl)carbamate (3a).

O I O OTBS + N Bu3Sn OTBS N Boc Boc Following the general procedure, the desired product was obtained as a pale

1 yellow solid (56 %, isolated yield). H NMR δ (CDCl3): 6.95-6.93 (d, 1H, J = 7.6 Hz,

Ar), 6.75-6.69 (m, 2H, Ar), 5.15 (s, 1H, vinyl), 5.02 (s, 1H, vinyl), 3.78 (s, 3H), 3.60-3.55

(m, 2H), 3.03 (s, 3H), 2.52-2.50 (m, 2H), 1.32 (s, 9H), 0.84 (s, 9H), -0.02 (s, 6H); 13C

NMR δ (CDCl3): 157.9, 155.3, 129.3, 114.9, 113.1, 79.7, 61.6, 55.4, 39.4, 28.3, 27.8,

26.8, 25.9, 18.2, -4.5.

Synthesis of tert-butyl(3-(3-methoxyphenyl)but-3-enyloxy)dimethylsilane (3d).

O I O + OTBS Bu Sn OTBS 3

Following the general procedure, the desired product was obtained as colorless

1 oil (70 %, isolated yield). H NMR δ (CDCl3): 7.31-7.27 (t, 1H, J = 7.8 Hz, Ar), 7.09-

7.02 (m, 2H, Ar), 6.89-6.86 (m, 1H, Ar), 5.40 (s, 1H, R=CH2), 5.17 (s, 1H, R=CH2), 3.85

(s, 3H, ArOMe), 3.80-3.77 (t, 2H, J = 7.2 Hz, RCH2OTBS), 2.81-2.78 (m, 2H,

13 RCH2CH2OTBS), 0.98 (s, 9H, tBu), 0.09 (s, 6H, Si(tBu)Me2); C NMR δ (CDCl3):

159.8, 145.4, 142.8, 129.4, 118.8, 114.2, 112.9, 112.2, 62.6, 55.3, 39.1, 26.1, 18.5, -5.2.

65 Synthesis of (3-(3-(benzyloxy)phenyl)but-3-enyloxy)(tert-butyl)dimethylsilane (3e).

BnO I BnO + OTBS Bu Sn OTBS 3

Following the general procedure, the desired product was obtained as colorless

1 oil (68 %, isolated yield). H NMR δ (CDCl3): 7.44-7.36 (m, 5H, Ar), 7.22-7.20 (d, 1H,

J = 8.0 Hz, Ar), 7.03-7.00 (m, 2H, Ar), 6.9-6.83 (m, 1H, Ar), 5.32 (s, 1H, R=CH2), 5.08 (s,

1H, R=CH2), 5.06 (s, 2H, benzylic), 3.71-3.67 (t, 2H, J = 7.2 Hz, RCH2OTBS), 2.72-2.68

13 (t, 2H, J = 7.2 Hz, RCH2CH2OTBS); C NMR δ (CDCl3): 159.0, 145.4, 142.9, 137.3,

129.6, 128.8, 128.2, 127.7, 119.1, 115.1, 114.3, 113.8, 113.3, 70.2, 62.6, 39.1, 26.1, 18.5;

IR cm-1 (neat) : 3064, 3031, 2952, 2927, 2855, 1598, 1574, 1495, 1462, 1380, 1288, 1253,

1096, 1041, 1027.

2-(3-(2-bromo-5-methoxyphenyl)but-3-enyl)isoindoline-1,3-dione (4b).

O I O + NPhth Bu3Sn NPhth Br Br

Following the general procedure, the desired product was obtained as colorless

1 oil (40 %, isolated yield). H NMR δ (CDCl3): 7.79-7.77 (m, 2H, Ar), 7.68-7.65 (m, 2H,

Ar), 7.35-7.33 (d, 1H, J = 8.8 Hz, Ar), 6.81-6.80 (d, 1H, J = 2.8 Hz, Ar), 5.21 (s, 1H,

R=CH2), 5.00 (s, 1H, R=CH2), 3.76-3.73 (m, 5H, ArOMe & RCH2NPhth), 2.85-2.82 (t,

13 2H, J = 7.0 Hz, RCH2CH2NPhth); C NMR δ (CDCl3): 168.3, 158.8, 146.6, 143.7, 134.0,

133.5, 132.2, 123.3, 117.8, 116.2, 114.9, 112.3, 55.6, 36.9, 34.9

66 Synthesis of 2-(3-(5-methoxy-2-nitrophenyl)but-3-enyl)isoindoline-1,3-dione (4c).

O I O NPhth + Bu3Sn NPhth NO2 NO2 Following the general procedure, the desired product was obtained as colorless

1 oil (39 % isolated yield). H NMR δ (CDCl3): 8.01-7.99 (d, 1H, J = 9.2 Hz, Ar), 7.81-

7.79 (m, 2H, Ar), 7.70-7.66 (m, 2H, Ar), 6.86-6.85 (d, 1H, J = 2.8 Hz, Ar), 6.83-6.80 (dd,

1H, J = 9.2, 2.8 Hz, Ar), 5.16 (s, 1H, R=CH2), 4.99 (s, 1H, R=CH2), 3.89 (s, 3H, ArOMe),

3.80-3.77 (t, 2H, J = 7.0 Hz, RCH2NPhth), 2.80-2.76 (t, 2H, J = 6.8 Hz,

13 RCH2CH2NPhth); C NMR δ (CDCl3): 168.4, 163.2, 144.9, 140.7, 134.3, 131.9, 127.5,

126.2, 123.4, 118.2, 116.6, 116.3, 113.7, 56.2, 37.0, 35.2; IR cm-1 (neat): 3085, 2943,

2848, 1770, 1722, 1601, 1574, 1514, 1392, 1336, 1249, 1187, 1096, 1064, 1027; HRMS

+• 353.1120 ((M+H ); 353.1137 calcd for C19H17N2O5).

Synthesis of 2-(3-(3-methoxyphenyl)but-3-enyl)isoindoline-1,3-dione (4d).

O I O + NPhth Bu Sn NPhth 3

Following the general procedure, the desired product was obtained as pale yellow

1 oil (63 %, isolated yield). H NMR δ (CDCl3): 7.80-7.78 (dd, 2H, J = 3.0, 2.4 Hz, Ar),

7.69-7.66 (dd, 2H, J = 3.0, 2.4 Hz, Ar), 7.22-7.18 (t, 1H, J = 8.0 Hz, Ar), 7.04-7.02 (d, 1H,

J = 7.6 Hz, Ar), 6.99 (s, 1H, Ar), 6.75-6.73 (dd, 1H, J = 8.0, 2.4 Hz, Ar), 5.37 (s, 1H,

R=CH2), 5.16 (s, 1H, R=CH2), 3.85-3.79 (m, 5H, ArOMe & RCH2NPhth), 2.91-2.88 (t,

13 2H, J = 7.2 Hz, RCH2CH2NPhth) ); C NMR δ (CDCl3): 168.1, 159.6, 144.9, 141.6,

133.8, 132.1, 129.3, 123.0, 118.6, 114.7, 113.1, 111.7, 55.2, 37.5, 34.0; IR cm-1 (neat) :

67 3072, 2941, 2835, 1770, 1712, 1598, 1576, 1488, 1466, 1434, 1394, 1359, 1328, 1287,

1230, 1187, 1120, 1087, 1047, 1001.; HRMS 308.1272 ((M+H+•); 308.1287 calcd for

C19H17NO3).

Synthesis of 2-(3-(3-(benzyloxy)phenyl)but-3-enyl)isoindoline-1,3-dione (4e).

BnO I BnO + NPhth Bu Sn NPhth 3

Following the general procedure, the desired product was obtained as pale yellow

1 oil (63 %, isolated yield). H NMR δ (CDCl3): 7.79-7.77 (dd, 2H, J = 5.4, 3.2 Hz, Ar),

7.67-7.65 (dd, 2H, J = 5.4, 3.2 Hz, Ar), 7.45-7.31 (m, 5H, Ar), 7.20-7.18 (t, 1H, J = 8.0

Hz, Ar), 7.05-7.01 (m, 2H, Ar), 6.81-6.78 (m, 1H, Ar), 5.33 (s, 1H, R=CH2), 5.12 (s, 1H,

R=CH2), 5.06 (s, 2H, ROCH2Ph), 3.83-3.79 (t, 3H, J = 7.4 Hz, RCH2NPhth), 2.88-2.85 (t,

13 2H, J = 7.2 Hz, RCH2CH2NPhth); C NMR δ (CDCl3): 168.2, 158.8, 144.8, 141.6, 137.1,

133.8, 132.1, 129.4, 128.6, 128.0, 127.6, 123.2, 118.9, 114.9, 114.0, 112.7, 70.0, 37.4,

34.0; IR cm-1 (neat): 3062, 3031, 2945, 2869, 1770, 1713, 1596, 1574, 1488, 1435, 1395,

1360, 1288, 1223, 1121, 1087, 1026, 1001.; HRMS 384.1583 ((M+H+•); 384.1600 calcd

for C25H22NO3).

Synthesis of 2 1-(4-azidobut-1-en-2-yl)-3-methoxybenzene (5d).

O O OTBS N3

To a stirred solution of OTBS compound 3d (50 mg, 0.017 mmol) in EtOH (2

mL) was added 1 N HCl (0.1 mL) and the resulting solution were stirred at rt for 1 h.

68 After the deprotection was completed, the mixture was diluted with water (3 mL) and

extracted CH2Cl2 (3 mL*3). Combined organic layers were dried over MgSO4, and then filtered and evaporated. The crude alcohol was dissolved in CH2Cl2 (3 mL) and added

o Et3N (59 μL, 0.042 mmol) and MsCl (16 μl, 0.021 mmol) at 0 C. The resulting mixture

was stirred at rt for 2 h. The solvent was evaporated, and the residue was dissolved in

DMF (2 mL) and added NaN3 (23 mg, 0.034 mmol). The resulting mixture was heated

to 60 oC for 12 h. The solution was diluted with water (5 ml), and the compound was

extracted with EtOAc (5 mL*3). After evaporation, the crude compound was purified

1 by preparative TLC (28 mg, 82 %, colorless oil). H NMR δ (CDCl3): 7.33-7.29 (t, 1H,

J = 8.0 Hz, Ar), 7.03-6.98 (m, 2H, Ar), 6.90-6.88 (dd, 1H, J = 4.0, 2.4 Hz, Ar), 5.44 (s, 1H,

R=CH2), 5.22 (s, 1H, R=CH2), 3.86 (s, 3H, ArOMe), 3.42-3.38 (t, 3H, J = 7.2 Hz,

13 RCH2N3), 2.85-2.81 (t, 2H, J = 7.0 Hz, RCH2CH2N3); C NMR δ (CDCl3): 159.9, 144.8,

141.8, 129.6, 118.7, 115.1, 113.1, 112.3, 55.4, 49.9, 35.2.

General procedure of hydrovinylation48

In a N2-charged drybox, Schlenk tube was charged with [(allyl)NiBr]2 (5 mol%),

ligand (10 mol%), and NaBARF (10 mol%), and then mixture was dissolved in dry

CH2Cl2 (5~7 mL/mmol of olefin). The prepared catalyst was stirred at rt for 10 min,

and then taken out. After ethylene line was connected to the reaction vessel, the line

was evacuated 3 times to remove oxygen in a line, and then ethylene was introduced to

the vessel. Into the solution of the activated pre-catalyst, starting olefin in dry CH2Cl2

(1~2 mL/mmol of olefin) was added, and the resulting mixture was stirred at ambient temperature under the atmospheric pressure of ethylene. After the reaction, the solvent

69 was evaporated, and the crude product was purified by column chromatography.

Synthesis of (R)-2-(3-(3-methoxyphenyl)-3-methylpent-4-enyl)isoindoline-1,3-dione

(6d).

O O NPhth NPhth

o Following the general procedure using L1 as a ligand under 35 C for 12 h, the desired product was obtained (81 %, isolated yield, pale yellow oil). 1H NMR δ

(CDCl3): 7.74-7.72 (m, 2H, Ar), 7.67-7.63 (m, 2H, Ar), 7.15-7.11 (t, 1H, J = 8.0 Hz, Ar),

6.92-6.87 (m, 2H, Ar), 6.59-6.56 (dd, 1H, J = 8.0, 2.4 Hz, Ar), 6.09-6.02 (dd, 1H, J = 11.2,

6.0 Hz, RCH=CH2), 5.15 (s, 1H, RCH=CH2), 5.12-5.10 (d, 1H, J = 8.0 Hz, RCH=CH2),

3.76 (s, 3H, OMe), 3.64-3.60 (t, 2H, J = 8.0 Hz, RCH2NPhth), 2.24-2.18 (m, 1H,

13 RCH2CH2NPhth), 2.10-2.05 (m, 1H, RCH2CH2NPhth), 1.46 (s, 3H, RCH3); C NMR δ

(CDCl3): 168.4, 159.6, 147.9, 145.9, 133.9, 132.4, 129.4, 123.2, 119.1, 112.9, 112.7,

111.2, 55.3, 43.5, 38.6, 34.8, 25.2; IR cm-1 (neat): 3072, 2930, 2837, 1772, 1707, 1601,

1484, 1396, 1366, 1284, 1249, 1172, 1049.

Synthesis of (R)-2-(3-(3-(benzyloxy)phenyl)-3-methylpent-4-enyl)isoindoline-1,3- dione (6).

BnO BnO NPhth NPhth

o Following the general procedure using L1 as a ligand under 35 C for 12 h, the desired product was obtained (76 %, isolated yield, pale yellow oil). 1H NMR δ

70 (CDCl3): 7.76-7.74 (m, 2H, Ar), 7.66-7.63 (m, 2H, Ar), 7.44-7.30 (m, 5H, Ar), 7.16-7.12

(t, 1H, J = 8.0 Hz, Ar), 6.96-6.92 (m, 2H, Ar), 6.67-6.65 (m, 1H, Ar), 6.08-6.01 (dd, 1H, J

= 10.8, 6.0 Hz, RCH=CH2), 5.15 (s, 1H, RCH=CH2), 5.12-5.10 (d, 1H, J = 8.0 Hz,

RCH=CH2), 5.01 (s, 2H, ROCH2Ph), 3.63-3.59 (t, 2H, J = 8.0 Hz, RCH2NPhth), 2.25-

2.18 (m, 1H, RCH2CH2NPhth), 2.13-2.04 (m, 1H, RCH2CH2NPhth), 1.46 (s, 3H, RCH3);

13 C NMR δ (CDCl3): 168.4, 158.9, 148.1, 145.8, 137.4, 133.9, 132.4, 129.4, 128.7, 128.4,

128.1, 127.8, 126.6, 123.2, 119.3, 113.9, 112.7, 112.2, 70.1, 43.5, 38.6, 34.8, 25.2, 21.3;

IR cm-1 (neat): 3083, 3025, 2942, 2872, 1772, 1707, 1601, 1437, 1390, 1360, 1243, 1084,

1025.

Determination of enamtiomeric excess by Mosher’s amide derivatization

Phthalimide protecting group in hydrovinylated-product 6 (15 mg, mmol) was

removed by hydrazine hydrate (500 mol%) in ethanol (3 mL) under a refluxing condition

for 12 h. The crude amine was purified by acid-base work-up, and then it was dissolved

in CH2Cl2 (2 mL). This solution was treated with TEA (300 mol%), followed by

MTPA-Cl (110 mol%). The racemic compound was also prepared by the same

procedure. The enantiomeric excess of 6-MTPA was determined by 19F NMR of this

19 Mosher amide. F NMR δ (C6D6): racemic - 68.61, - 68.57; from L1 1 : 3.5; from L3

1 : 4.1

Synthesis of (S)-2-(3-(benzyloxy)phenyl)-4-(1,3-dioxoisoindolin-2-yl)-2-methyl- butanoic acid (7).

71 HO BnO O NPhth BnO NPhth

To a stirred solution of hydrovinylation product 6e (0.12 g, 0.293 mmol), NaIO4

(0.32 g, 1.465 mmol), CCl4 (5 mL), and H2O (7.5 mL) was added RuCl3·H2O (7.8 mg,

o 0.029 mmol) in CH3CN (5 mL). The resulting solution was warmed up to 30 C for 2

days. After adding citric acid (5 mL), the crude product was extracted with CH2Cl2

(3*20 mL) and combined organic layer was dried over Na2SO4. The crude product was

purified by column chromatography (95 mg, 76 %, pale yellow foamy solid). 1H NMR

δ (CDCl3): 7.72-7.69 (m, 2H, Ar), 7.64-7.62 (m, 2H, Ar), 7.42-7.29 (m, 5H, Ar), 7.16-

7.13 (t, 1H, J = 8.0 Hz, Ar), 7.00-6.96 (m, 2H, Ar), 6.70-6.68 (dd, 1H, J = 8.0, 2.0 Hz, Ar),

5.00 (s, 2H, -OBn), 3.66-3.62 (m, 2H, RCH2NPhth), 2.58-2.46 (m, 1H, RCH2CH2NPhth),

13 2.31-2.22 (m, 1H, RCH2CH2NPhth), 1.71 (s, 3H, RCH3); C NMR δ (CDCl3): 168.3,

159.0, 137.1, 134.5, 133.9, 132.2, 129.7, 128.8, 128.1, 127.8, 123.9, 123.2, 119.0, 113.6,

113.4, 113.2, 70.9, 36.8, 35.4, 34.4, 22.0; IR cm-1 (neat) : 3466, 3063, 2923, 1771, 1713,

1598, 1439, 1399, 1372, 1251, 1189, 1026.; HRMS 452.1454 ((M+Na)+• ; 452.1474 calcd

for C26H23NNaO5).

Synthesis of (S)-methyl 2-(3-(benzyloxy)phenyl)-4-(1,3-dioxoisoindolin-2-yl)-2-

methyl- butanoate (8).

HO MeO O O BnO BnO NPhth NPhth

Acid 7 (65 mg, 0.151 mmol) in acetone (20 mL) was treated with MeI (97.5 μL,

1.51 mmol) and K2CO3 (0.21 g, 1.51 mmol), and then the resulting solution was heated to

72 refluxed temperature for 12 h. After the reaction mixture was cooled to rt, the crude

product was filtered through celite pad, and the crude product was purified by column

1 chromatography (54 mg, 80 %). H NMR δ (CDCl3): 7.73-7.63 (m, 4H, Ar), 7.43- (m,

2H, Ar), 7.44-7.30 (m, 5H, Ar), 7.17-7.14 (t, 1H, J = 8.0 Hz, Ar), 6.93-6.90 (m, 2H, Ar),

6.71-6.69 (dd, 1H, J = 8.2, 2.2 Hz, Ar), 5.15 (s, 2H, ROCH2Ph), 3.66-3.61 (m, 5H,

RCO2CH3 & RCH2NPhth), 2.50-2.46 (m, 1H, RCH2CH2NPhth), 2.30-2.26 (m, 1H,

13 RCH2CH2NPhth), 1.68 (s, 3H, RCH3); C NMR δ (CDCl3): 176.1, 168.3, 159.0, 143.8,

137.1, 134.0, 132.3, 129.7, 128.8, 128.3, 128.2, 127.8, 123.2, 118.8, 113.2, 113.1, 70.1,

52.6, 49.0, 37.1, 34.5, 22.4; IR cm-1 (neat): 3031, 2949, 2926, 1772, 1713, 1598, 1581,

1435, 1398, 1372, 1293, 1245, 1152, 1026.

Synthesis of (S)-3-(3-(benzyloxy)phenyl)-3-methylpyrrolidin-2-one (9).

MeO O BnO NH BnO NPhth O

Hydrazine hydrate (23 mg, 0.45 mmol) was added to methylester 8 (40 mg,

0.090 mmol) in EtOH (5 mL), and then the resulting solution was heated to 80~85 oC for

2 d. After the reaction mixture was cooled to rt, the volatile materials were evaporated and the crude product was purified by column chromatography (22 mg, 83 %, colorless

1 oil). H NMR δ (CDCl3): 7.43-7.22 (m, 6H, Ar), 7.07-7.03 (t, 1H, J = 2.0 Hz, Ar), 7.03-

7.01 (d, 1H, J = 7.6 Hz, Ar), 6.85-6.82 (dd, 1H, J = 8.4, 2.4 Hz, Ar), 6.63 (br s, 1H, RNH),

5.04 (s, 2H, ROCH2Ph), 3.34-3.25 (m, 2H, -CH2NHCO-), 2.50-2.44 (m, 1H, -

13 CH2CH2NHCO-), 2.24-2.17 (m, 1H, -CH2CH2NHCO-), 1.53 (s, 3H, RCH3); C NMR

δ (CDCl3): 181.4, 159.1, 145.3, 137.2, 129.7, 128.8, 128.2, 127.8, 119.0, 113.7, 112.8,

73 70.2, 47.9, 39.1, 38.1, 24.7; IR cm-1 (neat) : 3379, 2951, 2911, 2872, 1694, 1605, 1580,

+• 1381, 1261, 1216.; HRMS 304.1313 ((M+Na) ; 304.1284 calcd for C18H19NNaO2);

22 [α] D = - 25.4 (c = 1.000, CHCl3); HPLC separation (OJ-H column, 10 % IPA/n-Hex, 0.5

ml/min) – 76.4 : 23.6. The absolute configuration was determined by the comparison of

42 the sign of similar compound’s [α]D in reported data.

Synthesis of (S)-3-(3-(benzyloxy)phenyl)-1,3-dimethylpyrrolidin-2-one (10).

BnO NH BnO N O O

To a stirred solution of pyrrolidinone 9 (14.3 mg, 0.051 mmol) and MeI (31.6 μg,

0.51 mmol) in THF (5 mL) was added NaH (19.4 mg, 0.51 mmol) slowly, and then the mixture was stirred at rt for 1h. The reaction was quenched with water (1 mL) and the crude product was extracted with EtOAc (3 mL*3). After evaporation, the crude product was purified by column chromatography (14.3 mg, 95 %, colorless oil). 1H

NMR δ (CDCl3): 7.43-7.20 (m, 6H, Ar), 7.03-7.02 (t, 1H, J = 2.0 Hz, Ar), 6.97-6.95 (d,

1H, J = 7.6 Hz, Ar), 6.84-6.81 (dd, 1H, J = 8.2, 2.6 Hz, Ar), 5.03 (s, 2H, ROCH2Ph),

3.28-3.25 (m, 2H, -CH2NHCO-), 2.40-2.36 (m, 1H, -CH2CH2NHCO-), 2.15-2.09 (m, 1H,

13 -CH2CH2NHCO-), 1.50 (s, 3H, RCH3); C NMR δ (CDCl3): 177.5, 159.1, 145.9, 137.3,

129.7, 128.8, 128.1, 127.8, 118.9, 113.7, 112.8, 70.2, 48.8, 46.4, 35.6, 30.4, 25.3; IR cm-1

(neat): 3030, 2924, 2868, 1682, 1605, 1580, 1488, 1454, 1432, 1400, 1292, 1276, 1211,

+• 23 1026.; HRMS 318.1465 ((M+Na) ; 318.1470 calcd for C19H21NNaO2); [α] D = - 27.2 (c

= 0.700, CHCl3).

74 Synthesis of (S)-3-(5-(benzyloxy)-2-bromophenyl)-1,3-dimethylpyrrolidin-2-one (11).

N BnO N BnO O O Br

-5 N-Me compound 10 (7.1 mg, 2.4*10 mol) in CH3CN was treated with N-

bromosuccimide (4.7 mg, 2.6*10-5 mol) at 0 oC, and the mixture was stirred at the same temperature for 1 h. The reaction was warmed up to rt and the mixture was stirred at rt

for 5 d. After evaporation, the crude product was purified by preparative TLC (6.7 mg,

1 75 %). H NMR δ (CDCl3): 7.45-7.29 (m, 6H, Ar), 7.12-7.11 (d, 1H, J = 3.0 Hz, Ar),

6.71-6.68 (dd, 1H, J = 7.7, 2.7 Hz, Ar), 5.01 (s, 2H, ROCH2Ph), 2.89 (s, 3H, -NCH3),

2.74-2.67 (m, 2H, -CH2NHCO-), 2.04-1.99 (m, 1H, -CH2CH2NHCO-), 2.15-2.09 (m, 1H,

13 -CH2CH2NHCO-), 1.62 (s, 3H, RCH3); C NMR δ (CDCl3): 177.0, 158.2, 143.2, 136.8,

135.7, 128.8, 128.3, 127.8, 117.4, 114.4, 113.8, 70.5, 50.2, 46.6, 33.4, 30.5, 24.2; IR cm-1

(neat): 2923, 2872, 2852, 1688, 1592, 1567, 1496, 1454, 1401, 1289, 1213, 1015.; HRMS

+• 23 398.0572 ((M+Na) ; 398.0557 calcd for C19H20BrNNaO2); [α] D = - 7.6 (c = 0.525,

CHCl3)

Synthesis of ((S)-3-(5-(benzyloxy)-2-nitrophenyl)-3-methylpyrrolidin-2-one (12a).

NH BnO NH BnO O O NO2

To a stirred solution of HNO3 (0.1 mL) and Ac2O (0.1 mL) in CCl4 (2 mL) was

added pyrrolidinone 9 (10 mg, 3.55*10-5 mol) at 0 oC, and the mixture was stirred at the

same temperature for 3 d. Then the reaction was diluted with CH2Cl2 (5 mL) and water

(5 mL), and then organic phase was separated. After evaporation, the crude product was

75 purified by preparative TLC (3.8 mg, 33 %) and a mixture of other isomers. 1H NMR δ

(CDCl3): 7.88-7.86 (d, 1H, J = 9.0 Hz, Ar), 7.40-7.33 (m, 5H, Ar), 7.22-7.21 (d, 1H, J =

3.0 Hz, Ar), 6.89-6.87 (dd, 1H, J = 8.7, 2.7 Hz, Ar), 5.54 (br s, 1H, -NH), 5.11 (s, 2H,

ROCH2Ph), 3.51-3.44 (m, 2H, -CH2NHCO-), 2.79-2.73 (m, 1H, -CH2CH2NHCO-), 2.18-

13 2.13 (m, 1H, -CH2CH2NHCO-), 1.64 (s, 3H, RCH3); C NMR δ (CDCl3): 161.9, 135.9,

129.0, 128.7, 128.5, 127.8, 117.3, 112.5, 70.8, 53.1, 39.2, 36.9, 24.7; IR cm-1 (neat): 3398,

2915, 2850, 1694, 1576, 1517, 1383, 1281.; HRMS 349.1159 ((M+Na)+• ; 349.1164 calcd

23 for C18H18N2NaO4); [α] D = - 78.4 (c = 0.310, CHCl3)

Synthesis of (S)-3-(5-(benzyloxy)-2-nitrophenyl)-1,3-dimethylpyrrolidin-2-one (13a).

BnO NH BnO N O O NO2 NO2 The nitro-compound 12a (11.5 mg, 3.5*10-5 mol) was N-methylated by the same

condition as the compound 9 to yield the desired N-methylated compound 13a (12.0 mg,

1 > 99 %). H NMR δ (CDCl3): 7.85-7.84 (d, 1H, J = 8.5 Hz, Ar), 7.41-7.34 (m, 5H, Ar),

7.19-7.18 (d, 1H, J = 3.0 Hz, Ar), 6.88-6.86 (dd, 1H, J = 9.0, 2.5 Hz, Ar), 5.11 (s, 2H,

ROCH2Ph), 3.46-3.41 (m, 2H, -CH2NHCO-), 2.89 (s, 3H, -NCH3), 2.60-2.57 (m, 1H, -

13 CH2CH2NHCO-), 2.08-2.04 (m, 1H, -CH2CH2NHCO-), 1.54 (s, 3H, RCH3); C NMR δ

(CDCl3): 176.2, 161.6, 140.1, 135.7, 128.8, 128.5, 128.2, 127.6, 117.0, 112.1, 70.6, 48.3,

46.4, 34.2, 30.1, 24.7; IR cm-1 (neat): 2924, 2855, 1691, 1610, 1574, 1519, 1454, 1403,

20 1350, 1290, 1258, 1215, 1063.; [α] D = - 61.6 (c = 0.305, CHCl3). The absolute

configuration was determined by the comparison of the sign of similar compound’s [α]D

in reported data.41,42

76 Synthesis of (R)-4-methyl-4-vinylchroman (14a).

O O

Following the general procedure using 4-methylenechroman51 (14) (0.20 g, 1.37

+ - o mmol) and 10 mol% of pre-catalyst [(allyl)Ni(L3)] BARF at 35 C for 12 h, the title

compound was obtained and purified by column chromatography (0.167g, 70 %,

93.8 %ee by chiral GC).; GC condition: 100 oC isothermal with cyclodex-B column,

1 retention time - (R)-isomer 48.76 min, (S)-isomer 47.03 min. H NMR δ (CDCl3): 7.15-

7.07(m, 2H, Ar), 6.88-6.84 (m, 1H, Ar),6.81-6.79 (dd, 1H, J = 8.2, 1.2 Hz, Ar), 5.92-5.87

(dd, 1H, J = 17.5, 10.5 Hz, RCH=CH2), 5.12-5.10 (dd, 1H, J = 10.5, 1.5 Hz, RCH=CH2),

4.87-4.82 (dd, 1H, J = 12.2, 1.2 Hz, RCH=CH2), 4.18-4.13 (m, 2H, ROCH2R’), 1.89-1.86

13 (m, 2H, ROCH2CH2R’), 1.43 (s, 3H, RCH3); C NMR δ (CDCl3): 154.3, 147.5, 128.9,

127.9, 127.7, 120.4, 117.1, 114.2, 62.9, 37.9, 36.1, 27.9; IR cm-1 (neat): 2958, 2829, 1722,

1637, 1605, 1579, 1487, 1443, 1368, 1321, 1223, 1190, 1121, 1064. For spectral data of

the dimer, see experimental section in chapter 3.

Synthesis of (S)-2-(4-methylchroman-4-yl)ethanol (15).

OH

O O

A solution of HV-product 14a (18 mg, 0.1 mmol) and Wilkinson’s catalyst

o (Rh(PPh3)3Cl, 2 mg, 0.002 mmol) in THF (2 mL) was cooled to - 40 C, and then 1 M

THF solution of catecholborane (0.3 mL, 0.3 mmol) was added dropwise to the mixture.

After the resulting mixture was stirred at rt for 4 h, the solution was cooled to 0 oC and

77 then added 3 N NaOH (0.5 mL) slowly, followed by addition of H2O2(30 %, 0.1 mL).

The resulting solution was stirred at rt for 18 h. The solution was diluted with water (5

ml), and then the crude alcohol was extracted by CH2Cl2 (5 mL*3). The combined

organic layer was dried over Na2SO4 and then evaporated. The crude alcohol was purified by column chromatography (17 mg, 4:1 mixture of regio-isomers). 1H NMR of

major compound δ (CDCl3): 7.21-7.19 (dd, 1H, J = 1.6, 8.0 Hz, Ar), 7.08-7.04 (m, 1H,

Ar), 6.88-6.76 (m, 2H, Ar), 4.21-4.12 (m, 2H), 3.68-3.59 (m, 2H), 2.04-1.93 (m, 2H),

13 1.74-1.66 (m, 2H), 1.35 (s, 3H).; C NMR of major compound δ (CDCl3): 154.3, 130.1,

127.5, 127.2, 121.0, 117.4, 63.0, 59.8, 45.0, 35.0, 32.9, 30.1.

Synthesis of (R)-triisopropyl(2-(4-methylchroman-4-yl)ethoxy)silane (15a).

OH OTIPS

O O

Alcohol 15 (18 mg, 0.1 mmol) in dry CH2Cl2 (3 mL) was treated with imidazole

(8.2 mg, 0.12 mmol), DMAP (0.2 mg, 0.00015 mmol), and TIPSCl (26 μl, 0.12 mmol), and the resulting solution was stirred at rt for 1 h. After the reaction was quenched with water (1 mL), the crude product was extracted with CH2Cl2 (2 mL*3). The combined

organic layer was dried over Na2SO4 and then evaporated. The crude alcohol was purified by preparative TLC (26 mg, 77 %). 1H NMR of major compound δ 7.21-7.19

(dd, 1H, J = 1.6, 7.6 Hz, Ar), 7.07-7.02 (m, 1H, Ar), 6.87-6.83 (m, 1H, Ar), 6.77-6.75 (dd,

1H, J = 0.6, 7.8 Hz, Ar), 4.21-4.12 (m, 2H), 3.72-3.65 (m, 2H), 2.15 (m, 1H), 2.05-1.89

13 (m, 3H), 1.78-1.49 (m, 3H), 1.36 (s, 3H), 1.08-1.00 (m, 18H).; C NMR δ (CDCl3):

154.2, 130.8, 127.3, 120.6, 117.2, 63.2, 60.3, 45.2, 35.0, 33.0, 29.8, 28.2, 17.9, 12.5, 12.2.

78 Ring-opening reaction using TIPS-protected substrate [(2-(4-methyltetrahydro-2H- pyran-4-yl)phenol)] (16).

O OTIPS

O OH

To a stirred solution of BI3 (15.7 mg, 0.004 mol) and TEA (0.8 μL, 0.0006 mmol)

o in CH2Cl2 under N2 at 0 C was added TIPS-protected substrate 15a (14 mg, 0.04 mmol)

in CH2Cl2 dropwise. After overnight stirring at rt, the mixture was evaporated and

purified by preparative TLC (3.5 mg, 45 %). 1H NMR δ 7.12-7.7.06 (m, 1H, Ar), 6.88-

6.85 (m, 1H, Ar), 6.64-6.63 (dd, 1H, J = 1.2, 12.5 Hz, Ar), 4.84 (s, 1H), 2.99-2.88 (m,

4H), 2.72-2.67 (m, 2H), 2.12-2.07 (m, 2H), 1.33 (s, 3H).

Ring-opening reaction using TBDPS-protected substrate for synthesizing (16a).

OTBDPS OTBDPS

O OH I Using the procedure aforementioned, the desired ring opening product was

obtained (1.0 mg, 5 %) with recovered starting material (14 mg, 93 %). 1H NMR δ

7.67-7.65 (m, 4H, Ar), 7.42-7.34 (m, 6H, Ar), 7.21-7.19 (dd, 1H, J = 1.6, 8.0 Hz, Ar),

7.06-7.04 (m, 1H, Ar), 6.88-6.86 (m, 1H), 6.79-6.76 (dd, 1H, J = 1.2, 8.4 Hz, Ar), 4.21-

4.12 (m, 2H), 3.72-3.56 (m, 2H), 2.44 (br s, 1H), 2.08-1.93 (m, 3H), 1.77-1.66 (m, 1H),

1.34 (s, 3H), 0.99 (s, 9H).

79 Synthesis of 7-methoxy-1-methylene-1,2,3,4-tetrahydronaphthalene (17a).

O MeO MeO

To a stirred solution of MePPh3 (8.1 g, 22.7 mmol) in THF was added nBuLi

(1.45 M, 16 mL) in THF dropwise at rt under N2. After 10 min stirring, 7-methoxy α- tetralone (2.0 g, 11.35 mmol) prepared by reported procedures in THF was added dropwise. The resulting mixture was stirred at rt for 2 h. The reaction was quenched with water (10 mL), and the product was extracted with EtOAc (10 mL*3). The combined organic layer was dried over MgSO4 and evaporated. The crude compound was

purified by column to yield 1.02 g of pale yellow oil (50 %) with 0.98 g of the starting

1 ketone. H NMR δ (CDCl3): 7.18 (d, 1H, J = 2.0 Hz, Ar), 7.04-7.02 (d, 1H, J = 8.4 Hz,

Ar), 6.80-6.77 (dd, 1H, J = 2.0, 8.4 Hz, Ar), 5.47 (s, 1H, vinyl), 4.97 (s, 1H, vinyl), 3.82

(s, 3H, OMe), 2.81-2.78 (t, 2H, J = 7.0 Hz, RCOCH2R’), 2.55-2.52 (t, 2H, J = 7.0 Hz,

13 ArCH2R), 1.91-1.84 (m, 2H, ArCH2CH2R).; C NMR δ (CDCl3): 158.0, 143.8, 135.8,

130.3, 130.0, 114.5, 108.8, 108.2, 55.5, 33.4, 29.8, 24.3.

Synthesis of 7-bromo-1-methylene-1,2,3,4-tetrahydronaphthalene (17b).

O Br Br

To a stirred solution of MePPh3 (0.54 g, 1.34 mmol) in THF was added nBuLi in

THF (1.4 M, 0.96 ml) dropwise at rt under N2. After 10 min stirring, 7-bromo α-

tetralone (0.1 g, 0.446 mmol) prepared by reported procedures in THF was added

dropwise. The resulting mixture was stirred at rt for 2 h. The reaction was quenched

80 with water (10 mL), and the product was extracted with EtOAc (10 mL*3). The

combined organic layer was dried over MgSO4 and evaporated. The crude compound was

1 purified by column (80 mg, 80%, pale yellow oil). H NMR δ (CDCl3): 7.78 (s, 1H, Ar),

7.31-7.28 (m, 1H, Ar), 7.08-6.99 (m, 1H, Ar), 5.54 (s, 1H, vinyl), 5.08 (s, 1H, vinyl),

2.83-2.79 (t, 2H, J = 7.2 Hz, RCOCH2R’), 2.57-2.48 (m, 2H, ArCH2R), 1.98-1.86 (m, 2H,

13 ArCH2CH2R).; C NMR δ (CDCl3): 142.4, 137.0, 136.3, 131.0, 130.5, 127.3, 119.8,

109.4, 32.9, 30.1, 23.6.

Synthesis of (R)-1-methyl-1-vinyl-1,2,3,4-tetrahydronaphthalene (18).

+

71 % ~28% Following the general procedure using 1-methylene-1,2,3,4-tetrahydro-

+ - o naphthalene with [(allyl)Ni(L3)] BARF (2 mol%) at - 70 C for 6 h, the title compound

was obtained and purified by column chromatography (71 %, > 99 %ee by chiral GC

with ~ 28 % of isomerized starting material).; GC condition: 100 oC isothermal with

1 cyclodex-B column, tR - (R)-isomer 48.76 min, (S)-isomer 47.03 min. H NMR δ

(CDCl3): 7.15-7.07(m, 2H, Ar), 6.88-6.84 (m, 1H, Ar),6.81-6.79 (dd, 1H, J = 8.2, 1.2 Hz,

Ar), 5.92-5.87 (dd, 1H, J = 17.5, 10.5 Hz, RCH=CH2), 5.12-5.10 (dd, 1H, J = 10.5, 1.5

Hz, RCH=CH2), 4.87-4.82 (dd, 1H, J = 12.2, 1.2 Hz, RCH=CH2), 4.18-4.13 (m, 2H,

13 ROCH2R’), 1.89-1.86 (m, 2H, ROCH2CH2R’), 1.43 (s, 3H, RCH3); C NMR δ (CDCl3):

22 154.3, 147.5, 128.9, 127.9, 127.7, 120.4, 117.1, 114.2, 62.9, 37.9, 36.1, 27.9; [α] D =

35 -35.8 (c = 0.500, CHCl3), Lit. -35.4 (c = 1.15, CHCl3).

81 Synthesis of (R)-7-methoxy-1-methyl-1-vinyl-1,2,3,4-tetrahydronaphthalene (18a).

O O

Following the general procedure using 7-methoxy-1-methylene-1,2,3,4-

+ - tetrahydronaphthalene (50.0 mg, 0.287 mmol) and 4 mol% of [(allyl)Ni(L3)] BARF for

4 h at - 70 oC, the title compound was obtained and purified by column chromatography

(50.0 mg, mixture of HV product (82 %) and starting material (15 %), > 99 %ee by chiral

GC separation).; GC condition: 120 oC isothermal with Cyclodex-B column, retention

1 time - (R)-isomer 56.09 min, (S)-isomer (obtained by using L3*) 57.10 min. H NMR δ

(CDCl3): 7.01-6.96 (m, 2H, Ar), 6.68-6.65 (m, 1H, Ar), 5.95-5.88 (dd, 1H, J = 17.2, 10.4

Hz, RCH=CH2), 5.02-4.99 (dd, 1H, J = 10.4, 1.2 Hz, RCH=CH2), 4.87-4.82 (dd, 1H, J =

17.6, 1.2 Hz, RCH=CH2), 3.75 (s, 3H, ROMe), 2.71-2.68 (t, 2H, J = 6.2 Hz, ArCH2R),

13 1.85-1.73 (m, 4H, ArCH2CH2CH2R & ArCH2CH2CH2R), 1.36 (s, 3H, q-CCH3); C

NMR δ (CDCl3): 157.7, 148.8, 143.7, 130.0, 129.0, 130.0, 129.0, 113.8, 112.2, 111.9,

55.4, 41.4, 37.7, 29.6, 28.4, 19.6.; IR cm-1 (neat): 2958, 2829, 1722, 1637, 1606, 1580,

1488, 1443, 1368, 1322, 1223, 1190, 1121, 1064; GC (cyclodex-B column, isothermal,

o 22 120 C); tR = 56.09 (R-isomer), 57.10 min (S-isomer); > 99 %ee; [α] D = - 19.8 (c =

28 20 0.104, CHCl3), Lit. [α] D = - 21.1 (c = 3.8, CHCl3).

Synthesis of (R)-7-methoxy-1-methyl-1-vinyl-1,2,3,4-tetrahydronaphthalene (18b

and 18b’).

Br Br

82 Following the general procedure using 7-bromo-1-methylene-1,2,3,4- tetrahydronaphthalene (15.0 mg, 0.0675 mmol) and 5 mol% of AllylNi(L3)BARF for 6 h

at - 70 oC then rt overinght, the title compound was obtained and purified by column

chromatography (mixture of SM 17b, isomerized product 18b’, and hydrovinylation

product 18b, 1:1:0.2 based on 1H NMR) 1H NMR (assigned only distinctive peaks) δ

(CDCl3) of isomerized product 18b’: 5.94-5.89 (m, 1H, vinyl), 2.07 (s, 3H, RCH3); hydrovinylation product 18b: 5.32-5.07 (dd, 1H, J = 9.5, 1.5 Hz, vinyl), 4.87-4.84 (dd,

1H, J = 17.0, 1.0 Hz, vinyl).

Synthesis of (S)-1-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (19a).

HO O

The mixture (0.5 g, 71 % conv.) of HV product 18 and remaining starting styrene

(29 %) was dissolved in CCl4 (10 mL) and water (20 mL), and then added NaIO4 (2.17 g,

10.16 mmol). The resulting solution was treated with RuCl3 trihydrate (21.1 mg,

0.01016 mmol) in CH3CN (10 mL), and the mixture was stirred for 3 h at rt. After the starting material was completely consumed, water (20 mL) and EtOAc (20 mL) were added to the solution. The organic layer was separated and product was extracted 2 times with EtOAc (20 mL*2). The combined organic layer was dried over Na2SO4 and then evaporated. The crude black oil was purified by column chromatography (0.39 g,

1 70 % 2 steps overall). H NMR δ (CDCl3): 7.30-7.28 (m, 1H, Ar), 7.16-7.12 (m, 2H,

Ar), 7.08-7.06 (d, 1H, J = 5.0 Hz, Ar), 2.84-2.77 (m, 2H, ArCH2R), 2.36-2.31 (m, 1H,

ArCH2CH2CH2R); 1.94-1.72 (m, 3H, ArCH2CH2CH2R & ArCH2CH2CH2R), 1.56 (s, 3H,

83 13 q-CCH3); C NMR δ (CDCl3): 183.6, 138.5, 136.8, 129.5, 128.3, 127.0, 126.2, 46.3,

22 35.5, 30.1, 27.6, 19.9; [α] D = - 29.1 (c = 0.905, CHCl3).

Synthesis of (S)-methyl 1-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylate (19).

HO MeO O O

Carboxylic acid 19a (0.32 g, 1.68 mmol) in acetone (25 mL) was treated with

MeI (2.32 g, 16.8 mmol) and K2CO3 (1.1 ml, 16.8 mmol). The resulting mixture was

stirred at refluxed temperature for 4 h. After the mixture was cooled to rt, it was filtered

and evaporated. The crude product was purified by column chromatography to yield the

1 title compound as colorless oil (0.304 g, 88 %). H NMR δ (CDCl3): 7.20-7.17 (m, 1H,

Ar), 7.14-7.06 (m, 3H, Ar), 3.64 (s, 3H, RCO2CH3), 2.83-2.75 (m, 2H, ArCH2R), 2.32-

2.27 (m, 1H, ArCH2CH2CH2R); 1.89-1.70 (m, 3H, ArCH2CH2CH2R & ArCH2CH2CH2R),

13 1.54 (s, 3H, q-CCH3); C NMR δ (CDCl3): 178.0, 139.3, 136.6, 129.5, 128.1, 126.7,

22 126.1, 52.4, 46.6, 35.4, 30.1, 27.9, 19.9.; [α] D = - 31.9 (c = 1.300, CHCl3).

Synthesis of (S)-methyl 1-methyl-4-oxo-1,2,3,4-tetrahydronaphthalene-1-carboxylate

(20). MeO MeO O O

O

To a solution of CrO3 (0.284 g, 2.84 mmol) in AcOH (5 mL) and Ac2O (5 mL) was added ester 19 (0.290 g, 1.42 mmol) in AcOH (5 mL) was added at 0 oC over 10 min.

The resulting mixture was stirred at the same temperature for 1 h and additional 12 h at rt.

84 After the starting material was completely disappeared in TLC analysis, the mixture was

poured into ice water (20 ml), and then the crude product was extracted with CHCl3 (20 mL*3). The combined organic layer was washed with sat. NaHCO3 (20 mL) and brine

(20 mL), and then it was dried and evaporated under reduced pressure. The crude

product was purified by column chromatography to yield the title compound as colorless

1 oil (0.310 g, > 99 %). H NMR δ (CDCl3): 8.05-8.03 (dd, 1H, J = 8.2, 1.2 Hz, Ar), 7.55-

7.52 (m, 1H, Ar), 7.37-7.35 (m, 2H, Ar), 3.66 (s, 3H, RCO2CH3), 2.81-2.58 (m, 3H,

13 ArCOCH2CH2R); 2.11-2.06 (m, 1H, ArCOCH2CH2R), 1.67 (s, 3H, q-CCH3); C NMR δ

(CDCl3):197.4, 175.8, 145.5, 134.0, 131.9, 127.7, 127.6, 127.5, 52.8, 46.2, 35.4, 34.0,

22 26.1.; [α] D = - 26.3 (c = 1.250, CHCl3).

Synthesis of (S)-methyl 5-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5- carboxylate by Beckman rearrangement: oxime (21) preparation.

MeO MeO O O

O NOH Mixture of ketone 20 (0.18 g, 0.825 mmol), hydroxylamine HCl salt (0.092 g,

1.32 mmol), pyridine (0.12 mL) and EtOH (10 mL) was stirred at 110 oC for 12 h. After

the solvent was evaporated, the crude oxime was purified by column chromatography

1 (0.17 g, 89 %). H NMR δ (CDCl3): 9.34 (br s, 1H, R=NOH), 7.95-7.94 (dd, 1H, J =

8.0, 1.0 Hz, Ar), 7.39-7.36 (m, 1H, Ar), 7.33-7.28 (m, 1H, Ar), 3.69 (s, 3H, RCO2CH3),

2.96-2.92 (m, 2H, ArC(=NOH)CH2R), 2.47-2.42 (m, 1H, ArC(=NOH)CH2CH2R); 1.88-

13 1.83 (m, 1H, ArC(=NOH)CH2CH2R), 1.64 (s, 3H, q-CCH3); C NMR δ (CDCl3): 176.3,

154.6, 141.1, 129.9, 129.8, 127.5, 127.0, 124.4, 52.6, 46.3, 32.2, 25.5, 20.5; IR cm-1

85 (neat): 3424, 3066, 2977, 2954, 1727, 1713, 1626, 1597, 1486, 1454, 1433, 1378, 1345,

22 1306, 1246, 1194, 1102, 1076, 1031.; [α] D = - 47.2 (c = 0.0125, CHCl3).

Synthesis of (S)-methyl 5-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5- carboxylate by Beckman rearrangement: O-tosyl oxime (21a) preparation. MeO MeO O O

NOH NOTs To a solution of oxime 21 (34 mg, 0.146 mmol) in pyridine (1 mL) was added

TsCl (42 mg, 0.219 mmol). The mixture was stirred at rt for 12 h. After the solvent

was evaporated, the crude product was purified by column chromatography (50.5 mg

1 (mixture of E/Z), 89 %). H NMR δ (CDCl3) only major compound was assigned: 7.97-

7.91 (m, 1H, Ar), 7.45-7.25 (m, 3H, Ar), 3.64 (m, 1H, Ar), 3.64 (s, 3H, RCO2CH3), 2.99-

2.89 (m, 2H, ArC(=NOTs)CH2R), 2.46 (s, 3H, ROSO2PhCH3), 2.41-2.35 (m, 1H,

ArC(=NOTs)CH2CH2R), 1.82-1.74 (m, 1H, ArC(=NOH)CH2CH2R), 1.59 (s, 3H, q-

13 CCH3); C NMR δ (CDCl3): 175.5, 161.7, 145.2, 142.3, 132.9, 131.6, 129.8, 129.7,

129.1, 127.7, 127.5, 127.4, 127.2, 125.6, 52.6, 45.9, 31.8, 25.6, 22.1, 21.9.

Synthesis of (S)-methyl 5-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5- carboxylate (22) by Beckman rearrangement: rearrangement of oxime under PPA.

MeO MeO O O

N NOH H O

PPA (5 g) was added to oxime 21 (0.130 g, 0.557 mmol), and the resulting

86 mixture was mechanically stirred at 110 oC for 20 min. After cooling, the mixture was diluted with ice water (10 mL) and the crude compound was extracted with CHCl3 (10 mL*3). The combined organics was dried and purified by column chromatography

1 (0.121 g, 93 %). H NMR δ (CDCl3): 7.58 (br s, 1H, RNHCOR’), 7.40-7.39 (dd, 1H, J

= 7.5, 1.0 Hz, Ar), 7.30-7.22 (m, 2H, Ar), 6.97-6.95 (dd, 1H, J = 7.5, 1.0 Hz, Ar), 3.64 (s,

3H, RCO2CH3), 3.17-3.10 (m, 1H, ArNHCOCH2CH2R), 2.32-2.26 (m, 2H,

ArNHCOCH2CH2R and ArNHCOCH2CH2R); 1.82-1.60 (m, 1H, ArNHCOCH2CH2R),

13 1.60 (s, 3H, q-CCH3); C NMR δ (CDCl3): 177.2, 174.7, 137.6, 136.4, 128.4, 126.5,

126.3, 123.1, 52.9, 48.3, 38.3, 31.9, 25.1; IR cm-1 (neat): 3194.7, 3061.8, 2973.6, 2954.1,

1732.4, 1678.8, 1604.3, 1582.7, 1482.8, 1434.1, 1385.9, 1371.8, 1321.1, 1260.4, 1223.0,

+• 1170.2, 1125.8, 1097.6; HRMS 234.1130 ((M+H) ; 234.1130 calcd for C13H16NO3);

22 [α] D = + 181.9 (c = 0.0160, CHCl3).

Synthesis of (S)-methyl 5-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5- carboxylate by Schmidt rearrangement.

MeO MeO MeO O O O + N NH O 45 % H O 31 % O

PPA (1 g) and NaN3 (4.5 mg, 0.0687 mmol) were added to ketone 20 (10.0 mg,

0.0458 mmol) respectively, and the resulting mixture was mechanically stirred at 60 oC

for 24 h. After cooling, the mixture was diluted with ice water (2 mL) and the crude

compound was extracted with CHCl3 (2 mL*3). The combined organics was dried and

purified by column chromatography (5.1 mg (45 %) of 22 and 3.5 mg (31 %) of 22a).

87 22: all spectral data were same as the product from Beckman rearrangement; (S)-methyl

5-methyl-1-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepine-5-carboxylate (22a): 1H

NMR δ (CDCl3): 7.72-7.70 (dd, 1H, J = 7.5, 1.5 Hz, Ar), 7.51-7.48 (dt, 1H, J = 14.0, 1.5

Hz, Ar), 7.42-7.38 (m, 2H, Ar), 6.04 (br s, 1H, ArCONHR’), 3.58 (s, 3H, RCO2CH3),

3.21-3.14 (m, 2H, ArCONHCH2CH2R), 3.06-2.95 (m, 2H, ArCONHCH2CH2R), 1.67 (s,

13 3H, q-CCH3), 1.63-1.58 (m, 1H, ArCONHCH2CH2R); C NMR δ (CDCl3): 177.4, 172.9,

139.0, 135.5, 131.3, 129.2, 128.0, 125.2, 53.0, 49.1, 42.6, 39.2, 25.2; IR cm-1 (neat): 3243,

3064, 2924, 2853, 1731, 1660, 1602, 1572, 1463, 1433, 1398, 1360, 1332, 1299, 1262,

+• 22 1232, 1210.; HRMS 234.1130 ((M+H) ; 234.1130 calcd for C13H16NO3 ); [α] D =

- 131.3 (c = 0.0150, CHCl3).

Synthesis of (S)-methyl 1,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-

5-carboxylate (23).

MeO MeO O O

N N H O O

To a solution of benzazepinone 22 (0.120 g, 0.514 mmol) and MeI (0.32 mL,

5.14 mmol) in THF (5 mL) was added NaH (0.200 g, 5.14 mmol) at 0 oC. After 1 h

stirring at rt, the mixture was diluted with water (10 mL) and the crude compound was

extracted with EtOAc (10 mL*3). The combined organics was dried and purified by

column chromatography (0.127 g, > 99 %). This pure product was recrystallized in

MeOH/Ether for preparing a single crystal for X-ray analysis (0.105 g, 82 %). 1H NMR

δ (CDCl3): 7.37-7.33 (m, 2H, Ar), 7.28-7.25 (m, 2H, Ar), 7.14-.13 (d, 1H, J = 8.0 Hz, Ar),

88 3.64 (s, 3H, RCO2CH3), 3.19-3.14 (m, 1H, ArNMeCOCH2CH2R), 3.12 (s, 3H, RR’NMe),

2.28-2.19 (m, 2H, ArNMeCOCH2CH2R and ArNMeCOCH2CH2R), 1.70-1.65 (m, 1H,

13 ArNMeCOCH2CH2R), 1.59 (s, 3H, q-CCH3); C NMR δ (CDCl3): 177.1, 172.6, 143.4,

137.4, 128.5, 126.8, 125.7, 123.4, 52.8, 48.2, 39.0, 34.7, 32.5, 24.8; IR cm-1 (KBr pellet):

3075, 2973, 2967, 2921, 1724, 1657, 1599, 1494, 1439, 1368, 1301, 1257, 1221, 1179,

+• 1141, 1112, 1038.; HRMS 270.1117 ((M+Na) ; 270.1106 calcd for C14H17NaNO3);

22 [α] D = + 166.0 (c = 0.0265, CHCl3).

Synthesis of (S)-3-(1,3-dimethyl-2-oxoindolin-3-yl)propanoic acid (24).

MeO O CO2H

O N N O N-methyl benzazepinone 23 (61.0 mg, 0.247 mmol) was dissolved in conc. HCl

(2 mL) and AcOH (1 mL). The resulting solution was heated to refluxed temperature

for 24 h. After the solution was cooled to rt, the solvent was evaporated under reduced

pressure. The residue was dissolved in 3 N NaOH (2 mL), and this basic aqueous

solution was washed with ether (3 mL). Then, the aqueous solution was acidified by 3

N HCl to pH 1. The crude compound was extracted with ether (10 mL*3). The

combined organics was dried and purified by column chromatography (55.2 mg, 96 %).

1 H NMR δ (CDCl3): 7.35-7.31 (t, 1H, J = 7.0 Hz, Ar), 7.24-7.22 (d, 2H, J = 7.2 Hz, Ar),

7.14-7.10 (t, 1H, J = 7.2 Hz, Ar), 6.91-6.90 (d, 1H, J = 8.0 Hz, Ar), 3.27 (s, 3H, RR’NMe),

2.31-2.26 (t, 1H, J = 10.8 Hz, RCH2CH2CO2H), 2.19-2.10 (m, 2H, RCH2CH2CO2H and

RCH2CH2CO2H), 1.98-1.92 (t, 1H, J = 11.2 Hz, RCH2CH2CO2H), 1.44 (s, 3H, q-CCH3);

13 C NMR δ (CDCl3): 180.2, 178.5, 143.3, 133.0, 128.4, 123.0, 122.8, 108.4, 47.7, 32.9,

89 29.5, 26.4, 23.7; IR cm-1 (neat): 3177, 2969, 2927, 1738, 1713, 1681, 1667, 1613, 1494,

1470, 1454, 1383, 1351, 1304, 1258, 1177, 1128, 1102.; HRMS 234.1127 ((M+H)+• ;

22 234.1130 calcd for C13H16NO3 ); [α] D = + 37.2 (c = 0.0140, CHCl3).

Synthesis of (S)-ethyl 2-(1,3-dimethyl-2-oxoindolin-3-yl)ethylcarbamate (25).

CO2H NHCO2Et

O O N N A mixture of acid 24 (33.0 mg, 0.142 mmol), Diphenylphosphoryl azide (61.5 μL,

0.283 mmol), and TEA (39.4 μL, 0.283 mmol) in distilled EtOH (2 mL) was refluxed for

48 h. After the solvent was evaporated under reduced pressure, the residue was purified

1 by column chromatography (28.7 mg, 73 %). H NMR δ (CDCl3): 7.26-7.23 (t, 1H, J =

7.8 Hz, Ar), 7.18-7.16 (d, 1H, J = 7.5 Hz, Ar), 7.08-7.04 (t, 1H, J = 7.5 Hz, Ar), 6.82-6.81

(d, 1H, J = 8.0 Hz, Ar), 4.64 (br s, 1H, RNHCO2Et), 4.00-3.96 (q, 2H, J = 2.0 Hz,

RCO2Et), 3.18 (s, 3H, RR’NMe), 2.93-2.82 (m, 2H, RCH2CH2NHCO2Et), 2.13-2.07 (m,

1H, RCH2CH2NHCO2Et), 2.01-1.96 (m, 2H, RCH2CH2NHCO2Et), 1.34 (s, 3H, q-CCH3),

13 1.16-1.13 (t, 3H, J = 7.0 Hz, RCO2Et); C NMR δ (CDCl3): 180.5, 156.5, 143.2, 133.4,

128.2, 123.0, 122.8, 108.4, 60.8, 47.2, 37.8, 37.4, 26.4, 24.3, 14.8; IR cm-1 (neat): 3330,

3058, 2973, 2929, 1721, 1697, 1613, 1537, 1493, 1470, 1453, 1377, 1350, 1302, 1254..;

+• 22 HRMS 277.1552 ((M+H) ; 277.1552 calcd for C15H21N2O3 ); [α] D = + 2.5 (c = 0.0315,

CHCl3).

90 Synthesis of (-)-desoxyeseroline.

NHCO2Et N O N N (-)-desoxyeseroline Oxindole carbamate 25 (8.1 mg, 0.0293 mmol) in anhydrous THF (1 mL) was

treated with LAH (4.5 mg, 0.117 mmol), and then the reaction mixture was refluxed for

1.5 h. After the reaction was cooled to rt, the reaction was quenched with aqueous 50 %

KOH (1 mL). The product was extracted with ether (2 mL*3), and dried over Na2SO4.

After the solvent was evaporated under reduced pressure, the residue was purified by preparative TLC (3.4 mg, 57 %). All spectral data were well-matched reported data.52,53

1 H NMR δ (CDCl3):7.08-7.05 (t, 1H, J = 7.2 Hz, Ar), 6.98-6.97 (d, 1H, J = 7.0 Hz, Ar),

6.67-6.64 (t, 1H, J = 7.5 Hz, Ar), 6.40-6.39 (d, 1H, J = 8.0 Hz, Ar), 4.10 (br s, 1H,

NMeCHNMe), 2.93 (s, 3H, NMe), 2.73-2.70 (m, 1H, RCH2CH2NMe), 2.64-2.59 (q, 1H,

7.5 Hz, RCH2CH2NMe), 2.54 (s, 3H, NMe), 1.97-1.94 (m, 2H, RCH2CH2NMe), 1.42 (s,

13 3H, q-CCH3); C NMR δ (CDCl3): 152.2, 136.9, 127.9, 122.4, 117.7, 106.8, 97.8, 53.5,

52.9, 41.1, 38.7, 36.7, 27.6; IR cm-1 (neat): 2924, 2853, 1605, 1491, 1463, 1377, 1290,

+• 22 1263, 1223, 1021.; HRMS 203.1558 ((M+H) ; 203.1548 calcd for C13H19N2); [α] D =

52 25 - 62.0 (c = 0.0170, CHCl3). Lit. [α] D = - 74 (c = 0.5, CHCl3).

Synthesis of (R)-4-methyl-4-vinyl-3,4-dihydronaphthalen-1(2H)-one (26).

O

To a stirred solution of CrO3 (0.29 g, 2.9 mmol) in acetic anhydride (4.5 mL) and

acetic acid (2 ml) was added dropwise a solution of (R)-1-methyl-1-vinyl-1,2,3,4-

91 tetrahydronaphthalene (0.25 g, 1.45 mmol) at 0 oC over 10 min. After the reaction was stirred at 50 oC overnight, the mixture was cooled to rt, and then the reaction mixture was

poured into ice water (20 mL). The product was extracted with CHCl3 (10 mL*3), and

the combined organics were washed with water and dried over Na2SO4. After the

solvent was evaporated under reduced pressure, the residue was purified by column (86

1 mg, 68 %). H NMR δ (CDCl3): 8.04-8.02 (dd, 1H, J = 9.0, 1.5 Hz, Ar), 7.53-7.49 (m,

1H, Ar), 7.33-7.26 (m, 1H, Ar), 5.97-5.92 (dd, 1H, J = 11.0, 17.5 Hz, RCH=CH2), 5.12-

5.10 (d, 1H, J = 10.5 Hz, RCH=CH2), 4.73-4.70 (d, 1H, J = 17.5 Hz, RCH=CH2), 2.70-

13 2.65 (m, 2H, RCOCH2R), 2.09-2.04 (m, 2H, RCOCH2CH2R), 1.50 (s, 3H, q-Me); C

NMR δ (CDCl3): 148.8, 145.9, 133.8, 127.8, 127.5, 126.9, 114.6, 41.3, 36.0, 35.3, 28.3,

27.0.

Synthesis of (R)-4-methyl-4-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (26a).

O NOH

A mixture of ketone 26 (16 mg, 0.086 mmol), HCl·H2NOH (9.6 mg, 0.14 mmol),

pyridine (0.01 mL), and EtOH (2 mL) was refluxed for 3 h. After the solvent was

1 evaporated, the residue was purified by column (16.3 mg, 94 %). H NMR δ (CDCl3):

8.76 (br s, 1H, OH), 7.91-7.89 (d, 1H, J = 8.0 Hz, Ar), 7.34-7.20 (m, 3H, Ar), 5.94-5.87

(dd, 1H, J = 10.7, 17.6 Hz, RCH=CH2), 5.08-5.05 (dd, 1H, J = 1.2, 10.8 Hz, RCH=CH2),

4.76-4.71 (dd, 1H, J = 1.2, 17.2 Hz, RCH=CH2), 2.91-2.75 (m, 2H, RCOCH2R), 1.90-

13 1.73 (m, 2H, RCOCH2CH2R), 1.40 (s, 3H, q-Me); C NMR δ (CDCl3): 155.6, 146.2,

144.6, 130.2, 129.7, 127.1, 126.8, 124.4, 114.1, 41.1, 34.2, 26.3, 20.4; IR cm-1 (neat):

92 3301, 3064, 2926, 2855, 1733, 1636, 1483, 1457, 1373, 1305, 1248, 1216, 1074, 1045.;

22 [α] D = - 37.8 (c = 0.815, CHCl3).

Synthesis of (1S,9bS)-1,9b-dimethyl-5,9b-dihydro-1H-pyrrolo[2,1-a]isoindol-3(2H)-

one (27, unexpected tandem ring expansion).

N

NOH O Oxime 26a (12 mg, 0.060 mmol) was treated with PPA (1 g), and then the

reaction mixture was heated to 110 oC for 10 min. After the reaction was cooled to rt,

ice water (5 mL) was added. The product was extracted with CHCl3 (5 mL*3), and the

combined organic layer was dried over Na2SO4. After the solvent was evaporated under

reduced pressure, the residue was purified by column and recrystallization (6.0 mg, 50 %).

Single crystal of unexpected compound was analyzed by NMR and X-ray. 1H NMR δ

(CDCl3): 7.54-7.52 (d, 1H, J = 8.0 Hz, Ar), 7.22-7.19 (t, 1H, J = 7.8 Hz, Ar), 7.11-7.04 (m,

2H, Ar), 3.31-3.22 (m, 1H, ArCH(CH3)R), 3.25-2.90 (m, 1H, RCOCH2CH2R’), 2.64-2.59

(m, 1H, RCOCH2CH2R’), 2.14-2.10 (m, 1H, RCOCH2CH2R’), 1.31-1.30 (d, 3H, J = 7.0

13 Hz, ArCH(CH3)R), 1.20 (s, 3H, q-CH3); C NMR δ (CDCl3): 170.6, 139.2, 137.9, 128.0,

124.6, 123.7, 115.5, 73.4, 47.5, 35.4, 34.6, 19.6, 11.6.; IR cm-1 (KBr pellet): 2967, 2922,

2872, 2850, 1685, 1601, 1484, 1462, 1403, 1383, 1322, 1299, 1242, 1208, 1167.; HRMS

+• 224.1041 ((M+Na) ; 224.1046 calcd for C13H15NNaO).

93 2.4. REFERENCES (1) Fuji, K. Chem. Rev. 1993, 93, 2037. (2) Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105. (3) Meyers, A. I.; Harre, M.; Garland, R. J. Am. Chem. Soc. 1984, 106, 1146. (4) Sundararaman, P.; Schultz, A. G. Tetrahedron Lett. 1984, 25, 4591. (5) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033. (6) Shibasaki, M.; Arai, T.; Emori, E.; Sasai, H. Tetrahedron Lett. 1996, 37, 5561. (7) Trost, B. M.; Ariza, X. Angew. Chem. Int. Ed. 1997, 36, 2635. (8) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590. (9) Stereochemistry of Radical Reactions; Curran, D. P.; Porter, N. A.; Giese, B., Eds.; VCH: Weinheim, 1995. (10) Zard, S. Z.; Cassayre, J.; Gagosz, F. Angew. Chem. Int. Ed. 2002, 41, 1783. (11) Johnson, J. S.; Olhava, E. J.; Evans, D. A. J. Am. Chem. Soc. 2000, 122, 1635. (12) Ghosh, A. K.; Mathivanan, P.; Cappiello, J.; Krishman, K. Tetrahedron Asymm. 1996, 7, 2165. (13) Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1984; Vol. 3, Chapter 7. (14) Ryu, D. U.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388. (15) For a recent review of Cu-catalyzed Diels-Alder reactions, see Reymond, S.; Cossy, J. Chem. Rev. 2008, 108, 5359. (16) Peddibhotla, S.; Jayakumar, S.; Tepe, J. J. Org. Lett. 2002, 4, 3533. (17) Viton, F.; Bernardinelli, G.; Kündic J. Am. Chem. Soc. 2002, 124, 4968. (18) Mita, T.; Ohtsuki, N.; Ikeno, T.; Yamada, T. Org. Lett. 2002, 4, 2457. (19) Paquette, L. A. Tetrahedron 1997, 53, 13971. (20) May, J. A.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 12426. (21) He, S.; Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 2000, 122, 190. (22) Sato, Y.; Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1989, 54, 4738. (23) Overman, L. E.; Poon, D. J. Angew. Chem. Int. Ed. 1997, 36, 518. (24) Ashimori, A.; Matsuura, T.; Overman, L. E.; Poon, D. J. J. Org. Chem. 1993, 58, 6949. (25) Lebsack, A. D.; Link, J. T.; Overman, L. E.; Stearns, B. A. J. Am. Chem. Soc. 2002, 9008. (26) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. USA 2004, 101, 5363. (27) Takemoto, T.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1993, 115, 94 8477. (28) Hulme, A. N.; Henry, S. S.; Meyers, A. I. J. Org. Chem. 1995, 60, 1265. (29) Hino, T.; Nakagawa, M. Alkaloids 1989, 34, 1. (30) Matsuura, T.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6500. (31) Bui, T.; Syed, S.; Barbas III, C. F. J. Am. Chem. Soc. 2009, 131, 8758. (32) Peterson, E. A.; Overman, L. E. Proc. Natl. Acad. Sci. USA 2004, 101, 11943. (33) Nakao, Y.; Ebata, S.; Yada, A.; Hiyama, T.; Ikawa, M.; Ogoshi, S. J. Am. Chem. Soc. 2008, 130, 12874. (34) Smith, C. R.; Lim, H. J.; Zhang, A.; RajanBabu, T. V. Synthesis 2009, 2089. (35) Zhang, A.; RajanBabu, T. V. J. Am. Chem. Soc. 2006, 128, 5620. (36) Sugiyama, H.; Yokokawa, F.; Shioiri, T. Tetrahedron 2003, 59, 6579. (37) Krogsgaard-Larsen, P. Comprehensive Medicinal Chemistry 1990, 3, 493. (38) Falch, E.; Perregaard, J.; Frølund, B.; Søkilde, B.; Buur, A.; Hansen, L. M.; Frydenvang, K.; Brehm, L.; Bolvig, T.; Larsson, O. M.; Sanchez, C.; White, H. S.; Schousboe, A.; Krogsgaard-Larsen, P. J. Med. Chem. 1999, 42, 5402. (39) Simonyi, M. Enantiomer 1996, 1, 403. (40) Calmés, M.; Escale, F.; Martinez, J. Tetrahedron Asymm. 2002, 13, 293. (41) Takano, S.; Goto, E.; Hirama, M.; Ogasawara, K. Chem. Pharm. Bull. 1982, 30, 2641. (42) Oda, K.; Meyers, A. I. Tetrahedron Lett. 2000, 41, 8193. (43) Lloyd, H. A.; Horning, E. C. J. Am. Chem. Soc. 1954, 76, 3651. (44) Walker, G. N.; Alkalay, D.; Smith, R. T. J. Org. Chem. 1965, 30, 2973. (45) Ainge, D.; Ennis, D.; Gidlund, M.; Stefinovic, M.; Vaz, L.-M. Org. Proc. Res. & Dev. 2003, 7, 198. (46) Carr, D.; Iddon, B.; Suschitzky, H.; Parfitt, R. T. J. Chem. Soc., PT1 1980, 2380. (47) Takano, S.; Moriya, M.; Iwabuchi, Y.; Ogasawara, K. Chem. Lett. 1990, 109. (48) Smith, C. R.; Zhang, A.; Man, D.; RajanBabu, T. V. Org. Synth. 2008, 85, 248. (49) Reger, D. L.; Little, C. A.; Brown, K. J.; Lamba, J. J. S.; Krumper, J. R.; Bergman, R. G.; Irwin, M.; Fackler, J. P. Inorg. Synth. 2004, 34, 5. (50) Herrmann, W. A.; Salzer, A. Synthetic Methods of Organometallic and Inorganic Chemistry; Thieme: Stuttgart, 1996; Vol. 1. (51) Barluenga, J.; Trincado, M.; Rubio, E.; González, J. M. J. Am. Chem. Soc. 2004, 126, 3416. (52) Kawahara, M.; Nishida, A.; Nakagawa, M. Org. Lett. 2000, 2, 675.

95 (53) Santos, P. F.; Almeida, P. S.; Lobo, A. M.; Prabhakar, S. Heterocycles 2001, 55, 1029.

96

CHAPTER 3

STRUCTURAL STUDIES OF Ni(II)-PHOSPHORAMIDITE COMPLEXES

3.1. INTRODUCTION

Rational design of catalytically active metal-complexes with desirable properties based on mechanistic insights is one of the most sought after goals in developing new reactions. Until now, many different types of chiral ligands have been designed and applied for the Ni(II)-catalyzed asymmetric hydrovinylation.1,2 Although there is no

direct evidence such as three dimensional structure of a catalyst, it has been clearly

shown that a hemilabile group plays a crucial role in the reaction by increasing stability

of the catalyst,3 improving the enantioselectivity.4,5 Such hemilabile coordination also

decreases the extent of other side-reactions such as olefin isomerizations.2,3

Phosphoramidite ligands developed by Feringa give the best results in Ni(II)-catalyzed hydrovinylation.5,6 However, there is no structural information on the Ni(II)-complexes

with Feringa-type phosphoramidite ligands, and the binding mode of a hemilabile group

with the central metal in the complexes is not known.

97 3.1.1. General Mechanism of HV

Mechanism of Ni-catalyzed asymmetric hydrovinylation has been discussed in depth in previous reports.7-9 Even though there is no unarguable proof, indirect evidence

from many experiments support a mechanism based on a cationic Ni-hydride with a

loosely binding counterion as the active catalytic species for HV (Scheme 3.1). The

dissociation of bromide from (allyl)Ni(PR3)Br complex Ni2, made by reaction with

(allyl)NiBr dimer and a phosphine-containing ligand, is assisted by a Lewis acid. At early stages of the development of HV, Lewis acids such as alkylaluminium halides were used, which caused considerable problems especially with substrates carrying Lewis

basic groups. Coordinatively unsaturated 14-electron Ni-H species Ni7 is generated from (allyl)Ni(PR3)Br (Ni2) and the Lewis acid. Coordination of olefin (Ni4), followed

by migratory insertion and subsequent β-hydride elimination gives a cationic nickel

- Y R X X R R3P=P Lewis ac id Ni Ni Ni Ni Ni Y- X P P P Ni1 Ni2 Ni3 Ni4

X=Cl,Br 16 e 14 e Inactive Active

H R Y- Y- Ni-H complex - Catalyst ? HNi Ni Ni Y Ni7 P P P Ni6 Ni5

Scheme 3.1. Generation of a Cationic Ni(II)-Hydride Complex from (allyl)NiBr Dimer

98 hydride (Ni7). This active Ni-hydride complex Ni7 which is the presumed catalyst is

then bound with hydrovinylation substrate such as a styrene (Scheme 3.2). It is believed

that the chirality transfer from the ligand occurs in the coordination step of styrene.2,10

The resulting complex further reacts with ethylene (Ni10) and undergoes subsequent migratory insertion (Ni11), which makes a new chiral C-C bond.

- ∗ Y HNi Ni-H complex Catalyst ? Ni7 P

Y- ∗ PR Ni+ 3 PR Ni+ Y- Ni11 3 H

Ni8

R3P + Y- Ni

R P - 3 - R3P + Y Ni10 Ni + Y Ni

Ni9' Ni9

Scheme 3.2. Mechanism of Ni-Hydride Catalyzed Hydrovinylation

β-Hydrogen elimination regenerates the catalyst (Ni7) and releases the hydrovinylation

product. According to the proposed mechanism, it is obvious that substrates containing a Lewis basic-group may pose problems in the asymmetric hydrovinylation, because the

99 catalytic Ni-H complex is highly electrophilic. That is, it can be expected that any

Lewis basic group in hydrovinylation substrate may influence the structure and/or

stability of a catalytic species.

So far, several different types of ligands and metals have been developed and

applied for asymmetric hydrovinylation. It was clearly shown that the combined effects

of hemilabile coordination of a ligand component and the counter anion involved are

important for successful asymmetric hydrovinylation. However, there is only one piece

of 31P NMR-based evidence for the existence of hemilabile coordination3 of pendant

group to a metal center. This is at best only a tentative structural information of a

catalyst. Therefore, structural elucidation of active catalytic species and establishing the

role of hemilabile coordination still remain important goals.

3.1.2. Hemilabile Pendant Groups for Hydrovinylation

The structures of a (allyl)Ni(L)+X- complexes and the effect of a hemilabile

coordination11 on hydrovinylation and the stability of metal complexes with several

different counter anions have been discussed by RajanBabu and his coworkers.3 They

describe BINAP ligands with pendant groups for hemilabile coordination to nickel. Those ligands were synthesized and tested for hydrovinylation with different counter-ions

(Figure 3.1).

100 BINAP X = PPh2 Ld X=O-i-Pr X La X=OH Le X=CH2CH3 PPh2 Lb X=OMe(MOP) Lf X = OC(O)CH3 L X=OCHPh L X=P(O)Ph c 2 g 2

Figure 3.1. “Tunable” Hemilabile 2-diphenylphosphino-2’-X-1,1’–binaphthyl Ligands

One of the most well-known chiral bidentate ligands, BINAP did not catalyze the reaction (entry 1, Table 3.1). When hemilabile ligands were used with appropriate

counter-ions, the desired hydrovinylation occurred with good to excellent yields and good

enantioselectivities (entries 2-4, Table 3.1). Hemilabile coordination groups such as an

alkoxy group (entries 2-4, Table 3.1) clearly play a beneficial role in improving the

conversion and enantioselectivity of HV. In addition, it was shown that the combination

of a monophosphine ligand without a hemilabile ligand works best with strongly

– – coordinating counter-ions such as OTf, or ClO4. Phosphine ligands with hemilabile

- – groups work best with weakly coordinating counter-ions such as SbF6 or BARF. The

later combination gave better enantioselectivity.

101

Entry Ligand Group X Yield (%) %ee

1 (R)-BINAP Ph2P 0 -

2 Lb OCH3 > 98 62

a 3 Lc OCH2Ph 93 80

4 Ld O-i-Pr 69 70

5 Le CH2CH3 12 < 3

6 Lf OC(O)CH3 0 -

7 Lg P(O)Ph2 0 -

a Typical procedure: 0.7 mol% [(allyl)NiBr]2 ,(MOP)-NaBARF, ethylene (1 atm); - 70 °C

Table 3.1. Hydrovinylation Using Hemilabile 2-Diphenylphosphino-2’-X-1,1’-binaphthyl

Ligands

In NMR studies using Ni-phospholanes, the stabilities of Ni-phospholanes with different counter-ions had been studied.3 Based on the assumption of a square planar structure, NMR results on the phospholanes have been interpreted.3 According to this report, enantiopure complexes with simple phospholanes ligand showed a single peak in

31P NMR, but it was split into two peaks in the (allyl)Ni(L)Br complex. This observation was explained by the presence of two possible diastereomeric square planar structures of (allyl)Ni(L)Br-complex exo and endo (Figure 3.2). 102 Ph H Ph C H2C P CH2 P Ni

Ni H2CX

H2C X C H

X = Br: 43.10, 42.08 (Stable complexes, no change till - 70 oC): INACTIVE

X = OTf: 43.89, 43.31 (Unstable, fluxional - 20 to - 70 oC): ACTIVE

Figure 3.2. Possible Two Diastereomeric Structures of (allyl)Ni(L)X Complexes

Ligands show single peaks in 31P NMR regardless of the existence of the

hemilabile pendant group, but (allyl)Ni(L)Br complex including the ligand N show two

peaks due to the two possible diastereomeric structures at rt (entry 1 or 2, Table 3.2).

Complex with the ligand H gives a single peak, and it split to two peaks at – 70 oC.

31 Variable temperature P NMR studies of the corresponding SbF6- and BARF-complexes

show significant shift (Δδ ~ 13 ppm) of the 31P NMR peak (entries 3-4, Table 3.2), which

might be responsible for hemilabile coordination.3

Several important observations were made with respect to the stability of the

allyl nickel complex as a function of the ligand and counter ion. (allyl)Ni(L)X

complexes with a combination of a simple phospholane ligand and a coordinating counter

ion such as -OTf is stable, but non-coordinating ion such as -BARF is quite unstable. In case of OBn-phospholane (H) as a hemilabile ligand, BARF-complex is quite stable in room temperature, which can also be an indirect evidence of hemilabile coordination.

103

Ligands 31P NMR in different temperature3 Entries (31P NMR) (allyl)Ni(L)Br (allyl)Ni(L)X X = OTf H 1 27 oC, δ = 43.9, 43.3 P 27 oC, δ = 43.1, 42.1 (1:1) - 70 oC, δ = > 8 peaks o -70 C, δ = no change b N X = BARF 2 δ = 13.2 27 oC, δ = a lot of peaks

OBn X = SbF6 o 3 o 27 C, δ = 23.7 27 C, δ = 37.1 o d P - 70 C, δ = no change (single peak) X = BARFc -20 oC, δ = 36.8, 36.3 4 H 27 oC, δ = 23.6 δ = - 1.06 - 70 oC, δ = no changed a Synthesis and characterization of C2-symmetric phospholane, see ref.3. b Rapid decomposition was reported in preparation at rt. c Stable at rt for several days. d slight shift of the peak (Δδ = ~ 2).

Table 3.2. (Allyl)Ni(L)X Complexes and Their 31P NMR Spectra

Similar to the previous binaphthyl ligands, the absence of a hemilabile pendant group with weakly coordinating counter-ions makes hydrovinylation sluggish (entry 2,

Table 3.3). In sharp contrast, the reaction gives the excellent yield with the moderate enantioselectivity with a coordinative triflate anion (entry 1, Table 3.3). As expected,

104 benzyloxymethyl pendant group completely changes the reactivity pattern. This ligand

H with NaBARF gives the best yield and enantioselectivity (entry 4, Table 3.3).

Moreover, the acetal-containing phospholanes give improved enantioselectivities and quantitative yields (A, B, and C in Table 3.3).12 The chiral acetal appendage in the

ligand B gives better enantioselectivities than that of achiral (A) (entry 6, Table 3.3).

Ethyl- (C) instead of methyl-substituent (B) in the ligands significantly slows down the

Entriesa Ligands Additives Yields/Selectivities

1 H AgOTf 94 % (37 %ee) P 2 NaBARF < 4 % N

OBn 3 AgOTf < 2 %

P 4 NaBARF 97 % (50 %ee) H

R 5 A NaBARF > 99 % (85 %ee) O R O R' 6 P B NaBARF > 99 % (91 %ee)

R' A:R=H,R'=Me 7 B:R=Me,R'=Me C NaBARF 83 % (88 %ee) C: R = Me, R'=Et

a All reactions are the hydrovinylation of styrene using Ni with phospholane ligands.

Table 3.3. Synergistic Effects of Hemilabile Coordination in Hydrovinylation of Styrene

105 reaction (entry 7).

Thus, indirect evidence points to hemilabile coordination of alkoxy group. A

synergistic effect of counter-ion to go with this also appears to be important for

successful asymmetric hydrovinylation. However, there is no direct evidence of

hemilabile coordination in the Feringa-type phosphoramidite ligands which gives the best

yield and enantioselectivity so far.

3.1.3. Structures Metal Complexes with Phosphoramidite Ligands

O Ir P O

PMe3 H2C N CH3

Ph Ph Ir-phosphoramidite complex

PF6 Cl O Ru P O N H Me H Me Np

Ru-phosphoramidite complex

Figure 3.3. Structures and Their Ortep Plots of Ru- and Ir-phosphoramidite Complexes

106 A number of structures of metal complexes with phosphoramidite ligands have

been reported and they show different modes of coordination. In case of a Ru-

13 complex, one of naphthyl group in C2-symmetric amine of the phosphoramidite

coordinates with the metal. In Ir,14 cyclometalation ensues resulting in an

intramolecular C-H activation (Figure 3.3 and Table 3.4).

Entry Bonds Lengths Entry Bonds Angles

1 C(1)-Ru 2.379(2) 1 C(29)-Ir 2.141(4)

2 C(2)-Ru 2.386(2) 2 P(1)-Ir 2.2119(11)

3 P-Ru 2.2783(5) 3 P(2)-Ir 2.3306(14)

4 Ru-Cl 2.3926(6) 4 C(29)-C(30) 1.547(6)

5 Cl-Ru-P 81.07(2) 5 P(1)-Ir-C(29) 80.30(15)

Table 3.4. Selected Bond Lengths and Angles of Ru-13 and Ir-complex14

According to these results, 3-D structure of each complex is quite different. No

nickel complex of Feringa-type phosphoramidite ligands are known.

107 3.2. RESULTS AND DISCUSSION

3.2.1. Structure of a Catalyst

In general, most of reported Ni-complexes have a square planar structure,15-18 so

Ni-phosphoramidite complexes would have the same type of the structure. Even though

there have been recent structural studies on phosphoramidite ligands,7,17 no 3D-structural

information on Ni-complexes of Feringa-type ligands is available in the literature.

At the outset it was not known whether the phosphoramidite complexes would

behave similarly. Accordingly, (allyl)Ni(L)Br complexes (L = phosphoramidite) and

corresponding BARF-derivatives ([(allyl)Ni(L)]+BARF-) were synthesized and their

spectroscopic properties were examined.

L AllylBr 2 L NaBARF + Ni(COD)2 [(allyl)NiBr]2 2(allyl)NiLBr Ni COD, rt CH2Cl 2,rt Ni1 Ni2 BARF- Ni3

F C COD = NaBARF = 3 L = Ph ∗ O BNa ∗ P N 4 O ∗ F C 3 Ph

Scheme 3.3. Syntheses of (allyl)Ni(L)Br and Corresponding BARF Derivatives

108 Ph Ph Ph Sc O O O P N P N Ra P N O O O Sc Ph Ph L L1 (ScSc) L3 (RaScSc) 10 (RaSc)

Ph Ph Ph O O O P N P N P N O O O Ph Ph Ph

L * L1 (RcRc) L3 (RaRcRc) 3 (SaRcRc)

Figure 3.4. Structures of Feringa-type Phosphoramidite Ligands

Syntheses of Ni-phosphoramidite complexes were accomplished according to a modification of the procedures described earlier.3,19 Compared to the original procedure

used for hydrovinylation, [(allyl)NiBr]2 was not isolated and purified. In situ

synthesized dimer was directly used with the phosphoramidite ligands (Figure 3.4) for

further complexation (Scheme 3.3). Recrystallization of the complexes was attempted.

Bromide complex 28a was recrystallized under slow diffusion of outer hexane into an

internal small vial containing the concentrated solution of the complex in

o benzene/CH2Cl2 at - 15 C. In general, the Ni-complexes are unstable and the complexes slowly degradated even in N2-charged drybox at rt. Fortunately, dark-red

single crystal of the (allyl)Ni(L1)Br complex (28a) obtained was suitable for

crystallographic analysis.

109

O CH O HC 2 P Ni N

CH2 Br

AllylNi(L1)Br Hydrogen atoms were omitted for clarity.

Figure 3.5. Structure of (allyl)Ni(L1)Br Complex (28a) and its Ortep Plot

Entry Bonds Lengths Entry Bonds Angles

1 N-P 1.6481(17) 1 N-P-Ni 116.22(6)

2 P-Ni 2.1588(5) 2 P-Ni-Br 97.690(17)

3 Ni-Br 2.3241(3) 3 C(1)-N-P 121.39(13)

4 C(1A)-Ni 2.008(2) 4 C(9)-N-P 116.47(14)

5 C(2A)-Ni 2.003 5 C(1A)-Ni-P 95.70(7)

6 C(3A)-Ni 2.059(2) 6 C(2A)-Ni-P 128.29(8)

7 C(1)-N 1.491(2) 7 C(3A)-Ni-P 167.58(8)

Table 3.5. Selected Bond Lengths and Angles of (allyl)Ni(L1)Br Complex (28a)

110 The structure clearly shows the expected square planar geometry, and Ni

coordinates only with phosphorous even in presence of an amine group due to weak

Lewis basic nature of an amine (Figure 3.5 & Table 3.5).7 Compared to the reported x-

7 ray structure of similar Feringa ligand itself (L3), the two methyl groups of C2- symmetric amine part in the new Ni-complex are pointed in the opposite direction.

Interestingly, the axial chirality of biphenyl-moiety in the Ni-complex synthesized from racemic biphenol is enantiopure R, due to the induced atropisomerism.

This aspect will be discussed in this chapter later.20,21 The corresponding BARF-

complex rather than the bromide is the precatalyst and it is likely that any hemilabile

coordination will be present in this complex.3 However, we were unable to get good

crystals of the BARF salts suitable for X-ray crystallography. Therefore, we relied on

indirect spectroscopic evidence, mostly based on 31P NMR spectroscopy, to gauge the

changes in the coordination environment of the metal.

3.2.2. Synergistic Effects of Hemilabile Coordination and a Counter Ion in Ni-

phosphoramidite Complexes

As mentioned earlier, most of (allyl)Ni(L)Br complexes with an enantiopure

ligand showed 2 peaks in 31P NMR due to slow inter-conversion of two endo/exo

orientation of the allylic group.3 These neutral Ni-complexes with a bromide showed no

significant change in NMR spectrum in case of not only simple phospholane ligand (N, p.

105) but also a similar ligand with the hemilabile OBn group (H, p. 105). That is, NMR

studies did not show any evidence of hemilabile coordination. However, variable

temperature NMR studies on the triflate with H (p. 105) as a ligand showed that the ratio

111 of two isomers changed from 1:1 in room temperature to 2.7:1.0 at 300 K, which tells

that triflate is more fluxional and hence more reactive (Table 3.2).3

Although, hemilabile coordination of a phenyl group in styrene after C-C bond formation had been suggested by DFT calculation,7 it is unclear which group in Feringa- type phosphoramidite ligand plays this role. The NMR data was collected for various

phosphoramidite-nickel complexes, and the results are interpreted based on two assumptions. (1) (allyl)Ni(L)Br complex 28a and 28b (L: 28a = L1, 28b = L3, 28c =

31 L10) would give two peaks in P NMR due to the endo/exo isomers, and (2) the

corresponding BARF complexes would give a different splitting pattern of 31P NMR due

to hemilabile coordination of an atom or a group in C2-symmetric amine which can break

the symmetry of the amine group (Scheme 3.4). Therefore, it can be expected to be

shown more peaks in BARF-complexes. Also, low temperature NMR can freeze out

most of the possible structures to reveal the most stable isomers, thereby simplifying the

NMR pattern. For this purpose, three sets of complexes were prepared, and analyzed by

NMR spectroscopy. In case of symmetric amine-containing ligands L1 and L3, Br-

31 complexes showed 2 peaks P NMR, and corresponding BARF-complexes (L: 29a = L1,

29b = L3, 29c = L10) peaks moved two sets in all cases (Table 3.6). The results of NMR studies can be rationalized by the initial assumptions that free rotation of C2-symmetric

amine group and amine’s lone pair inversion were slowed by hemilabile coordination in

+ - [(allyl)Ni(L)] BARF complexes (29a-c). Non-symmetric amine-containing ligand L10 also gives a similar pattern as other ligands. 31P NMR of Br-complex 28c shows 1:2:1

ratio of three peaks and its BARF-complex behaves like 29a and 29b, i.e., doubling of

these peaks. Presumably this is due to the involvement of the N-arylgroups. Further

112 studies are needed to confirm these conjectures.

H O O O C H2 O C P H2C P N N Ni Ni

H2CX H2C X C H

NaBARF

H O O C H2 O O C P H2C P Ni+ BARF- N Ni + BARF- N

H2C H2C C H

Scheme 3.4. Exchange of an Anion and Corresponding Possible Hemilabile Coordination

113

31P NMR spectraa Ligands (31P NMR) (allyl)Ni(L)Br (28a-c) [(allyl)Ni(L)]+BARF- (29a-c)b

O P N O

L1

δ = 146.4c δ = 152.3, 149.4 δ = 149.4,149.2, 146.1, 145.8.

O P N O

L3 50 145 δ = 145.4 δ = 152.7, 149.4 δ = 147.4, 147.2, 144.3, 144.0c

Ph O P N O

L10 153 152 151 150 149 148 ppm 165 160 155 150 145 140 135 δ = 145.0 δ = 153.0, 150.9, 145.4 δ = 152.6, 152.2, 149.1, 148.7 (1:2:1) (1:1:2:2) a all-complexes were prepared and analyzed at room temperature. b 31 P NMR was recorded using C6D6 in 162 MHz. c CDCl3 was used.

Table 3.6 (allyl)Ni(L)X Complexes and Their 31P NMR Spectra

114 This hemilabile coordination induced splitting of 31P NMR peaks can occur by

two possible modes; 1) one of aryl-group is bounded with cationic Ni strong enough to

completely block the N-inversion, or 2) weak hemilabile coordination significantly slows

down the N-inversion in the amine group, which gives two additional diastereomers of

each of Ni-complex (exo or endo) itself. However, 31P NMR studies did not give a clue

to find what is a real binding-mode based on this rational. In general, this interaction is

so weak that it is hard to be detected, so former case is more probable mode. Moreover,

1 1 + - H- H cosy NMR studies with [(allyl)Ni(L10)] BARF (29c) complex showed two sets of coupling between α-H and CH3 in the amine group (Scheme 3.5).

BARF- O BARF- O O O AllylNi+ P AllylNi+ P N Ph Ph With Hemilablile N Without Hemilablile Coordination Np Np Coordination H CH3 H CH3

H-H Coupling H-H Coupling

+ - Scheme 3.5. H-H Coupling of [(allyl)Ni(L10)] BARF (29c)

31 + - Moreover, variable temperature P NMR studies using [(allyl)Ni(L3)] BARF complex (29b) appear to show that doublet of doublet peaks clearly simplified into one

115 major singlet peak, each of which might suggested that the complex is converted into one

stable single isomer different only in the allylic configuration (exo or endo) (Figure 3.6).

That is, one of the two possible motions in phosphoramidite ligands, allyl rocking and

rotation or lone-pair electron inversion, is mostly blocked at the low temperature. This

assumes that the broad peak at 147.2 is extraneous, an assumption based on the spectrum

of 29a, which shows only two sets of peaks.

31 + - Figure 3.6. Variable Temperature P NMR Spectra of [(allyl)Ni(L3)] BARF Complex

(29b)

116 3.2.3. Induced Atropisomerism of the Biphenyl-phosphoramidite Ligand (L1)

Atropisomerism was defined “a type of stereoisomerism that may arise in

systems where free rotation about a single covalent bond is impeded sufficiently so as to

allow different stereoisomers to be isolated”.22 One of the most well-known examples is

ortho-substituted biphenyls (Eq. 3.1).

A B A B A B (Eq. 3.1) X Y X Y X Y

Due to existence of the atropisomeric motif in many natural products such as alkaloids, lignans, and so forth, asymmetric synthesis of a biaryl sub-unit has received great attention. The most general way of making symmetric as well as non-symmetric biaryls is Pd-catalyzed coupling reactions. Several enantioselective versions of

23 coupling reactions using chiral ligands have been reported. Since the ligand L1 was

synthesized from racemic biphenol, it was expected that L1 would be a mixture of

diastereomers based on the enantiopure amine. Interestingly, L1 showed only one set of

1H, 13C, and 31P NMR peaks, which means that it is most likely a single isomer. One

possible explanation is that if the cyclic phosphoramidite to more stable form is dynamic

kinetic resolution. Alternatively the two atropisomers could be in equilibrium and one

of them is more stable. C2-symmetric amine directs the formation equilibrium of the

axially chiral isomers (Eq. 3.2) into a single isomer. The configuration of an induced

axial chirality has been predicted by the chirality of the corresponding starting materials

117 21 in several independent studies. The solid state structure of (allyl)Ni(L1)Br (28a) clearly shows a single diastereomer of the ligand (L1 (RaScSc), Ra from induced axial chirality)

O O P N P N (Eq. 3.2) O O

That is, X-ray structure of (allyl)Ni(L1)Br (28a) (Figure 3.5) supports the

1 13 assignments. In solution, (allyl)Ni(L1)Br complex (28a) gave only one set of H, C,

and 31P NMR peaks for each of the endo/exo isomers, which indicated that equilibrium is favorable enough for the complex to exist as a pair of isomers that does not include

Atropisomerism of the biphenyls. Temperature dependent 31P NMR studies of

+ - [(allyl)Ni(L1)] BARF complex (29a) show no change in the spectrum from room

at rt at 60 oC

31 + - Figure 3.7. Variable Temperature P NMR of [(allyl)Ni(L1)] BARF Complex (29a)

118 temperature to 60 oC, thus confirming the stability of the two diastereomers with respect

to axial isomerization or nitrogen-inversion at temperature up to 60 oC (Figure 3.7).

3.2.4. Origin of Enantioselectivity and Matched/Mismatched Ligands for Asymmetric

HV

Phosphoramidite ligands have two different sources of chirality in the ligand, axial chirality in the biaryl unit and the chirality of the amine. In previous studies, it was revealed that axial chirality plays a decisive role determining chirality of products in most of cases such as Cu-catalyzed addition.21,24 Distinctive differential efficiencies of

matched/mismatched pairs of chiralities of the biaryl and the amine in Cu-catalyzed

addition had been reported by Feringa24 and Alexakis.21 These results have been confirmed in the asymmetric hydrovinylation of steroidal 1,3-dienes. 25 But, so far it has not been studied on asymmetric hydrovinylation of styrenes. An example is shown in the hydrovinylation of 4-methylenechroman (14) (Table 3.7). As expected, L1 gave

(R)-isomer of 14a with 84 %ee (entry 1, Table 3.7). Entries 2, 3, and 4 in Table 3.6 confirm the result that the asymmetric induction is governed by the axial chirality, not the chirality of the amine group in phosphoramidite ligands. Ligand with matched chirality pair (L3) gave better facial selectivity in the hydrovinylation (entry 3, Table 3.7).

Comparison of entries 2 and 4 also confirm the fact the amine does not play a significant

role in the asymmetric induction. Also, in L1 as we noted earlier the biphenyl chirality

is induced to be of (R).

119 [(allyl)NiBr]2, Ligand

NaBARF, CH Cl O 2 2 O Enantiomeric excess (%)b, Entry Ligand a Configuration

1 L1 (ScSc) 84, R

2 L2 (RaRcRc) 89, R

3 L3 (RaScSc) 94, R

4 L3* (SaRcRc) 87, S

a The structures of ligands, see Figure 3.4. b determined by chiral GC separation (cyclodex B column, 100 oC isothermal), and all ligands gave almost same 70 % conversion to desired HV product.

Table 3.7. Enantioselectivities of Hydrovinylation of 4-Methylenechroman (14)

120 3.3. SUMMARY

Until now, there has been only a limited effort to identify the intermediates in the

hydrovinylation reaction in attempts to delineate the origin of a facial selectivity in this

reaction. This study was aimed at isolating precatalysts and catalytically active

intermediates, and to establish the three-dimensional structures of metal-ligand

complexes. Studying the secondary interaction between a central metal and ligand

component has also been a goal. The hope was that further information for a more

rational design of a better catalyst could be extracted from this study.

In this study, it was clearly shown that at least one of the Ni-complexes with a

phosphoramidite ligand has a square planar structure, and only phosphorous is bound to

Ni as a single bond. Also, absolute configuration of induced axial chirality by the chiral

amine in phosphoramidite ligand L1 prepared from racemic biphenol was confirmed. In

31P NMR experiments, existence of hemilabile coordination of a phenyl group to the

metal core is hinted. Variable temperature NMR studies suggest that different

diastereomers of the resulting complex might be in equilibrium.

It is obvious that chirality of the amine-part of a phosphoramidite governs the

atropisomerism in biphenol-derived Ni-phosphoramidite complexes. The

enantioselectivity appears to be dependent mostly on the chirality of the biaryl unit. The amine component has only a minimal effect.

121 3.4. EXPERIMENTAL PROCEDURES

General Information.

For general information, see the general information in Chapter 2. Ni(COD)2 was purchased from Strem Co. and stored in refrigerator in a Vacuum Atomspheres drybox. Phosphoramidite ligands and NaBARF were freshly prepared by reported

26 procedure. NMR experiments were performed using CDCl3 with CHCl3 (δ 7.24) as an internal standard, and unless otherwise mentioned.

Synthesis of (allyl)Ni(L1)Br (28a) complex from Ni(COD)2.

In a N2-charged drybox, allylbromide (12.7 mL, 0.105 mmol) was slowly added

to a suspension of Ni(COD)2 (27.5 mg, 0.100 mmol) in COD (0.2 mL) at rt. After 10

min, a solution of L1 (43.7 mg, 0.100 mmol) in toluene (0.4 mL) was added to the in-situ

prepared dark blood-red [(allyl)NiBr]2 solution. The resulting solution was stirred at rt for 2 h. Volatile organics were evaporated under reduced pressure and the reddish brown residue was filtered through short celite pad and washed with CH2Cl2. After the

solvent was evaporated, bromide complex was recrystallized by slow diffusion of outer

hexane into concentrated solution of the product in a mixture of benzene and a small

o amount of CH2Cl2 in a small internal vial at around - 15 C. Reddish brown crystal was

obtained and it was suitable for X-ray analysis. The product is quite stable in solution

and in solid state at rt for a few days.

122 Synthesis of AllylNi(L1)Br complex (28a) from [(allyl)NiBr]2.

To a solution of [(allyl)NiBr]2 (10.0 mg, 0.0278 mmol) in CH2Cl2 was added L1

(25 mg, 0.0570 mmol) in CH2Cl2. The resulting solution was stirred at rt for 2 h, and

then the product was purified by celite filtration. This procedure is more convenient for

a small scale for NMR studies and former one is for larger one for making single crystals.

31 1 13 P NMR δ (CD2Cl2): 152.3, 149.4 (~ 1:1). H and C NMR were recorded, but the

spectra were not assigned due to line broadening. For spectra, see appendix.

Synthesis of (allyl)Ni(L1)BARF complex (29a).

Complex of (allyl)Ni(L1)Br (28a) prepared by either of two ways described earlier was dissolved in CH2Cl2 (2 mL), and then NaBARF (51.0 mg, 0.0570 mmol) in

CH2Cl2 (1 mL) was added. The resulting solution was stirred at rt for 2 h, and then the

product was purified by celite filtration. The same recrystallization method was tried,

but no single crystal was formed. Presumably due to the low stability of BARF-

complex in solution at rt, the precipitation of black cloudy material was observed within

31 19 two hours at rt. P NMR δ (CD2Cl2): 149.4,149.2, 146.1, 145.8 (~ 1:1:1:1); F NMR δ

1 13 (CD2Cl2): - 62.61. H and C NMR were recorded, but the spectra were not assigned due

to line broadening and resulting unintelligible nature of the spectra. For spectra, see

appendix.

31 Variable temperature P NMR studies of (allyl)Ni(L1)BARF (29a).

31 Using (allyl)Ni(L1)BARF (29a) prepared by the same way in C6D6, P NMR in

27, 50, and 60 oC were recorded. The NMR data did not show any detectable change

123 with increasing temperature.

Synthesis of (allyl)Ni(L3)Br complex (28b) from Ni(COD)2.

Using L3 (54 mg, 0.100 mmol) with the same scale of the reaction as L1,

(allyl)Ni(L3)Br (28b) was prepared quantitatively. The product is quite stable in

31 solution and solid itself at rt for a few days. P NMR δ (CD2Cl2): 152.7, 149.4 (~ 1:1).

For spectra, see appendix.

Synthesis of (allyl)Ni(L3)BARF complex (29b).

(Allyl)Ni(L3)Br complex (29b) prepared by either of two ways described earlier

was dissolved in CH2Cl2 , and then NaBARF (88.6 mg, 0.100 mmol) in CH2Cl2 was added. The resulting solution was stirred at rt for 2 h, and then the product was purified by celite filtration. The resulting product was immediately analyzed by NMR.

Precipitation of black cloudy material in NMR tube was observed within two hours at rt.

31 19 P NMR δ (CDCl3): 147.4, 147.2, 144.3, 144.0 (~ 1:1:1:1); F NMR δ (C6D6): - 61.86.

1H and 13C NMR were recorded, but the spectra were not assigned due to line broadening.

For spectra, see appendix.

Synthesis of (allyl)Ni(L10)Br complex (28c) from [(allyl)NiBr]2.

Using [(allyl)NiBr]2 (5.00 mg, 0.0139 mmol) and L10 (16.4 mg, 0.0285 mmol),

the reaction was performed. AllylNi(L10)Br (28c) was prepared quantitatively, and the product is quite stable in solution and solid itself at rt for a few days. 31P NMR δ

(CD2Cl2): 153.0, 150.9, 145.4 (1:2:1). For spectra, see appendix.

124 Synthesis of AllylNi(L10)BARF complex (29c).

(Allyl)Ni(L10)Br complex (28c) prepared by either of two ways described earlier

was dissolved in CH2Cl2 , and then NaBARF (25.3 mg, 0.0285 mmol) in CH2Cl2 was

added. The resulting solution was stirred at rt for 2 h, and then the product was purified

by celite filtration. The resulting product was immediately analyzed by NMR.

Precipitation of black cloudy material in NMR tube was observed within two hours at rt.

31 P NMR δ (CDCl3): 152.6, 152.2, 149.1, 148.7 (1:1:2:2); 2D H-H cosy experiment

showed two sets of different CH-CH3 correlations. For spectra, see appendix.

General procedure of hydrovinylation26

In a N2-charged drybox, Shlenk tube was charged with [(allyl)NiBr]2 (1 mol%), ligand (2 mol%), and NaBARF (2 mol%), and then mixture was dissolved in dry CH2Cl2

(5~7 mL/mmol of olefin). The resulting (allyl)Ni(L)BARF pre-catalyst was stirred at rt for 10 min, and then taken out. After ethylene line was connected to the reaction vessel, the line was evacuated 3 times to remove oxygen in a line, and then ethylene was introduced to the vessel. Into the activated catalyst, starting olefin in dry CH2Cl2 (1~2

mL/mmol of olefin) was added, and the resulting mixture was stirred at ambient

temperature under the atmospheric pressure of ethylene. After the reaction, the solvent

was evaporated, and the crude product was purified by column chromatography.

Synthesis of (R)-4-methyl-4-vinylchroman (14a) (entry 3, Table 3.7)

Following the general procedure using 10 mol% of (allyl)Ni(L3)BARF (29b) and

4-methylenechroman (14) (0.20 g, 1.37 mmol) under 35 oC for 12 h, the desired HV

125 product (0.167 g (70 %), pale yellow oil) and the dimeric product (15 %) were obtained

1 after column purification. H NMR δ (CDCl3): 7.15-7.07(m, 2H, Ar), 6.88-6.84 (m, 1H,

Ar),6.81-6.79 (dd, 1H, J = 8.2, 1.2 Hz, Ar), 5.92-5.87 (dd, 1H, J = 17.5, 10.5 Hz,

RCH=CH2), 5.12-5.10 (dd, 1H, J = 10.5, 1.5 Hz, RCH=CH2), 4.87-4.82 (dd, 1H, J = 12.2,

1.2 Hz, RCH=CH2), 4.18-4.13 (m, 2H, ROCH2R’), 1.89-1.86 (m, 2H, ROCH2CH2R’),

13 1.43 (s, 3H, RCH3); C NMR δ (CDCl3): 154.3, 147.5, 128.9, 127.9, 127.7, 120.4, 117.1,

114.2, 62.9, 37.9, 36.1, 27.9; IR cm-1 (neat): 2958, 2829, 1722, 1637, 1605, 1579, 1487,

1443, 1368, 1321, 1223, 1190, 1121, 1064.

GC condition (HP5890 with Cyclodex B column, isothermal 100 oC)- retention time of S- isomer (obtained by ent-9): 47.03 min, R-isomer: 48.76 min; enantiomeric excess 94 %.

Dimer from HV of 4-methylenechroman

Isolated yields of dimer from HV using ligand L1 and L3 were ~ 15 % (a pale

1 yellow oil). H NMR δ (CDCl3): 7.16-7.02 (m, 4H, Ar), 6.84-6.76 (m, 4H, Ar), 5.42-

5.40 (t, 1H, J = 3.8 Hz, vinyl), 4.63-4.62 (d, 2H, J = 3.6 Hz), 4.21-4.18 (m, 1H,

ROCH2CH2R’), 4.14-4.11 (m, 1H, ROCH2CH2R’), 2.89-2.86 (d, 1H, J = 14.0 Hz,

RCH2CR’), 2.71-2.67 (d, 1H, 14.0 Hz, RCH2CR’), 2.00-1.97 (m, 1H, ROCH2CH2R’),

13 1.75-1.69 (m, 1H, ROCH2CH2R’), 1.29 (s, 3H, RCH3); C NMR δ (CDCl3): 154.1, 128.9,

127.7, 127.5, 124.1, 122.8, 121.2, 120.5, 117.2, 116.4, 65.3, 63.0, 42.4, 34.9, 34.5, 29.7.;

IR cm-1 (neat): 3058, 2927, 2856, 1725, 1589, 1578, 1486, 1450, 1347, 1266, 1221, 1165,

1090.

H O H The structure of dimer was confirmed by 2D NMR CouplinginCosy1 Noe 2 H H H H H H Noe 1 experiments, COSY and NOESY. H H Coupling in Cosy 2 O H H

126 3.5. REFERENCES (1) RajanBabu, T. V. Chem. Rev. 2003, 203, 2845. (2) RajanBabu, T. V. Synlett 2008, 21, 853. (3) Nandi, M.; Jin, J.; RajanBabu, T. V. J. Am. Chem. Soc. 1999, 121, 9899. (4) Francio, G.; Faraone, F.; Leitner, W. J. Am. Chem. Soc. 2002, 124, 736. (5) Smith, C. R.; RajanBabu, T. V. Org. Lett. 2008, 10, 1657. (6) Feringa, B. L.; Pineschi, M.; A., A. L.; Imbos, R.; de Vries, A. H. M. Angew. Chem. Int. Ed. 1997, 36, 2620. (7) Holscher, M.; Francio, G.; Leitner, W. Organometallics 2004, 23, 5606. (8) Joseph, J.; RajanBabu, T. V.; Jemmis, E. D. Organometallics 2009, 28, 3552. (9) RajanBabu, T. V.; Nomura, N.; Jin, J.; Radetich, B.; Park, H.; Nandi, M. Chem. Eur. J. 1999, 5, 1963. (10) Saha, B.; RajanBabu, T. V. J. Org. Chem. 2007, 72, 2357. (11) Bader, A.; Lindner, E. Coord. Chem. Rev. 1991, 108, 27. (12) Zhang, A.; RajanBabu, T. V. Org. Lett. 2004, 6, 1515. (13) Huber, D.; Kumar, P. G. A.; Pregosin, P. S.; Mezzetti, A. Organometallics 2005, 24, 5221. (14) Kiener, C. A.; Shu, C.; Incarvito, C.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 14272. (15) Barnett, B. L.; Krüger, C. J. Organomet. Chem. 1974, 77, 423. (16) Suzuki, T.; Morikawa, A.; Kashibawara, K. Bull. Chem. Soc. Jpn. 1996, 69, 2539. (17) Diez-Holz, C. J.; Boing, C.; Francio, G.; Holscher, M.; Leitner, W. Eur. J. Org. Chem. 2007, 2995. (18) Rufińska, A.; Goddard, R.; Weidenthaler, C.; Bühl, M.; Pörschke, K.-R. Organometallics 2006, 25, 2308. (19) Shi, W.-J.; Zhang, Q.; Xie, J.-H.; Zhu, S.-F.; Hou, G.-H.; Zhou, Q.-L. J. Am. Chem. Soc. 2006, 128, 2780. (20) Mikami, K.; Korenaga, T.; Terada, M.; Ohkuma, T.; Pham, T.; Noyori, R. Angew. Chem. Int. Ed. 1999, 38, 495. (21) Alexakis, A.; Rosset, S.; Allamand, J.; March, S.; Guillen, F.; Benhaim, C. Synlett 2001, 9, 1375. (22) Moss, G. P. Pure Appl. Chem. 1996, 68, 2193. (23) Lloyd-Williams, P.; Giralt, E. Chem. Soc. Rev. 2001, 30, 145. (24) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346.

127 (25) Saha, B.; Smith, C. R.; RajanBabu, T. V. J. Am. Chem. Soc. 2008, 130, 9000. (26) Smith, C. R.; Zhang, A.; Man, D.; RajanBabu, T. V. Org. Synth. 2008, 85, 248.

128

CHAPTER 4

Pd(II)- AND Ni(II)-CATALYZED ISOMERIZATIONS OF TERMINAL ALKENES

4.1. INTRODUCTION

Isomerization of allylic derivatives1 has been developed for various synthetic

applications such as a removal of allylic-protecting group,2 and a preparation of chiral

vinyl-amines3 and ethers4. Since 1964, metal-catalyzed isomerization has been known

using various metals such as Pt,5 Rh,5 Pd,6 and Ni7. However, these methods are far

from a practical use, due to a low conversion and/or other side-reactions. The

stereoselectivity of the reaction is dependent upon the metal complexes and the

isomerization conditions. Even though the same type of metal-hydride catalyzed

reaction mechanism was proposed for both reaction conditions, Ni(o-tol3P)3/HCl gives

7 + - the highest Z-selectivity, whereas [Ir(PCy3)3] BPh4 delivers E-selectivity in the

isomerizations of allylethers.8

4.1.1. Notable Developments

Two recent examples reported significant improvements in the classical methodology. Nelson and his coworkers reported an Ir-catalyzed isomerization of an

129 allylic ether to yield a highly selective E-vinylether for in situ Claisen rearrangements

(Scheme 4.1).9,10 This Ir-catalyzed isomerization – initially developed by Felkin11

H

o O Ir(COE)Cl2,PCy3,NaBPh4 O 39 CO o Ph CH 2Cl 2/Acetone (50:1), 23 C Ph Ph 80 % E,E:Z,E >95:5 (syn:anti 94:6)

Scheme 4.1. Ir-catalyzed Isomerization of an Allylic Ether and Claisen Rearrangement of the Product

– gave the desired isomerization products in quantitative yields and high E-selectivity.

Another example is an isomerization catalyzed by ‘thermally modified’ Grubbs II catalyst developed by Hanessian (Eq. 4.1).12 This reaction was successfully used to isomerize

terminal olefins even in densely functionalized substrates with good to excellent yields.

Mes N N Mes Cl Ph Ru NHBoc Cl 10 mol% NHBoc PCy3 MeO MeO CO Me CO Me (Eq. 4.1) 2 MeOH, 60 oC 2 O O 96 % (E:Z 4:1)

130 However, both conditions have significant drawbacks. First, these reactions are only

applied for mono-substituted terminal double bonds, and no reaction of di-substituted

substrates has been reported. In addition, the Grubbs II-catalyzed conditions suffer from

harsh reaction conditions such as high temperature in a protic solvent, and also it had

inherent selectivity issue arising from original metathesis reactions. In case of the Ir-

and Ru-catalyzed isomerization, limited scope is to mainly due to extensive isomerization

such as ‘an alkene zipper’ (Scheme 4.2).13,14,15 Therefore, further exploration of regio-

and stereo-selective isomerization of a terminal double bond is an important goal.

[Ir(COE)PCy ]+BPh - (2 mol%) 3 4 Ir - 94 % (E only) CH2Cl2/Actone (50:1), rt, 3 h OTBS OTBS or Ru-Catalyst (5 mol%) Acetone-d6,70oC, 4 h Ru - 90 % (E only)

Ru-Catalyst Cp PF Ru 6 CH3CN P N N

(CH2)n O (CH2)n OH Ru-Catalyst, Acetone-d6,70oC a (n = 3) a - 97 % (2 mol% of cat., 1 h) b (n = 9) b -97%(5mol%ofcat.,4h) c (n = 30) c - 81 % (30 mol% of cat., 3 d)

Scheme 4.2. Extensive Isomerizations of Terminal Alkenes using Ir- or Ru-catalysis

131 4.1.2. Isomerizations During Hydrovinylation and Cycloisomerization

During the development of Ni and Pd catalyzed C-C bond formation reactions

such as cyclization of α, ω-dienes (Eq. 4.2) and hydrovinylation of vinylarenes for the

synthesis of (-)-physostigmine (chapter 2, Scheme 4.3), often a small amount of a

competing isomerization by double bond migration was detected. This is most likely

Z [(allyl)PdCl]2,AgOTf Z Z + (Eq. 4.2) Z Z Z o-Tol 3P, CH2Cl 2 20 % 70 % Z=CO2Me

caused by the in situ generated cationic metal hydride. Under these conditions, a

complex mixture of isomers was formed with low conversions, which rendered such

reactions less useful.16 If these reactions can be optimized for a regio- and stereo- selective isomerization of terminal alkenes, it could be quite useful for subsequent

synthetic operations. Preparations of di- or tri-substituted internal olefins by Wittig or

metathesis reactions sometimes suffer from low stereoselectivity and low yield due to sensitivity of sterically demanding substrates or otherwise incompatible functional groups within the molecule.17,18 Hence, the isomerization of a compound with a terminal

double bond prepared from a ketone, aldehyde or by allylation of an appropriate

electrophile could lead to more practical routes.19

132 BnO [(all yl)Ni Br] 2, L, NaBARF BnO NPhth NPhth Ethylene, CH Cl ,35oC 4e 2 2 6 69 % +

L = Ph BnO O Me NPhth P N 4e' 15 % O Me Ph

[(allyl)NiBr]2, L, NaBARF + o Ethylene, CH2Cl2,35 C 17 18 18' 71 % 29 %

Scheme 4.3. Isomerizations During Asymmetric Hydrovinylation

133 4.2. RESULT AND DISCUSSION

The proposed mechanism of the double bond migration is shown in scheme 4.4, which is based on what is known about other similar reactions such as hydrovinlyation catalyzed by a metal hydride.16,20

AgOTf X PPh3 PPh3 M M M M+ - + - OTf X PPh3 OTf PPh3 M=Ni,Pd M+ X=Cl,Br -OTf

- - OTf Ph3P + OTf + M HM M+ PPh PPh 3 3 H -OTf R2 R 1 R2 R1 PPh3 H + M -OTf R1 R R2 2 R - 1 OTf - Ph3P + OTf Ph P R M 3 M+ 2 C R R2 H 1 R1 A B

Scheme 4.4. Proposed Mechanism of Metal-Hydride Catalyzed Isomerization of Alkenes

The cationic metal hydride is inserted into an unsymmetrical double bond to give two different regio-isomeric alkyl-metal intermediates. The more substituted metal- intermediate B can preferentially produce internal double bond as a result of inherent

134 thermodynamic stability by a subsequent β-hydride elimination.

Initially, [(allyl)PdCl]2 was tried instead of [(allyl)NiBr]2, due to its relative

stability and commercial availability. Instead of a chiral phosphoramidite often used in

the hydrovinylation reactions, simple phosphines were applied, and silver triflate was

used as a substitute for NaBARF. Using this simplified catalytic system to generate

metal-hydride, isomerization of disubstituted terminal alkenes were tested on substrates

17 and 4e to find optimized condition (Table 4.1).

Based on proposed mechanism, any alkene including the isomerization substrate

can generate a metal-hydride by reacting with an allyl-metal complex (Scheme 4.4).

Since the reaction without an additive did not give any product from the di-substituted

exomethylene compound 4e (entries 1 and 6, Table 4.1), ethylene and diallylether were

tested as additives to generate the cationic metal hydride. As an operationally easier

way, generation of a metal-hydride by cycloisomerization of diallylether is a well-known

method.21,22 In the case of a simple bicyclic exomethylene substrate, 4-methylene

tetrahydronaphthalene, both Ni and Pd catalysts gave excellent conversions to the product with an internal double bond (entries 2-4, Table 4.1), regardless of the type of additives.

In case of heteroatom functionalized substrate 4e, although it needed higher catalyst loading and temperature, it gave the desired product with quite good yields and surprisingly good E-selectivities with both additives (entries 9 and 10, Table 4.1). Ni- catalyzed hydrovinylation condition (entry 5, Table 4.1) or Pd-catalyzed condition without additives (entry 6, Table 4.1) gave low conversions.

135

Catalyst(mol%) & Temp. (oC) Conv. (%) Entry Substrates additive (time or mol%)a & time (E/Z)b

[(allyl)NiBr]2 (5) 1 25, 24 h NR 1 atm Ethylene c [(allyl)NiBr]2 (1) 2 25, 2 d > 99 Diallylether (1)

[(allyl)lPdCl]2 (5) 3 17 25, 2 d 90c 1 atm Ethylene(20min)

[(allyl)PdCl]2 (1) 4 25, 1.5 d 90d Diallylether (1)

[(allyl)NiBr]2 (5) 5 35, 2 d < 5 1 atm Ethylene

[(allyl)PdCl]2 (5) 6 OBn 35, 2 d NR No additive

[(allyl)PdCl]2 (5) 7 35, 2 d 39 (>16:1) 1 atm Ethylene(2day) O N [(allyl)PdCl]2 (5) 8 O 35, 2 d 60 (>16:1) 1 atm Ethylene(20min)

[(allyl)PdCl]2 (8) 9 4e 35, 2 d 79 (15:1) 1 atm Ethylene(20min)

[(allyl)PdCl]2 (8) 10 35, 2 d 79 (8/1) Diallylether (8) a b 1 All reactions were used [(allyl)MX]2, PPh3, AgOTf, and additive in CH2Cl2; Determined by H and the structures of the isomerized products, see Scheme 4.3.; c NMR NaBARF was used instead of AgOTf.; d 10 % of unidentified compound was detected.

Table 4.1. Isomerizations of Disubstituted Exomethylene Double Bonds

136 Excess ethylene gas used for the generation of a cationic metal hydride all throughout the

reaction under the Pd-catalyzed conditions appears to decrease the reactivity of an active

catalytic species (entry 7, Table 4.1). If the ethylene is removed after 20 min of starting

the reaction, higher yields are obtained (entry 8, Table 4.1). Even though diallylether

condition has an operational advantage, ethylene procedure gave a higher selectivity

(entry 9 vs 10, Table 4.1). It is unclear why Ni-complex using ethylene as an additive

did not catalyze the reactions (entries 1 and 5, Table 4.1).

The optimized reaction conditions were successfully applied to other substrates

shown in Table 4.2. All substrates gave the desired isomerized products in excellent

yields with good E-selectivities where stereochemistry is relevant (entries 1-3, Table 4.2).

It is unclear why E/Z ratio is so drastically different in the case of entry 4. Furan-

containing substrate 32 underwent polymerization (entry 5, Table 4.2).

137

Entry Alkenes Time (h)a Products, yields (%) (E:Z)

1b 8 30 30a, 94 (-)

2b 16 Cl 30b Cl 30c, 87 (19:1)

3b 20 31 31a, 97 (9:1)

4b 12 31b 31c, 99 (2:1)

O 5b -- Polymer 32

a b [(allyl)PdCl]2 (5 mol%), (o-tol)3P (10 mol%), AgOTf (10 mol%), CH2Cl2 (0.05 M).; Performed by Craig R. Smith. For experimental details, see ref. 15.

Table 4.2. Isomerizations of HV’s Substrates for All-carbon Quaternary Centers

A vinylarene with α-(2-siloxyethyl) group or one carrying an ortho-nitro group did not undergo the migration (Figure 4.1), either because the TBS group is incompatible with the reaction conditions or the o-nitro group introduces steric problems. It is possible that the o-nitro group makes the alkene electron-poor thus reducing its reactivity in the metal hydride addition.

138 O MeO BnO N OTBS

NO2 O 3e 4c

Figure 4.1. Unreactive Substrates for Pd-catalyzed Isomerization

The substrates shown in Table 4.1 were tested using the two other representative

isomerization procedures for direct comparisons (Table 4.3). In the case of 4-methylene

tetrahydronaphthalene, the Pd-catalyzed reaction gave 90 % yield of the product (entry 1,

Table 4.3). Ir-catalyst did not catalyze the reaction at all, and the starting material was

fully recovered. Grubb II condition gave small amounts of the product. In case of

more functionalized styrene (4e), Pd-catalyst with an additive such as ethylene or

diallylether, gave the desired product in good yields and selectivities as mentioned before

(entry 4, Table 4.3). However, Ir-catalyst did not catalyze the reaction at all (entry 6,

Table 4.3), so starting material was fully recovered. Grubb II condition gave small

amount of the desired product (entry 2, Table 4.3), but it is unclear whether thermal protic

condition gave the product without metal. That is, Pd(II)-catalyzed isomerization is the

only catalytic system to isomerize disubstituted terminal double bonds with a high yield

and selectivity.

139

Entry Substrate Cat (Mol%)a Time & Temp Yields (%)

Pd (1) 1 2 d at rt 90 (diallylether) 2 Grubbs II (10) 1 d at 60oC 7 17 3 Ir (2) 3 h at rt Trace

Pd (16) o 79 4 O 2 d at 35 C BnO (allylether) (E/Z 8:1) N o 5 O Grubbs II (10) 1 d at 60 C 7

6 4e Ir (2) 3 h at rt Trace

a 12 9 Pd – [(allyl)PdCl]2 (0.5eq.), o-Tol3P(1eq.), AgOTf(1eq.), CH2Cl2; Grubbs II – Grubbs II , MeOH; Ir – b [Ir(COE)Cl]2 (0.5eq), PCy3,(3eq.) CH2Cl2/Acetone(50:1), NaBPh4 (1eq.).; For the preparation of both substrates, see experimental section in chapter 2.

Table 4.3. Comparison of Pd, Ru, and Ir Catalysts for Isomerization of Alkenes with

Geminal Disubstituted Double Bonds

In case of mono-substituted double bonds, isomerization occurred much easier than disubstituted substrates (Table 4.4). Initially, the reaction was done under ethylene to help generate ‘metal-hydride’ but soon it was discovered that an additional additive was not needed for mono-substituted substrates. Both Ni- and Pd-catalysts gave the desired isomerized product 36a in excellent yields (entries 1-2, Table 4.4). Even O- methoxyphenyl protected but-1-enol 37 was isomerized under optimized Pd-catalyzed

140

Time (h) & Products, yields Entry Substrates Catalyst (mol%)b Temp. (oC) (%) (E/Z)c

Ni (0.7), PPh3 (1.4), > 95 (3.5:1.0) 1 TBDMSO 4, - 55 AgOTf (1.4), ethylene TBDMSO

36a Pd (0.5), o-tol3P (1.0), 2 36 24, rt AgOTf (1.0) 80 (3.7 :1.0)

MeO MeO Pd (2.5), o-tol3P (5.0), 3 O 24, rt O 37a AgOTf (5.0) 37 96 (5.9:1.0)

Pd (0.5), PPh3 (1.0), 4a 2, rt 35a AgOTf (1.0) 35 90 (-)d

MeO2C MeO2C Pd (5), o-tol3P (10), 5a 24, rt 34a AgOTf (10) 34 90 (3.6:1.0)

a Pd (5), o-tol3P (10), 6 TBSO 24, rt TBSO 33a AgOTf (10) 33 92 (8:1) a Substrate preparations and isomerizations was performed by Branko Radetich. For experimental details b of these substrates, see Branko Radetich Ph.D. thesis or ref. 15.; .Pd = [(allyl)PdCl]2, Ni = [(allyl)NiBr]2; c Determined by GC or NMR; d Mixture of E/Z, configuration was not determined.

Table 4.4. Isomerizations of Mono-substituted Terminal Alkenes

141 condition in 95 % yield (entry 3, Table 4.4)!! Moreover, the substrate 35 containing two

double bonds gave 35a in excellent regioselectivities and yields (entry 4, Table 4.4). It

is also noteworthy that these isomerization conditions were extremely selective only to

terminal double bonds, and presence of an internal double bond or a triple bond (entries

5-6, Table 4.4) does not cause any problems. The triene 34 gave clean product 34a

arising from only terminal olefin isomerization. Also, the enyne 33 gave the desired

isomerized product 33a without a bisalkylidene from an enyne cyclization.23,24

Mono-substituted alkenes were also subjected to Ir- and Ru-catalyzed reaction conditions for a direct comparison with the Pd- and Ni-catalyzed reactions. Compared to highly selective Ni- or Pd-catalyzed reaction conditions (entries 1 and 4 Table 4.5), Ir- catalyzed reaction condition gave E-vinylethers 36b and 37b as major products by uncontrollable extensive isomerization (entries 3 and 6, Table 4.5). Also, Ru-catalyzed

reaction gave inseparable mixtures of compounds (entries 2 and 5, Table 4.5). These

results clearly show the advantages of the new Ni- or Pd-catalyzed isomerization

protocols.

142

Cat(Mol%)a & Time (h) & Product, Yields (%) Entry Substrate Additives temp (oC) (E/Z) Pd (1) 1 24, rt 36a, 80 (3.7:1) No additive

b 2 OTBS Grubbs II (10) 12, 60 -- 36 OTBS 3 Ir (2) 3, rt 36b 94 (E only) Pd (5) 4 24, rt 37a, 96 (5.9:1) No additive

5 MeO Grubbs II (10) 12, 60 -- b

O MeO 37b 37 O MeO 6 Ir (2) 3, rt + 37c O 96 (37b:37c = 3.5:1) a Ni - [(allyl)NiBr]2 (0.5eq.), Ph3P(1eq.), AgOTf(1eq.), and CH2Cl2; Pd – [(allyl)PdCl]2 (0.5eq.), 12 9 o-Tol3P(1eq.), AgOTf(1eq.), and CH2Cl2; Grubbs II – Grubbs II , MeOH; Ir – [Ir(COE)Cl]2 (0.5eq), b PCy3,(3eq.) CH2Cl2/Acetone(50:1), NaBPh4 (1eq.).; inseparable mixture of various compounds.

Table 4.5. Comparison of Pd, Ru, and Ir Catalysts for Isomerization of Alkenes with

Mono-substituted Terminal Double Bonds

143 4.3. SUMMARY

Efficient regioselective isomerizations of terminal double bonds catalyzed by cationic Pd- or Ni-hydride catalysts were developed. Commercially available

[(allyl)NiBr]2 or [(allyl)PdCl]2, o-Tol3P, and AgOTf were used to generate cationic allyl-

metal complexes as pre-catalysts to generate a cationic metal-hydride species for the isomerization of terminal double-bonds. Readily prepared [(allyl)NiBr]2 also enables

the isomerization under similar conditions. In case of di-substituted double-bonds

isomerization, additives such as ethylene or diallylether were necessary but none was

needed for the mono-substituted substrates. Compared to two known catalysts,

[Ir(COE)Cl]2/PCy3-system and the Grubbs II metathesis catalyst, only Pd-catalyst can

catalyzed the clean isomerization of di- and mono-substituted double-bonds without

further uncontrollable isomerization. The described protocols are the first practical and regioselective examples of metal-catalyzed isomerization reactions of mono-substituted terminal olefins.

144 4.4 EXPERIMENTAL PROCEDURES

General Information.

For general information, see beginning of the experimental section in Chapter 2.

All isomerization reactions were carried out under a nitrogen atmosphere by using

Schlenk techniques or with the aid of a Vacuum Atomspheres drybox. NMR

experiments were performed using CDCl3 with CHCl3 (δ 7.24) as an internal standard.

25 [(allyl)NiBr]2 was prepared from Ni(COD)2. [(Allyl)PdCl]2 and Grubbs second

generation metathesis catalyst were purchased from Sigma-Aldrich Inc. [IrCl(COE)2]2 was prepared by reported procedures.9 All Ni-, Pd-, and Ir- reagents were stored in the

drybox.

Attempted isomerization of 1-methylene-2,3,4-trihydronaphthalene 17 under Ni(II)-

catalyzed hydrovinylation conditions. General Procedure A (entries 1, 5, Table 4.1 &

entry 1, Table 4.4).

Ni(II)

ethylene

To a flame dried 3-necked flask, allylnickel chloride dimmer, phosphine ligand

and the counter ion were mixed in that order in CH2Cl2 solution in a drybox. After the

precipitated AgBr was removed by filtration though celite, the solution was taken out of

the drybox and was connected to an ethylene line. The system was evacuated and refilled

with ethylene 3 times. To the resulting complex was added the terminal alkene in CH2Cl2 dropwise at room temperature. After stirring for the prescribed time (Table 4.1) all

145 volatile materials were removed and the product was purified by column chromatography.

Gas chromatography and NMR showed complete recovery of starting materials.

Use of [(allyl)PdCl]2/phosphine/AgOTf activated by ethylene for the double bond

migration. General procedure B (entries 3 & 7-9, Table 4.1).

In a flame dried 3-neck flask, [(allyl)PdCl]2, PPh3, AgOTf were dissolved in

distilled CH2Cl2 in a glove box. After the reaction vessel was taken out of the box, an

ethylene line was connected to the vessel and the line was evacuated, then ethylene was

introduced. The process was repeated 3 times. The resulting monomeric allylic Pd

complex was stirred for 20 min under 1 atmosphere of ethylene at rt, and then an

exomethylene substrate in CH2Cl2 was added dropwise. The ethylene line was exchanged

for a N2 atmosphere, the resulting mixture was stirred at ambient temperature for the

prescribed time. All volatile materials were evaporated, and then the mixture was filtered using a short pad of silica gel EtOAc/Hex solvent. The product was analyzed by GC and

NMR.

Use of [(allyl)PdCl]2/phosphine/AgOTf activated by diallylether for the double bond

migration. General procedure C (entries 4, 10, Table 4.1 & entries 1, 4, Table 4.3).

To a premixed allyl Pd complex in CH2Cl2 which was prepared in the same

fashion as in the previous experiment, an equivalent amount of diallylether was added

instead of ethylene and then the mixture was stirred at rt for 20 min. The substrate

dissolved in CH2Cl2 (1 M) was added to the catalyst solution dropwise, and the resulting

mixture was stirred at ambient temperature for the indicated time. The product was

146 purified and analyzed as indicated before.

Use of [(allyl)PdCl]2/phosphine/AgOTf without any additive for the double bond

migration. General procedure D (entry 6, Table 4.1 & entries 1-5, Table 4.2 &

entries 2-6, Table 4.4 & entries 1, 4, Table 4.5).

To a premixed allyl Pd complex in CH2Cl2 which was prepared in the same

fashion as in the previous experiment (General procedure B), a substrate dissolved in

CH2Cl2 (1 M) was added to the catalyst solution dropwise, and the resulting mixture was

stirred at ambient temperature for the indicated time. The product was purified and

analyzed as indicated before.

Isomerization of 1-methylene-2,3,4-trihydronaphthalene 17 using diallylether (entry

3, in Table 4.1).

Ni(II)

Allylether

The pre-catalyst was prepared as follows in a glovebox: To [(allyl)NiBr]2

(10.8 mg, 0.03 mmol) in CH2Cl2 (1 mL) were added PPh3 (15.7 mg, 0.06 mmol) and

NaBARF (53.0 mg, 0.06 mmol). The catalyst solution prepared above was removed from the drybox, and diallylether (3.7 μL, 0.03 mmol) was added as a single portion under nitrogen and the mixture was allowed to stir for 2 min to form the active catalytic species. A solution of the substrate 17 (433 mg, 3.00 mmol) in 3 mL of CH2Cl2 was

added dropwise over a period of one minute and the reaction was allowed to proceed for

2 d. The resulting product was filtered by flash column chromatography (eluted with

147 isocratic pentane) to get the desired product 18’ (0.35 g, 82 %) as a colorless oil, which

was then used to acquire all analytical data without further purification. 1H NMR δ

(CDCl3): 7.23-7.17 (m, 2 H), 7.15-7.10 (m, 2 H), 5.85-5.83 (m, 1 H), 2.75 (t, J = 8.0 Hz,

13 2 H), 2.26-2.20 (m, 2 H), 2.04 (dd, J1 = 3.2 Hz, J2 = 1.6 Hz, 2 H). C NMR δ (CDCl3):

136.3, 135.9, 132.3, 127.3, 126.7, 126.3, 125.4, 122.8, 28.3, 23.2, 19.3.

Isomerization of 2-(3-(3-(benzyloxy)phenyl)but-3-enyl)isoindoline-1,3-dione 4e.

General procedure A (entry 9, Table 4.1).

BnO Pd(II) NPhth BnO NPhth Ethylene

In a 3-neck flask, [(allyl)PdCl]2 (2.4 mg, 0.0061 mmol), PPh3 (3.7 mg, 0.013

mmol) and AgOTf (3.4 mg, 0.013 mmol) were dissolved in dry CH2Cl2 (3 mL) in a glove

box. After the reaction vessel was taken out from a box, an ethylene line was connected up to the vessel and line was evacuated, and then ethylene was introduced. This process was repeated 3 times. The resulting Pd complex was stirred for 20 min under 1 atm of ethylene atmosphere at rt, and then the exomethylene substrate (29 mg, 0.076mmol) in

CH2Cl2 (1 mL) was added dropwise. Ethylene atmosphere was changed for a N2 atmosphere, the resulting mixture was stirred at 35 oC for 2 d. All volatile materials

were evaporated, and then the mixture was purified by flash column chromatography to

get 28 mg (79%) of the desired product 4e’ contaminated with 21% of starting olefin, E/Z

1 = 15:1). H NMR δ (CDCl3): 7.90 - 7.69 (m, 4 H, phthalimidyl), 7.49 - 7.29 (m, 5 H,

Ar), 7,19 (t, J = 6.4 Hz, 1 H, Ar), 7.05 - 6.85 (m, 2 H, Ar), 6.84 - 6.79 (m, 1 H, Ar), 5.85

(t, J = 7.0 Hz, 1 H, Ar(CH3)C=CHCH2N-phth), 5.03 (s, 2 H, OCH2Ph), 4.50 (d, 7.5 Hz, 2

148 H, Ar(CH3)C=CHCH2N-phth, E), 4.22 (d, 6.5 Hz, 2 H, Ar(CH3)C=CHCH2N-phth, Z),

2.23 (s, 3 H, Ar(CH3)C=CHCH2NPhth, E), 2.01 (s, 3 H, Ar(CH3)C=CHCH2N-phth, Z);

The configuration of the major product was established by nOe studies.

H N-phth X BnO H H nOe 13 C NMR δ (CDCl3): 168.4, 144.5, 139.4, 137.3, 134.1, 132.5, 129.6, 128.1, 127.8, 123.4,

121.6, 119.1, 113.7, 113.1, 70.2, 36.5, 16.4. HRMS 406.1400 (M+Na+• ; calcd for

C25H21NNaO3 406.1419)

Isomerization of 1-methylene-2,3,4-trihydronaphthalene 17 using Grubbs second- generation catalyst (entry 2, Table 4.3, Hanessian’s procedure26)

Grubbs II

Using the same procedure and the catalyst (10 mol%) for the isomerization of 37

(entry 5, Table 4.5), the isomerization of olefin 17 (15.0 mg, 0.104 mmol) was checked.

The crude product was purified by short column chromatography, and analyzed by 1H

NMR.

Isomerization of 1-methylene-2,3,4-trihydronaphthalene 17 using Ir-catalyst (entry

3, Table 4.3, Nelson’s procedure 8).

Ir-cat.

Using the same procedure for the isomerization 37 (entry 6, Table 4.7) and 5

149 mol% of Ir-catalyst (2.5 mol% of [IrCl(COE)2]2, 7.5 mol% of PCy3, and 5 mol% of

NaBPh4) aforementioned, the isomerization of di-substituted olefin (15.0 mg, 0.104

mmol) was checked. The crude product was purified by short column chromatography,

and analyzed by 1H NMR.

Isomerization of 2-(3-(3-(benzyloxy)phenyl)but-3-enyl)isoindoline-1,3-dione 4e using

Grubbs second-generation catalyst (entry 5, Table 4.3, Hanessian’s procedure26)

BnO Grubbs II BnO NPhth NPhth

Using the same procedure and catalyst (10 mol%) for the isomerization of 37

(entry 5, Table 4.5), the isomerization of olefin 4e (10.0 mg, 0.0261 mmol) was checked.

The crude product was purified by short column chromatography, and analyzed by 1H

NMR.

Isomerization of 2-(3-(3-(benzyloxy)phenyl)but-3-enyl)isoindoline-1,3-dione 4e using

Ir-catalyst (entry 6, Table 4.3, Nelson’s procedure8)

BnO Ir-cat. NPhth BnO NPhth

Using the same procedure for the isomerization of 37 (entry 6, Table 4.5) and 5

mol% of Ir-catalyst (2.5 mol% of [IrCl(COE)2]2, 7.5 mol% of PCy3, and 5 mol% pf

NaBPh4) aforementioned, the isomerization of di-substituted olefin (10.0 mg, 0.0261

mmol) was checked. The crude product was purified by short column chromatography,

and analyzed by 1H NMR.

150 Synthesis and Isomerization of tert-butyl(hex-5-enyloxy)dimethylsilane (36) by

Ni(II)-catalyst. General procedure A (entry 1, Table 4.4).

Ni(II) OH OTBS OTBS

To a solution of 0.581 g (5.81 mmol) of 5-hexene-1-ol in 5 mL of DMF at 0 oC

under nitrogen was added 1.19 g (17.4 mmol) of imidazole and 1.31 g (8.72 mmol) of t-

butyldimethylsilyl chloride. The mixture was stirred at rt for 2 days and subsequently

quenched with 10 mL of water. The aqueous layer was extracted 3 times with 10 mL

portions of ether. The combined organic layers were washed with 2N aqueous NaOH

solution and brine, dried over MgSO4 and concentrated in vacuo. The residue was

purified by flash chromatography on silica gel, eluting with hexane/ethyl acetate (98:2),

to get TBS-protected hex-5-en-1-ol 36 as clear oil (1.19 g, 96%). 1H NMR (250 MHz,

CDCl3): 0.05 (s, 6 H), 0.90 (s, 9 H), 1.38-1.60 (m, 4 H), 2.03-2.12 (m, 2 H), 3.62 (t, J =

6.4 Hz, 2 H), 4.91-5.06 (m, 2 H), 5.73-5.90 (m, 1 H).

To a solution of [(allyl)NiBr]2 (5.2 mg, 0.14 mmol) in 1 mL of CH2Cl2 under

nitrogen at room temperature was added a solution of Ph3P (7.6 mg, 0.28 mmol) in 1 mL

of CH2Cl2. The resulting brown solution was added to a mixture of AgOTf (10.3 mg,

0.40 mmol) in 1 mL of CH2Cl2. After stirring for 1.5 h at rt, the mixture was filtered

through a small plug of Celite, and the precipitate was rinsed with 2 mL of CH2Cl2. The filtrate was collected in a Schlenk flask, and was taken out of the drybox. The catalyst solution was cooled to -55 oC. Under an atmosphere of ethylene, 0.428 g (2.00 mmol)

of the teminal alkene 36 was added dropwise to the catalyst solution. After stirring at –

o 55 C for 4 h, the mixture was quenched with saturated NH4Cl solution and extracted 3

151 times with 10 mL portions of CH2Cl2. The combined organic layers were dried over

MgSO4 and concentrated in vacuo. The volatile crude product was analyzed by GC (>

95 %), which indicated that the alkene was completely isomerized to two new products in

a ratio of 3.5:1.0. The crude product was purified by chromatography on silica, eluting

1 with ethyl acetate/hexane (98:2), to get the product 36a. H NMR (250 MHz, CDCl3):

0.05 (s, 6 H), 0.90 (s, 9 H), 1.54-1.67 (m, 5 H), 1.97-2.10 (m, 2 H), 3.57-3.65 (m, 2 H),

5.40-5.46 (m, 2 H).

Isomerization of (tert-butyl[[2,2-dimethyl-1-(1-propynyl)-3-pentenyl]oxy] dimethyl- silane 36 by Pd(II)-catalyst. General procedure D (entry 2, Table 4.4, and entry 1,

Table 4.5).

Pd(II) OTBS OTBS

Isomerization was carried out using 0.5 mol% [(allyl)PdCl]2, 1.0 mol% of (o-Me-

C6H4)3P, 1.0 mol% of AgOTf (19 mg, 0.08 mmol), and CD2Cl2 with no other additives.

The reaction was followed by NMR, which indicated maximum conversion to the desired

isomerization at 24 h. The products (E)- and (Z)-products 36a (3.7:1) was identified by

comparison of GC traces and spectral properties of the sample from the previous run. In

addition to 10 % starting material, ~ 9 % of an unidentified product was also detected by

GC.

Synthesis and Isomerization of 1-(but-3-enyloxy)-4-methoxybenzene 37. General

procedure D (entry 3, Table 4.4, and entry 4, Table 4.5).

152 MeO MeO Pd(II) MeO

OH O O To a stirred solution of 4-methoxyphenol (1 g, 8.06 mmol), 3-buten-1-ol (0.99 g,

10.48 mmol), and triphenylphosphine (2.75 g, 10.48 mmol) in anhydrous THF (20 mL)

was added diisopropyl azodicarboxylate (2.12 g, 10.48 mmol) slowly under 0 oC. After the reaction was stirred overnight at rt, the mixture was diluted with EtOAc (20 mL) and water (20 mL), and then separated. The crude compound was extracted with EtOAc

(3*20 mL) and combined organics were dried over NaSO4. The resulting product was

purified by chromatography to get 1.5 g (93 %) of the desired product 37. 1H NMR δ

(CDCl3): 6.87-6.81 (m, 4 H, Aromatic), 5.94-5.86 (m, 1H, ROCH2CH2CH=CH2), 5.18-

5.09 (q, 2H, ROCH2CH2CH=CH2), 3.97-3.95 (t, J = 7 Hz, 2 H, ROCH2CH2CH=CH2),

2.53-2.49 (m, 2 H, ROCH2CH2CH=CH2), 3.75 (s, 3 H, ArOCH3), 1.75-1.70 (d, J = 5 Hz,

13 3 H, ROCH2CH=CHCH3); C NMR δ (CDCl3): 154.0, 153.2, 134.8, 117.1, 115.8, 114.8,

68.1, 55.9, 33.9.

1-(but-3-enyloxy)-4-methoxybenzene 37 (30 mg, 0.168 mmol) was reacted with

2.5 mol% [(allyl)PdCl]2 (1.6 mg, 0.0042 mmol), (p-OMe-Ph)3P (2.6 mg, 0.0084 mmol),

AgOTf (2.2 mg, 0.0084 mmol), and CH2Cl2 at rt for 1 d (See, General Procedure D).

The resulting product was purified by chromatography to get 30 mg (> 99 %) the desired

product 37a as a mixture of E and Z isomers with a small amount of unreacted starting

material. Based on the 1H NMR, the E/Z ratio and conversion were estimated as 6.2 : 1,

1 94 %, respectively. H NMR δ (CDCl3): 6.86-6.80 (m, 4 H, Aromatic), 5.84-5.80 (m,

1H, ROCH2CH=CHCH3, E and Z), 5.74-5.68 (m, 1H, ROCH2CH=CHCH3, E and Z),

4.54-4.53 (d, J = 5.5 Hz, 2 H, ROCH2CH=CHCH3, Z), 4.53-4.39 (m, 2 H,

153 ROCH2CH=CHCH3, E), 3.75 (s, 3 H, ArOCH3), 1.75-1.70 (d, J = 5 Hz, 3 H,

ROCH2CH=CHCH3);

The configuration of the major product was established by nOe studies.

Weak Noe Z isomer Strong Noe E isomer Noe H Noe O H O H H H HH H Noe H O H O H H H H Noe Noe

13 C NMR δ (CDCl3. E only): 154.2, 153.3, 130.3, 126.8, 116.0, 69.7, 56.0, 17.9, 13.5

Isomerization of tert-butyl(hex-5-enyloxy)dimethylsilane 36 using Grubbs second-

generation catalyst (entry 2, Table 4.5, Hanessian’s procedure26)

Grubbs II OTBS OTBS

Using the same procedure and catalyst (10 mol%) for the isomerization of 37

(entry 5, Table 4.5), the isomerization of OTBS protected olefin 9 (11.2 mg, 0.052 mmol)

was checked. The crude product was directly analyzed by GC (C18 column, 110 oC

isothermal).

Isomerization of tert-butyl(hex-5-enyloxy)dimethylsilane 36 using Ir-catalyst (entry

3, Table 4.5, Nelson’s procedure 8)

Ir-cat. OTBS OTBS

Using the same procedure and catalyst (1 mol% of [IrCl(COE)2]2, 6 mol% of

PCy3, and 2 mol% of NaBPh4) for the isomerization of 37 (entry 6, Table 4.5), the

154 isomerization of OTBS protected alkene 36 (25.5 mg, 0.119 mmol) was performed at rt

for 30 min. The crude product was purified by short column chromatography to yield

(E)-1-[(tert-Butyldimethylsilyl)oxy]-1-butene 36b as a major product. All spectral data

were matched with reported data.27

Isomerization of 1-(but-3-enyloxy)-4-methoxybenzene (37) using Grubbs second-

generation catalyst (entry 5, Table 4.5, Hanessian’s procedure 26)

MeO Grubbs II MeO O O The starting olefin 37 (9.3 mg, 0.052 mmol) in anhydrous MeOH (0.8 ml) was

treated with Grubbs second-generation catalyst (4.4 mg, 10 mol%). The resulting

solution was stirred at 60 oC for 12 h. After the solvent was evaporated in vacuo, the

residue was filtered with silica pad and washed with ether. The crude product was

directly analyzed by GC (C18 column, 110 oC isothermal).

Isomerization of 1-(but-3-enyloxy)-4-methoxybenzene (37) using Ir-catalyst (entry 6,

Table 4.5, Nelson’s procedure8)

MeO Ir-cat. MeO MeO + O O O

In a N2-charged drybox, a solution of NaBPh4 (0.8 mg, 0.0029 mmol) in

anhydrous acetone (0.020 ml) was added a solution of [IrCl(COE)2]2 (1.1 mg, 0.0012

mmol) and PCy3 (1.9 mg, 0.0068 mmol) in anhydrous CH2Cl2 (1.08 mL), and the

resulting catalyst was stirred at rt for 5 min. After the starting olefin (21.2 mg, 0.119 mmol) was added to the mixture, the resulting solution was stirred at rt for 3 h. Then,

155 the solvent was evaporated in vacuo, the residue was purified by short column

chromatography to yield the mixture of isomerized products (vinylether (37b): allylic

1 1 ether (37a) = 3.5 : 1, based on H NMR). H NMR δ (CDCl3): 6.92-6.88 (m, 2H, Ar),

6.84-6.79 (m, 2H, Ar), 6.36-6.33 (dt, 1H, J = 12.0, 1.5 Hz, ROCH=CHEt), 5.32-5.27 (m,

1H, ROCH=CHEt), 3.75 (s, 3H, OMe), 2.05-1.99 (m, 2H, RCH2CH3), 1.05-0.98 (t, 3H, J

= 6.0 Hz, RCH2CH3).

156 4.5. REFERENCES (1) Frauenrath, H. "In Houben-Weyl, E15/1"; Kropf, H., Schaumann, E., Eds.; Thieme: Stuttgart, 1995, p 1. (2) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; 2nd ed.; Wiley: New York. (3) Otsuka, S.; Tani, K. Synthesis 1991, 666. (4) Frauenrath, H.; Brethauer, D.; Reim, S.; Maurer, M.; G., R. Angew. Chem. Int. Ed. 2001, 40, 177. (5) Harrod, J. F.; Chalk, A. J. J. Am. Chem. Soc. 1964, 86, 1776. (6) Davies, N. R. Aust. J. Chem. 1964, 17, 212. (7) Gosser, L. W.; Parshall, G. W. Tetrahedron Lett. 1971, 2555. (8) Shen, X.; Wasmuth, A. S.; Zhao, J.; Zhu, C.; Nelson, S. G. J. Am. Chem. Soc. 2006, 128, 7438. (9) Nelson, S. G.; Bungard, C. J.; Wang, K. J. Am. Chem. Soc. 2003, 125, 13000. (10) Shen, X.; Wasmuth, A. S.; Zhao, J.; Zhu, C.; Nelson, S. G. J. Am. Chem. Soc. 2006, 128, 7438. (11) Baudry, D.; Ephritikhine, M.; Felkin, H. J. Chem. Soc., Chem. Commun. 1978, 694. (12) Hanessian, S.; Giroux, S.; Larsson, A. Org. Lett. 2006, 8, 5481. (13) Brown, C. A.; Yamashita, A. J. Am. Chem. Soc. 1975, 97, 891. (14) Grotjahn, D. B.; Larsen, C. R.; Gustafson, J. L.; Nair, R.; Sharma, A. J. Am. Chem. Soc. 2007, 129, 9592. (15) Lim, H. J.; Smith, C. R.; RajanBabu, T. V. J. Org. Chem. 2009, 74, 4565. (16) RajanBabu, T. V. Chem. Rev. 2003, 203, 2845. (17) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863. (18) Grubbs, R. H. Tetrahedron 2004, 60, 7117. (19) Justik, M. W.; Koser, G. F. Tetrahedron Lett. 2004, 45, 6159. (20) RajanBabu, T. V. Synlett 2008, 21, 853. (21) Radetich, B.; RajanBabu, T. V. J. Am. Chem. Soc. 1998, 120, 8007. (22) Lloyd-Jones, G. C. Org. Biomol. Chem. 2003, 215. (23) Trost, B. M.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781. (24) Trost, B. M. Acc. Chem. Res. 1990, 23, 34. (25) Smith, C. R.; Zhang, A.; Man, D.; RajanBabu, T. V. Org. Synth. 2008, 85, 248. (26) Hanessian, S.; Giroux, S.; Larsson, A. Org. Lett. 2006, 8, 5481. (27) Ohmura, T.; Yamamoto, Y.; Miyaura, N. Organometallics 1999, 18, 413.

157

PART B. DEVELOPMENT OF EFFICIENT CYCLIZATION METHODS

CHAPTER 5

INTRODUCTION

5.1. Cyclization Reactions

Development of new and efficient methods for the synthesis of cyclic compounds

has received a great deal of attention, due to the ubiquitous existence of such compounds

in nature and in useful organic materials. Until now, numerous cyclization methods

have been reported and developed for various purposes.1-8 Cyclizations can be

classified by two major types, traditional stoichiometric reactions and more modern

catalytic ones. Each reaction also can be divided into carbon-carbon and carbon- heteroatom bond forming reactions. Regardless of cyclization types, catalytic or

noncatalytic, majority of cyclizations use simple concepts – 1) activation of groups such as alkenes, alkynes, imines, or halides by Lewis acids or metal complexes, followed by a subsequent nucleophilic attack by various internal nucleophiles such as amines, alcohols, or carbon nucleophiles. 2) Activation of nucleophiles by Lewis bases or insertion of metal-complexes into X-Nu bonds such as H-N, H-O, followed by reactions with

158 electrophiles 3) using the activation of both elements. Another large class of cyclization

reactions involves cycloisomerization9-13 reactions of unsaturated systems catalyzed by metal complexes, with or without incorporation of other elements, most often main group elements during the cyclization event.8,14-16

5.1.1. General Stoichiometric Cyclizations

In the case of traditional stoichiometric reactions, radical cyclization,1,17 electrophilic cyclization,1,18 and pericyclic reactions1 are representative for carbo- and hetero-cycle syntheses by C-C bond formations. In a representative instance pertinent to this work, Friedel-Craft cyclization is one of the most useful reactions for synthesis of carbo- and hetero-cyclic compounds (Eq. 5.1).19,20 By virtue of the Lewis-acid

mediated generation of a partial carbocation as an electrophile, further bond-formation

X X O O (Eq. 5.1) X=OH,Cl,Br X=OH,Cl,Br

occurrs by attack of an internal nucleophile. This reaction is often of narrow scope

because of the need for a strong Lewis acid and high reaction temperature that are often

required for the reaction. Recent efforts have focused on developing reaction conditions

that are mild and compatible with various functional groups.

159 5.1.2. Electrophilic Cyclizations for Carbon-Carbon Bond Forming Reactions

As a part of Friedel-Craft alkylation, electrophilic cyclizations of alkenes

containing internal nucleophiles have been developed successfully using different

electrophiles such as proton, bromonium or iodonium, and seleniranium ions, for the

synthesis of diverse carbo- and hetero-cyclic compounds (Eq. 5.2).21 Total synthesis of

potent anti-inflammatory pseudopterosins – well-known class of terpene-type natural

products – by the electrophilic cyclization clearly shows the practical utility of the electrophilic cyclization reactions in ring formations (Eq. 5.3).22

R R X+ X X + (Eq. 5.2) Z R Z Z

OBn OBn O O OH OMs OMs HO OH MsOH H OH (Eq. 5.3) 100 % H

Pseudopterosin A dr (25:1)

In 2004, Barluenga and coworkers reported iodonium ion-induced cyclizations

23 for the synthesis of chorman and tetrahydroquinoline derivatives, using IPy2BF4 immobilized on silica gel as a convenient source of the electrophile.24 This reaction

condition gives desired cyclofunctionalized products with excellent yields and nearly

perfect anti-selectivities. Even when this reaction was applied to polycyclizations, good

yields and diastereoselectivities were observed as shown in Eqs. 5.4 and 5.5.

160

O IPy2BF4 O IPy2BF4 O HBF 4,CH2Cl 2 HBF ,CHCl 4 2 2 (Eq. 5.4) o -85 C, 3 d I -85oC, 15 h H 86 % 72 %

SO2Me SO2Me MeO N MeO N IPy BF (110 mol%), HBF H 2 4 4 (Eq. 5.5) o CH2Cl 2,-80 C, 15 h OMe OMe 41 % I H

Compared to carbon-heteroatom bond formations using selenium-mediate reactions, the development of carbon-carbon bond forming methods have not been very successful. In this area, carbocyclizations of dienes (Eqs. 5.6-8)25-27 and the cyclizations of 1,3-dicarbonyl containing alkenes are representative (Eq. 5.9).28,29

AcO H PhSeCl AcOH (Eq. 5.6) +Se Ph H SePh

SePh PhSe+ SePh PhSeSePh (Eq. 5.7) I2,CH3CN + NHCOMe

OH OAc OAc OAc (Eq. 5.8) PhSe + PhSe OH PhSe

161 CO2Me O PhSe

+SePh

(Eq. 5.9) CO Me 2 CO 2Me CO 2Me O OH O PhSe

Seleniranium-ion induced carbon-carbon bond forming Friedel-Craft type cyclization will be discussed in the next chapter.

5.1.3. Electrophilic Cyclizations for Carbon-Heteroatom Bond Forming Reactions Using

Selenium Electrophiles

In addition to the above electrophilic cyclizations involving carbon-nucleophiles, such cyclizations using heteroatom-nucleophiles also have been well studied (Eq.

5.10).18,30-33 Especially relevant to the present study are various types of seleniranium-

R R + X X X Nu + (Eq. 5.10) Nu Z R Nu Z Nu : NRH, OH, SH, Z CO2H, and so on.

ion mediated cyclizations for syntheses of many carbo- and hetero-cyclic compounds.

This reaction could have broad utility because of further possible uses of the seleno- moiety after the reaction.21,34 Selenocyclization of olefins using oxygen as an internal

nucleophile is the earliest and the most widely studied reaction.18,30-33 Not only simple

alcohol but also carboxylate nucleophiles undergo cyclization under PhSeCl-

162

OH PhSeCl O (Eq. 5. 11) SePh

PhSeCl SePh (Eq. 5.12) O BnOH BnO O

PhSeCl O CO2H O (Eq. 5.13) BnOH PhSe

mediated conditions in good yields (Eqs. 5.11-13).35-39 Even N-PSP (N-(phenylseleno)-

phthalimide) with ZnI2 can efficiently induce the cyclization of alkenes containing a

ketone (Eqs. 5.14-15).28 Secondary amines also give desired cyclization in good to

EtO C EtO2C 2 ZnI2 SePh (Eq. 5.14) O O O N SePh

O O SePh O (Eq. 5.15) EtO2C ZnI 2 EtO2C

excellent yields. For an example, alkenyl pyrrolidine also undergo cyclization to the pyrrolizidine nucleus under seleniranium ion-induced cyclization conditions (Eq. 5.16).21

Moreover, imino-nitogen is nucleophilic enough to undergo this electrophilic additions when PhSeBr is applied under appropriate conditions. Cyclization of alkenyl imidates,40-42 aldimines,43,44 and allyl oximes45,46 were reported in this area.

163 + PhSeBr SePh SePh (Eq. 5.16) NH MeCN NH N

For the synthesis of isooxazolidines, Tiecco and coworkers reported the cyclization of alkenyl oxime using the similar condition to yield either N-alkyl isoxazolidines46 or N-unsubstituted isooxazolidines45 by the treatment of cyclized

intermediates with either NaBH4 or water, respectively (Eq. 5.17).

SePh

O R NaBH 4 N SePh PhSeBr O (Eq. 5.17) O + R N R N - R= Me,Ph Br SePh Water O N R H

In an example illustrating the use of a chiral selenyl-reagent, (-)-salsolidine was synthesized with a high diastereoselectivity and yield (Eq. 5.18).47

MeO MeO MeO NB oc NHBoc MeO NBoc (Eq. 5.18) MeO MeO SeR* (-)-salsolidine

164 5.1.4. Catalytic Carbon-Carbon Bond Forming Cyclizations

Due to obvious practical and economic benefits, catalytic reactions are beginning to substitute many classical procedures for cyclizations. In case of metal-catalyzed reactions, many different types of cyclizations have been reported recently.48,49

Representative contributions in an area of a carbon-carbon bond forming cyclization are asymmetric Heck cyclizations (Eq. 5.19),50 catalytic ene-yne cycloisomerizations (Eq.

5.20),9 catalytic allyl-olefin couplings (Eq. 5.21)51 ring-closing metathesis reactions (Eq.

5.22),4 and Pauson-Khand reactions52 (Eq. 5.23).

X (Eq. 5.19) Z Z

Z R R Z (Eq. 5.20) R' R'

R X R (Eq. 5.21) Z Z

Z Z (Eq. 5.22)

O CO R (Eq. 5.23) R' R R'

Medium-size carbo- and hetero-cyclic rings can be found in a significant

proportion of natural products. Attempts to develop more efficient methods for the

synthesis of these compounds have also used metal catalyzed C-C bond-forming

165 reactions starting with readily available substrates.4,53 In one of the relevant cases of

these attempts, cyclizations of diynes using X-Y reagents such as borostannyl,54 silylstanyl,55 and borosilyl56 reagents have been studied in depth (Eq. 5.24).

Z Z X-Y Z (Eq. 5.24) M X Y X Y (when X and Y are large)

Potentially, the helical chiral product57 of these reactions can be subsequently used for

additional stereoselective reactions. Recently, how borylstannyl cyclization of a diyne

can efficiently construct biologically relevant dibenzooctadienes – e. g., interiotherin A –

was demonstrated by RajanBabu and Singidi (Eq. 5.25).58

O O O O O N O Me 3Sn-B N SnMe3 MeO MeO MeO MeO (Eq. 5.25) MeO PdCl (PPh ) MeO 2 3 2 B N C6H6,rt,6h OC(O)Ph N O OBn O O O O O interiotherin A

166 5.1.5. Catalytic Carbon-Heteroatom Bond Forming Cyclizations

For cyclizations involving carbon-heteroatom bond-formation, intramolecular

hydroamination (Eq. 5.26), hydroetherification (Eq. 5.27), and N-arylation (Eq. 5.28) are

NHR R N (Eq. 5.26)

OH O (Eq. 5.27)

R X N (Eq. 5.28) NHR

relevant. Development of new catalytic systems for hydrofunctionalizations such as hydroaminations and hydroetherifications have been attempted using various metals such as Zr,59 Ti,60 Pd,61 and so forth.62 In 2006, Yamamoto and coworkers disclosed Pd- catalyzed intramolecular hydroamination of alkynes using an Nf-protected amine (Nf = nonafluorobutanesulfonyl) (Eq. 5.29). 61 In this report, Pd(0) with Renorphos as a chiral

bidentate ligand under high temperature and acid catalysis was reported to yield the

desired heterocycles in high yields and enantioselectivities.

n n R R L* PPh Pd2dba3 CHCl3,PhH NNf 2 NHNf (Eq. 5. 29) o PPh n= 0,1 L*, PhCO2H, 100 C, 3 d 2 Yield(%) = 82 - 93 Nf = Nonafluorobutanesulfonyl ee (%) = 81 - 91 (R,R)-Renorphos R = aryl, alkyl

167 Among group 4 metal catalysts, Zr-imodo complexes give high selectivities. A

general mechanism of the reaction for this group of metals has been proposed, which is

based upon [2+2] cycloaddition of a neutral Zr-imido complex with an internal alkene

(Scheme 5.1).59 Despite recent successes in this area, hydroamination still awaits

further improvements before applications in natural product synthesis can be planned.

Zr L2(NMe2)2 NMe2 Ar ZrL2 NMe2 O NHR N NMe Zr 2 n=1,2 N NMe2 H NHMe O 2 N R N If R is not H, Ar n ZrL2 it can't mak e a Z r- imi do c omplex . Ar = 2,4,6-trimetylphenyl n= 1,2 NMe2

NHMe2,L NHR n N R L Zr H LZr N 2 N LZr Me2N n n [2+2] cycloaddition Me N H 2 N NHMe LZr 2 L

Scheme 5.1. Zr-catalyst for Asymmetric Hydroamination and its Proposed Mechanism

In other methods to form C-X bonds, N- and O-arylations were developed mainly under either Pd-63 or Cu-catalyzed64 reaction conditions. Pd-catalyzed conditions

168 broadly known as Buchwald-Hartwig reactions give desired cyclized products with good yields for simple model compounds in general.65,66 Many different versions of these reactions have been applied to the syntheses of simple heterocycles, even using less reactive arylchloride.67 Since the use of a strong base under high temperature decreases the potential of the reaction, uses of these cyclizations for the total synthesis of natural products are limited to simple structures. As rare examples, the syntheses of dehydrobufoteinine (A) and the known intermediate B of makaluvameine C (C) and damirones A (D) and B (E) are illustrated (Scheme 5.2).68

NHMe + MeN Me2N I Pd(PPh ) (10 mol%) MeO MeO MeO 3 4 o K2CO 3, TEA, Tol., 200 C N N N CO Et 81 % CO2Et 2 CO Et 2 dehydrobufoteinine (A)

N N MeN B Pd2dba3 (2.5 mol%), P(o-tol) 3

NHBn NaOt-Bu, tol., 80 oC N MeO N MeO I MeO Bn H OMe 72 % OMe OMe

R - N Cl + MeN

O N N O H2N damirones A (R=H, D) O B(R=Me,E) makaluvameine C (C)

Scheme 5.2. Pd-catalyzed Intramolecular Amination for Natural Product Syntheses

169 Cu-catalyzed reactions have also been applied for similar cyclizations as shown

in Eqs. 5.30 and 5.31.64,69 Compared to the Pd-catalyzed systems, the Cu-catalysts

usually need only milder reaction conditions, so more of functional groups are tolerated.

In an example of distinct comparisons, Pd- and Cu-catalyzed reaction conditions were

Ns = H O N CuI (10 mol%) Ns N S (Eq. 5.30) Cs CO ,DMSO O I 3 Ns 90 oC, 24 h 90 % NO 2

H CuI (5 mol %) N H L (10 mol%) (Eq. 5.31) N L = MeHN NHMe O CsCO3,Tol. H Br rt to 100 oC O 100 %

tested for the synthesis of corsifuran A (Eq. 5.32).70 During the cyclization reactions,

Pd-catalyzed conditions suffered from various side-reactions such as debromination,

oxidation of the alcohol to a ketone, and isomerization of the existing chiral center.

However, cyclization using CuCl gave 76 % of the desired compound without any

racemization.

OMe MeO Catalyst Yield (%ee)

Pd(OAc)2,BINAP,NaOtBu 5 (100) Catalyst OH (Eq. 5.32) O Pd(OAc)2,BINAP,Cs2CO 3 0(--) Br Tol., reflux Pd dba , L, NaOtBu 100 (45) 2 3 NMe2 PtBu2 Pd2dba3, L, NaOtBu 0 (--) MeO MeO CuCl, NaH 76 (100) =L corsifuran A

170 In addition to high selectivities, the cost of a metal and ligand also favor copper.

Hence, the stoichiometric version is still widely used, even though catalytic procedures are known for limited substrates. In addition to simple C-X bond formations, Cu- catalyzed tandem coupling/cyclization reactions (e.g., domino aryl-yne bond formation/heterocyclization) are also known (Eq. 5.33).71,72 This type of a tandem processes is possible due to exceptional functional group compatibilities of Cu-catalyzed reaction conditions. Catalytic intramolecular N-arylation will be discussed more thoroughly in a subsequent chapter.

Br R CuI (2 mol%) L= R R' CO 2H NH + N (Eq. 5.33) L (6 mol%), K CO N R' 2 3 H H L-proline F C O DMF, 80 oC 25 - 94 % 3

171 5.2. Summary

Traditional cyclization reactions are still used for a variety of purposes and

discovery of new electrophile/nucleophile combinations would enhance our repertoire of

synthetic methods. Therefore, our goal in this area is to develop more efficient and

effective methods of seleniranium ion-mediated cyclizations. Our investigations in this

area will be discussed in Chapter 6.

Among catalytic carbon-heteroatom bond forming cyclization reactions, Pd- and

Cu-catalyzed reactions have been applied to numerous syntheses of heterocycles and

related natural products successfully, which clearly indicate how a new enabling reaction

can improve the current level of a synthesis. Our efforts in this area involve the

development of a new C-N bond-forming cyclization method for the synthesis of natural products. These results will be discussed in Chapter 7.

172 5.3. REFERENCES (1) For reviews, see (a) Harding, K. E.; Tiner, T. H. Comprehensive Organic Synthesis; Pergamon: New York, 1991; Vol. 4. (b) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, Part B; 4th ed.; Plenum: New York, 2000. (2) Thebtaranonth, C.; Thebtaranonth, Y. Tetrahedron 1990, 46, 1385. (3) Thebtaranonth, C.; Thebtaranonth, Y. Cyclization Reactions; CRC Press Inc., 1994. (4) For a recent review of ring-closing metathesis, see Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (5) For a review of cyclic carbopalladation, see Negishi, E.; Copéret, C.; Ma, S.; Liou, S.- Y.; Liu, F. Chem. Rev. 1996, 96, 365. (6) Grotjahn, D. B. "Acetylene Cyclotrimerization" In Comprehensive Organometallic Chemistry II; Hegedus, L. S., Ed.; Pergamon/Elsevier: 1995, p 741. (7) Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49. (8) For a multi-component carbocyclization, see Itoh, A.; Matsuda, I.; Yamamoto, K. J. Synth. Org. Chem. Jpn. 1999, 57, 912. (9) For a review, see Trost, B. M.; Krische, M. J. Synlett 1998, 1. (10) Zhang, M.; Buchwald, S. L. J. Org. Chem. 1996, 61, 4498. (11) Oh, C. H.; Jung, H. H.; Kim, J. S.; Cho, S. W. Angew. Chem. Int. Ed. 2000, 39, 752. (12) Goeke, A.; Sawamura, M.; Kuwano, R.; Ito, Y. Angew. Chem. Int. Ed. 1996, 35, 662. (13) Cao, P.; Zhang, X. Angew. Chem. Int. Ed. 2000, 39, 4104. (14) Ojima, I.; Donovan, R. J.; Shay, W. R. J. Am. Chem. Soc. 1992, 114, 6580. (15) Ojima, I.; Tzamarioudaki, M.; Tsai, C. J. Am. Chem. Soc. 1994, 116, 3643. (16) Ojima, I.; Lee, S.-Y. J. Am. Chem. Soc. 2000, 122, 2385. (17) Marc, J. Acc. Chem. Res. 1967, 4, 386. (18) Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321. (19) Bradsher, C. K. Chem. Rev. 1987, 87, 1277. (20) Hofmann, J. E.; Schriesheim, A.; Olah, G. A. Friedel-Crafts and Related Reactions; Wiley: NY, 1963; Vol. 2. (21) Tiecco, M. "Electrophilic Selenium, Selenocyclizations" In Topics in Current Chemistry; Wirth, T., Ed.; Springer-Verlag: Berlin, 2000; Vol. 208. (22) Lazerwith, S. E.; Johnson, T. W.; Corey, E. J. Org. Lett. 2000, 2, 2389. (23) Barluenga, J.; Trincado, M.; Rubio, E.; González, J. M. J. Am. Chem. Soc. 2004, 126, 3416. (24) Barluenga, J.; González, J. M.; Campos, P. J.; Asensio, G. Angew. Chem. Int. Ed. 173 1985, 24, 319. (25) Kametani, T.; Suzuki, K.; Kurobe, H.; Nemoto, H. J. Chem. Soc., Chem. Commun. 1979, 1128. (26) Toshimitsu, A.; Uemura, S.; Okano, M. J. Chem. Soc., Chem. Commun. 1982, 87. (27) Kametani, T.; Suzuki, K.; Kurobe, H.; Nemoto, H. Chem. Pharm. Bull. 1981, 29, 105. (28) Jackson, W. P.; Ley, S. V.; Morton, J. A. J. Chem. Soc., Chem. Commun. 1980, 1028. (29) Jackson, W. P.; Ley, S. V.; Whittle, A. J. J. Chem. Soc., Chem. Commun. 1980, 1173. (30) Selenium in Natural Product Synthesis; Nicolau, K. C.; Petasis, N. A., Eds.; CIS: Philadelphia, 1984. (31) Selenium Reagents and Intermediates in Organic Synthesis; Paulmier, C., Ed.; Pergamon: Oxford, 1986. (32) Liotta, D. Organoselenium Chemistry; Wiley: New York, 1987. (33) Patai, S. The Chemistry of Organic Selenium and Tellurium Compounds; Wiley: New York, 1987; Vol. 1 and 2. (34) Petragnani, N.; Stefani, H. A.; Valduga, C. J. Tetrahedron 2001, 57, 1411. (35) Nicolaou, K. C.; Magolda, R. L.; Sipio, W. J.; Barnette, W. E.; Lynsenko, Z.; Joullie, M. M. J. Am. Chem. Soc. 1980, 102, 3784. (36) Clive, D. L. J.; Chittatu, G.; Wong, C. K. Can. J. Chem. 1987, 55, 3894. (37) Current, S.; Sharpless, K. B. Tetrahedron Lett. 1978, 5075. (38) Nicolaou, K. C.; Lynsenko, Z. J. Am. Chem. Soc. 1977, 99, 3185. (39) Nicolaou, K. C.; Seitz, S. P.; Sipio, W. J.; Blount, J. F. J. Am. Chem. Soc. 1979, 101, 3884. (40) Knapp, S.; Levorse, A. T. J. Org. Chem. 1988, 53, 4006. (41) Toshimitsu, A.; Terao, K.; Uemura, S. J. Org. Chem. 1987, 52, 2018. (42) Takahata, H.; Takamatsu, T.; Yamazaki, T. J. Org. Chem. 1989, 54, 4812. (43) De Kimpe, N.; Boelens, M. J. Chem. Soc., Chem. Commun. 1993, 916. (44) De Smaele, D.; De Kimpe, N. J. Chem. Soc., Chem. Commun. 1995, 2029. (45) Tiecco, M.; Testaferri, L.; Tingoli, M.; Bagnoli, L. J. Chem. Soc., Chem. Commun. 1995, 235. (46) Tiecco, M.; Testaferri, L.; Tingoli, M.; Bagnoli, L. Tetrahedron Lett., 51, 1277. (47) Wirth, T.; Fragale, G. Synthesis 1998, 162. (48) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285. (49) D'Souza, D. M.; Mueller, T. J. J. Chem. Soc. Rev. 2007, 36, 1095. (50) Shibasaki, M.; Vogl, E. M. ""Heck Reaction"" In Compregensive Asymmetric

174 Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 1, p 457. (51) Oppolzer, W. "Transition metal allyl complexes: Intramolecular alkene and alkyne insertions" In Comprehensive Organometallic Chemistry; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, 1995; Vol. 12; chapter 8.3, p 905. (52) Buchwald, S. L.; Hicks, F. A. "Pauson-Khand Type Reactions" In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 2, p 491. (53) Trost, B. M. Angew. Chem. Int. Ed. 1995, 34, 259. (54) For a borostannylative carbocyclization, see Onozawa, S.; Hatanaka, Y.; Choi, N.; Tanaka, M. Organometallics 1997, 16, 5389. (55) For silastannylative cyclization, see Kang, S., -K.; Ha, Y.-H.; Ko, B. S.; Lim, Y.; Jung, J. Angew. Chem. Int. Ed. 2002, 41, 343. (56) For a borylsilytive carbocyclization, see Onozawa, S.; Hatanaka, Y.; Tanaka, M. J. Chem. Soc., Chem. Commun. 1997, 1229. (57) Gréau, S.; Radetich, B.; RajanBabu, T. V. J. Am. Chem. Soc. 2000, 122, 8579. (58) Singidi, R. R.; RajanBabu, T. V. Org. Lett. 2008, 10, 3351. (59) Wood, M. C.; Leitch, D. C.; Yeung, C. S.; Kozak, J. A.; Schafer, L. L. Angew. Chem. Int. Ed. 2007, 46, 354. (60) For a recent review of Ti-catalyzed hydroamination, see Odom, A. Dalton Trans 2005, 225. (61) Patil, N.; Lutete, L.; Wu, H.; Pahadi, N.; Gridnev, I.; Yamamoto, T. J. Org. Chem. 2006, 71, 4270. (62) For a review of catalytic hydroaminations, see Mueller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675. (63) For a review of Pd-catalyzed reactions for heterocycles, see Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry: A Guide for the Synthetic Chemist; Pergamon: New York, 2000. (64) For a recent review of Cu-mediated and catalyzed C-X bond formations, see Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42, 5400. (65) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (66) Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046. (67) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 4177.

175 (68) Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 1028. (69) For a recent review of Cu-mediated reactions for natural products, see Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054 and references cited therein. (70) Adams, H.; Gilmore, N. J.; Jones, S.; Muldowney, M. P.; von Reuss, S. H.; Vemula, R. Org. Lett. 2008, 10, 1457. (71) Saejung, P.; Bates, C. G.; Venkataraman, D. Synthesis 2005, 1706. (72) Liu, F.; Ma, D. J. Org. Chem. 2007, 72, 4844.

176

CHAPTER 6

SELENIRANIUM-ION TRIGGERED CYCLIZATION REACTIONS

6.1. INTRODUCTION

Electrophilic cyclizations mediated by seleniranium ions have been broadly studied to develop the synthetic methods towards diverse heterocycles from various types of substrates.1-7 In this area, intermolecular carbon-carbon bond formations using

electron rich aryl-nucleophiles have also been reported. Even highly diastereoselective

intermolecular carbon-carbon bond formations have been developed recently by applying

several chiral selenium reagents.8-9 Compared to the intermolecular Friedel-Craft

arylations, an intramolecular version of this reaction has not been well-established.

Although this type of electrophilic cyclizations using seleniranium ions has been reported

since 1978,10 further developments in this area has not been forthcoming. In a

comparatively rare example in this area, Déziel and coworker reported carbocyclizations

of arylbutenes (Scheme 6.1). Using a chiral selenium reagent, the cyclization was

explored. In the presence of a small amount of methanol, a substrate was

methoxyselenylated, and then it was cyclized into a desired carbo-cycle by a Lewis acid.

Without methanol, the yield of the reaction was poor. Moreover, only electron-rich

177 arenes underwent the desired cyclization.11,12,13 That is, this type of cyclizations still

needs further investigations to develop into a more general and powerful method.

MeO MeO MeO MeO Se+Ar* MeO SeAr* MeO 1. Br2 Ph Ph Ph 2. AgOTf + + BF OEt CH Cl ,MeOH 3 O Se) O 2 2 MeO 2 -78oC MeO

+ MeO Se Ar* MeO Se+Ar* Ph O+Me Ph H OMe

Scheme 6.1. Seleniranium-ion Mediated Friedel-Crafts Cyclizations

During the course of our research on Ni(II)-catalyzed hydrovinylation for the construction of all-carbon quaternary centers (Eq. 6.1), we attemptted the synthesis of (-)- physostigmine via this asymmetric reaction. In this study, we needed a general method

C5H11 L= C5H11 Ph [AllylNiBr]2, L,ethylene ~90%,50 %ee O P N (Eq. 6.1) NaBARF, CH2Cl2 O Ph

~70%,95 %ee

178 for the preparation of exocyclic methylene derivatives of condensed heterocyclic

compounds (Figure 6.1).14,15 Among hydrovinylation substrates for the synthesis of the

intended target, cyclic vinylarenes give significantly better enantioselectivities than

acyclic linear substrates (Eq. 6.1).14,15 Therefore, simple preparation of 4-

exomethylenechroman type heterocycles is critical for a hydrovinylation-based synthetic

strategy for biologically important natural products such as (-)-physostigmine and related compounds16,17 (Figure 6.1).

X N N R Z Z R Z R R (-)-physostigmine (R = p-OC(O)NHMe)

Figure 6.1. Plan of Hydrovinylation-based Synthesis of (-)-Physostigmine

For the synthesis of 4-methylenechroman (14), most of known methods were based on Wittig reaction of a ketone (Eq. 6.2.),18 metal-catalyzed coupling reactions such

as Heck cyclization using a tethered olefin (Eq. 6.3),19 or electrophilic cyclizations

followed by an elimination (Eq. 6.4).20 Among these reactions, an electrophilic

cyclization followed by a subsequent olefination appears to be better than the others,

because of several reasons. Strongly basic reaction conditions of Wittig reaction might

179 cause undesired side reactions such as aldol reactions.21 Moreover, the required ketones

are not often commercially available or they are in general quite expensive. Heck

cyclizations suffer from a poor regioselectivity in the cyclization step.

O MePPh3Br (Eq. 6.2) KOtBu, Et2O O O 66 % 14

I Pd(OTf)2,P(2-furyl)3 + (Eq. 6.3) i o EtNPr2, Tol., 80 C O O O 14 85 % (45 : 55) I IPy2BF4,HBF4 DBU, Reflux (Eq. 6.4) o CH2Cl 2,-80 C CH2Cl 2 O O O 14c 76 % 83 % 14

Among different electrophiles, it is expected that seleniranium ion is better than the others such as an iodonium13,20 or sulfonium22 for the subsequent elimination to form

the double bond in cases of sensitive heterocyclic compounds.

180 6.2. RESULT AND DISCUSSION

For initial studies, oxygen tethered compound 14c and 38 were prepared by

Mitsunobu reaction. It is well-discussed in previous literatures that the reactivity and selectivity of seleniranium ion induced reactions are highly affected by counterions and additives.23-25 In 2003, iodonium-induced cyclization for the synthesis of tetralins was

reported by Appelbe and coworkers.13 In this report, it is claimed that PhSeCl/AgOTf

did not induce cyclization that was readily accomplished by iodonium electrophile (Eq.

6.5) or a combination of N-(phenylseleno)succimide/Lewis acid26 in case of electron-rich arenes. Therefore, our initial investigation was started with the use of different

Reagents iPr + iPr (Eq. 6.5) iPr o CH2Cl2,-78 C E:Z = 6:1 OMe OMe OMe

Py2IBF4,HBF4 :48% 1 3.5 PhSeCl, AgOTf : No cyclization PhSeCl only : No cyclization

counteranions. Thus using the 4-methoxy substituted compound 38, various silver salts were applied for the cyclization (Table 6.1). Among them, AgSbF6 was found to be the

best for this reaction at low temperature (entry 6, Table 6.1). It can be rationalized by

‘counter-ion effect’.27,28 That is, weaker coordinating anions may increase the

electrophilicity of cationic seleniranium ions without decreasing the stability of the

electrophiles. Appropriate temperature is another key for the success of this reaction.

For the cyclization of the same compound 38, - 90 oC for the generation of seleniranium

ions and - 80 oC for subsequent cyclization for 8 h gave the desired 6-exo cyclization

181

Entry Substrates Conditionsa Products, Yields(%)b

o 1 AgSbF6 (1.05 eq.), -78 C, 2 h SePh 50

O o O > 95 2 14c AgSbF6 (3.1eq.), -78 C, 2 h 14d

o 3 AgSbF6 (3.1eq.), -78 C, 2 h 7

AgOTf (3.1eq.), 4 o o SePh MeO -90 C, 2 h, -80 C 8 h. 61 MeO O AgBF4 (3.1eq.), 38 O 5 o o 75 -90 C, 2 h, - 80 C 8 h. 38a

AgSbF6 (3.1eq.), 6 85 -90 oC, 2h, - 80 oC 8 h.

SePh PhSeCl (1.1 eq.), AgSbF6 (3.1eq.) 7 < 5 -90 oC, 2 h, - 80 oC 8 h. N Ts o c 8 NaBARF (1.2eq.), -90 C 2 h 39a 38(19) N Ts AgSbF6 3.1eq., c 9 39 o o N 48(15) -90 C, 2h, -80 C 8 h SePh o 10 AgSbF6 3.1eq., -100 C, 2 h 39b 55(30)c a b PhSeBr (1.1 eq.) was used, and distilled CH2Cl2 was used as a solvent.; All reactions were quenched by stirring with MeOH for 1 h. Without quenching, the yield decreased significantly.; c yields of 39a(39b).

Table 6.1. Seleniranium ion-Induced Friedel-Craft Cyclization Reactions

182 product 38a in very high yield (entry 6, Table 6.1). However, the reaction under slightly

higher temperature (- 78 oC) within 2 h gave only 7 % of the desired product (entry 3,

Table 6.1). Electron-donating 4-methoxy group is not needed for the reaction; even the

unactivated alkene 14c underwent the cyclization in good yields using the excess silver

salt even at - 78 oC (entries 1-2, Table 6.1).

In case of N-Ts derivative 39, cyclization under the optimized condition gave the desired compound 39a in moderate yields and an unexpected detosylative cyclization product 39b as a minor product (entry, 9, Table 6.1). Instead of PhSeBr, if PhSeCl is used in conjunction with silver salts, poor yields resulted (entry 7, Table 6.1). The reaction at lower temperature (- 100 oC) was attempted, and the yield of the expected product was slightly higher (entry 10, Table 6.1). It is well-known that silver ions can

mediate cyclizations of alkenes.29 In order to investigate the potential participation of

silver ions in the cyclization, the cyclization of the NTs substrate 39 was attempted using

NaBARF (sodium tetrakis[3,5-di(fluoromethyl)-phenyl]borate). To generate non-

coordinating counterions in homogeneous catalysis, NaBARF is used in many cases.30-32

The result of cyclization using NaBARF is not very different (entry 8, Table 6.1), so the possible role of silver ions can be rule out. Regardless of reaction conditions, the cyclization of N-Ts substrate produced the unexpected side product, N-phenyl-3-

(phenylselanyl)pyrrolidine 39b (entries 8-10, Table 6.1). For maximum yields, MeOH quenching for 1h after the cyclization reactions is indispensable. It is not confirmed, but

MeOH slurry seemed to help the decomposition of Ag-complexes of the product.

Otherwise, the overall yield of both products (39a + 39b, 65 %) in entry 8, Table 6.1 was decreased to 30 %.

183

Entry Substrates Conditionsa Products, Yields (%)

SePh o b 1 O -78 C, 2 h O 38b 38c , -

SePh o b 2 N -78 C, 2 h Ts N Ts 40c , 29 40b

Ph Ph SePh 3 -90 oC, 2 h then -80 oC 8 h N N Ts Ts 40d 40e , 39

SePh 4 -90 oC, 2 h then -80 oC 8 h N N 40 Boc H 40a , 45

SePh 5 -90 oC, 1 h, then -70 oC 8 h 41b 41a , 80

SePh 6 -90 oC, 1 h, then -70 oC 8 h 41d , 52 41c

MeO SePh

MeO 42a, 41 OMe 7 -90 oC, 2 h then -80 oC 8 h + 42 MeO OMe 42b,27 SePh

a b PhSeBr 1.1 eq./AgSbF6 3.1 eq. was used.; Lower temp. did not increase the yields. c Starting olefin decomposed.

Table 6.2. Results of 6-Endotrig Cyclization Reactions

184 Using these results in hand, the optimized reaction conditions were applied to

various other substrates. In cases of heteroatom tethered allylic substrates, the yields

decreased significantly due to the cleavage of allylic C-heteroatom bonds during the

reaction (entries 1-3, Table 6.2). In case of allyl-N-Ts substrates 40b and 40d, the

reactions were sluggish. In case of Boc-protected substrate 40, it gave the cyclized

product 40a without Boc-group in moderate yield (entry 4, Table 6.2). This cyclized

product 40a indicated that the rate of cyclization should be faster than the deprotection of

the Boc-group under this condition. Otherwise, the most Lewis basic nitrogen should

have reacted with seleniranium ions faster than the aryl-nucleophile.

Non-activated carbon-tethered substrates 41a and 41c gave moderate to good

yields of only 6-endo cyclization products 41b and 41d respectively (entries 5-6, Table

6.2). Reaction using 4-methoxyallylbenzne 42 suitable for a 5-endo-trig cyclization

only gave methoxyselenylated products as a mixture of Markovnikov adduct 42a and

anti-Markovnikov adduct 42b (entry 7, Table 6.2). This result indicates the existence of

a stable seleniranium ion under these reaction conditions since methanol was added only

after 8 h at - 80 oC.

Detosylation33 and the migration of tosylates34 have been observed in other strongly electrophilic reaction conditions. The detosylative cyclization of the kind reported in Table 6.1 (entries 8-10) has never been reported as far as we know. The reaction itself is a novel transformation that results in the formation of a phenylselenylated-heterocycles. A plausible mechanism based on general electrophilic steps is shown in Scheme 6.2. After the seleniranium ion is formed, one of the two potential nucleophiles – an aryl group or the nitrogen – could attack the intermediate.

185

A B C-C bond formation SePh + 6-exotrig cyclization "PhSe " +SePh N N Ts A Ts N Ts C-N bond formation B 5-endotrig cyclization

Detosylation N SePh N SePh Ts

Scheme 6.2. Proposed Mechanism of Friedel-Craft Versus Detosylative Cyclization

Therefore, the ratio of products would depend on (1) the difference of nucleophilicity between Ts-protected amines and aryl-groups and (2) modes of each cyclization, C-C versus C-N. To validate these mechanistic assumptions, two types of substrates were prepared. First, the substrates including less nucleophilic aryl-groups would give more detosylative cyclization product than that of Friedel-Craft cyclization. Second, compounds containing a longer alkyl-chain tether would change the proportion of two cyclization products, and the preferences can be predicted by the modes of each cyclization a la Baldwin rules. In general, six-membered transition-state is preferred in electrophilic cyclizations. The results are shown in Table 6.3.

186

Entry Substrates Conditionsa Products and Yields (%)

CF 3 CF3

1 - 90 oC, 2 h, - 80 oC, 8 h N N SePh Ts 43 43a 56

O2N

O2N 2 - 80 oC 2 h, - 60 oC 8 h N N 44 Ts 44a SePh 75

SePh 3 -78 oC 2 h N N 45a 45 Ts > 95

O2N O N 2 SePh O N SePh 4 2 - 80 oC, 2 h, rt, 1 h N N 46b 46c N Ts 46a 71 (4.3:1)

CF3 CF3 CF 3 SePh o SePh 5 - 78 C, 2 h N N N 46e 46f 46d Ts 49 21

TsN o 6 - 80 C, 2 h, rt, 1 h SePh NTs 47a 47b 69

o TsN 7 - 80 C, 2 h, rt, 1 h SePh NTs 47c 47d > 95

a PhSeBr 1.1eq. and AgSbF6 3.1eq. were used.

Table 6.3. Intramolecular Detosylative Cyclizations

187 Compared to the relatively electron-rich substrate 39 (entries 7-10, Table 6.1),

substrates with electron withdrawing groups gave the detosylative cyclization products as

the major products in good yields (entries 1-5, Table 6.3). Also, extended carbon chain

clearly increased the selectivity toward the detosylative pathway even when the aryl ring is not electron-poor (entry 3, Table 6.3 vs entry 10, Table 6.1). These results can be

easily explained by the preference of a 6-membered transition state in electrophilic

cyclizations. In the detosylative cyclizations, 6-endo is more favored than 5-exo (entries

3-5, Table 6.3). Overall, these results clearly support the initial assumptions on the

mechanism of the detosylative cyclizations. In a competition between a benzyl group

and a tosyl group on nitrogen (entries 6-7, Table 6.3), the benzyl group is removed from

the cationic intermediate and deprotected products 47b and 47d are produced exclusively

(entries 6-7, Table 6.3). These debenzylative cyclizations can be explained by the ease

of removal of a benzyl than N-tosyl group.

Using an enantio-pure amine substrate, a chiral selenium ion maybe produced via

a diastereoselective reaction and it is conceivable that one could get a chiral selenium-

containing end product. To check this possibility, (S)-2-phenylethylamine was

converted into N-but-3-enyl-N-sulfonylamides 48a and 48b, and the cyclization

examined (Scheme 6.3). Both compounds cyclized under the same conditions and the

expected N-Ts derivative 47b and N-Ns derivative 47e (Ns = 4-nitrophenylsulfonyl) were

produced in good yields. However, both products were formed in ~ 0 %ee as

determined by chiral stationary phase HPLC analysis.

188

1.PG-Cl, Py., CH2Cl2 PhSeBr, AgSbF6 PhSe ∗ NH NPG 2 o N PG 2. 3-Buten-1-ol, THF CH2Cl2,-80 C, 2 h DIAD, TPP PG = Ts, Ns 48a (PG = Ts): 67 % (2 steps) 47b (PG = Ts): 89 % 48b (PG = Ns): 64 % (2 steps) 47e (PG = Ns): 76 %

Scheme 6.3. Diastereoselective Debenzylative Cyclization Reactions

189 6.3 SUMMARY

New cationic seleniranium ions mediated cyclization conditions have been developed for the synthesis of N and O-heterocyclic compounds starting with simple

precursors. Seleniranium ions generated by the reaction of the appropriate substrate

with PhSeBr/AgSbF6 under optimal temperatures also gave the desired Friedel-Craft

cyclization products from even non-activated arene-alkenes. During the cyclization

reactions of N-tosyl-protected substrates, unexpected detosylative cyclization was

detected. The intramolecular detosylative cyclizations can be made the major pathway

by the adjustment of the nucleophilicity of an aryl-group and the length of a carbon chain.

When substrates include both benzyl- and N-Ts-group, debenzylative cyclizations occur

exclusively.

190 6.4 EXPERIMENTAL PROCEDURES

General Information.

For general information, see the general information in Chapter 2. PhSeBr,

PhSeCl and silver salts were purchased from Alfa Aesar and Sigma-Aldrich Inc, and

stored in Vacuum Atmosphere drybox.

General procedure for preparing substrates.

Amines were protected by standard methods, and then protected amine was

coupled with an alkenyl alcohol using general Mitsunobu reaction protocols. In case of

allyl substrates, alkylations of protected amines with allyl bromide were used. All

spectral data were matched with the reported data for compounds 14c,35 38,36 39,37 40,38 and 41a.39 Compound 41c was prepared by Wittig reaction similar to 41a.

Synthesis of N-(but-3-enyl)-4-methyl-N-phenylbenzenesulfonamide (39).

NHTs N Ts To a stirred solution of N-tosylaniline (2.56 g, 10.35 mmol), 3-buten-1-ol (1.5 g,

15.53 mmol), and triphenylphosphine (4.1 g, 15.53 mmol) in anhydrous THF (20 mL)

was added diisopropylazodicarboxylate (3.2 g, 15.53 mmol) dropwise at 0 oC, and the

resulting solution was stirred at rt overnight. To the mixture, EtOAc (30 mL) was added and washed with 1 M HCl (20 mL) and brine (20 mL). After the organic layer was dried over MgSO4 and solvents were evaporated, the crude compound was purified by

191 1 column chromatography to yield the title compound (3.0 g, 96 %). H NMR δ (CDCl3):

7.46-7.44 (d, 1H, J = 8.0 Hz, Ar), 7.30-7.26 (m, 3H, Ar), 7.22-7.21 (d, 2H, J = 8.0 Hz, Ar),

7.03-7.01 (m, 2H, Ar), 5.75-5.68 (m, 1H, RCH=CH2), 5.01-4.96 (m, 2H, RCH=CH2),

3.59-3.56 (t, 2H, J = 7.2 Hz, ROCH2R), 2.40 (s, 3H, CH3), 2.19-2.14 (q, 2H, J = 7.0 Hz,

13 RCH2CH=CH2); C NMR δ (CDCl3): 143.5, 139.3, 135.6, 134.7, 129.6, 129.2, 128.1,

127.9, 117.3, 50.2, 33.0, 21.7; IR cm-1 (KBr pellet) : 3064, 2973, 2934, 2905, 1648, 1594,

1493, 1452, 1376, 1345, 1287, 1164, 1145, 1082.

Synthesis of N-(but-3-enyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzene sulfonamide (43).

F3C NHTs F3C N Ts The title compound was prepared by the same procedure aforementioned. 1H

NMR δ (CDCl3): 7.53-7.52 (d, 1H, J = 8.0 Hz, Ar), 7.44-7.40 (m, 3H, Ar), 7.26-7.22 (m,

4H, Ar), 5.72-5.64 (m, 1H, RCH=CH2), 5.01-4.94 (m, 2H, RCH=CH2), 3.60-3.57 (t, 2H,

13 J = 7.8 Hz, RN(Ts)CH2R), 2.38 (s, 3H, CH3), 2.17-2.13 (m, 2H, RCH2CH=CH2); C

NMR δ (CDCl3): 144.1, 140.1, 134.9, 134.3, 132.6, 131.7, 131.4, 129.7, 127.8, 125.8,

124.8, 122.6, 117.5, 50.0, 32.8, 21.6 ; IR cm-1 (neat) : 3079, 2982, 2927, 2873, 1642,

1597, 1492, 1446, 1352, 1327, 1166, 1092, 1070.

Synthesis of N-(but-3-enyl)-4-methyl-N-(4-nitrophenyl)benzenesulfonamide (44).

O N 2 O2N

NHTs N Ts 192 The title compound was prepared by the same procedure aforementioned. 1H

NMR δ (CDCl3): 8.21-8.19 (d, 1H, J = 9.0 Hz, Ar), 7.47-7.46 (d, 2H, J = 8.0 Hz, Ar),

7.29-7.28(d, 4H, J = 8.5 Hz, Ar), 5.80-5.66 (m, 1H, RCH=CH2), 5.07-5.00 (m, 2H,

RCH=CH2), 3.70-3.67 (t, 2H, J = 7.2 Hz, RN(Ts)CH2R), 2.44 (s, 3H, CH3), 2.25-2.20 (q,

13 2H, J = 7.0 Hz, RCH2CH=CH2); C NMR δ (CDCl3): 146.7, 145.4, 144.4, 134.8, 134.0,

129.9, 128.9, 127.7, 124.5, 117.9, 49.6, 32.8, 21.8 ; IR cm-1 (KBr pellet) : 3334, 3084,

2980, 2922, 2867, 1642, 1592, 1490, 1358, 1162, 1103, 1038.

Synthesis of 4-methyl-N-(4-nitrophenyl)-N-(pent-4-enyl)benzenesulfonamide (46a).

O N 2 O2N

NHTs N Ts

The title compound was prepared by the same procedure aforementioned. 1H

NMR δ (CDCl3): 8.21-8.19 (d, 1H, J = 9.0 Hz, Ar), 7.30-7.26 (m, 3H, Ar), 7.46-7.45 (d,

2H, J = 8.5 Hz, Ar), 7.30-7.28 (m, 5H, Ar), 5.77-5.69 (m, 1H, RCH=CH2), 5.01-4.97 (m,

2H, RCH=CH2), 3.64-3.61 (t, 2H, J = 7.2 Hz, RN(Ts)CH2R), 2.45 (s, 3H, CH3), 2.12-2.08

(q, 2H, J = 6.5 Hz, RCH2CH=CH2), 1.60-1.54 (sep., 2H, J = 7.0 Hz, RCH2CH2CH=CH2);

13 C NMR δ (CDCl3): 146.6, 145.5, 144.3, 137.1, 134.8, 129.9, 128.7, 127.7, 124.6, 115.9,

49.6, 30.6, 27.6, 21.8.

Synthesis of 4-methyl-N-(pent-4-enyl)-N-(3-(trifluoromethyl)phenyl)benzene- sulfonamide (46d).

193 F3C NHTs F3C N Ts

The title compound was prepared by the same procedure aforementioned. 1H

NMR δ (CDCl3): 7.56-7.55 (d, 1H, J = 8.0 Hz, Ar), 7.48-7.43 (m, 3H, Ar), 7.31-7.25 (m,

4H, Ar), 5.76-5.68 (m, 1H, RCH=CH2), 4.98-4.93 (m, 2H, RCH=CH2), 3.58-3.55 (t, 2H,

J = 7.0 Hz, RN(Ts)CH2R), 2.41 (s, 3H, CH3), 2.11-2.07 (q, 2H, J = 7.0 Hz,

13 RCH2CH=CH2), 1.56-1.50 (sep., 2H, J = 7.0 Hz, RCH2CH2CH=CH2); C NMR δ

(CDCl3): 144.0, 140.2, 137.3, 134.8, 132.6, 131.8, 131.4, 129.7, 127.8, 125.4, 125.0,

124.7, 115.6, 50.0, 30.5, 27.6, 21.6.

Synthesis of N-benzyl-N-(but-3-enyl)-4-methylbenzenesulfonamide (47a).

NHTs NTs The title compound was prepared by the same procedure aforementioned, using

1 N-Ts-benzylamine. H NMR δ (CDCl3): 7.77-7.75 (d, 2H, J = 7.5 Hz, Ar), 7.34-7.28 (m,

5H, Ar), 5.64-5.50 (m, 1H, RCH=CH2), 4.94-4.87 (m, 2H, RCH=CH2), 4,36 (s, 2H,

benzylic), 3.21-3.17 (m, 2H, ROCH2R), 2.44 (s, 3H, CH3), 2.13-2.07 (m, 2H,

13 RCH2CH=CH2); C NMR δ (CDCl3): 143.3, 137.2, 136.5, 134.7, 129.8, 128.6, 128.4,

127.8, 127.2, 116.9, 52.1, 47.5, 32.8, 21.5; IR cm-1 (KBr pellet) : 3065, 3031, 2977, 2866,

1641, 1598, 1495, 1454, 1338, 1159, 1091, 1045.

194 Synthesis of N-benzyl-4-methyl-N-(pent-4-enyl)benzenesulfonamide (47c).

NHTs NTs The title compound was prepared by the same procedure aforementioned, using

1 N-Ts-benzylamine. H NMR δ (CDCl3): 7.76-7.74 (m, 2H, Ar), 7.35-7.28 (m, 7H, Ar),

5.65-5.57 (m, 1H, RCH=CH2), 4.91-4.87 (m, 2H, RCH=CH2), 4.34 (s, 2H, benzylic),

3.13-3.10 (t, 2H, J = 7.7 Hz, RN(Ts)CH2R), 2.46 (s, 3H, CH3), 1.91-1.97 (m, 2H,

13 RCH2CH=CH2), 1.48-1.42 (m, 2H, RCH2CH2CH=CH2); C NMR δ (CDCl3): 143.4,

137.6, 137.2, 136.7, 129.8, 128.7, 128.4, 127.9, 127.3, 115.2, 52.3, 47.9, 30.8, 27.4, 21.6;

IR cm-1 (KBr pellet) : 3065, 3030, 2922, 2867, 1640, 1598, 1495, 1455, 1337, 1159, 1091.

General procedure for cationic seleniranium ion-mediated cyclizations.

To a flame-dried aluminum foil-wrapped 1-neck flask in N2-charged drybox,

PhSeBr (110 mol%) and silver salt (310 mol%) were added under dark. The flask was capped by robber stopper, and then it taken out from a box. Anhydrous CH2Cl2 was

added to the vessel, and the resulting solution was stirred at rt for 10 min (the color of

solution turns deep dark blue). The vessel was cooled to appropriate temperature using

TM Cryocool , and then tethered alkene in CH2Cl2 was slowly added to keep the internal

temperature less than +10 oC of bath temperature. After the reaction was finished, the

reaction was quenched by adding MeOH, and the solution was warmed up to rt, followed

by additional stirring for 1 h at rt. The mixture was filtered through celite pad to remove

inorganic materials, and washed filtrates thoroughly by EtOAc. After the solvents were

evaporated, the crude compound was purified by column chromatography.

195 Synthesis of 4-(phenylselanylmethyl)chroman (14d) (entry 2, Table 6.1). SePh

O O Following the general procedure using 20 mg (0.135 mmol) of alkene 14c, the

1 title compound (40.0 mg, 97 %) was obtained. H NMR δ (CDCl3): 7.56-7.54 (m, 2H, Ar),

7.30-7.25 (m, 3H, Ar), 7.12-7.06 (m, 2H, Ar), 6.86-6.79 (m, 2H, Ar), 4,19-4.09 (m, 2H,

ROCH2R), 3.42-3.40 (dd, 1H, J = 8.5, 5.0 Hz, PhSeCH2R), 3.05-3.01 (m, 2H,

13 PhSeCH2CHR) & PhSeCH2R), 2.14-2.11 (m, 2H, ROCH2CH2R); C NMR δ (CDCl3):

154.7, 133.1, 130.4, 129.4, 128.1, 127.3, 125.2, 120.5, 117.2, 63.1, 34.9, 34.1, 26.8; IR cm-1 (neat) : 3070, 2922, 1605, 1597, 1487, 1436, 1308, 1269, 1225, 1116.; HRMS

+• 323.0278 (M+Na ; calcd for C16H16NaOSe 323.0291)

Synthesis of 6-methoxy-4-(phenylselanylmethyl)chroman (38a) (entry 6, Table 6.1).

SePh O O O O Following the general procedure using 20 mg (0.112 mmol) of alkene 38, the title

1 compound (32.0 mg, 85 %) was obtained. H NMR δ (CDCl3): 7.40-7.38 (m, 2H, Ar),

7.15-7.10 (m, 3H, Ar), 6.59-6.57 (d, 1H, J = 9.0 Hz, Ar), 6.55-6.52 (dd, 1H, J = 8.8, 2.8

Hz, Ar), 6.46-6.45 (d, 1H, J = 2.5 Hz, Ar), 4,00-3.92 (m, 2H, ROCH2R), 3.57 (s, 3H,

OCH3), 3.25-3.23 (dd, 1H, J = 11.0, 2.5 Hz, PhSeCH2R), 2.90-2.84 (m, 2H,

13 PhSeCH2CHR) & PhSeCH2R), 1.97-1.93 (m, 2H, ROCH2CH2R); C NMR δ (CDCl3):

153.5, 148.8, 133.1, 130.4, 129.4, 127.4, 125.8, 117.7, 114.2, 114.1, 63.2, 56.0, 35.0, 34.4,

27.0; IR cm-1 (neat) : 3440, 3069, 2938, 2867, 2831, 1614, 1578, 1484, 1436, 1265, 1207,

196 1157, 1082, 1039, 1019.

Synthesis of 4-(phenylselanylmethyl)-1-tosyl-1,2,3,4-tetrahydroquinoline (39a) and

1-phenyl-3-(phenylselanyl)pyrrolidine (39b) (entry 10, Table 6.1).

SePh

+ N N SePh Ts N Ts

Following the general procedure using 20 mg (0.0664 mmol) of alkene 39, the

title compound 39a (16.6 mg, 52 %) and 39b (6.0 mg, 30 %) were isolated by column

1 chromatography. 39a: H NMR δ (CDCl3): 7.92-7.88 (d, 1H, J = Hz, Ar), 7.51-7.49 (d,

2H, J = 6.8 Hz, Ar), 7.49-7.43 (m, 2H, Ar), 7.30-7.18 (m, 6H, Ar), 7.13-7.04 (m, 2H, Ar),

3.86-3.75 (m, 2H, RN(Ts)CH2R), 3.02-2.98 (dd, 1H, J = 12.4, 4.4 Hz, PhSeCH2CHR),

2.82-2.79 (m, 1H, PhSeCH2CHR), 2.45-2.39 (dd, 1H, J = 10.6 Hz, PhSeCH2CHR), 2.35

13 (s, 3H, CH3), 1.83-1.79 (q, 2H, J = 6.0 Hz, RN(Ts)CH2CH2R); C NMR δ (CDCl3):

143.9, 136.7, 135.6, 133.0, 132.8, 130.1, 129.8, 129.4, 129.0, 127.4, 127.3, 125.2, 124.9,

44.2, 36.1, 34.3, 26.4, 21.7; IR cm-1 (neat) : 3066, 2926, 1598, 1578, 1485, 1448, 1353,

+• 1305, 1165.; HRMS 476.0539 (M+Na ; calcd for C23H23NaNO2SSe 476.0540). 39b:

1 H NMR δ (CDCl3): 7.58-7.55 (m, 2H, Ar), 7.28-7.19 (m, 5H, Ar), 6.68-6.65 (t, 1H, J =

7.4 Hz, Ar), 6.53-6.51 (d, 2H, J = 7.6 Hz, Ar), 3.96-3.88 (m, 1H, RNCH2CH(R)SePh),

3.74-3.70 (dd, 1H, J = 10.0, 6.8 Hz, RNCH2CH(R)SePh), 3.47-3.43 (m, 1H,

RNCH2CH2R), 3.38-3.30 (m, 2H, RNCH2CH2R & RNCH2CH(R)SePh), 2.48-2.38 (m,

13 1H, RNCH2CH2R), 2.18-2.05 (m, 1H, RNCH2CH2R); C NMR δ (CDCl3): 147.4, 134.6,

129.4, 129.3, 127.9, 112.0, 54.7, 47.2, 39.5, 33.1; IR cm-1 (neat) : 3057, 2920, 2849, 1597,

197 1505, 1477, 1366, 1263, 1185, 1072.

Synthesis of (3-(phenylselanyl)-1,2,3,4-tetrahydroquinoline (40a) (entry 4, Table 6.2).

SePh

N N Boc H

Following the general procedure using 20 mg (0.0847 mmol) of alkene 40, the

1 title compound (18.4 mg, 74 %) was obtained. H NMR δ (CDCl3): 7.56-7.54 (m, 2H,

Ar), 7.48-7.46 (d, 2H, J = 8.0 Hz, Ar), 7.36-7.26 (m, 4H, Ar), 7.13-7.10 (t, 1H, J = 7.4 Hz,

Ar), 4.74-4.67 (m, 1H, PhSeCHR), 4.11-4.07 (t, 1H, J = 8.8 Hz, NHCH2R), 3.78-3.74 (dd,

1H, J = 9.2, 6.4 Hz, NHCH2R), 3.38-3.34 (dd, 1H, J = 12.8, 4.4 Hz, benzylic), 3.07-3.01

13 (dd, 1H, J = 12.8, 9.2 Hz, benzylic); C NMR δ (CDCl3): 154.5, 138.3, 133.9, 129.7,

129.3, 128.3, 128.0, 124.3, 118.4, 71.9, 50.4, 31.2; IR cm-1 (neat) : 3401, 3071, 2926,

1742, 1598, 1503, 1480, 1372, 1304, 1225, 1133, 1022.

Synthesis of phenyl(1,2,3,4-tetrahydronaphthalen-2-yl)selane (41b) (entry 5, Table

6.2).

SePh

Following the general procedure using 10 mg (0.0755 mmol) of alkene 41a, the

1 title compound (17.3 mg, 80 %) was obtained. H NMR δ (CDCl3): 7.60-7.57 (m, 2H,

Ar), 7.29-7.26 (m, 3H, Ar), 7.10-6.98 (m, 4H, Ar), 3.63-3.61 (m, 1H, PhSeCHR), 3.22-

3.16 (dd, 1H, J = 16.4, 5.0 Hz, Benzylic), 2.98-2.82 (m, 3H, Benzylic), 2.28-2.23 (m, 1H,

13 ArCH2CH2R); 1.94-1.88 (m, 1H, ArCH2CH2R); C NMR δ (CDCl3): 135.7, 135.1, 129.2,

198 129.1, 129.0, 127.8, 126.2, 126.0, 39.2, 37.1, 30.5, 29.4; IR cm-1 (neat) : 3058, 2924,

2852, 1734, 1578, 1494, 1476, 1452, 1435, 1376, 1334, 1300, 1263.

Synthesis of (1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)(phenyl)selane (41d)

(entry 6, Table 6.2).

SePh

Following the general procedure using 12.1 mg (0.0755 mmol) of alkene 41c, the

1 title compound (12.3 mg, 52 %) was obtained. H NMR δ (CDCl3): 7.59-7.55 (m, 3H,

Ar), 7.33-7.31 (d, 1H, J = 8.0 Hz, Ar), 7.26-7.21 (m, 2H, Ar), 7.21-6.98 (m, 3H, Ar),

3.48-3.44 (dd, 1H, J = 21.6, 3.2 Hz, RR’CHSePh), 2.92-2.86 (m, 1H, benzylic), 2.79-2.75

(m, 1H, benzylic), 2.26-2.12 (m, 2H, ArCH2CH2R), 1.56 (s, 3H, RCH3), 1.39 (s, 3H,

13 RCH3); C NMR δ (CDCl3): 135.0, 134.6, 131.7, 129.4, 129.2, 129.1, 127.9, 127.4,

127.0, 126.3, 125.9, 56.7, 39.2, 31,1, 30.5, 29.9, 29.1, 27.9.

Attempted cyclization of 1-allyl-4-methoxybenzene (entry 7, Table 6.2).

MeO MeO SePh MeO OMe + OMe SePh 42a 42b

Following the general procedure using 16.7 mg (0.112 mmol) of alkene 42,

Markovnikov adduct 42a (14.7 mg, 41%) and anti-Markovnikov adduct 42b (9.6 mg,

1 27 %) were obtained. Major product (42a: H NMR δ (CDCl3): 7.45-7.43 (m, 2H, Ar),

7.22-7.20 (m, 3H, Ar), 7.09-7.08 (d, 2H, 8.5 Hz, Ar), 6.81-6.79 (dd, 2H, J = 6.5, 2.0 Hz,

Ar), 3.77 (s, 3H, ArOMe), 3.55-3.53 (t, 1H, J = 6.0 Hz), 3.31 (s, 3H, ROMe), 3.00-2.98

199 13 (m, 2H, benzylic), 2.86-2.84 (m, 2H, RCH2OMe); C NMR δ (CDCl3): 158.4, 132.7,

130.8, 130.6, 130.4, 129.3, 127.0, 114.0, 82.1, 57.6, 55.5, 39.2, 31.6. Minor product

1 (42b: H NMR δ (CDCl3): 7.52-7.50 (m, 2H, Ar), 7.25-7.20 (m, 3H, Ar), 7.10-7.07 (m,

2H, Ar), 6.82-6.79 (m, 2H, Ar), 3.77 (s, 3H, ArOMe), 3.48-3.45 (m, 3H, RCH2OMe &

RCHR’R”), 3.31 (s, 3H, ROMe), 3.09-3.06 (m, 1H, benzylic), 2.92-2.88 (m, 1H,

13 benzylic); C NMR δ (CDCl3): 158.4, 134.9, 131.5, 130.4, 129.4, 129.2, 127.7, 113.9,

74.3, 58.9, 55.4, 46.2, 37.8.

Synthesis of 3-(phenylselanyl)-1-(3-(trifluoromethyl)phenyl)pyrrolidine (43a) (entry

1, Table 6.3).

F3C N SePh F3C N Ts Following the general procedure using alkene 43, the title compound 43a (12.3

1 mg, 56 %) was obtained. H NMR δ (CDCl3): 7.56-7.51 (m ,2H, Ar), 7.32-7.27 (m, 3H,

Ar), 6.90-6.88 (d, 1H, 7.6 Hz, Ar), 6.67 (s, 1H, Ar), 6.64-6.62 (d, 1H, 8.0 Hz, Ar), 3.94-

3.87 (m, 1H), 3.75-3.71 (m, 1H), 3.51-3.45 (m, 1H, 3.38-3.31 (m, 2H), 2.47-2.37 (m, 1H),

13 2.17-2.02 (m, 1H); C NMR δ (CDCl3): 147.5, 134.8, 130.1, 129.7, 129.4, 129.0, 128.3,

128.1, 114.8, 112.5, 108.1, 54.6, 47.2, 39.3, 33.0, 29.9.; IR cm-1 (neat) : 3072, 2924, 2851,

1613, 1584, 1505, 1460, 1381, 1309, 1287, 1163, 1120, 1072.

Synthesis of 1-(4-nitrophenyl)-3-(phenylselanyl)pyrrolidine (44a) (entry 2, Table 6.3).

O2N O2N N N SePh Ts 200 Following the general procedure using 27.1 mg (0.0782 mmol) of alkene 44, the

1 title compound (20.4 mg, 75 %) was obtained. H NMR δ (CDCl3): 8.11-8.08 (m, 2H,

Ar), 7.57-7.55 (m, 2H, Ar), 7.32-7.26 (m, 3H, Ar), 6.44-6.40 (m, 2H, Ar), 3.95-3.88 (m,

1H, RNCH2CH(R)SePh), 3.81-3.77 (dd, 1H, J = 10.8, 6.4 Hz, RNCH2CH(R)SePh), 3.60-

3.54 (m, 1H, RNCH2CH2R), 3.47-3.40 (m, 2H, RNCH2CH2R & RNCH2CH(R)SePh),

13 2.52-2.43 (m, 1H, RNCH2CH2R), 2.20-2.13 (m, 1H, RNCH2CH2R); C NMR δ (CDCl3):

151.6, 135.1, 130.1, 129.5, 128.4, 128.3, 128.2, 126.5, 110.7, 54.7, 47.4, 38.9, 32.7; IR cm-1 (KBr pellet) : 3073, 2959, 2915, 2857, 1596, 1577, 1513, 1477, 1434, 1395, 1298,

+• 1238, 1110, 1021; HRMS 367.0297 (M+Na ; calcd for C16H16NaN2O2Se 367.0302).

Synthesis of 1-phenyl-3-(phenylselanyl)piperidine (45a) (entry 3, Table 6.3).

SePh N N Ts Following the general procedure using 20.6 mg (0.0653 mmol) of alkene 45, the

1 title compound (20.0 mg, 96 %) was obtained. H NMR δ (CDCl3): 7.58-7.57 (dd, 2H, J

= 4.4, 3.2 Hz, Ar), 7.30-7.19 (m, 5H, Ar), 6.84-6.78 (m, 3H, Ar), 3.77-3.73 (m, 1H), 3.51-

3.41 (m, 2H), 3.02-2.96 (dd, 1H, J = 12.4, 10.0 Hz), 2.87-2.81 (m, 1H), 2.18-2.13 (m, 1H),

13 1.89-1.71 (m, 2H), 1.65-1.58 (m, 1H); C NMR δ (CDCl3): 151.3, 134.9, 129.3, 129.2,

128.8, 127.8, 119.7, 116.7, 57.2, 50.0, 40.7, 32.0, 26.0; IR cm-1 (KBr pellet) :3056, 2932,

2851, 2802, 1598, 1578, 1494, 1476, 1436, 1379, 1332, 1236, 1175, 1107, 1022.; HRMS

+• 314.0780 (M+H ; calcd for C17H20NSe 314.0788).

201 Synthesis of N-(4-nitrophenyl)-3-(phenylselanyl)piperidine (46b) and N-(4-

nitrophenyl)-2-(phenylselanylmethyl)pyrrolidine (46c) (entry 4, Table 6.3).

O N 2 O2N SePh O N 2 SePh + N N N Ts Following the general procedure using 30 mg (0.0832 mmol) of alkene 46a, the

mixture of 46b and 46c (21.2 mg, 3.4:1 based on 1H NMR, 71 %) was obtained. 1H

NMR δ (CDCl3): 8.05-8.03 (d, 2H, J = 9.5 Hz, Ar-46b), 7.96-7.94 (d, 2H, J = 9.5 Hz, Ar-

46c), 7.61-7.58 (d, 2H, J = 8.0 Hz, Ar-46c), 7.58-7.56 (d, 2H, J = 8.0 Hz, Ar-46b), 7.36-

7.29 (m, 3H, Ar-46b), 6.62-6.60 (d, 2H, J = 9.5 Hz, Ar-46b), 6.15-6.13 (d, 2H, J = 9.0 Hz,

Ar-46c), 3.95-3.92 (m, 1H), 3.77-3.72 (m, 1H), 3.34-3.29 (m, 1H), 3.26-3.17 (m, 1H),

3.12-3.05 (m, 1H), 2.23-2.21 (m, 1H), 1.87-1.83 (m, 1H), 1.76-1.68 (m, 2H); 13C NMR

(major compound only) δ (CDCl3): 154.2, 138.1, 135.3, 129.5, 128.4, 126.4, 112.6, 54.6,

48.0, 39.7, 31.8, 25.7.

Synthesis of 3-(phenylselanyl)-1-(3-(trifluoromethyl)phenyl)piperidine (46e) and 2-

(phenylselanylmethyl)-1-(3-(trifluoromethyl)phenyl)pyrrolidine (46f) (entry 5, Table

6.3).

CF 3 CF3 SePh + SePh N F3C N N Ts 49 % 21 %

Following the general procedure using 26.0 mg (0.0677 mmol) of alkene 46d, the title compound (46e, 12.8 mg, 49 %) and (46f, 5.4 mg, 21 %) was isolated by column

1 chromatography. 46e: H NMR δ (CDCl3): 7.59-7.57 (m, 2H, Ar), 7.32-7.25 (m, 3H,

202 Ar), 7.01-6.92 (m, 3H, Ar), 3.77-3.74 (m, 1H), 3.54-3.52 (m, 1H), 3.43-3.38 (m, 1H),

3.08-3.03 (dd, 1H, J = 15.0, 10.0 Hz), 2.95-2.90 (m, 1H), 2.18-2.15 (m, 1H), 1.89-1.84

13 (m, 1H), 1.77-1.70 (m, 2H); C NMR δ (CDCl3): 151.1, 135.0, 131.8, 129.8, 129.4,

128.5, 128.0, 119.2, 115.7, 115.6, 112.6, 56.5, 49.4, 40.2, 31.8, 25.7; 46f: 1H NMR δ

(CDCl3): 7.60-7.58 (m, 2H, Ar), 7.30-7.27 (m, 3H, Ar), 7.16-7.13 (t, 1H, J = 8.0 Hz, Ar),

6.84-6.82 (d, 1H, J = 7.5 Hz, Ar), 6.57 (s, 1H), 6.41-6.39 (dd, 1H, J = 8.0, 2.0 Hz, Ar),

3.90-3.87 (m, 1H), 3.46-3.42 (m, 1H), 3.19-3.13 (m, 2H), 2.71-2.67 (dd, 1H, J = 12.5,

13 10.5 Hz), 2.13-1.99 (m, 4H); C NMR δ (CDCl3): 146.8, 134.2, 129.7, 129.5, 129.1,

127.8, 114.9, 112.3, 108.1, 58.9, 48.7, 30.6, 30.5, 23.2.

Synthesis of 3-(phenylselanyl)-1-tosylpyrrolidine (47b) (entry 6, Table 6.3).

N O PhSe O S N S O O

Following the general procedure using 30.0 mg (0.095 mmol) of alkene 47a, the

1 title compound 47b (25.1 mg, 69 %) was obtained. H NMR δ (CDCl3): 7.72-7.70 (d,

2H, J = 8.0 Hz, Ar), 7.47-7.45 (d, 2H, J = 8.0 Hz, Ar), 7.35-7.26 (m, 5H, Ar), 3.76-3.72

(dd, 1H, J = 9.0, 7.0 Hz), 3.59-3.56 (t, 1H, J = 6.8 Hz), 3.39-3.35 (m, 2H), 3.24-3.21 (dd,

1H, J = 10.5, 6.5 Hz), 2.47 (s, 3H), 2.25-2.20 (m, 1H), 1.85-1.80 (m, 1H); 13C NMR δ

(CDCl3): 143.7, 134.9, 134.0, 129.9, 129.4, 128.3, 127.8, 54.5, 47.4, 38.4, 32.7, 21.8; IR

cm-1 (neat) : 3056, 2922, 2872, 1597, 1578, 1477, 1438, 1345, 1304, 1180, 1098, 1022.;

+• HRMS 400.0215 (M+Na ; calcd for C17H19NNaO2SSe 400.0226).

203 Synthesis of 3-(phenylselanyl)-1-tosylpiperidine (47d) (entry 7, Table 6.3).

PhSe N O O S N S O O Following the general procedure using 30.0 mg (0.076 mmol) of alkene 47c, the

1 title compound 47d (22.6 mg, 75 %) was obtained. H NMR δ (CDCl3): 7.62-7.55 (m,

2H), 7.51-7.49 (d, 2H, J = 8.0 Hz), 7.32-7.12 (m, 5H), 3.66-3.57 (m, 2H), 3.49-3.45 (m,

1H), 3.13-3.08 (m, 1H), 2.85-2.80 (dd, 1H, J = 12.2, 9.2 Hz), 2.33 (s, 3H), 1.83-74 (m,

13 2H), 1.69-1.66 (m, 1H), 1.50-1.42 (m, 1H); C NMR δ (CDCl3): 143.6, 134.2, 132.6,

129.8, 129.5, 129.4, 127.7, 127.1, 60.0, 50.1, 33.1, 31.3, 24.0, 21.7; IR cm-1 (neat): 3060,

2922, 2870, 1597, 1579, 1493, 1436, 1345, 1158, 1091, 1023.; HRMS 414.0371

+• (M+Na ; calcd for C18H21NNaO2SSe 414.0383).

Synthesis of (S)-N-(but-3-enyl)-4-methyl-N-(1-phenylethyl)benzenesulfonamide

(48a).

H N O N O S S O O

The title compound was prepared by the same Mitsunobu reaction procedure

1 aformentioned. H NMR δ (CDCl3): 7.70-7.76 (m, 2H, Ar), 7.37-7.24 (m, 7H, Ar),

5.56-5.47 (m, 1H, RCH=CH2), 5.27-5.19 (m, 1H, benzylic-H), 4.92-4.82 (m, 2H,

RCH=CH2), 3.17-3.00 (m, 2H, RN(Ts)CH2R), 2.46 (s, 3H, CH3), 2.26-2.12 (m, 1H,

RCH2CH=CH2), 1.91-1.80 (m, 1H, RCH2CH=CH2).

204 Synthesis of 3-(phenylselanyl)-1-tosylpiperidine (47b) using the chiral substrate

(48a).

PhSe O N O S N S O O

Following the general procedure using 16.5 mg (0.050 mmol) of alkene 48a, the

1 title compound (17.0 mg, 89 %) was obtained. H NMR δ (CDCl3): 7.62-7.55 (m, 2H),

7.51-7.49 (d, 2H, J = 8.0 Hz), 7.32-7.12 (m, 5H), 3.66-3.57 (m, 2H), 3.49-3.45 (m, 1H),

3.13-3.08 (m, 1H), 2.85-2.80 (dd, 1H, J = 12.2, 9.2 Hz), 2.33 (s, 3H), 1.83-74 (m, 2H),

13 1.69-1.66 (m, 1H), 1.50-1.42 (m, 1H); C NMR δ (CDCl3): 143.6, 134.2, 132.6, 129.8,

129.5, 129.4, 127.7, 127.1, 60.0, 50.1, 33.1, 31.3, 24.0, 21.7; IR cm-1 (neat) :3060, 2922,

2870, 1597, 1579, 1493, 1436, 1345, 1158, 1091, 1023.; HRMS 414.0371 (M+Na+• ;

calcd for C18H21NNaO2SSe 414.0383); HPLC separation (AD-H column, 3 % IPA/n-Hex,

0.5 ml/min) – tR 53.12, 55.68 (49.86:50.14).

Synthesis of (S)-N-(but-3-enyl)-4-nitro-N-(1-phenylethyl)benzenesulfonamide (48b).

H N O N O S S O O NO 2 NO2 The title compound was prepared by the same Mitsunobu reaction procedure

1 aformentioned. H NMR δ (CDCl3): 8.36-8.33 (m, 1H, Ar), 8.04-8.00 (m, 2H, Ar),

7.33-7.25 (m, 5H, Ar), 5.58-5.51 (m, 1H, RCH=CH2), 5.28-5.20 (q, 1H, J = 6.8 Hz,

benzylic), 4.96-4.86 (m, 2H, RCH=CH2), 3.25-3.08 (m, 2H, RN(Ts)CH2R), 2.27-2.18 (m,

13 1H, RCH2CH=CH2), 1.98-1.82 (m, 1H, RCH2CH=CH2); C NMR δ (CDCl3): 149.9,

147.2, 139.5, 134.5, 128.8, 128.4, 128.3, 127.7, 124.5, 117.3, 56.4, 44.4, 35.4, 17.5.

205 Synthesis of 1-(4-nitrophenylsulfonyl)-3-(phenylselanyl)pyrrolidine (47e) using the

chiral substrate 48b.

N O PhSe O S N S NO2 O O NO2 Following the general procedure using 18.0 mg (0.050 mmol) of alkene 48b, the

1 title compound 47e (15.6 mg, 76 %) was obtained. H NMR δ (CDCl3): 8.39-8.36 (m,

2H), 8.01-7.98 (m, 2H), 7.43-7.26 (m, 5H), 3.82-3.77 (dd, 2H, J = 6.4, 10.8 Hz), 3.69-

3.65 (m, 1H), 3.48-3.41 (m, 2H), 3.30-3.26 (dd, 1H, J = 5.6, 5.2 Hz), 2.35-2.25 (m, 1H),

13 1.92-1.85 (m, 1H).; C NMR δ (CDCl3): 150.3, 143.0, 134.9, 129.6, 128.7, 128.5, 127.8,

124.6, 54.5, 47.5, 38.4, 32.6.; IR cm-1 (KBr pellet): 3110, 2961, 2922, 2867, 1600, 1543,

1474, 1345, 1314, 1194, 1159, 1057, 1022.

206 6.3. REFERENCES (1) Jones, A. D.; Redfern, A. L.; Knight, D. W.; Morgan, I. R.; Williams, A. C. Tetrahedron 2006, 62, 9247. (2) Selenium in Natural Product Synthesis; Nicolau, K. C.; Petasis, N. A., Eds.; CIS: Philadelphia, 1984. (3) Selenium Reagents and Intermediates in Organic Synthesis; Paulmier, C., Ed.; Pergamon: Oxford, 1986. (4) Wirth, T. Angew. Chem. Int. Ed. 2000, 39, 3740. (5) Ranganathan, S.; Muraleedharan, K. M.; Vaish, N. K.; Jayaraman, N. Tetrahedron 2004, 60, 5273. (6) "Electrophilic Selenium, Selenocyclizations", In Topics in Current Chemistry: Organoselenium Chemistry; Wirth, T., Ed.; Springer-Verlag: Berlin, 2000; Vol. 208. (7) Browne, D. M.; Wirth, T. Curr. Org. Chem. 2006, 10, 1893. (8) Toshimitsu, A.; Nakano, K.; Mukai, T.; Tamao, K. J. Am. Chem. Soc. 1996, 118, 2756. (9) Okamoto, K.; Nishibayashi, Y.; Uemura, S.; Toshimitsu, A. Tetrahedron Lett. 2004, 45, 6137. (10) Clive, D. L. J.; Chittatu, G.; Wong, C. K. J. Chem. Soc., Chem. Commun. 1978, 1128. (11) Déziel, R.; Malenfant, E.; Thibault, C. Tetrahedron Lett. 1998, 39, 5493. (12) Edstrom, T.; Livinghouse, T. Tetrahedron Lett. 1986, 27, 3483. (13) Appelbe, R.; Casey, M.; Dunne, A.; Pascarella, E. Tetrahedron Lett. 2003, 44, 7641. (14) Zhang, A.; RajanBabu, T. V. J. Am. Chem. Soc. 2006, 128, 5620. (15) Smith, C. R.; Lim, H. J.; Zhang, A.; RajanBabu, T. V. Synthesis 2009, 2089. (16) Jobst, J.; Hesse, O. Ann. Chem. Pharm. 1864, 129, 115. (17) Grieg, N. H.; Pei, X. F.; Soncrant, T. T.; Ingram, D. K.; Brossi, A. Med. Res. Rev. 1995, 15, 3. (18) Wittig, G.; Geissler, G. Liebigs Ann. Chem. 1953, 580, 44. (19) Heck, R. F. Org. React. 1982, 27, 345. (20) Barluenga, J.; Trincado, M.; Rubio, E.; González, J. M. J. Am. Chem. Soc. 2004, 126, 3416. (21) Wittig, G.; Böll, W.; KrűcK, K. H. Chem. Ber. 1963, 95, 2514. (22) Edstrom, E. D.; Livinghouse, T. J. Am. Chem. Soc. 1986, 108, 1334. (23) Schmid, G. H.; Garratt, D. G. Tetrahedron Lett. 1975, 3991. (24) Khokhar, S. S.; Wirth, T. Eur. J. Org. Chem. 2004, 4567. (25) Denmark, S. E.; Collins, W. R. Org. Lett. 2007, 9, 3801.

207 (26) Jackson, W. P.; Ley, S. V.; Morton, J. A. Tetrahedron Lett. 1981, 22, 2601. (27) Nandi, M.; Jin, J.; RajanBabu, T. V. J. Am. Chem. Soc. 1999, 121, 9899. (28) RajanBabu, T. V. Chem. Rev. 2003, 203, 2845. (29) Weibel, J.-M.; Blanc, A.; Pale, P. Chem. Rev. 2008, 108, 3149. (30) DiRenzo, G. M.; S., W. P.; Brookhart, M. J. Am. Chem. Soc. 1996, 118, 6225. (31) Brookhart, M.; Grant, B.; Volpe, A. F. J. Organometallics 1992, 11, 3920. (32) Nomura, N.; Jin, J.; Park, H.; RajanBabu, T. V. J. Am. Chem. Soc. 1998, 120, 459. (33) Pelkey, E. T.; Gribble, G. W. Can. J. Chem. 2006, 84, 1338. (34) Lee, Y. T.; Chung, Y. K. J. Org. Chem. 2008, 73, 4698. (35) Van der Eycken, E.; De Keukeleire, D.; De Bruyn, A. Tetrahedron Lett. 1995, 36, 3573. (36) Youn, S. W.; Pastine, S. J.; Sames, D. Org. Lett. 2004, 6, 581. (37) Closson, W. D.; Ji, S.; Schulenberg, S. J. Am. Chem. Soc. 1970, 92, 650. (38) Kabalka, G. W.; Li, N.; Pace, R. D. Synth. Commun. 1995, 25, 2135. (39) Orita, A.; Watanabe, A.; Tsuchiya, H.; Otera, J. Tetrahedron 1999, 55, 2889.

208

CHAPTER 7

Cu-MEDIATED TANDEM DIKETOPIPERAZINE FORMATION/N-ARYLATION

7.1 INTRODUCTION

Several molecules containing 2,5-Diketopiperazine (49a, DKP) moiety shows

promising biological activities helpful in treating human diseases.1 Chiral derivatives of

diketopiperazines known as the Schöllkopf chiral auxiliary2 have been used to install

alkyl groups for preparing unnatural α-amino acids with chiral sidechains.3-5 In addition,

there are numerous reports of DKP containing natural products in nature.2,6-8

Pyrazino[1,2-a]indole-1,4-dione (49b), a structurally simplified analog of gliotoxin

(49c),9,10 which is an epidithiodiketopiperazine based natural product has potent

immunosuppressive and antimicrobial activities (Figure 7.1). This compound interacts

with various biological targets such as an allosteric ligand of the M2 muscarinic receptor, and causes selective inhibition of geranylgeranyltransferase I, a process useful for the development of an anticancer drug.11-14 However, there is no general method for the

synthesis of enantiopure pyrazino[1,2-a]indole-1,4-diones (49b). Reported non-

stereoselective methods needs stepwise synthesis started from indole 2-carboxylic acid

derivatives. Also, harsh reaction conditions, such as high temperature are required.14

Therefore, a facile method is needed for the asymmetric synthesis of these bioactive

209 pharmacophores.

O O OH OH O NH S N NH N N S HN O O O 2,6-DiketopiperazinePyrazino[1,2-a]indole-1,4-dione gliotoxin 49a 49b 49c

Figure 7.1. 2,5-Diketopiperazine, Pyrazino[1,2-a]indole-1,4-dione, and Gliotoxin

7.1.1. Ni-catalyzed Asymmetric Hydrovinylation to Generate an All-carbon Center:

Search for a Synthesis of Lynbyatoxin A

During the course of our ongoing efforts to develop a new synthetic pathway to

generate chiral all-carbon quaternary carbon centers by Ni(II)-catalyzed asymmetric

hydrovinylation (Eq. 7.1),15 we became interested in the synthesis of biologically active

natural products which contain chiral all-carbon quaternary centers such as lynbyatoxin A

(50a) and teleocidin B (50d). As model for the eventual construction of the

cyclopeptide we also decided to target benzolactam-V8 (50e) as a simplified synthetic congener (Figure 7.2).

210 [AllylNiBr]2, L3 When R is ethyl R R (Eq. 7.1) NaBARF, CH2Cl2 96 %, 98 %ee

Ph

L1 = Ph L3 = Ph L10 = O P N O O O P N P N O O Ph Ph

To the best of our knowledge, no enantioselective total synthesis of lynbyatoxin

A (50a) or teleocidin B (50d) has been reported to date. However, these compounds have significance for the development of an anticancer drug, as well as understanding human cancer induced by the malfunction of protein kinase C (PKC).16,17,18,19 The structural analogues of these compounds have been made for developing the new drugs.

Especially 7-alkyl group bearing indolactam V have been studied, because those analogues gave improved bioactivities.17 Hence, 7-bromo indolactam V (50b) could be one of key sub-targets for medicinal studies and for total synthesis.

Due to the structural flexibility of the macrolactam ring, it is still unclear which conformation is biologically active.20 Therefore conformationally restricted synthetic congeners are also of interest to develop a lead compound for a new cancer drug.

211 OH OH H H N N H O N N N O O N OH NH OH O N N N H N H H R

Lyngbyatoxin A TeleocidinB Indolactam (R = H) 50c Benzolactam-V8 7-bromo indolactam (R = Br) 50b 50a 50d 50e

Figure 7.2. Structures of Teleocidine Family and Benzolactam-V8

7.1.2. Metal-Catalyzed Intramolecular N-Arylation

As described in Chapter 5, the formation of C-N bonds via metal-catalyzed reactions is a well-established area in modern synthetic chemistry. Due to the mild reaction conditions, Cu-based reactions can even mediate amination with chiral amines21 such as α-aminoacids (Eq. 7.2). Using Cu-mediated condition, Ma and coworkers reported the asymmetric synthesis of benzolactam-V8,22 which is an analogue of protein

kinase C activator – indolactam V.23

Intramolecular versions of N-arylations have also been developed and used for

the syntheses of natural products. In 2006, Fukuyama and coworkers reported a total

O

I NH CuI, K2CO3 HN CO H N OH + 2 (Eq. 7.2) o H2N CO2H DMA, 90 C OH OH 81 % benzolactam-V8 212

CO Bn HO NHNs HO 2 CbzHN Br CuI, CsOAc Br Br 77 % DMSO, rt, 12 h CuI, CsOAc MeO Br MeO N ~85% Ns MeO N DMSO, rt, 12 h OMe OMe Ns OMe BnO2C

CbzN

OTBS OTBS O MeO N MeS Ns OMe CuI, CsOAc MeO2C NH NH + HN MeO C CbzHN DMSO, rt, 12 h 2 N Br >99% MeO N Cbz Fmoc OBn OBn OMe

SMe OH O (+)-Yatakemycin OMe HN NH N MeO N OH O O N H O

Scheme 7.1. Fukuyama’s Synthesis of (+)-Yatakemycin

synthesis of (+)-yatakemycin using CuI/CsOAc catalyzed intramolecular N-arylation24 developed by them as a key step.25 In this report, catalytic as well as stoichiometric Cu-

mediated intramolecular N-arylations were successfully applied for the cyclization of heavily functionalized substrates to build 5- to 6-membered amine-containing heterocyclic subunits of the target.

213 Hayes and coworkers reported the synthesis of lotrafiban (SB-214857) via a

similar Cu-catalyzed cyclization (Scheme 7.2).26 In this report, the oxidation state of the metal was found to be the major factor for the success of the cyclization with the following order reflecting the reactivity (Cu0>CuI>CuII). A mixture of copper(I) oxide

(1 mol%) with Raney copper (19 mol%) gave the best results in terms of chemical yields,

but this condition suffered from the isomerization of α-stereocenter under the prolonged

reaction times needed.

I H CO H NHFmoc CuI (10 mol%) N 2 N CO2Me O o t-BuO2C DMF, H O, 90 C 2 t-BuO C N O 2 67 %

HN H N CO 2H O N N O SB-214857

Scheme 7.2. Hayes Synthesis of SB-214857 via Cu-catalyzed Cyclizations

Using similar conditions, 2-aminobenzimidazoles were synthesized in good to

excellent yields (Eq. 7.3).27 In this study, a CuI/phenanthroline catalytic system was

214 directly compared to the more well-known Pd-catalyzed systems. The results clearly proved the superiority of Cu-systems in terms of yield and selectivity.

R1 R1 HN 5 mol% CuI, 10 mol% phen N R2 R2 N (Eq. 7.3) N N Cs Co ,DME,80oC, 16 h 2 3 N R N X R3 3 phenanathroline (phen)

N-arylation for macrocyclization has been developed successfully. Using similar conditions as mentioned, cyclopeptide alkaloids such as reblastatin

(intramolecular macroamidation),28 paliurine F (intramolecular macroenamidations),29 and many macrocyclic arylether containing natural products such as vancomycin30 have been prepared.31,32,33

215 7.2 RESULTS AND DISCUSSION

According to a recent report, the biosynthethic pathway of lynbyatoxin A (50a) involves a unique cyclization.34 Surprisingly, the macrolactam structure is formed by an

intramolecular C-N bond forming reaction that follows an enzyme-mediated epoxidation

of an aryl group (Scheme 7.3).

H H N N N Reductive N OH H OH Cleavage H Enzyme O Lynbyatoxin O O Gene Cluster

N N H H Enzyme : P450 mono-oxygenase/cyclase

H N H N OH N OH O N O

N OPP H N Geranyl Pyrophosphate H (Enzymes)

Scheme 7.3. Biosynthesis of Lynbyatoxin A

216 Most of the previous syntheses of related cyclopeptides relied upon the amide-

bond formation to build the dipeptide ring. Therefore, we thought it would be

interesting to attempt a biogenesis-inspired total synthesis using metal-mediated

intramolecular N-arylation of a linear substrate. Along the biosynthesis route, a linear valine-tryptophane dipeptide could in principle cyclize into the desired macrocyclic lactam structure. Thus a retrosynthetic strategy along this line was envisioned (Scheme

7.4).

H CO2Et N Intramolecular Br O N OH Amination HN Lynbyatoxin A O NB oc N Boc N Br H 53a Br 7-Br Indolactam V (50b) Asymmetric Hydrogenation

CO2Et Br O Br O H HN N CO Et + BocN 2 NBoc N O PO(OEt) Modified Horner- N Boc 2 Boc Br Emmons Reaction Br 51 52 53

Scheme 7.4. Retrosynthetic Analysis of the Target Molecule(s)

217 7.2.1. Unexpected Formation of Tetracyclic DKPs by Tandem Cyclizations under

Copper-Mediated Cyclizations

The plan calls for the substitution of the key enzyme cyclization by a metal- catalyzed intramolecular N-arylation. For this plan, the linear dipeptides 53b in Table

7.2 will be prepared by modified Horner-Emmons reaction of the Schmidt phosphonate

52 and 4,7-dibromoindole carboxaldehyde 51, followed by Rh-catalyzed asymmetric hydrogenation (Scheme 7.5). The key intermediate – N-Boc-4,7-dibromo indole-3-

carboxaldehyde 51 – was prepared via Bartoli indole synthesis.35,36 Vilsmier

formylation and protection of indolyl amine gave the key indole part (51) (Scheme 7.5).

Schmidt’s phosphonate 52 was prepared by Rh-catalyzed carbene chemistry.37 Horner-

Emmons reaction of the aldehyde 51 with the phosphonate 52 under reported procedures

gave 71 % of the pure Z-dehydro dipeptide 53 after column purification.37

218

Br Br Br O Br O POCl MgBr 3 NaH, Boc2O NO THF N DMF N THF N 2 H H Boc Br 47 % Br 79 % Br 83 % Br 51 51a 51b

52

1.IBC, NMM, DME N2 CO 2Et Rh(OAc)2 H NH2 N CO Et OH BocN + BocN 2 BocN 2. NH gas PO(OEt)2 tol., reflux 3 O O PO(OEt) O 73 % 2 80 % 52a 52b

CO2Et CO2Et Br Br O O + - DBU HN [Rh(S,S-EtDuphos)NBD] BF4 HN 51 + 52 NBoc NBoc CH Cl 2 2 N MeOH, 90 psi N Boc Boc 71 % 90 % (8.5:1) Br 53a Br 53

Scheme 7.5. Syntheses of the Key Intermediates and Horner-Emmons Reaction

219 CO 2Et CO2Et Br O Br O [Rh(L)NBD]+BF - HN 4 HN NBoc NB oc N MeOH, H2 gas N Boc Boc Br Br 53 53a

Entry Ligand Conditiona Conversion (dr)b

1 R R = Me (10 mol%), 90 psi, 3 d > 99 % (3.2:1) PPh2 PPh2 2 R = i-Pr (10 mol%), 90 psi, 3 d 92 % (2.9:1) R

3 R R = Me (10 mol%), 70 psi, 4 d 85 % (4.6:1)

P 4 R R = Me (10 mol%), 90 psi, 2 d 88 % (4.6:1) R P

5 R R = Et (10 mol%), 90 psi, 4 d 90% (8.5:1)

a High pressure Parr hydrogenater was used, and deoxygenated MeOH was used as a solvent. b Selectivities were determined by 1H NMR.

Table 7.1. Rh-catalyzed Asymmetric Hydrogenations of Z-Dehydroaminoacid 53

The resulting olefin was reduced by Rh-catalyzed asymmetric hydrogenation to

yield the desired dipeptide 53a in good stereoselectivities (Table 7.1). Although both

chiraphos ligands (Me and i-Pr) gave higher conversions (entries 1-2, Table 7.1), in the

Rh-catalyzed hydrogenations, Et-Duphos ligand gave better stereoselectivity for this

substrate under these conditions (entries 3-5, Table 7.1). Deoxygenated methanol gave a

220 better yield than other solvents such as THF.

Selective deprotection of the N-Boc-group of valine in 53a was tested under

different conditions. Weakly acidic conditions such as 3 M HCl in EtOAc or formic

acid were not enough acidic to deprotect it (entries 1-2, Table 7.2). Reaction under

20 % of trifluoroacetic acid in CH2Cl2 at low temperature gave good selectivities in desired mono-deprotection product 53b (entry 5, Table 7.2). Both Boc-groups were

removed (giving 53c) quantitatively under more acidic conditions (entry 3, Table 7.2).

CO Et CO 2Et CO2Et 2 Br Br Br O O O HN HN HN NBoc NH + NH N N N Boc Boc H Br Br Br 53a 53b 53c

Entry Conditions Time & Temp. Yield of 53b (53c)

1 3 M HCl in EtOAc 12 h, rt NRa

2 Formic acid 12 h, rt NRa

3 30 % TFA in CH2Cl2 1 h, rt 0 % (> 99 %)

4 20 % TFA in CH2Cl2 1h, rt 50 % (50 %)

5 20 % TFA in CH2Cl2 12h, 0 ºC 67 % (30 %)

a Starting material was recovered.

Table 7.2. Selective Deprotections of N-Boc Groups in the Dipeptide 53a

221 Using the mono-deprotected linear substrate 53b, various Pd-catalyzed intramolecular amination procedures were attempted, but none of these trials led to any cyclized product (Table 7.3).38-41 When a strong base such as sodium or potassium t- butoxide was useed as in a usual Buchwald-Hartwig protocol under elevated temperature, most of starting dipeptide 53b degradated without any cyclization (entries 1-2, 4-5, Table

7.3). A catalytic system with a weaker base such as cesium carbonate also failed (entry

3, Table 7.3).

Entry Conditions38-41 Time & Temp. Results

Pd(OAc)2 (5 mol%), DPPP (10 mol%), 1 80 oC, 14 h --b NaOt-Bu (200 mol%), Toluenea

Pd2dba3·CHCl3(5 mol%), m-Tol3P (10 2 rt, 4 d -- b mol%), NaOtBu (200 mol%), Toluene

Pd(OAc)2 (3.3 mol%), MOP (10 mol%), o SM 3 a 100 C, 20 h Cs2CO3 (200 mol%), Toluene recovered

Pd2dba3·CHCl3(10 mol%), BINAP o b 4 (10 mol%), KOt-Bu (200 mol%), K2CO3 90 C, 14 h -- (200 mol%), Toluenea

Pd2dba3·CHCl3(8 mol%), BINAP (9 mol%), 5 100 oC, 5 h -- b NaOt-Bu (200 mol%), Dioxane a Reaction was performed in sealed tube. b No desired product without any starting material.

Table 7.3. Pd-catalyzed Intramolecular N-Arylation Reactions

222 Next, a Cu-mediated N-arylation condition was tried for this

macrocyclization.24,25 Surprisingly, even the amine 53c underwent cyclization to an

unexpected tetracyclic DKP structure 54 in good yield under the CuI/CsOAc cyclization

condition (Eq. 7.4). During the reaction, a small amount of an unidentified compound

(10 %) was also formed, but none of the expected 9-membered macro-cyclization product

was detected.

N O CO 2Me Br O HN CuI, CsOAc O N (Eq. 7.4) NH o N DMSO, 90 C H Br 63 % N 53c H 54 Br

It is noteworthy that not only the 7-Br group survived under the N-arylation

conditions, but also there was no serious isomerization of the chiral centers.

Isomerization during N-arylation is a notorious problem in the synthesis of Tadalafil

(CialisTM).42 The structure of the cyclized product 54 was confirmed by X-ray crystallography (Figure 7.3 and Table 7.4). During the attempts of the crystallization, mono-hydrate from of 54 (absorbed moisture in the air) was obtained as good quality

single crystals.

223

N O

O N

N 54 H Br

(O3 is from water)

Figure 7.3. Ortep Plot of Tetracyclic DKP 54

Entry Bonds Lengths Entry Bonds Angles

1 C(1)-Br 1.9056(17) 1 C(6)-C(1)-Br 120.17(14)

2 C(6)-N(1) 1.370(2) 2 C(6)-N(1)-C(7) 108.85(15)

3 C(4)-N(2) 1.435(2) 3 C(5)-C(8)-C(7) 106.04(15)

4 C(8)-C(9) 1.496(2) 4 C(5)-C(4)-N(2) 113.82(14)

5 C(10)-C(11) 1.514(2) 5 C(8)-C(7)-N(1) 109.58(15)

6 C(11)-O(1) 1.237(2) 6 C(11)-N(3)-C(12) 124.49(14)

7 C(12)-N(3) 1.468(2) 7 C(9)-C(10)-C(11) 105.6

Table 7.4. Selected Bond Lengths and Angles of Tetracyclic DKP 54

224 This tetracyclic DKP 54 is a new rigid synthetic congener of 7-bromoindolactam

V (50b, p. 217), and it could be used to build the core structure of pyrroloquinoline alkaloids such as mycenarubins A and B (Figure 7.4).43

H2N CO2H H2N CO2H O N N O

N N N N HN H O H O O CO2H Mycenarubins A Mycenarubins B

Figure 7.4. Structures of Mycenarubins A and B

A plausible mechanism of the unexpected tandem reaction is shown in Scheme

7.6. After a head-to-tail 2,6-diketopiperazine (DKP) formation, the nitrogen in diketopiperazine becomes nucleophilic enough to effect an intramolecular N-arylation at the 4-Br site to make the tetracyclic DKP. However, Pd-catalyzed Buchwald-Hartwig amination conditions under less polar solvent such as toluene or 1,4-dioxane could not mediate the first step. Further studies are needed to confirm the actual mechanism and the scope of the tandem reaction sequence.

225 CO Me H 2 N CO Me Br O Path A 2 HN N O NH N H N Br H Br

Path C Path B O N O CO Me HN 2 Br Br O HN Path B N Path C O N NH O N N H H 54b Br Br N H 54 Br Path C Path B

NH CO2Me O N Path A: Macro intramolecular N-arylation. Path B: DKP-ring formation. Path C: Micro intramolecular N-arylation. N H Br 54c

Scheme 7.6. Proposed Steps in the Cu-mediated Tandem Cyclization

7.2.2. Synthesis of Simplified Substrates and Their Cyclizations

In order to study the mechanism and scope of this new Cu-mediated tandem cyclization, simple dipeptide structures, including a linear dipeptide precursor for benzolactam-V8 (50e), were designed. Two approaches for the preparation of the desired dipeptide bearing an aryl bromide were considered. One approach uses the same strategy that was used previously. Another is the use of the Schöllkopf reagent-

226 based unnatural amino acid synthesis, followed by a general peptide coupling with a

protected valine unit.

As described earlier, the Schmidt’s phosphonate (52) was coupled with 2-bromo

benzaldehyde to yield the Z-dehydro dipeptide (Scheme 7.7).37 The resulting olefin was

reduced by Rh-catalyzed asymmetric hydrogenation using several different asymmetric

Rh-catalysts to obtain the desired isomer 55a (Table 7.5). Unlike the more complex

substrate 53 described earlier, in this instance the sugar-based ligand developed by

RajanBabu and coworker gave higher stereoselectivity than the well-known ethyl-

Duphos ligand (entry 3, Table 7.5).44

Boc N Br O H DB U HN O + N BocN O O CH2Cl2 O O OP(OEt)2 58% Br O 52 55 Asymmetric Hydrogenation

H Boc N N

30% TFA/CH2Cl 2 HN O HN O O rt, 1 h O

Br O >99% Br O 55b 55a

Scheme 7.7. Synthesis of Dipeptide 55b by Rh-cat. Hydrogenations

227

Boc Boc N N + - [Rh(L)NBD] BF4 HN O HN O O MeO H, H 2 (g) O

Br O Br O 55 55a

Entry Ligand Conditiona Conversion (Selectivity) b

P Cat. 5 mol%, MeOH 100 % 1 P 60 psi, rt, 1 day (SS/SR = 3.6:1)

Cat. 5 mol%, THF 38% 2 O Ph O O OPh 40 psi, rt, 1 day (SS/SR = 10:1) Ar2PO OPAr2 Cat. 5 mol%, THF 100 % 3 Ar = 3,5 dimethylphenyl 60 psi, rt, 2 day (SS/SR = 6.8:1)

a Selectivities were determined by 1H NMR. b High pressure Paar hydrogenater was used.

Table 7.5. Rh-catalyzed Asymmetric Hydrogenations of Z-Dehydroaminoacid 55

In addition, the desired dipeptides were prepared by Schöllkopf reagent.

Diastereoselective alkylations of o-halobenzylbromide with the reagent, followed by hydrolysis of the alkylated products 56a-b gave the desired enantio-pure o-halo

substituted L-phenylalanine in good yields. HBTU coupling reactions with N-Boc

protected L-valine gave the dipeptides 58a-b that was previously made by the

228

O O N NH nBuLi, -78 oC O 2 O N 0.5 N HCl N O N THF, o-X-BnBr THF O Schollkopf reagent 56a:X=Br,93% 57a:X=Br,93% X 56b:X=I,75% X 57b:X=I,85%

HO H Boc NBoc N N O 30% TFA/CH 2Cl2 HBTU, DIPEA, CH Cl HN O HN O 2 2 O rt, 1 h O 58a:X=Br,93% 59a:X=Br,>99% 58b:X=I,85% X O 59b:X=I,>99% X O

Scheme 7.8. Syntheses of Dipeptides 59a-b using the Schöllkopf Reagent

hydrogenation strategy (Scheme 7.8).45 Boc-group was deproteded under a general acid

condition.

Using the dipeptides 55b and 59a-c, the Cu-mediated tandem cyclizations were

tested.40,46 Boc-protected substrate 55a that cannot make the DKP was subjected to

cyclization conditions under CuI/CsOAc. A reaction was conducted using only CsOAc

to investigate whether there is sufficient nucleophilicity for the amide N to do a simple

aromatic nucleophilic displacement. Both reaction conditions did not give any

cyclization product, which suggests that DKP formation is the first step of the tandem

reaction sequences (entries 1-2, Table 7.6). Cyclization of the free amine 55b under

229

X O O CuI, CsOAc (2.5 eq.) O + o N N N NH N R DMSO, 90 C, 12 h N EtO2C O O 55a:R=Boc,X=Br 60 60a 55b :R=H,X=Br 59b :R=H,X=I

Entry Substrates Conditionsa Yieldsc (%) of 60 (60a)

No cyclized product 1 Br CuI (1 eq.) O (55a was recovered) NH N Boc No cyclized product EtO2C b 2 55a CsOAc (2.5 eq.) only (55a was recovered with 23 % of racemization) Br 3 O CuI (1 eq.) 59 (18)

NH NH EtO2C 4 CuI (0.1 eq.) 20 (69) 55b I 5 O CuI (1 eq.) 77 (8)

NH NH MeO2C 6 CuI (0.1 eq.) 32 (61) 59b a o All reactions were used 2.5 eq. of CsOAc and heated to 90 C for 12 h under N2 using DMSO as a solvent.; b Reaction temperature was 110 oC without CuI.; c Isolated yields, and the extent of isomerization was determined by 1H NMR

Table 7.6. Selected Results of Cu-mediated Tandem Cyclizations

230 stoichiometric amount of CuI and CsOAc gave the expected cis-tricyclic diketopiperazine

(DKP) 60 with a small amount of the isomerized product 60a in good yields (entry 3,

Table 7.6). With only catalytic amount of CuI, isomerized product 60a was obtained as

a major product instead of 60 (entry 4, Table 7.6). In the stoichiometric reaction, the

substrate 59b gave better yields with a smaller proportion of the isomerization products

(entry 5, Table 7.6).

These results confirm the sequence of reactions as proposed in Scheme 7.9 for

the formation of the products. Typical head-to-tail type 2,5-DKP ring formations of a

free amine with an ester occurs in situ first.8,47 It appears that before the DKP formation,

NH in the amide can not undergo N-arylation. However, the nucleophilicity of NH was

increased enough to affect the cyclization after the DKP ring was formed. Hence, DKP

ring formation occurs first, and then it undergoes intramolecular N-arylation.

The selectivities in the reactions depend upon the amount of CuI, and this can be

rationalized by the proposed theme. The relative rate differences of the epimerization

and the N-arylation reactions govern the ratio of two products. Presumably, in presence

of stoichiometric amount of CuI, intramolecular N-arylation is faster than isomerization,

so this procedure gives the product with the retention of the configuration as a major product. The catalytic N-arylation is slower to permit isomerization of the cis-DKP intermediate into the thermodynamically more stable trans-DKP. Therefore, a catalytic condition gives more trans-isomer.

231

C X B 60 O O O AB X N NH HN HN N N RO 2C O O A B C Isomerization

RO O 60a O O N O H NH B N CO2R X HN N N N N O O O

A : Head-to-tail DKP formation B : 5-membered intramolecular N-arylation C : 8-membered intramolecular N-arylation

Scheme 7.9. Possible Routes to the Tricyclic Diketopiperazines via Tandem Reactions

7.2.3. Intermolecular N-Arylations of DKP

Surprisingly, reports of intermolecular N-arylation of diketopiperazines are rare

and conditions such as microwave irradiation at high temperature (>190 oC) are needed to

get reasonable yields of products that could result from such a reaction.48 The conditions similar to the ones used in the intramolecular reactions were applied to selective intermolecular N-arylation of DKP (Table 7.7). Even with the weak nucleophilicity of the nitrogen in the DKP, these reaction conditions gave a mono-N- arylated product 61 regioselectively in good yields using the catalytic amount of CuI

232 (entry 4, Table 7.7).46 Only the aryl iodide works and the bromide gives only trace

amounts of the expected product (entries 1-2, Table 7.7). Compared to the known

reaction condition for the Cu-catalyzed intermolecular N-arylation of DKP derivatives,48 the CuI/CsOAc system is superior in terms of a chemical yield and the simplicity of the procedure. The reported procedure needs microwave irradiation (190 ~ 200 oC) with

200 mol% of NMP (N-methylpyrrolidone) without an additional solvent to get 51 % of the desired product. It is highly unlikely that a chiral center on a DKP (e. g., 61) will retain its configuration under these harsh conditions.

OMe

O O X OMe CuI, CsOAc O N HN HN + + N NH DMSO, 90 oC N OMe O O O X=Br,I 61 61a MeO Isolated yields of Entry Substrates Conditionsa 61 (%) 1 X = Br CuI (1 eq.) & CsOAc (2.5 eq.) Trace

2 X = Brc CuI (1 eq.) & CsOAc (2.5 eq.) Trace

3 X = I CuI (1 eq.) & CsOAc (2.5 eq.) 58

4 X = I CuI (0.1 eq.) & CsOAc (2.5 eq.) 64b

a Reaction conditions were not optimized (1eq. of DKP and arylhalide were used).; b 5 % of dialkyated product 61a was obtained.; c Instead of 3-bromoanisole, bromobenzene was used.

Table 7.7. Intermolecular N-Arylation of the DKP with Arylhalides

233 To validate this method, the trans-isomer of the pyrazino[1,2-a]indole-1,4-dione

derivative 60b (see Scheme 7.10) – enantiomer of isomerized product 60a (Scheme 7.9)

– was synthesized successfully by using the Schöllkopf chiral auxiliary as a synthetic

building block. Schöllkopf reagent has found only rare use for the synthesis of enantio-

pure DKP-containing heterocycles (Scheme 7.10).49,50

O O 63 O 60b O N TMSI NH CuI NaH N HN CsOAc N NH N N O CH2Cl 2 O MeI O O 90 - 93 % 79 - 95 % 99 % (see Table 7.8) + X X O 56a:X=Br 62a:X=Br 63a 56b:X=I 62b:X=I N NH O

Scheme 7.10. Synthesis of the trans-isomer 60b Using the Schöllkopf Chiral Auxiliary

Starting with an alkylation, the dimethoxy-2,5-dihydropyrazine ring (56a and 56b) was converted into 2,5-diketopiperazine ring 62a-b in excellent yields using trimethylsilyl iodide. The N-arylation procedure described earlier gave the desired

product 63 in excellent yields under both stoichiometric and catalytic versions of the

234 reactions with a small amount of isomerized product 63a (Scheme 7.10 and Table 7.8).

The iodide substrate 56b is especially good for the conversion to the corresponding

DKP 62b in excellent yields. The resulting DKP 62a-b was cyclized almost quantitatively to the desired tricyclic-DKP 63 regardless of the amount of copper iodide

(entries 3-4, Table 7.8).

Yields of Ether Entry Substrates CuI (mol%)a Yields (%) of 63 (63a) Cleavage (%)

1 56a 100 84 (13) 90 2 (X=Br) 10 79 (16)

3 56b 100 99 (--) 93 4 (X=I) 10 95 (1.5)

a In all cyclizations, 2.5 eq. of CsOAc was used.

Table 7.8. Results of Ether Cleavage and Cyclization Reactions

7.2.4. Synthesis of Proline-based Tetracyclic DKP 65

Further utility of this procedure for the synthesis of complex DKP derivatives is illustrated in Scheme 7.11 with the synthesis of a proline-derived compound 65. This

235 compound was synthesized using 2-bromophenylalanine. This unnatural amino acid precursor was prepared by Schöllkopf method as shown in Scheme 7.10. The resulting

2-bromo-L-phenylalanine 57a was coupled with N-Boc protected L-proline using the same peptide-coupling protocol used before. The subsequent deprotection of the Boc- group, followed by the tandem cyclization, gave the desired tetracyclic DKP product 65 and isomerized product 65a in a reasonable yield.

O O O O NH N HCl O 2 NBoc HBTU, DIPEA NH N O Boc N + O THF CH2Cl 2 93 % HO O 99 % Br Br 64 56a Br 57a 30% TFA/CH Cl 2 2 99 % rt, 1 h

O O O O CuI, CsOAc N N N N NH N + O H DMSO, 90 oC O O

65, 48 % 65a, 12 % Br 64a

Scheme 7.11. Synthesis of Tetracyclic DKP Derivartives Containing an L-Proline Residue

236 7.2.5. Attempted Macro N-arylation Using an Oxazolidinone

Although Cu-mediated tandem reaction was successfully applied to several

DKP-containing heterocycles, initial goal of the macrocyclization still needed to be solved. Not only cyclization methods but also the structure of substrates should affect feasibility of such a desired macrocyclization. During Cu-mediate tandem reactions, a free amine was found to undergo a lactamization to form a DKP, before intramolecular N- arylation. Hence, the ester group has to be removed for the prevention of the initial 6- membered lactamization. In order to test this idea, a new type of an oxazolidinone- containing substrate was designed and synthesized.

First, the key intermediate 66 – (S)-4-(2-bromobenzyl)oxazolidin-2-one – was prepared from o-bromo-L-phenylalanine 57a which in turn made by the Schöllkopf methods (Scheme 7.12). Free-aminoacid ester 57a was converted into ethyl carbamate

57b, and the resulting ester was reduced into alcohol 57c. Intramolecular cyclization under basic condition gave the desired oxazolidinone 66 in good yields. The oxazolidinone was coupled with a valine unit using activated valine-ester 67 with lithiated oxazolidinone 66 (Scheme 7.13). The ester-group activated N-Boc,N’-Me-L- valine 67 was prepared by transesterification using ethyl choroformate (ECF). The Boc- group in the resulting dipeptide 68 was deprotected with TFA in dichloromethane to obtain the desired free-amine 68a. Disappointingly, this substrate did not give any cyclization product under several Cu- or Pd-catalyzed cyclization conditions listed in

Table 7.3. Therefore, further investigations are needed to find an appropriate substrate or a general method for a macrocyclization via an intramolecular N-arylation.

237

O O OEt O OEt H2N CO2Me O HN CO Me HN K CO HN ECF 2 NaBH4 OH 2 3

NaHCO3 CaCl2 Tol. Br 97 % Br Br Br 57a 57b 57c 66

Scheme 7.12. Synthesis of the Oxazolidinone Intermediate 66

O O O O O HN N O O nBuLi N + N Boc THF O O Boc Br 67 Br 68 66 TFA >99% CH2Cl 2

O O O N N O Cyclization Benzolactam-V8 N N O H O 68a Br

Scheme 7.13. Synthesis of an Oxazolidinone-based Dipeptide and its Attempted

Cyclization

238 7.3 SUMMARY

During an attempted biomimetic synthesis of 7-bromoindolactam V, an unexpected Cu-mediated tandem cyclization was discovered. It is shown that the DKP- based heterocycles can be efficiently synthesized through a Cu-mediated tandem DKP ring formation and intramolecular N-arylation. The resulting heterocycles can act as rigid synthetic congeners of biologically active indole alkaloids such as bezolactam-V8 and indolactam V.

To reveal the mechanism and scope of the reaction, simplified substrates – a linear benzolactam – was prepared by two different strategies. Initially, it was achieved by Rh-catalyzed asymmetric hydrogenation-based dipeptide synthesis. Later,

Schöllkopf aminoacid synthesis was used and the primary product was turned into a dipeptide by standard coupling chemistry. Using these substrates, the mechanism of the

Cu-mediated tandem cyclization was delineated. Initial head-to-tail DKP formation facilitated intramolecular N-arylation to give the cis-DKP as a major product. Also, the initial cis-product underwent isomerization to a trans-product when intramolecular N-

arylation was slow.

Overall, we report a facile and general method for the stereoselective

preparations of pyrazino[1,2-a]indole-1,4-dione and pyrazino[1,2-a] pyrrolo[4,3,2-

de]quinoline-7,10-dione templates. In addition, it is revealed that Schöllkopf reagent itself can be used for synthesis of enantio-pure 2,5-DKP containing molecules. Further applications of this reaction toward a natural product will be forthcoming.

239 7.4 EXPERIMENTAL PROCEDURES

General Information.

For general information, see the general information in Chapter 2. Rhodium catalysts for asymmetric hydrogenation, CuI, and CsOAc were stored in a Vacuum

Atomspheres drybox. CuI and CsOAc were purchased from Sigma-Aldrich Inc., and

both RhCOD(S,S-MeDuPhos)BF4 and ethyl analogue were purchased from Strem

Chemicals Inc. NMR experiments were performed using CDCl3 with CHCl3 (δ 7.24) as an internal standard. (R)-Schöllkopf reagent51 and Rh-sugar complex52 were prepared

by reported procedures. For pressurized hydrogenation reaction, Parr Pressure Reactor was used.

Synthesis of 4,7-dibromo-1H-indole (51a).

Br Br

N NO2 H Br Br

Under N2 atmosphere, 1 M vinyl magnesium bromide (160.5 mL, 16.05 mmol) in

anhydrous THF (320 mL) was added to a stirred solution of 2,5-dibromonitrobenzene (15

g, 5.34 mmol) at – 70 oC. The resulting mixture was stirred additional 20 min at - 50 oC,

and then poured into sat. NH4Cl. After the crude product was extracted with EtOAc

(300 mL*3), combined organics were dried over MgSO4 and evaporated under reduced

pressure. The crude product was purified by column chromatography (10 % EtOAc in

1 n-Hex.) to yield 6.95 g (47 %) of the title compound. H NMR δ (CDCl3): 8.39 (br s,

240 1H, NH), 7.28-7.21 (m, 3H, Ar 2, 5, and 6), 6.73-6.71 (dd, 1H, J = 3.2, 2.4 Hz, Ar 3); 13C

NMR δ (CDCl3): 134.6, 129.5, 125.5, 125.1, 123.1, 104.4, 103.9.

Synthesis of 4,7-dibromo-1H-indole-3-carboxaldehyde (51b).

Br Br O

N N H H Br Br

To an ice-cooled reaction vessel containing DMF (50 mL) under N2 atmosphere,

POCl3 (2.6 mL, 27.2 mmol) was added dropwise. Indole 51a (6.8 g, 24.7 mmol) in

DMF (100 mL) was slowly added to the mixture. The resulting solution was stirred for

1 h at 0 oC then 5 h at rt. After the starting indole was consumed completely, the solution was poured into crushed ice. The mixture was treated with 1 M NaOH to

adjust pH to 10 ~ 11, followed by quick heating to boil for 5 min. The mixture was cooled to 0 oC, and then acidified with 3 M HCl. The desired aldehyde was collected by

filtration, and washed with water and n-Hex (5.9 g, 79 %). of the title compound was

1 obtained. H NMR δ (DMSO-d6): 10.67 (s, 1H, CHO), 8.28 (s, 1H, Ar 2), 7.40 (s, 2H,

13 Ar 5 and 6); C NMR δ (DMSO-d6): 146.1, 144.3, 136.7, 135.8, 135.6, 128.5, 121.4,

114.7.

Synthesis of 4,7-dibromo-N-Boc-indole carboxaldehyde (51).

Br O Br O

N N H Boc Br Br To a stirred solution of 4,7-dibromo-1H-indole-3-carboxaldehyde 51b (10 g, 33.0

241 mmol) in THF (500 mL) was added NaH (3.4 g, 83.0 mmol) at 0 oC portionwise. After

H2 gas evolution ceased, Boc2O (8.8 g, 44.0 mmol) in THF (200 mL) was added slowly.

The resulting mixture was stirred overnight at rt, and then the reaction was quenched by

slow addition of water (500 mL). The crude product was extracted by ether (500 mL*3)

and the combined organics were dried over MgSO4 and evaporated under reduced

pressure. The crude product was purified by column chromatography (10 % EtOAc in

1 n-Hex.) to yield 11.1 g (83 %) of the title compound. H NMR δ (CDCl3): 10.92 (s, 1H,

CHO), 8.25 (s, 1H, Ar), 7.43-7.37 (dd, 2H, J = 12.8, 8.4 Hz, Ar), 1.65 (s, 9H, tBu); 13C

NMR δ (CDCl3): 186.5, 147.1, 135.4, 135.3, 131.2, 129.9, 129.7, 121.0, 113.0, 107.5,

87.1, 28.0; IR cm-1 (KBr pellet) : 3142, 2978, 2937, 2887, 1764, 1668, 1544, 1534, 1470,

1374, 1310, 1235, 1144, 1021.

Synthesis of N,N-Boc,Me-L-valine amide (52a).53

OH NH BocN BocN 2 O O

To a stirred solution of N,N-Boc,Me-L-valine (5 g, 21.6 mmol) and N-methyl

morpholine (2.38 mL, 21.6 mmol) in anhydrous DME (100 mL) was added isobutyl

o chloroformate (2.82 mL, 21.65 mmol) dropwise at -15 C. After 0.5 h stirring, NH3 gas was bubbled into the reaction mixture for 15 min at - 15 oC and additional 15 min at rt.

After addition of water (100 mL), the crude product was extracted by chloroform (100

mL*3) and the combined organics were dried over MgSO4 and evaporated under reduced

pressure. The crude product was purified by recrystallization (10 % EtOAc in n-Hex.)

1 to yield 3.9 g (78 %) of the title compound. H NMR δ (CDCl3); 6.14 (br s, 1H,

242 CONH2), 5,35 (br s, 1H, CONH2), 4.07-4.04 (d, 1H, J = 10.8 Hz, α-H), 2.78 (s, 3H,

NCH3), 2.27-2.18 (m, 1H, -CH(CH3)2), 1.45 (s, 9H, tBu), 0.96-0.94 (d, 3H, J = 6.4 Hz, -

13 CH(CH3)2), 0.86-0.84 (d, 3H, J = 6.8 Hz, -CH(CH3)2); C NMR δ (CDCl3): 173.2, 157.0,

80.3, 64.0, 30.2, 28.5, 26.1, 19.8, 18.6.

Synthesis of ethyl 2-diazo-2-(diethoxyphosphoryl)acetate (52b).54

CO2Et N2 CO2Et

PO(OEt)2 PO(OEt)2 To a stirred solution of triethyl phosphonate (2.5 g, 11.15 mmol) in anhydrous

THF was added a mixture of NaH (0.54 g, 13.38 mmol) and p-toluenesulfonyl azide

(2.64 g, 13.38 mmol) in THF (5 mL) slowly at 0 oC. The resulting mixture was stirred at the same temperature for 10 min, and then stirred additional 10 min at rt. After ether

(10 mL) and water (10 mL) were added, the crude product was extracted by ether (10

mL*3). The combined organics were dried over MgSO4 and evaporated under reduced

pressure. The crude product was purified by column chromatography (25 % EtOAc in

1 n-Hex.) to yield 2.35 g (84 %) of the title compound. H NMR δ (CDCl3): 4.24-4.10 (m,

13 4H, -OCH2CH3), 1.32-1.23 (m, 6H, -OCH2CH3); C NMR δ (CDCl3): 163.6, 163.4, 63.7,

61.8, 16.3, 14.5.

Synthesis of Schmidt’s phosphonate 52.54

N CO Et H NH 2 2 N CO Et BocN 2 + BocN 2 PO(OEt)2 O O PO(OEt)2 To 1-neck rb, triethyl diazophosphonate (2.2 g, 4.34 mmol), N,N-Boc,Me-L-

243 valine amide (2 g, 4.34 mmol) were added. After the solution was treated with rhodium acetate (19 mg, 0.087 mmol), the mixture was heated to refluxed temperature until the starting diazo-compound was completely consumed. The solvent was evaporated, and the crude product was purified by column chromatography (10 % EtOAc in n-Hex.) to

1 yield 11.1 g (83 %) of the title compound. H NMR δ (CDCl3): 4.30-4.05 (m, 8H,

3OCH2CH3, 2α-H), 2.76 (s, 3H, NCH3), 2.30-2.14 (m, 1H, iPr), 1.43 (s, 9H, tBu), 1.35-

13 1.20 (m, 9H, 3OCH2CH3), C NMR δ (CDCl3): 167.5, 166.3, 80.2, 68.5, 64.5, 63.6, 61.7,

31 51.2, 49.7, 30.0, 28.3, 19.7, 18.9, 18.4, 16.3, 14.9, 14.1; P NMR δ (CDCl3): 15.9, 14.4;

IR cm-1 (KBr pellet): 3372, 3195, 2973, 1743, 1677, 1471, 1444, 1366, 1311, 1255, 1166,

1028.

Synthesis of enamide 53 using Horner-Emmons reaction.54

Br CO2Et O Br O H N CO Et HN + BocN 2 N NBoc Boc O PO(OEt)2 N Br Br Boc

After aldehyde 51 (2.3 g, 5.71 mmol) and Schmidt’s phosphonate 52 in

o anhydrous CH2Cl2 were treated with DBU (0.94 mL, 5.80 mmol) at 0 C, the resulting

mixture was stirred for 1 d at rt. The solvent was evaporated, and the crude product was purified by column chromatography (20 % to 50 % EtOAc in n-Hex.) to yield 2.7 g

1 (71 %) of the title compound. H NMR δ (CDCl3): 8.23 (s, 1H, enamide), 7.76 (s, 1H,

Ar2), 7.34-7.32 (d, 1H, J = 8.4 Hz, Ar), 7.28-7.26 (d, 1H, J = 8.4 Hz, Ar), 4.30-4.20 (m,

3H, -OCH2CH3 & α-H of Val.), 2.82 (s, 3H, -NCH3), 2.29 (br s, 1H, -CH(CH3)2), 1.65 (s,

9H, tBu), 1.43 (s, 9H, tBu), 1.33-1.30 (t, 3H, J = 7.2 Hz, -OCH2CH3), 1.01-0.99 (d, 3H, J

244 13 = 6.4 Hz, -CH(CH3)2), 0.87-0.85 (d, 3H, J = 6.8 Hz, -CH(CH3)2); C NMR δ (CDCl3):

169.8, 164.6, 157.3, 147.6, 134.9, 131.0, 130.7, 130.5, 129.1, 125.6, 124.0, 114.5, 113.5,

107.5, 85.9, 80.6, 61.5, 30.6, 28.4, 27.9, 25.9, 20.2, 18.6, 14.4; IR cm-1 (KBr pellet) :

3423, 3256, 2969, 2921, 2873, 1755, 1666, 1468, 1367, 1241, 1146; HRMS 724.1034

+• (M+Na ; calcd for C29H39Br2NaN3O7 724.1029).

General procedure of Rh-catalyzed asymmetric hydrogenation (Table 7.1).

CO2Et CO2Et Br O Br O HN HN NBoc NBoc N N Boc Br Br Boc

To a high-pressure Parr reactor, enamide 53, Rh-catalyst (10 mol%) and degassed

MeOH (10 mL) were added in N2-charged drybox. The resulting equipment was

brought out, and set up to the reactor. The reactor was evacuated with H2-gas three

times and pressurized to 90 psi and stirred for 4 d at rt. After the pressure was released,

the solvent was evaporated, and the crude product was purified by column

chromatography.

Synthesis of dipeptide 53a using Rh(Chiraphos)-catalyzed asymmetric

hydrogenation (entries 1-2, Table 7.1).

CO2Et CO2Et Br O Br O HN HN NBoc NBoc N N Boc Br Br Boc

+ - Following general procedure using [Rh(ChiroPhos)NBD] BF4 , 53a was

245 obtained. Me-ChiroPhos (entry 1, Table 7.1): > 99 % (dr = 2.3:1); iPr-ChiroPhos (entry

2, Table 7.1): 92 % (dr = 2.9:1).

Synthesis of dipeptide 53a using Rh(S,S-Et-Duphos)-catalyzed asymmetric

hydrogenation (entry 5, Table 7.1).

CO2Et CO2Et Br O Br O HN HN NBoc NBoc N N Boc Br Br Boc

Following general procedure, enamide 53 (0.5 g, 0.73 mmol) was reduced using

+ - RhCOD(Et-S,S-Duphos) BF4 (44.0 mg, 0.073 mmol) and degassed MeOH (10 mL)

under 90 psi for 4 d at rt. The crude product was purified by column chromatography

(20 % EtOAc in n-Hex.) to yield 0.5 g (conv. 90 %, S:R = 8.5:1) of the title compound

1 with 10 % of the unreacted starting enamide. H NMR δ (CDCl3): 7.41 (s, 1H, Ar),

7.34-7.32 (d, 1H, J = 8.4 Hz, Ar), 7.28-7.24 (t, 1H, J = 8.0 Hz, Ar), 4.9 (br s, α-H of Typ.),

4.18-4.09 (m, 2H, -OCH2CH3), 4.03-4.00 (d, 1H, J = 10 Hz, α-H of Val.), 3.55-3.50 (dd,

1H, J = 15.2, 5.6 Hz, -CH2-), 3.38-3.32 (dd, 1H, J = 14.8, 8.8 Hz, -CH2-), 2.70 (s, 3H, -

NCH3), 2.25 (br s, 1H, -CH(CH3)2), 1.64 (s, 9H, tBu), 1.36 (s, 9H, tBu), 1.33-1.30 (t, 3H,

J = 7.0 Hz, -OCH2CH3), 0.94-0.93 (d, 3H, J = 6.4 Hz, -CH(CH3)2), 0.85-0.84 (d, 3H, J =

13 6.4 Hz, -CH(CH3)2); C NMR δ (CDCl3): 171.1, 170.5, 147.6; 135.5, 131.2, 130.3, 129.2,

128.4, 113.3, 107.4, 84.9, 80.2, 61.4, 60.4, 28.2, 27.9, 21.0, 18.5, 14.2; IR cm-1 (neat) :

3322, 3119, 3057, 2976, 2873, 1746, 1693, 1530, 1469, 1392, 1315, 1242, 1153; HRMS

+• 726.1192 ((M+Na ); 726.1186 calcd for C29H41Br2NaN3O7)

246 Attempts of indolyl N-Boc protected NHMe dipeptide 53b by selective deprotection

of the Boc group in Valine (entries 1-2, Table 7.2).

CO2Et CO2Et Br O Br O HN HN NBoc NH N N Boc Br Boc Br

Diboc-protected dipeptide 53a was treated with 3 M HCl (entry 1, Table 3-2) or only

formic acdid (entry 2, Table 3-2) at 0 oC, and then the reaction mixture was stirred at rt

for 12 h. After, the solvent was evaporated, the residue was diluted with CH2Cl2 (10 mL) and washed with sat. NaHCO3 (10 mL). The organic layer was dried over MgSO4 and evaporated under reduced pressure. Only starting diBoc compound 53a was recovered.

Synthesis of free NHMe dipeptide 53c by deprotection of both Boc groups (entry 3,

Table 7.2).

CO2Et CO2Et Br O Br O HN HN NBoc NH N N H Br Boc Br

Diboc-protected dipeptide 53a (91 mg, 0.132 mmol) was treated with 30 % TFA

in CH2Cl2 (5 mL), and then the reaction mixture was stirred for 1 h at rt. After the

starting diBoc compound was consumed completely, the mixture was evaporated. The

residue was diluted with CH2Cl2 (10 mL) and washed with sat. NaHCO3 (10 mL). The

organic layer was dried over MgSO4 and evaporated under reduced pressure. The crude

product was purified by column chromatography (only EtOAc) to yield 66 mg (99 %) of

247 1 the desired amine 53c. H NMR δ (CDCl3): 8.38 (br s, 1H, NH of indole), 7.69-7.66 (d,

1H, J = 9.3 Hz, NH of amide), 7.22-7.21 (d, 1H, J = 1.0 Hz, Ar), 7.13 (s, 2H, Ar), 4.99-

4.95 (m, 1H, α-H of Typ.), 4.20-4.12 (m, 2H, -OCH2CH3), 3.65-3.40 (m, 2H, benzylic H),

2.70-2.68 (d, 1H, J = 5.0 Hz, α-H of Val.), 2.32 (s, 3H, -NCH3), 1.91-1.72 (m, 1H, -

CH(CH3)2), 1.23-1.17 (t, 3H, J = 7.1 Hz, -OCH2CH3), 0.86-0.83 (d, 3H, J = 6.7 Hz, -

13 CH(CH3)2), 0.63-0.60 (d, 3H, J = 6.7 Hz, -CH(CH3)2); C NMR δ (CDCl3): 173.8, 172.4,

136.0, 126.6, 125.3, 125.2, 113.9, 113.6, 104.4, 75.9, 71.1, 61.5, 53.1, 36.1, 34.3, 31.4,

29.9, 28.8, 19.5, 17.9, 14.3; IR cm-1 (neat) : 3323, 2959, 2922, 2852, 1737, 1659, 1517,

1478, 1371, 1335, 1247, 1170, 1070, 1029.; HRMS 526.0117 (M+Na+•); 526.0141 calcd

22 for C19H25Br2NaN3O3); [α] D 589nm = -8.3 (c = 0.405, CHCl3)

Synthesis of indolyl N-Boc protected NHMe dipeptide 53b by selective deprotection of the Boc group in Valine (entry 5, Table 7.2).

CO2Et CO2Et Br O Br O HN HN NBoc NH N N Boc Br Boc Br

Diboc-protected dipeptide 53a (0.36 g, 0.52 mmol) was treated with 20 % TFA in

o CH2Cl2 (5 mL) at 0 C, and then the reaction mixture was stirred for 12 h at the same

temperature. The solvent was evaporated, and the residue was diluted with CH2Cl2 (10 mL) and washed with sat. NaHCO3 (10 mL). The organic layer was dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography (only EtOAc) to yield mono-protected amine 53b (0.21 g, 67 %) as well

1 as di-deprotected amine 53c (71 mg, 30 %). 53b; H NMR δ (CDCl3): 7.72-7.70 (d, 1H,

248 J = 9.2 Hz, NH of amide), 7.47 (s, 1H, Ar), 7.35-7.33 (d, 1H, J = 8.0, Ar), 7.28-7.26 (d,

1H, J = 8.0 Hz, Ar), 5.06 (m, 1H, α-H of Typ.), 4.23-4.17 (q, 2H, J = 7.2 Hz, -OCH2CH3),

3.65-3.60 (dd, 1H, J = 14.0, 5.2 Hz, benzylic H), 3.42-3.36 (dd, 1H, J = 15.6, 9.6 Hz, benzylic H), 2.76-2.75 (d, 1H, J = 4.8 Hz, α-H of Val.), 2.39 (s, 3H, -NCH3), 1.97-1.86

(m, 1H, -CH(CH3)2), 1.65 (s, 9H, tBu), 1.25-1.22 (t, 3H, J = 7.2 Hz, -OCH2CH3), 0.85-

13 0.83 (d, 3H, J = 6.8 Hz, -CH(CH3)2), 0.73-0.72 (d, 3H, J = 6.8 Hz, -CH(CH3)2); C NMR

δ (CDCl3): 173.5, 172.0, 147.6, 131.3, 130.4, 129.3, 128.4, 115.8, 113.33, 107.3, 84.86,

70.8, 61.4, 52.1, 36.0, 31.3, 27.9, 19.4, 17.8, 14.1; IR cm-1 (KBr pellet) : 3326, 2971,

2794, 1737, 1659, 1515, 1459, 1376, 1315, 1238, 1143, 1088, 1016.; HRMS 604.0840

+• ((M+H ); 604.0841 calcd for C24H33Br2N3O5).

General procedure of Buchwald-Hartwig amination for macrocyclization (Table 7.3).

In a sealed tube, Pd-source such as Pd2dba3·CHCl3 (5-10 mol%), a phosphine

ligand such as m-Tol3P (10 mol%), and strong base like NaOtBu (200 mol%) were added

to a solution of starting amine 53b in toluene or 1,4-dioxane. The vessel was heated to

80 - 100 oC for 4-20 h. The mixture was cooled to rt, and then diluted with water (10

mL) and EtOAc (10 mL). The product was extracted by EtOAc (10 mL*3), and the

combined organic layers were dried over MgSO4 and evaporated under reduced pressure.

The crude product was purified by column chromatography.

General procedure of Cu-mediated tandem cyclizations.

CuI (100 mol%, or see Table 7.3) and CsOAc (250 mol%) were added to a 1- neck rb in N2 charged drybox, and then the vessel was taken out. To the vessel, Free

249 amine (100 mol%) in anhydrous DMSO (1~1.5 mL/0.1 mmol of starting amines) was

o added. The resulting mixture was heated to 90 C for 12 h under N2 atmosphere. After

the starting material was completely consumed, the mixture was cooled to rt, and then

diluted with water (10 mL) and EtOAc (10 mL). The product was extracted by EtOAc

(10 mL*3), and the combined organic layer was dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by preparative TLC or column chromatography.

Synthesis of tetracyclic DKP 54 by the Cu-mediated tandem cyclization.

N O CO2Me Br O HN O N NH N H Br N H 54 Br

CuI (62 mg, 0.123 mmol) and CsOAc (60 mg, 0.307 mmol) were added to a 1-

neck flask in N2 charged drybox, and then the vessel was taken out. To the vessel, Free

amine 53c (62 mg, 0.123 mmol) in anhydrous DMSO (1.5 mL) was added. The

o resulting mixture was heated to 90 C for 12 h under N2 atmosphere. After the starting

material was completely consumed, the mixture was cooled to rt, and then diluted with

water (10 mL) and EtOAc (10 mL). The product was extracted by EtOAc (10 mL*3),

and the combined organic layer was dried over MgSO4 and evaporated under reduced

pressure. The crude product was purified by preparative TLC (67% EtOAc in n-Hex.) to

yield 29.3 mg (63 %) of 54 and 4.8 mg (10 %) of an unidentified compound. Pure major

product 54 was crystallized under ether/EtOAc (2:1) for X-ray crystallography. 54: 1H

250 NMR δ (CDCl3): 8.15 (br s, 1H, NH of indole), 7.78-7.74 (d, J = 8.0 Hz, Ar), 7.33-7.29

(d, J = 8.3 Hz, Ar), 6.97 (s, 1H, Ar), 4.50-4.44 (dd, 1H, J = 12.2, 3.0 Hz, Benzylic), 4.04-

4.03 (d, 1H, J = 3.7 Hz, α-H of Typ.), 3.80-3.72 (dd, 1H, J = 15.7, 3.2 Hz, Benzylic),

3.16-3.08 (m, 4H, -NCH3 & α-H of Val.), 2.35-2.28 (m, 1H, -CH(CH3)2), 1.16-1.13 (d,

13 3H, J = 7.0 Hz, -CH(CH3)2), 0.88-0.86 (d, 3H, J = 6.2 Hz, -CH(CH3)2); C NMR δ

(CDCl3): 165.5, 163.6, 133.6, 130.5, 125.6, 122.0, 118.7, 113.8, 110.1, 100.3, 68.4, 60.2,

34.5, 32.4, 29.1, 19.8, 18.2; IR cm-1 (KBr pellet): 3299, 2922, 1650, 1494, 1402, 1344,

+• 22 1292, 1260, 1080.; HRMS 376.0644 ((M+H ); 376.0661 calcd for C17H19BrN3O2); [α] D

589nm = -51.1 (c = 0.355, CHCl3)

Synthesis of simplified enamide 55 using Horner-Emmons reaction.54

Boc N Br H + N CO2Et O BocN HN O O PO(OEt)2 O Br OEt After 2-Bromobenzladehyde (0.5 g, 2.7 mmol) and Schmidt’s phosphonate 52

(1.25 g, 2.7 mmol) in anhydrous CH2Cl2 were treated with DBU (0.41 mL, 0.54 mmol) at

0 oC, the resulting mixture was stirred for 1 d at rt. The solvent was evaporated, and the

crude product was purified by column chromatography (10 % to 20 % EtOAc in n-Hex.)

1 to yield 0.85 g (65 %) of the title compound. H NMR δ (CDCl3): 7.76 (br s, 1H, CH in

enamide), 7.54-7.52 (d, 1H, J = 8.0 Hz, Ar), 7.40 (s, 1H, NH), 7.33-7.32 (d, 1H, J = 7.2

Hz, Ar), 7.17-7,14 (t, 1H, J = 7.2 Hz, Ar), 7.10-7.06 (m, 1H, Ar), 4.27-4.22 (q, 2H, 6.8 Hz,

-OCH2CH3), 4.09-4.06 (d, 1H, J = 11.2 Hz, α-H of Val.), 2.65 (s, 3H, -NCH3), 2.20-2.06

(m, 1H, -CH(CH3)2), 1.41 (s, 9H, tBu), 1.30-1.27 (t, 3H, J = 7.1 Hz, -OCH2CH3), 0.85-

251 13 0.83 (d, 3H, J = 6.4 Hz, -CH(CH3)2), 0.79-0.77 (d, 3H, J = 6.4 Hz, -CH(CH3)2); C NMR

δ (CDCl3): 168.6, 164.5; 157.1, 134.9, 133.0, 130.2, 130.1, 129.5, 127.1, 126.1, 124.4,

80.6, 64.5, 61.9, 30.2, 28.5, 25.9, 19.6, 18.5, 14.3; IR cm-1 (neat): 3277, 2973, 2932, 2874,

1725, 1666, 1480, 1392, 1368, 1296, 1256, 1153, 1100, 1026.; HRMS 483.1472

+• ((M+H ); 483.1495 calcd for C22H32BrN2O5).

Synthesis of dipeptide 55a using Rh-catalyzed asymmetric hydrogenation (entry 3,

Table 7.5).

Boc Boc N N

HN O HN O O O Br OEt Br OEt To a high-pressure Parr reactor, enamide 55 (0.36 g, 0.74 mmol), Rh(2,3-

52 Sugar)(NBD)BF4 (3.9 mg, 0.037 mmol) and anhydrous THF (10 mL) were added in N2 charged drybox. The resulting equipment was brought out, and set up to the reactor, and then evacuated with H2 gas. The reactor was pressurized to 90 psi and stirred for 4 d at rt.

After the pressure was released, the solvent was evaporated, and the crude product was purified by column chromatography (20 % EtOAc in n-Hex.) to yield 0.36 g (conv. >

1 1 99 %, S:R = 6.8:1, based on H NMR) of the title compound. H NMR δ (CDCl3): 7.47-

7.45 (d, 1H, J = 8.0 Hz, Ar), 7.15-7.10 (m, 2H, Ar), 7.04-7.00 (m, 1H, Ar), 6.58 (br s, 1H,

NH), 4.85-4.84 (br d, 1H, 6.8 Hz, α-H of Tyr.), 4.13-3.99 (m, 3H, -OCH2CH3, & α-H of

Val.), 3.29-3.24 (dd, 1H, J = 14.0, 5.6 Hz, benzylic), 3.06-2.98 (br m, 1H, Benzylic), 2.67

(s, 3H, -NCH3, minor isomer), 2.53 (s, 3H, -NCH3, major isomer), , 2.17-2.06 (m, 1H, -

CH(CH3)2), 1.42 (s, 9H, tBu), 1.19-1.14 (t, 3H, J = 7.0 Hz, -OCH2CH3), 0.85-0.83 (d, 3H,

252 13 J = 6.4 Hz, -CH(CH3)2), 0.77-0.75 (d, 3H, J = 6.4 Hz, -CH(CH3)2); C NMR δ (CDCl3):

171.1, 170.1, 156.7, 136.1, 132.9, 131.2, 128.5, 127.3, 124.9, 80.1, 64.4, 61.4, 60.3, 51.7,

38.4, 29.9, 28.4, 26.0, 21.0, 19.7, 18.4, 14.0; IR cm-1 (neat): 3330, 3058, 2964, 2870,

1740, 1677, 1510, 1469, 1442, 1369, 1333, 1307, 1155, 1030.; HRMS 485.1630

+• 22 ((M+H ); 485.1651 calcd for C22H34BrN2O5); [α] D 589nm = -79.3 (c = 0.75, CHCl3).

Synthesis of simplified free NHMe dipeptide 55b by deprotection of the Boc group.

Boc H N N

HN O HN O O O Br OEt Br OEt Boc-protected dipeptide 55a (0.16 g, 0.33 mmol) was treated with 30 % TFA in

CH2Cl2 (5 mL), and then the reaction mixture was stirred overnight at rt. After the

starting Boc compound was consumed completely, the mixture was evaporated. The

residue was diluted with CH2Cl2 (10 mL) and washed with sat. NaHCO3 (10 mL). The

organic layer was dried over MgSO4 and evaporated under reduced pressure. The crude

product was purified by column chromatography (only EtOAc) to yield 0.13 g (> 99 %)

1 of the desired amine. H NMR δ (CDCl3): 7.66-7.64 (d, 1H, J = 8.8 Hz, NH), 7.52-7.50

(d, 1H, J = 8.0 Hz, Ar), 7.28-7.26 (d, 1H, J = 8.0 Hz, Ar), 7.23-7.19 (t, 1H, J = 6.8 Hz, Ar),

7.08-7.05 (t, 1H, J = 6.8 Hz, Ar), 4.96-4.93 (m, 1H, α-H of Tyr.), 4.19-4.14 (q, 2H, J = 7.2

Hz, -OCH2CH3), 3.35-3.30 (dd, 1H, J = 14.0, 5.6 Hz, benzylic), 3.19-3.13 (dd, 1H, J =

14.4, 10.0 Hz, Benzylic), 2.73- 2.72 (d, 1H, J = 4.8 Hz, α-H of Val.), 2.34 (s, 3H, -NCH3),

1.95-1.83 (m, 1H, -CH(CH3)2), 0.94-0.93 (d, 3H, J = 7.0 Hz, -CH(CH3)2, minor isomer

(RS)), 0.88-0.86 (d, 3H, J = 7.0 Hz, -CH(CH3)2, minor isomer (RS)), 0.80-0.78 (d, 3H, J =

253 6.8 Hz, -CH(CH3)2), major isomer (SS)), 0.73-0.71 (d, 3H, J = 6.8 Hz, -CH(CH3)2, major

13 isomer (SS)); C NMR δ (CDCl3): 173.5, 171.8, 136.4, 133.0, 131.3, 128.7, 127.6, 125.1,

70.9, 70.5, 61.6, 53.6, 51.9, 38.1, 36.1, 35.9, 31.3, 19.4, 18.1, 14.2; IR cm-1 (neat): 3319,

3055, 2964, 2801, 1736, 1655, 1513, 1473, 1437, 1366, 1199, 1133, 1026.

Synthesis of o-bromo phenylalanine (57a) using Schöllkopf reagent.51

O O N NH2 O N O N O N O Br Br n-BuLi (3.7 ml, 5.43 mmol, 1.47 M in n-Hex.) was added dropwise to the

solution of Schöllkopf reagent (1.0 g, 5.43 mmol) in anhydrous THF (5 mL) at -78 oC

under N2. The resulting solution was stirred additional 20 min. A solution of 2- bromobenzyl bromide (1.29 g, 5.43 mmol) was added to the mixture over 5 min periods, and the resulting mixture was stirred for 3 h at -78 oC. After the reaction was quenched

with sat. NH4Cl (5 mL), the reaction was warmed up to rt, and diluted with EtOAc (20

mL) and water (10 mL). The crude product was extracted with EtOAc (3*20 mL), and

combined organic phase was dried over MgSO4. After volatiles were evaporated, the

crude product was purified by column chromatography (5 % EtOAc in n-Hex.). 1.7 g

1 (93 %) of desired alkylated compound 56a was obtained. H NMR δ (CDCl3): 7.51-

7.50 (d, 1H, J = 7.5 Hz, Ar), 7.21-7.16 (m, 2H, Ar), 7.05-7.02 (m, 1H, Ar), 4.33-4.30 (m,

1H, α-H of Tyr.), 3.71 (s, 3H, OCH3), 3.66-3.65 (t, 1H, J = 3.5 Hz, α-H of Val.), 3.62 (s,

3H, OCH3), 3.47-3.43 (dd, 1H, J = 13.8, 4.8 Hz, benzylic), 2.95-2.90 (dd, 1H, J = 13.8,

8.2 Hz, benzylic), 2.21-2.18 (m, 1H, -CH(CH3)2), 1.00-0.99 (d, 3H, J = 7.0 Hz, -

254 13 CH(CH3)2), 0.65-0.63 (d, 3H, J = 6.5 Hz, -CH(CH3)2); C NMR δ (CDCl3): 163.8, 163.1,

137.9, 132.6, 131.9, 127.9, 126.8, 125.4, 60.5, 55.9, 52.5, 40.3, 31.4, 19.1, 16.6; IR cm-1

(neat): 3056, 2962, 2870, 1685, 1587, 1461, 1458, 1374, 1239, 1109, 1026.

The alkylated compound 56a (0.5 g, 1.42 mmol) in CH3CN (10 mL) was treated

with 0.3 N HCl (10 mL), and the resulting solution was stirred at rt for 30 min. The

solution was basified with sat. NaHCO3, and the product was extracted with CH2Cl2 (3*

20 mL). After drying and evaporation, the product was purified by column chromatography (EtOAc) to yield 0.34 g (92 %) of 2-bromo-L-phenylalanine methyl

5 1 ester 57a. All spectral data were matched with reported data. H NMR δ (CDCl3):

7.58-7.56 (d, 1H, J = 8.0 Hz, Ar), 7.28-7.24 (m, 2H, Ar), 7.15-7.10 (m, 1H, Ar), 3.90 (br s,

1H, α-H of Tyr.), 3.73 (s, 3H, OCH3), 3.30-3.26 (dd, 1H, J = 13.4, 5.4 Hz, benzylic),

2.97-2.92 (dd, 1H, J = 13.6, 8.8 Hz, benzylic).

Synthesis of o-iodo phenylalanine (57b) using Schöllkopf reagent.51

O O N NH2 O N O N O N O I I

Using the same procedure with 2-iodobenzyl bromide (0.385 g, 1.3 mmol), 0.388

1 g (75 %) of desired alkylated compound 56b was obtained. H NMR δ (CDCl3): 7.80-

7.79 (d, 1H, J = 7.5 Hz, Ar), 7.24-7.19 (m, 2H, Ar), 6.88-6.84 (m, 1H, Ar), 4.30-4.27 (m,

1H, α-H of Tyr.), 3.72-3.71 (4H, OCH3 & α-H of Val.), 3.63 (s, 3H, OCH3), 3.44-3.40 (dd,

1H, J = 13.8, 4.8 Hz, benzylic), 2.95-2.91 (dd, 1H, J = 13.8, 7.8 Hz, benzylic), 2.22-2.19

(m, 1H, -CH(CH3)2), 1.01-1.00 (d, 3H, J = 7.0 Hz, -CH(CH3)2), 0.66-0.64 (d, 3H, J = 6.5

255 13 Hz, -CH(CH3)2); C NMR δ (CDCl3): 163.9, 163.2, 141.4, 139.5, 131.1, 128.2, 127.9,

102.0, 60.7, 56.3, 52.8, 52.7, 45.0, 31.6, 19.3, 16.8; IR cm-1 (neat): 3222, 2969, 1722,

1681, 1585, 1462, 1373, 1342, 1215, 1168, 1014.

The alkyated compound 56b (0.24 g, 0.601 mmol) in CH3CN (10 mL) was

treated with 0.3 N HCl (5 mL), and the resulting solution was stirred at rt for 30 min.

The solution was basified with sat. NaHCO3, and the product was extracted with CH2Cl2

(3* 20 mL). After drying and evaporation, the product was purified by column chromatography (EtOAc) to yield 0.184 g of the mixture of 2-iodo-L-phenylalanine methyl ester 57b (85 %) with valine methyl ester (15 %). This mixture was used for a coupling reaction without further purification. All spectral data were matched with

5 1 reported data. H NMR δ (CDCl3): 7.86-7.85 (d, 1H, J = 7.8 Hz, Ar), 7.31-7.28 (m, 1H,

Ar), 7.24-7.22 (dd, 1H, J = 7.8, 1.8 Hz, Ar), 6.96-6.92 (m, 1H, Ar), 3.86-3.83 (dd, 1H, J =

8.2, 4.2 Hz, α-H of Tyr.), 3.73 (s, 3H, OCH3), 3.27-3.23 (dd, 1H, J = 13.8, 4.2 Hz,

13 benzylic), 2.95-2.90 (dd, 1H, J = 13.5, 8.0 Hz, benzylic); C NMR δ (CDCl3): 175.4,

140.5, 139.9, 130.9, 128.8, 128.4, 101.1, 54.8, 52.2, 45.9.

Synthesis of dipeptide 59b using a peptide coupling reaction, followed by deprotection.

H O N NH O 2 OH BocN + HN O O O I I OMe To a stirred solution of N,N-Boc,Me-L-valine (52 mg, 0.224 mmol), 2-Iodo-L-

phenylalanine methylester (57 mg, 0.187 mmol), and DIEA (79 μL, 0.449 mmol) in

256 anhydrous CH2Cl2 (3 mL) was added HBTU (72 mg, 0.224 mmol), and the resulting

solution was stirred for 12 h at rt. After the solvent was evaporated, the crude product was

purified by column chromatography (10 to 20 % EtOAc in n-Hex.) to yield 95 mg (98 %)

1 of the dipeptide compound. H NMR δ (CDCl3): 7.79-7.77 (d, 1H, J = 7.6 Hz, Ar), 7.49

(br s, 1H, Ar), 7.11-7.09 (d, 1H, J = 7.2 Hz, Ar), 6.90-6.86 (t, 1H, J = 7.6 Hz, Ar), 6.55 (br

s, 1H, NH), 4.88 (br s, 1H, α-H of Tyr.), 4.10-3.99 (d, 1H, J = 10.8 Hz, α-H of Val.), 3.69

(s, 3H, -OCH3) 3.30-3.25 (dd, 1H, J = 14.0, 5.6 Hz, benzylic), 3.06-2.98 (br d, 1H, J = 6.0

Hz, Benzylic), 2.54 (s, 3H, -NCH3), 2.20-2.10 (m, 1H, -CH(CH3)2), 1.44 (s, 9H, tBu),

13 0.87-0.85 (d, 3H, J = 6.4 Hz, -CH(CH3)2), 0.79-0.78 (d, 3H, J = 6.4 Hz, -CH(CH3)2); C

NMR δ (CDCl3): 171.7, 170.3, 157.0, 139.9, 139.4, 130.5, 128.8, 128.4, 101.1, 80.36,

22 64.7, 52.6, 51.9, 43.1, 30.2, 28.6, 26.1, 19.8, 18.6; [α] D 589nm = -74.4 (c = 1.285, CHCl3).

The resulting compound (85 mg, 0.164 mmol) was deprotected by 30 % TFA in

CH2Cl2 (5 mL), and then the reaction mixture was stirred at rt for 8 h. After the starting

Boc compound was consumed completely, the mixture was evaporated. The residue was

diluted with CH2Cl2 (10 mL) and washed with sat. NaHCO3 (10 mL). The organic layer

was dried over MgSO4 and evaporated under reduced pressure. The crude product was

purified by column chromatography (only EtOAc) to yield 67.2 mg (98 %) of the desired

1 amine 7a. H NMR δ (CDCl3): 7.78-7.77 (d, 1H, J = 8.0 Hz, Ar), 7.59-7.57 (d, 1H, J =

8.5 Hz, NH), 7.24-7.22 (m, 2H, Ar), 6.89-6.85 (m, 1H, Ar), 4.95-4.91 (m, 1H, α-H of

Tyr.), 3.71 (s, 3H, -OCH3), 3.34-3.30 (dd, 1H, J = 14.0, 6.0 Hz, benzylic), 3.14-3.09 (dd,

1H, J = 14.0, 10.0 Hz, Benzylic), 2.69-2.68 (d, 1H, J = 5.0 Hz, α-H of Val.), 2.33 (s, 3H, -

NCH3), 1.88-1.84 (m, 1H, -CH(CH3)2), 0.77-0.76 (d, 3H, J = 7.0 Hz, -CH(CH3)2), 0.69-

13 0.67 (d, 3H, J = 7.0 Hz, -CH(CH3)2); C NMR δ (CDCl3): 173.7, 172.4, 139.8, 130.4,

257 128.9, 128.6, 101.4, 71.1, 52.6, 52.1, 42.7, 36.1, 31.5, 19.5, 18.1.

Synthesis of the tricyclic DKP 60 and 60a by stoichiometric amount of Cu-mediated

tandem cyclization (entry 3, Table 7.6).

H N O O HN O N N + N O N O Br OEt O Using the general procedure with 25 mg (0.065 mmol) of amine 55b and

stoichiometric amount of CuI, 60 (10.0 mg, 59 %) and 60a (3.1 mg, 18 %) were obtained.

1 For 60 H NMR δ (CDCl3): 8.01-8.00 (d, 1H, J = 8.0 Hz, Ar), 7.28-7.22 (m, 2H, Ar),

7.11-7.08 (t, 1H, J = 7.5 Hz, Ar), 4.74-4.70 (dd, 1H, J = 11.2, 9.2 Hz, α-H of Tyr.), 4.00-

3.99 (d, 1H, J = 1.0 Hz, α-H of Val.), 3.40-3.28 (m, 2H, , benzylic), 3.04 (s, 3H, -NCH3),

2.45-2.42 (m, 1H, -CH(CH3)2), 1.24-1.23 (d, 3H, J = 7.0 Hz, -CH(CH3)2), 0.94-0.92 (d,

13 3H, J = 7.0 Hz, -CH(CH3)2); C NMR δ (CDCl3): 166.7, 162.8, 141.5, 130.1, 127.9,

125.2, 124.9, 116.9, 67.5, 60.1, 32.8, 32.7, 30.7, 19.5, 16.3; IR cm-1 (neat): 2984, 2922,

1668, 1602, 1485, 1421, 1394, 1249, 1092.; HRMS 259.1431 ((M+H+•); 259.1447 calcd

22 for C15H19N2O2); [α] D 589nm = -71.9 (c = 0.42, CHCl3).

1 60a: H NMR δ (CDCl3): 8.10-8.09 (d, 1H, J = 8.0 Hz, Ar), 7.27-7.25 (s, 2H, Ar),

7.14-7.11 (t, 1H, J = 7.2 Hz, Ar), 4.91-4.87 (t, 1H, J = 10.0 Hz, α-H of Tyr.), 3.73-3.71 (d,

1H, J = 7.5 Hz, α-H of Val.), 3.59-3.54 (dd, 1H, J = 16.2, 10.2 Hz, benzylic), 3.13 (s, 3H,

-NCH3), 2.35-2.21 (m, 1H, -CH(CH3)2), 1.20-1.19 (d, 3H, J = 7.0 Hz, -CH(CH3)2), 1.16-

13 1.15 (d, 3H, J = 6.5 Hz, -CH(CH3)2); C NMR δ (CDCl3): 167.4, 164.1, 141.3, 130.0,

128.0, 125.3, 125.0, 116.70, 72.0, 59.6, 35.6, 32.4, 32.1, 20.3, 19.5; IR cm-1 (neat): 2962,

258 2924, 1713, 1672, 1601, 1483, 1464, 1390, 1242, 1149, 1049; HRMS 281.1247

+• 22 ((M+Na ); 281.1266 calcd for C15H18NaN2O2); [α] D 589nm = +24.6 (c = 0.570, CHCl3).

Synthesis of the tricyclic DKP 60 and 60a by catalytic amount of Cu-mediated tandem cyclization (entry 4, Table 7.6).

H N O O HN O N N + N O N O Br OEt O Using the general procedure, 11 mg (0.027 mmol) of amine 55b and catalytic

amount of CuI (0.43 mg, 0.0027 mmol) gave 60 (1.2 mg, 20 %) and 60a (4.0 mg, 69 %).

General procedure of intermolecular N-arylations.

CuI (see Table 7.7) and CsOAc (250 mol%) were added to a 1-neck rb in N2 charged drybox, and then the vessel was taken out. To the vessel, Free amine (100 mol%) and arylhalide (100 mol%) in anhydrous DMSO (1~1.5 ml/0.1 mmol of starting

o amide) were added. The resulting mixture was heated to 90 C for 12 h under N2 atmosphere. The mixture was cooled to rt, and then diluted with water (10 mL) and

EtOAc (10 mL). The product was extracted by EtOAc (10 mL*3), and the combined organic layer was dried over MgSO4 and evaporated under reduced pressure. The crude

product was purified by preparative TLC

259 Synthesis of mono-arylated DKP 61 (entry 4, Table 7.7).

O O HN MeO N O + HN N OMe N OMe NH O O O Using the general procedure, 25 mg (0.16 mmol) of DKP and 3-iodoanisole (41.2

mg, 0.176 mmol) were reacted to yield mono-arylated product 61 (26.7 mg, 64 %) and

1 2.9 mg (5 %) of diarylated product 61a. 61: H NMR δ (CDCl3): 7.34-7.30 (t, 1H, J =

8.2 Hz, Ar), 7.26 (br s, 1H, NH), 6.86-6.78 (m, 3H, Ar), 4.41-4.17 (dd, 2H, J = 76.8, 17.6

Hz, -CH2-), 4.00-3.98 (t, 1H, 3.0 Hz, α-H of Val.), 3.79 (s, 3H, OMe), 2.51-2.40 (m, 1H, -

CH(CH3)2), 1.08-1.06 (d, 3H, J = 6.8 Hz, -CH(CH3)2), 1.03-1.01 (d, 3H, J = 6.8 Hz, -

13 CH(CH3)2); C NMR δ (CDCl3): 166.8, 165.9, 141.4, 130.5, 117.9, 113.6, 111.9, 61.3,

55.6, 52.5, 33.4, 25.8, 19.0, 16.7; IR cm-1 (KBr pellet): 3229, 2963, 2921, 2872, 1681,

22 1603, 1493, 1453, 1346, 1295, 1215, 1159, 1044.; [α] D 589nm = +31.2 (c = 1.325, MeOH).

1 61a: H NMR δ (CDCl3): 7.36-7.32 (m, 2H, Ar), 6.95-6.85 (m, 6H, Ar), 4.70-4.66 (d, 1H,

J = 12.5 Hz), 4.38-4.37 (d, 1H, J = 4.5 Hz), 4.29-4.26 (d, 1H, J = 17.5 Hz), 3.81 (s, 6H,

OMe), 2.33-2.29 (m, 1H, -CH(CH3)2), 1.11-1.08 ( two d, 6H, J = 4.5 and 5.0 Hz , -

13 CH(CH3)2); C NMR δ (CDCl3): 160.6, 130.4, 130.3, 119.4, 117.6, 113.7, 113.5, 113.2,

111.7, 70.0, 55.7, 55.6, 52.7, 33.2, 20.0, 18.0.

General procedure of demethylations of dimethoxy-2,5-dihydropyrazine to 2,5-

diketopiperazine.

To a stirred solution of alkylated dimethoxy-2,5-dihydropyrazine (100 mol%) in

CHCl3 was added TMSI (300 mol%) under N2, and the resulting solution was stirred for

1 h ar rt. The reaction was quenched with few drops of MeOH, and then evaporated

260 under reduced pressure. The crude product was purified by recrystallization.

Synthesis of (3S,6R)-3-(2-bromobenzyl)-6-isopropylpiperazine-2,5-dione (62a)

(entries 1-2, Table 7.8).

O O N HN N NH O O

Br Br Using the general demethylation procedure with 30 mg (0.0852 mmol) of

dimethyl substrate 56a, 25 mg (90 %) of the title compound was obtained. 1H NMR δ

(DMSO-d6): 8.07 (s, 1H, NH of Val.), 7.89-7.88 (d, 1H, J = 2.0 Hz, NH of Tyr.), 7.59-

7.58 (d, 1H, J = 7.5 Hz, Ar), 7.33-7.29 (m, 2H, Ar), 7.20-7.17 (m, 1H, Ar), 4.14-4.11 (m,

1H, α-H of Tyr.), 3.50 (d, 1H, J = 1.5 Hz, α-H of Val.), 3.34 (s, 3H, -NCH3), 3.25-3.21 (dd,

1H, J = 14.2, 5.2 Hz, benzylic), 3.11-3.07 (dd, 1H, J = 14.0, 7.0 Hz, benzylic), 2.23-

2.2.17 (m, 1H, -CH(CH3)2), 0.94-0.93 (d, 3H, J = 7.0 Hz, -CH(CH3)2), 0.83-0.82 (d, 3H, J

13 = 7.0 Hz, -CH(CH3)2); C NMR δ (DMSO-d6): 167.9, 167.3, 136.0, 132.5, 131.8, 128.7,

127.5, 124.6, 58.9, 54.9, 53.9, 38.5, 30.6, 18.2, 16.7; IR cm-1 (KBr pellet): 3446, 3190,

3056, 2962, 2876, 1673, 1471, 1447, 1346, 1290, 1105, 1028.; HRMS 347.0352

+• 22 ((M+Na ); 347.0371 calcd for C14H17BrNaN2O2); [α] D 589nm = -19.5 (c = 0.465, MeOH).

Synthesis of (3S,6R)-3-(2-iodobenzyl)-6-isopropylpiperazine-2,5-dione (62b) (entries

3-4, Table 7.8).

261 O O N HN N NH O O

I I Using the general demethylation procedure with 30 mg (0.0852 mmol) of

dimethyl substrate 56b, 25 mg (90 %) of the title compound was obtained. 1H NMR δ

(DMSO-d6): 8.09 (s, 1H, NH of Val.), 7.85-7.84 (2H, NH of Tyr. & Ar), 7.35-7.32 (t, 1H,

J = 7.2 Hz, Ar), 7.29-7.27 (q, 1H, J = 6.5 Hz, Ar), 7.01-6.98 (m, 1H, Ar), 4.11-4.09 (t, 1H,

J = 4.8 Hz, α-H of Tyr.), 3.55 (d, 1H, J = 2.5 Hz, α-H of Val.), 3.30 (s, 3H, -NCH3), 3.20-

3.16 (dd, 1H, J = 14.0, 5.0 Hz, benzylic), 3.09-3.04 (dd, 1H, J = 14.0, 7.0 Hz, benzylic),

2.22-2.2.18 (m, 1H, -CH(CH3)2), 0.95-0.94 (d, 3H, J = 7.0 Hz, -CH(CH3)2), 0.84-0.83 (d,

13 3H, J = 7.0 Hz, -CH(CH3)2); C NMR δ (DMSO-d6): 167.9, 167.3, 139.2, 130.7, 128.6,

128.2, 60.0, 54.9, 42.8, 30.5, 18.2, 16.7; IR cm-1 (KBr pellet): 3444, 3190, 3055, 2961,

2874, 1665, 1448, 1384, 1344, 1288, 1105, 1010.

Synthesis of tricyclic DKP 63 using stoichiometric amount of CuI (entry 1, Table 7.8).

O O HN HN NH N O O

Br Followed the general procedure using 30 mg (0.0923 mmol) of bromide substrate

62a, 19.0 mg (84 %) of the title compound 63 and 3.0 mg of isomerized product 63a

1 (13 %) were obtained. 63: H NMR δ (CDCl3): 8.16-8.14 (d, 8.0 Hz, 1H, Ar), 7.29-7.26

(m, 2H, Ar), 7.15-7.20 (t, 7.5 Hz, Ar), 7.10 (br s, 1H, NH), 4.89-4.85 (t, J = 10.2 Hz, α-H of Tyr.), 3.87-3.85 (dd, J = 6.0, 2.0 Hz, 1H, α-H of Val.), 3.50-3.46 (dd, J = 16.5, 10.5 Hz,

262 1H, Benzylic H), 3.42-3.37 (dd, J = 16.0, 10.2 Hz, 1H, Benzylic H), 2.38-2.33 (q, J = 6.5

Hz, 1H, CH3CHRCH3), 1.16-1.14 (d, J = 6.5 Hz, 3H, CH3CHRCH3), 1.11-1.10 (d, J = 7.0

13 Hz, 3H, CH3CHRCH3); C NMR δ (CDCl3): 169.3, 164.4, 141.5, 129.5, 128.1, 125.4,

125.0, 64.2, 59.4, 33.2, 32.2, 19.4, 18.3; IR cm-1 (neat) : 3237, 2965, 2931, 2874, 1681,

+• 1601, 1463, 1417, 1284.; HRMS 267.1093 (M+Na ; calcd for C14H16N2O2Na 267.1109);

22 1 [α] D 589nm = -14.6 (c = 0.600, CHCl3). 63a: H NMR δ (CDCl3): 8.12-8.11 (d, 7.5 Hz,

1H, Ar), 7.26-7.22 (m, 2H, Ar), 7.10-7.07 (m, 1H, Ar), 5.93 (br s, 1H, NH), 4.79-4.75 (t, J

= 10.0 Hz, α-H of Tyr.), 4.06-4.05 (d, J = 1.5 Hz, 1H, α-H of Val.), 3.59-3.54 (dd, J = 10.0,

16.0 Hz, 1H, Benzylic H), 3.39-3.34 (dd, J = 10.0, 16.0 Hz, 1H, Benzylic H), 2.74-2.71

(m, 1H, CH3CHRCH3), 1.13-1.11 (d, J = 7.5 Hz, 3H, CH3CHRCH3), 0.99-0.97 (d, J = 7.0

13 Hz, 3H, CH3CHRCH3); C NMR δ (CDCl3): 169.9, 141.3, 129.6, 128.1, 125.2, 116.4,

22 60.9, 60.1, 31.1, 28.0, 19.6, 16.4.; [α] D 589nm = + 88.6 (c = 0.150, CHCl3).

Synthesis of tricyclic DKP 63 using catalytic amount of CuI and bromo substrate

62a (entry 2, Table 7.8).

O O HN HN NH N O O

Br Followed the general procedure using 20 mg (0.0615 mmol) of bromo-substrate

62b, 11.9 mg (79 %) of the title compound and 2.4 mg (16 %) of isomerized product 63a were obtained

263 Synthesis of tricyclic DKP 63 using stoichiometric amount of CuI and iodo substrate

62b (entry 3, Table 7.8).

O O HN HN NH N O O

I Followed the general procedure using 11.8 mg (0.0317 mmol) of iodo-substrate

62b, 7.8 mg (> 99 %) of the title compound was obtained.

Synthesis of tricyclic DKP 63 using catalytic amount of CuI and iodo-substrate 62b

(entry 4, Table 7.8).

O O HN HN NH N O O

I Followed the general procedure using 10 mg (0.0267 mmol) of iodo-substrate

62b, 6.2 mg (95 %) of the title compound and 0.1 mg (1.5 %) of isomerized product were obtained.

Synthesis of tricyclic DKP 60b.

O O HN N N N O O

To a stirred solution of 63 (5.0 mg, 0.0205 mmol) and MeI (6.2 μL, 0.1 mmol) in

THF (2 mL), was added NaH (4.0 mg, 0.1 mmol) at 0 oC. The resulting solution was

stirred at rt for 1 h, and then quenched with water. The product was extracted with

264 EtOAc (3*5 mL), and combined organics were dried over MgSO4. After the solvent

was evaporated, the crude product was purified by prep. TLC to yield the title compound

1 60b (5.3 mg, > 99 %). H NMR δ (CDCl3): 8.07-8.05 (d, 7.6 Hz, 1H, Ar), 7.22-7.21

(2H, Ar), 7.10-7.06 (t, 7.2 Hz, Ar), 4.87-4.82 (t, J = 10.0 Hz, α-H of Tyr.), 3.69-3.67 (d,

1H, J = 7.2 Hz, α-H of Val.), 3.56-3.3.50 (dd, J = 16.4, 10.0 Hz, benzylic), 3.41-3.44 (dd,

J = 16.4, 10.0 Hz, 1H, Benzylic H), 3.08 (s, 3H, NCH3), 2.32-2.25 (m, 1H, CH3CHRCH3),

1.16-1.14 (d, J = 7.2 Hz, 3H, CH3CHRCH3), 1.12-1.11 (d, J = 6.8 Hz, 3H, CH3CHRCH3;

13 C NMR δ (CDCl3): 167.2, 163.8, 141.1, 129.8, 127.8, 125.1, 124.8, 116.5, 71.9, 67.1,

59.4, 35.3, 32.2, 32.0, 20.1, 19.3; IR cm-1 (neat) : 2930, 2922, 1667, 1601, 1483, 1402,

+• 1241, 1110, 1050.; HRMS 281.1248 ((M+Na ); 281.1266 calcd for C15H18NaN2O2);

22 [α] D 589nm = -49.1 (c = 0.285, CHCl3)

Synthesis of proline-containing dipeptide 64a by an aminoacid coupling reaction,

and deprotection.

O NH NH O 2 N OH + HN O Boc O O Br Br OMe

To a stirred solution of N-Boc-L-proline (25 mg, 0.116 mmol), 2-bromo-L- tyrosine methylester 57a (20 mg, 0.0077 mmol), and DIEA (40.5 μL, 0.233 mmol) in anhydrous CH2Cl2 (3 mL) was added HBTU (38 mg, 0.116 mmol). The resulting

solution was stirred for 12 h at rt. After the solvent was evaporated, the crude product

was purified by column chromatography (20 % EtOAc in n-Hex.) to yield 35 mg (99 %)

1 of the title compound. H NMR δ (CDCl3): 7.51-7.49 (d, 1H, J = 8.0 Hz, Ar), 7.20-7.18

265 (2H, Ar), 7.08-7.05 (t, 1H, J = 6.6 Hz, Ar), 6.59 (br s, 1H, NH), 4.93-4.86 (d, 1H, J = 6.0

Hz, α-H of Tyr.), 4.16 (br s, 1H, α-H of Pro.), 3.70 (s, 3H, OCH3), 3.33-3.10 (m, 4H,

benzylic & N(BOC)CH2R in proline), 2.25-1.72 (m, 4H, CHCH2CH2 in proline), 1.43 (s,

13 9H, tBu); C NMR δ (CDCl3): 171.9, 133.1, 131.4, 128.9, 125.3, 52.6, 52.3, 47.3, 28.5;

23 [α] D 589nm = -50.7 (c = 0.38, CHCl3).

Boc-protected dipeptide 64 (25 mg, 0.055 mmol) was treated with 30 % TFA in

CH2Cl2 (5 mL), and then the reaction mixture was stirred overnight at rt. After the

starting material was consumed completely, the mixture was evaporated. The residue

was diluted with CH2Cl2 (10 mL) and washed with sat. NaHCO3 (10 mL). The organic

layer was dried over MgSO4 and evaporated under reduced pressure. The crude product

was purified by column chromatography (only EtOAc) to yield 19.3 mg (> 99 %) of the

1 desired amine 64a. H NMR δ (CDCl3): 8.06-8.05 (d, 1H, J = 8.0 Hz, NH), 7.51-7.50 (d,

1H, J = 7.5 Hz, Ar), 7.22-7.18 (m, 2H, Ar), 7.08-7.05 (m, 1H, Ar), 4.92-4.87 (m, 1H, α-H of Tyr.), 3.71 (s, 3H, OCH3), 3.68-3.65 (m, 1H, α-H of Pro.), 3.35-3.31 (dd, 2H, J = 14.0,

6.0 Hz, benzylic), 3.15-3.11 (dd, 2H, J = 13.8, 8.8 Hz, benzylic), 2.95-2.91 (m, 1H,

NHCH2R in proline), 2.83-2.78 (m, 1H, NHCH2R in proline), 2.02-1.96 (m, 1H,

13 CHCH2CH2 in proline) 1.64-1.47 (m, 3H, CHCH2CH2 in proline); C NMR δ (CDCl3):

175.2, 172.4, 136.3, 133.1, 131.4, 128.8, 127.6, 125.3, 60.5, 52.6, 51.8, 47.4, 38.3, 30.8,

+• 26.2; HRMS 379.0448 ((M+Na ); 379.0458 calcd for C15H19BrNaN2O3).

Synthesis of the tetracyclic DKP 65 by Cu-mediated tandem cyclization.

NH O O

HN O N N + N N O O O Br OMe 266 The proline amine 64a (12 mg, 0.0338 mmol) was cyclized to yield the title compound 65 (3.9 mg, 48%) and 1.0 mg (12 %) of isomerized product 65a, using general

1 procedure (stoichiometric amount of CuI). 65: H NMR δ (CDCl3): 8.07-8.05 (d, 1H, J

= 8.0 Hz, Ar), 7.22-7.20 (2H, Ar), 7.09-7.05 (m, 1H, Ar), 4.86-4.82 (t, 1H, 9.8 Hz, α-H of

Tyr.), 4.32-4.29 (t, 1H, J = 6.8 Hz, α-H of Pro.), 3.71-3.66 (dd, 1H, J = 16.8, 9.2 Hz,

benzylic), 3.61-3.58 (dd, 2H, J = 8.2, 5.8 Hz, NCH2R in proline), 3.38-3.32 (dd, 1H, J =

16.5, 9.5 Hz, benzylic), 2.40-2.32 (m, 2H, CHCH2CH2 in proline), 2.05-1.96 (m, 2H,

13 CHCH2CH2 in proline); C NMR δ (CDCl3): 165.8, 165.4, 140.9, 130.2, 128.0, 125.2,

125.1, 116.0, 61.6, 61.1, 45.8, 30.5, 27.9, 23.7; IR cm-1 (neat) : 2959, 2925, 2855, 1666,

1601, 1485, 1462, 1410, 1245, 1215, 1131, 1087.; HRMS 265.0935 (M+Na+• ; calcd for

22 1 C14H14NaN2O2 265.0953); [α] D 589nm = -10.2 (c = 0.380, CHCl3); 65a: H NMR δ

(CDCl3): 8.04-8.03 (d, 1H, J = 8.0 Hz, Ar), 7.28-7.20 (2H, Ar), 7.11-7.08 (t, 1H, J = 7.5

Hz, Ar), 5.15-5.10 (m, 2H, α-H of Tyr. & α-H of Pro.), 3.85-3.81 (t, 1H, J = 9.0 Hz,

benzylic), 3.61-3.54 (m, 2H, NCH2R in proline), 3.39-3.33 (m, 1H, benzylic), 2.59-2.45

(m, 1H, CHCH2CH2 in proline), 3.32-2.18 (m, 2H, CHCH2CH2 in proline).

Synthesis of (S)-methyl 3-(2-bromophenyl)-2-(ethoxycarbonylamino)propanoate

(57b).

O OEt H2N CO2Me HN CO2Me

Br Br

Amine 57a (0.1 g, 0.39 mmol) and NaHCO3 (0.164 g, 1.95 mmol) were

dissolved in water (5 mL). To the solution, ethyl chloroformate (0.045 mL, 0.468

267 mmol) was added dropwise, and the resulting mixture was stirred vigorously for 4 h.

White solid of the desired product was filtered and washed with water and hexane (0.125

g, 97 %). The crude product was used without further purification. 1H NMR δ

(CDCl3): 7.52-7.50 (d, 1H, J = 8.0 Hz, Ar), 7.22-7.16 (m, 2H, Ar), 7.08-7.05 (m, 1H, Ar),

5.26-5.25 (d, 1H, J = 7.5 Hz), 4.66-4.63 (m, 1H), 4.09-4.00 (m, 2H), 3.68 (s, 3H), 3.29-

3.25 (dd, 1H, J = 6.0, 14.0 Hz), 3.13-3.08 (dd, 1H, J = 8.2, 13.8 Hz), 1.17-1.15 (m, 3H).;

13 C NMR δ (CDCl3): 172.2, 155.9, 135.9, 133.0, 131.2, 128.7, 127.5, 125.0, 61.1, 53.9,

52.4, 38.4, 14.5.

Synthesis of (S)-ethyl 1-(2-bromophenyl)-3-hydroxypropan-2-ylcarbamate (57c).

O OEt O OEt HN CO Me HN 2 OH

Br Br Ester 57b (0.105 g, 0.319 mmol) was dissolved in THF/EtOH (6mL/12mL), and

then CaCl2 (75 mg, 0.670 mmol) and NaBH4 (52 mg, 1.37 mmol) were added to a

solution. After the resulting mixture was stirred at rt for 12 h, the mixture was poured

into aq. citric acid (1 M, 15 mL) and the product was extracted with EtOAc (15 mL * 2).

After evaporation, the crude product was purified by short silica-pad filtration washed

with EtOAc (72.2 mg, 75 %). The product was used without further purification. 1H

NMR δ (CDCl3): 7.56-7.54 (d, 1H, J = 8.0 Hz, Ar), 7.28-7.23 (m, 2H, Ar), 7.11-7.07 (m,

1H, Ar), 5.22 (br s, 1H), 4.05-3.90 (m, 3H), 3.74-3.61 (m, 2H), 3.08-2.85 (m, 2H), 1.20

13 (br s, 3H).; C NMR δ (CDCl3): 157.0, 137.7, 133.0, 131.6, 128.4, 127.7, 125.1, 64.3,

61.1, 53.5, 37.5, 29.8, 14.7.

268 Synthesis of (S)-4-(2-bromobenzyl)oxazolidin-2-one (66).

O OEt O O HN HN OH

Br Br

Alcohol 57c (90 mg, 0.30 mmol) in dry toluene (10 mL) was treated with K2CO3

(1.4 mg, 0.01 mmol), and the mixture was refluxed using Dean-Stark apparatus for 12 h.

The hot solution was filtered and allowed to cool to rt. The product was obtained by

1 filtration (56 mg, 73 %). H NMR δ (CDCl3): 7.60-7.58 (d, 1H, J = 8.0 Hz, Ar), 7.33-

7.15 (m, 3H, Ar), 5.89 (br s, 1H), 4.49-4.45 (t, 1H, J = 7.8 Hz), 4.27-4.18 (m, 2H), 3.11-

13 3.00 (m, 2H).; C NMR δ (CDCl3): 159.6, 135.7, 133.5, 131.6, 129.3, 128.1, 124.7, 69.6,

+• 52.2, 41.5.; HRMS 279.9754 ((M+Na ); 279.9773 calcd for C10H10BrNaNO2).

Synthesis of tert-butyl (S)-1-((S)-4-(2-bromobenzyl)-2-oxooxazolidin-3-yl)-3-methyl-

1-oxobutan-2-yl(methyl)carbamate (68).

O O O O O HN N O O + N N Boc O O Boc Br Br To a stirred solution of N,N-Boc,Me-L-valine (24 mg, 0.14 mmol) and TEA (14.6

μL, 0.14 mmol) in CH2Cl2 (3 mL) was added isobutyl chloroformate (13.6 μL, 0.14 mol).

After 1 h stirring, the solvent was evaporated and the crude ester was dissolved with

EtOAc and washed with water and brine. Then, organic layer was dried over MgSO4 and evaporated. The crude ester was purified by short column. In other flask, oxazolidinone (20 mg, 0.0781 mmol) was dissolved in dry THF (3 mL) and nBuLi (60

μL, 0.0862 mmol) was slowly added at – 78 oC. After 1 h stirring at the same

269 temperature, previously prepared active ester in THF (3 mL) was slowly added into the

reaction vessel. The resulting mixture was stirred at – 78 oC for 1 h and 0 oC for 12 h.

After the solvent was evaporated, the crude product was purified by preparative TLC (19

1 mg, 49 %). H NMR δ (CDCl3): 7.56-7.55 (d, 1H, J = 8.0 Hz, Ar), 7.26-7.07 (m, 3H,

Ar), 4.89 (br s, 1H), 4.19-4.13 (m, 3H), 3.39-3.37 (br d, 1H, J = 13.0 Hz), 3.03-2.84 (m,

4H), 2.29 (br s, 1H), 1.47 (s, 9H), 0.95-0.93 (m, 6H).

Synthesis of (S)-4-(2-bromobenzyl)-3-((S)-3-methyl-2-(methylamino)butanoyl)

oxazolidin-2-one (68a).

O O O O O O N N

N N Boc H Br Br Boc-protected compound 68 (18.0 mg, 0.0383 mmol) was treated with 20 %

TFA/CH2Cl2 (3 mL), and the resulting solution was stirred at rt for 1 h. After the

solvent was evaporated, sat. NaHCO3 (5 mL) was added to the residue, and the amine

was extracted with CH2Cl2 (5 mL*3). Combined organics were dried over MgSO4 and evaporated (14.2 mg, > 99 %). The crude amine was used for the next step without

1 further purification. H NMR δ (CDCl3): 7.51-7.49 (dd, 1H, J = 8.0, 1.5 Hz, Ar), 7.26-

7.15 (m, 2H, Ar), 7.06-7.024 (m, 1H, Ar), 4.67-4.64 (m, 1H), 3.96-3.88 (br s, 1H), 3.84-

3.81 (dd, 1H, J = 12.0, 3.0 Hz), 3.67-3.66 (d, 1H, J = 3.0 Hz), 3.35-3.22 (m, 2H), 2.89 (s,

3H), 2.19-2.13 (m, 1H), 0.97-0.96 (d, 3H, J = 7.0 Hz), 0.74-0.72 (d, 3H, J = 8.0 Hz).:

+• HRMS 393.0605 ((M+Na ); 393.0615 calcd for C16H21BrNaN2O3).

270 Attempt of cyclization of 68a.

O O O N N O N N O H Br O Cyclization of 68a was tried by the general procedure of Cu-mediated tandem reaction, but only starting material was recovered. Also, Pd-catalyzed reaction

conditions in Table 7.3 were tried, but none of cyclizations gave any desired cyclized

product.

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289

APPENDIX A

NMR SPECTRA OF SELECTED COMPOUNDS

290 OTBS I 2

1H and 13C NMR spectra of 2

291 OTBS

Bu3Sn 3

1H and 13C NMR spectra of 3

292 Bu3Sn NPhth 4

1H and 13C NMR spectra of 4

293 O OTBS N Boc 3a

1H and 13C NMR spectra of 3a

294 O OTBS

3d

1H and 13C NMR spectra of 3d

295 BnO OTBS

3e

1H and 13C NMR spectra of 3e

296 O NPhth Br 4b

1H and 13C NMR spectra of 4b

297 O NPhth

NO2 4c

1H and 13C NMR spectra of 4c

298 O NPhth

4d

1H and 13C NMR spectra of 4d

299 BnO NPhth 4e

1H and 13C NMR spectra of 4e

300 O N3 5d

1H and 13C NMR spectra of 5d

301 O NPhth

6d

1H and 13C NMR spectra of 6d

302 BnO NPhth

6

1H and 13C NMR spectra of 6

303 O BnO Ph N ∗ OMe H CF3 MTPA-6(racemic)

1H and 19F NMR spectra of MTPA-derivative of 6(racemic)

304 O BnO Ph N ∗ OMe H CF3 MTPA-6 (from L1)

1 31 H and C NMR spectra of MTPA-derivative of 6 (from L1)

305 -68.54 -68.58

Current Data Parameters NAME PS-A75-A01-F EXPNO 3 PROCNO 1 F2 - Acquisition Parameters Date_ 20071016 Time 15.19 INSTRUM spect PROBHD 5 mm QNP 1H/13 PULPROG zgfhigqn TD 131072 SOLVENT C6D6 NS 128 DS 4 SWH 75187.969 Hz FIDRES 0.573639 Hz AQ 0.8716788 sec RG 4096 DW 6.650 usec DE 6.00 usec TE 0.0 K D1 1.00000000 sec d11 0.03000000 sec d12 0.00002000 sec ======CHANNEL f1 ======NUC1 19F P1 19.50 usec PL1 -4.00 dB SFO1 376.4607044 MHz

======CHANNEL f2 ======CPDPRG2 waltz16 NUC2 1H PCPD2 80.00 usec PL2 -6.00 dB PL12 14.56 dB SFO2 400.1316005 MHz

F2 - Processing parameters SI 65536 SF 376.4983540 MHz WDW EM SSB 0 LB 0.30 Hz GB 0 PC 1.00

-68.2 -68.3 -68.4 -68.5 -68.6 -68.7 -68.8 -68.9 -69.0 ppm

19 F NMR spectrum of MTPA-derivative of 6 (from L1 and L3)

306 HO O BnO NPhth 7

1H and 13C NMR spectra of 7

307 MeO O BnO NPhth

8

1H and 13C NMR spectra of 8

308 BnO NH O 9

1H and 13C NMR spectra of 9

309 BnO N O 10

1H and 13C NMR spectra of 10

310 BnO N O Br 11

1H and 13C NMR spectra of 11

311 BnO N O H Br H Cosy 11

nOe H H O N HH O H Br nOe H nOe 11

2D-cosy and Noesy NMR spectra of 11

312 BnO NH O NO 12a 2

1H and 13C NMR spectra of 12a

313 BnO NH O H NO2 H Cosy 12a

nOe H H O NH HH O H NO2 nOe H nOe 12a

2D-cosy and Noesy NMR spectra of 12a

314 BnO N O NO2 13a

1H and 13C NMR spectra of 13a

315 O

1H and 13C NMR spectra of (R)-4-methyl-4-vinylchroman 14a

316 OH

O

1H and 13C NMR spectra of 15

317 OTIPS

O

1H and 13C NMR spectra of 15a

318 O

OH

1H and 2D-cosy NMR spectra of 16

319 OTBDPS

OH I 16a

1H and 2D-cosy NMR spectra of 16a

320 17

1H and 13C NMR spectra of 17

321 7.183 7.178 7.040 7.019 6.800 6.795 6.779 6.774 5.471 4.973 3.818 3.814 2.807 2.792 2.776 2.554 2.539 2.524 1.906 1.901 1.890 1.886 1.875 1.859 1.844

Current Data Parameters NAME PS-B45-A01 EXPNO 1 PROCNO 1

F2 - Acquisition Parameters Date_ 20081121 Time 13.38 INSTRUM spect PROBHD 5 mm QNP 1H/13 MeO PULPROG zg30 TD 65536 SOLVENT CDCl3 NS 1 DS 2 SWH 8278.146 Hz FIDRES 0.126314 Hz 17a AQ 3.9584243 sec RG 203.2 DW 60.400 usec DE 6.00 usec TE 300.2 K D1 1.00000000 sec MCREST 0.00000000 sec MCWRK 0.01500000 sec

======CHANNEL f1 ======NUC1 1H P1 13.00 usec PL1 0.00 dB SFO1 400.1324710 MHz

F2 - Processing parameters SI 32768 SF 400.1300176 MHz WDW EM SSB 0 LB 0.30 Hz GB 0 PC 1.00

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

1.00 1.01 0.99 1.01 1.00 3.02 2.02 2.03 2.04 157.97 143.78 135.76 130.30 130.04 114.53 108.78 108.18 77.56 77.24 76.92 55.48 33.37 29.84 24.27

Current Data Parameters NAME PS-B45-A01-C EXPNO 1 PROCNO 1 F2 - Acquisition Parameters Date_ 20081121 Time 13.41 INSTRUM spect PROBHD 5 mm QNP 1H/13 PULPROG zgpg30 TD 65536 SOLVENT CDCl3 NS 34 DS 4 SWH 23980.814 Hz FIDRES 0.365918 Hz AQ 1.3664756 sec RG 1149.4 DW 20.850 usec DE 6.00 usec TE 300.2 K D1 2.00000000 sec d11 0.03000000 sec DELTA 1.89999998 sec MCREST 0.00000000 sec MCWRK 0.01500000 sec ======CHANNEL f1 ======NUC1 13C P1 10.50 usec PL1 0.00 dB SFO1 100.6228298 MHz

======CHANNEL f2 ======CPDPRG2 waltz16 NUC2 1H PCPD2 80.00 usec PL2 -6.00 dB PL12 14.56 dB PL13 16.50 dB SFO2 400.1316005 MHz

F2 - Processing parameters SI 32768 SF 100.6127535 MHz WDW EM SSB 0 LB 1.00 Hz GB 0 PC 1.40

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

1H and 13C NMR spectra of 17a

322 7.500 7.476 7.471 7.457 7.453 7.438 7.434 7.387 7.375 7.359 7.345 7.314 7.309 7.294 7.289 7.284 7.206 7.185 7.080 7.061 7.041 7.010 6.990 6.810 6.790 5.687 5.545 5.495 5.441 5.298 5.228 5.084 5.032 4.981 4.832 4.041 2.981 2.965 2.950 2.874 2.858 2.823 2.808 2.792 2.754 2.730 2.713 2.663 2.647 2.620 2.569 2.566 2.557 2.554 2.546 2.541 2.538 2.485 2.393 2.376 2.097 2.087 2.055 1.978 1.962 1.927 1.911 1.902 1.896 1.880 1.864 1.748 1.732

Current Data Parameters NAME PS-B123-A01 EXPNO 1 PROCNO 1 F2 - Acquisition Parameters Date_ 20090526 Br Time 11.33 INSTRUM spect PROBHD 5 mm QNP 1H/13 PULPROG zg30 TD 65536 SOLVENT CDCl3 NS 2 17b DS 2 SWH 8278.146 Hz FIDRES 0.126314 Hz AQ 3.9584243 sec RG 45.3 DW 60.400 usec DE 6.00 usec TE 298.2 K D1 1.00000000 sec MCREST 0.00000000 sec MCWRK 0.01500000 sec

======CHANNEL f1 ======NUC1 1H P1 13.00 usec PL1 0.00 dB SFO1 400.1324710 MHz

F2 - Processing parameters SI 32768 SF 400.1300000 MHz WDW EM SSB 0 LB 0.30 Hz GB 0 PC 1.40

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

1.00 1.11 0.98 1.04 1.01 2.10 2.11 2.10 142.43 136.98 136.30 131.02 130.53 127.28 119.85 109.38 77.55 77.23 76.91 32.95 30.14 23.64

Current Data Parameters NAME PS-B123-A01-C EXPNO 1 PROCNO 1

F2 - Acquisition Parameters Date_ 20090526 Time 11.37 INSTRUM spect PROBHD 5 mm QNP 1H/13 PULPROG zgpg30 TD 65536 SOLVENT CDCl3 NS 20 DS 4 SWH 23980.814 Hz FIDRES 0.365918 Hz AQ 1.3664756 sec RG 3649.1 DW 20.850 usec DE 6.00 usec TE 298.2 K D1 2.00000000 sec d11 0.03000000 sec DELTA 1.89999998 sec MCREST 0.00000000 sec MCWRK 0.01500000 sec ======CHANNEL f1 ======NUC1 13C P1 10.50 usec PL1 0.00 dB SFO1 100.6228298 MHz

======CHANNEL f2 ======CPDPRG2 waltz16 NUC2 1H PCPD2 80.00 usec PL2 -6.00 dB PL12 14.56 dB PL13 16.50 dB SFO2 400.1316005 MHz

F2 - Processing parameters SI 32768 SF 100.6127535 MHz WDW EM SSB 0 LB 1.00 Hz GB 0 PC 1.40

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

1H and 13C NMR spectra of 17b

323 7.240 7.207 7.190 7.172 7.145 7.128 7.121 7.112 7.106 7.096 7.094 7.091 7.088 7.077 7.073 7.061 7.059 7.057 5.961 5.935 5.918 5.891 5.460 5.025 5.022 4.999 4.996 4.832 4.830 4.789 4.786 2.835 2.781 2.767 2.749 2.728 2.048 2.044 2.040 1.803 1.794 1.788 1.783 1.774 1.759 1.753 1.662 1.642 1.509 1.372

Current Data Parameters NAME PS-B51-B01 EXPNO 1 PROCNO 1

F2 - Acquisition Parameters Date_ 20081216 Time 14.34 INSTRUM spect PROBHD 5 mm QNP 1H/13 PULPROG zg30 TD 65536 SOLVENT CDCl3 18 NS 16 DS 2 SWH 8278.146 Hz FIDRES 0.126314 Hz AQ 3.9584243 sec RG 812.7 DW 60.400 usec DE 6.00 usec TE 299.2 K D1 1.00000000 sec MCREST 0.00000000 sec MCWRK 0.01500000 sec

======CHANNEL f1 ======NUC1 1H P1 13.00 usec PL1 0.00 dB SFO1 400.1324710 MHz F2 - Processing parameters SI 32768 SF 400.1300176 MHz WDW EM SSB 0 LB 0.30 Hz GB 0 PC 1.00

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

6.87 1.00 0.43 0.25 1.02 0.26 1.01 0.63 2.98 0.52 0.88 1.34 0.58 3.06 1.30 3.11

1H and 13C NMR spectra of 18

324 6.997 6.977 6.962 6.947 6.841 6.837 6.803 6.774 6.769 6.715 6.710 6.698 6.694 6.638 6.622 6.608 6.603 6.533 6.099 6.094 5.982 5.961 5.947 5.926 5.893 5.476 5.060 5.039 4.979 4.907 4.872 4.149 4.134 3.963 3.846 3.821 3.777 3.743 3.641 3.596 3.428 2.879 2.857 2.847 2.836 2.822 2.809 2.797 2.785 2.744 2.732 2.720 2.712 2.695 2.672 2.495 2.469 2.369 2.249 2.201 2.174 2.082 2.063 2.060 2.002 1.941 1.929 1.917 1.909 1.893 1.880 1.867 1.845 1.827

Current Data Parameters NAME PS-B94-B01 EXPNO 1 O PROCNO 1 F2 - Acquisition Parameters Date_ 20090403 Time 11.11 INSTRUM spect PROBHD 5 mm Multinucl PULPROG zg30 TD 65536 SOLVENT CDCl3 NS 16 DS 2 SWH 10330.578 Hz FIDRES 0.157632 Hz 18a AQ 3.1719923 sec RG 80.6 DW 48.400 usec DE 6.00 usec TE 300.2 K D1 1.00000000 sec MCREST 0.00000000 sec MCWRK 0.01500000 sec

======CHANNEL f1 ======NUC1 1H P1 14.80 usec PL1 -1.00 dB SFO1 500.0230878 MHz

F2 - Processing parameters SI 32768 SF 500.0200213 MHz WDW EM SSB 0 LB 0.30 Hz GB 0 PC 1.00

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

1.26 1.09 1.41 0.14 0.98 0.18 0.04 1.00 0.04 0.99 0.83 3.19 2.88 0.52 1.36 0.96 3.52 1.24 3.37

157.71 148.83 143.70 130.05 129.05 113.81 112.16 111.92 77.48 77.23 76.97 55.39 41.38 37.69 29.65 28.37 19.63

Current Data Parameters NAME PS-B94-B01-C EXPNO 1 PROCNO 1 F2 - Acquisition Parameters Date_ 20090403 Time 11.28 INSTRUM spect PROBHD 5 mm Multinucl PULPROG zgpg30 TD 65536 SOLVENT CDCl3 NS 22 DS 4 SWH 30030.029 Hz FIDRES 0.458222 Hz AQ 1.0912244 sec RG 4597.6 DW 16.650 usec DE 12.00 usec TE 300.2 K D1 2.00000000 sec d11 0.03000000 sec DELTA 1.89999998 sec MCREST 0.00000000 sec MCWRK 0.01500000 sec

======CHANNEL f1 ======NUC1 13C P1 12.00 usec PL1 3.00 dB SFO1 125.7427020 MHz ======CHANNEL f2 ======CPDPRG2 waltz16 NUC2 1H PCPD2 100.00 usec PL2 -1.00 dB PL12 15.59 dB PL13 22.50 dB SFO2 500.0220001 MHz

F2 - Processing parameters SI 32768 SF 125.7301106 MHz WDW EM SSB 0 LB 1.00 Hz GB 0 PC 1.40

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

1H and 13C NMR spectra of 18a

325

1H NMR spectrum of a mixture of 17b, 18b, and 18b’

326 HO O

19a

1H and 13C NMR spectra of 19a

327 MeO O

19

1H and 13C NMR spectra of 19

328 MeO O

O 20

1H and 13C NMR spectra of 20

329 MeO O

21 NOH

1H and 13C NMR spectra of 21

330 MeO O

21a NOTs

1H and 13C NMR spectra of 21a

331 MeO O

N O 22 H

1H and 13C NMR spectra of 22

332 MeO O

NH O 22a

1H and 13C NMR spectra of 22a

333 MeO O

N O 23

1H and 13C NMR spectra of 23

334 CO2H

O N 24

1H and 13C NMR spectra of 24

335 NHCO2Et

O N 25

1H and 13C NMR spectra of 25

336 7.240 7.076 7.061 7.046 6.981 6.967 6.666 6.651 6.637 6.400 6.385 4.088 2.926 2.713 2.705 2.695 2.684 2.644 2.630 2.614 2.597 2.534 1.958 1.954 1.944 1.931 1.669 1.420 1.241 1.145 1.126 1.115 1.089 1.063 0.878 0.865 0.852 0.840 0.827 0.816 0.738 0.731 0.716 0.701

Current Data Parameters NAME PS-B78-A01P EXPNO 1 N PROCNO 1 F2 - Acquisition Parameters Date_ 20090223 Time 17.10 N INSTRUM spect PROBHD 5 mm Multinucl PULPROG zg30 TD 65536 SOLVENT CDCl3 NS 16 DS 2 (-)-desoxyeseroline SWH 10330.578 Hz FIDRES 0.157632 Hz AQ 3.1719923 sec RG 228.1 DW 48.400 usec DE 6.00 usec TE 300.2 K D1 1.00000000 sec MCREST 0.00000000 sec MCWRK 0.01500000 sec

======CHANNEL f1 ======NUC1 1H P1 14.80 usec PL1 -1.00 dB SFO1 500.0230878 MHz

F2 - Processing parameters SI 32768 SF 500.0200216 MHz WDW EM SSB 0 LB 0.30 Hz GB 0 PC 1.00

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

1.00 0.96 0.95 0.93 0.92 2.77 0.96 1.07 2.88 1.97 3.43

1H and 13C NMR spectra of (-)-desoxyeseroline

337 26 O

148.85 145.94 133.81 127.79 127.46 126.95 114.63 77.55 77.23 76.91 41.29 35.97 35.28 28.28 27.05

Current Data Parameters NAME PS-B38-A01-C EXPNO 1 PROCNO 1 F2 - Acquisition Parameters Date_ 20081114 Time 16.18 INSTRUM spect PROBHD 5 mm QNP 1H/13 PULPROG zgpg30 TD 65536 SOLVENT CDCl3 NS 22 DS 4 SWH 23980.814 Hz FIDRES 0.365918 Hz AQ 1.3664756 sec RG 1824.6 DW 20.850 usec DE 6.00 usec TE 300.2 K D1 2.00000000 sec d11 0.03000000 sec DELTA 1.89999998 sec MCREST 0.00000000 sec MCWRK 0.01500000 sec

======CHANNEL f1 ======NUC1 13C P1 10.50 usec PL1 0.00 dB SFO1 100.6228298 MHz ======CHANNEL f2 ======CPDPRG2 waltz16 NUC2 1H PCPD2 80.00 usec PL2 -6.00 dB PL12 14.56 dB PL13 16.50 dB SFO2 400.1316005 MHz F2 - Processing parameters SI 32768 SF 100.6127505 MHz WDW EM SSB 0 LB 1.00 Hz GB 0 PC 1.40

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

1H and 13C NMR spectra of 26

338 N OH 26a

1H and 13C NMR spectra of 26a

339 N

27 O

1H and 13C NMR spectra of 27

340

1 13 H and C NMR spectra of AllylNi(L1)Br 28a

341

31 P NMR spectrum of AllylNi(L1)Br 28a

342

1 13 H and C NMR spectra of AllylNi(L1)BARF 29a

343

19 31 F and P NMR spectra of AllylNi(L1)BARF 29a

344

31 P NMR spectra of AllylNi(L1)BARF 29a (Variable temperature NMR at 60 and 50 oC, respectively)

345

1 13 H and C NMR spectra of AllylNi(L3)Br 28b

346

31 P NMR spectrum of AllylNi(L3)Br 28b

347

1 13 H and C NMR spectra of AllylNi(L3)BARF 29b

348

19 31 F and P NMR spectra of AllylNi(L3)BARF 29b at rt

349 0.07

The Ohio State University Department of Chemistry NMR Facility

Current Data Parameters NAME Hwan-VT-Nicat-20H EXPNO 1 PROCNO 1 F2 - Acquisition Parameters Date_ 20090514 Time 11.51 INSTRUM spect PROBHD 5 mm BBI 1H-BB PULPROG zg30 TD 65536 SOLVENT CDCl3 NS 1 DS 2 SWH 8250.825 Hz FIDRES 0.125898 Hz AQ 3.9715922 sec RG 80.6 DW 60.600 usec DE 6.00 usec TE 253.2 K D1 1.00000000 sec TD0 1

======CHANNEL f1 ======NUC1 1H P1 6.62 usec PL1 -3.00 dB SFO1 400.1724712 MHz

F2 - Processing parameters SI 32768 SF 400.1700000 MHz WDW EM SSB 0 LB 0.30 Hz GB 0 PC 1.00

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

147.79 146.38 143.75

Current Data Parameters NAME Hwan-VT-Nicat-30P EXPNO 1 PROCNO 1 F2 - Acquisition Parameters Date_ 20090514 Time 11.45 INSTRUM spect PROBHD 5 mm BBI 1H-BB PULPROG zgpg30 TD 65536 SOLVENT CD2Cl2 NS 16 DS 4 SWH 64724.918 Hz FIDRES 0.987624 Hz AQ 0.5063233 sec RG 8192 DW 7.725 usec DE 6.00 usec TE 253.2 K D1 2.00000000 sec d11 0.03000000 sec DELTA 1.89999998 sec TD0 1 ======CHANNEL f1 ======NUC1 31P P1 10.38 usec PL1 3.00 dB SFO1 161.9917850 MHz ======CHANNEL f2 ======CPDPRG2 waltz16 NUC2 1H PCPD2 80.00 usec PL2 -3.00 dB PL12 18.64 dB PL13 120.00 dB SFO2 400.1716010 MHz F2 - Processing parameters SI 32768 SF 161.9921197 MHz WDW EM SSB 0 LB 1.00 Hz GB 0 PC 1.00 175 170 165 160 155 150 145 140 135 130 125 ppm

1 31 H and P NMR spectra of AllylNi(L3)BARF 29b (Variable temperature NMR at – 20 oC)

350 8.25 8.17 8.10 8.04 8.00 7.81 7.59 7.46 7.41 7.36 7.28 7.20 7.09 6.97 6.91 6.76 6.47 6.22 5.66 5.09 4.67 4.40 4.17 4.06 3.84 3.01 2.87 2.71 2.63 2.41 2.22 2.02 1.79 1.47 1.35 0.91 0.18

The Ohio State University Department of Chemistry NMR Facility

Current Data Parameters NAME Hwan-VT-Nicat-0H EXPNO 1 PROCNO 1 F2 - Acquisition Parameters Date_ 20090514 Time 12.10 INSTRUM spect PROBHD 5 mm BBI 1H-BB PULPROG zg30 TD 65536 SOLVENT CDCl3 NS 16 DS 2 SWH 8250.825 Hz FIDRES 0.125898 Hz AQ 3.9715922 sec RG 101.6 DW 60.600 usec DE 6.00 usec TE 273.3 K D1 1.00000000 sec TD0 1

======CHANNEL f1 ======NUC1 1H P1 6.62 usec PL1 -3.00 dB SFO1 400.1724712 MHz

F2 - Processing parameters SI 32768 SF 400.1700000 MHz WDW EM SSB 0 LB 0.30 Hz GB 0 PC 1.40

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm 147.59 144.19 143.95

Current Data Parameters NAME Hwan-VT-Nicat-0P EXPNO 1 PROCNO 1 F2 - Acquisition Parameters Date_ 20090514 Time 12.07 INSTRUM spect PROBHD 5 mm BBI 1H-BB PULPROG zgpg30 TD 65536 SOLVENT CDCl3 NS 16 DS 4 SWH 64724.918 Hz FIDRES 0.987624 Hz AQ 0.5063233 sec RG 6502 DW 7.725 usec DE 6.00 usec TE 273.3 K D1 2.00000000 sec d11 0.03000000 sec DELTA 1.89999998 sec TD0 1 ======CHANNEL f1 ======NUC1 31P P1 10.38 usec PL1 3.00 dB SFO1 161.9917850 MHz

======CHANNEL f2 ======CPDPRG2 waltz16 NUC2 1H PCPD2 80.00 usec PL2 -3.00 dB PL12 18.64 dB PL13 120.00 dB SFO2 400.1716010 MHz F2 - Processing parameters SI 32768 SF 161.9921197 MHz WDW EM SSB 0 LB 1.00 Hz GB 0 PC 1.00 175 170 165 160 155 150 145 140 135 130 125 ppm

1 31 H and P NMR spectra of AllylNi(L3)BARF 29b (Variable temperature NMR at 0 oC)

351 8.02 7.80 7.58 7.38 7.27 6.97 6.86 6.66 6.52 6.40 5.02 4.50 4.15 2.92 2.63 2.12 1.45 1.30 0.98 0.16

The Ohio State University Department of Chemistry NMR Facility

Current Data Parameters NAME Hwan-VT-Nicat+50H EXPNO 1 PROCNO 1 F2 - Acquisition Parameters Date_ 20090514 Time 12.40 INSTRUM spect PROBHD 5 mm BBI 1H-BB PULPROG zg30 TD 65536 SOLVENT CDCl3 NS 16 DS 2 SWH 8250.825 Hz FIDRES 0.125898 Hz AQ 3.9715922 sec RG 161.3 DW 60.600 usec DE 6.00 usec TE 323.2 K D1 1.00000000 sec TD0 1

======CHANNEL f1 ======NUC1 1H P1 6.62 usec PL1 -3.00 dB SFO1 400.1724712 MHz

F2 - Processing parameters SI 32768 SF 400.1700000 MHz WDW EM SSB 0 LB 0.30 Hz GB 0 PC 1.00

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

1 31 H and P NMR spectra of AllylNi(L3)BARF 29b (Variable temperature NMR at 50 oC)

352

1 31 H and P NMR spectra of AllylNi(L10)Br 28c

353

1 H and 2D-cosy NMR spectra of AllylNi(L10)BARF 29c

354

31 P NMR spectrum of AllylNi(L10)BARF 29c

355

O BnO N O Catalyst: Pd(II) Additive: ethylene (20min)

1H and 13C NMR spectra of isomerization (entry 9, Table 4.1)

356 HE HE BnO BnO NPhth HZ HZ NPhth E isomer Z isomer

nOe H HE HE BnO NPhth E isomer

No nOe H BnO HZ HZ NPhth Z isomer E isomer

1H(expanded) and 2D-noesy NMR spectra of isomerization (entry 9, Table 4.1)

357 OTBS

1H and 13C NMR spectra of O-TBS hex-5-enol 36

358 After 1 h at rt, conversion: 43 %

After 3 h at rt, conversion: 68 %

After 18 h at rt, conversion: 88 %

After 24 h at rt, conversion: 89 %

1H NMR spectra of isomerization (entry 2, Table 4.4, and entry 1, Table 4.5)

359

31C NMR spectrum of isomerization (entry 2, Table 4.4, and entry 1, Table 4.5)

360 OTBS

1H and 13C NMR spectra of isomerization using Ir-cat. (entry 3, Table 4.5)

361

O

O 37

1H and 13C NMR spectra of 37

362

MeO

O

1H and 13C NMR spectra of 37a by isomerization using Pd-cat. (entry 3, Table 4.4 and entry 4, Table 4.5)

363

Weak nOe E isomer nOe nOe O HH H H O H H H Z isomer Strong nOe nOe H O H H H H O H H nOe

2D-cosy and noesy NMR spectra of isomerization using Pd-cat. (entry 3, Table 4.4 and entry 4, Table 4.5)

364 MeO

O 3.5 MeO + 1.0 O

1H and 2D-cosy NMR spectra of isomerization using Ir-cat. (entry 6, Table 4.5)

365 O 14c

1H and 13C NMR spectra of 14c

366 SePh

O 14d

1H and 13C NMR spectra of 14d

367 MeO

O 38

1H and 13C NMR spectra of 38

368 SePh

MeO

O 38a

1H and 13C NMR spectra of 38a

369 N Ts 39

1H and 13C NMR spectra of 39

370 SePh

N Ts 39a

1H and 13C NMR spectra of 39a

371 N

SePh 39b

1H and 13C NMR spectra of 39b

372 N Ts 40b

1H and 13C NMR spectra of 40b

373 SePh

N Ts 40c

1H NMR spectrum of 40c

374 Ph SePh

N Ts 40e

1H and 13C NMR spectra of 40e

375 N 40 Boc

1H and 13C NMR spectra of 40

376 SePh

N H 40a

1H and 13C NMR spectra of 40a

377 SePh

41b

1H and 13C NMR spectra of 41b

378 41c

1H and 13C NMR spectra of 41c

379 SePh

41d

1H and 13C NMR spectra of 41d

380 MeO SePh

42a OMe

1H and 13C NMR spectra of 42a

381 MeO OMe

42b SePh

1H and 13C NMR spectra of 42b

382 CF 3

N Ts 43

1H and 13C NMR spectra of 43

383 CF3

N SePh 43a

1H and 13C NMR spectra of 43a

384 O2N

N 44 Ts

1H and 13C NMR spectra of 44

385 O2N

N

44a SePh

1H and 13C NMR spectra of 44a

386 N 45 Ts

1H and 13C NMR spectra of 45

387 SePh N

45a

1H and 13C NMR spectra of 45a

388 O2N

N 46a Ts

1H and 13C NMR spectra of 46a

389 O2N O N 2 SePh SePh N N 46b 46c

1H and 13C NMR spectra of 46b and 46c

390 CF3

N 46d Ts

1H and 13C NMR spectra of 46d

391 CF3

SePh N 46e

1H and 13C NMR spectra of 46e

392 CF3 SePh N 46f

1H and 13C NMR spectra of 46f

393 NTs 47a

1H and 13C NMR spectra of 47a

394 TsN SePh 47b

1H and 13C NMR spectra of 47b

395 NTs 47c

1H and 13C NMR spectra of 47c

396 TsN SePh 47d

1H and 13C NMR spectra of 47d

397 PhSe ∗ N Ns 47e

1H and 13C NMR spectra of 47e

398 NTs 48a

1H NMR spectrum of 48a

399 NNs 48b

1H and 13C NMR spectra of 48b

400 Br

N H Br 51a

1H and 13C NMR spectra of 51a

401 Br O

N H Br 51b

1H and 13C NMR spectra of 51b

402 Br O

N Boc Br 51

1H and 13C NMR spectra of 51

403 NH BocN 2 O 52a

1H and 13C NMR spectra of 52a

404 N2 CO2Et

PO(OEt)2 52b

1H and 13C NMR spectra of 52b

405 H N CO Et BocN 2 O PO(OEt)2 52

1H and 13C NMR spectra of 52

406 CO2Et Br O HN NBoc N Br Boc 53

1H and 13C NMR spectra of 53

407 CO2Et Br O HN NBoc N Br Boc 53a

1H and 13C NMR spectra of 53a

408 CO2Et Br O HN NH N Br Boc 53b

1H and 13C NMR spectra of 53b

409 CO2Et Br O HN NH N Br H 53c

1H and 13C NMR spectra of 53c

410 N O

O N

N Br H 54

1H and 13C NMR spectra of 54

411

1H NMR spectrum of 54a

412 Boc N

HN O O Br OEt 55

1H and 13C NMR spectra of 55

413 Boc N

HN O O Br OEt 55a

1H and 13C NMR spectra of 55a

414 H N

HN O O Br OEt 55b

1H and 13C NMR spectra of 55b

415 O N N O

56a Br

1H and 13C NMR spectra of 56a

416 O N N O

56b I

1H and 13C NMR spectra of 56b

417

1H and NMR spectra of 57a and 57b

418 Boc N

HN O O I OMe 58b

1H and 13C NMR spectra of 58b

419 H N

HN O O I OMe 59b

1H and 13C NMR spectra of 59b

420 O

N N O 60

1H and 13C NMR spectra of 60

421 O

N N O 60a

1H and 13C NMR spectra of 60a

422 O HN N OMe O 61

1H and 13C NMR spectra of 61

423 O MeO N N OMe O 61a

1H and 13C NMR spectra of 61a

424 O HN NH O

62a Br

1H and 13C NMR spectra of 62a

425 O HN NH O

62b I

1H and 13C NMR spectra of 62b

426 O HN N O

63

1H and 13C NMR spectra of 63

427 O HN N O

63a

1H and 13C NMR spectra of 63a

428 O N N O

60b

1H and 13C NMR spectra of 60b

429 NBoc

HN O O Br OMe 64

1H and 13C NMR spectra of 64

430 NH

HN O O Br OMe 64a

1H and 13C NMR spectra of 64a

431 O

N N O 65

1H and 13C NMR spectra of 65

432 O

N N O 65a

1H NMR spectrum of 64a

433 O OEt

HN CO2Me

Br 57b

1H and 13C NMR spectra of 57b

434 O OEt HN OH

Br 57c

1H and 13C NMR spectra of 57c

435 O O HN

Br 66

1H and 13C NMR spectra of 66

436 O O N Boc O O 67

1H and 13C NMR spectra of 67

437 O O O N

N Boc 68 Br

O O O N

N H 68a Br

1H NMR spectra of 68 and 68a

438

APPENDIX B

X-RAY CHRYSTALLOGRAPHY DATA

439 X-ray crystallographic data of (S)-methyl 1,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-

benzo[b]azepine-5-carboxylate 23

C12 C14 C2 C10 C3 C13 C1 C4 C6 C9

C5 C11

C8 C7

Ortep plot of 23

The Ortep plot is drawn with 50 % probablility ellipsoids for the non-hydrogen atoms.

The hydrogen atoms are drawn with an artificial radius.

440 Table 1. Crystallographic details for (S)-methyl 1,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-

1H-benzo[b]azepine-5-carboxylate 23

Formula C14 H17 N O3

Formula weight 247.29

Temperature 150(2) K

Wavelength 0.71073 Å

Crystal system orthorhombic

Space group P212121

Unit cell dimensions a = 6.3728(1) Å

b = 12.4132(1) Å

c = 15.5812(2) Å

Volume 1232.58(3) Å3

Z 4

Density (calculated) 1.333 Mg/m3

Absorption coefficient 0.094 mm-1

F(000) 528

Crystal size 0.19 x 0.23 x 0.27 mm3

Theta range for data collection 2.10 to 27.46°

Index ranges -8<=h<=8, -15<=k<=16, -20<=l<=20

Reflections collected 37104

441 Independent reflections 2815 [R(int) = 0.046]

Completeness to theta = 27.46° 100.0 %

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 2815 / 0 / 166

Goodness-of-fit on F2 1.063

Final R indices [I>2sigma(I)] R1 = 0.0328, wR2 = 0.0724

R indices (all data) R1 = 0.0442, wR2 = 0.0798

Largest diff. peak and hole 0.134 and -0.219 e/Å3

442 Table 2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters

(Å2x 103) for (S)-methyl 1,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5- carboxylate 23. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

x y z U(eq)

______

C(1) 10824(2) -420(1) 9353(1) 17(1)

C(2) 11896(2) -964(1) 10000(1) 20(1)

C(3) 12875(2) -1946(1) 9846(1) 22(1)

C(4) 12813(2) -2399(1) 9034(1) 23(1)

C(5) 11744(2) -1876(1) 8381(1) 21(1)

C(6) 10743(2) -900(1) 8537(1) 17(1)

C(7) 7587(2) -100(1) 7889(1) 21(1)

C(8) 6552(2) -284(1) 8747(1) 23(1)

C(9) 7311(2) 471(1) 9463(1) 24(1)

C(10) 9708(2) 646(1) 9496(1) 19(1)

C(11) 10785(2) -215(1) 7031(1) 24(1)

C(12) 10277(3) 1191(1) 10356(1) 27(1)

443 C(13) 10338(2) 1476(1) 8811(1) 20(1)

C(14) 13125(2) 2173(1) 7968(1) 29(1)

N 9676(2) -361(1) 7849(1) 18(1)

O(1) 6657(2) 259(1) 7260(1) 29(1)

O(2) 9173(2) 2153(1) 8526(1) 29(1)

O(3) 12381(2) 1417(1) 8610(1) 24(1)

______

444 Table 3. Bond lengths [Å] and angles [°] for (S)-methyl 1,5-dimethyl-2-oxo-2,3,4,5- tetrahydro-1H-benzo[b]azepine-5-carboxylate 23

______

C(1)-C(2) 1.3933(19)

C(1)-C(6) 1.4037(19)

C(1)-C(10) 1.5194(19)

C(2)-C(3) 1.390(2)

C(2)-H(2) 0.9500

C(3)-C(4) 1.386(2)

C(3)-H(3) 0.9500

C(4)-C(5) 1.386(2)

C(4)-H(4) 0.9500

C(5)-C(6) 1.3910(19)

C(5)-H(5) 0.9500

C(6)-N 1.4358(17)

C(7)-O(1) 1.2282(16)

C(7)-N 1.3714(18)

C(7)-C(8) 1.508(2)

C(8)-C(9) 1.536(2)

445 C(8)-H(8A) 0.9900

C(8)-H(8B) 0.9900

C(9)-C(10) 1.5435(19)

C(9)-H(9A) 0.9900

C(9)-H(9B) 0.9900

C(10)-C(13) 1.5366(19)

C(10)-C(12) 1.5443(19)

C(11)-N 1.4689(17)

C(11)-H(11A) 0.9800

C(11)-H(11B) 0.9800

C(11)-H(11C) 0.9800

C(12)-H(12A) 0.9800

C(12)-H(12B) 0.9800

C(12)-H(12C) 0.9800

C(13)-O(2) 1.2065(16)

C(13)-O(3) 1.3412(18)

C(14)-O(3) 1.4508(16)

C(14)-H(14A) 0.9800

C(14)-H(14B) 0.9800

C(14)-H(14C) 0.9800

C(2)-C(1)-C(6) 117.89(12)

C(2)-C(1)-C(10) 123.04(12)

C(6)-C(1)-C(10) 119.05(12)

446 C(3)-C(2)-C(1) 121.31(12)

C(3)-C(2)-H(2) 119.3

C(1)-C(2)-H(2) 119.3

C(4)-C(3)-C(2) 120.09(13)

C(4)-C(3)-H(3) 120.0

C(2)-C(3)-H(3) 120.0

C(3)-C(4)-C(5) 119.60(13)

C(3)-C(4)-H(4) 120.2

C(5)-C(4)-H(4) 120.2

C(4)-C(5)-C(6) 120.31(13)

C(4)-C(5)-H(5) 119.8

C(6)-C(5)-H(5) 119.8

C(5)-C(6)-C(1) 120.77(12)

C(5)-C(6)-N 119.47(12)

C(1)-C(6)-N 119.72(12)

O(1)-C(7)-N 121.18(13)

O(1)-C(7)-C(8) 123.41(13)

N-C(7)-C(8) 115.41(12)

C(7)-C(8)-C(9) 114.47(12)

C(7)-C(8)-H(8A) 108.6

C(9)-C(8)-H(8A) 108.6

C(7)-C(8)-H(8B) 108.6

C(9)-C(8)-H(8B) 108.6

447 H(8A)-C(8)-H(8B) 107.6

C(8)-C(9)-C(10) 114.95(12)

C(8)-C(9)-H(9A) 108.5

C(10)-C(9)-H(9A) 108.5

C(8)-C(9)-H(9B) 108.5

C(10)-C(9)-H(9B) 108.5

H(9A)-C(9)-H(9B) 107.5

C(1)-C(10)-C(13) 111.03(11)

C(1)-C(10)-C(9) 109.64(11)

C(13)-C(10)-C(9) 109.26(12)

C(1)-C(10)-C(12) 113.53(11)

C(13)-C(10)-C(12) 104.37(11)

C(9)-C(10)-C(12) 108.84(12)

N-C(11)-H(11A) 109.5

N-C(11)-H(11B) 109.5

H(11A)-C(11)-H(11B) 109.5

N-C(11)-H(11C) 109.5

H(11A)-C(11)-H(11C) 109.5

H(11B)-C(11)-H(11C) 109.5

C(10)-C(12)-H(12A) 109.5

C(10)-C(12)-H(12B) 109.5

H(12A)-C(12)-H(12B) 109.5

C(10)-C(12)-H(12C) 109.5

448 H(12A)-C(12)-H(12C) 109.5

H(12B)-C(12)-H(12C) 109.5

O(2)-C(13)-O(3) 123.31(13)

O(2)-C(13)-C(10) 124.18(13)

O(3)-C(13)-C(10) 112.33(11)

O(3)-C(14)-H(14A) 109.5

O(3)-C(14)-H(14B) 109.5

H(14A)-C(14)-H(14B) 109.5

O(3)-C(14)-H(14C) 109.5

H(14A)-C(14)-H(14C) 109.5

H(14B)-C(14)-H(14C) 109.5

C(7)-N-C(6) 122.40(11)

C(7)-N-C(11) 118.50(11)

C(6)-N-C(11) 118.57(11)

C(13)-O(3)-C(14) 116.29(11)

______

449 Table 4. Anisotropic displacement parameters (Å2x 103) for (S)-methyl 1,5-dimethyl-

2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-carboxylate 23. The anisotropic displacement factor exponent takes the form: -2 2[ h2a*2U11 + ... + 2 h k a* b* U12 ]

U11 U22 U33 U23 U13 U12

______

C(1) 15(1) 17(1) 19(1) 1(1) 1(1) -2(1)

C(2) 19(1) 23(1) 18(1) 3(1) -1(1) -2(1)

C(3) 18(1) 23(1) 26(1) 7(1) -2(1) -1(1)

C(4) 18(1) 19(1) 33(1) 1(1) 1(1) 1(1)

C(5) 19(1) 21(1) 23(1) -2(1) 1(1) -2(1)

C(6) 14(1) 18(1) 18(1) 2(1) -1(1) -3(1)

C(7) 19(1) 19(1) 24(1) -1(1) -4(1) -2(1)

C(8) 16(1) 25(1) 29(1) 3(1) 0(1) 0(1)

C(9) 22(1) 27(1) 23(1) 2(1) 4(1) 5(1)

C(10) 21(1) 19(1) 16(1) 0(1) 1(1) 2(1)

C(11) 29(1) 26(1) 18(1) 0(1) 3(1) -2(1)

C(12) 39(1) 23(1) 20(1) -3(1) -1(1) 3(1)

C(13) 24(1) 18(1) 18(1) -2(1) -1(1) 1(1)

450 C(14) 32(1) 26(1) 28(1) 7(1) 4(1) -5(1)

N 19(1) 21(1) 16(1) 1(1) -1(1) 1(1)

O(1) 26(1) 35(1) 27(1) 3(1) -8(1) 4(1)

O(2) 32(1) 26(1) 30(1) 7(1) 1(1) 7(1)

O(3) 22(1) 21(1) 28(1) 6(1) 2(1) -3(1)

______

451 Table 5. Calculated hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 103) for (S)-methyl 1,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-carboxylate

23.

x y z U(eq)

______

H(2) 11959 -658 10559 24

H(3) 13588 -2306 10298 27

H(4) 13499 -3065 8925 28

H(5) 11695 -2186 7823 25

H(8A) 6810 -1038 8925 28

H(8B) 5018 -193 8678 28

H(9A) 6848 174 10022 29

H(9B) 6622 1180 9389 29

H(11A) 10558 -848 6666 36

H(11B) 12290 -128 7140 36

H(11C) 10247 428 6740 36

H(12A) 9812 734 10833 41

452 H(12B) 9580 1893 10393 41

H(12C) 11800 1291 10389 41

H(14A) 12360 2059 7430 43

H(14B) 14628 2061 7871 43

H(14C) 12888 2911 8170 43

______

453 Table 6. Torsion angles [°] for (S)-methyl 1,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepine-5-carboxylate 23

______

C(6)-C(1)-C(2)-C(3) 0.66(19)

C(10)-C(1)-C(2)-C(3) 179.13(12)

C(1)-C(2)-C(3)-C(4) 0.5(2)

C(2)-C(3)-C(4)-C(5) -0.9(2)

C(3)-C(4)-C(5)-C(6) 0.2(2)

C(4)-C(5)-C(6)-C(1) 1.03(19)

C(4)-C(5)-C(6)-N 178.88(12)

C(2)-C(1)-C(6)-C(5) -1.42(18)

C(10)-C(1)-C(6)-C(5) -179.96(12)

C(2)-C(1)-C(6)-N -179.27(11)

C(10)-C(1)-C(6)-N 2.19(18)

O(1)-C(7)-C(8)-C(9) -111.78(15)

N-C(7)-C(8)-C(9) 68.09(16)

C(7)-C(8)-C(9)-C(10) -43.43(17)

C(2)-C(1)-C(10)-C(13) 130.12(13)

C(6)-C(1)-C(10)-C(13) -51.42(16)

C(2)-C(1)-C(10)-C(9) -109.06(15)

454 C(6)-C(1)-C(10)-C(9) 69.40(15)

C(2)-C(1)-C(10)-C(12) 12.90(18)

C(6)-C(1)-C(10)-C(12) -168.64(12)

C(8)-C(9)-C(10)-C(1) -42.17(16)

C(8)-C(9)-C(10)-C(13) 79.72(14)

C(8)-C(9)-C(10)-C(12) -166.90(11)

C(1)-C(10)-C(13)-O(2) 145.93(13)

C(9)-C(10)-C(13)-O(2) 24.88(19)

C(12)-C(10)-C(13)-O(2) -91.39(16)

C(1)-C(10)-C(13)-O(3) -38.80(16)

C(9)-C(10)-C(13)-O(3) -159.85(11)

C(12)-C(10)-C(13)-O(3) 83.88(13)

O(1)-C(7)-N-C(6) -172.37(12)

C(8)-C(7)-N-C(6) 7.76(18)

O(1)-C(7)-N-C(11) -0.81(19)

C(8)-C(7)-N-C(11) 179.32(12)

C(5)-C(6)-N-C(7) 122.50(14)

C(1)-C(6)-N-C(7) -59.62(17)

C(5)-C(6)-N-C(11) -49.05(17)

C(1)-C(6)-N-C(11) 128.82(13)

O(2)-C(13)-O(3)-C(14) -4.49(19)

C(10)-C(13)-O(3)-C(14) -179.81(11)

______

455 X-ray crystallographic data of (1S,9bS)-1,9b-dimethyl-5,9b-dihydro-1H-pyrrolo[2,1- a]isoindol-3(2H)-one 27

C12 C13

C11 C1 C9 C2 C8 C10

C5 C3 C7 C4 C6

Ortep plot of 27

Non-hydrogen atoms are drawn with 50 % ellipsoids. Only selected hydrogen atoms are shown.

456 Table 1. Crystallographic details for (1S,9bS)-1,9b-dimethyl-5,9b-dihydro-1H-

pyrrolo[2,1-a]isoindol-3(2H)-one 27

Formula C13 H15 N O

Formula weight 201.26

Temperature 150(2) K

Wavelength 0.71073 Å

Crystal system monoclinic

Space group P21/n

Unit cell dimensions a = 8.5745(2) Å

b = 14.1089(3) Å

c = 8.8408(2) Å

= 94.154(1)°

Volume 1066.72(4) Å3

Z 4

Density (calculated) 1.253 Mg/m3

Absorption coefficient 0.079 mm-1

F(000) 432

Crystal size 0.15 x 0.19 x 0.35 mm3

Theta range for data collection 2.72 to 25.02°

Index ranges -10<=h<=10, -16<=k<=16, -10<=l<=10

457 Reflections collected 17458

Independent reflections 1881 [R(int) = 0.031]

Completeness to theta = 25.02° 99.9 %

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 1881 / 0 / 138

Goodness-of-fit on F2 1.063

Final R indices [I>2sigma(I)] R1 = 0.0346, wR2 = 0.0814

R indices (all data) R1 = 0.0461, wR2 = 0.0864

Largest diff. peak and hole 0.135 and -0.182 e/Å3

458 Table 2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters

(Å2x 103) for (1S,9bS)-1,9b-dimethyl-5,9b-dihydro-1H-pyrrolo[2,1-a]isoindol-3(2H)-one

27. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

x y z U(eq)

______

C(1) -646(1) 8115(1) 3619(1) 24(1)

C(2) -1960(2) 8281(1) 4684(2) 34(1)

C(3) -1098(2) 8368(1) 6260(2) 38(1)

C(4) 499(2) 8758(1) 5958(2) 30(1)

C(5) 1715(1) 8982(1) 3458(1) 22(1)

C(6) 3230(2) 9309(1) 3746(2) 29(1)

C(7) 3975(2) 9667(1) 2523(2) 35(1)

C(8) 3232(2) 9681(1) 1080(2) 35(1)

C(9) 1715(2) 9337(1) 810(2) 29(1)

C(10) 946(1) 8993(1) 2015(1) 22(1)

C(11) -723(2) 8645(1) 2083(1) 25(1)

C(12) -1354(2) 8087(1) 700(2) 39(1)

C(13) -266(2) 7065(1) 3468(2) 31(1)

N 693(1) 8592(1) 4473(1) 23(1)

O 1452(1) 9148(1) 6854(1) 41(1)

459 Table 3. Bond lengths [Å] and angles [°] for (1S,9bS)-1,9b-dimethyl-5,9b-dihydro-1H- pyrrolo[2,1-a]isoindol-3(2H)-one 27.

______

C(1)-N 1.4874(16)

C(1)-C(13) 1.5243(18)

C(1)-C(2) 1.5381(18)

C(1)-C(11) 1.5480(18)

C(2)-C(3) 1.534(2)

C(2)-H(2A) 0.9900

C(2)-H(2B) 0.9900

C(3)-C(4) 1.517(2)

C(3)-H(3A) 0.9900

C(3)-H(3B) 0.9900

C(4)-O 1.2266(17)

C(4)-N 1.3556(16)

C(5)-C(6) 1.3840(18)

C(5)-C(10) 1.3938(18)

C(5)-N 1.4110(16)

C(6)-C(7) 1.390(2)

460 C(6)-H(6) 0.9500

C(7)-C(8) 1.384(2)

C(7)-H(7) 0.9500

C(8)-C(9) 1.393(2)

C(8)-H(8) 0.9500

C(9)-C(10) 1.3803(18)

C(9)-H(9) 0.9500

C(10)-C(11) 1.5179(18)

C(11)-C(12) 1.5207(19)

C(11)-H(11) 1.0000

C(12)-H(12A) 0.9800

C(12)-H(12B) 0.9800

C(12)-H(12C) 0.9800

C(13)-H(13A) 0.9800

C(13)-H(13B) 0.9800

C(13)-H(13C) 0.9800

N-C(1)-C(13) 108.78(10)

N-C(1)-C(2) 101.16(10)

C(13)-C(1)-C(2) 111.85(11)

N-C(1)-C(11) 102.08(9)

C(13)-C(1)-C(11) 112.84(11)

C(2)-C(1)-C(11) 118.49(11)

461 C(3)-C(2)-C(1) 103.98(11)

C(3)-C(2)-H(2A) 111.0

C(1)-C(2)-H(2A) 111.0

C(3)-C(2)-H(2B) 111.0

C(1)-C(2)-H(2B) 111.0

H(2A)-C(2)-H(2B) 109.0

C(4)-C(3)-C(2) 104.54(11)

C(4)-C(3)-H(3A) 110.8

C(2)-C(3)-H(3A) 110.8

C(4)-C(3)-H(3B) 110.8

C(2)-C(3)-H(3B) 110.8

H(3A)-C(3)-H(3B) 108.9

O-C(4)-N 125.49(13)

O-C(4)-C(3) 128.07(12)

N-C(4)-C(3) 106.44(12)

C(6)-C(5)-C(10) 122.70(12)

C(6)-C(5)-N 129.14(12)

C(10)-C(5)-N 108.16(11)

C(5)-C(6)-C(7) 117.13(13)

C(5)-C(6)-H(6) 121.4

C(7)-C(6)-H(6) 121.4

C(8)-C(7)-C(6) 121.02(13)

C(8)-C(7)-H(7) 119.5

462 C(6)-C(7)-H(7) 119.5

C(7)-C(8)-C(9) 120.96(13)

C(7)-C(8)-H(8) 119.5

C(9)-C(8)-H(8) 119.5

C(10)-C(9)-C(8) 118.88(13)

C(10)-C(9)-H(9) 120.6

C(8)-C(9)-H(9) 120.6

C(9)-C(10)-C(5) 119.30(12)

C(9)-C(10)-C(11) 130.42(12)

C(5)-C(10)-C(11) 110.19(11)

C(10)-C(11)-C(12) 114.67(11)

C(10)-C(11)-C(1) 102.15(10)

C(12)-C(11)-C(1) 116.45(11)

C(10)-C(11)-H(11) 107.7

C(12)-C(11)-H(11) 107.7

C(1)-C(11)-H(11) 107.7

C(11)-C(12)-H(12A) 109.5

C(11)-C(12)-H(12B) 109.5

H(12A)-C(12)-H(12B) 109.5

C(11)-C(12)-H(12C) 109.5

H(12A)-C(12)-H(12C) 109.5

H(12B)-C(12)-H(12C) 109.5

C(1)-C(13)-H(13A) 109.5

463 C(1)-C(13)-H(13B) 109.5

H(13A)-C(13)-H(13B) 109.5

C(1)-C(13)-H(13C) 109.5

H(13A)-C(13)-H(13C) 109.5

H(13B)-C(13)-H(13C) 109.5

C(4)-N-C(5) 132.33(11)

C(4)-N-C(1) 115.18(11)

C(5)-N-C(1) 110.25(10)

______

464 Table 4. Anisotropic displacement parameters (Å2x 103) for (1S,9bS)-1,9b-dimethyl-

5,9b-dihydro-1H-pyrrolo[2,1-a]isoindol-3(2H)-one 27. The anisotropic displacement factor exponent takes the form: -2 2[ h2a*2U11 + ... + 2 h k a* b* U12 ]

U11 U22 U33 U23 U13 U12 ______C(1) 22(1) 25(1) 26(1) 2(1) 1(1) -2(1)

C(2) 29(1) 35(1) 38(1) 7(1) 10(1) 3(1)

C(3) 44(1) 41(1) 30(1) 9(1) 14(1) 11(1)

C(4) 40(1) 26(1) 22(1) 2(1) 1(1) 13(1)

C(5) 24(1) 17(1) 26(1) -1(1) 3(1) 1(1)

C(6) 26(1) 24(1) 36(1) -3(1) -4(1) 1(1)

C(7) 24(1) 27(1) 54(1) -1(1) 7(1) -3(1)

C(8) 34(1) 29(1) 43(1) 4(1) 17(1) 1(1)

C(9) 34(1) 27(1) 26(1) 0(1) 5(1) 2(1)

C(10) 25(1) 18(1) 23(1) -1(1) 2(1) 2(1)

C(11) 24(1) 25(1) 26(1) 2(1) -2(1) -1(1)

C(12) 45(1) 37(1) 34(1) 2(1) -11(1) -9(1)

C(13) 30(1) 26(1) 37(1) 2(1) -2(1) -2(1)

N 26(1) 24(1) 20(1) 1(1) 1(1) -1(1) O 52(1) 42(1) 27(1) -8(1) -8(1) 12(1) ______

465 Table 5. Calculated hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 103) for (1S,9bS)-1,9b-dimethyl-5,9b-dihydro-1H-pyrrolo[2,1- a]isoindol-3(2H)-one 27.

x y z U(eq)

______

H(2A) -2545 8869 4409 40

H(2B) -2700 7741 4646 40

H(3A) -1656 8806 6910 45

H(3B) -1003 7742 6763 45

H(6) 3737 9290 4737 35

H(7) 5010 9906 2680 42

H(8) 3766 9928 261 41

H(9) 1217 9339 -185 35

H(11) -1406 9213 2174 30

H(12A) -1402 8499 -195 59

H(12B) -2405 7853 863 59

H(12C) -663 7548 540 59

H(13A) 680 6994 2919 46

H(13B) -1142 6744 2908 46

H(13C) -93 6784 4479 46

______

466 Table 6. Torsion angles [°] for (1S,9bS)-1,9b-dimethyl-5,9b-dihydro-1H-pyrrolo[2,1- a]isoindol-3(2H)-one 27.

______

N-C(1)-C(2)-C(3) -27.18(13)

C(13)-C(1)-C(2)-C(3) 88.45(13)

C(11)-C(1)-C(2)-C(3) -137.65(12)

C(1)-C(2)-C(3)-C(4) 28.66(14)

C(2)-C(3)-C(4)-O 161.41(13)

C(2)-C(3)-C(4)-N -18.64(14)

C(10)-C(5)-C(6)-C(7) 0.62(19)

N-C(5)-C(6)-C(7) -179.68(12)

C(5)-C(6)-C(7)-C(8) -0.84(19)

C(6)-C(7)-C(8)-C(9) 0.1(2)

C(7)-C(8)-C(9)-C(10) 0.9(2)

C(8)-C(9)-C(10)-C(5) -1.15(18)

C(8)-C(9)-C(10)-C(11) 175.11(12)

C(6)-C(5)-C(10)-C(9) 0.37(19)

N-C(5)-C(10)-C(9) -179.38(11)

C(6)-C(5)-C(10)-C(11) -176.59(11)

467 N-C(5)-C(10)-C(11) 3.66(14)

C(9)-C(10)-C(11)-C(12) 37.86(19)

C(5)-C(10)-C(11)-C(12) -145.62(12)

C(9)-C(10)-C(11)-C(1) 164.74(13)

C(5)-C(10)-C(11)-C(1) -18.74(13)

N-C(1)-C(11)-C(10) 25.23(12)

C(13)-C(1)-C(11)-C(10) -91.34(12)

C(2)-C(1)-C(11)-C(10) 135.19(11)

N-C(1)-C(11)-C(12)

C(13)-C(1)-C(11)-C(12) 34.39(16)

C(2)-C(1)-C(11)-C(12) -99.08(15)

O-C(4)-N-C(5) -18.4(2)

C(3)-C(4)-N-C(5) 161.68(12)

O-C(4)-N-C(1) -179.36(12)

C(3)-C(4)-N-C(1) 0.68(14)

C(6)-C(5)-N-C(4) 32.8(2)

C(10)-C(5)-N-C(4) -147.47(13)

C(6)-C(5)-N-C(1) -165.50(12)

C(10)-C(5)-N-C(1) 14.23(13)

C(13)-C(1)-N-C(4) -100.61(13)

C(2)-C(1)-N-C(4) 17.27(13)

C(11)-C(1)-N-C(4) 139.91(11)

C(13)-C(1)-N-C(5) 94.25(12)

468 C(2)-C(1)-N-C(5) -147.87(10)

C(11)-C(1)-N-C(5) -25.22(12)

______

469 X-ray crystallographic data of AllylNi(L1)Br (28a)

Ortep plot of AllylNi(L1)Br

Non-hydrogen atoms are drawn with 50 % ellipsoids. Only selected hydrogen atoms are shown.

470 Table 1. Crystallographic details for AllylNi(L1)Br

Molecular formula C31 H31 Br N Ni O2 P

Formula weight 619.16

Temperature 150(2) K

Wavelength 0.71073 Å

Crystal system monoclinic

Space group P21

Unit cell dimensions a = 8.2162(1) Å

b = 18.1432(2) Å

c = 9.8241(1) Å

= 110.383(4)°

Volume 1372.76(3) Å3

Z 2

Density (calculated) 1.498 Mg/m3

Absorption coefficient 2.250 mm-1

F(000) 636

Crystal size 0.12 x 0.31 x 0.38 mm3

Theta range for data collection 2.21 to 27.48°

Index ranges -10<=h<=10, -23<=k<=23, -12<=l<=12

471 Reflections collected 25363

Independent reflections 6207 [R(int) = 0.052]

Completeness to theta = 27.48° 99.9 %

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 6207 / 1 / 356

Goodness-of-fit on F2 1.029

Final R indices [I>2sigma(I)] R1 = 0.0237, wR2 = 0.0523

R indices (all data) R1 = 0.0280, wR2 = 0.0538

Absolute structure parameter -0.004(5)

Largest diff. peak and hole 0.565 and -0.276 e/Å3

472 Table 2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters

(Å2x 103) for AllylNi(L1)Br. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

x y z U(eq)

______

C(1) 9712(2) 4051(1) 403(2) 16(1)

C(2) 10934(3) 3816(1) -396(2) 22(1)

C(3) 7850(3) 4186(1) -604(2) 18(1)

C(4) 7351(3) 4120(1) -2103(2) 23(1)

C(5) 5648(3) 4251(1) -2993(2) 30(1)

C(6) 4419(3) 4455(1) -2397(2) 29(1)

C(7) 4897(3) 4527(1) -903(2) 26(1)

C(8) 6597(3) 4395(1) -14(2) 20(1)

C(9) 9374(3) 2748(1) 1391(2) 17(1)

C(10) 7522(3) 2610(1) 352(2) 24(1)

C(11) 10765(3) 2292(1) 1061(2) 18(1)

C(12) 12521(3) 2422(1) 1827(2) 23(1)

C(13) 13799(3) 1984(1) 1618(3) 30(1)

C(14) 13339(3) 1405(1) 642(3) 34(1)

C(15) 11615(3) 1270(1) -126(3) 31(1)

473 C(16) 10339(3) 1711(1) 76(2) 23(1)

C(1A) 12824(3) 2698(2) 5500(3) 32(1)

C(2A) 12273(4) 2686(2) 6692(3) 38(1)

C(3A) 10778(3) 2298(2) 6583(3) 31(1)

C(1B) 9955(3) 5057(1) 4426(2) 17(1)

C(2B) 8879(3) 5071(1) 5247(2) 22(1)

C(3B) 9301(3) 5529(1) 6451(2) 30(1)

C(4B) 10776(3) 5964(1) 6817(2) 29(1)

C(5B) 11830(3) 5955(1) 5979(2) 25(1)

C(6B) 11426(3) 5496(1) 4753(2) 18(1)

C(7B) 12554(3) 5489(1) 3853(2) 19(1)

C(8B) 13262(3) 6145(1) 3552(2) 24(1)

C(9B) 14394(3) 6141(1) 2794(2) 27(1)

C(10B) 14877(3) 5481(1) 2341(2) 27(1)

C(11B) 14193(3) 4819(1) 2616(2) 21(1)

C(12B) 13021(2) 4836(1) 3350(2) 16(1)

N 9804(2) 3546(1) 1625(2) 14(1)

O(1) 9483(2) 4611(1) 3182(1) 16(1)

O(2) 12496(2) 4152(1) 3724(2) 16(1)

P 10528(1) 3832(1) 3324(1) 14(1)

Ni 10362(1) 3053(1) 4931(1) 18(1)

Br 7379(1) 3117(1) 4401(1) 28(1)

______

474 Table 3. Bond lengths [Å] and angles [°] for AllylNi(L1)Br.

C(1)-N 1.491(2)

C(1)-C(3) 1.525(3)

C(1)-C(2) 1.534(3)

C(1)-H(1) 1.0000

C(2)-H(2A) 0.9800

C(2)-H(2B) 0.9800

C(2)-H(2C) 0.9800

C(3)-C(4) 1.389(3)

C(3)-C(8) 1.398(3)

C(4)-C(5) 1.388(3)

C(4)-H(4) 0.9500

C(5)-C(6) 1.384(3)

C(5)-H(5) 0.9500

C(6)-C(7) 1.386(3)

C(6)-H(6) 0.9500

C(7)-C(8) 1.386(3)

C(7)-H(7) 0.9500

C(8)-H(8) 0.9500

475 C(9)-N 1.490(2)

C(9)-C(10) 1.529(3)

C(9)-C(11) 1.533(3)

C(9)-H(9) 1.0000

C(10)-H(10A) 0.9800

C(10)-H(10B) 0.9800

C(10)-H(10C) 0.9800

C(11)-C(16) 1.391(3)

C(11)-C(12) 1.395(3)

C(12)-C(13) 1.388(3)

C(12)-H(12) 0.9500

C(13)-C(14) 1.383(3)

C(13)-H(13) 0.9500

C(14)-C(15) 1.375(4)

C(14)-H(14) 0.9500

C(15)-C(16) 1.388(3)

C(15)-H(15) 0.9500

C(16)-H(16) 0.9500

C(1A)-C(2A) 1.395(4)

C(1A)-Ni 2.008(2)

C(1A)-H(11A) 0.97(3)

C(1A)-H(12A) 1.02(3)

C(2A)-C(3A) 1.386(4)

476 C(2A)-Ni 2.003(3)

C(2A)-H(21A) 1.11(3)

C(3A)-Ni 2.059(2)

C(3A)-H(31A) 0.96(3)

C(3A)-H(32A) 0.92(4)

C(1B)-C(6B) 1.388(3)

C(1B)-C(2B) 1.389(3)

C(1B)-O(1) 1.403(2)

C(2B)-C(3B) 1.387(3)

C(2B)-H(2B1) 0.9500

C(3B)-C(4B) 1.385(4)

C(3B)-H(3B) 0.9500

C(4B)-C(5B) 1.387(3)

C(4B)-H(4B) 0.9500

C(5B)-C(6B) 1.406(3)

C(5B)-H(5B) 0.9500

C(6B)-C(7B) 1.487(3)

C(7B)-C(12B) 1.389(3)

C(7B)-C(8B) 1.400(3)

C(8B)-C(9B) 1.379(3)

C(8B)-H(8B) 0.9500

C(9B)-C(10B) 1.383(3)

C(9B)-H(9B) 0.9500

477 C(10B)-C(11B) 1.392(3)

C(10B)-H(10D) 0.9500

C(11B)-C(12B) 1.391(3)

C(11B)-H(11B) 0.9500

C(12B)-O(2) 1.404(2)

N-P 1.6481(17)

O(1)-P 1.6333(14)

O(2)-P 1.6318(14)

P-Ni 2.1588(5)

Ni-Br 2.3241(3)

N-C(1)-C(3) 112.29(15)

N-C(1)-C(2) 112.52(16)

C(3)-C(1)-C(2) 113.57(16)

N-C(1)-H(1) 105.9

C(3)-C(1)-H(1) 105.9

C(2)-C(1)-H(1) 105.9

C(1)-C(2)-H(2A) 109.5

C(1)-C(2)-H(2B) 109.5

H(2A)-C(2)-H(2B) 109.5

C(1)-C(2)-H(2C) 109.5

H(2A)-C(2)-H(2C) 109.5

H(2B)-C(2)-H(2C) 109.5

478 C(4)-C(3)-C(8) 118.34(19)

C(4)-C(3)-C(1) 122.20(18)

C(8)-C(3)-C(1) 119.44(17)

C(5)-C(4)-C(3) 120.9(2)

C(5)-C(4)-H(4) 119.5

C(3)-C(4)-H(4) 119.5

C(6)-C(5)-C(4) 120.2(2)

C(6)-C(5)-H(5) 119.9

C(4)-C(5)-H(5) 119.9

C(5)-C(6)-C(7) 119.6(2)

C(5)-C(6)-H(6) 120.2

C(7)-C(6)-H(6) 120.2

C(8)-C(7)-C(6) 120.1(2)

C(8)-C(7)-H(7) 119.9

C(6)-C(7)-H(7) 119.9

C(7)-C(8)-C(3) 120.77(19)

C(7)-C(8)-H(8) 119.6

C(3)-C(8)-H(8) 119.6

N-C(9)-C(10) 112.90(17)

N-C(9)-C(11) 113.73(17)

C(10)-C(9)-C(11) 114.42(17)

N-C(9)-H(9) 104.8

C(10)-C(9)-H(9) 104.8

479 C(11)-C(9)-H(9) 104.8

C(9)-C(10)-H(10A) 109.5

C(9)-C(10)-H(10B) 109.5

H(10A)-C(10)-H(10B) 109.5

C(9)-C(10)-H(10C) 109.5

H(10A)-C(10)-H(10C) 109.5

H(10B)-C(10)-H(10C) 109.5

C(16)-C(11)-C(12) 117.74(19)

C(16)-C(11)-C(9) 121.98(19)

C(12)-C(11)-C(9) 120.14(18)

C(13)-C(12)-C(11) 121.1(2)

C(13)-C(12)-H(12) 119.4

C(11)-C(12)-H(12) 119.4

C(14)-C(13)-C(12) 120.0(2)

C(14)-C(13)-H(13) 120.0

C(12)-C(13)-H(13) 120.0

C(15)-C(14)-C(13) 119.7(2)

C(15)-C(14)-H(14) 120.1

C(13)-C(14)-H(14) 120.1

C(14)-C(15)-C(16) 120.2(2)

C(14)-C(15)-H(15) 119.9

C(16)-C(15)-H(15) 119.9

C(15)-C(16)-C(11) 121.2(2)

480 C(15)-C(16)-H(16) 119.4

C(11)-C(16)-H(16) 119.4

C(2A)-C(1A)-Ni 69.46(15)

C(2A)-C(1A)-H(11A) 121.4(16)

Ni-C(1A)-H(11A) 123.5(19)

C(2A)-C(1A)-H(12A) 122.8(16)

Ni-C(1A)-H(12A) 101.5(16)

H(11A)-C(1A)-H(12A) 110(2)

C(3A)-C(2A)-C(1A) 118.7(3)

C(3A)-C(2A)-Ni 72.22(15)

C(1A)-C(2A)-Ni 69.82(14)

C(3A)-C(2A)-H(21A) 119.1(12)

C(1A)-C(2A)-H(21A) 119.1(13)

Ni-C(2A)-H(21A) 112.1(14)

C(2A)-C(3A)-Ni 67.89(14)

C(2A)-C(3A)-H(31A) 120.9(15)

Ni-C(3A)-H(31A) 119.3(16)

C(2A)-C(3A)-H(32A) 116(2)

Ni-C(3A)-H(32A) 96(2)

H(31A)-C(3A)-H(32A) 120(3)

C(6B)-C(1B)-C(2B) 122.26(18)

C(6B)-C(1B)-O(1) 119.13(17)

C(2B)-C(1B)-O(1) 118.53(17)

481 C(3B)-C(2B)-C(1B) 119.1(2)

C(3B)-C(2B)-H(2B1) 120.5

C(1B)-C(2B)-H(2B1) 120.5

C(4B)-C(3B)-C(2B) 119.9(2)

C(4B)-C(3B)-H(3B) 120.1

C(2B)-C(3B)-H(3B) 120.1

C(3B)-C(4B)-C(5B) 120.7(2)

C(3B)-C(4B)-H(4B) 119.6

C(5B)-C(4B)-H(4B) 119.6

C(4B)-C(5B)-C(6B) 120.3(2)

C(4B)-C(5B)-H(5B) 119.8

C(6B)-C(5B)-H(5B) 119.8

C(1B)-C(6B)-C(5B) 117.71(19)

C(1B)-C(6B)-C(7B) 122.01(17)

C(5B)-C(6B)-C(7B) 120.28(19)

C(12B)-C(7B)-C(8B) 117.57(19)

C(12B)-C(7B)-C(6B) 121.71(18)

C(8B)-C(7B)-C(6B) 120.62(19)

C(9B)-C(8B)-C(7B) 121.2(2)

C(9B)-C(8B)-H(8B) 119.4

C(7B)-C(8B)-H(8B) 119.4

C(8B)-C(9B)-C(10B) 120.1(2)

C(8B)-C(9B)-H(9B) 120.0

482 C(10B)-C(9B)-H(9B) 120.0

C(9B)-C(10B)-C(11B) 120.3(2)

C(9B)-C(10B)-H(10D) 119.8

C(11B)-C(10B)-H(10D) 119.8

C(12B)-C(11B)-C(10B) 118.7(2)

C(12B)-C(11B)-H(11B) 120.6

C(10B)-C(11B)-H(11B) 120.6

C(7B)-C(12B)-C(11B) 122.08(18)

C(7B)-C(12B)-O(2) 120.91(16)

C(11B)-C(12B)-O(2) 116.54(17)

C(9)-N-C(1) 122.00(17)

C(9)-N-P 116.47(14)

C(1)-N-P 121.39(13)

C(1B)-O(1)-P 116.61(12)

C(12B)-O(2)-P 128.31(12)

O(2)-P-O(1) 99.25(7)

O(2)-P-N 109.48(8)

O(1)-P-N 101.14(8)

O(2)-P-Ni 111.47(5)

O(1)-P-Ni 117.59(5)

N-P-Ni 116.22(6)

C(2A)-Ni-C(1A) 40.72(10)

C(2A)-Ni-C(3A) 39.89(11)

483 C(1A)-Ni-C(3A) 72.10(11)

C(2A)-Ni-P 128.29(8)

C(1A)-Ni-P 95.70(7)

C(3A)-Ni-P 167.58(8)

C(2A)-Ni-Br 131.18(8)

C(1A)-Ni-Br 163.70(8)

C(3A)-Ni-Br 94.73(8)

P-Ni-Br 97.690(17)

______

484 Table 4. Anisotropic displacement parameters (Å2x 103) for AllylNi(L1)Br. The anisotropic displacement factor exponent takes the form: -2 2[ h2a*2U11 + ... + 2 h k a* b* U12 ]

U11 U22 U33 U23 U13 U12

______

C(1) 17(1) 16(1) 13(1) 2(1) 4(1) -1(1)

C(2) 22(1) 28(1) 19(1) 2(1) 9(1) 1(1)

C(3) 18(1) 16(1) 16(1) 3(1) 3(1) -3(1)

C(4) 24(1) 29(1) 16(1) 2(1) 5(1) -4(1)

C(5) 29(1) 38(1) 16(1) 5(1) -1(1) -5(1)

C(6) 20(1) 28(1) 27(1) 7(1) -7(1) -2(1)

C(7) 22(1) 23(1) 32(1) 1(1) 8(1) 2(1)

C(8) 19(1) 20(1) 17(1) -1(1) 3(1) -1(1)

C(9) 22(1) 13(1) 15(1) -2(1) 6(1) -2(1)

C(10) 24(1) 17(1) 28(1) -2(1) 5(1) -4(1)

C(11) 26(1) 14(1) 15(1) 3(1) 9(1) 2(1)

C(12) 25(1) 22(1) 19(1) -2(1) 4(1) 3(1)

C(13) 27(1) 29(1) 34(1) 1(1) 9(1) 8(1)

C(14) 40(2) 28(1) 40(1) -3(1) 21(1) 11(1)

C(15) 48(2) 18(1) 31(1) -6(1) 18(1) 1(1)

485 C(16) 30(1) 20(1) 18(1) -1(1) 7(1) -3(1)

C(1A) 30(1) 32(1) 29(1) 12(1) 5(1) 9(1)

C(2A) 46(2) 31(1) 29(1) 10(1) 4(1) 4(1)

C(3A) 47(2) 25(1) 19(1) 5(1) 9(1) -6(1)

C(1B) 24(1) 12(1) 12(1) -1(1) 3(1) 4(1)

C(2B) 26(1) 20(1) 22(1) -2(1) 11(1) 1(1)

C(3B) 46(2) 22(1) 28(1) -2(1) 20(1) 5(1)

C(4B) 48(2) 20(1) 20(1) -7(1) 11(1) 3(1)

C(5B) 32(1) 15(1) 23(1) -4(1) 5(1) 0(1)

C(6B) 22(1) 13(1) 17(1) 1(1) 4(1) 3(1)

C(7B) 16(1) 19(1) 17(1) 0(1) 1(1) -1(1)

C(8B) 26(1) 15(1) 29(1) 0(1) 5(1) -1(1)

C(9B) 26(1) 24(1) 29(1) 4(1) 6(1) -7(1)

C(10B) 21(1) 34(1) 28(1) -1(1) 10(1) -5(1)

C(11B) 18(1) 21(1) 23(1) -2(1) 5(1) 0(1)

C(12B) 14(1) 16(1) 14(1) 2(1) -1(1) -2(1)

N 18(1) 11(1) 11(1) -1(1) 4(1) 0(1)

O(1) 18(1) 16(1) 13(1) -3(1) 3(1) 2(1)

O(2) 16(1) 13(1) 18(1) 0(1) 4(1) 0(1)

P 15(1) 13(1) 11(1) -1(1) 3(1) 1(1)

Ni 23(1) 18(1) 13(1) 2(1) 5(1) -1(1)

Br 26(1) 27(1) 32(1) -2(1) 15(1) -3(1)

______

486 Table 5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x

103) for AllylNi(L1)Br.

x y z U(eq)

______

H(1) 10153 4538 858 19

H(2A) 12109 3747 308 33

H(2B) 10952 4199 -1094 33

H(2C) 10522 3352 -912 33

H(4) 8187 3984 -2525 28

H(5) 5326 4200 -4016 36

H(6) 3254 4546 -3006 35

H(7) 4057 4667 -488 31

H(8) 6915 4448 1008 24

H(9) 9387 2563 2353 20

H(10A) 6712 2916 639 36

H(10B) 7227 2089 393 36

H(10C) 7439 2736 -639 36

H(12) 12848 2818 2503 27

487 H(13) 14988 2081 2146 36

H(14) 14212 1102 502 41

H(15) 11297 873 -798 38

H(16) 9153 1615 -468 28

H(11A) 13780(40) 3010(19) 5490(30) 53(8)*

H(12A) 12690(40) 2258(18) 4820(30) 43(8)*

H(21A) 12750(30) 3117(17) 7540(30) 41(6)*

H(31A) 10210(30) 2366(14) 7280(30) 34(7)*

H(32A) 10550(50) 1890(20) 6000(40) 88(13)*

H(2B1) 7869 4771 4988 26

H(3B) 8579 5544 7025 36

H(4B) 11070 6271 7651 35

H(5B) 12830 6261 6235 29

H(8B) 12958 6600 3877 29

H(9B) 14842 6592 2582 33

H(10D) 15680 5479 1841 33

H(11B) 14521 4364 2307 26

*Refined isotropically

488 Table 6. Torsion angles [°] for AllylNi(L1)Br.

______

N-C(1)-C(3)-C(4) -130.9(2)

C(2)-C(1)-C(3)-C(4) -1.8(3)

N-C(1)-C(3)-C(8) 50.3(2)

C(2)-C(1)-C(3)-C(8) 179.36(18)

C(8)-C(3)-C(4)-C(5) -0.7(3)

C(1)-C(3)-C(4)-C(5) -179.6(2)

C(3)-C(4)-C(5)-C(6) 0.5(3)

C(4)-C(5)-C(6)-C(7) -0.1(3)

C(5)-C(6)-C(7)-C(8) 0.0(3)

C(6)-C(7)-C(8)-C(3) -0.3(3)

C(4)-C(3)-C(8)-C(7) 0.6(3)

C(1)-C(3)-C(8)-C(7) 179.52(19)

N-C(9)-C(11)-C(16) -142.99(19)

C(10)-C(9)-C(11)-C(16) -11.2(3)

N-C(9)-C(11)-C(12) 41.3(3)

C(10)-C(9)-C(11)-C(12) 173.11(19)

C(16)-C(11)-C(12)-C(13) -0.4(3)

489 C(9)-C(11)-C(12)-C(13) 175.51(19)

C(11)-C(12)-C(13)-C(14) -0.2(3)

C(12)-C(13)-C(14)-C(15) 0.4(4)

C(13)-C(14)-C(15)-C(16) 0.0(4)

C(14)-C(15)-C(16)-C(11) -0.6(3)

C(12)-C(11)-C(16)-C(15) 0.8(3)

C(9)-C(11)-C(16)-C(15) -175.0(2)

Ni-C(1A)-C(2A)-C(3A) 55.1(2)

C(1A)-C(2A)-C(3A)-Ni -53.9(2)

C(6B)-C(1B)-C(2B)-C(3B) -1.2(3)

O(1)-C(1B)-C(2B)-C(3B) -177.89(19)

C(1B)-C(2B)-C(3B)-C(4B) 0.1(3)

C(2B)-C(3B)-C(4B)-C(5B) 0.9(4)

C(3B)-C(4B)-C(5B)-C(6B) -0.8(3)

C(2B)-C(1B)-C(6B)-C(5B) 1.3(3)

O(1)-C(1B)-C(6B)-C(5B) 177.96(17)

C(2B)-C(1B)-C(6B)-C(7B) -178.84(19)

O(1)-C(1B)-C(6B)-C(7B) -2.1(3)

C(4B)-C(5B)-C(6B)-C(1B) -0.2(3)

C(4B)-C(5B)-C(6B)-C(7B) 179.9(2)

C(1B)-C(6B)-C(7B)-C(12B) -43.4(3)

C(5B)-C(6B)-C(7B)-C(12B) 136.5(2)

C(1B)-C(6B)-C(7B)-C(8B) 140.2(2)

490 C(5B)-C(6B)-C(7B)-C(8B) -39.9(3)

C(12B)-C(7B)-C(8B)-C(9B) -0.5(3)

C(6B)-C(7B)-C(8B)-C(9B) 176.05(19)

C(7B)-C(8B)-C(9B)-C(10B) -1.4(3)

C(8B)-C(9B)-C(10B)-C(11B) 1.6(3)

C(9B)-C(10B)-C(11B)-C(12B) 0.0(3)

C(8B)-C(7B)-C(12B)-C(11B) 2.1(3)

C(6B)-C(7B)-C(12B)-C(11B) -174.36(19)

C(8B)-C(7B)-C(12B)-O(2) 173.99(17)

C(6B)-C(7B)-C(12B)-O(2) -2.5(3)

C(10B)-C(11B)-C(12B)-C(7B) -1.9(3)

C(10B)-C(11B)-C(12B)-O(2) -174.09(18)

C(10)-C(9)-N-C(1) -59.0(3)

C(11)-C(9)-N-C(1) 73.6(2)

C(10)-C(9)-N-P 125.38(16)

C(11)-C(9)-N-P -102.08(18)

C(3)-C(1)-N-C(9) 69.4(2)

C(2)-C(1)-N-C(9) -60.2(2)

C(3)-C(1)-N-P -115.13(16)

C(2)-C(1)-N-P 115.24(17)

C(6B)-C(1B)-O(1)-P 80.4(2)

C(2B)-C(1B)-O(1)-P -102.81(18)

C(7B)-C(12B)-O(2)-P 63.2(2)

491 C(11B)-C(12B)-O(2)-P -124.49(17)

C(12B)-O(2)-P-O(1) -27.62(16)

C(12B)-O(2)-P-N 77.76(16)

C(12B)-O(2)-P-Ni -152.25(13)

C(1B)-O(1)-P-O(2) -60.35(14)

C(1B)-O(1)-P-N -172.46(13)

C(1B)-O(1)-P-Ni 59.88(14)

C(9)-N-P-O(2) 117.94(15)

C(1)-N-P-O(2) -57.72(16)

C(9)-N-P-O(1) -137.97(14)

C(1)-N-P-O(1) 46.36(16)

C(9)-N-P-Ni -9.43(17)

C(1)-N-P-Ni 174.91(12)

C(3A)-C(2A)-Ni-C(1A) -130.9(3)

C(1A)-C(2A)-Ni-C(3A) 130.9(3)

C(3A)-C(2A)-Ni-P -174.62(13)

C(1A)-C(2A)-Ni-P -43.7(2)

C(3A)-C(2A)-Ni-Br 28.8(2)

C(1A)-C(2A)-Ni-Br 159.78(14)

C(2A)-C(1A)-Ni-C(3A) -30.60(17)

C(2A)-C(1A)-Ni-P 147.00(16)

C(2A)-C(1A)-Ni-Br -67.9(3)

C(2A)-C(3A)-Ni-C(1A) 31.18(17)

492 C(2A)-C(3A)-Ni-P 20.0(5)

C(2A)-C(3A)-Ni-Br -158.64(16)

O(2)-P-Ni-C(2A) -2.40(12)

O(1)-P-Ni-C(2A) -116.00(12)

N-P-Ni-C(2A) 123.98(13)

O(2)-P-Ni-C(1A) -29.31(10)

O(1)-P-Ni-C(1A) -142.91(10)

N-P-Ni-C(1A) 97.06(11)

O(2)-P-Ni-C(3A) -18.6(4)

O(1)-P-Ni-C(3A) -132.2(4)

N-P-Ni-C(3A) 107.7(4)

O(2)-P-Ni-Br 160.01(6)

O(1)-P-Ni-Br 46.41(6)

N-P-Ni-Br -73.61(7)

______

493 X-ray crystallographic data of tetracyclic DKP 54

Ortep plot of 54

Non-hydrogen atoms are drawn with 50 % ellipsoids. Only selected hydrogen atoms are shown.

494 Table 1. Crystallographic details for tetracyclic DKP 54

Molecular formula C17 H18 Br N3 O2 + 0.39 H2O

Formula weight 383.24

Temperature 150(2) K

Wavelength 0.71073 Å

Crystal system trigonal

Space group P32

Unit cell dimensions a = 8.0855(1) Å

c = 22.4109(2) Å

Volume 1268.83(2) Å3

Z 3

Density (calculated) 1.505 Mg/m3

Absorption coefficient 2.446 mm-1

F(000) 588

Crystal size 0.23 x 0.35 x 0.38 mm3

Theta range for data collection 2.73 to 27.47°

Index ranges -10<=h<=10, -8<=k<=8, -29<=l<=29

Reflections collected 29488

Independent reflections 3840 [R(int) = 0.054]

Completeness to theta = 27.47° 100.0 %

495 Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 3840 / 1 / 226

Goodness-of-fit on F2 1.036

Final R indices [I>2sigma(I)] R1 = 0.0212, wR2 = 0.0483

R indices (all data) R1 = 0.0240, wR2 = 0.0494

Absolute structure parameter 0.008(5)

Largest diff. peak and hole 0.295 and -0.233 e/Å3

496 Table 2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters

(Å2x 103) for tetracyclic DKP 54. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

x y z U(eq)

______

C(1) 10313(3) 9906(3) -206(1) 26(1)

C(2) 10164(3) 8329(3) 77(1) 29(1)

C(3) 8842(3) 7375(3) 546(1) 26(1)

C(4) 7647(2) 8062(2) 725(1) 20(1)

C(5) 7783(2) 9636(2) 423(1) 20(1)

C(6) 9086(3) 10569(3) -40(1) 23(1)

C(7) 7368(3) 12017(3) 112(1) 23(1)

C(8) 6708(2) 10564(2) 518(1) 20(1)

C(9) 5286(2) 9855(2) 1015(1) 21(1)

C(10) 5987(2) 8909(2) 1474(1) 20(1)

C(11) 4751(3) 8317(3) 2028(1) 22(1)

C(12) 4027(2) 4975(2) 1917(1) 22(1)

C(13) 5611(2) 5639(2) 1457(1) 22(1)

497 C(14) 2797(3) 6018(3) 2774(1) 33(1)

C(15) 2066(3) 3552(3) 1636(1) 27(1)

C(16) 1453(3) 4502(3) 1165(1) 42(1)

C(17) 2037(3) 1778(3) 1394(1) 37(1)

Br 12226(1) 11233(1) -796(1) 41(1)

N(1) 8805(2) 12021(2) -230(1) 25(1)

N(2) 6299(2) 7401(2) 1207(1) 19(1)

N(3) 3945(2) 6533(2) 2226(1) 23(1)

O(1) 4585(2) 9580(2) 2285(1) 31(1)

O(2) 6151(2) 4536(2) 1302(1) 34(1)

O(3) 7896(7) 3294(7) 2180(2) 53(2)*

*Occupancy factor refined to 0.388(7)

______

498 Table 3. Bond lengths [Å] and angles [°] for tetracyclic DKP 54

.

______

C(1)-C(2) 1.375(3)

C(1)-C(6) 1.394(3)

C(1)-Br 1.9056(17)

C(2)-C(3) 1.419(3)

C(2)-H(2) 0.9500

C(3)-C(4) 1.393(2)

C(3)-H(3) 0.9500

C(4)-C(5) 1.396(2)

C(4)-N(2) 1.435(2)

C(5)-C(6) 1.400(2)

C(5)-C(8) 1.420(2)

C(6)-N(1) 1.370(2)

C(7)-C(8) 1.365(2)

C(7)-N(1) 1.391(2)

C(7)-H(7) 0.9500

C(8)-C(9) 1.496(2)

C(9)-C(10) 1.548(2)

499 C(9)-H(9A) 0.9900

C(9)-H(9B) 0.9900

C(10)-N(2) 1.488(2)

C(10)-C(11) 1.514(2)

C(10)-H(10) 1.0000

C(11)-O(1) 1.237(2)

C(11)-N(3) 1.327(2)

C(12)-N(3) 1.468(2)

C(12)-C(13) 1.518(2)

C(12)-C(15) 1.552(2)

C(12)-H(12) 1.0000

C(13)-O(2) 1.223(2)

C(13)-N(2) 1.363(2)

C(14)-N(3) 1.469(2)

C(14)-H(14A) 0.9800

C(14)-H(14B) 0.9800

C(14)-H(14C) 0.9800

C(15)-C(17) 1.523(3)

C(15)-C(16) 1.527(3)

C(15)-H(15) 1.0000

C(16)-H(16A) 0.9800

C(16)-H(16B) 0.9800

C(16)-H(16C) 0.9800

500 C(17)-H(17A) 0.9800

C(17)-H(17B) 0.9800

C(17)-H(17C) 0.9800

N(1)-H(1N1) 0.85(2)

C(2)-C(1)-C(6) 118.92(16)

C(2)-C(1)-Br 120.87(14)

C(6)-C(1)-Br 120.17(14)

C(1)-C(2)-C(3) 122.60(17)

C(1)-C(2)-H(2) 118.7

C(3)-C(2)-H(2) 118.7

C(4)-C(3)-C(2) 118.72(17)

C(4)-C(3)-H(3) 120.6

C(2)-C(3)-H(3) 120.6

C(3)-C(4)-C(5) 118.02(16)

C(3)-C(4)-N(2) 128.12(16)

C(5)-C(4)-N(2) 113.82(14)

C(4)-C(5)-C(6) 123.04(16)

C(4)-C(5)-C(8) 128.27(15)

C(6)-C(5)-C(8) 108.69(15)

N(1)-C(6)-C(1) 134.50(17)

N(1)-C(6)-C(5) 106.83(15)

C(1)-C(6)-C(5) 118.67(16)

501 C(8)-C(7)-N(1) 109.58(15)

C(8)-C(7)-H(7) 125.2

N(1)-C(7)-H(7) 125.2

C(7)-C(8)-C(5) 106.04(15)

C(7)-C(8)-C(9) 136.14(16)

C(5)-C(8)-C(9) 117.75(15)

C(8)-C(9)-C(10) 106.43(14)

C(8)-C(9)-H(9A) 110.4

C(10)-C(9)-H(9A) 110.4

C(8)-C(9)-H(9B) 110.4

C(10)-C(9)-H(9B) 110.4

H(9A)-C(9)-H(9B) 108.6

N(2)-C(10)-C(11) 115.20(14)

N(2)-C(10)-C(9) 113.13(13)

C(11)-C(10)-C(9) 110.69(14)

N(2)-C(10)-H(10) 105.6

C(11)-C(10)-H(10) 105.6

C(9)-C(10)-H(10) 105.6

O(1)-C(11)-N(3) 122.95(16)

O(1)-C(11)-C(10) 116.63(15)

N(3)-C(11)-C(10) 120.39(15)

N(3)-C(12)-C(13) 114.15(14)

N(3)-C(12)-C(15) 111.06(14)

502 C(13)-C(12)-C(15) 110.82(14)

N(3)-C(12)-H(12) 106.8

C(13)-C(12)-H(12) 106.8

C(15)-C(12)-H(12) 106.8

O(2)-C(13)-N(2) 122.52(17)

O(2)-C(13)-C(12) 118.71(16)

N(2)-C(13)-C(12) 118.66(15)

N(3)-C(14)-H(14A) 109.5

N(3)-C(14)-H(14B) 109.5

H(14A)-C(14)-H(14B) 109.5

N(3)-C(14)-H(14C) 109.5

H(14A)-C(14)-H(14C) 109.5

H(14B)-C(14)-H(14C) 109.5

C(17)-C(15)-C(16) 111.77(17)

C(17)-C(15)-C(12) 111.81(15)

C(16)-C(15)-C(12) 112.06(15)

C(17)-C(15)-H(15) 106.9

C(16)-C(15)-H(15) 106.9

C(12)-C(15)-H(15) 106.9

C(15)-C(16)-H(16A) 109.5

C(15)-C(16)-H(16B) 109.5

H(16A)-C(16)-H(16B) 109.5

C(15)-C(16)-H(16C) 109.5

503 H(16A)-C(16)-H(16C) 109.5

H(16B)-C(16)-H(16C) 109.5

C(15)-C(17)-H(17A) 109.5

C(15)-C(17)-H(17B) 109.5

H(17A)-C(17)-H(17B) 109.5

C(15)-C(17)-H(17C) 109.5

H(17A)-C(17)-H(17C) 109.5

H(17B)-C(17)-H(17C) 109.5

C(6)-N(1)-C(7) 108.85(15)

C(6)-N(1)-H(1N1) 126.0(15)

C(7)-N(1)-H(1N1) 125.1(15)

C(13)-N(2)-C(4) 122.40(14)

C(13)-N(2)-C(10) 122.91(14)

C(4)-N(2)-C(10) 113.90(13)

C(11)-N(3)-C(12) 124.49(14)

C(11)-N(3)-C(14) 119.05(15)

C(12)-N(3)-C(14) 116.37(14)

______

504 Table 4. Anisotropic displacement parameters (Å2x 103) for tetracyclic DKP 54. The anisotropic displacement factor exponent takes the form: -2 2[ h2a*2U11 + ... + 2 h k a* b* U12 ]

U11 U22 U33 U23 U13 U12

______

C(1) 27(1) 30(1) 22(1) -1(1) 7(1) 14(1)

C(2) 32(1) 33(1) 29(1) -4(1) 5(1) 20(1)

C(3) 31(1) 24(1) 27(1) -2(1) 2(1) 16(1)

C(4) 21(1) 20(1) 19(1) -2(1) -1(1) 10(1)

C(5) 20(1) 21(1) 17(1) -2(1) -1(1) 11(1)

C(6) 25(1) 24(1) 19(1) -3(1) -2(1) 11(1)

C(7) 26(1) 24(1) 22(1) 0(1) -1(1) 13(1)

C(8) 23(1) 21(1) 18(1) -1(1) -2(1) 12(1)

C(9) 21(1) 22(1) 24(1) 3(1) 2(1) 13(1)

C(10) 21(1) 18(1) 19(1) -1(1) 1(1) 9(1)

C(11) 23(1) 26(1) 18(1) -1(1) 0(1) 13(1)

C(12) 25(1) 20(1) 22(1) 3(1) 0(1) 12(1)

C(13) 22(1) 20(1) 26(1) 0(1) -5(1) 11(1)

505 C(14) 38(1) 34(1) 23(1) 7(1) 9(1) 16(1)

C(15) 20(1) 24(1) 33(1) 2(1) -1(1) 8(1)

C(16) 33(1) 33(1) 55(1) 0(1) -20(1) 13(1)

C(17) 30(1) 24(1) 49(1) -8(1) -11(1) 8(1)

Br 45(1) 43(1) 40(1) 7(1) 23(1) 25(1)

N(1) 31(1) 24(1) 20(1) 4(1) 5(1) 13(1)

N(2) 22(1) 19(1) 19(1) -2(1) -1(1) 12(1)

N(3) 26(1) 25(1) 19(1) 3(1) 2(1) 13(1)

O(1) 40(1) 28(1) 26(1) -1(1) 11(1) 17(1)

O(2) 35(1) 24(1) 47(1) 6(1) 10(1) 18(1)

O(3) 44(3) 42(3) 68(3) -5(2) -6(2) 18(2)

506 Table 5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x

103) for tetracyclic DKP 54.

x y z U(eq)

______

H(2) 10978 7859 -45 35

H(3) 8772 6288 733 32

H(7) 6915 12892 70 28

H(9A) 4003 8914 864 25

H(9B) 5215 10928 1202 25

H(10) 7276 9941 1605 23

H(12) 4296 4253 2228 27

H(14A) 3366 7093 3054 49

H(14B) 2765 4902 2957 49

H(14C) 1493 5715 2677 49

H(15) 1100 3120 1964 33

H(16A) 2345 4909 828 63

H(16B) 1458 5616 1339 63

H(16C) 164 3589 1025 63

507 H(17A) 716 791 1310 55

H(17B) 2587 1300 1691 55

H(17C) 2788 2102 1026 55

H(1N1) 9410(30) 12800(30) -512(10) 31(6)*

*Refined isotropically

______

508 Table 6. Torsion angles [°] for tetracyclic DKP 54.

______

C(6)-C(1)-C(2)-C(3) -1.8(3)

Br-C(1)-C(2)-C(3) 175.85(15)

C(1)-C(2)-C(3)-C(4) 0.0(3)

C(2)-C(3)-C(4)-C(5) 1.5(3)

C(2)-C(3)-C(4)-N(2) -175.89(17)

C(3)-C(4)-C(5)-C(6) -1.4(3)

N(2)-C(4)-C(5)-C(6) 176.34(15)

C(3)-C(4)-C(5)-C(8) 178.97(17)

N(2)-C(4)-C(5)-C(8) -3.3(2)

C(2)-C(1)-C(6)-N(1) -178.01(19)

Br-C(1)-C(6)-N(1) 4.4(3)

C(2)-C(1)-C(6)-C(5) 1.8(3)

Br-C(1)-C(6)-C(5) -175.78(13)

C(4)-C(5)-C(6)-N(1) 179.62(15)

C(8)-C(5)-C(6)-N(1) -0.72(19)

C(4)-C(5)-C(6)-C(1) -0.3(3)

C(8)-C(5)-C(6)-C(1) 179.39(15)

N(1)-C(7)-C(8)-C(5) 0.12(19)

509 N(1)-C(7)-C(8)-C(9) 176.85(18)

C(4)-C(5)-C(8)-C(7) -179.99(17)

C(6)-C(5)-C(8)-C(7) 0.37(19)

C(4)-C(5)-C(8)-C(9) 2.6(3)

C(6)-C(5)-C(8)-C(9) -177.07(15)

C(7)-C(8)-C(9)-C(10) -150.9(2)

C(5)-C(8)-C(9)-C(10) 25.5(2)

C(8)-C(9)-C(10)-N(2) -54.72(18)

C(8)-C(9)-C(10)-C(11) 174.26(14)

N(2)-C(10)-C(11)-O(1) 174.65(15)

C(9)-C(10)-C(11)-O(1) -55.4(2)

N(2)-C(10)-C(11)-N(3) -3.6(2)

C(9)-C(10)-C(11)-N(3) 126.37(16)

N(3)-C(12)-C(13)-O(2) 159.38(16)

C(15)-C(12)-C(13)-O(2) -74.3(2)

N(3)-C(12)-C(13)-N(2) -24.4(2)

C(15)-C(12)-C(13)-N(2) 101.93(18)

N(3)-C(12)-C(15)-C(17) -171.58(16)

C(13)-C(12)-C(15)-C(17) 60.4(2)

N(3)-C(12)-C(15)-C(16) 62.0(2)

C(13)-C(12)-C(15)-C(16) -66.0(2)

C(1)-C(6)-N(1)-C(7) -179.3(2)

C(5)-C(6)-N(1)-C(7) 0.79(19)

510 C(8)-C(7)-N(1)-C(6) -0.6(2)

O(2)-C(13)-N(2)-C(4) 2.9(3)

C(12)-C(13)-N(2)-C(4) -173.25(15)

O(2)-C(13)-N(2)-C(10) -166.33(17)

C(12)-C(13)-N(2)-C(10) 17.6(2)

C(3)-C(4)-N(2)-C(13) -19.2(3)

C(5)-C(4)-N(2)-C(13) 163.26(15)

C(3)-C(4)-N(2)-C(10) 150.85(17)

C(5)-C(4)-N(2)-C(10) -26.7(2)

C(11)-C(10)-N(2)-C(13) -3.3(2)

C(9)-C(10)-N(2)-C(13) -131.99(16)

C(11)-C(10)-N(2)-C(4) -173.28(14)

C(9)-C(10)-N(2)-C(4) 57.99(18)

O(1)-C(11)-N(3)-C(12) 176.73(17)

C(10)-C(11)-N(3)-C(12) -5.2(2)

O(1)-C(11)-N(3)-C(14) 0.2(3)

C(10)-C(11)-N(3)-C(14) 178.32(16)

C(13)-C(12)-N(3)-C(11) 18.7(2)

C(15)-C(12)-N(3)-C(11) -107.44(18)

C(13)-C(12)-N(3)-C(14) -164.70(15)

C(15)-C(12)-N(3)-C(14) 69.14(19)

______

511 Table 7. Hydrogen bonds for tetracyclic DKP 54 [Å and °].

D-H...A d(D-H) d(H...A) d(D...A) <(DHA)

______

N(1)-H(1N1)...O(1)#1 0.85(2) 1.96(2) 2.783(2) 162(2)

O(3)…O(2)

2.879(5)

O(3)…O(1)#2

2.864(5)

______

Symmetry transformations used to generate equivalent atoms:

#1 -y+2, x-y+2, z-1/3

#2 x, -1+y, z

512

APPENDIX C

GC AND LC CHROMATOGRAMS

513 HPLC traces of pyrroldinone 9 (entries 1 and 3, Table 2.2)

From L1 BnO NH O 9

From L10

BnO NH O 9

HPLC conditions – OJ-H column, 10 % iPA/n-Hex., 0.5(L1) ~ 0.75(L10) mL/min

514 GC traces of 4-methylenechroman HV product 14a from L3 (entry 3, Table 3.7), L3*

(entry 4, Table 3.7), and mixture of both compounds.

(S)-isomer from L3*

O (R)-isomer from L3

Mixture of (S) and (R)

(S)-isomer

GC condition - Cyclodex-B column, 100 oC isothermal, 1 mL/min

515 GC traces of 4-methylenechroman HV product 14a from L1 (entry 1, Table 3.7)

and L2 (entry 2, Table 3.7)

GC condition - Cyclodex-B column, 100 oC isothermal, 1 mL/min

516 GC traces of hydrovinylation product 18a from L3 (entry 3, Table 2.3),

L3* (SaRcRc), and mixture of both compounds

(S)-isomer from L3*

O

(R)-isomer from L3 Mixture of (S) and (R)

Starting alkene

GC condition - Cyclodex-B column, 120 oC isothermal, 1 mL/min

517 GC trace of SM (36) and isomerization product (36a)

from Ni-catalyzed condition (entry 1, Table 4.4)

GC condition - Cyclodex-B column, 110 oC 10 min, 4 oC/min, 250 oC, 1 mL/min

518 GC chromatograms of SM (36) and product (36a) from Pd-catalyzed condition

(entry 2, Table 4.4)

GC condition - Cyclodex-B column, 110 oC isothermal, 1 mL/min

519 GC trace of Grubbs II catalyzed isomerization of 36 (entry 2, Table 4.5)

GC condition - Cyclodex-B column, 110 oC isothermal, 1 mL/min

520 GC trace of Ir-catalyzed isomerization product (36b) of 36 (entry 3, Table 4.5)

GC condition - Cyclodex-B column, 110 oC isothermal, 1 mL/min

521 GC trace of 37

GC condition - Cyclodex-B column, 140 oC isothermal, 1 mL/min

522 GC trace of Pd-catalyzed isomerization product (37a)

GC condition - Cyclodex-B column, 140 oC isothermal, 1 mL/min

523 GC-trace of Grubbs II-catalyzed isomerization of 37

GC condition - Cyclodex-B column, 140 oC isothermal, 1 mLl/min

524 GC trace of Ir-catalyzed isomerization products (37b and 37c) of 37

GC condition - Cyclodex-B column, 140 oC isothermal, 1 mL/min

525 LC trace of debenzylative cyclization product 47b (racemic)

LC condition – AD-H column, 3% iPA/n-Hex, 0.5 mL/min.

526 LC trace of debenzylative cyclization product 47b from 48a (chiral)

LC condition – AD-H column, 3% iPA/n-Hex, 0.5 mL/min.

527