Copyright by Peter Andrew Webber 2008

The Dissertation Committee for Peter Andrew Webber Certifies that this is the approved version of the following dissertation:

Studies Toward the Total Synthesis of Quinine

Committee:

Michael J. Krische, Supervisor

Stephen F. Martin

Philip D. Magnus

Hung-wen Liu

Sean Kerwin Studies Toward The Total Synthesis of Quinine

by

Peter Andrew Webber, B. S.

Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of

Doctor of Philosophy

The University of Texas at Austin May, 2008

Dedication

To my wife, Erinn Webber, without her love and support this would not be possible.

Acknowledgements

I would like to thank Professor Michael J. Krische for allowing me the opportunity to work in his laboratory. During my graduate career, Professor Krische has provided an extremely stimulating environment which has led to my immense growth as a scientist. I am also extremely grateful to the members of the Krische group past and present for their support and memories, especially Regan Jones and Vanessa Williams for proofreading this dissertation.

v Studies Toward the Total Synthesis of Quinine

Publication No.______

Peter Andrew Webber, Ph.D. The University of Texas at Austin, 2008

Supervisor: Michael J. Krische

Quinine is an alkaloid natural product isolated from the bark of the cinchona tree. It has long served as a synthetic target due to its antimalarial properties. The total synthesis of quinine can be envisioned employing a recently developed catalytic enone cycloallylation methodology. This new process merges phosphine organocatalysis and transition metal catalysis. The pursuit of quinine details the first application of this novel method in organic synthesis.

Herein, phosphine-catalyzed transformations of α,β-unsaturated compounds as well as a historical overview of the alkaloid target are thoroughly reviewed. The following chapters discuss both racemic and asymmetric approaches toward quinine, including the completion of a formal synthesis. Not only has the cycloallylation proved successful in this synthetic application, but this body of work has seen the development of many highly selective transformations.

vi Table of Contents

List of Tables ...... xi

List of Figures...... xiii

List of Schemes...... xiv

Chapter 1 Historical Overview of Nucleophilic Organocatalysis via Conjugate Addition of Phosphines to α,β-Unsaturated Compounds...... 1 1.1 Introduction...... 1 1.2 Rauhut-Currier and Morita-Baylis-Hillman Reactions...... 2 1.2.1 Intramolecular Rauhut-Currier Reaction ...... 4 1.2.2 Synthetic Applications of the Intramolecular Rauhut-Currier Reaction ...... 9 1.3 Modern Morita-Baylis-Hillman Applications...... 10 1.3.1 Intermolecular Phosphine-Catalyzed Morita-Baylis-Hillman Reaction ...... 10 1.3.2 Intramolecular Phosphine-Catalyzed Morita-Baylis-Hillman Reaction ...... 15 1.3.3 Asymmetric Morita-Baylis-Hillman Reaction...... 19 1.3.4. Aza-Morita-Baylis-Hillman Reaction...... 23 1.3.5 Asymmetric Aza-Morita-Baylis-Hillman ...... 25 1.4 Expansion of Electrophilic Scope of Phosphine-Catalyzed Transformations of α,β-Unsaturated Acceptors...... 28 1.4.1 Phosphine-Catalyzed α-Allylation ...... 28 1.4.2 Phosphine-Catalyzed α-Alkylation...... 31 1.4.3 Phosphine-Catalyzed α-Arylation ...... 34 1.4.4 Other Phosphine-Catalyzed Transformation of α,β-Unsaturated Compounds ...... 36 1.5 Allylic Substitution of Morita-Baylis-Hillman Adducts ...... 39 1.5.1 Tertiary Amine-Promoted Allylic Substitution ...... 40 1.5.2 Phosphine-Catalyzed Allylic Substitution ...... 43 1.6 Summary and Outlook ...... 52 1.7 References...... 53

vii Chapter 2 Historical Survey of Quinine...... 59 2.1 Introduction...... 59 2.2 Structural Determination...... 61 2.3 The First Total Synthesis of Quinine...... 64 2.4 Quinine Syntheses From Hoffman-La Roche...... 66 2.4.1 Quinine via Benzylic Oxidation...... 67 2.4.2 Quinine via Aminoepoxide Cyclization...... 68 2.4.3 Quinine via Stereoselective Carbonyl Reduction ...... 68 2.4.4 Quinine via Lithiated Quinoline Aldehyde Addition...... 69 2.5 Quinine via Novel Olefination Reactions...... 70 2.6 The First Stereoselective Synthesis of Quinine ...... 71 2.7 Synthetic Approaches of the 21st Century ...... 73 2.7.1 Synthetic Approach of Jacobsen...... 73 2.7.2 Synthetic Approach of Kobayashi ...... 74 2.7.3 Synthetic Approach of Williams...... 76 2.8 Summary and Concluding Remarks ...... 77 2.9 References...... 79

Chapter 3 Racemic Approach to Quinine ...... 82 3.1 First Generation Retrosynthetic Analysis ...... 82 3.2 Cycloallylation Substrate Synthesis and Optimization...... 83 3.2.1 N-Tosyl Substrate Synthesis ...... 83 3.2.2 Cycloallylation of N-Tosyl Substrate...... 84 3.2.3 N-Trisyl Substrate Synthesis...... 85 3.2.4 Cycloallylation of N-Trisyl Substrate ...... 86 3.2.5 Additive Effect in Cycloallylation Optimization...... 87 3.2.6 α,β-Unsaturated Acceptor in Cycloallylation Optimization...... 90 3.3 Conjugate Reduction of Cycloallylation Adduct...... 91 3.4 Introduction of the Quinoline ...... 96 3.5 Nucleophilic Epoxidation ...... 97 3.6 Aminoepoxide Cyclization ...... 99 3.6.1 Sulfonamide Deprotection ...... 99 viii 3.7 Second Generation Retrosynthetic Analysis...... 101 3.8 Protecting Group Exchange ...... 102 3.9 Elaboration to Quinuclidine Cyclization ...... 103 3.9.1 Epimerization in the Deprotection/Boc Protection Sequence...106 3.9.2 Epimerization in the Aldol/Dehydration Sequence ...... 107 3.10 Allylic Alcohol Directed Epoxidation ...... 109 3.10.1 Vanadium-Catalyzed Epoxidation Mechanism Studies...... 110 3.10.2 Ligand Effects in Vanadium-Catalyzed Epoxidation ...... 112 3.10.3 Optimization of Vanadium-Catalyzed Epoxidation ...... 115 3.11 C7 Alcohol Deoxygenation Prior to Quinuclidine Formation...... 118 3.12 Quinuclidine Formation...... 120 3.12.1 Quinuclidine Formation in Previous Syntheses...... 120 3.12.2 Quinuclidine Formation Optimization...... 120 3.13 C7 Alcohol Deoxygenation Following Quinuclidine Formation ...... 123 3.13.1 Regioselective C9 Alcohol Protection...... 123 3.13.2 Barton-McCombie C7 Alcohol Deoxygenation ...... 124 3.13.3 Additional Alcohol Deoxygenations ...... 126 3.12.4 Deoxygenation via Nucleophilic Displacement at C7...... 128 3.13.5 Deoxygenation From MOM Ether...... 133 3.14 Formal Synthesis...... 134 3.14.1 Deoxygenation from N-Boc Series ...... 134 3.14.2 Deoxygenation from N-Cbz Series ...... 136 3.15 Summary and Conclusions ...... 137 3.16 Experimental Procedures ...... 138 3.17 1H and 13C NMR Spectra ...... 164 3.18 References...... 194

Chapter 4 Asymmetric Approach To Quinine...... 198 4.1 Chiral Auxiliary Based Approach...... 198 4.2 Asymmetric Cycloallylation Approach ...... 202 4.3 Synthesis and Cycloallylation of Chiral Allylic Carbonate...... 205 4.4 Asymmetric Morita-Baylis-Hillman Cyclization ...... 208 ix 4.4.1 Retrosynthetic Analysis ...... 209 4.4.2 Deprotection of Chiral Allylic Carbonate...... 209 4.4.2 Synthesis and Deprotection of Chiral Allylic Silyl Ether...... 210 4.4.3 Synthesis of Chiral Allylic Tosylate...... 211 4.4.4 Synthesis of Key Allylic Alcohol via Lactol Olefination...... 212 4.4.5 Synthesis and Cyclization of Chiral Allylic Phosphonate ...... 214 4.5 Summary and Conclusions ...... 215 4.6 Experimental Procedures ...... 215 4.7 1H and 13C NMR Spectra ...... 230 4.8 References...... 249

Vita ...... 251

x List of Tables

Table 1.1: Catalyst optimization in MBH reaction...... 11

Table 1.2: PPh3-promoted intramolecular MBH cyclizations examining the effect of alkene geometry...... 19 Table 3.1: Cycloallylation optimization with N-tosyl substrate ...... 85 Table 3.2: Cycloallylation optimization with N-trisyl substrate...... 87 Table 3.3: Cycloallylation optimization with Lewis acid additive effects ...... 89

Table 3.4: Cycloallylation with varying α,β-unsaturated substrates...... 91 Table 3.5: Screened conditions for conjugate reduction...... 93 Table 3.6: Conjugate reduction optimization...... 95 Table 3.7: Nucleophilic epoxidation optimization...... 98 Table 3.8: Deprotection of N-trisyl sulfonamide ...... 100 Table 3.9: Optimization of allylic alcohol directed epoxidation ...... 110 Table 3.10: Optimization of epoxidation; effect of ligand loading ...... 116 Table 3.11: Optimization of epoxidation; effect of bishydroxamate catalyst...... 117 Table 3.12: Deoxygenation prior to quinuclidine formation ...... 119 Table 3.13: Previous conditions for quinuclidine formation ...... 120 Table 3.14: Optimization of quinuclidine formation ...... 122 Table 3.15: Conditions for thionoester formation...... 126

Table 3.16: Deoxgenation via mesylate displacement by tosylhydrazide ...... 130 Table 3.17: Deoxgenation via mesylate displacement by sulfur nucleophiles ....131 Table 3.18: Deoxgenation via mesylate displacement by hydride ...... 132

Table 4.1: Cycloallylation with varying α,β-unsaturated partner ...... 198 Table 4.2: Asymmetric cycloallylation with chiral bidentate ligands ...... 203

xi Table 4.3: Asymmetric cycloallylation with chiral additives ...... 205 Table 4.4: Conditions for carbonate deprotection...... 210 Table 4.5: Acetal hydrolysis to mixed acetal and lactol ...... 213

xii List of Figures

Figure 2.1: Quinine ...... 59 Figure 2.2: Malaria drugs based on the quinoline and amino alcohol scaffold .....60 Figure 2.3: Cinchona alkaloids and their key degradation products...... 62 Figure 2.4: 7-oxy-quinine analogues submitted for biological assay ...... 77 Figure 3.1: Single crystal X-ray diffraction analysis of cis-piperidine 3.33...... 95 Figure 3.2: Single crystal X-ray diffraction analysis of tosylate 3.48 ...... 105 Figure 3.3: Single crystal X-ray diffraction analysis of epoxy alcohol 3.43 ...... 118 Figure 3.4: Substrates for Yus’ reduction of sterically hindered mesylates ...... 129

xiii List of Schemes

Scheme 1.1: Rauhut-Currier reaction mechanism ...... 2 Scheme 1.2: Rauhut-Currier reaction of activated esters...... 3 Scheme 1.3: Rauhut-Currier cross coupling ...... 3 Scheme 1.4: Morita and Baylis and Hillman’s seminal results ...... 4

Scheme 1.5: PBu3-catalyzed intramolecular Rauhut-Currier cycloisomerism...... 6

Scheme 1.6: PBu3-catalyzed reaction showing reversibility of phosphine addition7

Scheme 1.7: PBu3-catalyzed cycloisomerization of vinyl sulfones...... 7

Scheme 1.8: PMe3-promoted intramolecular Rauhut-Currier cycloisomerism ...... 8

Scheme 1.9: PBu3-mediated cross-conjugated dienone synthesis ...... 9 Scheme 1.10: Approach towards ricciocarpin A ...... 9 Scheme 1.11: Approach towards (-)-spinosyn A...... 10 Scheme 1.12: Enolate conformers of MBH reaction at reduced temperature ...... 12 Scheme 1.13: Phosphine and Brønsted acid co-catalyzed MBH reaction...... 14 Scheme 1.14: Proposed catalytic cycle for the co-catalyzed MBH reaction ...... 15

Scheme 1.15: First intramolecular PBu3-catalyzed MBH reaction ...... 15

Scheme 1.16: PBu3-catalyzed intramolecular MBH reaction...... 16

Scheme 1.17: PMe3-catalyzed intramolecular MBH reactions of thioenoates...... 17

Scheme 1.18: PPh3-promoted intramolecular MBH cyclization ...... 18 Scheme 1.19: First phosphine-catalyzed asymmetric intramolecular MBH reaction19 Scheme 1.20: First phosphine-catalyzed asymmetric intermolecular MBH reaction20 Scheme 1.21: Asymmetric intermolecular MBH reaction...... 20

Scheme 1.22: Substituted BINOL and PEt3 co-catalyzed intermolecular MBH reaction...... 21

xiv Scheme 1.23: Asymmetric MBH reaction in synthesis of clerodanes...... 22 Scheme 1.24: Phosphine-catalyzed aza-MBH reaction...... 23 Scheme 1.25: Phosphine-catalyzed aza-MBH reactions with aryl N-tosyl imines24

Scheme 1.26: Single-pot PPh3 and TiCl4 co-catalyzed aza-MBH reaction...... 24 Scheme 1.27: Phosphine-catalyzed aza-MBH reaction of β-substituted substrates25 Scheme 1.28: Asymmetric aza-MBH reaction with bifunctional catalyst...... 26 Scheme 1.29: Second and third generation bifunctional aza-MBH catalysts...... 27 Scheme 1.30: Asymmetric aza-MBH reaction with bisphenol bifunctional catalyst27

Scheme 1.31: PBu3-mediated and Pd-catalyzed enone cycloallylation reaction...29 Scheme 1.32: Proposed mechanism for catalytic enone cycloallylation ...... 30

Scheme 1.33: PBu3-promoted enone intramolecular cycloallylation ...... 31

Scheme 1.34: Mechanistic implications in the PMe3-promoted α-alkylation...... 33

Scheme 1.35: PMe3-mediated cyclization with tethered epoxide electrophiles ....34

Scheme 1.36: PBu3-catalyzed α-arylation of cyclic enones...... 35

Scheme 1.37: Proposed mechanism for PBu3-catalyzed enone α-arylation...... 36

Scheme 1.38: PBu3-catalyzed enone α-arylation in (-)-paroxetine total synthesis36

Scheme 1.39: PCy3-catalyzed [3,3] rearrangement of allylic acrylates...... 37

Scheme 1.40: PEt2Ph-mediated [4+2] annulation of 1,4-dien-3-ones ...... 38

Scheme 1.41: PMe3-catalyzed hydration and hydroalkylation of activated alkenes39 Scheme 1.42: Proposed mechanism for β-hydration and hydroalkylation...... 39 Scheme 1.43: DABCO-promoted allylic substitution of MBH acetates ...... 40 Scheme 1.44: DABCO-catalyzed trichloroacetimidate rearrangement...... 41

Scheme 1.45: (DHDQ)2PHAL-catalyzed kinetic resolution ...... 41 Scheme 1.46: Tertiary amine-catalyzed kinetic resolution of MBH adducts ...... 42 Scheme 1.47: Tertiary amine-promoted reaction of MBH bromides ...... 42

xv Scheme 1.48: PPh3-catalyzed allylic amination of MBH acetates ...... 44

Scheme 1.49: PBu3-catalyzed allylic substitution of cyclic MBH acetates...... 44 Scheme 1.50: Proposed mechanism for phosphine-catalyzed allylic amination ...46 Scheme 1.51: Deracemization of racemic chiral MBH allylic acetate ...... 46

Scheme 1.52: Deracemization of MBH allylic acetate with chiral monophosphine47

Scheme 1.53: PPh3-catalyzed allylic substitution of vinyl phosphonates...... 48

Scheme 1.54: PPh3-catalyzed allylic substitution to afford γ-butenolides...... 49

Scheme 1.55: Proposed mechanism for PPh3-catalyzed γ-butenolide formation ..49 Scheme 1.56: Phosphine-catalyzed asymmetric γ-butenolide formation ...... 50

Scheme 1.57: PBu3-catalyzed and TiCl4-promoted tandem MBH reaction ...... 50

Scheme 1.58: PPh3-catalyzed annulations of MBH adducts ...... 51 Scheme 2.1: Rabe protocol for the conversion of quinotoxine to quinine...... 63 Scheme 2.2: Prelog’s degradation and reconstruction of quinotoxine ...... 63 Scheme 2.3: Woodward’s retrosynthetic approach to quinine ...... 64 Scheme 2.4: Woodward’s synthetic approach to homomeroquinene...... 65 Scheme 2.5: Meroquinene as a key intermediate in the synthesis of quinine...... 66 Scheme 2.6: Uskoković’s first approach via benzylic oxidation...... 67 Scheme 2.7: Model for stereoselectivity in benzylic oxidation...... 68 Scheme 2.8: Uskoković’s second approach via aminoepoxide cyclization...... 68 Scheme 2.9: Uskoković’s third approach via stereoselective carbonyl reduction.69

Scheme 2.10: Uskoković’s fourth approach via aldehyde addition...... 70 Scheme 2.11: Gates’ olefination route to quinine...... 71 Scheme 2.12: Taylor and Martin’s olefination route to quinine...... 71 Scheme 2.13: Stork’s stereoselective synthesis of quinine...... 72 Scheme 2.14: Jacobsen’s catalytic asymmetric approach to quinine ...... 74

xvi Scheme 2.15: Kobayashi’s stereocontrolled approach to quinine ...... 75 Scheme 2.16: Williams’ approach to (R)-7-hydroxyquinine...... 76 Scheme 3.1: First generation retrosynthetic approach to quinine...... 82 Scheme 3.2: Preparation of N-tosyl cycloallylation substrate ...... 84

Scheme 3.3: Preparation of N-trisyl cycloallylation substrate...... 86

Scheme 3.4: Proposed cycloallylation mechanism with AlCl3 additive ...... 90 Scheme 3.5: Buchwald’s asymmetric conjugate reduction ...... 91 Scheme 3.6: Proposed conjugate reduction/diastereoselective protonation ...... 92 Scheme 3.7: Stereochemical model for selectivity in conjugate reduction ...... 96

Scheme 3.8: Preparation of quinoline aldehyde ...... 97 Scheme 3.9: Aldol/dehydration sequence to install full carbon framework...... 97 Scheme 3.10: Aminoepoxide cyclization to construct quinuclidine...... 99 Scheme 3.11: Necessity of trisyl group in conjugate reduction...... 101 Scheme 3.12: Second generation retrosynthetic approach to quinine ...... 101 Scheme 3.13: Sodium naphthalenide deprotection of trisyl sulfonamide...... 102 Scheme 3.14: Deprotection/Boc protection sequence with EtOH quench ...... 103 Scheme 3.15: Structural elaboration to determine relative stereochemistry...... 104 Scheme 3.16: Proposed epimerization manifold to trans-piperidine...... 105 Scheme 3.17: Potential epimerization in sulfonamide cleavage...... 106 Scheme 3.18: Revised deprotection/Boc protection sequence ...... 107

Scheme 3.19: Potential epimerization in aldol/dehydration step...... 107 Scheme 3.20: Revised aldol/dehydration sequence...... 108 Scheme 3.21: Chemo- and diastereoselective 1,2-reduction of enone ...... 109 Scheme 3.22: Stereochemical model for diastereoselective 1,2-reduction...... 109 Scheme 3.23: Stereochemical model in the vanadium-catalyzed epoxidation....111

xvii Scheme 3.24: Diastereoselection in VO(acac)2-catalyzed epoxidation...... 112 Scheme 3.25: Chiral ligands in the asymmetric vanadium-catalyzed epoxidation113 Scheme 3.26: Ligand screening for directed epoxidation...... 114 Scheme 3.27: Catalytic cycle for epoxidation of allylic alcohols...... 115

Scheme 3.28: Preparation of epoxidation precatalyst...... 116 Scheme 3.29: Deoxygenation following quinuclidine formation...... 118 Scheme 3.30: Epoxide activation via internal hydrogen bond ...... 121 Scheme 3.31: Regioselective PMB protection...... 123 Scheme 3.32: Deoxygenation in quinine model study...... 124

Scheme 3.33: Potential undesired radical cyclization pathway...... 125

Scheme 3.34: Proposed mechanism for InCl3-catalyzed deoxygenation...... 126 Scheme 3.35: Proposed mechanism for deoxygenation via Mitsunobu conditions127 Scheme 3.36: Mesylation of the hindered C7 alcohol ...... 128 Scheme 3.37: Deoxygenation via metal-halogen exchange ...... 128 Scheme 3.38: Experiment for product stability to reductive deoxygenation...... 133 Scheme 3.39: MOM protection and deoxygenation via mesylate displacement.134 Scheme 3.40: Jacobsen’s viable intermediate for formal synthesis...... 134 Scheme 3.41: Retrosynthetic approach toward formal total synthesis ...... 135 Scheme 3.42: Deoxygenation and formal synthesis with N-Boc series...... 136 Scheme 3.43: Deoxygenation and formal synthesis with N-Cbz series...... 137

Scheme 4.1: Stereochemical model for diastereoselective cycloallylation ...... 199 Scheme 4.2: Synthesis and cycloallylation of acyl oxazolidinone substrate...... 199 Scheme 4.3: Synthesis and cycloallylation of acyl sultam substrate...... 200

Scheme 4.4: Synthesis and cycloallylation of α-methylnaphthyl amine substrate201 Scheme 4.5: Alcohol-assisted enolate stabilization...... 203

xviii Scheme 4.6: Asymmetric cycloallylation of chiral allylic carbonate ...... 206 Scheme 4.7: Synthesis of chiral allylic carbonate substrate ...... 206 Scheme 4.8: Cycloallylation of chiral allylic carbonate substrate...... 207 Scheme 4.9: Possible alternative cycloallylation mechanism...... 208

Scheme 4.10: PBu3-mediated MBH cyclization with varying electrophile...... 209 Scheme 4.11: Retrosynthetic approach to quinine...... 209 Scheme 4.12: Synthesis and deprotection of chiral silyl ether ...... 211 Scheme 4.13: Synthesis of chiral allylic tosylate...... 212 Scheme 4.14: Lactol olefination ...... 213

Scheme 4.15: Synthesis and cyclization of allylic phosphonate substrate ...... 214

xix

Chapter 1 Historical Overview of Nucleophilic Organocatalysis via Conjugate Addition of Phosphines to α,β-Unsaturated Compounds

1.1 INTRODUCTION

Organocatalytic transformations are rapidly becoming a powerful tool for the

construction of carbon-carbon bonds.1 Organophosphorus compounds specifically are

becoming more common in such applications. Though traditionally employed

stoichiometrically in processes such as the Wittig, Mitsunobu, and Staudinger reactions,

the use of phosphines as a nucleophilic organocatalyst has seen tremendous growth in the

last 15 years.2

Phosphines will undergo 1,4-addition to activated alkenes and alkynes as well as

1,2-addition to carbonyl groups, all of which are reversible processes. Phosphines are

commonly compared to amines in the development of organocatalytic processes.

Although both tertiary amines and phosphines are pyramidal in geometry, the inversion

of amines is rapid as room temperature while phosphines are configurationally stable.

Accordingly, the development of P-chiral phosphines opens the door to asymmetric

organocatalysis.

Phosphines are generally less basic and more nucleophilic than their

corresponding amines as determined in competition experiments with alkyl halides.3

PPh3 has historically been utilized as the most common phosphine catalyst in a wide

range of applications attributed to its low cost and air-stability. Recently,

trialkylphosphines have found wider application due to their increased nucleophilicity. In

7 the displacement of methyl iodide, PBu3 was found to be more than 10 more

1

3c nucleophilic than PPh3. In terms of basicity, PBu3 has been found to be approximately

6 10 more basic than PPh3 and around 100 times less basic than NEt3. Although

trialkylphosphines are quite air-sensitive, one can rationalize their effectiveness as organocatalysts in terms of their propensity toward nucleophilic addition and lack of overwhelming basicity.

1.2 RAUHUT-CURRIER AND MORITA-BAYLIS-HILLMAN REACTIONS

In 1963, Rauhut and Currier patented a process for the phosphine-catalyzed

dimerization of acrylates (α,β-unsaturated esters).4 In 1965, McClure5 and Baizer and

Anderson6 independently reported the phosphine-catalyzed dimerization of acrylonitrile.

Mechanistically, this reaction is thought to proceed by first, reversible 1,4-addition of

phosphine to activated alkene 1.1 to afford zwitterionic enolate 1.4 (Scheme 1.1). This

nucleophile will then add in 1,4-fashion to a second activated alkene to generate

zwitterionic dicarbonyl 1.5. Proton shift and elimination of phosphine provides dimer 1.7

and regenerates the catalyst.

EWG P(Alkyl)3 or P(Ar)3 EWG EWG 1.1 1.2

CO2R

CO2R PR3 CO2R 1.7 1.3

CO2R R3P R3P CO2R CO2R 1.6 1.4

CO2R CO2R 1.3 R3P CO2R 1.5

Scheme 1.1: Rauhut-Currier reaction mechanism

2

In 1969, Morita and Kobayashi reported the PCy3-catalyzed cross-coupling of methyl acrylate (1.8) and fumaric acid ethyl ester (1.9) to afford adduct 1.10 in 96% yield

(Scheme 1.2).7

O O

O OEt O OEt PCy (1 mol%) OEt 3 OEt MeO MeO O O 1.8 1.9 1.10 96%

Scheme 1.2: Rauhut-Currier reaction of activated esters

The first cross-coupling of ethyl acrylate (1.11) and acrylonitrile (1.12) was reported by McClure in 1970.8 Cross coupling of the partners was the major product to furnish 1.13 in 48% yield, though dimerization of each partner to afford 1.14 and 1.15 was significant (Scheme 1.3).

O

PBu3 (1 mol%) CN OEt CN O O O CN CN tBuOH, 100 °C OEt OEt OEt 1.11 1.12 1.13, 48% 1.14,22% 1.15, 25%

Scheme 1.3: Rauhut-Currier cross coupling

The scope of the electrophilic partner and organocatalyst have both been expanded by the development of a catalytic reaction utilizing aldehydes. In 1968, Morita

9 and coworkers reported a PCy3-catalyzed process and in 1972 Baylis and Hillman utilized tertiary amines such as DABCO, pyrrocoline, and quinuclidine in catalytic quantities (Scheme 1.4).10 These contributors also extended the activated alkene partner beyond acrylates and acrylonitriles to enones (α,β-unsaturated ketones), enals (α,β-

3

unsaturated aldehydes), phenyl vinyl sulfone, phenyl vinyl sulfonate esters, and vinyl

phosphonates. β-substituted alkenes were resistant to triarylphosphine-catalyzed coupling, though trialkylphosphines were sufficient.

O OH PCy3 (0.6 mol%) EWG EWG H R R Dioxane, 120 °C 1.1 1.16 1.17 70-90%

O O O OH DABCO (cat.) MeO H Me MeO Me 120 °C 1.8 1.18 1.19 82%

Scheme 1.4: Morita and Baylis and Hillman’s seminal results

Both the Rauhut-Currier reaction11 and Morita-Baylis-Hillman12 reaction detail a

novel method for regioselective enolate generation via phosphine catalysis. While substrate scope was expanded to include a variety of activated alkenes, nucleophilic phosphine catalysis remained underdeveloped from initial reports in the 1960s until interest surged in the 1990s.

1.2.1 Intramolecular Rauhut-Currier Reaction

The lack of chemoselectivity in the Rauhut-Currier reaction was addressed by the

groups of Krische and Roush in the development of an intramolecular process in which

activated alkene partners are tethered. Krische and coworkers detailed that symmetrical

bis(enones) cyclize smoothly to afford cyclopentene 1.21 in 86% and cyclohexene 1.22 in

13 82% yield upon exposure to catalytic PBu3 at 10 mol% loading (Scheme 1.5).

Incorporation of a heteroatom was tolerated in the formations of tetrahydropyran 1.23 and N-tosylpiperidine 1.24 in yields of 95% and 90% respectively. In the absence of

4

electronic factors, it was found that cycloisomerism is controlled by steric factors.

Chemoselectivity can be controlled via the introduction of a geminal dimethyl residue as cycloisomerization is initiated at the distal α,β-unsaturation in the formation of

cyclopentenes 1.25 and 1.26.

Electronic differentiation of reacting partners was investigated by the preparation

of unsymmetrical substrates. The comparatively more electron deficient p-nitrophenyl

enone initiates cycloisomerism in a completely chemoselective fashion over the p- methoxyphenyl enone in the formation of cyclohexene 1.27 in 75% yield. Additionally, the more electrophilic enone is found to chemoselectively initiate cycloisomerism in the presence of an enoate in the formation of adduct 1.28. Lastly, a xylose-derived enone- enoate substrate was prepared and subjected to catalytic PBu3 (20 mol%). In this final example, pentasubstituted cyclohexene 1.29 is obtained in 81% yield as a single diastereomer. Reaction media included EtOAc, acetone, and tBuOH. Several reactions

required heated to proceed to completion.

5

O

O R2 O O R2 PBu3 (10 mol%) R1 R1 n n 1.20 1.21-1.29

O O O

O Ph O Ph O R2

Ph Ph R1 n X

1.21, n = 1, 86% 1.23, X = O, 95% 1.25, R1 = Ph, R2 = Ph, 85% 1.22, n = 2, 82% 1.24, X = NTs, 90% 1.26, R1 = Me, R2 = Ph, 81%

O O O

O O OEt O Me OBn OMe Me Me

O2N OBn OBn 1.27, 75% 1.28, 87% 1.29, 81% >20:1 dr (PBu3 20 mol%)

Scheme 1.5: PBu3-catalyzed intramolecular Rauhut-Currier cycloisomerism

An additional group of experiments performed by Krische and colleagues continued to probe the effect of electronic differentiation on chemoselectivity. Mixed aromatic-aliphatic mixed bis(enone) 1.30 were subjected to catalytic PBu3 (Scheme 1.6).

In the case of five-membered ring formation, cyclopentenes 1.31 and 1.32 were obtained as a 1:1 mixture of isomers. In the six-membered ring formation, cyclohexenes 1.31 and

1.32 were obtained as a 7:1 mixture of regioisomers with reaction initiating at the aromatic enone. This indicates that initial addition of PBu3 in indiscriminate. For cyclopentene formation, the kinetic phosphine adducts are rapidly trapped via cyclization.

Regarding cyclohexene formation, a reduction in rate allows for equilibration of phosphine adducts, thus making the cyclization both the chemo- and rate-determining step.

6

O O O Me O O Me O Ph PBu3 (10 mol%) Ph Ph Me n n n 1.30 1.31 1.32

n = 1, 79%, 1:1 (1.31:1.32) n = 2, 77%, 7:1 (1.31:1.32)

Scheme 1.6: PBu3-catalyzed reaction showing reversibility of phosphine addition

In 2004, Krische and Luis reported the chemoselective PBu3-catalyzed cyclization

of enones and α,β-unsaturated thioesters (thioenoates) onto vinyl sulfones (Scheme

1.7).2b Both five and six-membered rings are formed in excellent yield with cyclization initiating at the more electrophilic enone or thioenoate partner.

SO2(p-NO2Ph) O SO2(p-NO2Ph) O PBu3 (10 mol%) R R n n 1.33 1.34-1.40

SO2Ar SO2Ar SO2Ar SO2Ar O O O O

EtS EtS Ph Me n NTs n n 1.34, n = 1, 90% 1.36, 76% 1.37, n = 1, 97% 1.39, n = 1, 84% 1.35, n = 2, 86% (PBu3 20 mol%) 1.38, n = 2, 74% 1.40, n = 2, 80% (PBu3 20 mol%)

Scheme 1.7: PBu3-catalyzed cycloisomerization of vinyl sulfones

Roush and colleagues further explored this field in the expansion of the substrate

scope.14 Interestingly, Roush and coworkers found that traditional Morita-Baylis-Hillman

catalysts such as DABCO, DBU, DMAP, and Et2NH were unable to facilitate the

intramolecular Rauhut-Currier reaction. PMe3 was found to be superior in identical

reactions comparing PBu3, PCy3, and PPh3. Additionally, Roush noted that

7

cycloisomerization proceeds well in MeCN but is best in tAmOH under fairly dilute conditions (0.01 M). This corroborates previous work reporting rate enhancements of related nucleophilic organocatalytic reactions in this protic media.15

It was found that enals initiate five- and six-member ring formation when coupled with both enone and enoate partners in the formation of cyclic adducts 1.41-1.44 in good to excellent yield (Scheme 1.8). Quaternary stereocenters can be accessed by this method in the formation of cyclopentene 1.45 in 51% yield. Lastly, a bis(enal) is found to be a suitable substrate in the diastereoselective PBu3-catalyzed cycloisomerization to cyclopentene 1.46 in 90% yield. Significant optimization was performed in this report including frequent adjustments of phosphine catalyst loading.

O

O R2 O O R2 PMe3 R1 R1 t AmOH n n 1.20 1.41-1.46

O O O O O Me O OMe O Me O H OMe OTBS H H Me H n n OTBS 1.41, n = 1, 79% 1.43, n = 1, 90% 1.45, 51% 1.46, 90% 1.42, n = 2, 55% 1.44, n = 2, 67% 10:1 dr (PBu3 30 mol%)

Scheme 1.8: PMe3-promoted intramolecular Rauhut-Currier cycloisomerism

In the optimization of the intramolecular Rauhut-Currier reaction, an aldol/dehydration product was frequently observed in the approach toward six-membered rings. This unexpected reactivity was further probed and developed into a novel method for the construction of dienones by Roush and Thalji.16 Extended reaction times for six- membered ring formation and basic reaction conditions were found to promote the

8

enolization of cycloisomerism product 1.48 and regioselective condensation onto the

tethered ketone to afford cross-conjugated dienone 1.49 (Scheme 1.9).

O O Me

O Me PBu3 (100 mol%) O Me

Me CF3CH2OH, 60 °C Me O

1.47 1.48 1.49 80%

Scheme 1.9: PBu3-mediated cross-conjugated dienone synthesis

1.2.2 Synthetic Applications of the Intramolecular Rauhut-Currier Reaction

The newly developed trialkylphosphine-catalyzed intramolecular Rauhut-Currier

cycloisomerization has been utilized as a key step in three total synthesis applications.

Krische and Agapiou first explored the scope of the α,β-unsaturated partners in the

aforementioned reaction. It was found that with thioenoate-enone and thioenoate-enoate

systems, the thioenoates moiety would preferentially initiate the cyclization.17 This new

method was then utilized in the racemic total synthesis of the furanosesquiterpene lactone

ricciocarpin A. Cycloisomerization of thioenoate-enone 1.50 proceeded at 20 mol%

t loading of PBu3 in BuOH at 135 ˚C in a sealed tube to afford cyclohexene 1.51 in 81%

yield (Scheme 1.10). Cycloisomerization adduct 1.51 was then efficiently converted to

ricciocarpin A (1.52) in three subsequent steps.

O O O SEt SEt H O PBu3 (20 mol%) O 3 steps O

t BuOH, 135 °C H sealed tube O O O 1.50 1.51 1.52 81%

Scheme 1.10: Approach towards ricciocarpin A

9

Roush and coworkers reported a transannular Rauhut-Currier cyclization as a key

step in the synthesis of (-)-spinosyn A. Treatment of adduct 1.53 with an 8-fold excess of

t PMe3 in BuOH at room temperature allowed for cyclization to tricycle 1.54 in 93% yield

observed as a single diastereomer (Scheme 1.11).18 This tricycle was then converted to

(-)-spinosyn A (1.55) in 7 steps. Roush and Methot have also detailed a second PMe3- promoted Rauhut-Currier cyclization utilized in an approach toward antimitotic agent

FR182877.19

OMe OMe Me OMe Me OMe OPMB OPMB O Me O Me OMe PMe (800 mol%) OMe H 3 H O H H O H H O O tAmOH O O O O H H H H H Br Me Br Me 1.53 93% 1.54 20:1 dr

NMe OMe 2 Me OMe O O Me H 7 steps O Me OMe H O H H O O O H H H Me

1.55

Scheme 1.11: Approach towards (-)-spinosyn A

1.3 MODERN MORITA-BAYLIS-HILLMAN APPLICATIONS

1.3.1 Intermolecular Phosphine-Catalyzed Morita-Baylis-Hillman Reaction

Applications of the phosphine-catalyzed Morita-Baylis-Hillman (MBH) reaction

have remained limited due to a variety of challenges. Low conversion rate, substrate

10

dependant chemical yields, and the ease of catalyst air-oxidation have slowed the

development of this promising transformation. Kinetic studies conducted by Bode and

Kaye have revealed that the rate-determining step is most often the bimolecular coupling

of the zwitterionic phosphonium intermediate and aldehyde.20 Although tertiary amines are cheaper and less toxic that phosphines, phosphines are still preferred due to their

increased reaction rates and chemical yields.

To further enumerate the efficiency of phosphine catalysis, Leahy and Rafel

21 explored the coupling of acrylates and alkyl aldehydes. PBu3 was found superior among phosphines as well as in direct comparison to DABCO in the coupling of ethyl acrylate

(1.8) and propanal (1.56) (Table 1.1, entry 3).

O O OH O Me Me OMe H OMe

1.8 1.56 1.57

Entry Catalyst (10 mol%) Time Yield 1 DABCO 10 days 84%

2PCy3 6 days 20% n 3PBu3 2 days 80% 4PMe3 - -

Table 1.1: Catalyst optimization in MBH reaction

A second contribution by this duo was the discovery that the reaction proceeds at

a much faster rate when performed at 0 ˚C. The coupling of methyl acrylate and acetaldehyde normally requires one week at room temperature to reach completion, though at 0 ˚C, reaction is complete in only eight hours. This unexpected result is explained by considering transient enolates 1.58 and 1.59 obtained upon addition of phosphine to methyl acrylate (1.8) (Scheme 1.12). This equilibrium process would

11

provide different ratios of enolates 1.58 and 1.59 as a function of temperature. Enolates

1.58 and 1.59 would also react with the aldehyde at different rates proportional to their relative concentrations. One would expect enolate 1.58 to have a longer lifetime than zwitterionic enolate 1.59 due to a stabilizing intramolecular O-P interaction, especially at reduced temperatures. The significance of this O-P interaction has been recognized in the addition of phosphites to enones in that the phosphorus bound enolate (oxaphospholene) is isolable by distillation.22

R3P O O O PR3 PR3 OMe OMe OMe

R3P 1.58 1.8 1.59

Scheme 1.12: Enolate conformers of MBH reaction at reduced temperature

Additional modifications have greatly increased the utility and ease of the

phosphine-catalyzed Morita-Baylis-Hillman reaction. Trialkylphosphines are extremely

air-sensitive, pyrophoric materials. Fu and Netherton detailed the preparation of

trialkylphosphine salts via treatment of a trialkylphosphine with HBF4 to function as

practical replacements for sensitive trialkylphosphines.23 The authors then proved that

n catalytic [HP Bu3]BF4, when treated in situ with mild base, provides identical reactivity

n to P Bu3 in the Morita-Baylis-Hillman reaction, disulfide reduction, alcohol acylation,

Staudinger reaction, as well as Heck, Stille, and Suzuki cross couplings.

Several have detailed that sluggish MBH reactions and related phosphine-

catalyzed transformations can be accelerated under high pressure.24 Recyclable polymer

supported phosphine catalysts have also been developed.25 Solvent has been effectively

screened and biphasic26 as well as aqueous27 conditions have been found to increase

12

reaction rate. Ito and colleagues have developed an efficient one-carbon homologation in

which cyclic enones react with an aqueous formaldehyde solution under conditions of

28 PBu3 or PMe2Ph catalysis.

A significant breakthrough came in 1984 when Kawanisi utilized a Lewis acid-

base complex consisting of AlEt3 and PBu3 which dramatically increased reaction

efficiency.29 This co-catalyst system found utility in the total synthesis of the

epoxycyclohexenone natural product, epi-epoxydon.30 This concept of incorporating of a

Lewis acid-base pair has significantly advanced the efficiency of the MBH reaction as

well as development of asymmetric variants.

Shi and Liu have reported the effect of phenol as an additive in traditional MBH

31 reactions. They disclosed that PPh3 was unable to catalyze the coupling of methyl vinyl

ketone with benzaldehyde in THF. Other phosphines including PMePh2, PMe2Ph, PBu3, and PMe3 also failed to provide the corresponding MBH adducts in appreciable yield or high purity. At this juncture, various phenols were screened as catalytic additives in hopes that a weak Brønsted acid would accelerate the reaction and p-nitrophenol was found to be optimum. Methyl vinyl ketone (1.60) and benzaldehyde could now be coupled to afford adduct 1.62 in 52% yield (Scheme 1.13). Electron deficient aryl aldehydes worked best in the transformation with p-nitro adduct 1.63, o-nitro adduct

1.64, p-chloro adduct 1.66, o,p-dichloro adduct 1.67, and m-fluoro adduct 1.68 all

obtained in excess of 90% isolated yield. Notably, electron rich p-methoxy adduct 1.65 was furnished in only 35% yield. Yamada and Ikegami have disclosed a similar result in

32 reactions co-catalyzed by PBu3 and (±)-BINOL.

13

O O OH O PPh3 (20 mol%) Me H Me p-nitrophenol (30 mol%) R THF or DMSO R 1.60 1.61 1.62-1.69

OH O OH O NO2 OH O OH O Me Me Me Me

O2N MeO

1.62, 52% 1.63, 98% 1.64, 98% 1.65, 35%

OH O Cl OH O OH O OH O F N Me Me Me Me

Cl Cl

1.66, 92% 1.67, 95% 1.68, 93% 1.69, 80%

Scheme 1.13: Phosphine and Brønsted acid co-catalyzed MBH reaction

Mechanistically, it is proposed that upon 1,4-addition of PPh3 to methyl vinyl ketone (1.60), the oxygen anion of zwitterionic adduct 1.70 can accept a proton from the

Brønsted acid co-catalyst (Scheme 1.14). This nucleophilic intermediate then undergoes

carbonyl addition to aldehyde 1.16 to afford zwitterionic 1.71. The Brønsted acid can now donate a proton to the newly formed alkoxide increasing the stability of this intermediate by preventing retro-addition. This is followed by loss of both PPh3 and the

Brønsted acid to furnish MBH product 1.72. One could next envision the catalytic use of

chiral alcohols in the development of a catalytic, asymmetric MBH reaction.

14

OH O O

R Me Me

1.72 1.60 B-H, PPh3

B-H H-B O O O

R Me Me

Ph3P Ph3P 1.71 1.70

O

H R 1.16

Scheme 1.14: Proposed catalytic cycle for the co-catalyzed MBH reaction

1.3.2 Intramolecular Phosphine-Catalyzed Morita-Baylis-Hillman Reaction

The first phosphine-catalyzed intramolecular variant of the MBH reaction was

33 reported by Fráter and colleagues in 1992. These researches found PBu3 to be the optimum catalyst for the cyclization of enoate-ketone 1.73 to cyclopentenol 1.74 in an isolated 39% yield (Scheme 1.15).

O O Me OH PnBu (25 mol%) Me O 3 EtO EtO neat

1.73 1.74 39%

Scheme 1.15: First intramolecular PBu3-catalyzed MBH reaction

Murphy and coworkers further investigated the intramolecular reaction and reported the traditional MBH cyclization of enones onto aldehydes to form five- and six-

34 membered rings when subjected to PBu3 catalysis (Scheme 1.16). As expected, the

15

more electrophilic enones cyclized in better overall yields in comparison to enoates.

Notably, six-membered ring formation occurred in higher chemical yield than did five- membered rings.

O O OH PBu (20 mol%) O 3 R R CHCl3 n n 1.75 1.76-1.79

O OH O OH

Ph EtO n n

1.76, n = 1, 57% 1.78, n = 1, trace 1.77, n = 2, 75% 1.79, n = 2, 50%

Scheme 1.16: PBu3-catalyzed intramolecular MBH reaction

Keck and Welch were able to further extend the scope of the intramolecular phosphine-catalyzed MBH reaction with the implementation of thioenoate substrates

35 (Scheme 1.17). With PMe3 loading as low as 10 mol%, cyclopentenol 1.81 as well as

gem-dimethyl cyclopentenols 1.83 and 1.84 can be obtained in yields in excess of 80%. It

was found that increased phosphine loadings led to a large decrease in yield and

halogenated solvent was essential for reaction. Interestingly, in contrast to the

intramolecular Rauhut-Currier cycloisomerizations developed by Krische13 and Roush14, the use of tAmOH as solvent led to the rapid formation of a number of unidentifiable

materials, none of which were the desired MBH adduct.

16

O O OH PMe (10 mol%) O 3 EtX EtX DCM n n 1.80 1.81-1.85

O OH O OH O OH O OH

EtX EtS EtS EtS

1.81, X = S, 82% 1.83, 83% 1.84, 80% 1.85, 75% 1.82, X = O, 33% (PMe3 25 mol%)

Scheme 1.17: PMe3-catalyzed intramolecular MBH reactions of thioenoates

In 2004, Koo and coworkers reported a facile phosphine-catalyzed intramolecular

MBH reaction.36 Delicate cyclization substrates 1.75 were accessed in a new method via

Pb(OAc)4 mediated oxidative cleavage of 1,2-diols 1.86 (Scheme 1.18). Optimized MBH cyclization was found to proceed with stoichiometric PPh3 in polar solvents such as

MeCN and tBuOH at a concentration of 0.1 M. Contrary to previous results, high dilution was not mandatory for these reactions. Enals and enones underwent smooth cyclization to afford cyclopentenols 1.76, 1.87, 1.89, and 1.90 and cyclohexenol 1.88 in excellent yield.

The cyclization of the less electrophilic enoates nor thioenoates were detailed in this report. Cyclization substrates underwent decomposition when PMe3 was employed as promoter.

17

R OH O O OH Pb(OAc)4 PPh (100 mol%) OH O 3 R R MeCN or tAmOH n n n 1.86 62-97% 1.75 1.87-1.90

O OH O OH O OH O OH

H Ph Me Bu n

1.87, n = 1, 98% 1.76, 99% 1.89, 83% 1.90, 83% 1.88, n = 2, 73%

Scheme 1.18: PPh3-promoted intramolecular MBH cyclization

Lastly, Toy and colleagues recently reported a study indicating that alkene

geometry of the α,β-unsaturated acceptor had a dramatic influence in the intramolecular

MBH cyclization.37 In previous studies, the α,β-unsaturated substrates were prepared via

Wittig olefination leading exclusively to E-olefins. Upon the release of Koo’s Pb(OAc)4 mediated oxidative protocol to afford enone-aldehyde substrates, both alkene isomers could now be accessed. Accordingly, the PPh3-mediated cyclization of E- and Z-enones

1.91 and 1.92 to afford cyclopentenols 1.93 was examined (Table 1.2). As evidenced in cross comparison experiments, Z-alkenes consistently outperformed their E- counterparts in terms of chemical yield under identical reaction conditions. This result is attributed to the lack of steric interactions associated with phosphine addition to the Z-enone.

18

O O O OH PPh3 (100 mol%) R R R t O O MeCN or AmOH 1.91 1.92 1.93

Entry Geometry R Time Yield 1 Z Et 60 h 72% 2 E Et 60 h 12% 3 Z Ph 32 h 69% 4 E Ph 32 h 8% 5 Z Bu 24 h 69% 6 E Bu 24 h 13%

Table 1.2: PPh3-promoted intramolecular MBH cyclizations examining the effect of alkene geometry

1.3.3 Asymmetric Morita-Baylis-Hillman Reaction

In 1992, Fráter and coworkers documented the first asymmetric intramolecular

MBH reaction38 utilizing P-chiral phosphine catalyst, (-)-CAMP (1.94), in the cyclization

of enoate-ketone 1.73 to cyclopentenol 1.74 in 40% yield and 14% ee (Scheme 1.19).33 In this example though, the (-)-CAMP (1.94) catalyst was only reported to be 66% optically pure.

P Me Ph

OMe O O Me OH 1.94 (18 mol%) Me O EtO EtO

1.73 1.74 40%, 14% ee

Scheme 1.19: First phosphine-catalyzed asymmetric intramolecular MBH reaction

Recognizing the daunting challenge of preparing optically pure P-chiral

phosphines, Soai disclosed the first asymmetric intermolecular MBH reaction in 1998.

Here, the reliable chirality of the bisphosphine substituted binaphthyl system is utilized in

19

the coupling of methyl acrylate (1.8) and pyrimidine carboxaldehydes 1.95 catalyzed by

20 mol% of (S)-BINAP (1.96) (Scheme 1.20).39 Yields of adducts 1.97 ranged from 8-

26% with ee ranging from 9-44%.

PPh2 PPh2

O O OH O 1.96, (20 mol%) OMe N H N OMe CHCl3, 20 °C R N R N

1.8 1.95 1.97 8-26% 9-44% ee

Scheme 1.20: First phosphine-catalyzed asymmetric intermolecular MBH reaction

Zhang and coworkers detailed the preparation and utilization of chiral dialkylmonoarylphosphines 1.100-1.102 derived from D-mannitol in the asymmetric intermolecular MBH reaction (Scheme 1.21).40 These catalysts all afforded less than 20% ee in the MBH coupling of ethyl acrylate (1.11) with pyridine 4-carboxaldehyde (1.98).

O O OH O Catalyst (20 mol%) OEt H OEt N N

1.11 1.98 1.99

Me Me Me HO BnO O P Ph P Ph Ph B P Ph HO BnO O Me Me Me 1.100 1.101 1.102 83%, 17% ee 29%, 19% ee 56%, 18% ee

Scheme 1.21: Asymmetric intermolecular MBH reaction

20

In their 2000 publication, Ikegami and Yamada reported racemic BINOL and

PBu3 co-catalyze the MBH coupling of cyclopentenone and various aldehydes at

increased reaction rates.32 This report detailed one experiment in which (R)-BINOL was

i treated with Ca(O Pr)2 to afford a chiral calcium alkoxide complex which in conjunction

with PBu3 afforded the desired MBH adduct in 62% yield with 56% ee. Schaus and

McDougal further developed this concept in 2003 when they employed disubstituted

BINOL 1.104 at 10 mol% in conjunction with PEt3 (10 mol%) to afford excellent

enantioselection in the asymmetric MBH reaction of cyclohexenone (1.103) with both

aliphatic and aromatic aldehydes 1.16 (Scheme 1.22).41 This report is the first in which appreciable levels of asymmetric induction are observed over a variety of substrates.

R

OH OH

R O O OH O 1.104, R = 3,5-Me2Ph R H (10 mol%) R

PEt3 (10 mol%) 1.103 1.16 THF, -10 °C 1.105-1.110

OH O OH O OH O

Ph BnO

1.105 1.106 1.107 88%, 90% ee 74%, 82% ee 71%, 96% ee

OH O OH O OH O O Ph O 1.108 1.109 1.110 40%, 67% ee 70%, 92% ee 39%, 95% ee (20 mol% 1.104)

Scheme 1.22: Substituted BINOL and PEt3 co-catalyzed intermolecular MBH reaction

21

This methodology has been utilized as a key step in the efficient construction of the decalin core of the clerodane diterpene natural products.42 In the presence of catalytic

disubstituted BINOL 1.104 and superstoichiometric PEt3, cyclohexanone (1.103) and

aldehyde 1.111 bearing an allylic silane were coupled in 96% yield and 93% ee to furnish

MBH adduct 1.112 (Scheme 1.23). Allyl silane 1.112 then underwent a Lewis-acid

promoted diastereoselective annulation to access trans-decalin 1.113 in excellent yield.

O O O OH 1.104 (10 mol%) H Si(iPr) PEt3 (200 mol%) Si(iPr) 3 THF, -10 °C 3

1.103 1.111 1.112 96%, 93% ee

O OH . BF3 OEt2 H

DCM, -78 °C to -10 °C H

1.113 85%,98% ee

Scheme 1.23: Asymmetric MBH reaction in synthesis of clerodanes

In 2005, Sasai and coworkers detailed an enantioselective MBH protocol using a boron-lithium-mono(bisnaphthoxide) heterobimetallic complex with catalytic PBu3, again utilizing the chirality of the binaphthyl framework.43 Lastly, a group headed by

Carretero readdressed the challenge of phosphine synthesis in the use of air-stable

ferrocenyldialkylphosphines as effective catalysts for the coupling of acrylates with

aliphatic and aromatic aldehydes in excellent yield, yet moderate enantioselection (up to

65% ee).44

22

1.3.4. Aza-Morita-Baylis-Hillman Reaction

In 1989, Kahn and Bertenshaw reported a novel PPh3-catalyzed MBH reaction in which acrylates 1.114 and aldehydes 1.115 were coupled in the presence of a sulfonamide or carbamate 1.116 (Scheme 1.24).45 Obtained were β-amino acrylates

1.117, valuable precursors to β-amino acids, produced via initial imine formation

between aldehyde 1.115 and sulfonamide or carbamate 1.116. This newly generated

electrophile then underwent addition by the phosphine activated acrylate to afford β- amino acrylate 1.117.

R O O 3 NH O PPh3 OR1 R2 H H2NR3 R2 OR1 iPrOH, 40 °C 1.114 1.115 1.116 1.117 50-98%

Scheme 1.24: Phosphine-catalyzed aza-MBH reaction

Following this report, Shi and colleagues performed extensive studies on the

development of the phosphine-catalyzed aza-MBH reaction.46 They have found aryl N-

tosyl imines to be some of the most highly reactive imine coupling partners.47 To summarize their results, cyclopentenone (1.118) and methyl vinyl ketone (1.60) react with a variety of electronically differentiated aryl N-tosyl imines 1.119 to afford adducts

1.120 and 1.121 in excellent yield (Scheme 1.25). When cyclohexenone (1.103) is utilized, a mixture of products is obtained. The desired aza-MBH product 1.122 is obtained in 25-40% yield while bicycle 1.123, as a mixture of diastereomers, is frequently the major product. One can envision the formation of bicycle 1.123 by traditional Mannich reaction followed by sulfonamide conjugate addition.

23

O Ts O NHTs N PBu (20 mol%) 3 Ar Ar THF 1.118 1.119 1.120 70-99%

O O NHTs Ts N PPh3 (20 mol%) Me Me Ar Ar THF 1.60 1.119 1.121 67-92%

O Ts O NHTs O N PBu (20 mol%) 3 Ar Ar Ar THF NTs 1.103 1.119 1.122 1.123 25-40% 35-48%

Scheme 1.25: Phosphine-catalyzed aza-MBH reactions with aryl N-tosyl imines

Often, imine insolubility in traditional organic solvents is a major challenge in the

aza-MBH. Shi and Zhao addressed this challenge in a single-pot aza-MBH protocol

48 involving in situ imine formation promoted by TiCl4. Aryl N-diphenylphosphino imines

can serve as active electrophiles to react with methyl vinyl ketone (1.60) under PPh3 catalysis to afford adduct 1.126 in excellent yield with a variety of aryl functionality

(Scheme 1.26). Shi has also utilized acrylates and acrylonitrile as pronucleophiles in

49 related transformations with PMePh2 and DABCO.

O P O O PPh (10 mol%) Ph NH O O 3 2 TiCl4 (80 mol%) Me Ar H H2N PPh2 Ar Me Et3N, DCM 1.60 1.124 1.125 1.126 51-86%

Scheme 1.26: Single-pot PPh3 and TiCl4 co-catalyzed aza-MBH reaction

24

A final contribution from Shi in this field addresses a lingering challenge in the

substitution pattern of the α,β-unsaturated acceptor. Shi and coworkers have developed

reaction conditions in which β-substituted enals, enones, enoates, and thioenoates 1.127

effectively couple with a number of electronically differentiated aryl N-tosyl imines

50 1.119 under conditions of PMePh2 or PMe2Ph catalysis (Scheme 1.27). Traditionally,

1,4-addition of phosphine nucleophiles requires the use of trialkylphosphines. Coupling

adducts 1.128 can be obtained in good yield as mixtures of E- and Z-stereoisomers.

O O NHTs Ts PPh2Me or PPhMe2 N (20 mol%) R R Ar Ar THF Me Me 1.127 1.119 1.128 42-86%

Scheme 1.27: Phosphine-catalyzed aza-MBH reaction of β-substituted substrates

1.3.5 Asymmetric Aza-Morita-Baylis-Hillman

Shi has been the dominant player in the development of the asymmetric aza-MBH

reaction.51 In observing the success of chiral binaphthyl phosphines and alcohols in the

development towards an asymmetric MBH process, Shi and coworkers utilized a chiral

bifunctional phosphine catalyst for the aza variant.52 Activated alkenes 1.129 are coupled with aryl N-tosyl imines 1.119 catalyzed by bifunctional phosphine catalyst 1.130 to afford aza-MBH adducts 1.131-1.135 in good yield and good ee (Scheme 1.28). Methyl vinyl ketone is the best substrate in this protocol with aza-MBH adducts 1.131 being obtained in 49-85% yield and in 76-94% ee. Acrolein and phenyl acrylate participate in the coupling reaction, though heating in DCM is required to afford products 1.132 and

25

1.133 in good to excellent yield and moderate ee. Cyclic enones are viable substrates in

this reaction, but enantioselection is not well controlled in the formation of

cyclohexenones 1.134 and cyclopentenones 1.135. Shi and Li have developed a more

nucleophilic dimethylphosphino variant of catalyst 1.130 capable of increasing both yield

and enantioselection in the MBH couplings of cyclic enones.53 It is speculated that

bifunctional catalyst 1.130 performs so well because it contains both the alkene activating

Lewis base phosphine functionality and enolate stabilizing Brønsted acidic alcohol

moiety in close proximity within the chiral scaffold.

OH

PPh2 O Ts O NHTs N R 1.130 (10 mol%) R Ar 1 Ar 1

R2 THF or DCM R2 1.129 1.119 1.131-1.135

O NHTs O NHTs O NHTs O NHTs O NHTs

Me Ar H Ar PhO Ar Ar Ar

1.131 1.132 1.133 1.134 1.135 49-85% 63-99% 60-97% 66-90% 70-93% 76-94% ee 49-86% ee 52-77% ee 14-23% ee 30-55% ee

Scheme 1.28: Asymmetric aza-MBH reaction with bifunctional catalyst

Shi and colleagues have also reported the synthesis of second54 and third

generation55 bifunctional catalysts. In the aza-MBH coupling of methyl vinyl ketone

(1.60) and o-chlorophenyl N-tosyl imine (1.136), bisperfluoroalkyl catalyst 1.138

improved the previously reported yield faintly, but ee is significantly increased in the formation of adduct 1.137 (Scheme 1.29). The third generation catalyst 1.139, bearing

multiple phenol linkages, was found to increase enantioselection slightly to 90%.

26

Ts O N O NHTs Catalyst (10 mol%) Me Me THF, -20 or -30 °C Cl Cl 1.60 1.136 1.137

O C F OH 6 13 OH OH HO

PPh2 PPh2 PPh2 HO C6F13

1.130 1.138 1.139 85%, 61% ee 90%, 89% ee 85%, 90% ee

Scheme 1.29: Second and third generation bifunctional aza-MBH catalysts

In similar fashion, Sasai and collaborators have developed phosphine catalyst

1.141 bearing two phenol groups based on the BINOL framework (Scheme 1.30).56 At 10 mol% loading, this catalyst is able to facilitate extremely high yielding and enantioselective MBH reactions of methyl, ethyl, and phenyl vinyl ketone to furnish product 1.142.

PPh2 OH OH O Ts O NHTs N R 1.141 (10 mol%) R Ar Ar tBuOMe, -20 °C 1.140 1.119 1.142

85-100% 82-95% ee

Scheme 1.30: Asymmetric aza-MBH reaction with bisphenol bifunctional catalyst

27

1.4 EXPANSION OF ELECTROPHILIC SCOPE OF PHOSPHINE-CATALYZED TRANSFORMATIONS OF α,β-UNSATURATED ACCEPTORS With clear evidence that phosphines can efficiently render α,β-unsaturated

systems nucleophilic at the α-carbon following conjugate addition, the scope of

electrophilic partners in inter and intramolecular processes has been thoroughly

examined.

1.4.1 Phosphine-Catalyzed α-Allylation

In 2003, Krische and coworkers published a protocol for a tandem intramolecular

cyclization/α-allylation termed cycloallylation.57 This method was part of a continued

effort in expanding the scope of electrophilic partners in phosphine-catalyzed enone

coupling processes. This method takes advantage of the nucleophilic features of the

phosphine-catalyzed Morita-Baylis-Hillman reaction with the electrophilic features of the

palladium-catalyzed Trost-Tsuji allylation58 in one of the first applications of a two-

component catalyst system.

Upon exposure to both an organic nucleophilic catalyst and a transition metal

catalyst, substrates 1.143 bearing both enone and allylic carbonate functionalities were

found to afford products of cycloallylation 1.144-1.152 (Scheme 1.31). Optimized

t reaction conditions were catalytic Pd(PPh3)4 (1 mol%) and PBu3 (100 mol%) in BuOH

with heating at 60 ˚C. Cycloallylation would occur with substoichiometric quantities of

PBu3, but stoichiometric loading worked best. Also note that a Brønsted acidic reaction

medium, tBuOH, was necessary. This methodology was used for the construction of both

five- and six-membered rings. Five-membered ring formation proceeded in significantly

higher chemical yield. Enones bearing aryl, alkyl, heteroaryl, and heteroatom

functionalities were all tolerated. Thioenoates were viable pronucleophiles in this

28

transformation as evidenced by the formation of cyclopentene 1.152 in 73% yield, though enoates were insufficiently electrophilic as cyclopentene 1.151 is observed in only trace quantities.

OCO Me O 2 O Pd(PPh3)4 (1 mol%) R R PBu (100 mol%) 3 n n tBuOH, 60 °C 1.143 1.144-1.152

O O O

n n Me Me 1.144, n = 1, 92% 1.146, n = 1, 76% 1.148, 65% 1.145, n = 2, 64% 1.147, n = 2, 66%

O O O O BzO EtX

1.149, 83% 1.150, 81% 1.151, X = O, <5% 1.152, X =S,73%

Scheme 1.31: PBu3-mediated and Pd-catalyzed enone cycloallylation reaction

From a mechanistic standpoint, C-C bond formation via this cycloallylation

process requires dual activation of a single molecule (Scheme 1.32). In both reversible

processes, PBu3 adds in Michael fashion to the α,β-unsaturated acceptor and Pd(0)

ionizes the allylic carbonate to furnish zwitterionic enolate, Pd π-allyl intermediate 1.153.

The cross-section of the lifetime of these tethered transient intermediates must be long

lived enough to facilitate C-C bond formation to afford adduct 1.154. Decomplexation of the Pd metal from the alkene and base promoted elimination of PBu3 yields

cycloallylated product 1.155 and enters both catalysts back into the cycle.

29

OCO Me O 2 O Pd(PPh3)4 (1 mol%) R R PBu3 (100 mol%)

n n PBu3 PBu 3 1.143 1.155 LnPd0 LnPd0 MeOH

CO2 LnPd0 O LnPdII O H OCO2Me OCO2Me R R

Bu3P n Bu3P n 1.153 1.154

Scheme 1.32: Proposed mechanism for catalytic enone cycloallylation

This cycloallylation methodology will be used in a synthetic application toward

the total synthesis of the alkaloid natural product quinine in the construction of a

functionalized piperidine. In this venture, the substrate scope will be tested to investigate

the effects of the introduction of a heteroatom in the tether.

In 2005, Krafft and coworkers reported the α-alkylation of enones via cyclization

onto allylic halides.59 Allylic alcohols 1.156 were treated with thionyl chloride in pyridine to afford regioisomeric allylic chlorides 1.157 and 1.158 (Scheme 1.33). These

t allylic chlorides, without purification, were subjected to stoichiometric PBu3 in BuOH,

followed by treatment with base in a second step to reestablish the α,β-unsaturation to

yield cycloallylation adducts 1.159-1.164. This method can be used for the construction

of both five- and six-membered rings, though only aryl and alkyl functionality was

examined. In the formation of cycloallylation adducts 1.162-1.164, the newly introduced

allyl fragment can possess terminal substitution with high degrees of E/Z selectivity.

30

R2 R2 OH R2 Cl R2 O O O 1. PBu3 (100 mol%) O t SOCl2, pyr Cl BuOH R1 R1 R1 R1 2. KOH, BnEt3NCl n n n n DCM/H2O 1.156 1.157 1.158 1.159-1.164

O O O

Me Ph Ph n

1.160, 80% 1.1161, 84% 1.144, n = 1, 82% 1.145, n = 2, 75% (PMe3 100 mol%)

Me Me Me

O O O

Me Ph Ph

1.162, 78% 1.163, 74% 1.164, 80% (>10:1 E:Z) (>10:1 E:Z) (>10:1 E:Z) (PMe3 100 mol%)

Scheme 1.33: PBu3-promoted enone intramolecular cycloallylation

Mechanistically, from control experiments, the authors ruled that allylic chlorides

1.157 and 1.158 are not interconverting and most likely the reaction proceeds via both

SN2 and SN2’ mechanisms. However, the possibility of an SN1 mechanism can not be

excluded.

1.4.2 Phosphine-Catalyzed α-Alkylation

Krafft and colleagues have also reported the intramolecular α-alkylation of

enones using saturated alkyl halides.60 This report is the first protocol for C-C bond

forming process onto an sp3 hybridized center in this family of phosphine-catalyzed

transformations. Substrate scope again included aryl and alkyl enones. Alkyl bromides were superior to their respective chlorides and iodides for this transformation. Again, in

31

control experiments, phosphine was not found to displace the primary bromide inferring

that the alkyl halide is indeed the active electrophile. This SN2 enone alkylation was more

61 recently rendered catalytic in PBu3.

During the development of the phosphine-mediated intramolecular enone α- alkylation, Krafft and coworkers isolated an intermediate providing significant mechanistic insight.62 The generally accepted mechanism of the MBH reaction includes a

stabilizing electrostatic interaction between the enolate alkoxide and positively charged

phosphorus center of the zwitterionic intermediate obtained upon 1,4-addition of

phosphine. Trans-phosphonium salt 1.166 was obtained upon treatment of bromo enone

1.155 with one equivalent of PMe3 and its relative stereochemical relationship confirmed by X-ray crystallography (Scheme 1.34). Consideration of chair-like transition structures

1.167 and 1.168 as well as boat-like structures 1.169 and 1.170 leading to trans- phosphonium salt 1.166 all lack any obvious electrostatic interaction between the aforementioned charged oxygen and phosphorus atoms. Additional experiments concluded that salt 1.166 is the kinetically formed product in the transformation. A cis relationship about the cyclopentane would be mandatory to support the postulated O-P electrostatic interaction. Therefore, this evidence strikingly adds a new twist to the mechanism of these intramolecular phosphine-catalyzed processes.

32

O O Br PMe3 (100 mol%) Ph Ph tBuOH Br Me3P 1.165 1.166 98%

O Ph H Br O H Br Ph Br Br Ph H O Ph O H Me P Me P 3 3 Me P H H H Me3P H 3 1.167 1.168 1.169 1.170

Scheme 1.34: Mechanistic implications in the PMe3-promoted α-alkylation

Krafft’s final contribution in this area is the use of epoxides as electrophilic

partners in the intramolecular phosphine-promoted enone cyclization.63 Regiochemistry

of epoxide opening was controlled via substrate design. Regiochemistry was not

controlled in an unbiased system as observed in the formation of adducts 1.174 and 1.175 in roughly equal ratios (Scheme 1.35). Introduction of a methyl group on either carbon atom of the epoxide forced cyclization at the sterically less hindered site. Additionally a gem-dimethyl residue was found to establish the same directing effect.

33

R2 OH O R O O R O 2 2 PMe3 (100 mol%) OH R1 R1 R1 tBuOH 1.171 1.172 1.173

OH Me OH O O O OH R1 R1 R1

1.174 1.175 1.176, R1 = Me, 67% R1 = Me, 65% (1.7:1, 1.174:1.175) 1.177, R1 = Ph, 66% R1 = Ph, 73% (1.7:1, 1.174:1.175)

OH O O O Me OH R1 R1 R1 OH

1.178, R1 = Me, 43% 1.180, R1 = Me, 76% 1.182, R1 = Me, 60% 1.179, R1 = Ph, 92% 1.181, R1 = Ph, 70% 1.183, R1 = Ph, 50%

Scheme 1.35: PMe3-mediated cyclization with tethered epoxide electrophiles

1.4.3 Phosphine-Catalyzed α-Arylation

In 2004, Krische and Koech developed a method for the α-arylation of cyclic

enones and enals.64 They discovered that subjection of cyclic enones or enals to catalytic

PBu3 (20 mol%) and electrophilic BiAr3Cl2 reagents effectively transfer aryl groups to

afford products of α-arylation (Scheme 1.36). This approach distinctly complements the

well developed Pd-catalyzed methods65 for enolate arylation. The phenyl group

undergoes facile transfer in the preparation of adducts 1.185 and 1.186 in favorable yields. Aryl halides can be transferred to afford aryl bromides 1.187 and 1.188 as well as

aryl fluorides 1.189 and 1.190 all in good yield. Notably, aryl bromides 1.187 and 1.188, capable of undergoing Pd(0) C-Br oxidative addition, would be unattainable via standard

Pd-catalyzed arylation protocols. Electron withdrawing (CF3) and electron donating

34

(OMe) meta-substituted aryl groups can both be introduced as well as disubstituted arenes in the formation of adducts 1.195 and 1.196.

O PBu3 (20 mol%) O Ar3BiCl2 (100 mol%) Ar DIPEA (100 mol%) n n DCM:tBuOH (9:1) 1.184 1.185-1.196

Br F O O O

n n n 1.185, n = 1, 70% 1.187, n = 1, 80% 1.189, n = 1, 79% 1.186, n = 2, 93% 1.188, n = 2, 71% 1.190, n = 2, 66%

F O O O

CF3 OMe Me

n n n 1.191, n = 1, 72% 1.193, n = 1, 85% 1.195, n = 1, 89% 1.192, n = 2, 65% 1.194, n = 2, 67% 1.196, n = 2, 75%

Scheme 1.36: PBu3-catalyzed α-arylation of cyclic enones

Mechanistically, one can envision a catalytic cycle incorporating the Lewis base

(PBu3)/Lewis acid (BiAr3Cl2) pair. PBu3 can add in 1,4-fashion to cyclic enone 1.184 to afford zwitterionic enolate 1.197 (Scheme 1.37). This alkoxide can then displace chloride on the electrophilic BiAr3Cl2 reagent to furnish intermediate 1.198. Intramolecular aryl transfer followed by phosphine elimination affords α-arylated enone 1.199 and frees the

PBu3 catalyst.

35

O PBu3 (20 mol%) O Ar3BiCl2 (100 mol%) Ar DIPEA (100 mol%) n n DCM:tBuOH (9:1) 1.184 1.199 PBu3 PBu3 BiAr2Cl HCl

O OBiAr3Cl

Cl n n PBu3 PBu3 1.197 1.198 BiAr3Cl2

Scheme 1.37: Proposed mechanism for PBu3-catalyzed enone α-arylation

This α-arylation methodology has been utilized in the total synthesis of the blockbuster antidepressant GlaxoSmithKline drug (-)-paroxetine (PAXIL).66 The key

step of this synthesis included the α-arylation of nitrogen containing cyclohexenone

1.200 to deliver p-fluorophenyl cyclohexenone 1.201 in 79% yield (Scheme 1.38). This

intermediate was then carried on to (-)-paroxetine (1.202) in eight linear steps.

F O O F O PBu3 (10 mol%) O (p-F-Ph)3BiCl2 8 steps O BnN DIPEA BnN HN DCM:tBuOH (9:1) 1.200 1.201 1.202 79%

Scheme 1.38: PBu3-catalyzed enone α-arylation in (-)-paroxetine total synthesis

1.4.4 Other Phosphine-Catalyzed Transformation of α,β-Unsaturated Compounds

Evans and coworkers first reported a method for phosphonisilylation of α,β-

67 unsaturated compounds in the presence of PPh3 and silylating agents in 1978. Inanaga

36

and colleagues have utilized this method to develop a PCy3-catalyzed Ireland-Claisen

68 rearrangement. It is believed that PCy3 adds in Michael fashion to acrylate 1.203

followed by silylation of the resulting enolate to afford silyl ketene acetal 1.204 (Scheme

1.39). This intermediate can then undergo [3,3] sigmatropic rearrangement to afford silyl

ester 1.205. Exogenous DBU can next facilitate deprotonation and reinstallation of the

unsaturation to afford product 1.206 in good to excellent yield.

O OTES OTES O PCy3 (10 mol%) O O PCy3 O PCy3 HO TESCl, DBU Cl Cl R MeCN R R R 1.203 1.204 1.205 1.206 66-87%

Scheme 1.39: PCy3-catalyzed [3,3] rearrangement of allylic acrylates

Schaus and McDougal reported the phosphine-mediated condensation of 1,4-dien-

ones in 2006.69 In this report, 1,4-dien-3-ones were cleverly used as latent 1,3-dienes in

[4+2] annulation reactions. PEt2Ph adds selectively in Michael fashion to the

unsubstituted terminal alkene of 1.207 to afford 1,3-diene intermediate 1.208 (Scheme

1.40). 1,3-diene 1.208 then undergoes formal cycloaddition with a second molecule of

substrate 1.207 to afford diene 1.209. At this point the basic additive, pyridine,

transforms diene 1.209 to ylide 1.210 via deprotonation. Ylide 1.210 then initiates an

intramolecular olefination to afford [3.2.1] bicycle 1.211 possessing two quaternary

carbon centers in moderate to good yield observed as single diastereomers.

37

O PR3 O PR3 R2 R2

O O PR3 R R PEt2Ph (100 mol%) 1.207 1 pyr 1 R2 O R2 O pyridine, DCM R2 R2 R1 R1 R1 R1 1.207 1.208 1.209 1.210

R2 H R1 R1 R 2 O 1.211 41-76%

Scheme 1.40: PEt2Ph-mediated [4+2] annulation of 1,4-dien-3-ones

Toste and colleagues in 2003 reported the PMe3-catalyzed hydration and

hydroalkoxylation of activated alkenes.70 Acyclic enones, enoates, and nitriles 1.212

could effectively undergo β-hydration or alkoxylation to obtain adducts 1.213-1.218 in

good to excellent yield (Scheme 1.41). In order to rationalize the mechanism,

experiments employing cyclic enones, varying alcoholic additives, and 31P NMR studies

were performed and results suggest that addition of phosphine to methyl vinyl ketone

(1.60) results in zwitterionic adduct 1.219 (Scheme 1.42). This enolate is protonated by the alcoholic media to afford alkoxide-phosphonium ion pair 1.220. The alkoxide ion pair then undergoes conjugate addition to a second equivalent of enone to afford enolate- phosphonium ion pair 1.221 which will then undergo protonation to afford hydroalkylation product 1.222. In 2007, Wang and coworkers reported a PPh3-catalyzed

71 variant of this reaction mitigating the use of the toxic and pyrophoric PMe3.

38

EWG EWG PMe3 (5 mol%)

R1 R2OH R1 OR2 1.212 1.213-1.218

O O O CN OEt Me OMe

Me OR2 H OR2 Me OMe H OMe

1.213, R2 = H, 77% 1.215, R2 = Me, 56% 1.217, 71% 1.218, 79% 1.214, R2 = Me, 85% 1.216, R2 = Ph, 59%

Scheme 1.41: PMe3-catalyzed hydration and hydroalkylation of activated alkenes

O RO H O O O

Me Me RO Me Me 1.60 1.219 1.220 1.60 R3P R3P

:PR3

RO H O O O

Me Me Me

RO RO R3P 1.222 1.221

Scheme 1.42: Proposed mechanism for β-hydration and hydroalkylation

Phosphine-catalyzed reactions of alkynes, allenes, and allenoates are known72, but

will not be covered in this review.

1.5 ALLYLIC SUBSTITUTION OF MORITA-BAYLIS-HILLMAN ADDUCTS

The Morita-Baylis-Hillman reaction allows for the construction of highly functionalized allylic alcohol frameworks, adducts frequently used as intermediates in the synthesis of complex molecules. A number of transformations of the MBH allylic alcohol adducts and resulting allylic acetates have been developed.

39

1.5.1 Tertiary Amine-Promoted Allylic Substitution

DABCO has been frequently utilized in allylic substitution reactions of MBH

acetates. In two step procedures, DABCO can add in SN2’ fashion to MBH acetate 1.223

to afford amine salt 1.224 (Scheme 1.43). A nucleophile can then add in a second SN2’ event to displace DABCO and afford products of allylic substitution 1.225. Alternatively, a nucleophile can add in SN2 fashion displacing DABCO to furnish substitution product

1.226. Nucleophiles including hydride, potassium cyanide, p-toluenesulfonamide, and

73 anilines are found to give product 1.225, indicative of a SN2’ process. Nitrogen

heterocycles such as isatin, phthalimide, benzotriazole, oxindole, uracil, thymine, and

1,2,4-triazole have been examined, though mixtures of substitution at the primary and secondary positions are most often obtained.74 A single report by Drewes and coworkers

describes the formation of allylic substitution product 1.225 which is then isomerized to

1.226 when 2-formyl imidazole is employed as nucleophile.75 Regretfully, these reactions

require superstoichiometric amounts of DABCO. Frequently, the acetic acid generated in

the reaction will render the tertiary amine base inactive via protonation.

O OAc O O Nu O DABCO NuH R1 R2 R1 R2 R1 R2 R1 R2 N Nu OAc N 1.223 1.224 1.225 1.226 SN2' SN2

Scheme 1.43: DABCO-promoted allylic substitution of MBH acetates

Tertiary amines have found recent success in related catalytic transformations of

MBH adducts. DABCO has been used to catalyze the rearrangement of

40

trichloroacetimidate 1.228 obtained from MBH adduct 1.227 to provide products of

allylic amination 1.229 (Scheme 1.44).76 A similar procedure including the DABCO-

catalyzed rearrangement from tosyl carbamates has also been reported.77

CCl3 CCl3 O OH O O NH O HN O Cl3CCN DABCO R1 R2 R1 R2 R1 R2 DBU 1.227 1.228 1.229

Scheme 1.44: DABCO-catalyzed trichloroacetimidate rearrangement

In 2003, Kim and coworkers reported a cinchona alkaloid catalyzed kinetic

resolution via ester hydrolysis of MBH acetates (Scheme 1.45).78 This was presented as an alternative to the asymmetric Morita-Baylis-Hillman reaction. A similar protocol establishes a single-pot nonenzymatic acylative kinetic resolution of MBH adducts.79

DBU first mediates the MBH coupling between methyl acrylate (1.8) and aryl aldehyde

1.233 (Scheme 1.46). Next, 4-N,N-dialkylaminopyridine catalyst 1.235 at 5 mol% loading facilitates enantioselective acylation with isobutyric anhydride to afford enantioenriched MBH adduct 1.236. Tertiary amine catalysts derived from quinidine have found additional success in the asymmetric allylic substitution of MBH carbonates with dimethyl malonate.80

O OAc O OH O OAc (DHQD)2PHAL (20 mol%) MeO Ph MeO Ph MeO Ph NaHCO3, THF/H2O 40-50 °C 1.230 1.231 1.232 42%,84% ee 24%, 53% ee

Scheme 1.45: (DHDQ)2PHAL-catalyzed kinetic resolution

41

N O

N

N HO Ar Ar OMe O O OMe OH O OMe OH O 1.235 (5 mol%) H OMe DBU OMe Ar = 3,5-(CF3)2Ph OMe

i ( PrCO)2O, DCM 1.233 1.8 1.234 -78 °C 1.236 25%, 89% ee

Scheme 1.46: Tertiary amine-catalyzed kinetic resolution of MBH adducts

Basavaiah and colleagues have explored reactions of the allylic halides obtained

from MBH allylic alcohols. With DABCO loading at 200 mol%, allylic bromide 1.237

can serve as electrophile in a MBH-type coupling with acrylonitrile to furnish 1,4-

pentadiene 1.238 in moderate yield in a 7-day reaction (Scheme 1.47).81 The same group

identified alcohols as suitable nucleophiles in substitution reactions. Accordingly,

quinidine, at 200 mol% loading, has found to promote the allylic substitution of MBH

bromide 1.237 by propargyl alcohol to furnish propargylic ether 1.239 in moderate yield

82 and 25-40% ee. In these two examples, regiochemistry is consistent with SN2 displacement at the carbon center bonded to the amine promoter.

O R O Br O O DABCO (200 mol%) quinidine (200 mol%) CN MeO MeO MeO R acrylonitrile propargyl alcohol R DCM 1.238 1.237 1.239 37-67% 25-40%ee

Scheme 1.47: Tertiary amine-promoted reaction of MBH bromides

42

The highly functionalized MBH adduct framework has been utilized in an

increasing number of subsequent chemical manipulations83 too expansive to be covered

in this review. In the examples utilizing tertiary amines, reactions are rarely catalytic.

Additionally, regioselectivity of allylic substitution following amine conjugate addition

(SN2 versus SN2’) is not easily controlled and frequently varies according to substrate. In cross comparison, phosphines prove to be superior promoters in the allylic substitution reactions of MBH adducts. Phosphines are less basic and more nucleophilic than their corresponding tertiary amines. Several regiocontrolled protocols have been developed that are catalytic in phosphine.

1.5.2 Phosphine-Catalyzed Allylic Substitution

In 2004, Krische and coworkers reported the first phosphine-catalyzed allylic amination of MBH acetates.84 In this protocol, the MBH acetate undergoes regioselective

allylic substitution upon treatment with catalytic PPh3 (20 mol%) and 4,5-

dichlorophthalimide or phthalimide via a tandem SN2’-SN2’ mechanism.

Enones and enoates both participate in this phosphine-catalyzed process (Scheme

1.48). In all examples, 4,5-dichlorophthalimide provides a better yield of allylic substitution product. Both alkyl and aryl substituents are tolerated at the carbon center undergoing substitution. The use of phthalimide as pronucleophile provided allylic amination products 1.240, 1.244, and 1.250 in low yield (8-20%). Notably, the reactions utilizing the allylic acetate derived from the methyl vinyl ketone MBH adduct were less

sensitive to the nature of the pronucleophile, and afforded the desired allylic amination

products in excellent yield (86-95%).

43

X X

O O O OAc PPh3 (20 mol%) O N

R1 R2 4,5-dichlorophthalimide (200 mol%) R1 R2 or phthalimide (200 mol%), THF 1.223 1.240-1.251

X X X X X X

O O O O O O O N O N O N

MeO MeO MeO Me

NO2

1.240, X = H, 8% 1.242, X = H, 76% 1.244, X = H, 15% 1.241, X = Cl, 90% 1.243, X = Cl, 95% 1.245, X = Cl, 73%

X X X X X X

O O O O O O O N O N O N

Me Me Me Me

NO2 1.246, X = H, 91% 1.248, X = H, 92% 1.250, X = H, 20% 1.247, X = Cl, 92% 1.249, X = Cl, 95% 1.251, X = Cl, 86%

Scheme 1.48: PPh3-catalyzed allylic amination of MBH acetates

Cyclic MBH acetates also participate in this regioretentive allylic substitution reaction. The more nucleophilic PBu3 is required for the allylic amination of enoate 1.252 and thioenoate 1.253, though allylic substitution products 1.254 and 1.255 are obtained in good yield (Scheme 1.49).

OAc O Nu O PBu3 (20 mol%) XEt XEt 4,5-dichlorophthalimide (200 mol%) THF 1.252, X = O 1.254, X = O, 86% 1.253, X = S 1.255, X = S, 71%

Scheme 1.49: PBu3-catalyzed allylic substitution of cyclic MBH acetates

44

In performing a detailed survey of leaving group and pronucleophile combinations, a distinct dependence on the difference in pKa between the pronucleophile

and conjugate acid of the leaving group was observed. This led to the hypothesis of a mechanism relying on the generation of an electrophile-nucleophile ion pair.

Mechanistically, 1,4-addition of phosphine to activated alkene 1.256 would displace

acetate to generate electrophile-leaving group ion pair 1.257 (Scheme 1.50). Acetate

anion could then deprotonate the phthalimide pronucleophile and the resulting stabilized

nitrogen anion would attract the phosphonium adduct to form electrophile-nucleophile

ion pair 1.258. This nucleophile would then add to the substrate in a second SN2’ reaction

to reestablish the α,β-unsaturation and displace the phosphine catalyst to afford allylic

amine 1.259. This proposed mechanism is supported by the result that the more acidic

4,5-dichlorophthalimide performs better than phthalimide presumably by a more

favorable acid-base interaction to liberate a larger concentration of the nitrogen anion.

Secondly, one would expect the intimately coordinated electrophile-nucleophile ion pair

1.258 to lead to the observed regioselective amination product versus a direct SN2’

addition of nucleophile to allylic acetate 1.256. Lastly, experiments with cyclic deuterium

labeled substrates corroborated the tandem SN2’- SN2’ mechanism.

45

NuH = 4,5-Dichlorophthalimide (200 mol%) EWG EWG AcO Nu

PR3 (20 mol%) R1 R2 R1 R2 1.256 1.259

Electrophile- EWG EWG Electrophile- Leaving Group PR3 PR3 Nucleophile Ion Pair Ion Pair OAc Nu: R1 R2 R1 R2 1.257 1.258

OAc + Nu-H HOAc + Nu:

Scheme 1.50: Proposed mechanism for phosphine-catalyzed allylic amination

As the phosphine-catalyzed allylic substitution proceeds through a mechanism in

which the pre-existing acetate stereocenter is destroyed and then recreated, it was

speculated that use of a chiral phosphine catalyst would allow for a dynamic kinetic

resolution or deracemization of chiral racemic MBH acetates.85 Accordingly, substitution

of the PPh3 catalyst with (R)-Cl-MeO-BIPHEP provided for the deracemization of allylic

acetate 1.260 to allylic amine 1.246 in 80% yield with a 56% ee lending feasibility to this assertion (Scheme 1.51).

O O O OAc (R)-Cl-MeO-BIPHEP (20 mol%) O N

Me phthalimide (200 mol%), THF Me

NO2 NO2 1.260 1.246 80%, 56% ee

Scheme 1.51: Deracemization of racemic chiral MBH allylic acetate

46

Hou and coworkers have developed a series of planar chiral [2.2]paracyclophane

monophosphines86 which have been utilized in applications of asymmetric

organocatalysis. Monophosphine 1.261 was investigated as an organocatalyst in the

deracemization via allylic substitution of MBH acetate 1.260 with phthalimide and was

found to increase the chemical yield of allylic amine 1.246 to 95% with a 71% ee

(Scheme 1.52).87

PCy2 O O O OAc 1.261 (20 mol%) O N

Me phthalimide (200 mol%), THF Me

NO2 NO2 1.260 1.246 95%, 71% ee

Scheme 1.52: Deracemization of MBH allylic acetate with chiral monophosphine

Krische and colleagues have also developed conditions to utilize vinyl

phosphonates as substrates to access β-aminophosphonic acids.88 Vinyl phosphonates

1.262 bearing the allylic acetate functionality underwent regioselective allylic amination upon treatment with catalytic PPh3 and 4,5-dichlorophthalimide in refluxing dioxane to afford allylic amines 1.263-1.268 in good to excellent yield (Scheme 1.53). Notably, to

obtain favorable yield, the carbon center undergoing substitution must bear an aromatic

substituent.

47

Cl Cl

O O O OAc PPh3 (20 - 40 mol%) O N (EtO)2P (EtO)2P R1 4,5-dichlorophthalimide (200 mol%) R1 dioxane, 110 °C 1.262 1.263-1.268

Cl Cl Cl Cl Cl Cl

O O O O O O O N O N O N (EtO) P (EtO) P (EtO) P 2 Ar 2 2 O N 1.263, Ar = Ph, 65% 1.267, 82% 1.268, 67% 1.264, Ar = 4-NO2Ph, 90% 1.265, Ar = 4-CO2MePh, 89% 1.266, Ar = 3-BrPh, 75%

Scheme 1.53: PPh3-catalyzed allylic substitution of vinyl phosphonates

This methodology was further extended to carbon nucleophiles in 2005 by

Krische and Cho.89 By utilizing 2-trimethylsiloxy furan as nucleophile, MBH acetates

1.223 could undergo regioselective allylic substitution to provide γ-butenolides 1.269-

1.276 in good to excellent yields observed as single diastereomers (Scheme 1.54). The observed diastereoselectivity does not appear consistent with reaction through open transition state 1.283. Therefore, it is thought that the phosphine adduct and siloxy furan

“ate” complex undergo endo-selective Diels-Alder cycloaddition 1.284 followed by

Grob-type fragmentation to afford γ-butenolide 1.285 (Scheme 1.55). Absolute stereochemistry could also be controlled in this transformation when the (-)-8- phenylmenthol ester was substituted for the methyl ester to obtain the γ-butenolide in a

>98:2 ratio of diastereomers.

48

O O

O O O OAc O O H H O OTMS (200 mol%) R1 R2 R1 R2 R1 PPh3 (20 mol%) THF R2 1.223 1.269-1.276 1.277-1.281

O O O O

O O O O O H O H O H O H H H H H Me Me Me Me Me Me Me NO2 1.269, 88%, >95:5 dr 1.270, 63%, >95:5 dr 1.271, 45%, >95:5 dr 1.272, 80%, 95:5 dr 1.277, 9% 1.278, 7% 1.279, 10% 1.280, 5%

O O O O

O O O O O H O H O H O H H H H H MeO MeO Me MeO Me MeO Me NO2 1.273, 84%, >95:5 dr 1.274, 67%, >95:5 dr 1.275, 62%, >95:5 dr 1.276, 83%, 3.5:1 dr 1.281, 6%

Scheme 1.54: PPh3-catalyzed allylic substitution to afford γ-butenolides

O PPh3 addition via open R1 transition state H R2 O O O O OAc O PPh3 O O OTMS LnSiO H H 1.283 R1 R2 (200 mol%) R1 R1 R2

PPh3 (20 mo%) R2 O OSiLn 1.223 1.282 1.285 R2 PPh3 endo-Diels-Alder R O [4+2] cycloaddition 1 1.284

Scheme 1.55: Proposed mechanism for PPh3-catalyzed γ-butenolide formation

Hou and colleagues have detailed the feasibility of an asymmetric variant of this

reaction.87 Accordingly, the allylic substitution of allylic acetate 1.286 by 2-

49

trimethylsiloxy furan with monophosphine 1.261 at 20 mol% loading results in the

formation of γ-butenolide 1.287 in 85% yield, observed as a single diastereomer in 36%

ee (Scheme 1.56).

O PCy2 O O OAc 1.261 (20 mol%) O H H MeO MeO

O OTMS (200 mol%) 1.286 THF 1.287

85%, >95:5 dr 36% ee

Scheme 1.56: Phosphine-catalyzed asymmetric γ-butenolide formation

PBu3 has been used in conjunction with TiCl4 as a Lewis acid-base pair to afford

90 chlorinated MBH adducts. It is thought that PBu3 first attacks the Ti metal center

displacing a chloride anion at -78 ˚C in DCM which initiates the MBH reaction to obtain

β-chloride 1.289 in 80% yield (Scheme 1.57). If the reaction is warmed to room temperature, subsequent alcohol elimination affords haloenone 1.290. Control experiments indicate that PBu3 is not required for the elimination step, and that the

elimination most likely proceeds through the intermediacy of 1.289. Similar results were

obtained when catalytic PBu3 was employed with BCl3 or ZrCl4.

O O O OH O PBu3 (5 mol%) Me H Me Me TiCl4 (200 mol%) NO2 DCM Cl NO2 Cl NO2 1.60 1.288 1.289 1.290 -78 °C rt

Scheme 1.57: PBu3-catalyzed and TiCl4-promoted tandem MBH reaction

50

Lu and colleagues have developed a number of annulation reactions in which

MBH frameworks are rapidly elaborated in additional phosphine-catalyzed transformations.91 MBH bromide 1.291 undergoes annulation with N-phenyl maleimide

(1.292) to afford products 1.293 of [3+2] annulation (Scheme 1.58). Additionally, MBH adducts 1.294 with allylic leaving groups (Br, Cl, OAc, OBoc) participate in the analogous reaction with tropone (1.295) to afford the novel [3+6] adduct 1.296. [3+2] annulations with 1,1-dicyanoalkenes are also known.92 Mechanistic studies and product regiochemistry indicate adduct 1.291 most likely undergoes SN2 displacement of leaving group and followed by K2CO3-mediated deprotonation to afford a reactive phosphorus ylide. PBu3 and PPh3 are also known to catalyze the addition of α,β-unsaturated ketones, esters, nitriles, and phosphonates to the α-position of 1,3-dicarbonyl compounds through the intermediacy of phosphorus ylides.93

R O R H O PPh (10 mol%) Br NPh 3 EWG NPh EWG K CO , PhH, Δ O 2 3 H O 1.2911.292 1.293 50-88%

O O

PPh3 (10 mol%) LG EWG K2CO3, PhH, Δ EWG 1.2941.295 1.296 57-92%

Scheme 1.58: PPh3-catalyzed annulations of MBH adducts

51

1.6 SUMMARY AND OUTLOOK

The area of phosphine organocatalysis has significantly advanced since the seminal reports of Rauhut and Currier, Morita, and Baylis and Hillman in the 1960s and early 1970s. The scope of phosphine catalysts has tremendously expanded, including the development of chiral organocatalysts for asymmetric Morita-Baylis-Hillman processes.

The pairing of phosphines (Lewis bases) with Lewis acids or Brønsted acids in co- catalytic systems has dramatically impacted the development of reliable and asymmetric transformations. Selectivity issues have often been addressed by tethering reacting partners in intramolecular processes. These processes have become so efficient that the electrophilic scope has diverged radically from the traditional highly activated α,β- unsaturated and aldehyde acceptors. The outlook is quite promising for the continued development of new methods to rapidly build molecular complexity under the direction of phosphine catalysis.

52

1.7 REFERENCES

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54

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55

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57

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58

Chapter 2 Historical Survey of Quinine

2.1 INTRODUCTION

Quinine (2.1) is an alkaloid natural product isolated from the bark of the Cinchona tree. Structurally, it is a [2.2.2] nitrogen-containing bicycle (quinuclidine) and a quinoline heterocycle tethered by a secondary alcohol functionality (Figure 2.1). Quinine contains two basic nitrogen atoms, one at N-1 and the second within the quinoline. It possesses five stereogenic centers, two of which (N1 and C4) constitute a single asymmetric unit based on their bridgehead location. The remaining stereogenic centers are found at C3 which bears the characteristic vinyl residue, the C8 methine, and C9 which bears the alcohol functionality.

10 11 3 H OMe 2 4 7 5 8 N 6 1 9 OH N 2.1

Figure 2.1: Quinine

Cinchona bark was first recognized around 1600 by Peruvian Indians as an effective antidote for fever treatment.1 The Natives called the cinchona tree “quina- quina”; translated “bark of barks” in the native Indian tongue.2 Jesuit Brother Agostino

Salumbrino observed the natives utilizing the powdered cinchona tree bark for the treatment of shivering, a symptom of malaria. He then sent a small quantity to Rome in

1631. Malaria was endemic to Rome due to the city’s surrounding marshes and swamps.

59 The deaths of several Catholic popes and cardinals were attributed to malaria. Following

the discovery of the bark as an effective malaria treatment, the disease was less feared.

The bark of the cinchona tree was in high demand in Europe and became one of the most

valuable commodities shipped from Peru. Interestingly, cinchona bark was so valued that it was suitable for a distinguished gift to royalty.2

Although malaria is a disease of little concern in America, it remains an extreme

health problem in sub-Saharan Africa where it accounts for 90% of all deaths.3 The

World Health Organization reports that malaria claims 1.5–2.7 million lives annually, mostly children.4 Drug resistant parasites are escalating the medical threat to a level of

potential disaster. Though several antimalarial drugs have been developed, quinine

remains quite important due to its high solubility and resulting intravenous treatment in

severe cases. Common synthetic malaria drugs such as mefloquine (2.2), amodiaquine

(2.3), and lumefantrine (2.4), (Figure 2.2) all possess structural features, specifically the

quinoline and amino alcohol framework, inspired by the quinine scaffold.

HO OH N H Cl OMe N Cl N N Cl H H NH OH F3C OH N N N

CF3 Cl 2.1 2.2 2.3 2.4

Figure 2.2: Malaria drugs based on the quinoline and amino alcohol scaffold

The 4-aminoquinoline framework is accepted to hinder the detoxification of free

heme generated during the degradation of hemoglobin.5 Once inside the host, digested

hemoglobin is released to the cytoplasm of the malaria parasite. At this point in the

60 degradation, the heme moiety undergoes a process termed heme polymerization

converting the heme to the insoluble hemozoin crystal. Heme can also be destroyed in the

cytoplasm of the parasite by a reduced glutathione.6 Convincing data indicates that both

the heme polymerization and glutathione mediated degradation are halted by 4-

aminoquinolines.7 Less evidence exists for the potency of the aryl amino alcohol moiety,

though experiments have shown that quinine (2.1) and mefloquine (2.2) curb the uptake

of hemoglobin from the host cell.8

2.2 STRUCTURAL DETERMINATION Though quinine is not extremely structurally complex, a great challenge to late

19th and early 20th century organic chemists was structural determination. A significant

effort was devoted to the determination of structure and connectivity by methods of

derivitization, degradation, and combustion.9 Following the determination of the

empirical formula of quinine by Strecker10 in 1854, more than 50 years were invested by

several prominent chemists to determine connectivity. Early degradation experiments

concluded that quinine possessed an aromatic moiety, soon identified as the quinoline11, though the alkyl framework proved to be more of a challenge.

In 1853, Pasteur completed a key experiment in which quinotoxine (2.9) was identified from the degradation of quinine (2.1) in slightly acidic media.12 It was from

quinotoxine (2.9) that the presence of a tertiary bridgehead nitrogen on the bicycle was

concluded.13

A second critical discovery document by Königs in 1894 was that quinine (2.1),

cinchonine (2.5), quinidine (2.6), and cinchonidine (2.7) were all degraded to the same compound, meroquinene (2.8) upon exposure to dilute acid (Figure 2.3).14 This pivotal

result provided identity to the unknown portion linked to the quinoline moiety but also

61 proved that the relative configuration at C3 and C4 were identical for these four natural products.

R H H H H R OH OMe

N N HO C N N 2 H H N OH O N N

2.1, R = OMe 2.6, R = OMe 2.8 2.9 2.5, R = H 2.7, R =H

Figure 2.3: Cinchona alkaloids and their key degradation products

In 1908, German chemist Paul Rabe established himself as a major player in the quinine story by suggesting the accurate connectivity of the alkaloid.15 Rabe additionally is credited with reconstructing quinine from degraded quinotoxine (2.9), therefore establishing a strategy for forthcoming synthetic attempts.16 Unfortunately, Rabe’s procedures from his 1918 report were not carefully reviewed or fully substantiated leaving this strategy under constant scrutiny, even into the 21st century.2,17,18

Rabe’s protocol included the bromination of quinotoxine (2.9) with sodium hypobromite to furnish N-bromoquinotoxine (2.10) (Scheme 2.1). The intermediate electrophilic N-bromo compound underwent base-mediated cyclization to give quininone

(2.11). Quininone was then reduced by aluminum powder in ethanol and sodium ethoxide to give quinine (2.1) as one of four possible diastereomers from the sequence. The 1918 report provided only a brief summary of this three-step process and referenced a paper from 1911 concerning the identical transformations in the cinchonidinone series. In 1932

Rabe did publish full experimental details for the reduction sequence.19 In 2008,

Williams and coworkers experimentally substantiated the Rabe protocol finding that trace

Al(III) was necessary was for the reduction of quininone (2.11).18

62 H H OMe OMe NaBrO NaOEt, EtOH N N H Br O O N N 25%

2.9 2.10

H H OMe OMe Al powder N N NaOEt, EtOH O OH N 13% N 2.11 2.1

Scheme 2.1: Rabe protocol for the conversion of quinotoxine to quinine

In 1943, Prelog and Proštenik made a significant discovery in a degradation and reconstruction experiment.20 Prelog was able to degrade quinotoxine (2.9) to homomeroquinene (2.12) via Beckman degradation (Scheme 2.2). Next, homomeroquinene was esterified and underwent Claisen condensation with ethyl quininate to afford β-ketoester (2.13). β-ketoester (2.13) was then saponified and

decarboxylated to refurnish quinotoxine (2.9).

H OMe N H O N

2.9 H H OMe EtO2C N N H H CO H O 2 N

2.13 2.12

Scheme 2.2: Prelog’s degradation and reconstruction of quinotoxine

63 2.3 THE FIRST TOTAL SYNTHESIS OF QUININE

The first total synthesis of quinine came in 1944 by Woodward and Doering.21

Woodward rationalized that a total synthesis of quinine could be achieved by accessing quinotoxine based on the Rabe protocol. Additionally, Prelog’s degradation and reconstruction experiment indicated that quinotoxine (2.9) could be prepared from homomeroquinene (2.12), therefore Woodward needed to develop a synthesis of homomeroquinene (2.12) to constitute a total synthesis of quinine (2.1) (Scheme 2.3).

H H H OMe OMe Rabe (1918) Prelog (1943) N N N H H CO H OH O 2 N N

2.1 2.9 2.12

Scheme 2.3: Woodward’s retrosynthetic approach to quinine

Woodward accessed quinotoxine (2.9) in enantiopure form via resolution.

Quinotoxine (2.9) was obtained from homomeroquinene (2.12). Homomeroquinene

(2.12) was furnished by ester saponification, amide hydrolysis, and Hofman elimination

of amine 2.15 (Scheme 2.4). Amine 2.15 was produced by nitrosation mediated ring

opening of ketone 2.16 establishing the required syn stereochemistry about the piperidine.

Ketone 2.16 was obtained from the hydrogenation of isoquinoline 2.17 followed by

oxidation. Isoquinoline 2.17 came from a Pomerantz-Fritsch reaction of 3-

hydroxybenzaldhyde (2.18) followed by C8 methylation.

64 H2N H

HO C NH EtO C NAc NAc 2 2 O H Me 2.14 2.15 2.16

N HO 8 HO CHO Me 2.17 2.18

Scheme 2.4: Woodward’s synthetic approach to homomeroquinene

Woodward’s reported total synthesis has been the victim of scrutiny more than 50

years after its publication. Though the title of his 1945 article is “The Total Synthesis of

Quinine”, it has often been described as a “formal” total synthesis relying on Rabe’s

three-step conversion of quinotoxine to quinine. Woodward and Doering never reported

completion of this controversial sequence. Many have questioned the validity of their

claim of completing the first “total synthesis” until 2008 when the Rabe protocol was confirmed by Williams.

With that controversy now settled, Woodward’s work constituted one of the first syntheses of a complex, optically active natural product. It came at a time when modern analytical techniques to aid in structural determination were not yet developed and before the birth of the concept of “retrosynthetic analysis”. Woodward’s deep knowledge of

chemistry as well as his great intuition secured him a place in history. With the quinine

22 23 synthesis, as well as the more demanding vitamin B12 and erythromycin A syntheses,

Woodward received the 1965 Nobel Prize for Chemistry for “outstanding achievement in

the art of organic synthesis.”2

65 Woodward’s report of the total synthesis came in the middle of World War II.

Prior to that time, the Dutch had transported cinchona trees from Peru to the tropics and

established a bustling plantation in Java that accounted for over 90% of the world’s supply of quinine. Following the Japanese invasion of the island of Java, the Allied forces were severed from their precious quinine supply and began suffering mass casualties due

to malaria.1,7 When the media heard of Woodward’s total synthesis, it was hailed by the

New York Times “as one of the greatest scientific achievements in a century”.24

2.4 QUININE SYNTHESES FROM HOFFMAN-LA ROCHE

In the 1970s, workers at Hoffman-La Roche under the leadership of Uskoković

developed a program to access a number of important cinchona alkaloids. As Königs degradation experiments of the 1890s indicated, Uskoković focused on meroquinene

(2.8) to serve as a key intermediate to access the quinine framework via a C8 - N1

disconnect (Scheme 2.5). Accordingly, Uskoković and co-workers developed three routes

to meroquinene (2.8) from amine 2.19, two of which were racemic, one enantioselective via optical resolution utilizing d- and l-tartaric acids.25

H OMe O H 8 N 1 HO C 2 H OH NH NBz N 2.1 2.8 2.19

Scheme 2.5: Meroquinene as a key intermediate in the synthesis of quinine

66 2.4.1 Quinine via Benzylic Oxidation

With meroquinene in hand, the group shifted attention to the total synthesis of

quinine and quinidine. They were successful in developing four distinct routes to quinine

though each lacked stereocontrol.26 In Uskoković’s first approach, quinine (2.1) is

obtained as 5:1 ratio of diastereomers at C9 by base-promoted benzylic oxidation of deoxyquinine (2.20) (Scheme 2.6). Stereoselectivity is proposed due to the preferred backside attack of the oxygen radical anion on benzylic radical 2.24 in order to avoid the repulsive interaction with the lone electron pair of the quinuclidine nitrogen (Scheme

2.7). Deoxyquinine (2.20) was accessed via a vinylquinoline cyclization of secondary amine 2.21. Secondary amine 2.21 was the product of ketone and amide reduction followed by alcohol acetylation and dehydration from ketone 2.22. Ketone 2.22 was in turn accessed by the addition of lithiated 6-methoxy-4-methylquinoline to N-benzoyl meroquinene ethyl ester 2.23. In this route, the stereoselective oxidation at C9 establishing the alcohol functionality was discovered, though this series was not stereoselective in the inability to control the olefin geometry of vinylquinoline 2.21.

H H H OMe OMe OMe N N N H 9 OH N N N

2.1 2.20 2.21

OMe H O MeO2C NBz NBz

N 2.22 2.23

Scheme 2.6: Uskoković’s first approach via benzylic oxidation

67 H H H OMe OMe OMe KOtBu, O N 2 N N DMSO/tBuOH H OH (4:1) N N N

2.20 2.24 2.1

Scheme 2.7: Model for stereoselectivity in benzylic oxidation

2.4.2 Quinine via Aminoepoxide Cyclization

The second approach by the team at Hoffman-La Roche introduced the idea of an

aminoepoxide cyclization, an approach that has been repeated in several subsequent

synthetic approaches (Scheme 2.8). N-deprotection of aminoepoxide 2.25 followed by

thermal cyclization afforded quinine (2.1) in addition to three other possible C8 and C9

diastereomers. Aminoepoxide 2.25 was accessed by the carbonyl reduction and spontaneous epoxide cyclization of 2.26 which in turn came from α-bromination of

ketone 2.22.

H H OMe OMe OMe H O N 8 N O Bz 9 NBz OH Br N N N 2.1 2.25 2.26

Scheme 2.8: Uskoković’s second approach via aminoepoxide cyclization

2.4.3 Quinine via Stereoselective Carbonyl Reduction

The third approach developed by Uskoković and colleagues stereoselectively introduced the C9 alcohol functionality by DIBAL reduction of quininone (2.11), though

68 stereocontrol lacked in the construction of the C8 stereogenic center (Scheme 2.9).27

Quininone (2.11) was furnished by a similar aminoepoxide cyclization of chloroepoxide

2.27 in which the intermediate alkoxide displaces the geminal chloride to acquire the carbonyl oxidation level. Chloroepoxide 2.27 was obtained from reduction of dichloroketone 2.28 which stemmed from ketone 2.22.

H H H OMe OMe OMe

8 N N N Bz 9 O OH O Cl N N N

2.1 2.11 2.27

OMe OMe H H O O

Cl NBz NBz Cl N N 2.28 2.22

Scheme 2.9: Uskoković’s third approach via stereoselective carbonyl reduction

2.4.4 Quinine via Lithiated Quinoline Aldehyde Addition The fourth, and final, approach developed the new idea to generate the

quinuclidine prior to the introduction of the quinoline.28 Quinine (2.1) was prepared via

the addition of lithiated 4-bromo-6-methoxyquinoline to aldehyde 2.29 (Scheme 2.10).

Quinuclidine 2.29 was obtained in similar fashion to the third approach through the

intermediacy of chloroepoxide 2.30 and dichloride 2.31. Dichloride 2.31 was prepared by

the addition of LiCHCl2 to N-benzoyl meroquinene aldehyde 2.32.

69 H H H OMe N N N O H OH HO Cl N

2.1 2.29 2.30

H H

HO N O N H Bz H Cl Cl 2.31 2.32

Scheme 2.10: Uskoković’s fourth approach via aldehyde addition

In each case the workers at Hoffman-La Roche cleverly built on the chemistry

they had previously developed. Though they developed four distinct routes to quinine,

none were stereoselective. As a testament to their efforts, many of strategies that they

developed have been utilized in subsequent syntheses.

2.5 QUININE VIA NOVEL OLEFINATION REACTIONS Two approaches reported in the 1970s by Gates and coworkers29 and Taylor and

Martin30 utilized the developed base-promoted hydroxylation to efficiently synthesize

deoxyquinine from meroquinene via novel olefination reactions. Gates reported that

deoxyquinine (2.20) was obtained by the deprotection and cyclization of vinylquinoline

2.33 (Scheme 2.11). Vinyl quinoline 2.33 was produced by Wittig olefination of

quinoline-bearing aldehyde 2.34 by phosphonium salt 2.35. Phosphonium salt 2.35 was

obtained from PPh3 displacement of the primary bromide which is easily accessed from

meroquinene.

70 H H OMe OMe OMe N N Ac CHO PPh3 NAc N N N

2.20 2.33 2.34 2.35

Scheme 2.11: Gates’ olefination route to quinine

Conversely, Taylor utilized the quinoline moiety as the olefinating reagent in its

reaction with meroquinene aldehyde 2.37 (Scheme 2.12). In this example, the olefinating reagent 2.37 is prepared directly from the aryl chloride and methylenetriphenylphosphorane.

H H OMe OMe OMe

N N PPh Ac 3 OHC NAc N N N

2.20 2.33 2.36 2.37

Scheme 2.12: Taylor and Martin’s olefination route to quinine

2.6 THE FIRST STEREOSELECTIVE SYNTHESIS OF QUININE It took more than 50 years after Woodward’s synthesis for the first stereoselective

synthesis of quinine to be completed by Stork and coworkers.31 This stands as a testament to the challenge this alkaloid has posed as well as the reverence of the synthetic community for Woodward’s accomplishment.

Stork capitalized on the observation by the Hoffman-La Roche chemists in that deoxyquinine (2.20) could be selectively oxidized to quinine.32 Therefore, a

71 stereoselective synthesis of quinine could be achieved if a stereoselective route to deoxyquinine was developed. This led to Stork’s approach in which only 3 of the 4 stereogenic centers of the alkaloid needed attention.

Accordingly, Stork synthesized quinine (2.1) by subjecting deoxyquinine (2.20) to base promoted oxidative conditions utilizing molecular oxygen (Scheme 2.13).

Deoxyquinine (2.20) was obtained in stereoselective fashion by silyl deprotection, mesylation of the resulting primary alcohol, and its displacement with the tethered piperidine of 2.38. Piperidine 2.38 was prepared by alcohol oxidation and intramolecular

Staudinger reaction of azidoalcohol 2.39. Azidoalcohol 2.39 was obtained by the addition of lithiated 6-methoxy-4-methylquinoline to aldehyde 2.40. Aldehyde 2.40 was accessed in a number of steps from vinylbutyrolactone 2.42 which was obtained in enantiopure form by resolution via formation of amide diastereomers.33

TBDPSO H H OMe OMe OMe N N NH

OH N N N

2.1 2.20 2.38

TBDPSO TBDPSO TBDPSO

N N OMe 3 3 OH O O O O O

N 2.39 2.40 2.41 2.42

Scheme 2.13: Stork’s stereoselective synthesis of quinine

72 Stork completed the first stereoselective synthesis of the alkaloid natural product

in 20 steps. Stork’s elegant synthesis is extremely simple yet quite efficient. Stork’s work

is so highly regarded that members of the scientific community stated that the report “is

written with an insight and historical perspective rarely seen in the primary chemical

literature, and should be required reading for all students of organic chemistry”.34

2.7 SYNTHETIC APPROACHES OF THE 21ST CENTURY

2.7.1 Synthetic Approach of Jacobsen

In 2004, Jacobsen and colleagues published the catalytic asymmetric syntheses of

both quinine and it’s C8 epimer, quinidine.35 This synthesis highlighted the use of many

highly efficient catalytic reactions with the key step being an asymmetric conjugate

addition catalyzed by a (salen)Al complex.36

Jacobsen accessed quinine (2.1) via asymmetric dihydroxylation of alkene 2.43, single-pot conversion of the diol to the epoxide, N-deprotection, and microwave assisted quinuclidine cyclization (Scheme 2.14). Alkene 2.43 is obtained by silyl deprotection, alcohol oxidation, alkylation to the vinyl boronic ester of primary alcohol 2.44 followed

by Suzuki coupling with 4-bromo-6-methoxyquinoline. Primary alcohol 2.44 is accessed

in non-stereoselective fashion by first epimerization of ester 2.45 (1.7:1 to 1:3, trans:cis)

followed by LiAlH4-mediated lactam and ester reduction, alcohol oxidation, and Wittig

olefination. Lactam 2.45 is the product of hydrogenative lactamization of imide 2.46.

Imide 2.46 is the direct product of the aforementioned asymmetric conjugate addition of

methyl cyanoacetate to the Wadsworth-Emmons adduct of aldehyde 2.47 and β-

imidophosphonate 2.48.

73 H OMe OMe H H N TBSO NCbz NCbz OH N N 2.1 2.43 2.44

CO Me CO Me H 2 H 2 TBSO TBSO CN TBSO H H H NH N Ph O N Ph (EtO)2P O O O O O O 2.45 2.46 2.47 2.48

Scheme 2.14: Jacobsen’s catalytic asymmetric approach to quinine

Jacobsen’s synthesis of 17 steps remains the shortest in the chemical literature. It

is quite novel in displaying the expanding scope and utility of modern asymmetric

catalytic methods. The use of the asymmetric dihydroxylation protocol at the late stage of

alkene 2.43 cleverly allows access to both quinine and its pseudo-enantiomer quinidine.

Although, the sequence is not stereoselective as piperidine 2.45 is accessed via

epimerization in only a 3:1 ratio of cis:trans diastereomers.

2.7.2 Synthetic Approach of Kobayashi

In 2004, Kobayashi and coworkers published a stereocontrolled synthesis of

quinine and quinidine which was followed in 2005 by a second generation synthesis.37,38

This approach was not strikingly different from its predecessors nor did it display new chemistry. Though, it detailed full stereocontrol in the preparation of a cis-disubstituted piperidine en route to the desired natural product.

Kobayashi accessed quinine (2.1) in similar fashion to Jacobsen by asymmetric dihydroxylation of alkene 2.49, single-pot conversion of the diol to the epoxide, N-

74 deprotection, and thermal quinuclidine cyclization (Scheme 2.15). Alkene 2.49 was

obtained by Greico elimination39 of alcohol 2.50 followed by silyl deprotection, alcohol

oxidation, and Wadsworth-Emmons olefination with the appropriate quinoline-bearing

phosphonate. Piperidine 2.50 was achieved by disubstitution of bisiodide 2.51 with

benzylamine followed by protecting group exchange and ester hydrolysis. Bisiodide 2.51

was realized by the reduction of aldehyde 2.52 followed by protection, ozonolysis of the

cyclopentene functionality, reduction, and Appel iodination. The desired cis

stereochemistry about cyclopentene 2.52 was acquired selectively by O-alklyation of alcohol 2.53 with ethyl vinyl ether and subsequent Claisen rearrangement. Cyclopentene

2.53 was obtained from enantiomerically pure allylic acetate 2.54 which was accessed via

enzymatic resolution.40

H OMe OMe OH H H N NTeoc TBDPSO NTeoc OH N N 2.1 2.49 2.50

OPiv O H H I AcO

TBDPSO I TBDPSO TBDPSO OH OH 2.51 2.52 2.53 2.54

Scheme 2.15: Kobayashi’s stereocontrolled approach to quinine

Kobayashi’s synthesis of 22 steps provides a more classical approach to the

alkaloid though it rests heavily on previous work. The process for quinuclidine

construction is identical to the approach of Jacobsen. Additionally, the introduction of the

75 quinoline moiety via olefination was a strategy disclosed previously by Taylor and

Martin. Though, it is novel in its approach to control absolute stereochemistry at C3 and

C4.

2.7.3 Synthetic Approach of Williams

A final and distinctively novel approach to quinine has been pioneered by

Williams and coworkers though it currently rests at (R)-7-hydroxyquinine (2.55).41 The approach of Williams consists of a new disconnect that of C3 – C4 in which the quinuclidine is constructed by an intramolecular enolate allylic alkylation.

(R)-7-hydroxyquinine (2.55) was realized by the palladium catalyzed allylic alkylation of the enolate of ketone 2.56 followed by rapid carbonyl reduction of the intermediate β-siloxyketone, and silyl deprotection (Scheme 2.16). Ketone 2.56 was

prepared from α-aminoester 2.57 which in turn comes from a diastereoselective aldol

reaction of ester 2.58 and the appropriate quinoline-bearing aldehyde.

BzO

4 H OMe OMe OMe 3 O O OMe O O Ph N N NHBoc OH N Ph OH OTES OTES Cbz N N N

2.55 2.56 2.57 2.58

Scheme 2.16: Williams’ approach to (R)-7-hydroxyquinine

Williams’ 28 step synthesis of (R)-7-hydroxyquinine presents a fresh approach

toward the cinchona alkaloids utilizing a new disconnection strategy, though, the

synthesis fails in accessing the desired natural product. It is a chiral-auxiliary based

76 approach which adds extra manipulations in the introduction and cleavage of the chiral residue. Although the key enolate allylic alkylation is a new method for the construction

of the quinuclidine, the reaction suffers from low yield, side product formation, product

instability, high catalyst loading (20 mol% Pd), and the necessity of super-stoichiometric

Bu3SnF (150 mol%) to affect Pd-Sn transmetallation rendering the intermediate π-allyl

sufficiently electrophilic.

Interestingly, Williams submitted (R)-7-hydroxyquinine (2.55) and key side product, enone 2.59, formed by β-siloxy elimination of the intermediate β-siloxyketone, to screening against two strains of malaria parasites to examine if 7-oxy-quinine analogues possess biological activity (Figure 2.4). Unfortunately, both compounds were found to be inactive.

H H

OMe 7 OMe O 7 N N OH OH N N

2.55 2.59

Figure 2.4: 7-oxy-quinine analogues submitted for biological assay

2.8 SUMMARY AND CONCLUDING REMARKS

Although it has been 90 years since Rabe first reconstructed quinine through degradation experiments and over 60 years since Woodward and Doering’s first total synthesis, the alkaloid natural product is still a synthetic target for 21st century chemists.

Many chemists have developed highly advanced routes utilizing a variety of strategic

disconnects so one may ask, why attempt another quinine synthesis? Stork addressed this

issue following his 2001 synthesis in saying that “the value of a quinine synthesis has

77 essentially nothing to do with quinine…it is like the solution to a long-standing proof of an ancient theorem in mathematics: it advances the field.”2 There is a distinct evolution from the early protocols to modern catalytic, asymmetric methods but this is proof that total synthesis of natural products is not just a method for determining proof of structure, but an avenue for the testing of new reagents, reaction, concepts, and strategies in chemistry.

78 2.9 REFERENCES

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24 Lawrence, W. M. The New York Times, May 4, 1944.

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80

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81 Chapter 3 Racemic Approach to Quinine

3.1 FIRST GENERATION RETROSYNTHETIC ANALYSIS

One could envision accessing quinine (3.1) via N-deprotection and aminoepoxide

cyclization of piperidine 3.2 (Scheme 3.1). Piperidine 3.2 could be realized by

nucleophilic epoxidation of enone 3.3 followed by carbonyl deoxygenation. Enone 3.3

could be obtained from the 1,4-reduction of enone 3.4 followed by an aldol/dehydration

sequence with the indicated quinoline-bearing aldehyde. Piperidine 3.4 could be achieved

from enone-allyl carbonate 3.5 via the aforementioned catalytic cycloallylation1 employing both trialkylphosphine and palladium(0) catalysts. In this case, it would be used for the construction of a six-membered ring that incorporates a nitrogen atom which tethers the nucleophilic and electrophilic partners. This would be the first synthetic application of the cycloallylation methodology.

H OMe OMe OMe O H H N O N N OH PG PG N N N

3.1 3.2 3.3

OMe

OCO2Me CHO O O N PR Me 3 Me N Pd(PPh ) N PG 3 4 PG

3.4 3.5

Scheme 3.1: First generation retrosynthetic approach to quinine

82 3.2 CYCLOALLYLATION SUBSTRATE SYNTHESIS AND OPTIMIZATION

The first challenge in the preparation of enone-allyl carbonate 3.5 was the

selection of the nitrogen protecting group. The aryl sulfonyl protecting group was

selected for two distinct reasons. The electron withdrawing nature of this group

diminished the basicity of the nitrogen atom. Secondly, the introduction of an aryl

sulfonyl residue dramatically increases the acidity of the N-H bond rendering the nitrogen atom a suitable nucleophile.

3.2.1 N-Tosyl Substrate Synthesis

The synthesis toward quinine began with the known2 tosyl protection of

commercially available aminoacetaldehyde diethyl acetal (3.6) to afford sulfonamide 3.7

in 74% yield (Scheme 3.2). The increased acidity of the sulfonamide N-H next allowed it to participate as nucleophile in the N-alkylation with known allylic alcohol3 under

Mitsunobu conditions to install the proelectrophile of the cycloallylation substrate. The

resulting allylic sulfonamide was then refluxed in AcOH/H2O to hydrolyze the acetal

moiety to provide aldehyde 3.8 in 73% yield over two steps. Aldehyde 3.8 next

underwent olefination with the stabilized Wittig reagent4 to furnish the pronucleophilic handle in the generation of enone 3.9 in 69% yield.

83 OH 1. OCO2Me , DIAD,

OEt TsCl, Et3N, OEt PPh3, THF, 0 °C H NH2 N EtO DCM, 0 °C EtO Ts 2. AcOH, H2O, 100 °C

3.6 3.7 74% 73%

OCO2Me OCO2Me

O O Ph3P O Me, DCM Me N N H Ts Ts

3.8 3.9 69%

Scheme 3.2: Preparation of N-tosyl cycloallylation substrate

3.2.2 Cycloallylation of N-Tosyl Substrate

With enone-allyl carbonate 3.9 in hand, investigation began into the effect of the electron withdrawing sulfonamide in the cycloallylation step. Upon subjection of substrate 3.9 to the optimized reaction conditions for carbocycle formation, only a 3% yield of the desired piperidine 3.11 was obtained (Table 3.1, entry 1). It was clear that the electron withdrawing group in the tether enhanced the rate of reaction, most likely rendering the conjugate addition of phosphine more facile. It was thought that anionic polymerization of starting material and/or product could be operative when heating at 60

˚C. Notable increases in yield were obtained upon decreasing reaction temperature. This mitigated a change in solvent due to the freezing point of the alcoholic media.5 Piperidine

3.11 was obtained in 62% yield at room temperature (entry 3) and 55% yield when the reaction was performed at 0 ˚C (entry 4). These results display the pronounced effect of the electron withdrawing sulfonamide as compared to the parent methodology in which reactions must be heated to 60 ˚C to observe product formation.

84 Though, the tethered electron withdrawing group allowed for lower reaction

temperatures, it did promote the formation of an undesired side product. The electron withdrawing nature of the sulfonamide will increase the acidity of the protons on the adjacent carbon atom. Upon formation of phosphonium adduct 3.10, base can abstract either Hα or Hγ to initiate the elimination of phosphine. Due to the increased acidity of

protons at the γ-position, elimination via abstraction of Hγ was observed to furnish β,γ-

unsaturated enamine 3.12. Enamine 3.12 proved difficult to identify as it would further

react or hydrolyze upon reaction workup.

OCO2Me O Me O O H H Pd(PPh ) (5 mol%) α α Me 3 4 O Me Me N PR N N N Ts 3 P Ts Ts Ts R3 Hγ Hγ Hγ Hγ Hγ 3.9 3.10 3.11 3.12

Entry PR3 Solvent Temp Yield t 1PBu3 (100 mol%) BuOH (0.1 M) 60 °C 3% t 2PBu3 (100 mol%) BuOH (0.1 M) 35 °C 46% t 3PBu3 (100 mol%) AmOH (0.1 M) rt 62% t 4PBu3 (100 mol%) AmOH (0.1 M) 0 °C 55% t AmOH (0.1 M) rt 39% 5PMe3 (100 mol%)

Table 3.1: Cycloallylation optimization with N-tosyl substrate

3.2.3 N-Trisyl Substrate Synthesis

To circumvent this elimination manifold, a bulkier aryl sulfonyl protecting group

was introduced in hopes that its presence would prevent abstraction of Hγ. In this manner, the 2,4,6-triisopropylbenzenesulfonyl or trisyl group (Trs) was utilized.

85 Aminoacetaldehyde diethyl acetal (3.6) was protected with trisyl chloride and the resulting secondary sulfonamide underwent N-alkylation under Mitsunobu conditions to afford allylic sulfonamide 3.13 in essentially quantitative yield over two steps (Scheme

3.3). The acetal moiety of allylic sulfonamide 3.13 was then hydrolyzed and crude

aldehyde olefinated as before to afford enone-allyl carbonate 3.14 in 68% over two steps.

OCO2Me OCO2Me O 1. TrsCl, Et3N, 1. TFA, H2O, DCM, 0 °C CHCl , 0 °C OEt OEt 3 Me

NH2 N N EtO OH EtO Trs O Trs 2. Ph3P 2. OCO2Me, DIAD, Me, DCM 3.6 3.13 3.14 PPh3, THF, 0 °C 99% 68%

Scheme 3.3: Preparation of N-trisyl cycloallylation substrate

3.2.4 Cycloallylation of N-Trisyl Substrate

Cycloallylation of N-trisyl protected enone-allyl carbonate 3.14 under the

previously optimized conditions for the analogous N-tosyl substrate yielded the

cycloallylation adduct 3.16 in only 27% yield (Table 3.2, entry 1). Thin-layer

chromatography analysis of the reaction mixture observed a large amount of baseline

material indicating decomposition or polymerization was operative. Conversion of

starting material to product was quite slow when matching the PBu3 reagent with the N-

trisyl substrate most likely due to the retardation of 1,4-phosphine addition by the bulky

sulfone residue. Gratifyingly, none of side product 3.17 was observed under these

conditions. When employing the smaller, and more nucleophilic PMe3, the yield more

than doubled to 63% (entry 2). This chemical yield eclipsed that for the N-tosyl substrate

though, undesired vinyl sulfonamide 3.17 was again observed. Yield could be further

86 optimized to 68% by decreasing PMe3 loading to 80 mol% (entry 3). Continued lowering of PMe3 loading to 65 mol% and 50 mol% were met with a steady decrease in yield

(entry 4, 5). A decrease in palladium loading (entry 6, 7) extended the reaction time

resulting in a net decrease in yield due to suspected polymerization or decomposition

pathways. Finally, in hopes of attenuating polymerization, the reaction concentration was

diluted to 0.05 M (entry 9). Unfortunately, the overall yield was decreased to 27%.

Although unable to halt the formation of undesired vinyl sulfonamide 3.17, the yield of

68% (entry 3) remains the highest yield obtained for the construction of a six-membered ring via this method.

OCO2Me O Me O O H H Pd(PPh ) , PR α α Me 3 4 3 O Me Me N tAmOH N N N Trs P Trs Trs Trs R3 Hγ Hγ Hγ Hγ Hγ 3.14 3.15 3.16 3.17

Entry Pd(PPh3)4 PR3 Solvent Yield t 15 mol%PBu3 (100 mol%) AmOH (0.1 M) 27% t 25 mol%PMe3 (100 mol%) AmOH (0.1 M) 63% t 35 mol%PMe3 (80 mol%) AmOH (0.1 M) 68% t 45 mol%PMe3 (65 mol%) AmOH (0.1 M) 60% t 55 mol%PMe3 (50 mol%) AmOH (0.1 M) 52% t 62.5 mol%PMe3 (80 mol%) AmOH (0.1 M) 57% t 71 mol%PMe3 (80 mol%) AmOH (0.1 M) 48% t 85 mol%PMe3 (80 mol%) AmOH (0.2 M) 42% t 95 mol%PMe3 (80 mol%) AmOH (0.05 M) 27%

Table 3.2: Cycloallylation optimization with N-trisyl substrate

3.2.5 Additive Effect in Cycloallylation Optimization

Unable to halt the formation of undesired vinyl sulfonamide 3.17, investigations

were focused on the development of a method to isomerize the alkene into conjugation.

87 6 Al2O3 has been found to isomerize β,γ-ketones into conjugation , though no precedence

was found with substrates possessing vinyl heteroatoms. When Al2O3 served as additive

in the cycloallylation reaction, thin-layer chromatography analysis observed only a trace

quantity of vinyl sulfonamide 3.17, though the yield of piperidine 3.16 remained

unimproved at 67%. If the crude reaction mixture, following aqueous workup, was

absorbed to Al2O3 and further stirred in DCM, the yield dropped to 47%.

With preliminary evidence that metal additives could suppress the formation of undesired vinyl sulfonamide 3.17, investigation continued with a screen of additives.

Accordingly, a number of oxophilic Lewis acids were screened in the cycloallylation reaction. Sc(OTf)3 (Table 3.3, entry 2) and CeCl3 (entry 3) both diminished the amount of

undesired vinyl sulfonamide 3.17 observed by thin-layer chromatography analysis, but

yields failed to exceed 68%. AlCl3 was also found effective in attenuating the undesired

elimination manifold, specifically at 20 mol% loading (entry 5), though the isolated yield

of piperidine 3.16 peaked at 61%. By changing reaction media to DCM (entry 7), the

formation of vinyl sulfonamide 3.17 was completely suppressed, though yield dropped to

51%. A number of Al(III) additives were screened but all failed to provide chemical

yields exceeding 68%.

88 OCO2Me O O O PMe3 (80 mol%) Pd(PPh ) (5 mol%) Me 3 4 Me Me N Additive N N Trs Trs Trs 3.14 3.16 3.17

Entry Additive Solvent Temp Yield 3.16 Side Product 1 - t AmOH (0.1 M) rt 68% observed t 2 Sc(OTf)3 (20 mol%) AmOH (0.1 M) rt 20% trace t 3 CeCl3·7H2O (20 mol%) AmOH (0.1 M) rt 50% trace t 4 AlCl3 (10 mol%) AmOH (0.1 M) rt 58% observed t 5 AlCl3 (20 mol%) AmOH (0.1 M) rt 61% trace t 6 AlCl3 (30 mol%) AmOH (0.1 M) rt nr - 7 AlCl3 (20 mol%) DCM (0.1 M) rt 51% none i t 8 Al(O Pr)3 (20 mol%) AmOH (0.1 M) rt 43% trace t 9 AlI3 (20 mol%) AmOH (0.1 M) rt 55% none t 10 Al(OTf)3 (20 mol%) AmOH (0.1 M) rt 50% trace t 11 AlCl3 (20 mol%) AmOH (0.1 M) 40 ˚C 62% trace

Table 3.3: Cycloallylation optimization with Lewis acid additive effects

A mechanism could be envisioned in which the enolate formed via 1,4-addition of

PMe3 could react with oxophilic Lewis acid (AlCl3) to form aluminum enolate 3.18

(Scheme 3.4). Following carbon-carbon bond formation to intermediate 3.19, the

carbonyl remains coordinated to the AlCl3. This coordination greatly increases the acidity

of Hα, and elimination of PMe3 proceeds exclusively to afford α,β-unsaturated ketone

3.16.

89 OCO2Me PMe (cat.) O 3 O LnPd0 (cat.) Me Me AlCl (cat.) N 3 N Trs Trs 3.14 3.16 AlCl3,PMe3 PMe3, AlCl3 LnPd0 MeOH, CO2

OCO2Me OCO2Me II LnAl OAlLn Pd Ln O Hα Me Me N N Me3P Trs Me3P Trs 3.18 Hγ Hγ 3.20 LnPd0 LnAl O LnPd0

Me N Me3P Trs 3.19

Scheme 3.4: Proposed cycloallylation mechanism with AlCl3 additive

3.2.6 α,β-Unsaturated Acceptor in Cycloallylation Optimization

In a second group of experiments to examine substrate reactivity, the α,β- unsaturation was varied. In the development of the parent methodology for carbocycle formation, enones and thioenoates both participated to afford cyclopentenes in similar chemical yield.1 Enoates however were not sufficiently electrophilic and cycloallylation

products were obtained in only trace quantities. Thioenoate 3.21 and enoate 3.22 were

prepared in similar fashion to enone 3.14 and subjected to standard cycloallylation

conditions. Accordingly, enone 3.14 and thioenoate 3.21 afforded their respective

cycloallylation adducts in 63% and 57% yield respectively (Table 3.4, entry 1, 2). Enoate

3.22 failed in the cycloallylation and only a trace amount of piperidine 3.24 was

observed. (entry 3). This result indicates that the electrophilicity of the α,β-unsaturated

90 acceptor overrides the increased substrate reactivity attributed to the tethered sulfonamide.

OCO2Me O O Pd(PPh3)4 (5 mol%) R R PMe3 (100 mol%) N N Trs tAmOH Trs

3.14, R = Me 3.16, R = Me 3.21, R = SEt 3.23, R = SEt 3.22, R = OEt 3.24, R = OEt

Entry R Yield 1 Me 63% 2 SEt 57% 3OEttrace

Table 3.4: Cycloallylation with varying α,β-unsaturated substrates

3.3 CONJUGATE REDUCTION OF CYCLOALLYLATION ADDUCT

With enone 3.16 now in hand, efforts were focused on the 1,4-reduction of the

enone to set the cis relationship at C3 and C4 about the piperidine. Conjugate reduction is

often utilized for the asymmetric generation of a β-stereocenter of α,β-unsaturated

systems. Buchwald and coworkers have developed conditions utilizing a chiral copper

hydride to introduce asymmetry in cyclic enones (Scheme 3.5).7

O CuCl (5mol%) O (S)-BIPHEMP (5 mol%)

NaOtBu (5 mol%) R R PMHS, PhH 3.25, R = Me 3.27, R = Me, 61%, 92% ee 3.26, R = nBu 3.28, R = nBu, 82%, 87% ee

Scheme 3.5: Buchwald’s asymmetric conjugate reduction

Conversely, it was hoped that an effective method could be developed to establish

an α-stereocenter. Under the Buchwald conditions, hydride addition to the unsaturated

91 system assisted by a chiral ligand is the stereodetermining step. In this synthesis, the

stereoselective protonation of enolate 3.30 would be stereodetermining (Scheme 3.6).

Accordingly, it was hoped that enolate 3.30 would undergo a diastereoselective

protonation directed by the adjacent vinyl residue at C3.

O OM O M-H H 4 Me Me 3 Me N N N R H R R

3.29 3.30 3.31

Scheme 3.6: Proposed conjugate reduction/diastereoselective protonation

Initial screening employing the Buchwald conditions resulted in none of desired

piperidine 3.33, with only a small amount of the starting material present (Table 3.5, entry 1). Red-Al is also known to serve as hydride donor in the formation of active

copper hydride reducing reagents8, though this protocol was also ineffective. Yamamoto

has developed two procedures for highly chemoselective 1,4-reduction utilizing

extremely bulky aluminum phenoxide Lewis acids to shield the carbonyl of the 1,4-

system from reduction.9 When employing both methods utilizing aluminum tris(2,6-

diphenylphenoxide) (ATPH) and methyl aluminum bis(2,6-di-tertbuyl-4-

methylphenoxide) (MAD) in conjunction with DIBAL-H, none of piperidine 3.33 was

obtained (entry 2, 3). Standard hydride reducing agents favored 1,2- versus 1,4-reduction

(entry 5-9).10 This result was consistent with the result that acyclic enones such as

acetylcyclohexane undergo extremely rapid 1,2-reduction.11 Silanes were screened in

conjunction with metal catalysts12 as well as iridium catalyzed transfer hydrogenation13 though all failed to produce the desired transformation.

92 O OM O M-H H Me Me Me N N N Trs H Trs Trs

3.16 3.32 3.33

Entry Reagent(s) Solvent Temp Yield 1 CuCl, NaOt Bu, PMHS, rac -BINAP PhMe -78 °C to rt - 2 CuBr, Red-Al, sec -butanol THF -78 °C to rt - 3 ATPH, n BuLi, DIBAL-H THF -78 °C to rt - n 4 MAD, BuLi, DIBAL-H Et2O -78 °C to rt - 5 L-Selectride THF -78 °C to rt -

6 NaBH4 pyridine rt -

7 NiCl·6 H2O, NaBH4 MeOH 0 °C to rt -

8 Co(acac)2, DIBAL-H THF -78 °C to rt - 9 Raney Nickel THF rt -

10 Mo(CO)6, PhSiH3 THF rt to Δx -

11 (Ph3P)3RhCl, Et3SiH, PhH rt to 50 °C -

12 ZnCl2, Pd(PPh3)4, Ph2SiH2 CHCl3 rt - i PhMe rt to Δ - 13 [Ir(COD)Cl]2, dppp, Cs2CO3, PrOH x

Table 3.5: Screened conditions for conjugate reduction

After exhausting the many developed protocols for conjugate reduction, efforts were next focused on the preparation and modification of copper hydride reagents generated in situ. The reducing agent formed upon the mixing of CuI with LiAlH4 in

THF14 at 0 ˚C was found to chemoselectively afford piperidine 3.33, though in a mere

8% yield (Table 3.6, entry 1). It was soon found that yield could be increased to 29% by cooling the reaction to -78 ˚C and introducing HMPA as co-solvent15 (entry 2).

Gratifyingly, it was discovered that the cis-diastereomer was preferred under these reaction conditions, though in a modest 2:1 ratio. This diastereoselectiviy increased dramatically to 6:1 (cis:trans) when DIBAL-H was employed, though the yield dropped to 17% (entry 3). With the correlation that a larger hydride reagent translated to increased diastereoselection, the well-characterized Stryker’s reagent ([Ph3PCuH]6) was carefully prepared.16 Stoichiometric employment of this metallic cluster at room temperature in

93 toluene provided cis-piperidine 3.33 in a 5:1 ratio of diastereomers with an improved

yield of 44% (entry 4). Unfortunately, this reduction was sluggish and experiments at

suppressed temperatures or catalytic in metal were unfruitful. A report by Tsuda and

Saegusa provided the final solution. They detailed that a catalytic amount of MeLi will react with the CuI to form MeCu which dramatically affects chemoselectivity and reaction rate when treated with DIBAL-H in THF/HMPA mixtures.17 When employing

this protocol with N-tosyl enone 3.11, catalytic in MeCu, a 26% yield was obtained with

1:1 dr (entry 5). Conversely, reduction of N-trisyl enone 3.16 under identical conditions

afforded piperidine 3.33 in 17% yield, though observed as a single cis-diastereomer

(entry 6). It was clear that the bulkier trisyl protecting group was necessary to achieve high levels of diastereoselection. Rendering this reaction stoichiometric in the MeCu reagent bolstered the yield to 88% yield, though selectivity dropped to 10:1.

Experimentally, the active copper hydride is formed in situ over 1.5 hours with temperature maintained stringently between -60 and -50 ˚C. The complete control of diastereoselection observed in the catalytic reaction (entry 6) was reestablished by cooling the reduction to -78 ˚C following the preparation of the reducing reagent. In this manner, piperidine 3.33 was obtained in 77% yield observed exclusively as the cis- diastereomer (entry 8). The stereochemical assignment of piperidine 3.33 is based on a single crystal X-ray diffraction analysis (Figure 3.1).

94 O OM O M-H H Me Me Me N N N R H R R

3.29 3.30 3.31

Entry R Reagent(s) Solvent Temp Yield Dr

1 Trs CuI, LiAlH4 THF 0 °C 8% N/A

2 Trs CuI, LiAlH4 THF/HMPA -78 °C 29% 2:1, cis 3 Trs CuI, DIBAL-H THF/HMPA -78 °C 17% 6:1, cis

4 Trs [Ph3PCuH]6 PhH rt 44% 5:1, cis 5 Ts MeLi (cat), CuI (cat), DIBAL-H THF/HMPA -60 to -50 °C 26% 1:1 6 Trs MeLi (cat), CuI (cat), DIBAL-H THF/HMPA -60 to -50 °C 17% >20:1, cis 7 Trs MeLi (stoich), CuI (stoich), DIBAL-H THF/HMPA -60 to -50 °C 88% 10:1, cis 8 Trs MeLi (stoich), CuI (stoich), DIBAL-H THF/HMPA -78 °C 77% >20:1, cis

Table 3.6: Conjugate reduction optimization

O H Me N Trs H 3.33

Figure 3.1: Single crystal X-ray diffraction analysis of cis-piperidine 3.33

A stereochemical model to confer the high level of diastereoselectivity for this step has been developed (Scheme 3.7). Upon 1,4-addition of hydride to enone 3.16, the resulting enolate can exist in two conformers. Enolate conformer 3.34 places the vinyl residue in an axial position and conformer 3.35 places it equatorially. Although equatorial

95 displacement of substituents is generally favored, equatorial enolate conformer 3.35

possess a great deal of A1,3-strain. In the optimization it was found that DIBAL-H as

hydride donor and HMPA as co-solvent were pivotal to confer high levels of

diastereoselectivity. This is consistent with the proposed model of A1,3-strain by the

presence of branched isobutyl ligands on the aluminum center and the necessity of

HMPA as co-solvent indicating a highly solvated metal center. Therefore, axial

conformer 3.34 is preferred. The vinyl residue is now situated above the chair requiring

protonation of enolate 3.34 to occur from the bottom face providing observed cis-

diastereomer 3.33.

N Trs

LnAlO Me 3.34 H N Trs MeCuH O H N Trs O i Me Me Al( Bu)2Ln H LnAlO 3.16 3.33 Me N Trs H 3.35

Scheme 3.7: Stereochemical model for selectivity in conjugate reduction

3.4 INTRODUCTION OF THE QUINOLINE

Following this careful optimization, the stage was set for the introduction of the quinoline. The quinoline was first prepared via Skraup reaction in which p-anisidine

(3.36) and methyl vinyl ketone were condensed under acidic conditions to furnish 6- methoxy-4-methyl quinoline 3.37 in 42% yield (Scheme 3.8).18 This was followed by

SeO2-mediated benzylic oxidation in refluxing xylenes to furnish quinoline aldehyde 3.38 in 51% yield.19

96 OMe O OMe OMe

Me SeO2

. Me CHO FeCl3 6 H2O xylenes, 135 °C AcOH, Δ NH2 x N N 42% 51% 3.36 3.37 3.38

Scheme 3.8: Preparation of quinoline aldehyde

Methyl ketone 3.33 was treated with LDA at -78 ˚C and the resulting enolate was

reacted with quinoline aldehyde 3.38 at -78 ˚C with overnight warming to room

temperature. Upon warming, the aldol addition product spontaneously dehydrated to

afford enone 3.39, though the preservation of stereochemistry at the epimerizable α- position remained in question (Scheme 3.9). After only 7 linear steps, the entire carbon skeleton of the natural product was now assembled.

O OMe O H LDA, THF, -78 °C H Me then CHO N N Trs MeO Trs N N 3.33 3.39 -78 °C to rt

59%

Scheme 3.9: Aldol/dehydration sequence to install full carbon framework

3.5 NUCLEOPHILIC EPOXIDATION

Efforts were next focused on the epoxidation of the electron poor alkene. This key

transformation would set the stage for the desired aminoepoxide cyclization to dictate stereochemistry and both C8 and C9. It was hoped that a nucleophilic epoxidation protocol could be developed to constitute a novel approach to the quinuclidine precursor.

97 After observing such a high level of chirality transfer in the conjugate reduction, it was hoped for a similar diastereoselection in this transformation.

Initial investigation utilizing the Meth-Cohn protocol20 of lithium tbutyl

hydroperoxide at -78 ˚C in THF afforded epoxy ketone 3.40 in an excellent 88% yield,

though a disappointing 1.3:1 ratio of diastereomers (Table 3.7, entry 1). With the inability

to further cool this reaction significantly, a larger reagent derived from Ph3COOH was

employed. Under these conditions, the yield of epoxy ketone 3.40 diminished to 53% and

diastereoselectivity was reversed to 1:1.8 (entry 2). Triton B (benzyltrimethylammonium

hydroxide) is commonly used to deprotonate hydroperoxides to form nucleophilic

epoxidization reagents.21 The employment of Triton B as base with TBHP at -78 ˚C in

THF afforded none of epoxy ketone 3.40 (entry 3). The identical reaction was warmed to

-40 ˚C and 0 ˚C. Though epoxidation occurred with increasing temperature, no significant

diastereoselectivity was achieved (entry 4, 5).

OMe O OMe O H H Nucleophilic O N N Trs Epoxidation Trs N N 3.39 3.40

Entry Reagent(s) Solvent Temp Yield Dr 1TBHP, n BuLi THF -78 ˚C 88% 1.3:1 n 2Ph3COOH, BuLi THF -78 ˚C 53% 1:1.8 3 TBHP, Triton B THF -78 ˚Cnr- 4 TBHP, Triton B THF -40 ˚C 52% 1.4:1 5 TBHP, Triton B THF 0 ˚C 89% 1:1

Table 3.7: Nucleophilic epoxidation optimization

98 With evidence that nucleophilic epoxidation of enone 3.39 was capable though

diastereoselectivity was absent, efforts were focused on continuing the forward synthesis.

It was thought that this oxidation could be later rendered diastereoselective via the use of

the asymmetric Juliá-Colonna epoxidation using a polyamino acid catalyst.22

3.6 AMINOEPOXIDE CYCLIZATION

At this juncture, it was hoped to first deprotect sulfonamide 3.40 to free amine

3.41 and then cyclize onto the epoxide to form quinuclidine 3.42 (Scheme 3.10).

H OMe O OMe O OMe O H H N O O N NH Trs OH N N N 3.40 3.41 3.42

Scheme 3.10: Aminoepoxide cyclization to construct quinuclidine

3.6.1 Sulfonamide Deprotection Sulfonamide protecting groups are generally cleaved under harshly acidic

conditions or by single electron-transfer reduction.23 It was unclear if the additional

functionality of compound 3.40 would tolerate such conditions. Potential problems include α-stereocenter epimerization, epoxide opening, or Birch reduction.

Magnesium in anhydrous MeOH has been found to be an extremely mild method for the deprotection of tosyl sulfonamides.24 Subjection of trisyl sulfonamide 3.40 to

these conditions failed to give secondary amine 3.41 with a 76% yield of recovered 3.40

(Table 3.8, entry 1). Trisyl groups have been removed from primary sulfonamides via

sonication in THF in the presence of lithium wire and catalytic 4,4’-di-tert-butylbiphenyl

(DTBB)25, though these conditions failed to afford deprotection of 3.40 (entry 2). The

99 traditional dissolving metal reduction is known to cleave the N-S bond of sulfonamides26.

Treatment of sulfonamide 3.40 with sodium in liquid ammonia at -78 ˚C failed to furnish any identifiable compound (entry 3). Sodium naphthalenide was also screened though it failed to generate the desired product and only 47% recovery of sulfonamide 3.40 (entry

4). Strongly acidic (entry 5, 6) as well as microwave assisted conditions27 (entry 7) were

considered, though all failed in the deprotection.

OMe O OMe O H H Deprotection O O N NH Trs N N 3.40 3.41

Entry Reagent(s) Solvent Temp Yield 3.41 Recovered 3.40 1 Mg, sonication MeOH rt - 76% 2 Li, DTBB, sonication THF rt - 87%

3 Na NH3 (l ) -78 ˚C- - 4 Na, naphthalene DME -78 ˚C- 47% 5 HBr (33% in HOAc), phenol DCM rt - - 6HF·pyr anisole 0 ˚C- 85% - 300 W, 300 ˚C- - 7KF on Al2O3, μw

Table 3.8: Deprotection of N-trisyl sulfonamide

Unable to affect the necessary deprotection under the standard conditions, it was clear that the aryl sulfone group could not be easily cleaved at this late stage in the

forward synthesis. Therefore, it was necessary to identify both a more labile protecting

group and a juncture in the route for its introduction. This approach seemed more rational then engaging in a completely new route when considering the necessity of the bulky

trisyl sulfonamide for diastereocontrol in the conjugate reduction step (Scheme 3.11).

100 O O CuI, MeLi, DIBAL Me Me N THF/HMPA, - 78 °C N R R

3.11, R = Ts 3.42, R = Ts, 1:1 (syn:anti) 3.16, R = Trs 3.33, R = Trs, >20:1 (syn:anti)

Scheme 3.11: Necessity of trisyl group in conjugate reduction

3.7 SECOND GENERATION RETROSYNTHETIC ANALYSIS

With this in mind, the protecting group exchange was planned to follow the

conjugate reduction. Additionally, with lack of diastereoselection in the nucleophilic

epoxidation, it was planned to investigate a directed epoxidation. Retrosynthetically,

quinine (3.1) could be accessed from epoxy alcohol 3.43 via aminoepoxide cyclization

and alcohol deoxygenation at C7 (Scheme 3.12). Epoxy alcohol 3.43 could in turn be

obtained from the 1,2-reduction of enone 3.44 followed by directed epoxidation of the

resulting allylic alcohol. Quinoline enone 3.44 would be accessed from a Trs to Boc

amine protecting group exchange of sulfonamide 3.16 and then aldol/dehydration with

the quinoline bearing aldehyde.

H OMe OMe OH OMe O H H N 7 O N N OH Boc Boc N N N

3.1 3.43 3.44 OMe

OCO2Me CHO O O N PR Me 3 Me N Pd(PPh ) N Trs 3 4 Trs

3.16 3.14

Scheme 3.12: Second generation retrosynthetic approach to quinine

101 3.8 PROTECTING GROUP EXCHANGE

To implement the Trs to Boc protecting group exchange, the deprotection of

epoxide bearing sulfonamide 3.40 to free secondary amine 3.41 was reconsidered. The dissolving metal conditions screened were found to fully refurnish the starting materials with the exceptions of Na/NH3 (l) and Na/naphthalene (Table 3.8, entry 3, 4). In the first

case, no starting material was recovered. In the second, only 47% of the starting material

was recovered (Scheme 3.13). When implementing sodium naphthalenide as reductant,

neither ketone reduction nor epoxide opening28 was observed. Therefore, one could speculate that the C-S bond is being cleaved, and then undergoing further reaction. For this reason, this radical anion reducing agent was selected for the protecting group exchange.

OMe O OMe O H H Na, naphthalene O O N NH Trs DME, -78 °C N N 3.40 3.41 47% recovered SM (not observed)

Scheme 3.13: Sodium naphthalenide deprotection of trisyl sulfonamide

The reduction of sulfonamides by sodium naphthalenide can be an extremely challenging reaction to control. At room temperature one equivalent of sulfonamide

requires two to six equivalents of the radical anion for complete cleavage to the amine

anion.29 At lower temperatures (-60 to -80 ˚C) stoichiometry can be lowered to 2:1

(radical anion:sulfonamide). The rate of arenesulfonamide cleavage, even at suppressed temperature, is so rapid that the reaction is often performed as a titration. One will often quench the reaction mixture immediately after the green end point is achieved (indicative

102 of excess radical anion). Anthracene has also found use in reductive cleavage of

sulfonamides.30

In an effort to facilitate the Trs to Boc protecting group exchange, sodium

naphthalenide was found to be effective for the reductive cleavage to liberate the free

amine 3.45. Optimization of this reaction sequence was quite challenging in attempting to

improve two steps simultaneously. The deprotection must be carefully performed with quenching at the appropriate moment to ensure maximum yield of the crude amine. The

Boc protection requires an excess of Boc2O which can make product purification

challenging by contamination with tBuOH. Additionally, reaction conditions must remain

fairly neutral to avoid α-epimerization. This reaction was performed as a titration with

dropwise addition of the green radical anion solution to sulfonamide 3.33 in DME at -78

˚C and immediate quenching with EtOH once the green color persisted to afford amine

3.45 (Scheme 3.14). Crude amine 3.45 was then subjected to Boc2O and Et3N in DCM at

0 ˚C to afford Boc piperidine 3.46 in 63% over steps. However, this chemical yield was

not always reproducible and often varied accordingly to reaction scale.

O O O H Na, naphthalene H Boc2O, Et3N H Me Me Me DME, -78 °C DCM, 0 °C N NH N Trs then EtOH Boc

3.33 3.45 3.46 63%

Scheme 3.14: Deprotection/Boc protection sequence with EtOH quench

3.9 ELABORATION TO QUINUCLIDINE CYCLIZATION

With N-Boc piperidine 3.46 now in hand, the quinoline moiety was introduced via

the previously described aldol/dehydration sequence to afford enone 3.44 in 63% yield

103 (Scheme 3.15). Enone 3.44 underwent exclusive 1,2-reduction upon treatment with L-

Selectride to furnish allylic alcohol 3.47 in 89% yield, observed as a single diastereomer.

This claim was determined by the presence of a single doublet of doublets in the 1H NMR

spectrum indicative of the proton at C8. Allylic alcohol 3.47 was subjected to vanadium-

catalyzed directed epoxidation to furnish epoxy alcohol 3.43 in 71% yield in a 3:1 dr.

Next, alcohol 3.43 was treated with LHMDS and TsCl in THF to afford tosylate 3.48 in modest yield with no Payne rearrangement. At this juncture, it was imperative to establish relative stereochemistry of epoxy tosylate 3.48. Single crystal X-ray diffraction analysis of epoxy tosylate 3.48 revealed that stereochemistry had been inverted at C4 with full epimerization to trans-piperidine 3.48 (Figure 3.2).

Na, naphthalene O O H DME, -78 °C H LHMDS, THF, -78 °C Me Me then Boc O CHO N 2 N Trs Et3N, DCM, 0 °C Boc MeO 3.33 3.46 then N THF, -78 °C to rt 63% 77%

OMe O OMe OH H H L-Selectride 8 VO(acac)2, TBHP N N Boc THF, -78 °C Boc DCE, 50 °C N N

3.44 89% 3.47 71% (>20:1) (3:1 dr)

OMe OH OMe OTs OMe OTs H H H LHMDS, THF, 0 °C 4 O O O N N N Boc then TsCl, THF Boc Boc N N N

3.43 42% 3.48 3.48 observed by X-ray

Scheme 3.15: Structural elaboration to determine relative stereochemistry

104 N

OMe O

H OTs N Trs 3.48

Figure 3.2: Single crystal X-ray diffraction analysis of tosylate 3.48

The cis relationship at C3 and C4 was established during the conjugate reduction

step and confirmed via X-ray crystallography. Therefore, epimerization must have

occurred in the protecting group exchange or aldol/dehydration sequence. The subsequent

carbonyl reduction would preserve configuration at C4 by eliminating the potential for

epimerization. Epimerization would be not be unexpected in this sequence due to the

thermodynamic preference of placing two substituents equatorial on trans-piperidine 3.49

versus the one axial, one equatorial alignment of cis-piperidine 3.49 (Scheme 3.16).

R2 H R2 O N base N H H R2 H R2 N N R 1 H O O O R1 H R1 H R1 cis-3.49 3.50 3.51 trans-3.49

Scheme 3.16: Proposed epimerization manifold to trans-piperidine

105 3.9.1 Epimerization in the Deprotection/Boc Protection Sequence

Knowing that epimerization occurred in one of these two steps, the mechanisms

of each were carefully considered. In the sulfonamide deprotection/Boc protection

sequence, the highly basic sodium naphthalenide reagent will rapidly cleave the N-S

bond to generate the extremely basic amine anion 3.53 (Scheme 3.17). Following this

cleavage, dihydronaphthalene anion 3.54 is sufficiently basic to abstract an acidic proton

leading to epimerization. Finally, quenching of the excess reducing agent with EtOH will

liberate ethoxide anion 3.55, also a suitable base to facilitate epimerization.

O O O H H H Me Me EtOH Me EtO N N (quench) NH SO2Ar

3.523.533.54 3.45 3.55

Scheme 3.17: Potential epimerization in sulfonamide cleavage

In an effort to circumvent the epimerization manifold the green radical anion

solution was added dropwise to sulfonamide 3.33 in DME at -78 ˚C (Scheme 3.18). The

basic reaction mixture was immediately quenched with saturated aqueous NH4Cl at -78

˚C upon standing of the dark green color. The reaction mixture was then filtered, taken up in DCM and converted to carbamate 3.46 by treatment with Boc2O, DMAP, and Et3N at

0 ˚C in 76% yield over two steps. With the immediate quench of the reaction by a weak acid, once the sulfonamide cleavage was complete, the basic reaction conditions the lead to potential epimerization were avoided.

106 O Na, naphthalene O H DME, -78 °C H Me Me then aq. NH Cl N 4 N Trs Boc2O, DMAP, Boc Et3N, DCM, 0 °C 3.33 3.46 76%

Scheme 3.18: Revised deprotection/Boc protection sequence

3.9.2 Epimerization in the Aldol/Dehydration Sequence

Secondly, in the aldol/dehydration sequence, upon addition of enolate 3.56 to the aldehyde, β-alkoxyketone 3.57 is formed (Scheme 3.19). One could envision intra- or intermolecular protonation of basic alkoxide 3.57 via deprotonation at C4 effectively erasing this stereocenter. Additionally, upon warming to room temperature β- alkoxyketone 3.57 will spontaneously dehydrate to furnish enone 3.44. One could imagine expulsion of hydroxide ion (3.58) would also be capable of promoting epimerization to the thermodynamically preferred trans-piperidine 3.46 under these equilibrating conditions.

CHO MeO O OLi H LHMDS, THF H N Me -78 °C THF, -78 °C N N Boc Boc

3.46 3.56

OMe O OMe O H H 4 -78 to 25 °C OH N N O Boc Boc N N 3.57 3.44 3.58

Scheme 3.19: Potential epimerization in aldol/dehydration step

107 To address these issues, a protocol was developed to intercept intermediate β-

alkoxyketone 3.57 as acetate 3.59 by treatment with Ac2O and DMAP with warming

from -78 to -40 ˚C (Scheme 3.20). Acetate 3.59 can then undergo rapid elimination

mediated by DBU at -40 ˚C to introduce the desired α,β-unsaturation in the formation of

enone 3.44 in 70% yield without stereochemical degradation.

LHMDS, THF, -78 °C CHO MeO O OMe O OMe O H then N H DBU H Me -40 °C N then Ac2O, DMAP N N Boc -78°C to -40 °C OAc Boc Boc N N 3.46 xx 3.44 70%

Scheme 3.20: Revised aldol/dehydration sequence

With clear evidence for the thermodynamic preference of a trans relationship

about the piperidine of quinoline enone 3.44, it was imperative to immediately reduce the carbonyl functionality. After observing the L-Selectride-mediated 1,2-reduction in the trans series of compounds to be fully diastereoselective, it was hoped that the reduction

in the cis series would proceed in analogous fashion. Accordingly, sensitive enone 3.44

was subjected to reduction with L-Selectride and allylic alcohol 3.47 was obtained in

94% yield as a single diastereomer (Scheme 3.21). Relative stereochemistry is attributed

to reduction from the si-face as the re-face is shielded by the axial vinyl group (Figure

3.22).

108 OMe O OMe OH H H L-Selectride

N THF, -78 °C N Boc Boc N N 3.44 94% 3.47 (>20:1)

Scheme 3.21: Chemo- and diastereoselective 1,2-reduction of enone

MeO O NBoc MeO OH NBoc

H H H N N H 3.60 3.47

Scheme 3.22: Stereochemical model for diastereoselective 1,2-reduction

3.10 ALLYLIC ALCOHOL DIRECTED EPOXIDATION

With three contiguous stereogenic centers addressed by two diastereoselective

protocols, it was hoped that the established chirality could direct the ensuing epoxidation

in the setting of five contiguous stereocenters. The epoxidation was first attempted

employing VO(acac)2 in toluene with TBHP as oxidant at 50 ˚C (Table 3.9, entry 1).

Epoxide 3.43 was obtained in a near-quantitative 98% yield, though in a disappointing

3:1 dr. The reaction could be performed at room temperature, but conversion was slow

i and diastereoselectivity increased only to 4:1 (entry 2). Ti(O Pr)4 is known to promote

i epoxidation in the presence of TBHP. Employing Ti(O Pr)4 stoichiometrically (entry 3) or

catalytically (entry 4) provided epoxide 3.43 in acceptable yield, though as a 1:1 ratio of

diastereomers. With clear evidence that allylic alcohol 3.47 lacked the inherent facial bias

109 to mandate significant diastereoselection, a chiral epoxidizing agent was next examined.

The Sharpless asymmetric epoxidation protocol31 was implemented using both the

diisopropyl (entry 5) and diethyl tartrate ligands (entry 6) though these reactions failed to

produce epoxide 3.43 with full recovery of allylic alcohol 3.47.

OMe OH OMe OH H H

O N N Boc Boc N N 3.47 3.43

Yield Recovered Entry Reagent(s) Oxidant Solvent Temp 3.43 Dr 3.47

1 VO(acac)2 (5 mol%) TBHP PhMe 50 ˚C 98% 3:1 -

2 VO(acac)2 (5 mol%) TBHP PhMe rt 64% 4:1 22% i 3Ti(OPr)4 (250 mol%) TBHP DCM rt 75% 1:1 - i 4Ti(OPr)4 (5 mol%) TBHP DCM 0 ˚C 73% 1:1 8% i 5Ti(OPr)4, D-(-)-DIPT TBHP DCM -20 ˚C to rt - - 98% i TBHP DCM -20 ˚C to rt - - 100% 6Ti(OPr)4, L-(+)-DET

Table 3.9: Optimization of allylic alcohol directed epoxidation

3.10.1 Vanadium-Catalyzed Epoxidation Mechanism Studies

It was next pondered why the directed epoxidation proceeded with such low

levels of diastereoselectivity. Relative stereochemistry was readily controlled in the

previous transformations with full chirality transfer. In evaluating the mechanism of the

vanadium-catalyzed epoxidation of acyclic allylic alcohols, Sharpless determined a

dihedral angle of 50˚ between the vanadate ester and alkene undergoing oxidation

(Scheme 3.23).32 This geometrical requirement places the two additional groups approximately 10˚ apart. Therefore, if one can partition between acyclic conformers 3.61

and 3.62 on the basis of A1,2-strain, one would expect to confer high levels of diastereoselection. Accordingly, conformer 3.61 depicts a 10˚ angle between R and H as

110 conformer 3.62 depicts that same angle between R and Me. Conformer 3.61 in this case would be vastly favored due to a minimal A1,2-interaction, and one would expect significant diastereoselection in the formation of threo-epoxy alcohol 3.63 especially as the size of the R substituent increases.

R H Me 50° OH VO VO(acac)2 H H R H R H H 10° H Me 10° Me 50° VO 3.61 3.62

R R Me Me O O OH OH 3.63 3.64

Scheme 3.23: Stereochemical model in the vanadium-catalyzed epoxidation

Accordingly, one would expect methyl-substituted allylic alcohol 3.65 and TMS- substituted allylic alcohol 3.67 to undergo highly diastereoselective epoxidation on the basis of A1,2-strain (Scheme 3.24). As predicted, epoxidation products 3.66 and 3.68 are obtained essentially as single diastereomers. Monosubstituted allylic alcohol 3.69 lacks the necessary substitution pattern to differentiate ground state conformers on the basis of

A1,2-strain and only a 4:1 dr is observed in epoxy alcohol 3.70. Lastly, trans-disubstituted allylic alcohol 3.71 presents the most challenging scenario and is thought to be the worst performing class of substrates in this directed epoxidation with only a 2.5:1 ratio of epoxy alcohol diastereomers 3.72 observed.33

111 Me Me TMS TMS Me Me Me Me O O OH OH OH OH 3.65 3.66 3.67 3.68 19:1 dr >99:1 dr

Me Me Me Me Me Me O O OH OH OH OH 3.69 3.70 3.71 3.72 4:1 dr 2.5:1 dr

Scheme 3.24: Diastereoselection in VO(acac)2-catalyzed epoxidation

3.10.2 Ligand Effects in Vanadium-Catalyzed Epoxidation

VO(acac)2 was providing the desired level of reactivity, however 1,2-disubstituted trans-allylic alcohols are the most challenging class of substrates in terms of diastereoselection. Hydroxamic acid ligands have been utilized in the development of an asymmetric variant of the vanadium-catalyzed epoxidation of allylic alcohols. In as early as 1977, Sharpless recognized that a chiral epoxidation catalyst can be formed in situ by pre-mixing of VO(acac)2 with a superstoichiometric amount of campholyl hydroxamic

acid ligand 3.75 (Scheme 3.25).34 This chiral epoxidation system was found to epoxidize

α-phenylcinnamyl alcohol (3.73) to epoxy alcohol 3.74 in 30% yield and 50% ee.

Although this ee is unacceptable by modern standards, it serves as proof of concept.

Yamamoto has made significant contributions to chiral ligand design in the preparation of

amino acid derived hydroxamate 3.7635 and bishydroxamate 3.7736. These ligands, at catalytic loading, have been effective in generating yields and ee’s in excess of 90% for the epoxidation of α-phenylcinnamyl alcohol (3.73).

112 VO(acac)2 Ph Ligand Ph O OH OH Ph TBHP, PhMe Ph 3.73 3.74

Ph O Ph O Me O N OH O OH N Me N OH Ph N N O OH Ph O Ph 3.75 3.76 3.77 (500 mol%) (1.5 mol %) (2 mol%)

30% yield 93% yield 91% yield 50% ee 96% ee 97% ee

Scheme 3.25: Chiral ligands in the asymmetric vanadium-catalyzed epoxidation

In hope that an achiral hydroxamic acid would increase diastereoselectivity, a

number of ligands were screened. VO(acac)2 and hydroxamic acid ligand in a 1:1.5 ratio

were stirred for 1 hour prior to the introduction of TBHP and allylic alcohol 3.47

(Scheme 3.26). Hydroxamic acid 3.78, prepared from N-methylhydroxylamine and

pivaloyl chloride, afforded epoxy alcohol 3.43 in 85% yield as a 6:1 ratio of

diastereomers. This ligand doubled the diastereoselectivity achieved with the unmodified

catalyst. Similar selectivity was observed with hydroxamic acid 3.81, prepared from N-

methylhydroxylamine and benzoyl chloride, though the yield dropped to 76% in this

experiment. Hydroxamic acid 3.78 became the ligand of choice in the continuing optimization effort.

113 OMe OH VO(acac) (5 mol%) OMe OH 2 H H ligand (7.5 mol%) O N TBHP, PhMe N Boc Boc 50 °C N N 3.47 3.43

O O O O O OH OH OH OH OH N N N N N Me Bn Me Bn

3.78 3.79 3.80 3.81 3.82 85% 81% 95% 76% 100% 6:1 dr 4:1 dr 4:1 dr 6:1 dr 4:1 dr

O OH O O O OH OH OH OH N N N N N Me Me Me OH O O2N 3.83 3.84 3.85 3.86 86% 65% 80% 92% 4:1 dr 4:1 dr 5:1 dr 4:1 dr

Scheme 3.26: Ligand screening for directed epoxidation

At this juncture, the 6:1 ratio of diastereomers remained unacceptable so the

epoxidation mechanism of this epoxidation was carefully considered. For epoxidation,

both TBHP and the allylic alcohol substrate must both be bound by the vanadium metal

as indicated in intermediate 3.88 (Scheme 3.27). This allows for coordination of only one

ligand to the metal center. Additionally, Sharpless has shown the exchange of

hydroxamic acid ligands for the acac to be an example of ligand deceleration catalysis.37

This means that the VO(acac)2 catalyst facilitates epoxidation at a rate four times faster

than that of a hydroxamate ligand vanadyl catalyst. In optimizing this reaction one faces

two major challenges. The first being that the reaction proceeds at a much faster rate with

the ligand that fails to increase diastereoselectivity. One must be certain that the less

active ligand is bound to the vanadyl center. Secondly, assuming the two ligands are

114 competing for coordination to the metal, the metal can become saturated with ligand and unable to coordinate the necessary oxidant and substrate to facilitate epoxidation.

tBuOH O tBuOOH OH V V OH RO OR O OR 3.87

O O tBu V t V O Bu V V O RO O RO O O O 3.90 3.88

t O Bu V O V RO O O

3.89

Scheme 3.27: Catalytic cycle for epoxidation of allylic alcohols

3.10.3 Optimization of Vanadium-Catalyzed Epoxidation

To address these issues, metal to ligand ratio was first probed. The increased 6:1 ratio of diastereomers was achieved at a metal:ligand ratio of 1:1.5 (Table 3.10, entry 2).

This ratio was increased to 1:3 and was met with an increase in dr to 8:1 (entry 3). This effect was examined further and a ratio of 1:4 provided an 8:1 dr (entry 4), 1:5 provided a

9:1 dr (entry 5), and 1:6 afforded a >20:1 dr (entry 6). Unfortunately, this final result at a

1:6 ratio led to much longer reaction times and incomplete conversion. A metal:ligand ratio of 1:4 was found to be optimal in terms of yield, dr, and reaction time. An increase in oxidant loading to 500 mol% maintained the excellent levels of chemical yield while increasing dr to 10:1 (entry 7). With the increase in oxidant loading, temperature could be reduced to room temperature and dr climbed to 11:1 (entry 8).

115 O OH N OMe OH Me OMe OH H H VO(acac)2 (5 mol%) O N TBHP, PhMe N Boc Boc N N 3.47 3.43

Entry Ligand Oxidant Temp Yield Dr 1 - TBHP (170 mol%) 50 ˚C 98% 3:1 2 7.5 mol% TBHP (170 mol%) 50 ˚C 85% 6:1 3 15 mol% TBHP (170 mol%) 50 ˚C 91% 8:1 4 20 mol% TBHP (170 mol%) 50 ˚C 86% 8:1 5 25 mol% TBHP (170 mol%) 50 ˚C 84% 9:1 6 30 mol% TBHP (170 mol%) 50 ˚C 60% >20:1 7 20 mol% TBHP (500 mol%) 50 ˚C 76% 10:1 8 20 mol% TBHP (500 mol%) rt 84% 11:1

Table 3.10: Optimization of epoxidation; effect of ligand loading

As one would expect, the competition between the hydroxamate ligand and acac

persisted. If acac could be completely eliminated from the reaction the true potential of the hydroxamic acid ligand could be evaluated. Therefore, VO(hydroxamate)2 catalyst

3.90 was prepared from hydroxamic acid 3.78 and vanadyl sulfate in 26% yield (Scheme

3.28).

O VO(SO ).H O O O O Me OH 4 2 N N V Na CO , H O N Me 2 3 2 Me O O 3.78 3.90 26%

Scheme 3.28: Preparation of epoxidation precatalyst

With catalyst 3.90 in hand, it was employed in the epoxidation of allylic alcohol

3.47 under the previously optimized conditions (Table 3.11, entry 2). Chemical yield of

epoxy alcohol 3.43 remained favorable, but diastereoselectivity dropped from 11:1 to

116 10:1. Though, this reaction proceeded at a much faster rate in the absence of excess

ligands. Accordingly, the reaction was performed at 4 ˚C and diastereoselectivity

increased dramatically to 16:1 (entry 3). Another increase in oxidant loading and brief

solvent screen found conversion to epoxy alcohol 3.43 in 91% yield as a 17:1 ratio of

separable diastereomers (entry 5). To prove this increase was a result of catalyst 3.90 and

not the other reaction parameters, VO(acac)2 was substituted for VO(hydroxamate)2 3.90

and found to confer only a 6:1 ratio of diastereomers (entry 6). The stereochemical

assignment of epoxy alcohol 3.43 was based on a single crystal X-ray diffraction analysis

(Figure 3.3).

O OH N OMe OH Me OMe OH H H VO(acac)2 O N OR N Boc Boc O O O Me N N N V 3.47 N 3.43 Me O O 3.90

Entry Catalyst (5 mol%) Ligand Oxidant Solvent Temp Yield Dr

1 VO(acac)2 20 mol% TBHP (500 mol%) PhMe rt 84% 11:1

2 VO(hydroxamate)2 - TBHP (500 mol%) PhMe rt 87% 10:1

3 VO(hydroxamate)2 - TBHP (500 mol%) PhMe 4 ˚C 86% 16:1

4 VO(hydroxamate)2 - TBHP (1000 mol%) PhMe 4 ˚C 90% 15:1

5 VO(hydroxamate)2 - TBHP (1000 mol%) DCM 4 ˚C 91% 17:1 - TBHP (1000 mol%) DCM 4 ˚C 86% 6:1 6 VO(acac)2

Table 3.11: Optimization of epoxidation; effect of bishydroxamate catalyst

117 OH H H O N H Trs N

OMe

3.43

Figure 3.3: Single crystal X-ray diffraction analysis of epoxy alcohol 3.43

3.11 C7 ALCOHOL DEOXYGENATION PRIOR TO QUINUCLIDINE FORMATION

With the epoxide functionality now in place, efforts were focused on the removal of the unwanted C7 alcohol functionality. Epoxy alcohol 3.43 was tosylated via

deprotonation with LHMDS followed by TsCl addition to afford tosylate 3.48 in 65%

yield (Scheme 3.29). The Boc group was next cleaved by treatment with TFA and the

crude amine was heated in DMF in hopes of cyclization to the desired [2.2.2] bicycle.

Unfortunately, the tosylate was found to be a better electrophile than the epoxide and

[2.2.1] bicycle 3.91 was obtained in 35% yield.

H OMe OH OMe OTs OMe H H 7 LHMDS, THF, 0 °C 1. TFA, DCM, 0 °C N O O O N N Boc then TsCl Boc 2. DMF, Δ N N N 3.43 3.48 3.91 65% 35%

Scheme 3.29: Deoxygenation following quinuclidine formation

118

It was clear that deoxygenation must be performed prior to quinuclidine

formation. Epoxy alcohol 3.43 underwent mesylation in 96% yield to furnish mesylate

3.92 (Table 3.12). It was hoped to selectively displace the mesylate by hydride without

epoxide opening to furnish adduct 3.93. The use of NaBH4 in polar aprotic media has

found wide applicability in the displacement of alkyl and aryl sulfonates.38 Under a

variety of conditions, regiochemistry of hydride addition could not be controlled giving

complex mixtures of free alcohol 3.43, recovered mesylate 3.92, deoxygenation and epoxide opening product 3.94, and trace amounts of the desired deoxygenation product

3.93 (Table 3.12, entry 1-4). Reduction with LiBHEt3 afforded exclusively mesylate 3.92

(entry 5). With these results, it was clear that deoxygenation must follow quinuclidine formation.

OMe OH OMe OMs H H MsCl, Et3N O O N N Boc DCM, 0 °C Boc N N 96% 3.43 3.92

OMe OMe H H HO O N N Boc Boc N N 3.93 3.94

Yield Recovered Yield Entry Hydride Solvent Temp 3.93 3.92 3.94

1NaBH4 DMSO rt trace 64% -

2NaBH4 DMSO 55 ˚C - - 25%

3NaBH4 HMPA rt - 21% -

4NaBH4 NMP rt - 23% - 5LiBHEt3 THF rt to 55 ˚C - 93% -

Table 3.12: Deoxygenation prior to quinuclidine formation

119 3.12 QUINUCLIDINE FORMATION

3.12.1 Quinuclidine Formation in Previous Syntheses

In examining the previous quinine syntheses, cyclization to the quinuclidine was facilitated under a variety of conditions. In the 1978 synthesis by workers at Hoffman-La

Roche, crude amine 3.95 underwent cyclization to quinine (3.1) in refluxing toluene with

EtOH as additive (Table 3.13, entry 1). 39 Jacobsen was able to effect the identical

transformation under microwave irradiation in MeCN at 185 ˚C (entry 2).40 Kobayashi

developed thermal cyclization conditions at 160 ˚C in DMF (entry 3).41

H OMe OMe H N O N H OH N N 3.95 3.1

Entry Additive Solvent Temp Yield 1 EtOH (1000 mol%) PhMe 110 ˚C73% 2 - MeCN 185 ˚C, μw68% 3-DMF160 ˚C66%

Table 3.13: Previous conditions for quinuclidine formation

3.12.2 Quinuclidine Formation Optimization

With evidence that EtOH in ten-fold excess was sufficient to activate epoxide

3.43 towards opening, it was hoped that the adjacent alcohol functionality present in

epoxy alcohol 3.43 could assist in epoxide activation via intramolecular hydrogen bonding as depicted in intermediate 3.96 (Scheme 3.30).

120 H N H H OMe OH OMe OMe H H Deprotection O N O O OH N H Boc OH N N N 3.43 3.96 3.97

Scheme 3.30: Epoxide activation via internal hydrogen bond

Carbamate 3.43 underwent facile deprotection upon treatment with TFA in DCM

at 0 ˚C to furnish crude amine 3.96 which was subjected to quinuclidine cyclization to

afford 7-hydroxyquinine (3.97). Cyclization of crude amine 3.96 in the absence of any

additive in refluxing toluene afforded quinuclidine 3.97 in only 11% yield (Table 3.14,

entry 1). Seemingly, epoxide activation by the adjacent alcohol moiety was insufficient to

promote cyclization. Employment of the Hoffman-La Roche conditions with EtOH as

additive in refluxing toluene was met with an increase in yield to 23% (entry 2). It was

next thought that a Lewis acid may provide the necessary activation to facilitate this

i transformation. Sharpless has shown that Ti(O Pr)4 can promote the regioselective

42 i intermolecular addition of amines to epoxy alcohols. Accordingly, Ti(O Pr)4 was found

to facilitate cyclization of crude amine 3.96 to bicycle 3.97 at room temperature in 33% yield (entry 3). This result dramatically displays the effect of the adjacent alcohol in the cyclization wherein previous syntheses required heating in excess of 110 ˚C. The low yield obtained under these conditions is partially attributed to the challenge of cleaving diol 3.97, which possess multiple Lewis basic sites, from the titanium center. Lithium

43 salts have been successful additives in the aminolysis of epoxides, though in our system

their insolubility in toluene mitigated a change to MeCN (entries 4-9). A significant

121 increase in yield to 46% was observed when LiOTf was employed (entry 9). Additive

screening next moved to various metal triflates. The larger zinc cation associated with

Zn(OTf)2 was found to be extremely effective when the cyclizations were heated to 80

˚C. At 150 mol% loading of Zn(OTf)2 a 70% yield of diol 3.97 over two steps could be

achieved (entry 10). Employing 100 mol% of Zn(OTf)2 led to a slightly diminished yield

of 65% over two steps. After viewing the necessity of a strong Lewis acid to promote the

cyclization, it is more likely that the adjacent alcohol functionality actually renders the

free amine less nucleophilic via hydrogen-bond donation.

H OMe OH OMe OH OMe H H TFA Na2CO3 N O O OH N NH Boc DCM, 0 °C Additive OH N N N

3.43 3.96 3.97

Entry Additive Solvent Temp Yield 1 - PhMe 110 ˚C 11% 2 EtOH (1000 mol%) PhMe 110 ˚C 23% i 3 Ti(O Pr)4 (500 mol%) PhMe rt 33% 4 LiClO4 (500 mol%) PhMe rt 13%

5 LiClO4 (500 mol%) PhMe 60 ˚C 23%

6 LiClO4 (500 mol%) MeCN 60 ˚C 29%

7 LiBF4 (500 mol%) MeCN 60 ˚C 35%

8 LiBF4 (150 mol%) MeCN 60 ˚C 27% 9 LiOTf (150 mol%) MeCN 60 ˚C 46%

10 Zn(OTf)2 (150 mol%) MeCN 60 ˚C 42%

11 Zn(OTf)2 (150 mol%) MeCN 80 ˚C 70% 12 Zn(OTf)2 (100 mol%) MeCN 80 ˚C 65%

Table 3.14: Optimization of quinuclidine formation

122 3.13 C7 ALCOHOL DEOXYGENATION FOLLOWING QUINUCLIDINE FORMATION

3.13.1 Regioselective C9 Alcohol Protection

The C7 deoxygenation of diol 3.97 began on a sour note. In 2006 Williams

published a synthetic approach to quinine which concluded at the intermediate 7-

hydroxyquinine (3.97) (Scheme 3.31).44 This group has yet to publish a protocol for the

deoxygenation of this diol at C7. Efforts toward deoxygenation began with the protection

of the alcohol functionality at C9. The p-methoxybenzyl group was selected as protecting

group because it would most likely not undergo intramolecular transfer with the

neighboring alcohol functionality and could be removed under a variety of mild

conditions.23 Optimized conditions were found to be deprotonation of diol 3.97 with KH

(120 mol%) in DMF at 4 ˚C followed by treatment with PMBCl (140 mol%) for 2 days at

4 ˚C to afford PMB ether 3.98 in 67% yield (Scheme 3.31). These conditions were

completely regioselective with alkylation observed exclusively at the benzylic alcohol.

1H NMR analysis of PMB ether 3.98 provided some interesting information. When

analyzed in CDCl3, there was significant peak broadening indicative of rotamers. In d6-

DMSO, the rotamers are fully resolved to afford an easily interpreted spectra. Clearly, there is significant hydrogen bonding between the C7 alcohol and C9 ether in the non- competitive solvent. In the attempted regioselective C9 acetylation and silylation intramolecular group transfer was observed.

H H OMe OMe 7 1. KH, DMF, 4 °C N N OH OH 9 2. PMBCl, 4 °C OH OPMB N N 3.97 3.98 67%

Scheme 3.31: Regioselective PMB protection

123 3.13.2 Barton-McCombie C7 Alcohol Deoxygenation

With the alcohol functionalities now clearly differentiated, the Barton-McCombie

deoxygenation was first investigated.45 This strategy seemed quite attractive especially

with the precedence from a quinine model study.46 Stotter and coworkers found that diol

3.99 underwent regioselective benzylic acetylation to afford acetate 3.100 (Scheme 3.32).

The free alcohol functionality was converted to the intermediate thiocarbamate 3.101 by

treatment with TCDI (1,1’-thiocarbonyldiimidazole) followed by radical deoxygenation

to furnish 3.101 in 88% yield.

N N S HO HO O Ac2O, pyr TCDI Bu3SnH N N N N H THF, Δ PhMe, Δ Ph OH Ph OAc Ph OAc Ph OAc 3.99 3.100 3.101 3.102 84% 74% 88%

Scheme 3.32: Deoxygenation in quinine model study

This model study provided an attractive sequence for the ensuing deoxygenation

of alcohol 3.98. Unfortunately the lack of the vinyl residue on the bicycle and epimeric

C7 stereochemistry were large discrepancies between this model and the system in

question. The vinyl residue provides a perfectly situated template for intramolecular

radical cyclization of secondary radical 3.104 to form tricycle 3.105 (Scheme 3.33).

Additionally, the differing alcohol stereochemistry places the reacting center directly

below the quinuclidine making accessibility a question.

124 H H OMe OMe

N TCDI N Bu3SnH OH O S OPMB O R N N PMB 3.98 3.103

H H H OMe OMe OMe N N Bu3SnH N

OPMB OPMB OPMB N N N 3.104 3.105 3.106

Scheme 3.33: Potential undesired radical cyclization pathway

Treatment of alcohol 3.98 with TCDI in DCE at reflux (Table 3.15, entry 1) afforded none of desired thiocarbamate 3.107. Access to thiocarbamate 3.107 was

restricted even upon treatment of alcohol 3.98 with strong base to increase its nucleophilicity (entry 2, 3). Implementation of the classic conditions of NaH, CS2, then

MeI in refluxing THF also failed to provide xanthate 3.107 (entry 4). Reaction of the

alcohol with an acid chloride reagent employing bases of varying strength also failed to

provide key intermediate 3.107 (entry 5, 6).

Protocols for the radical deoxygenation of tertiary alcohols and hindered

secondary alcohols were additionally explored. Upon treatment with oxalyl chloride followed by N-hydroxy-2-thiopyridone, tertiary alcohols form mixed oxalate esters which

readily undergo radical-mediated deoxygenation.47 Thioformates48 as well as

phenylselenocarbonates49 both serve as radical-mediated deoxygenation precurors of

hindered alcohols. Under all reported conditions, alcohol 3.98 failed to undergo

conversion to the thiono or selenointermediate.

125 H H H OMe OMe OMe nBu SnH N N 3 N OH O S AIBN, Δ OPMB O x OPMB R N N PMB N 3.98 3.107 3.108

Yield Recovered Entry Reagent(s) Base Solvent Temp 3.108 3.98 1 TCDI - DCE rt to Δx - 70% 2 TCDI KH THF 0 ˚C to Δx - 93% 3 TCDI KH DMF 0 ˚C to 100 ˚C - 80%

4 CS2, MeI NaH THF rt to Δx - 56% 5 ClC(=S)OPh pyr DCM rt - 98% 6 ClC(=S)OPh KH THF 0 ˚C to Δx -trace

Table 3.15: Conditions for thionoester formation

3.13.3 Additional Alcohol Deoxygenations

Catalytic InCl3 in conjunction with Ph2SiHCl is known to directly reduce

secondary or tertiary alcohols to their corresponding alkanes.50 This is thought to proceed

via first alcohol silylation to yield 3.110 (Scheme 3.34). Silyl ether 3.110 is next activated

by InCl3 to form complex 3.111 which undergoes hydride transfer to furnish alkane 3.112

regenerating InCl3 and forming siloxane (3.113).

Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph2SiHCl InCl3 - InCl3 Si O OH O O H H SiHPh Cl In Si Ph 2 3 n Ph2 3.109 3.110 3.111 3.112 3.113

Scheme 3.34: Proposed mechanism for InCl3-catalyzed deoxygenation

The utilization of these novel conditions failed in the deoxygenation of alcohol

3.98. Modifications included stoichiometric InCl3 and heating but all screened conditions

126 failed to give the desired product. This again suggests that the C7 alcohol is in an

extremely sterically encumbered environment below the quinuclidine.

An additional single step process for the reductive deoxygenation of alcohols under Mitsunobu conditions51 was also examined. It is thought that alcohol 3.114 undergoes standard Mitsunobu activation and is displaced by o- nitrobenzenesulfonylhydrazine (NBSH) to give diazene 3.115 (Scheme 3.35). Warming the reaction mixture leads to the loss of the sulfinic acid and dinitrogen to afford alkane

3.116.

NO2 O O S NHNH2 ≥ 0 °C R OH R N(NH2)SO2Ar R H PPh3, DEAD, -HSO2Ar, -N2 3.114 THF, -30 °C 3.115 3.116

Scheme 3.35: Proposed mechanism for deoxygenation via Mitsunobu conditions

Implementation of this method in the deoxygenation of alcohol 3.98 afforded only

starting material. It is noted that this method works well for unhindered alcohols.

Secondary acyclic alcohols are viable substrates though, cyclic alcohols do not

participate. Although related methods for borohydride reduction of activated phosphonium ethers exist52, these methods were unfruitful. These facts confirm that

access to this alcoholic center is extremely limited.

Although Williams reported the instability of the 7-oxo-quinine analog at the

carbonyl oxidation level44 in it’s propensity to eliminate to the enone, the oxidation of alcohol 3.98 was investigated. Chromium-based reagents as well as Swern-type reagent systems all resulted in the recovery of 3.98.

127 3.12.4 Deoxygenation via Nucleophilic Displacement at C7

With evidence that the alcohol at C7 was extremely hindered and O-alkylation

was challenging, efforts were focused on a displacement reaction at C7. Gratifyingly, it

was found that alcohol 3.98 underwent mesylation by treatment with mesyl chloride in

pyridine to afford mesylate 3.117 in good yield (Scheme 3.36). Additionally, this alcohol

could be functionalized as the triflate, though complete conversion was challenging.

H H OMe OMe 7 MsCl, pyr. N N OH OMs OPMB OPMB N N 3.98 3.117 80%

Scheme 3.36: Mesylation of the hindered C7 alcohol

It was hoped that a halide could substitute either the alcohol functionality of 3.98 or mesylate 3.117 (Scheme 3.37). Metal-halogen exchange of halide 3.118 would form an organometallic intermediate which would then undergo protonation upon treatment with acid to yield 9-PMB quinine (3.108). Reaction conditions from alcohol 3.98 or mesylate

3.117 for halide introduction included treatment with SOCl2, PCl5, Me4NBr, and KI,

though all resulted in no reaction.

H H H OMe OMe OMe X X 1. Mg or Li H N N N OR H 2. Acid H OPMB OPMB OPMB N N N 3.98, R = H 3.118 3.108 3.117, R = Ms

Scheme 3.37: Deoxygenation via metal-halogen exchange

128 Yus has developed a system capable of reducing alkyl and vinyl sulfonates via

treatment with CuCl2·2 H2O, lithium sand, and catalytic DTBB (4,4’-di-tert-

butylbiphenyl) in THF at room temperature.53 Under these conditions, Yus was able to

reduce sterically hindered menthol derived secondary mesylate 3.119 and adamanatane

mesylate 3.120 in 65% and 80% yields respectively (Figure 3.4). In the system of

interest, mesylate 3.117 failed to react under these reducing conditions.

OMs MsO 3.119 3.120

Figure 3.4: Substrates for Yus’ reduction of sterically hindered mesylates

Displacement of mesylate 3.117 by tosylhydrazide was next attempted. Upon successful displacement of the mesylate, hydrazide 3.121, an intermediate in the Wolff-

Kishner reaction, could undergo further reduction to afford 9-PMB quinine (3.108). It

was found that a large excess of tosylhydrazide would begin to facilitate mesylate

displacement, though conversion to intermediate 3.121 was minimal (Table 3.16). The

addition of base to the mixture of mesylate 3.117 and hydrazide 3.121 failed to afford

deoxygenation product 3.108. As expected, the combination tosylhydrazide and strong

base prompted the formation of the powerful reducing agent diimide. Accordingly,

reduction of the vinyl residue on the quinuclidine was observed.

129 H H H TsHN OMe OMe HN OMe H H NNHTs Base N 2 N N OMs H H EtOH, Δx Δx OPMB OPMB OPMB N N N 3.117 3.121 3.108

Yield Recovered Entry H2NNHTs Base 3.108 3.117 1 130 mol% NaOH (3000 mol%) - 76% 2 300 mol% NaOH (3000 mol%) - 53% 3 1000 mol% NaOH (3000 mol%) - mixture 4 2000 mol% NaOH (3000 mol%) - mixture 5 1000 mol% NaOAc (500 mol%) -- 6 1000 mol% NaOAc (3000 mol%) --

Table 3.16: Deoxgenation via mesylate displacement by tosylhydrazide

Displacement with sulfur nucleophiles was also examined. Sulfur is a small nucleophile and can easily be reduced upon treatment with Raney Nickel.54 Treatment of mesylate 3.117 with thiophenol and K2CO3 in DMF with heating afforded only recovered mesylate 3.117 in 26% yield (Table 3.17, entry 1). Similar reaction conditions employing the deprotonated thiol also failed to deliver desired sulfide 3.122 (entry 2, 3).

Employment of potassium thioacetate failed in the desired transformation though mesylate 3.117 was recovered in near-quantitative fashion (entry 4, 5) Lastly, reaction with sodium sulfide failed to provide the desired thiol, instead furnishing a trace amount of cyclization product 3.123 (entry 6).

130 H H H OMe OMe OMe R R R S H 1 S 2 1 Raney Ni N N N OMs DMF H H OPMB OPMB OPMB N N N 3.117 3.122 3.108 H OMe S N H OPMB N 3.123

Yield Recovered Entry R1-S-R2 Temp 3.108 3.117 1 PhSH (1000 mol%), K2CO3 rt to 60 ˚C - 26% 2 PhSNa (150 mol%) rt to 60 ˚C - 23% 3 PhSNa (2000 mol%) 150 ˚C- - 4 AcSK (2000 mol%) rt - 98% 5 AcSK (2000 mol%) 80 ˚C - 91% 6 Na2S (2000 mol%) 80 ˚C trace 3.123 -

Table 3.17: Deoxgenation via mesylate displacement by sulfur nucleophiles

Hydride nucleophiles were next examined in the displacement of mesylate 3.117.

Reduction of mesylate 3.117 with LiBHEt3 in THF at reflux afforded only 24% recovery of the starting material (Table 3.18, entry 1). The use of LiAlH4 as reductant under

identical conditions failed to convert mesylate 3.117 to 9-PMB quinine (3.108), though

46% of the mesylate was recovered (entry 2). The nucleophilicity of borohydrides has been found to be greatly increased in the presence of polar solvents such as HMPA,

DMSO, NMP, and sulfolane in the displacement of primary and secondary alkyl halides,

38 sulfonate esters, and tertiary amines. Therefore, NaBH4 was examined in a variety of

extremely polar, aprotic solvents. Reaction in DMSO was unfruitful with only recovery

of mesylate 3.117 (entry 3). With 2000 mol% of NaBH4 at 90 ˚C in HMPA (entry 4) and

NMP (entry 5), the product of deoxygenation was observed by mass spectrometry.

131 Unfortunately, the reaction mixture was quite complex. Mass spectrometry analysis also indicated the presence of mesylate 3.117 and alcohol 3.98. These three compounds were

inseparable by chromatography. Increasing the reaction temperature to 105 and 120 ˚C

(entries 6-9) as well as subjection to microwave irradiation (entries 10-12) provided no further insight to product distribution.

H H OMe OMe H H N N OMs H OPMB OPMB N N 3.117 3.108

Yield 3.108 in Recovered Entry Hydride Solvent Temp Time 3.108 MS 3.117 1 LiBHEt3 (500 mol%) THF 65 ˚C 20 h - - 24%

2 LiAlH4 (500 mol%) THF 65 ˚C 20 h - - 46%

3 NaBH4 (2000 mol%) DMSO 90 ˚C 20 h - - 51%

4 NaBH4 (2000 mol%) HMPA 90 ˚C 20 h trace yes -

5 NaBH4 (2000 mol%) NMP 90 ˚C 20 h trace yes -

6 NaBH4 (2000 mol%) NMP 105 ˚C 20 h observed yes observed

7 NaBH4 (2000 mol%) NMP 105 ˚C 67 h trace yes trace

8 NaBH4 (2000 mol%) HMPA 120 ˚C 20 h trace yes -

9 NaBH4 (2000 mol%) NMP 120 ˚C 20 h trace yes -

10 NaBH4 (2000 mol%) NMP 105 ˚C (μw) 15 min trace yes -

11 NaBH4 (2000 mol%) NMP 95 ˚C (μw) 15 min trace yes observed

12 NaBH4 (2000 mol%) NMP 80 ˚C (μw) 15 min trace yes observed

Table 3.18: Deoxgenation via mesylate displacement by hydride

Given the fact that the developing conditions were quite harsh, it was reasoned

that the 9-PMB quinine (3.108) product may not survive these reductive conditions.

Accordingly, 9-PMB quinine (3.108), prepared from quinine (3.1) in 82% yield, was

subjected to NaBH4 reduction in NMP at 105 ˚C for 20 hours (Scheme 3.38). In this

experiment, only 66% of 9-PMB quinine (3.108) was recovered establishing that the deoxygenation product is not stable to the reductive conditions.

132 H H OMe OMe 1. NaH, DMF, 0 °C NaBH , NMP N N 4 66% recovery of starting material 2. PMBCl 105 °C, 20 h OH OPMB N N 3.1 3.108 82%

Scheme 3.38: Experiment for product stability to reductive deoxygenation

The reduction of mesylate 3.117 via NaBH4 in NMP was beginning to shows

signs of conversion to the desired deoxygenation product of 9-PMB quinine (3.108).

Unfortunately, the reaction is sluggish, suffers from competing mesylate hydrolysis, and

the product has been found to be unstable to the reaction conditions.

Oxidative addition to the C7 - O bond of mesylate 3.117 by nucleophilic

55 56 transition metals such as the Collman reagent (Na2Fe(CO)4) and Rieke manganese were examined, but all efforts resulted in the decomposition of the starting material.

3.13.5 Deoxygenation From MOM Ether

To examine if the PMB protecting group is having a negative effect in the hydride

mediated deoxygenation, the smaller MOM ether was also prepared. Diol (3.97)

underwent analogous O-alkylation to afford MOM ether 3.124 in 58% yield (Scheme

3.39). Mesylation of alcohol 3.124 proceeded as expected though this compound failed to

survive the NaBH4 deoxygenation in NMP or provide the desired 9-MOM quinine

(3.125). As a control experiment, 9-MOM quinine (3.125), the desired product of deoxygenation was prepared from quinine. When subjected to the NaBH4-mediated

deoxygenation, none of the starting material was recovered from the reaction mixture.

133

H H H OMe OMe OMe 1. KH, DMF, 4 °C 1. MsCl, pyr. N N N R R 2. MOMCl, 4 °C 2. NaBH4, NMP, OH OMOM 105 °C, 20 h OMOM N N N 3.97, R = OH 3.124, R = OH, 58% 3.125 3.1, R = H 3.125, R = H, 49%

Scheme 3.39: MOM protection and deoxygenation via mesylate displacement

3.14 FORMAL SYNTHESIS

Though quinine could not be accessed via C7 deoxygenation, a formal total synthesis has been completed. One could envision intercepting N-Cbz alkene 3.126, an

intermediate from the 2004 Jacobsen synthesis40, en route to quinine (3.1) (Scheme 3.40).

H OMe OMe H N N OH Cbz N N

3.1 3.126

Scheme 3.40: Jacobsen’s viable intermediate for formal synthesis

3.14.1 Deoxygenation from N-Boc Series

Retrosynthetically, N-Cbz alkene 3.126 could be intercepted via acetylation of allylic alcohol 3.47 followed by displacement of the resulting allylic acetate and carbamate protecting group exchange (Scheme 3.41). Palladium-catalyzed reductions of allylic acetates mediated by hydride, formic acid, and ammonium formate are well documented.57 Additionally, deoxygenation of allylic acetates conjugated to aromatic

rings are known to almost exclusively produce the conjugated alkene.57b

134 H OMe OMe OMe OH H H N N N OH Cbz Boc N N N

3.1 3.126 3.47

OMe

OCO2Me CHO O O N PR Me 3 Me N Pd(PPh ) N Trs 3 4 Trs

3.16 3.14

Scheme 3.41: Retrosynthetic approach toward formal total synthesis

Accordingly, allylic alcohol 3.47 was acetylated with Ac2O, DMAP, and Et3N in

DCM at 0 ˚C to afford allylic acetate 3.127 in 92% yield (Scheme 3.42). Deoxygenation

of allylic acetate 3.127 to afford N-Boc alkene 3.128 as a single regioisomer proceeded in

a near-quantitative 96% yield upon treatment with catalytic Pd(PPh3)4 and formic acid

which served as hydride donor. N-Boc alkene 3.128 underwent deprotection with TFA

followed by Cbz protection of the crude secondary amine to furnish N-Cbz alkene 3.126

in 76% yield. Thus, the Jacobsen intermediate was intercepted in 13 linear steps with a

12% overall yield. N-Cbz alkene 3.126 is accessed in a fully stereoselective manner and

in one fewer step than in the Jacobsen synthesis.

135 OMe OH OMe OAc H H Ac2O, DMAP Pd(PPh3)4, PBu3 N N Boc Et3N, DCM, 0 °C Boc HCO2H, Et3N, THF N N 3.47 3.127 92% 96%

OMe OMe H H 1. TFA, DCM, 0 °C N N Boc 2. CbzCl, K2CO3, Cbz THF, 0 °C N N 3.128 3.126 76%

Scheme 3.42: Deoxygenation and formal synthesis with N-Boc series

3.14.2 Deoxygenation from N-Cbz Series

A second approach was also considered to avoid the use of three different amine

protecting groups, including two carbamates. The deprotection-reprotection step of

sulfonamide 3.33 was optimized replacing Boc2O with CbzCl to afford N-Cbz piperidine

3.129 in 61% yield (Scheme 3.43). This substrate underwent analogous aldol-dehydration

to introduce the quinoline moiety to furnishing enone 3.130 in 64% yield. Sensitive

enone 3.130 was treated with L-Selectride to afford allylic alcohol 3.131 in 96% yield, again observed as a single diastereomer. Allylic alcohol 3.131 was acetylated to furnish allylic acetate 3.132 which was then deoxygenated via the developed Pd-catalyzed method to afford N-Cbz alkene 3.126 in 78% yield, again observed as a single regioisomer. In this second generation approach, the introduction of the Cbz group does not significantly alter the previously developed route and favorably reduces the step count to 12 linear manipulations with an 8% overall yield.

136 LHMDS, THF, -78 °C CHO MeO O Na, naphthalene O OMe O H DME, -78 °C H then N H Me Me then aq. NH Cl N 4 N then Ac2O, DMAP N Trs CbzCl, Et3N Cbz DBU, -40 °C Cbz DCM, 0°C N 3.33 3.129 3.130 61% 64%

OMe OH OMe OAc H H L-Selectride Ac2O, DMAP N N THF, -78 °C Cbz Et3N, DCM, 0 °C Cbz N N 3.131 3.132 96% 81% (>20:1)

OMe H Pd(PPh3)4, PBu3

HCO H, Et N, THF N 2 3 Cbz N 3.126 78%

Scheme 3.43: Deoxygenation and formal synthesis with N-Cbz series

3.15 SUMMARY AND CONCLUSIONS

The cycloallylation methodology has been successfully extended to a new class of heteroatom tethered substrates in the application toward the total synthesis of the alkaloid natural product quinine. The cycloallylation product has been obtained in 68% yield representing the highest chemical yield for the construction of a six-membered ring by this method. This compound has been further elaborated by a number of highly diastereoselective transformations displaying efficient chirality transfer. This elaboration has notably seen the development of a novel and highly selective vanadium epoxidation catalyst. Although the total synthesis remains one step from accessing the natural

137 product, a formal synthesis has been completed in two fewer steps than the most concise

route to date.

3.16 EXPERIMENTAL PROCEDURES

General Procedures All reactions were run under an atmosphere of argon, unless otherwise indicated. Anhydrous solvents were transferred by an oven-dried syringe. DCM, tBuOH, tAmOH, i MeCN, Pr2NH, and HMPA were dried by distillation over CaH2. Et2O, DME, THF, and toluene were dried by distillation over sodium benzophenone. DMF and pyridine were stored over molecular sieves and KOH respectively. Chemical reagents were purchased from Aldrich, Fischer, and Strem Chemicals and used as received without further purification unless otherwise stated. Flasks were flame-dried and cooled under a stream of argon. Analytical thin-layer chromatography (TLC) was carried out using 0.2 mm

commercial silica get plates (DC-Fertigplatten Kieselgel 60 F254). Flash chromatography was performed on silica gel 60 (200 – 400 mesh) according to the method of Still.58 Solvents for chromatography are listed as volume:volume ratios. Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a Varian Inora 500, Varian Mercury 400, or Varian UNITY + 300 spectrometer. 1H NMR spectra were obtained at either 500, 400, or 300 MHz, as indicated. Chemical shifts are reported in delta (δ) units, parts per million (ppm) downfield from trimethylsilane. Coupling constants are reported in Hertz (Hz). Carbon-13 nuclear magnetic resonance (13C NMR) spectra were recorded on a Varian Inora 500, Varian Mercury 400, or Varian UNITY + 300 spectrometer. 13C NMR spectra were obtained at either 125, 100, or 75 MHz, as indicated. Chemical shifts are reported in delta (δ) units, parts per million (ppm) relative to the residual solvent. 13C NMR spectra were routinely run with broadband decoupling. Vanadium-51 nuclear magnetic resonance (51V NMR) spectra were recorded on a Varian Inora 500. 51V NMR spectra were obtained at 131 MHz. Chemical shifts are reported in delta (δ) units, parts per million

(ppm) relative to the singlet at 2.0 ppm for VOCl3. FT-IR spectra were obtained using a Nicolet Impact 410 spectrometer. High-resolution mass spectra (HRMS) were obtained on a Micromass ZAB-E spectrometer and are reported m/z (relative intensity). Accurate masses are reported for the molecular ion (M + 1) or a suitable fragment ion. Optical

138 rotations were obtained on an Atago AP-300 polarimeter at a path length of 1 dm. Melting points were obtained on a Thomas-Hoover Unimelt apparatus in open capillaries and are uncorrected.

Synthetic Procedures OEt NHTs EtO N-(2,2-Diethoxy-ethyl)-4-methyl-benzenesulfonamide (3.7) To a solution of aminoacetaldehyde diethyl acetal (2.18 mL, 15.0 mmol) in DCM (24

mL) at 0 ˚C was added Et3N (2.78 mL, 19.9 mmol, 133 mol%) and tosyl chloride (3.81 g, 20.0 mmol, 133 mol%). The reaction mixture slowly warmed to room temperature over 20 hours at which time it was quenched with water and extracted with DCM (3x). The combined organic layers were washed with saturated aqueous Cu2SO4 (1x), brine (1x),

dried over Na2SO4, and concentrated to afford pure sulfonamide 3.7 (3.3097 g, 11.6 mmol, 77%) as a white solid. Spectral data matched that of the literature reference.2

OH OCO2Me cis-Carbonic acid 4-hydroxy-but-2-enyl ester methyl ester (3.133) To a solution of cis-butene-1,4-diol (80 mL, 0.97 mol) in THF (900 mL) and pyridine (70 mL, 0.87 mol, 90 mol%) at 0 ˚C was added dropwise via addition funnel methyl chloroformate (48 mL, 0.62 mol, 64 mol %) in THF (180 mL). Following the 1.5 hour addition, the reaction mixture warmed to room temperature over 21 h at which time it was quenched with 1N HCl and extracted with EtOAc (3x). The combined organic extracts were washed with saturated aqueous NaHCO3 (1x), brine (1x), dried over

Na2SO4, and concentrated. The crude product was purified by flash column chromatography (3:1 hexanes:EtOAc to 1:2) to afford allylic carbonate 3.133 (71.02 g, 0.49 mol, 77%) as a colorless oil. Spectral data matched that of the literature reference.3

139 OCO2Me

O NTs H Carbonic acid methyl ester 4-[(2-oxo-ethyl)-(toluene-4-sulfonyl)-amino]-but-2-enyl ester (3.8) To a solution of acetal 3.7 (9.33 g, 32.5 mmol) in THF (325 mL) at 0 ˚C was added allylic alcohol 3.133 (5.72 g, 39.1 mmol, 120 mol%), DIAD (8.32 mL, 42.3 mmol, 130 mol%), and PPh3 (11.1 g, 42.3 mmol, 130 mol%). The reaction vessel was wrapped in foil and the reaction mixture slowly warmed to room temperature over 20 h at which time it was concentrated. The crude product was purified by flash column chromatography (10:1 hexanes:EtOAc to 5:1, 3:1, 2:1) to afford the intermediate allyl carbonate (14.26 g) as a thick yellow oil. The allyl carbonate was taken up in AcOH (277 mL) and water (67 mL) and heated at 100 ˚C for 2 h. The reaction mixture was then cooled to room temperature, quenched with solid NaHCO3, and extracted with DCM (3x). The combined

organic extracts were washed with saturated aqueous NaHCO3 (3x), brine (1x), dried

over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (5:1 hexanes:EtOAc to 3:1, 2:1, 1.5:1, 1:1) give aldehyde 3.8 (8.07 g, 1 23.7 mmol, 73% over 2 steps) as a yellow oil. H NMR (300 MHz, CDCl3): δ 9.56 (s, 1 H), 7.69 (d, 2 H, J = 8.2 Hz), 7.33 (d, 2 H, J = 8.2 Hz), 5.78-5.70 (m, 1 H), 5.61-5.53 (m, 1 H), 4.55 (d, 2 H, J = 6.7 Hz), 3.94 (d, 2 H, J = 6.9 Hz), 3.86 (s, 2 H), 3.74 (s, 3 H), 2.43 13 (s, 3 H); C NMR (75 MHz, CDCl3): δ 197.7, 155.5, 144.1, 135.5, 129.9, 128.9, 128.5, 127.3, 62.3, 56.1, 54.9, 45.8, 21.5; IR (neat) ν 2958, 1598, 1445, 1345, 1267, 1161, 763;

HRMS (CI) calcd. for C15H20NO6S [M + 1]: 342.1011, found: 342.1011.

O Ph3P Me (1-(triphenylphosphoranylidene)-2-propane) (3.134) To a solution of chloroacetone (25.8 mL, 324.2 mmol) in DCM (255 mL) at room

temperature was added PPh3 (84.9 g, 323.7 mmol, 100 mol%). The reaction mixture was heated at reflux for 20 h, cooled to room temperature, filtered, and rinsed with DCM. The

collected solid was then taken up in H2O (1200 mL) at room temperature and Na2CO3 (180 g, 1.7 mol, 500 mol%) was added in three portions. The reaction mixture stirred for 20 h and was filtered. The resulting solid was dissolved in boiling toluene and then

140 hexane was added to precipitate Wittig reagent 3.134 (52.64 g, 165.1 mmol, 51%) which was collected by filtration as a white solid. Spectral data matched that of the literature reference.4

OCO2Me

O

Me NTs Carbonic acid methyl ester 4-[(4-oxo-pent-2-enyl)-(toluene-4-sulfonyl)-amino]-but- 2-enyl ester (3.9) To a solution of aldehyde 3.8 (0.26 g, 0.75 mmol) in DCM (7.5 mL) at room temperature was added Wittig reagent 3.134 (0.24 g, 0.76 mmol, 100 mol%). The reaction mixture stirred for 20 h at which time it was concentrated. The crude product was purified by flash column chromatography (5:1 hexanes:EtOAc to 3:1, 2:1) to give enone 3.9 (0.20 g, 1 0.52 mmol, 69%) as a yellow oil. H NMR (400 MHz, CDCl3): δ 7.64 (d, 2 H, J = 8.2 Hz), 7.27 (d, 2 H, J = 7.9 Hz), 6.51 (dt, 1 H, J = 16.1 Hz), 6.06 (dt, 1 H, J = 16.4, 1.4 Hz), 5.66-5.60 (m, 1 H), 5.49-5.42 (m, 1 H), 4.51 (dd, 2 H, J = 6.8, 1.0 Hz), 3.86 (m, 4 H), 13 3.69 (s, 3 H), 2.37 (s, 3 H), 2.14 (s, 3 H); C NMR (100 MHz, CDCl3): δ 197.4, 155.2, 143.7, 141.1, 136.2, 132.4, 129.7, 129.1, 127.2, 127.0, 62.3, 54.6, 48.2, 44.6, 26.9, 21.2;

IR (neat) ν 3055, 2985, 1599, 1422, 1265, 741, 706; HRMS (CI) calcd. for C18H24NO6S [M + 1]: 382.1324, found: 382.1329.

O

Me NTs 1-[1-(Toluene-4-sulfonyl)-3-vinyl-1,2,3,6-tetrahydro-pyridin-4-yl]-ethanone (3.11) To a degassed solution enone 3.9 (0.083 g, 0.20 mmol) in tAmOH (2.2 mL) at room

temperature was added Pd(PPh3)4 (0.013 g, 0.01 mmol, 5 mol%) and freshly distilled

PBu3 (0.05 mL, 0.2 mmol, 100 mol%). The reaction mixture stirred at room temperature for 20 min at which time it was concentrated. The crude product was purified by flash column chromatography (5:1 hexanes:EtOAc to 3:1, 2:1) to furnish piperidine 3.11 1 (0.042 g, 0.12 mmol, 62%) as a yellow oil. H NMR (400 MHz, CDCl3): δ 7.66 (d, 2 H, J = 8.2 Hz), 7.32 (d, 2 H, J = 8.2 Hz), 6.72 (t, 1 H, J = 3.5 Hz), 5.83 (ddd, 1 H, J = 17.1, 10.3, 6.8 Hz), 5.12-5.07 (m, 2 H), 4.20 (dd, 1 H, J = 19.0, 3.8 Hz), 3.74 (dd, 1 H, J = 11.6, 2.1 Hz), 3.51 (br s, 1 H), 3.36 (dt, 1 H, J = 19.1, 2.4 Hz), 2.54 (dd, 1 H, J = 11.5,

141 13 3.8 Hz), 2.42 (s, 3 H), 2.26 (s, 3 H); C NMR (100 MHz, CDCl3): δ 196.4, 143.9, 139.2, 136.6, 134.0, 132.8, 129.7, 127.6, 116.9, 47.2, 44.8, 36.8, 25.6, 21.5; IR (neat) ν 2924,

2854, 1674, 1597, 1354, 1166, 1093, 668; HRMS (CI) calcd. for C16H20NO3S [M + 1]: 306.1164, found: 306.1173.

OCO2Me

OEt NTrs EtO Carbonic acid 4-[(2,2-diethoxy-ethyl)-(2,4,6-triisopropyl-benzenesulfonyl)-amino]- but-2-enyl ester methyl ester (3.13) To a solution of sulfonamide 4.31 (10.76 g, 26.9 mmol) in THF (328 mL) at 0 ˚C was added allylic alcohol 3.133 (5.84 g, 40.00 mmol, 150 mol%), DIAD (8.50 mL, 43.2

mmol, 160 mol%), and PPh3 (11.39 g, 43.4 mmol, 160 mol%). The reaction vessel was wrapped in foil and the reaction mixture slowly warmed to room temperature over 20 h at which time it was concentrated. The crude product was purified by flash column chromatography (15:1 hexanes:EtOAc to 5:1, 3:1) to afford allyl carbonate 3.13 (14.2 g, 1 26.9 mmol, 100%) as a thick yellow oil. H NMR (400 MHz, CDCl3): δ 7.16 (s, 2 H), 5.78-5.72 (m, 1 H), 5.63-5.56 (m, 1 H), 4.66 (dd, 2 H, J = 6.8, 1.0 Hz), 4.53 (t, 1 H, J = 5.3 Hz), 4.15-4.07 (m, 2 H), 4.04 (d, 2 H, J = 7.2 Hz), 3.76 (s, 3 H), 3.68-3.60 (m, 2 H), 3.52-3.44 (m, 2 H), 3.26 (d, 2 H, J = 5.5 Hz), 2.89 (hp, 1 H, J = 6.8 Hz), 1.25 (dd, 18 H, J 13 = 6.9, 1.1 Hz), 1.18 (t, 6 H, J = 7.0 Hz). C NMR (100 MHz, CDCl3): δ 155.4, 153.1, 151.2, 131.2, 129.5, 127.5, 123.8, 102.3, 63.0, 63.0, 54.6, 47.1, 43.6, 34.0, 29.1, 24.6, 23.4, 15.1; IR (neat) ν 2962, 2872, 1752, 1601, 1445, 1425, 1365, 1012, 940. HRMS (CI)

calc. for C27H44NO7S [M – 1]: 526.2839, found: 526.2845.

OCO2Me

O

Me NTrs Carbonic acid methyl ester 4-[(4-oxo-pent-2-enyl)-(2,4,6-triisopropyl- benzenesulfonyl)-amino]-but-2-enyl ester (3.14)

To a solution of acetal 3.13 (29.38 g, 55.70 mmol) in CHCl3 (137 mL) and H2O (68 mL) at 0 ˚C was added TFA (68 mL, 915 mmol, 1640 mol%). The reaction mixture slowly

142 warmed to room temperature over 20 h at which time it was quenched with solid

NaHCO3, poured into H2O, and extracted with DCM (3x). The combined organic extracts

were washed with saturated aqueous NaHCO3 (1x), brine (1x), dried over Na2SO4, and concentrated. The yellow residue was then taken up in DCM (520 mL) and Wittig reagent 3.134 (19.73 g, 61.98 mmol, 110 mol%) was added at room temperature. The reaction mixture stirred for 18 h at which time it was concentrated. The crude product was purified by flash column chromatography (5:1 hexanes:EtOAc to 4:1, 3:1) to give exclusively trans-enone 3.14 (18.70 g, 37.88 mmol, 68%) as a white solid. mp: 42 ˚C; 1H

NMR (400 MHz, CDCl3): δ 7.18 (s, 2 H), 6.65 (dt, 1 H, J = 16.1, 6.4 Hz), 6.14 (d, 1 H, J = 16.1 Hz), 5.79-5.73 (m, 1 H), 5.68-5.62 (m, 1 H), 4.56 (d, 2 H, J = 6.8 Hz), 4.10 (hp, 2 H, J = 6.8 Hz), 3.97 (dd, 2 H, J = 5.2, 1.0 Hz), 3.89 (d, 2 H, J = 7.2 Hz), 3.77 (s, 3 H), 2.90 (hp, 1 H, J = 6.8 Hz), 2.23 (s, 3 H), 1.26 (dd, 18 H, J = 6.8, 1.4 Hz); 13C NMR (75

MHz, CDCl3): δ 197.5, 155.3, 153.5, 151.4, 141.0, 133.3, 130.3, 129.1, 127.6, 124.0, 70.9, 62.4, 54.8, 46.6, 42.8, 36.2, 34.0, 29.2, 28.5, 26.9, 24.7, 23.4; IR (film) ν 2960,

2931, 2871, 1601, 1384, 1107, 1072, 1060, 703; HRMS (CI) calc. for C26H40NO6S [M + 1]: 494.2576, found: 494.2579.

O

Me NTrs 1-[1-(2,4,6-Triisopropyl-benzenesulfonyl)-3-vinyl-1,2,3,6-tetrahydro-pyridin-4-yl]- ethanone (3.16) To a degassed solution of enone 3.14 (0.50 g, 1.0 mmol) in tAmOH (10.0 mL) at room

temperature was added Pd(PPh3)4 (0.059 g, 0.05 mmol, 5 mol%) and PMe3 (1.0 M in toluene, 0.82 mL, 0.8 mmol, 80 mol%). The reaction mixture stirred for 30 min at which

time it was poured into water and extracted with DCM (3x). The combined organic

extracts were washed with brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (10:1 hexanes:EtOAc to 5:1) afforded piperidine 3.16 (0.29 g, 0.68 mmol, 68%) as a yellow oil. 1H NMR (400 MHz,

CDCl3): δ 7.18 (s, 2 H), 6.80 (t, 1 H, J = 3.6 Hz), 5.70 (ddd, 1 H, J = 17.1, 10.3, 6.8 Hz), 5.03-4.96 (m, 2 H), 4.12 (hp, 2 H, J = 6.8 Hz), 3.93 (dd, 1 H, J = 18.7, 4.0 Hz), 3.80 (dt, 1 H, J = 18.7, 2.6 Hz), 3.68 (dd, 1 H, J = 12.2, 2.6 Hz), 3.55 (br s, 1 H), 3.04 (dd, 1 H, J = 12.0, 3.8 Hz), 2.90 (hp, 1 H, J = 6.8 Hz), 2.29 (s, 3 H), 1.26-1.23 (m, 18 H); 13C NMR

143 (100 MHz, CDCl3): δ 196.5, 153.5, 151.8, 139.3, 136.9, 134.4, 129.4, 123.9, 116.7, 45.6, 43.8, 36.8, 34.1, 29.4, 28.5, 25.6, 25.0, 24.7, 23.4, 23.4; IR (neat) ν 3068, 2962, 2870,

2823, 2255, 1674, 1601, 1562, 1462, 1385, 1152, 918; HRMS (CI) calc. for C24H36NO3S [M + 1]: 418.2410, found: 418.2407.

OCO2Me

O

EtS NTrs 4-[(4-Methoxycarbonyloxy-but-2-enyl)-(2,4,6-triisopropyl-benzenesulfonyl)-amino]- but-2-enethioic acid S-ethyl ester (3.21) A solution of acetal 3.13 (6.26 g, 11.86 mmol) in AcOH (89 mL) and water (24 mL) was heated at 100 ˚C for 1.5 h. The reaction mixture was then cooled to room temperature, quenched with solid NaHCO3, and extracted with DCM (3x). The combined organic

extracts were washed with saturated aqueous NaHCO3 (3x), brine (1x), dried over

Na2SO4, and concentrated. The yellow residue was then taken up in DCM (120 mL) and the stabilized thioester Wittig reagent59 (5.29 g, 14.53 mmol, 120 mol%) was added at room temperature. The reaction mixture stirred for 21 h at which time it was concentrated. The crude product was purified by flash column chromatography (7:1 hexanes:EtOAc to 5:1) to give exclusively trans-thioenoate 3.21 (4.74 g, 8.79 mmol, 1 74%) as a slightly yellow oil. H NMR (300 MHz, CDCl3): δ 7.17 (s, 2 H), 6.68 (dt, 1 H, J = 15.5, 6.2 Hz), 6.18 (d, 1 H, J = 15.6 Hz), 5.81-5.64 (m, 2 H), 4.57 (d, 2 H, J = 6.4 Hz), 4.10 (hp, 2 H, J = 6.7 Hz), 3.93-3.84 (m, 4 H), 3.77 (s, 3 H), 3.00-2.84 (m, 3 H), 13 1.27-1.24 (m, 21 H); C NMR (100 MHz, CDCl3): δ 189.1, 155.4, 153.5, 151.4, 137.9, 131.1, 130.4, 129.2, 127.7, 124.0, 65.7, 62.5, 54.8, 46.2, 42.9, 34.1, 29.3, 24.7, 24.7, 23.4, 23.2, 15.2, 14.5; IR (film) ν 2961, 2930, 2871, 1751, 1684, 1675, 1653, 1600, 1457,

1319, 1266, 1152; HRMS (CI) calc. for C27H42NO6S2 [M + 1]: 540.2454, found: 540.2454.

O

EtS NTrs 1-(2,4,6-Triisopropyl-benzenesulfonyl)-3-vinyl-1,2,3,6-tetrahydro-pyridine-4- carbothioic acid S-ethyl ester (3.23) To a degassed solution of thioenoate 3.21 (0.099 g, 0.18 mmol) in tAmOH (1.9 mL) at

room temperature was added Pd(PPh3)4 (0.011 g, 0.010 mmol, 5 mol%) and PMe3 (1.0 M

144 in toluene, 0.18 mL, 0.18 mmol, 100 mol%). The reaction mixture stirred for 30 min at which time it was poured into water and extracted with DCM (3x). The combined organic

extracts were washed with brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (10:1 hexanes:EtOAc to 7:1, 5:1) afforded piperidine 3.23 (0.043 g, 0.10 mmol, 57%) as a yellow oil. 1H NMR (400 MHz,

CDCl3): δ 7.18 (s, 2 H), 6.86 (t, 1 H, J = 3.2 Hz), 5.76-5.67 (m, 1 H), 5.07-5.02 (m, 2 H), 4.11 (hp, 2 H, J = 6.8 Hz), 3.86 (dd, 1 H, J = 18.6, 3.9 Hz), 3.76 (dt, 1 H, J = 18.6, 2.6 Hz), 3.67 (dd, 1 H, J = 12.0, 2.7 Hz), 3.55 (m, 1 H), 3.10 (dd, 1 H, J = 12.0, 4.1 Hz), 13 3.00-2.84 (m, 3 H), 1.27-1.23 (m, 21 H); C NMR (100 MHz, CDCl3): δ 191.7, 153.6, 151.8, 138.9, 136.3, 131.9, 129.4, 124.0, 117.3, 45.6, 43.8, 38.3, 34.1, 29.5, 25.1, 24.8, 23.5, 23.4, 23.2, 14.6; IR (film) ν 2967, 2930, 2871, 1663, 1653, 1599, 1458, 1365, 1152,

1115, 806; HRMS (CI) calc. for C25H38NO3S2 [M + 1]: 464.2293, found: 464.2288.

OCO2Me

O

EtO NTrs 4-[(4-Methoxycarbonyloxy-but-2-enyl)-(2,4,6-triisopropyl-benzenesulfonyl)-amino]- but-2-enoic acid ethyl ester (3.22)

To a solution of acetal 3.13 (1.57 g, 2.97 mmol) in CHCl3 (7.3 mL) and H2O (3.6 mL) at 0 ˚C was added TFA (3.6 mL, 48.87 mmol, 1650 mol%). The reaction mixture slowly warmed to room temperature over 20 h at which time it was quenched with solid

NaHCO3, poured into H2O, and extracted with DCM (3x). The combined organic extracts

were washed with saturated aqueous NaHCO3 (1x), brine (1x), dried over Na2SO4, and concentrated. The yellow residue was then taken up in DCM (29.7 mL) and (carbethoxymethylene)triphenylphosphorane (1.42 g, 4.08 mmol, 140 mol%) was added at room temperature. The reaction mixture stirred for 20 h at which time it was concentrated. The crude product was purified by flash column chromatography (7:1 hexanes:EtOAc to 5:1) to give exclusively trans-enoate 3.22 (1.08 g, 2.05 mmol, 69%) as 1 a colorless oil. H NMR (400 MHz, CDCl3): δ 7.17 (s, 2 H), 6.78 (dt, 1 H, J = 16.0, 6.2 Hz), 5.94 (d, 1 H, J = 15.7 Hz), 5.79-5.73 (m, 1 H), 5.70-5.64 (m, 1 H), 4.57 (d, 2 H, J = 6.5 Hz), 4.18 (q, 2 H, J = 7.2 Hz), 4.10 (hp, 2 H, J = 6.8 Hz), 3.94 (d, 2 H, J = 5.1 Hz), 3.89 (d, 2 H, J = 6.8 Hz), 3.77 (s, 3 H), 2.90 (hp, 1 H, J = 6.8 Hz), 1.57 (m, 21 H); 13C

145 NMR (100 MHz, CDCl3): δ 164.9, 155.1, 153.1, 151.1, 141.8, 130.3, 128.9, 127.4, 124.2, 123.7, 62.2, 60.0, 54.4, 45.9, 42.4, 33.8, 29.0, 24.4, 23.1, 13.8; IR (film) ν 2960, 2870, 2361, 2340, 1751, 1723, 1600, 1444, 1367, 1266, 1152; HRMS (CI) calc. for

C27H42NO7S [M + 1]: 524.2682, found: 524.2682.

O H Me NTrs cis-1-[1-(2,4,6-Triisopropyl-benzenesulfonyl)-3-vinyl-piperidin-4-yl]-ethanone (3.33) To a solution of CuI (2.92 g, 15.37 mmol, 110 mol%) in THF (480 mL) at -60 ˚C was

added MeLi (1.6 M in Et2O, 10.8 mL, 17.3 mmol, 130 mol%), HMPA (59.3 mL, 340.8 mmol, 2500 mol%), and DIBAL (1.0 M in cyclohexane, 69 mL, 69 mmol, 500 mol%). The resulting mixture was stirred between -60 ˚C and -55 ˚C for 1.5 h and then cooled to -78 ˚C. Enone 3.16 (5.74 g, 13.76 mmol) in THF (19 mL) was added to the reaction mixture at -78 ˚C. The reaction mixture stirred for 10 min at which time it was quenched with 2 M aqueous HCl at -78 ˚C and the cooling bath was immediately removed. The reaction mixture was brought to room temperature and poured into H2O and extracted

with Et2O (3x). The combined organic layers were washed with brine (1x), dried over

Na2SO4, and concentrated. The crude product was purified by flash column chromatography (5:1 hexanes:EtOAc to 4:1) to afford methyl ketone 3.33 (4.47 g, 10.60 mmol, 77%) as a white solid observed exclusively as the syn-diastereomer. mp: 112-113 1 ˚C; H NMR (400 MHz, CDCl3): δ 7.16 (s, 2 H), 5.83 (ddd, 1 H, J = 17.2, 10.5, 8.7 Hz), 5.30-5.06 (m, 2 H), 4.16-4.07 (m, 2 H), 3.78-3.73 (m, 1 H), 3.44-3.40 (m, 1 H), 3.12 (dd, 1 H, J = 11.8, 3.3 Hz), 2.94-2.84 (m, 3 H), 2.66 (dt, 1 H, J = 10.3, 4.4 Hz), 2.12 (s, 3 H), 13 1.88-1.79 (m, 2 H), 1.24 (dt, 18 H, J = 6.9, 1.5 Hz); C NMR (100 MHz, CDCl3): δ 208.5, 153.4, 151.8, 135.0, 129.6, 123.9, 117.7, 51.6, 48.4, 43.9, 40.4, 34.1, 31.6, 29.4, 28.6, 25.1, 24.7, 23.5, 22.6, 22.6, 14.1; IR (film) ν 2959, 2929, 2869, 1711, 1601, 1276,

1261, 1151, 764, 750; HRMS (CI) calcd. for C24H38NO3S [M + 1]: 420.2572, found: 420.2585.

146 OMe

Me N 6-Methoxy-4-methyl-quinoline (3.37)

To a solution of p-anisidine (17.18 g, 139.50 mmol) and FeCl3·6 H2O (75.73 g, 280.17 mmol, 200 mol%) in AcOH (450 mL) at 60 ˚C was added dropwise methyl vinyl ketone (12.3 mL, 147.76 mmol, 110 mol%). The reaction mixture was then heated at reflux for 3 h and cooled to room temperature, stirring for 36 h. The reaction mixture was then concentrated and the resulting black residue was made basic with 50% aqueous NaOH. The resulting mixture was dried overnight under vacuum, taken up in DCM, sonicated for 45 min, and then extracted with DCM (6x). The combined organic extracts were filtered

over celite, washed with 10% aqueous K2CO3 (2x), dried over Na2SO4, and concentrated. The crude dark solid was purified by flash column chromatography (2:1 hexanes:EtOAc to 1:1) to give methyl quinoline 3.37 (10.12 g, 58.59 mmol, 42%) as a dark brown solid. Spectral data matched that of the literature reference.18

OMe

CHO N 6-Methoxy-quinoline-4-carbaldehyde (3.38) To a solution of 6-methoxy-4-methyl-quinoline (3.37) (11.23 g, 64.82 mmol) in xylenes

(76 mL) at 135 ˚C was added SeO2 (11.67 g, 105.16 mmol, 160 mol%) in small portions over 1 h. The reaction mixture was heated at 135 ˚C for an additional 2 h at which time it was cooled to room temperature, filtered over celite, and celite pad rinsed with EtOAc.

The organic filtrate was washed with 10% aqueous K2CO3 (1x), H2O (1x), dried over

Na2SO4, and concentrated. The crude dark solid was purified by flash column chromatography (2:1 hexanes:EtOAc to 1:1, 1:2) to afford aldehyde 3.38 (6.15 g, 33.06 mmol, 51%) as an orange solid. Spectral data matched that of the literature reference.19

147 OMe O H

NTrs N trans-3-(6-Methoxy-quinolin-4-yl)-1-[1-(2,4,6-triisopropyl-benzenesulfonyl)-3-vinyl- piperidin-4-yl]-propenone (3.39) i To a solution of Pr2NH (0.040 mL, 0.25 mmol, 110 mol%) in THF (3.75 mL) at 0 ˚C was added nBuLi (2.5 M in hexanes, 0.1 mL, 0.25 mmol, 110 mol%). The resulting LDA mixture stirred for 30 min at 0 ˚C and was then cooled to -78 ˚C. At this time, methyl ketone 3.33 (0.093 g, 0.22 mmol) in THF (1.8 mL) was added dropwise. The reaction mixture stirred at -78 ˚C for 30 min at which time aldehyde 3.38 (0.049 g, 0.26 mmol, 120 mol%) in THF (1.8 mL) was added dropwise. The reaction mixture stirred at -78 ˚C for 30 min and then slowly warmed to room temperature over 18 h at which time it was quenched with saturated aqueous NH4Cl and extracted with Et2O (3x). The combined

ethereal extracts were washed with brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (5:1 hexanes:EtOAc to 3:1) to give enone 3.39 (0.064 g, 0.11 mmol, 50%) as a yellow oil. 1H NMR (300 MHz,

CDCl3): δ 8.78 (s, 1 H), 8.26 (d, 1 H, J = 15.9 Hz), 8.07 (d, 1 H, J = 9.2), 7.53 (d, 1 H, J = 4.1), 7.42 (dd, 1 H, J = 9.2, 2.6), 7.29 (br s, 1 H), 7.18 (s, 2 H), 6.98 (d, 1 H, J = 15.6 Hz), 5.67-5.62 (m, 1 H), 5.15-5.04 (m, 2 H), 4.18 (hp, 2 H, J = 6.8 Hz), 3.96 (s, 3 H), 3.76-3.69 (m, 2 H), 2.91-2.81 (m, 2 H), 2.73-2.69 (m, 2 H), 2.04-1.99 (m, 1 H), 1.78-1.75 13 (m, 1 H), 1.27 (dd, 18 H, J = 6.8, 3.2 Hz); C NMR (125 MHz, CDCl3): δ 199.7, 158.8, 153.4, 151.8, 151.8, 137.4, 136.7, 135.0, 130.8, 130.1, 129.7, 129.7, 127.7, 123.9, 123.2, 118.4, 117.8, 117.7, 101.1, 55.8, 53.0, 47.9, 43.7, 41.3, 34.2, 34.1, 29.4, 29.3, 24.5, 23.5; IR (film) ν 2959, 2927, 2868, 1690, 1619, 1506, 1470, 1430, 1103, 1032, 735; HRMS

(CI) calcd. for C35H45N2O4S [M + 1]: 589.3100, found: 589.3116.

O H Me NBoc cis-4-Acetyl-3-vinyl-piperidine-1-carboxylic acid tert-butyl ester (3.46) To a solution of naphthalene (9.57 g, 74.64 mmol, 940 mol%) in DME (22.8 mL) at room temperature was added freshly cut sodium (1.42 g, 61.72 mmol, 780 mol%). The resulting green radical anion solution was stirred for 2 h at which time it was added

148 dropwise to a solution of N-trisyl piperidine 3.33 (3.33 g, 7.94 mmol) in DME (50 mL) at

-78 ˚C. Saturated aqueous NH4Cl was added immediately as the green radical anion color persisted for 10 seconds. The crude reaction mixture was warmed to room temperature,

filtered, rinsed with CHCl3, and concentrated. The residue was taken up in DCM (79

mL), cooled to 0 ˚C and Et3N (3.0 mL, 21.52 mmol, 270 mol%), Boc2O (8.66 g, 39.68 mmol, 500 mol%), and DMAP (0.98 g, 8.02 mmol, 100 mol%) were added. The reaction mixture stirred, warming to room temperature for 18 h at which time it was quenched

with saturated aqueous NH4Cl and extracted with DCM (3x). The combined organic

extracts were washed with brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (5:1 hexanes:EtOAc) to yield cis- 1 piperidine 3.46 (1.52 g, 6.03 mmol, 76%) as a colorless oil. H NMR (500 MHz, d6- DMSO, 90 ˚C): δ 5.65 (ddd, 1 H, J = 17.3, 10.5, 2.8 Hz), 5.11 (ddd, 1 H, J = 17.3 Hz, 1.8 Hz, 1.2 Hz), 5.03 (ddd, 1 H, J = 10.6, 1.7, 1.0 Hz), 3.93 (ddd, 1 H, J = 13.2 Hz, 3.5 Hz, 1.6 Hz), 3.95-3.88 (m, 1 H), 3.11 (dd, 1 H, J = 13.2 Hz, 3.3 Hz), 2.85-2.80 (m, 2 H), 2.77 (dt, 1 H, J = 10.7 Hz, 4.2 Hz), 2.07 (s, 3 H), 1.62-1.59 (m, 1 H), 1.58-1.52 (m, 1 H), 1.39 13 (s, 9 H); C NMR (100 MHz, CDCl3): δ 208.8, 154.7, 134.8, 117.2, 79.4, 79.3, 52.3, 40.6, 28.4, 28.2, 28.1, 22.5; IR (neat) ν 2976, 2930, 2854, 1478, 1464, 1423, 1366, 1241,

1164, 1119; HRMS (CI) calcd for C14H24NO3 [M + 1]: 254.1756, found: 254.1757.

O H Me NBoc trans-4-Acetyl-3-vinyl-piperidine-1-carboxylic acid tert-butyl ester (3.46) To a solution of naphthalene (0.44 g, 3.46 mmol, 840 mol%) in DME (1.8 mL) at room temperature was added freshly cut sodium (0.60 g, 2.61 mmol, 640 mol%). The resulting green radical anion solution was stirred for 2 h at which time it was added dropwise to a solution of N-trisyl piperidine 3.33 (0.17 g, 0.41 mmol) in DME (2.6 mL) at -78 ˚C. EtOH was added immediately as the green radical anion color persisted for 10 seconds. The crude reaction mixture was warmed to room temperature, filtered, rinsed with

CHCl3, and concentrated. The residue was taken up in DCM (4.1 mL), cooled to 0 ˚C and

Et3N (0.09 mL, 0.65 mmol, 160 mol%), and Boc2O (0.49 g, 2.24 mmol, 550 mol%) were added. The reaction mixture stirred, warming to room temperature for 24 h at which time

it was quenched with saturated aqueous NH4Cl and extracted with DCM (3x). The

149 combined organic extracts were washed with brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (5:1 hexanes:EtOAc) to yield trans-piperidine 3.46 (0.065 g, 0.26 mmol, 63%) as a colorless 1 oil. H NMR (400 MHz, CDCl3): δ 5.63-5.54 (m, 1 H), 5.12-5.06 (m, 2 H), 4.17-4.11 (m, 2 H), 2.73-2.66 (m, 1 H), 2.52-2.39 (m, 3 H), 2.12 (s, 3 H), 1.76 (dd, 1 H, J = 13.2, 2.9 13 Hz), 1.55-1.48 (m, 1 H), 1.45 (s, 9 H); C NMR (100 MHz, CDCl3): δ 210,0, 154.3, 137.0, 117.0, 79.6, 54.5, 41.8, 29.3, 28.2, 27.6.

OMe O H

NBoc N cis-4-[3-(6-Methoxy-quinolin-4-yl)-acryloyl]-3-vinyl-piperidine-1-carboxylic acid tert-butyl ester (3.44) To a solution of methyl ketone 3.46 (0.11 g, 0.44 mmol) in THF (1.4 mL) at -78 ˚C was added rapidly LHMDS (1.0 M in THF, 0.53 mL, 0.53 mmol, 120 mol%). The reaction mixture was stirred at -78 ˚C for 1 h at which time aldehyde 3.38 (0.11 g, 0.57 mmol, 130 mol%) in THF (0.3 mL) was added. The reaction mixture was stirred at -78 ˚C for 45 min

at which time Ac2O (0.08 mL, 0.89 mmol, 200 mol%) and DMAP (0.054 g, 0.44 mmol, 100 mol%) were added. The reaction was stirred at -78 ˚C for an additional 45 min at

which time it was warmed to -40 ˚C (MeCN/solid CO2) and stirred for 30 min. DBU (0.34 mL, 2.27 mmol, 500 mol%) was then added to the reaction mixture at -40 ˚C. The reaction mixture was stirred for 15 min at -40 ˚C at which time it was quenched with saturated aqueous NH4Cl and extracted with Et2O (3x). The combined ethereal extracts

were washed with brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (1:1 hexanes:EtOAc to 1:2, 1:3) to afford 1 cis-piperidine 3.44 (0.13 g, 0.31 mmol, 70%) as a yellow foam. H NMR (500 MHz, d6- DMSO, 90 ˚C): δ 8.76 (d, 1 H, J = 4.5 Hz), 8.18 (d, 1 H, J = 15.8 Hz), 7.99 (dd, 1 H, J = 6.8 Hz, 3.1 Hz), 7.74 (d, 1 H, J = 4.5 Hz), 7.48-7.45 (m, 2 H), 7.23 (d, 1 H, J = 15.8 Hz), 5.72 (ddd, 1 H, J = 17.3, 10.6, 2.8 Hz), 5.11-5.07 (m, 1 H), 5.05-5.02 (m, 1 H), 3.98-3,92 (m, 2 H), 3.97 (s, 3 H), 3.31-3.24 (m, 2 H), 2.98-2.95 (m, 2 H), 1.84-1.76 (m, 1 H), 1.71- 13 1.66 (m, 1 H), 1.41 (s, 9 H); C NMR (100 MHz, CDCl3): δ 199.0, 170.6, 158.0, 154.5, 146.9, 144.5, 138.1, 136.6, 134.6, 131.3, 128.7, 127.1, 122.1, 117.9, 117.1, 100.6, 79.3, 55.3, 55.3, 51.0, 40.5, 28.0, 22.6; IR (film) ν 2974, 1690, 1619, 1506, 1472, 1429, 1366,

150 1318, 1227, 1165; HRMS (CI) calcd for C25H31N2O4 [M + 1]: 423.2284, found: 423.2284.

OMe O H

NBoc N trans-4-[3-(6-Methoxy-quinolin-4-yl)-acryloyl]-3-vinyl-piperidine-1-carboxylic acid tert-butyl ester (3.44) To a solution of methyl ketone 3.46 (0.19 g, 0.75 mmol) in THF (6.3 mL) at -78 ˚C was added rapidly LHMDS (1.0 M in THF, 0.93 mL, 0.93 mmol, 120 mol%). The reaction mixture was stirred at -78 ˚C for 1 h at which time aldehyde 3.38 (0.20 g, 1.04 mmol, 140 mol%) in THF (1.0 mL) was added. The reaction mixture slowly warmed to room

temperature over 22 h at which time it was quenched with saturated aqueous NH4Cl and

extracted with Et2O (3x). The combined ethereal extracts were washed with brine (1x),

dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (1:1 hexanes:EtOAc to 1:2, 1:3) to afford trans-piperidine 3.44 (0.24 g, 1 0.58 mmol, 77%) as a yellow foam. H NMR (400 MHz, CDCl3): δ 8.75 (m, 1 H), 8.24 (d, 1 H, J = 15.7 Hz), 8.03 (d, 1 H, J = 9.2 Hz), 7.50 (d, 1 H, J = 4.1 Hz), 7.39 (dd, 1 H, J = 9.2, 2.7 Hz), 7.28-7.27 (m, 1 H), 6.97 (d, 1 H, J = 15.4 Hz), 5.70-5.62 (m, 1 H), 5.15- 5.07 (m, 2 H), 4.20-4.08 (m, 1 H), 3.94 (s, 3 H), 2.79-2.74 (m, 2 H), 2.59 (m, 2 H), 1.90- 1.87 (m, 1 H), 1.70-1.60 (m, 1 H), 1.46 (s, 9 H), 1.30-1.16 (m, 1 H); 13C NMR (100 MHz,

CDCl3): δ 200.0, 158.0, 154.1, 146.9, 144.5, 138.0, 137.1, 136.9, 131.3, 129.4, 127.1, 122.1, 118.0, 116.9, 100.7, 79.5, 65.5, 55.3, 52.9, 41.4, 28.1, 27.7, 15.0.

OMe OH H

NBoc N 4-[1-Hydroxy-3-(6-methoxy-quinolin-4-yl)-allyl]-3-vinyl-piperidine-1-carboxylic acid tert-butyl ester (3.47) To a solution of enone 3.44 (0.98 g, 2.33 mmol) in THF (65.8 mL) at -78 ˚C was added dropwise L-Selectride (1.0 M in THF, 3.1 mL, 3.07 mmol, 130 mol%). The reaction mixture was stirred for 5 min at which time it was quenched with saturated aqueous

NH4Cl and extracted with Et2O (3x). The combined ethereal extracts were washed with

151 brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (1:1 hexanes:EtOAc to 1:2, 1:3) to afford allylic alcohol 3.47 (0.93 g, 2.19 mmol, 94%) as a white solid observed as a single diastereomer. mp: 148- 1 149 ˚C; H NMR (500 MHz, d6-DMSO, 90 ˚C): δ 8.66 (d, 1 H, J = 4.5 Hz), 7.92 (d, 1 H, J = 9.2 Hz), 7.51 (d, 1 H, J = 4.7 Hz), 7.48 (d, 1 H, J = 2.7 Hz), 7.40 (dd, 1 H, J = 9.2, 2.8 Hz), 7.24 (d, 1 H, J = 15.3 Hz), 6.49 (dd, 1 H, J = 15.8, 7.0 Hz), 5.93 (ddd, 1 H, J = 17.4, 10.5, 2.3 Hz), 5.22 (ddd, 1 H, J = 17.4, 2.4, 1.1 Hz), 5.16 (dd, 1 H, J = 10.9, 1.9 Hz), 4.73 (brs, 1 H), 4.08-4.02 (m, 3 H), 3.94 (s, 3 H), 2.90 (dd, 1 H, J = 13.2, 3.0 Hz), 2.79 (brs, 1 H), 2.70 (td, 1 H, J = 12.4, 3.0 Hz), 1.77-1.71 (m, 1 H), 1.45-1.41 (m, 1 H), 1.40 (s, 9 H), 13 1.36-1.33 (m, 1 H); C NMR (100 MHz, CDCl3): δ 157.5, 154.9, 147.0, 144.0, 141.2, 138.4, 135.4, 130.8, 126.9, 125.6, 121.7, 117.5, 101.2, 79.3, 73.5, 65.7, 55.3, 55.3, 45.2, 39.1, 28.2, 23.8, 15.1; IR (film) ν 3630, 3264, 2359, 2341, 2018, 1693, 1620, 1392, 1366,

1230, 1164, 1138, 1034; HRMS (CI) calcd for C25H33N2O4 [M + 1]: 425.2440, found: 425.2441.

O OH N Me N-Hydroxy-2,2,N-trimethyl-propionamide (3.78)

To a solution of N-methylhydroxylamine hydrochloride (1.00 g, 11.97 mmol) in Et2O

(41.2 mL) at 0 ˚C was added Na2CO3 (2.55 g, 24.02 mmol, 200 mol%), pyridine (0.12 mL, 1.48 mmol, 12 mol%), and pivaloyl chloride (1.50 mL, 12.19 mmol, 100 mol%).

The reaction mixture warmed to room temperature over 20 h at which time H2O was added and the mixture was extracted with Et2O (3x). The combined ethereal extracts were

dried over Na2SO4 and concentrated. The crude solid was purified by flash column chromatography (1:1 hexanes:EtOAc) to afford hydroxamic acid 3.78 (0.98 g, 7.42 mmol, 62%) as a white solid. Spectral data matched that of the literature reference.60

O O O Me N V N Me O O

VO(hydroxamate)2 3.90

To a solution of hydroxamic acid 3.78 (1.00 g, 7.64 mmol, 160 mol%) in H2O (12 mL) at

room temperature was added Na2CO3 (0.80 g, 7.52 mmol, 160 mol%) and VO(SO)4·H2O

152 (0.80 g, 4.89 mmol) in H2O (12 mL). The reaction mixture immediately turned purple and stirred for 5 min at which time it was cooled to 0 ˚C and VO(hydroxamate)2 3.90 (0.32 g, 1.27 mmol, 26%) was collected by Hirsch funnel filtration as a light purple solid 51 and washed with cold H2O. mp:134-135 ˚C; V NMR (130 MHz, C6D6): δ -375.3, - 412.7, -492.4, -552.0; IR (film) ν 2978, 2939, 2361, 1572, 1483, 1422, 1368, 1111, 983,

956, 718, 606; HRMS (CI) calcd for C12H25N2O5V [M + 1]: 328.1203, found: 328.1206.

OMe OH H O NBoc N 4-{Hydroxy-[3-(6-methoxy-quinolin-4-yl)-oxiranyl]-methyl}-3-vinyl-piperidine-1- carboxylic acid tert-butyl ester (3.43) To a solution of allylic alcohol 3.47 (1.00 g, 2.27 mmol) in DCE (22.3 mL) at 4 ˚C was

added VO(hydroxamate)2 3.90 (0.038 g, 0.11 mmol, 5 mol%) and TBHP (5.0 M in decane, 2.2 mL, 11.1 mmol, 500 mol%). The reaction mixture stirred at 4 ˚C for 71 h at which time it was concentrated. The crude product was purified by flash column chromatography (1:1 hexanes:EtOAc to 1:2) to yield epoxide 3.43 (0.88 g, 2.00 mmol, 1 91%) as a white foam in a 17:1 ratio of separable diastereomers. H NMR (500 MHz, d6- DMSO, 90 ˚C): δ 8.69 (d, 1 H, J = 4.4 Hz), 7.96 (d, 1 H, J = 2.7 Hz), 7.44 (dd, 1 H, J = 9.2, 2.8 Hz), 7.28 (d, 1 H, J = 4.4 Hz), 5.88 (ddd, 1 H, J = 17.4, 10.5, 2.3 Hz) 5.25 (ddd, 1 H, J = 17.4, 2.3, 1.1 Hz), 5.15 (dd, 1 H, J = 10.5, 2.3 Hz), 4.96 (dd, 1 H, J = 6.2, 2.1 Hz), 4.42 (d, 1 H, J = 2.0 Hz), 4.10-4.05 (m, 2 H), 3.95 (s, 3 H), 3.23 (ddd, 1 H, J = 12.6, 9.5, 6.4 Hz), 3.01-2.99 (m, 1 H), 2.91 (dd, 1 H, J = 13.0, 2.8 Hz), 2.75-2.70 (m, 2 H), 1.91- 1.85 (m, 1 H), 1.65 (dd, 1 H, J = 13.6, 2.9 Hz), 1.40 (s, 9 H), 1.39-1.34 (m, 1 H); 13C

NMR (100 MHz, CDCl3): δ 158.1, 154.9, 147.4, 143.3, 141.6, 135.1, 131.2, 127.2, 122.0, 118.1, 116.8, 109.7, 100.9, 79.6, 70.5, 63.3, 55.7, 52.1, 44.7, 39.4, 29.7, 28.3, 22.9; IR (film) ν 2975, 2932, 2858, 2358, 2338, 2029, 1689, 1621, 1429, 1238, 1167, 1147, 853;

HRMS (CI) calcd for C25H33N2O5 [M + 1]: 441.2389, found: 441.2383.

153 H OMe H N OH OH N 7-Hydroxy-quinine (3.97) To a solution of epoxide 3.43 (0.053 g, 0.12 mmol) in DCM (1.4 mL) at 0 ˚C was added TFA (0.30 mL, 3.90 mmol, 3300 mol%). The reaction mixture stirred at 0 ˚C for 1 h at which time the mixture was concentrated with toluene (2x). The yellow residue was taken up in MeCN (3 mL) and Na2CO3 (0.064 g, 0.60 mmol, 500 mol%) and Zn(OTf)2 (0.065 g, 0.18 mmol, 150 mol%) were added. After 41 h at 80 ˚C, the reaction mixture was

cooled to room temperature, poured into H2O, and extracted with DCM (3x). The

combined organic extracts were washed with brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (20:1 DCM:MeOH to 15:1) to yield diol 3.97 (0.028 g, 0.084 mmol, 70%) as a white solid. mp: 1 196 ˚C (decomp); H NMR (400 MHz, d6-DMSO): δ 8.69 (d, 1 H, J = 4.8 Hz), 7.91 (d, 1 H, J = 9.2 Hz), 7.59 (d, 1 H, J = 2.7 Hz), 7.51 (d, 1 H, J = 4.4 Hz), 7.37 (dd, 1 H, J = 9.2, 2.7 Hz), 5.99-5.90 (m, 1 H), 5.60 (dd, 1 H, J = 9.4, 4.3 Hz), 5.46 (d, 1 H, J = 4.1 Hz), 5.07-5.01 (m, 2 H), 4.81 (d, 1 H, J = 2.4 Hz), 4.26-4.23 (m, 1 H), 3.89 (s, 3 H), 3.14-3.02 (m, 2 H), 2.65 (dd, 1 H, J = 13.2, 10.1 Hz), 2.49-2.24 (m, 3 H), 2.08-1.99 (m, 2 H), 1.18- 13 1.11 (m, 1 H); C NMR (100 MHz, d6-DMSO): δ 156.6, 148.9, 147.5, 144.0, 142.0, 131.0, 127.8, 120.9, 120.0, 114.5, 102.8, 66.9, 64.9, 63.8, 55.4, 54.5, 48.6, 41.4, 34.3, 20.0; IR (film) ν 3310, 2918, 2868, 2216, 2159, 2035, 1622, 1509, 1476, 1275, 1261,

1242, 1094, 1025, 750; HRMS (CI) calcd for C20H25N2O3 [M + 1]: 341.1865, found: 341.1863. H OMe H N OH OPMB N 7-Hydroxy-9-(4-methoxybenzyloxy)-quinine (3.98) To a solution of KH (30% in oil, 0.047 g, 0.35 mmol, 120 mol%) in DMF (2.9 mL) at 0 ˚C was added diol 3.97 (0.100 g, 0.30 mmol). The reaction mixture stirred at 0 ˚C for 35 min at which time PMBCl (0.04 mL, 0.42 mmol, 140 mol%) was added and the mixture

was warmed to 4 ˚C. After 46 h at 4 ˚C, the reaction mixture was poured into H2O, and

154 extracted with Et2O (3x). The combined ethereal extracts were washed with water (3x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (40:1 DCM:MeOH to 30:1) to yield PMB ether 3.98 (0.11 g, 0.23 mmol, 1 78%) as a white foam. H NMR (400 MHz, d6-DMSO): δ 8.71 (d, 1 H, J = 4.4 Hz), 7.95 (d, 1 H, J = 8.9 Hz), 7.55 (m, 1 H), 7.49 (d, 1 H, J = 4.4 Hz), 7.41 (dd, 1 H, J = 9.2, 2.7 Hz), 7.18 (d, 2 H, J = 8.5 Hz), 6.88 (d, 2 H, J = 8.5 Hz), 5.91-5.82 (m, 1 H), 5.13 (brs, 1 H), 4.98-4.91 (m, 2 H), 4.30 (d, 1 H, J = 10.9 Hz), 4.20 (d, 1 H, J = 10.9 Hz), 3.86 (s, 3 H), 3.72 (s, 3 H), 3.13 (m, 2 H), 2.88-2.72 (m, 1 H), 2.42-2.32 (m, 2 H), 2.17 (m, 1 H), 13 1.83 (m, 1 H), 1.72 (m, 1 H), 1.60-1.59 (m, 2 H), 1.42 (m, 1 H); C NMR (100 MHz, d6- DMSO): δ 158.6, 156.4, 147.5, 142.2, 141.9, 131.2, 131.0, 130.9, 130.3, 130.1, 129.4, 129.2, 129.0, 121.0, 114.4, 113.6, 71.5, 70.8, 70.1, 63.0, 55.3, 55.0, 54.4, 34.6, 30.5; IR (film) ν 2931, 2360, 2340, 1684, 1618, 1518, 1543, 1363, 1240, 1036; HRMS (CI) calcd for C28H33N2O4 [M + 1]: 461.2440, found: 461.2442.

H OMe N

OPMB N 9-(4-Methoxybenzyloxy)-quinine (3.108) To a solution of NaH (60% in oil, 0.27 g, 6.75 mmol, 110 mol%) in DMF (60 mL) at 0 ˚C was added quinine (3.1) (2.00 g, 6.16 mmol). The reaction mixture stirred at 0 ˚C for 40 min at which time PMBCl (0.80 mL, 7.91 mmol, 130 mol%) was added. After slowly

warming to room temperature over 21 h, the reaction mixture was poured into H2O, and

extracted with Et2O (3x). The combined ethereal extracts were washed with water (3x),

dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (40:1 DCM:MeOH to 20:1) to yield PMB quinine 3.108 (2.24 g, 5.05 25 1 mmol, 82%) as a thick colorless gum. [α]D : -31.2˚ (c = 0.1 in DCM); H NMR (400

MHz, CDCl3): δ 8.77 (d, 1 H, J = 4.4 Hz), 8.05 (d, 1 H, J = 9.2 Hz), 7.47 (d, 1 H, J = 4.1 Hz), 7.39 (dd, 1 H, J = 9.2, 2.4 Hz), 7.34 (m, 1 H), 7.22 (d, 2 H, J = 8.2 Hz), 6.88 (d, 2 H, J = 8.5 Hz), 5.78-5.69 (m, 1 H), 4.96-4.89 (m, 2 H), 4.39 (d, 1 H, J = 10.9 Hz), 4.31 (d, 1 H, J = 11.3 Hz), 3.91 (s, 3 H), 3.82 (s, 3 H), 3.49-3.47 (m, 1 H), 3.14-3.04 (m, 2 H), 2.67- 2.58 (m, 2 H), 2.25 (m, 1 H), 1.79-1.64 (m, 5 H), 1.49 (m, 1 H); 13C NMR (100 MHz,

155 CDCl3): δ 158.9, 157.4, 147.3, 144.6, 144.4, 141.7, 131.5, 129.6, 129.1, 127.2, 121.3, 113.8, 113.4, 70.4, 60.0, 56.7, 55.3, 55.2, 54.8, 54.8, 42.7, 39.7, 27.5; IR (film) ν 2936,

2864, 2360, 2340, 1619, 1512, 1472, 1247, 1033, 832; HRMS (CI) calcd for C28H33N2O3 [M + 1]: 445.2491, found: 445.2491.

H OMe H N OH OMOM N 7-Hydroxy-9-(4-methoxymethyl)-quinine (3.124) To a solution of KH (30% in oil, 0.047 g, 0.35 mmol, 120 mol%) in DMF (2.9 mL) at 0 ˚C was added diol 3.97 (0.100 g, 0.30 mmol). The reaction mixture stirred at 0 ˚C for 35 min at which time MOMCl (0.03 mL, 0.39 mmol, 130 mol%) was added and the mixture

was warmed to 4 ˚C. After 45 h at 4 ˚C, the reaction mixture was poured into H2O, and

extracted with Et2O (3x). The combined ethereal extracts were washed with water (3x),

dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (40:1 DCM:MeOH to 30:1) to yield MOM ether 3.124 (0.06 g, 0.17 1 mmol, 58%) as a colorless oil. H NMR (400 MHz, CDCl3): δ 8.74 (brs, 1 H), 8.02 (d, 1 H, J = 9.2 Hz), 7.46 (brs, 1 H), 7.38-7.35 (m, 2 H), 5.92-5.79 (m, 1 H), 5.07-5.04 (m, 2 H), 4.57 (d, 1 H, J = 5.8 Hz), 4.40 (m, 1 H), 3.94 (s, 3 H), 3.68-3.52 (m, 1 H), 3.36 (s, 3 H), 3.30-3.16 (m, 1 H), 2.79 (m, 1 H), 2.52-2.43 (m, 3 H), 2.23-2.19 (m, 3 H), 1.28-1.17 13 (m, 3 H); C NMR (125 MHz, d6- DMSO): δ 156.6, 156.5, 147.5, 142.2, 131.1, 131.0, 120.8, 120.7, 114.7, 114.4, 102.8, 95.9, 79.1, 55.4, 55.3, 54.3, 41.7, 34.6, 32.6, 30.4, 29.0, 20.4; IR (film) ν 3246 (br), 2929, 2361, 2340, 1622, 1508, 1473, 1244, 1101, 1032, 668;

HRMS (CI) calcd for C22H29N2O4 [M + 1]: 385.2127, found: 385.2124.

H OMe N

OMOM N 9-(4-methoxymethyl)-quinine (3.125) To a solution of NaH (60% in oil, 0.16 g, 3.38 mmol, 110 mol%) in DMF (30 mL) at 0 ˚C was added quinine (3.1) (1.00 g, 3.08 mmol). The reaction mixture stirred at 0 ˚C for

156 40 min at which time MOMCl (0.30 mL, 3.95 mmol, 130 mol%) was added. After slowly

warming to room temperature over 24 h, the reaction mixture was poured into H2O, and

extracted with Et2O (3x). The combined ethereal extracts were washed with water (3x),

dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (40:1 DCM:MeOH to 30:1) to yield MOM quinine 3.125 (0.56 g, 1.51 25 1 mmol, 49%) as a thick colorless gum. [α]D : -96.0˚ (c = 0.08 in DCM); H NMR (400

MHz, CDCl3): δ 8.74 (d, 1 H, J = 4.4 Hz), 8.02 (d, 1 H, J = 9.2 Hz), 7.41-7.35 (m, 3 H), 5.82-5.75 (m, 1 H), 5.00-4.93 (m, 2 H), 4.60 (d, 1 H, J = 6.5 Hz), 4.51 (d, 1 H, J = 6.8 Hz), 3.94 (s, 3 H), 3.39 (s, 3 H), 3.32 (m, 2 H), 3.03-3.00 (m, 1 H), 2.66-2.60 (m, 2 H), 13 2.26 (m, 1 H), 1.84-1.70 (m, 5 H), 1.54 (m, 1 H); C NMR (100 MHz, CDCl3): δ 157.6, 147.4, 144.6, 141.9, 131.7, 127.4, 121.5, 114.2, 95.0, 59.9, 56.8, 56.4, 55.5, 39.9, 27.8, 27.7; IR (film) ν 2939, 2360, 2340, 1635, 1621, 1507, 1240, 1030, 668, 403; HRMS (CI)

calcd for C22H29N2O3 [M + 1]: 369.2178, found: 369.2180.

OMe OAc H

NBoc N 4-[1-Acetoxy-3-(6-methoxy-quinolin-4-yl)-allyl]-3-vinyl-piperidine-1-carboxylic acid tert-butyl ester (3.127) To a solution of allylic alcohol 3.47 (0.25 g, 0.59 mmol) in DCM (10.1 mL) at 0 ˚C was

added Et3N (0.42 mL, 3.01 mmol, 510 mol%), Ac2O (0.33 mL, 3.49 mmol, 590 mol%), and DMAP (0.014 g, 0.12 mmol, 20 mol%). The reaction mixture was stirred for 30 min

at which time it was poured into H2O and extracted with DCM (3x). The combined organic extracts were washed with brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (1:1 hexanes:EtOAc to 1:2) to afford allylic acetate 3.127 (0.25 g, 0.54 mmol, 92%) as a white foam. 1H NMR (500

MHz, d6-DMSO, 90 ˚C): δ 8.67 (d, 1 H, J = 4.4 Hz), 7.93 (d, 1 H, J = 8.8 Hz), 7.51 (d, 1 H, J = 4.4 Hz), 7.42 (d, 1 H, J = 2.9 Hz), 7.41-7.40 (m, 1 H), 7.31 (d, 1 H, J = 15.6 Hz), 6.37 (dd, 1 H, J = 15.9, 7.6 Hz), 5.93-5.85 (m, 1 H), 5.18-5.12 (m, 2 H), 4.10-4.07 (m, 1 H), 4.02 (d, 1 H, J = 13.2 Hz), 3.94 (s, 3 H), 3.06 (m, 1 H), 2.98 (dd, 1 H, J = 13.2, 2.9 Hz), 2.75 (td, 1 H, J = 12.6, 3.3 Hz), 2.65-2.63 (m, 1 H), 2.13-2.10 (m, 1 H), 2.08 (s, 3 13 H), 1.52-1.44 (m, 2 H), 1.40 (s, 9 H); C NMR (100 MHz, CDCl3): δ 169.6, 157.6, 154.6,

157 147.0, 144.1, 140.6, 132.3, 130.8, 130.3, 126.9, 121.9, 117.6, 101.1, 79.3, 77.2, 75.8, 55.2, 42.6, 28.1, 20.9; IR (film) ν 3073, 2975, 2932, 2864, 2360, 2340, 1739, 1690, 1619,

1431, 1366, 1172, 1148 ; HRMS (CI) calcd for C27H35N2O5 [M + 1]: 467.2546, found: 467.2547.

OMe H

NBoc N 4-[3-(6-Methoxy-quinolin-4-yl)-allyl]-3-vinyl-piperidine-1-carboxylic acid tert-butyl ester (3.128) To a solution of allylic acetate 3.127 (0.20 g, 0.43 mmol) in THF (4.3 mL) at room

temperature was added Pd2dba3·CHCl3 (0.011 g, 0.011 mmol, 2.5 mol%), freshly distilled

PBu3 (0.07 mL, 0.28 mmol, 70 mol%), Et3N (0.40 mL, 2.87 mmol, 670 mol%), and

formic acid (88% in H2O, 0.07 mL, 1.63 mmol, 350 mol%). The reaction mixture was

stirred for 2 h at which time it was poured into H2O and extracted with Et2O (3x). The

combined ethereal extracts were washed with brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (1:1 hexanes:EtOAc to 1:2) to afford alkene 3.128 (0.17 g, 0.41 mmol, 96%) as a colorless oil. 1 H NMR (500 MHz, d6-DMSO, 90 ˚C): δ 8.64 (d, 1 H, J = 4.4 Hz), 7.91 (d, 1 H, J = 9.0 Hz), 7.50 (d, 1 H, J = 4.6 Hz), 7.46 (d, 1 H, J = 2.7 Hz), 7.40 (dd, 1 H, J = 9.2, 2.8 Hz), 7.16 (d, 1 H, J = 15.6 Hz), 6.55-6.49 (m, 1 H), 5.88 (ddd, 1 H, J = 17.3, 10.5, 2.2 Hz), 5.21-5.16 (m, 2 H), 3.94 (s, 3 H), 3.86 (ddd, 1 H, J = 13.2, 3.5, 1.5 Hz), 3.07 (dd, 2 H, J = 13.2, 3.2 Hz), 2.92-2.86 (m, 1 H), 2.44-2.42 (m, 1 H), 2.36-2.23 (m, 2 H), 1.95-1.88 (m, 1 13 H), 1.59-1.54 (m, 1 H), 1.46-1.42 (m, 1 H), 1.40 (s, 9 H); C NMR (100 MHz, CDCl3): δ 157.4, 154.8, 147.2, 144.2, 141.8, 135.3, 131.0, 126.8, 126.3, 121.5, 117.4, 116.9, 101.2, 79.1, 77.2, 55.2, 42.4, 38.8, 37.1, 28.2, 27.3; IR (neat) ν 2975, 2929, 2359, 2340, 1685,

1653, 1617, 1507, 1430, 1365, 1228, 1165; HRMS (CI) calcd for C25H33N2O3 [M + 1]: 409.2491, found: 409.2488.

158 OMe H

NCbz N 4-[3-(6-Methoxy-quinolin-4-yl)-allyl]-3-vinyl-piperidine-1-carboxylic acid benzyl ester (3.126) from carbamate protecting group exchange: To a solution of N-Boc carbamate 3.128 (0.055 g, 0.14 mmol) in DCM (1.6 mL) at 0 ˚C was added TFA (0.33 mL, 4.30 mmol, 3200 mol%). The reaction mixture stirred at 0 ˚C for 30 min at which time it was concentrated with toluene (2x). The yellow reside was

taken up in THF (0.70 mL), cooled to 0 ˚C, and K2CO3 (0.091 g, 0.66 mmol, 500 mol%) and CbzCl (0.05 mL, 0.36 mmol, 250 mol%) were added. After warming to room

temperature over 20 h the reaction mixture was poured into H2O and extracted with Et2O

(3x). The combined ethereal extracts were washed with brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (1:1 hexanes:EtOAc to 1:2) to yield N-Cbz alkene 3.126 (0.046 g, 76%) as a colorless oil. 1H

NMR (500 MHz, d6-DMSO, 90 ˚C): δ 8.65 (d, 1 H, J = 4.6 Hz), 7.92 (d, 1 H, J = 9.3 Hz), 7.51 (d, 1 H, J = 4.6 Hz), 7.46 (d, 1 H, J = 2.7 Hz), 7.40 (dd, 1 H, J = 9.1, 2.8 Hz), 7.39- 7.28 (m, 5 H), 7.16 (d, 1 H, J = 15.6 Hz), 6.56-6.50 (m, 1 H), 5.87 (ddd, 1 H, J = 17.3, 10.4, 2.1 Hz), 5.20-5.05 (m, 4 H), 4.02-3.98 (m, 1 H), 3.93 (s, 3 H), 3.17 (dd, 1 H, J = 13.2, 3.2 Hz), 3.02-2.97 (m, 1 H), 2.48-2.45 (m, 1 H), 2.37-2.24 (m, 2 H), 1.97-1.91 (m, 1 H), 1.60 (dd, 1 H, J = 13.4, 3.7 Hz), 1.50-1.42 (m, 1 H), 1.26 (m, 1 H); 13C NMR (100

MHz, CDCl3): δ 157.6, 155.4, 147.3, 144.3, 142.0, 136.8, 135.4, 131.1, 128.3, 127.8, 127.7, 127.0, 126.6, 121.7, 117.5, 117.4, 101.4, 66.9, 55.4, 49.0, 48.5, 43.9, 42.5, 38.9, 37.3, 27.2; IR (film) ν 2928, 2360, 2340, 1695, 1619, 1506, 1470, 1432, 1365, 1229;

HRMS (CI) calcd for C28H30N2O3 [M + 1]: 443.2335, found: 443.2332.

from Pd-catalyzed deoxygenation: To a solution of allylic acetate 3.132 (0.05 g, 0.13 mmol) in THF (1.0 mL) at room

temperature was added Pd2dba3·CHCl3 (0.003 g, 0.003 mmol, 2.5 mol%), freshly distilled

PBu3 (0.02 mL, 0.08 mmol, 80 mol%), Et3N (0.09 mL, 0.65 mmol, 650 mol%), and

formic acid (88% in H2O, 0.02 mL, 0.53 mmol, 530 mol%). The reaction mixture was

stirred for 4 h at which time it was poured into H2O and extracted with Et2O (3x). The

159 combined ethereal extracts were washed with brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (1:1 hexanes:EtOAc to 1:2) to afford alkene 3.126 (0.034 g, 0.08 mmol, 78%) as a colorless oil.

O

Me NCbz cis-4-Acetyl-3-vinyl-piperidine-1-carboxylic acid benzyl ester (3.129) To a solution of naphthalene (0.57 g, 4.45 mmol, 1850 mol%) in DME (1.35 mL) at room temperature was added freshly cut sodium (0.90 g, 3.8 mmol, 1600 mol%). The resulting green radical anion solution was stirred for 2 h at which time it was added dropwise to a solution of N-trisyl piperidine 3.33 (0.10 g, 0.24 mmol) in DME (1.42 mL) at -78 ˚C.

Saturated aqueous NH4Cl was added immediately as the green radical anion color

persisted. The crude reaction mixture was filtered through a Na2SO4-packed pipet, rinsed

with CHCl3, and concentrated. The residue was taken up in DCM (2.4 mL), cooled to 0

˚C and Et3N (0.20 mL, 1.43 mmol, 600 mol%) and CbzCl (0.11 mL, 0.78 mmol, 330 mol%) were added. The reaction mixture stirred, warming to room temperature for 18 h

at which time it was quenched with saturated aqueous NH4Cl and extracted with DCM

(3x). The combined organic extracts were washed with brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (3:1 hexanes:EtOAc) to yield N-Cbz piperidine 3.129 (0.042 g, 0.15 mmol, 61%) as a 1 colorless oil. H NMR (500 MHz, d6-DMSO, 90 ˚C): δ 7.37- 7.28 (m 5 H), 5.65 (ddd, 1 H, J = 17.3, 10.5, 2.7 Hz), 5.12-4.99 (m, 4 H), 4.01-3.94 (m, 2 H), 3.21 (dd, 1 H, J = 13.3, 3.5 Hz), 2.97-2.91 (m, 1 H), 2.85-2.83 (m, 1 H), 2.80 (dt, 1 H, J = 10.6, 4.2 Hz), 13 2.08 (s, 3 H), 1.71-1.58 (m, 2 H); C NMR (125 MHz, d6-DMSO): δ 208.5, 154.5, 136.9, 135.6, 128.3, 128.3, 127.7, 127.6, 127.4, 117.0, 66.1, 51.0, 47.6, 42.6, 28.1, 22.0; IR (film) ν 2923, 2361, 2340, 1717, 1700, 1696, 1684, 1653, 1559, 1437, 1233, 668; HRMS

(CI) calcd for C17H22NO3 [M + 1]: 288.1600, found: 288.1599.

160 OMe O H

NCbz N cis-4-[3-(6-Methoxy-quinolin-4-yl)-acryloyl]-3-vinyl-piperidine-1-carboxylic acid benzyl ester (3.130) To a solution of methyl ketone 3.129 (0.042 g, 0.15 mmol) in THF (0.54 mL) at -78 ˚C was added rapidly LHMDS (0.9 M in methylcyclohexane, 0.19 mL, 0.17 mmol, 110 mol%). The reaction mixture was stirred at -78 ˚C for 1 h at which time aldehyde 3.38 (0.039 g, 0.21 mmol, 140 mol%) was added. The reaction mixture was stirred at -78 ˚C

for 1 h at which time Ac2O (0.03 mL, 0.32 mmol, 210 mol%) and DMAP (0.018 g, 0.14 mmol, 100 mol%) were added. The reaction was stirred at -78 ˚C for an additional 45 min at which time it was warmed to -40 ˚C (MeCN/solid CO2) and stirred for 30 min. DBU (0.11 mL, 0.74 mmol, 500 mol%) was then added to the reaction mixture at -40 ˚C. The reaction mixture was stirred for 15 min at -40 ˚C at which time it was quenched with

saturated aqueous NH4Cl and extracted with Et2O (3x). The combined ethereal extracts

were washed with brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (1:1 hexanes:EtOAc to 1:2, 1:3) to afford 1 enone 3.130 (0.043 g, 0.10 mmol, 64%) as a yellow oil. H NMR (500 MHz, d6-DMSO, 90 ˚C): δ 8.78 (d, 1 H, J = 4.6 Hz), 8.19 (d, 1 H, J = 15.9 Hz), 8.02-8.00 (m, 1 H), 7.78 (d, 1 H, J = 4.4 Hz), 7.50-7.47 (m, 2 H), 7.38-7.29 (m, 5 H), 7.24 (d, 1 H, J = 15.9 Hz), 5.71 (ddd, 1 H, J = 17.3, 10.5, 2.7 Hz), 5.13-5.00 (m, 4 H), 4.04-3.98 (m, 2 H), 3.97 (s, 3 H), 3.38-3.31 (m, 2 H), 3.12-3.07 (m, 1 H), 3.02-2.99 (m, 1 H), 1.88-1.80 (m, 1 H), 1.75- 13 1.70 (m, 1 H); C NMR (125 MHz, d6-DMSO): δ 199.8, 157.8, 154.5, 147.5, 144.4, 138.2, 137.0, 135.8, 135.3, 131.3, 130.4, 128.3, 127.8, 127.4, 126.8, 122.1, 118.7, 117.0, 66.1, 55.6, 49.4, 42.4, 30.4; IR (film) ν 2960, 2360, 2340, 1700, 1695, 1684, 1617, 1506,

1436, 1227, 668; HRMS (CI) calcd for C28H29N2O4 [M + 1]: 457.2122, found: 457.2128.

OMe OH H

NCbz N 4-[1-Hydroxy-3-(6-methoxy-quinolin-4-yl)-allyl]-3-vinyl-piperidine-1-carboxylic acid benzyl ester (3.131)

161 To a solution of enone 3.130 (0.027 g, 0.065 mmol) in THF (1.8 mL) at -78 ˚C was added dropwise L-Selectride (1.0 M in THF, 0.07 mL, 0.070 mmol, 110 mol%). The reaction mixture was stirred for 5 min at which time it was quenched with saturated aqueous

NH4Cl and extracted with Et2O (3x). The combined ethereal extracts were washed with

brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (1:2 hexanes:EtOAc to 1:3) to afford allylic alcohol 3.131 (0.029 g, 0.062 mmol, 96%) as a colorless oil observed as a single diastereomer. 1H

NMR (500 MHz, d6-DMSO, 90 ˚C): δ 8.66 (d, 1 H, J = 4.6 Hz), 7.93 (d, 1 H, J = 9.3 Hz), 7.51 (d, 1 H, J = 4.4 Hz), 7.48 (d, 1 H, J = 2.7 Hz), 7.40 (dd, 1 H, J = 9.1, 2.8 Hz), 7.37- 7.28 (m, 5 H), 7.25 (d, 1 H, J = 15.6 Hz), 6.49 (dd, 1 H, J = 15.7, 7.0 Hz), 5.92 (ddd, 1 H, J = 17.3, 10.5, 2.2 Hz), 5.28-5.24 (m, 1 H), 5.14 (dd, 1 H, J = 10.6, 2.3 Hz), 5.10 (d, 1 H, J = 12.9 Hz), 5.06 (d, 1 H, J = 12.9 Hz), 4.76 (brs, 1 H), 4.15-4.12 (m, 2 H), 4.06-4.03 (m, 1 H), 3.93 (s, 3 H), 3.00 (dd, 1 H, J = 13.2, 2.9 Hz), 2.84-2.78 (m, 2 H), 1.80-1.74 (m, 13 1 H), 1.50-1.40 (m, 2 H); C NMR (125 MHz, CDCl3): δ 157.3, 154.6, 147.5, 144.2, 140.8, 139.6, 137.0, 135.7, 130.9, 128.3, 127.7, 127.4, 126.7, 124.7, 121.6, 117.4, 117.1, 101.9, 79.1, 72.3, 66.0, 55.6, 44.6, 43.6, 38.1, 30.4; IR (film) ν 2927, 2360, 2340, 1700,

1695, 1684, 1507, 1472, 1436, 1231, 668, 417; HRMS (CI) calcd for C28H31N2O4 [M + 1]: 459.2284, found: 459.2280.

OMe OAc H

NCbz N 4-[1-Acetoxy-3-(6-methoxy-quinolin-4-yl)-allyl]-3-vinyl-piperidine-1-carboxylic acid benzyl ester (3.132) To a solution of allylic alcohol 3.131 (0.022 g, 0.052 mmol) in DCM (0.87 mL) at 0 ˚C

was added Et3N (0.04 mL, 0.29 mmol, 560 mol%), Ac2O (0.03 mL, 0.32 mmol, 620 mol%), and DMAP (0.0012 g, 0.0098 mmol, 20 mol%). The reaction mixture was stirred

for 45 min at which time it was poured into H2O and extracted with DCM (3x). The

combined organic extracts were washed with brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (1:1 hexanes:EtOAc to 1:2) to afford allylic acetate 3.132 (0.021 g, 0.042 mmol, 81%) as a 1 white foam. H NMR (500 MHz, d6-DMSO, 90 ˚C): δ 8.70 (d, 1 H, J = 4.4 Hz), 7.97 (d,

162 1 H, J = 8.0 Hz), 7.56 (d, 1 H, J = 4.6 Hz), 7.46-7.42 (m, 2 H), 7.37-7.28 (m, 6 H), 6.41 (dd, 1 H, J = 15.6, 7.6 Hz), 5.89 (ddd, 1 H, J = 17.1, 10.5, 1.5 Hz), 5.19-5.05 (m, 5 H), 4.17-4.14 (m, 1 H), 4.10-4.07 (m, 1 H), 3.94 (s, 3 H), 3.08 (dd, 1 H, J = 13.4, 2.9 Hz), 2.89-2.83 (m, 1 H), 2.69-2.66 (m, 1 H), 2.16-2.09 (m, 1 H), 2.08 (s, 3 H), 1.56-1.48 (m, 2 13 H); C NMR (125 MHz, d6-DMSO): δ 169.5, 157.6, 154.5, 146.8, 143.1, 140.9, 137.0, 135.1, 133.8, 130.2, 128.3, 128.3, 127.7, 127.4, 126.7, 122.2, 117.7, 117.5, 102.0, 79.1, 75.5, 66.1, 55.6, 43.3, 41.8, 40.1, 38.9, 20.8; IR (film) ν 3009, 2931, 2863, 2360, 2340,

1734, 1700, 1696, 1685, 1617, 1507, 1231, 1027; HRMS (CI) calcd for C30H33N2O5 [M + 1]: 501.2389, found: 501.2391.

163 3.17 1H AND 13C NMR SPECTRA

OCO2Me

O NTs H 3.8

164 OCO2Me

O

Me NTs 3.9

165 O

Me NTs 3.11

166 OCO2Me

OEt NTrs EtO 3.13

167 OCO2Me

O

Me NTrs 3.14

168 O

Me NTrs 3.16

169 OCO2Me

O

EtS NTrs 3.21

170 O

EtS NTrs 3.23

171 OCO2Me

O

EtO NTrs 3.22

172 O H Me NTrs 3.33

173 OMe O H

NTrs N 3.39

174 O H Me NBoc cis-3.46

175 O H Me NBoc trans-3.46

176 OMe O H

NBoc N cis-3.44

177 OMe O H

NBoc N trans-3.44

178 OMe OH H

NBoc N 3.47

179 O O O Me N V N Me O O

3.90

180 OMe OH H O NBoc N 3.43

181 H OMe H N OH OH N 3.97

182 H OMe H N OH OPMB N 3.98

183 H OMe N

OPMB N 3.108

184 H OMe H N OH OMOM N 3.124

185 H OMe N

OMOM N 3.125

186 OMe OAc H

NBoc N 3.127

187 OMe H

NBoc N 3.128

188 OMe H

NCbz N 3.126

189 O

Me NCbz 3.129

190 OMe O H

NCbz N 3.130

191 OMe OH H

NCbz N 3.131

192 OMe OAc H

NCbz N 3.132

193 3.18 REFERENCES

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197 Chapter 4 Asymmetric Approach To Quinine

4.1 CHIRAL AUXILIARY BASED APPROACH

In the hopes of an asymmetric route toward quinine, efforts were first focused on the development of a chiral auxiliary based diastereoselective cycloallylation. In this new approach, it was wondered what effect altering the α,β-unsaturated acceptor have on substrate reactivity. In recalling the racemic approach, it was found that varying the α,β- unsaturated acceptor of the cycloallylation substrate drastically affected reactivity. Enone and thioenoate substrates 4.1 and 4.2 participated in the cycloallylation with chemical yields of 63% and 57% respectively (Table 4.1, entry 1, 2). Conversely, enoate 4.3 failed to undergo cycloallylation, likely due to a decreased electrophilicity (entry 3).

OCO2Me O O Pd(PPh3)4 (5 mol%) R R PMe3 (100 mol%) N N Trs tAmOH Trs

4.1, R = Me 4.4, R = Me 4.2, R = SEt 4.5, R = SEt 4.3, R = OEt 4.6, R = OEt

Entry R Yield 1 Me 63% 2 SEt 57% 3OEttrace

Table 4.1: Cycloallylation with varying α,β-unsaturated partner

To investigate the feasibility of a diastereoselective cycloallylation, the Evans oxazolidinone chiral auxiliary was first examined. Although its incorporation would

198 diminish the electrophilicity of the α,β-unsaturated system, it could easily be introduced

via its incorporation into a Wittig olefinating reagent. Secondly, it was hoped that after

1,4-addition of PMe3, coordination of both the carbonyl groups of α,β-unsaturated imide

4.7 would form rigid intermediate 4.8 that should confer facial selectivity in the C-C

bond formation (Scheme 4.1).

OR OCO Me 2 H O O Pd(PPh ) O O O O 3 4 LnPdII ON ON ON PMe , tAmOH N 3 N N Trs Trs Trs PMe3 PMe3 4.7 4.8 4.9

Scheme 4.1: Stereochemical model for diastereoselective cycloallylation

Synthesis of the oxazolidinone bearing substrate began with the hydrolysis of

acetal 4.10 by treatment with TFA and H2O in CHCl3 at 0 ˚C (Scheme 4.2). The crude aldehyde was then olefinated with the known oxazolidinone Wittig reagent1 to afford

α,β-unsaturated imide 4.11 in 50% yield over two steps. When α,β-unsaturated imide

4.11 was subjected to standard cycloallylation conditions, none of desired piperidine 4.12

was obtained. A complex mixture was observed by thin layer chromatography analysis

with complete loss of starting material 4.11.

OCO2Me OCO2Me 1. TFA, H2O, CHCl3, 0 °C O O Pd(PPh3)4 O O

OEt O ON t ON O PMe3, AmOH N 2.PPh3 , DCM N N EtO Trs ON Trs Trs

4.10 4.11 4.12

50%

Scheme 4.2: Synthesis and cycloallylation of acyl oxazolidinone substrate

199 A second substrate was then pursued incorporating Oppolzer’s sultam chiral

auxiliary. Acetal 4.10 was hydrolyzed as before and the crude aldehyde was reacted with

the chiral sultam Wadsworth-Emmons reagent2 under basic conditions to afford acyl

sultam 4.13 in 83% yield (Scheme 4.3). Acyl sultam 4.13 was next subjected to standard

cycloallylation conditions. Only a 4% yield of piperidine 4.14 was obtained as a 1:1 ratio

of diastereomers as determined by 1H NMR integrations of the aromatic protons.

1. TFA, H2O, CHCl , 0 °C OCO Me 3 Me Me 2 n OCO2Me 2. BuLi, H2O, Me Me Et2O, 0 °C O Pd(PPh3)4 O

OEt Me N t N PMe3, AmOH N Me S N S N EtO Trs O O O O Trs O O Trs P N (OEt)2 4.10 S 4.13 4.14 O O 83% 4% 1:1 dr

Scheme 4.3: Synthesis and cycloallylation of acyl sultam substrate

With clear evidence that these changes in the α,β-unsaturation dramatically

altered the reactivity in the cycloallylation, a new substrate bearing chirality elsewhere

was targeted. Chiral nitrogen protecting groups are often used to generate asymmetry.3

Accordingly, the α-methylnaphthyl residue was introduced to replace the trisyl sulfone.

(R)-(+)-1-(2-napthyl)ethylamine (4.15) first underwent alkylation with bromoacetaldehyde diethyl acetal with K2CO3 in MeCN at reflux (Scheme 4.4). The resulting secondary amine then underwent a second alkylation upon treatment with

4 known allylic bromide and K2CO3 in DMF at room temperature to afford tertiary amine

4.16 in 56% yield over 2 steps. The acetal moiety of tertiary amine 4.16 was carefully

200 hydrolyzed upon exposure to HBr/AcOH in DCM at -78 ˚C. The resulting aldehyde was

next olefinated with the stabilized Wittig reagent to afford enone 4.17 in 42% yield over

two steps. Substrate 4.17 bearing chirality in the tether was then subjected to standard

cycloallylation conditions. The reaction proceeded to afford piperidine 4.18 in 25% yield,

though as a disappointing 1:1 ratio of diastereomers as determined by the 1H NMR

integrations of the proton located at the β-carbon of enone 4.18.

OCO2Me 1. K2CO3, MeCN, Δx OEt 1. HBr, AcOH, Br OEt EtO DCM, -78 °C H N N 2 EtO 2. K2CO3, DMF O Me Me 2. Ph3P Br Me, DCM

4.15 OCO2Me 4.16

56% 42%

OCO2Me O O Pd(PPh ) , PBu Me 3 4 3 Me N tAmOH N Me Me 4.17 4.18 25% 1:1 dr

Scheme 4.4: Synthesis and cycloallylation of α-methylnaphthyl amine substrate

The incorporation of chirality at the acyl position of the α,β-unsaturation as well

as within the tether afforded no diastereoselection in the cycloallylation key step. The

introduction of these chiral auxiliaries significantly altered the reactivity of the system

rendering these substrates unsuitable for cycloallylation. Therefore, efforts were next

focused on the implementation of a chiral palladium catalyst to effect an asymmetric

cycloallylation.

201 4.2 ASYMMETRIC CYCLOALLYLATION APPROACH

As previously discussed, the cycloallylation is a merging of the Morita-Baylis-

Hillman reaction and the Trost-Tsuji allylic alkylation. Allylic alkylation is one of the

most developed transition metal catalyzed processes.5 Large classes of chiral mono- and

bidentate ligands have been developed for asymmetric allylic alkylation, especially for

kinetic resolution applications.6 Although these chiral ligands are frequently phosphines,

it was hoped that preferential binding of chiral ligand to the Pd center versus

trialkylphosphine could be realized in the development of an asymmetric cycloallylation.

It was thought that in order to obtain preferential binding of an exogenous chiral ligand,

that ligand must be bidentate.

Efforts toward the asymmetric cycloallylation began with the treatment of enone-

allyl carbonate 4.1 with 2.5 mol% of Pd2dba3·CHCl3 and 20 mol% of (R)-Cl-OMe-

BIPHEP (4.19) (Table 4.2, entry 1). Cycloallylation to piperidine 4.4 proceeded with this

P,P-ligand in 34% yield but with of 0% ee. Enantiomeric excess was determined by 1H

NMR with the chiral shift reagent, Eu(hfc)3 (tris-(3-heptafluorobutyryl-d-camphorato)- europium)7 and comparing peak integrations of the shifted acyl methyl group singlet of

enone 4.4. Unfortunately, separation conditions for apolar piperidine 4.4 via chiral HPLC

were unattainable. With the failure of the P,P-bidentate ligand 4.19, next N,P-bidentate

ligand was prepared.8 With ligand 4.20 loading of 5 mol% up to 50 mol%, fair chemical

yields of piperidine 4.4 were reported, though enantiomeric excess was consistently 0%

(entries 2-4). Lastly, chiral N,N-bidentate ligand 4.21 was synthesized.9 Employment of

ligand 4.21 at 25 mol% loading in conjunction with 2.5 mol% of Pd2dba3·CHCl3 and stoichiometric PMe3 afforded only a 21% yield of cycloallylated piperidine 4.4, again ee

was 0% (entry 5). As suspected, chiral ligands are not a suitable avenue for the

202 development of an asymmetric cycloallylation. Stoichiometric trialkylphosphine serves

too well as ligand for the palladium metal and the ratio of trialkylphosphine:chiral ligand

is too crippling to obtain asymmetric induction.

OCO2Me

. O Pd2dba3 CHCl3 (2.5 mol%) O Ligand Me Me N t N Trs PMe3, AmOH Trs 4.1 4.4

Cl O O O MeO PPh2 N N N MeO PPh2 PPh2 Cl 4.19 4.20 4.21

Entry PR3 Ligand Yield ee

1PMe3 (100 mol%) 4.19 (20 mol%) 34% 0%

2PMe3 (100 mol%) 4.20 (5 mol%) 50% 0%

3PBu3 (100 mol%) 4.20 (5 mol%) 23% 0%

4PMe3 (100 mol%) 4.20 (50 mol%) 41% 0% 4.21 (25 mol%) 5PMe3 (100 mol%) 21% 0%

Table 4.2: Asymmetric cycloallylation with chiral bidentate ligands

In a second effort to render the cycloallylation asymmetric, the use of chiral

additives was investigated. The parent methodology required the use of an alcoholic

solvent which is theorized to assist in the stabilization of enolate 4.22 generated upon 1,4-

addition of phosphine (Scheme 4.5).

t OCO Me BuO-H O 2 O LnPdII R LnPdII Pd(PPh3)4 R R O t PBu3, BuOH n Bu3P n P n Bu3 4.22 4.23 4.24

Scheme 4.5: Alcohol-assisted enolate stabilization

203 Accordingly, an asymmetric cycloallylation utilizing chiral BINOL additives was

investigated. Subjection of substrate 4.1 to the standard cycloallylation conditions in

tAmOH with (R)-BINOL (4.25) at 10 mol% loading afforded piperidine 4.4 in 48% yield

(Table 4.3, entry 1). Again, enantiomeric excess was determined to be 0%. This result

was not unexpected as the alcoholic solvent most likely outcompetes the chiral alcohol

additive. When switching to aprotic solvents such as THF (entry 2) and DCM (entry 3)

reaction yield fluctuates to 31% and 50% respectively, though a 0% ee is again obtained.

Uang has found that aluminum-BINOL complexes effectively catalyze asymmetric

ketone reductions.10 In similar fashion, chiral aluminum catalysts were prepared from

i mixing (R)-BINOL (4.25) with Al(O Pr)3 (entry 4) and AlMe3 (entry 5) and employed in

the cycloallylation. Yields of 33% and 31% respectively of racemic piperidine (4.4) were

obtained in these cases. The use of unsymmetrical BINOL derivative 4.26 also failed to

deliver an optically active product (entry 6, 7). List has found success in the use of

phosphoric acid 4.27 in applications of counterion directed asymmetric organocatalysis.11

Employment of phosphoric acid 4.27 in the cycloallylation yielded racemic piperidine 4.4 in 47% yield (entry 8). Lastly, as Eu(hfc)3 was found to be effective in binding piperidine

4.4 as a chiral shift reagent in 1H NMR experiments, its use as a chiral additive

diminished the yield of racemic piperidine 4.4 to 21%.

204 OCO2Me O O Pd(PPh ) , PMe Me 3 4 3 Me N N Trs Additive Trs 4.1 4.4

R R

CF2CF2CF3 OH O O P O OH O OH

O Eu R 3 4.25, R = H 4.27, R = 2,4,6,-iPrPh 4.28 4.26, R = 3,5-Me2Ph

Entry Additive(s) Solvent Yield ee 1 4.25 (10 mol%) t AmOH (0.1 M) 48% 0% 2 4.25 (10 mol%) THF (0.1 M) 31% 0% 3 4.25 (10 mol%) DCM (0.1 M) 50% 0% i 4 4.25 (10 mol%), Al(O Pr)3 (10 mol%) DCM (0.1 M) 33% 0%

5 4.25 (10 mol%), AlMe3 (10 mol%) DCM (0.1 M) 31% 0% 6 4.26 (10 mol%) DCM (0.1 M) nr - 7 4.26 (10 mol%) 1:1 t AmOH:DCM (0.1 M) 55% 0% 8 4.27 (10 mol%) t AmOH (0.1 M) 47% 0% t 9 4.28 (10 mol%) AmOH (0.1 M) 21% 0%

Table 4.3: Asymmetric cycloallylation with chiral additives

4.3 SYNTHESIS AND CYCLOALLYLATION OF CHIRAL ALLYLIC CARBONATE

With the inability to obtain any degree of enantioselection in the cycloallylation it

was questioned if a chiral π-allyl generated from a chiral allylic carbonate could be used

for asymmetry. It was hoped that upon ionization of allylic carbonate 4.29 to form a

chiral Pd π-allyl 4.30, cyclization via cycloallylation would be faster than π-facial

interconversion to form enantioenriched piperidine 4.4 (Scheme 4.6). Migration of Pd

from one enantiotopic face to the other is known to proceed through a η3- η1- η3 mechanism therefore racemizing a chiral precursor.5

205 O Me PdLn O Pd(0), PR3 Me OCO2Me O Me N tAmOH N N Trs P Trs Trs R3 4.29 4.30 4.4

Scheme 4.6: Asymmetric cycloallylation of chiral allylic carbonate

The synthesis of chiral allylic carbonate 4.29 began with the alkylation of sulfonamide 4.31 by deprotonation with KH and alkylation with the tartrate derived bistosylate12 to afford tosylate 4.32 in 80% yield (Scheme 4.7). Tosylate 4.32 underwent

Finkelstein reaction with NaI to afford primary iodide 4.33 in 83% yield. Iodide 4.33 was

converted to allylic alcohol 4.34 via reductive olefination in 96% yield. Allylic alcohol

4.34 was deprotonated with KH in THF at 0 ˚C and treated with methyl chloroformate at

60 ˚C to afford chiral allylic carbonate 4.35 in 70% yield. To install the enone

functionality, acetal 4.35 was hydrolyzed and the crude aldehyde subjected to Wittig

olefination to furnish chiral cycloallylation substrate 4.29 in 58% yield over two steps.

TsO O I O 1. KH, DMF, 0 °C NaI, acetone nBuLi, THF OEt OEt O OEt O H O Δx -78 °C N 2. OTs N N EtO Trs O OTs EtO Trs EtO Trs 4.31 DMF, 80 °C 4.32 4.33 80% 83% 96%

1. TFA, H O 2 O 1. KH, THF, 0 °C CHCl3, 0 °C OEt OH OEt OCO Me Me OCO Me 2. ClCO Me, 60 °C 2 2. O 2 N 2 N Ph P N EtO Trs EtO Trs 3 Me, DCM Trs 4.34 4.35 4.29 70% 58%

Scheme 4.7: Synthesis of chiral allylic carbonate substrate

206

Subjection of chiral cycloallylation substrate 4.29 to standard cycloallylation

conditions afforded piperidine 4.4 in 60% yield, but with a surprising 0% ee (Scheme

4.8). Though it wouldn’t be unexpected to encounter some enantiomeric erosion due to π-

facial interconversion, the formation of a racemic product was unanticipated. This result

provided a re-evaluation of the possible mechanism.

O O Pd(PPh3)4 Me OCO Me Me 2 t N PMe3, AmOH N Trs Trs 4.29 4.4 60% 0% ee

Scheme 4.8: Cycloallylation of chiral allylic carbonate substrate

Mechanistically, conjugate addition of PMe3 and Pd(0) ionization of allylic

carbonate 4.29 yields dually activated intermediate 4.36 (Scheme 4.9). At this point a

second molecule of the nucleophilic PMe3 can attack the π-allyl terminus to afford allylic

phosphonium adduct 4.37. During this event, the chirality initially associated with the

system is lost. Intermediate 4.37 can then undergo SN2’ cyclization to afford racemic

piperidine 4.4. This alternate mechanism accounts for two observations of the

cycloallylation reaction. First, in order to obtain a racemic product, the chiral center most

likely is destroyed in the formation of active phosphonium electrophile 4.37. Second, the

reaction is found to perform best with stoichiometric trialkylphosphine. In the proposed

mechanism two molecules of phosphine are necessary per molecule substrate to obtain

cyclization.

207 PdIILn O Pd(0) Me PMe3

Me OCO2Me O PMe3 N N 0 Trs P Trs Pd Me3 4.29 4.36

PMe3

Me SN2' O

O Me N PMe N P Trs 3 Trs Me3 4.37 4.4

Scheme 4.9: Possible alternative cycloallylation mechanism

4.4 ASYMMETRIC MORITA-BAYLIS-HILLMAN CYCLIZATION

With a lack of any encouraging results, the development of an asymmetric cycloallylation was halted. Under the ascribed conditions of trialkylphosphine and Pd(0) catalysis, the ability to create a chiral environment closely associated with the C-C bond forming process seemed unattainable. The asymmetric approach toward quinine took a new approach in a variation of the cycloallylation key step. It was now envisioned to implement a more traditional MBH cyclization as key step.

Based on the previous work of Krafft13, allylic tosylates, mesylates, and chlorides have been found suitable electrophiles in phosphine-mediated MBH-type intramolecular cyclizations. Of the three electrophiles, the allylic chloride was best in the formation of cyclopentene 4.43 in 80% yield (Scheme 4.10).

208 X O t O 1. PBu3, BuOH Me Me 2. KOH, BnEt3NCl

4.38, X = OTs 4.41, X = OTs, 36% 4.39, X = OMs 4.42, X = OMs, 40% 4.40, X = Cl 4.43, X = Cl, 80%

Scheme 4.10: PBu3-mediated MBH cyclization with varying electrophile

4.4.1 Retrosynthetic Analysis

Accordingly, quinine can be envisioned by implementing a phosphine-mediated

Morita-Baylis-Hillman cyclization as key step (Scheme 4.11). This retrosynthesis is identical to what has been previously proposed, with the exception of the phosphine- mediated cyclization of 4.47 to 4.4. This initiated the synthesis of substrates 4.47

possessing a chiral allylic leaving group.

H OMe OMe OH OMe O H H N O N N OH Boc Boc N N N

4.44 4.45 4.46

OMe

CHO O O N PR Me 3 Me LG N N Trs Trs

4.4 4.47

Scheme 4.11: Retrosynthetic approach to quinine

4.4.2 Deprotection of Chiral Allylic Carbonate

Krafft disclosed that allylic mesylate, tosylates, and halides all participate in

MBH cyclization reactions. Therefore, enone bearing allylic alcohol 4.48 was identified

209 as a key intermediate which could be functionalized to intercept all three of these

electrophiles. With allylic carbonate 4.29 in hand, deprotection under basic conditions led

to decomposition (Table 4.4, entries 1-3). Heating allylic carbonate 4.29 in aqueous acid

failed to provide deprotection to allylic alcohol 4.48 with quantitative recovery of starting

material.

O O Deprotection

Me OCO2Me Me OH N N Trs Trs 4.29 4.48

Entry Reagent Solvent Temp Yield

1 NaOH dioxane/H2Ort-

2K2CO3 MeOH rt - 3 - pyrrolidine 60 ˚C- 4 - 1.7 N HCl 100 ˚C-

Table 4.4: Conditions for carbonate deprotection

4.4.2 Synthesis and Deprotection of Chiral Allylic Silyl Ether A silyl protected substrate was also prepared in hopes of facile deprotection to

enone bearing allylic alcohol 4.48 (Scheme 4.12). Allylic alcohol 4.34 underwent smooth protection with TBDPSCl and imidazole in DMF to furnish TBDPS ether 4.49 in 84% yield. The acetal moiety of TBDPS ether 4.49 was next hydrolyzed, and the resulting crude aldehyde was olefinated to afford enone bearing TBDPS ether 4.50 in 74% yield

over two steps. Silyl ether 4.50 was subjected to TBAF in THF, as well as anhydrous HCl

in Et2O, though both resulted in rapid decomposition.

210 1. TFA,H2O TBDPSCl CHCl3, 0 °C OEt OH OEt OTBDPS imidazole, DMF 2. O N N Ph P EtO Trs EtO Trs 3 Me, DCM 4.34 4.49 84% 74%

O O Deprotection Me OTBDPS Me OH N N Trs Trs 4.50 4.48

Scheme 4.12: Synthesis and deprotection of chiral silyl ether

The inability to deprotect both carbonate 4.29 and TBDPS ether 4.50 under basic

and acidic conditions respectively led to speculation that enone bearing allylic alcohol

4.48 was quite sensitive. For this reason, efforts were focused on the introduction of the

electrophilic allylic leaving group prior to enone installation.

4.4.3 Synthesis of Chiral Allylic Tosylate

Following significant optimization, allylic alcohol 4.34 was converted to allylic

tosylate 4.51 in 40% yield upon treatment with TsCl in pyridine at room temperature

(Scheme 4.13). The allylic tosylate functionality was found to be quite sensitive and all

attempts to hydrolyze the acetal moiety of allylic tosylate 4.51 led to rapid and complete

decomposition. These experiments led to the conclusion that these allylic electrophiles were too reactive to be carried through additional steps.

211 1. TFA,H2O O TsCl, pyr CHCl3, 0 °C OEt OH OEt OTs Me OTs 2. O N N Ph P N EtO Trs EtO Trs 3 Me, DCM Trs 4.34 4.51 4.52 40%

Scheme 4.13: Synthesis of chiral allylic tosylate

4.4.4 Synthesis of Key Allylic Alcohol via Lactol Olefination

A new route was developed to access enone bearing allylic alcohol 4.48. The

acetal moiety was treated with aqueous acid in hopes of conversion to lactol 4.54. This

transformation required optimization to partition between intermediate mixed acetal 4.53

and lactol 4.54. Treatment of acetal 4.34 with TFA in H2O and CHCl3 at 0 ˚C afforded

exclusively the mixed acetal in 93% yield (Table 4.5, entry 1). Subjection of acetal 4.34

with HCl in H2O/THF at 100 ˚C lead to rapid formation of the mixed acetal in an isolated

61% yield, though lactol was not observed (entry 2). TsOH was similarly found to furnish mixed acetal 4.53 in a favorable 85% yield, but again none of lactol 4.54 was isolated

(entry 3). AcOH was found suitable to begin partitioning between the two hydrolysis products affording them as a 1:1 mixture by refluxing in H2O at a concentration of 0.4 M

(entry 4). Full partitioning between the mixed acetal and lactol was finally realized by

further reaction dilution to 0.1 M to obtain the lactol exclusively in 70% yield (entry 5).

One could also decrease reaction time by removing ethanol in vacuo once acetal 4.34 was

completely hydrolyzed by thin layer chromatography analysis. In all of the preceding

experiments, both mixed acetal 4.53 and lactol 4.54 were obtained as 1:1 ratios of

inseparable diastereomers.

212 OEt OH O O N N N EtO Trs EtO Trs HO Trs 4.34 4.53 4.54

Entry Acid Solvent Temp Time Yield 4.53 Yield 4.54

1 TFAH2O/CHCl3 0 °C to rt 24 h 93% -

2 HClH2O/THF 100 °C 1 h 61% -

3 TsOHH2O/acetone 50 °C 46 h 85% -

4 AcOHH2O (0.4 M) 100 °C 27 h 23% 14% 5AcOHH2O (0.1 M) 100 °C 46 h - 70%

Table 4.5: Acetal hydrolysis to mixed acetal and lactol

With lactol 4.54 now accessible, it was hoped that via equilibration, hydroxy

aldehyde 4.55 could undergo Wadsworth-Emmons olefination to afford key enone

bearing allylic alcohol 4.48 (Scheme 4.14). Unfortunately, following olefination, key

allylic alcohol 4.48 undergoes intramolecular conjugate addition to form morpholino

ketone 4.56 in 53% yield. No reaction was observed when the stabilized Wittig reagent was employed.

O O P O O OH Me (OEt)2 N N HO Trs H Trs LHMDS, THF, 60 °C 4.54 4.55 53%

O

Me OH O O N N Trs Me Trs 4.48 4.56

Scheme 4.14: Lactol olefination

213 4.4.5 Synthesis and Cyclization of Chiral Allylic Phosphonate

With this result, it was clear that enone bearing allylic alcohol 4.48 was not

accessible. It was hoped that the asymmetric MBH cyclization would proceed with a less

reactive electrophile; one that would tolerate acetal hydrolysis and aldehyde olefination

to install the required α,β-unsaturation. Allylic phosphonates are viable electrophiles in

14 15 SN2 and SN2’ reactions with organocuprates and organozinc nucleophiles .

The phosphonate functionality was introduced via deprotonation of allylic alcohol

4.34 with KH in THF at 0 ˚C followed by treatment with chlorodiethylphosphonate at

reflux to afford allylic phosphonate 4.57 in 81% yield (Scheme 4.15). The acetal moiety

of allylic phosphonate 4.57 was then hydrolyzed and olefinated under the standard

conditions to afford enone bearing allylic phosphonate 4.58 in 63% over two steps.

t Cyclization of substrate 4.58 was attempted with PMe3 (100 mol%) in AmOH though

reaction did not occur. Heating of the reaction mixture to 50 ˚C failed to facilitate

cyclization, and starting material was recovered unchanged. The cyclization was

attempted with the additive of CuOTf at 20 mol% loading though was met without

success. With these results it was determined that the allylic phosphonate is not

sufficiently electrophilic to participate in the intramolecular MBH cyclization.

1. TFA,H O O 2 1. KH, THF, 0 °C CHCl3, 0 °C P OEt OH OEt O (OEt) 2. ClPO(OEt) , Δ 2 2. O N 2 x N Ph P EtO Trs EtO Trs 3 Me, DCM 4.34 4.57 81% 63%

O O O P Me O (OEt)2 Me N N Trs Trs 4.58 4.4

Scheme 4.15: Synthesis and cyclization of allylic phosphonate substrate

214 4.5 SUMMARY AND CONCLUSIONS

Four distinct approaches have been developed towards an enantioselective route to quinine. The cycloallylation has attempted to be rendered diastereoselective via

substrates bearing chiral auxiliaries though the related changes in structure have

dramatically reduced reactivity. Attempts to render the cycloallylation enantioselective

by the use of chiral ligands, chiral additives, and a chiral substrate have all been

unfruitful in producing exclusively racemic products. In a second approach, substrates

bearing chiral allylic leaving groups have been pursued in hopes of developing a

phosphine-catalyzed Morita-Baylis-Hillman type cyclization. Unfortunately, key

substrates have been challenging to prepare or lack the necessary electrophilicity to

facilitate cyclization.

4.6 EXPERIMENTAL PROCEDURES

OCO2Me

O O

O N NTrs

Carbonic acid 4-[[4-(4-isopropyl-2-oxo-oxazolidin-3-yl)-4-oxo-but-2-enyl]-(2,4,6- triisopropyl-benzenesulfonyl)-amino]-but-2-enyl ester methyl ester (4.11)

To a solution of acetal 3.13 (0.58 g, 1.10 mmol) in CHCl3 (2.7 mL) and H2O (1.3 mL) at 0 ˚C was added TFA (1.3 mL, 18.02 mmol, 1640 mol%). The reaction mixture slowly warmed to room temperature over 20 h at which time it was quenched with solid

NaHCO3, poured into H2O, and extracted with DCM (3x). The combined organic extracts

were washed with saturated aqueous NaHCO3 (1x), brine (1x), dried over Na2SO4, and concentrated. The yellow residue was then taken up in DCM (11 mL) at room temperature oxazolidinone Wittig reagent16 (0.53 g, 1.20 mmol, 110 mol%) was added. The reaction mixture stirred for 58 h at which time it was concentrated. The crude

215 product was purified by flash column chromatography (5:1 hexanes:EtOAc to 3:1) to afford exclusively trans-enimide 4.11 (0.33 g, 0.55 mmol, 50%) as a yellow oil. 1H NMR

(400 MHz, CDCl3): δ 7.35 (d, 1 H, J = 15.4 Hz), 7.16 (s, 2 H), 6.92 (dt, 1 H, J = 15.4, 6.4 Hz), 5.80-5.65 (m, 2 H), 4.57 (d, 2 H, J = 6.5 Hz), 4.48-4.44 (m, 1 H), 4.29 (t, 1 H, J = 8.7 Hz), 4.21 (dd, 1 H, J = 9.1, 3.3 Hz), 4.14-4.07 (m, 3 H), 3.98 (m, 2 H), 3.92 (t, 2 H, J = 6.0 Hz), 3.75 (s, 3 H), 2.90 (hp, 1 H, J = 6.8 Hz), 2.43-2.35 (m, 1 H), 1.25 (d, 18 H, J = 13 6.5 Hz), 0.89 (dd, 6 H, J = 20.0, 7.0 Hz); C NMR (100 MHz, CDCl3): δ 164.3, 155.4, 153.7, 153.4, 151.6, 147.6, 130.5, 129.2, 127.6, 124.0, 121.2, 63.3, 62.8, 58.3, 54.8, 45.4, 43.1, 34.1, 29.3, 28.3, 24.7, 23.5, 18.0, 14.6; IR (neat) ν 2962, 2930, 1779, 1751, 1686,

1641, 1600, 1462, 1424, 1106, 939, 903; HRMS (CI) calcd. for C31H47N2O8S [M + 1]: 607.3053, found: 607.3055.

OCO2Me

O

S N O O NTrs Carbonic acid 4-[[4-(10,10-dimethyl-3,3-dioxo-3l6-thia-4-aza-tricyclo[5.2.1.01,5]dec- 4-yl)-4-oxo-but-2-enyl]-(2,4,6-triisopropyl-benzenesulfonyl)-amino]-but-2-enyl ester methyl ester (4.13)

To a solution of acetal 3.13 (1.04 g, 1.98 mmol) in CHCl3 (4.9 mL) and H2O (2.4 mL) at 0 ˚C was added TFA (2.4 mL, 32.43 mmol, 1640 mol%). The reaction mixture slowly warmed to room temperature over 20 h at which time it was quenched with solid

NaHCO3, poured into H2O, and extracted with DCM (3x). The combined organic extracts

were washed with saturated aqueous NaHCO3 (1x), brine (1x), dried over Na2SO4, and concentrated. To a separate solution of nBuLi (2.5 M in hexanes, 0.95 mL, 2.38 mmol,

120 mol%) in Et2O (5 mL) at 0 ˚C was added H2O (0.04 mL, 2.33 mmol, 120 mol%) in THF (10 mL). The resulting mixture was stirred for 10 min at 0 ˚C at which time Oppolzer sultam β-ketophosphonate17 (0.84 g, 2.13 mmol, 110 mol%) in THF (10 mL) was added. The reaction mixture was warmed to room temperature and the crude aldehyde was added. The reaction mixture stirred for 30 min after which it was poured into water and extracted with Et2O (3x) and EtOAc (1x). The combined organic extracts

were washed with brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (5:1 hexanes:EtOAc to 3:1) to furnish

216 ensulfonamide 4.13 (1.11 g, 1.64 mmol, 83%) as a orange foam. 1H NMR (400 MHz,

CDCl3): δ 7.15 (s, 2 H), 6.85 (dt, 1 H, J = 15.0, 6.4 Hz), 6.66 (d, 1 H, J = 15.4 Hz), 5.77- 5.64 (m, 2 H), 4.59 (d, 2 H, J = 6.5 Hz), 4.14-4.07 (m, 3 H), 3.96-3.88 (m, 3 H), 3.74 (s, 3 H), 3.46-3.38 (m, 3 H), 3.10 (d, 3 H, J = 4.4 Hz), 2.88 (hp, 1 H, J = 6.8 Hz), 1.91-1.85 (m, 5 H), 1.23 (dd, 18 H, J = 7.1, 1.7 Hz), 1.12 (s, 3 H), 0.92 (s, 3 H); 13C NMR (100

MHz, CDCl3): δ 163.0, 155.4, 153.5, 151.6, 143.5, 130.3, 129.0, 128.0, 124.0, 123.9, 65.0, 62.8, 55.0, 53.0, 50.3, 48.5, 47.4, 47.4, 44.6, 42.7, 38.3, 36.0, 34.1, 32.8, 31.8, 29.3, 26.8, 26.4, 24.8, 23.5 20.7, 20.4, 20.4, 19.8; IR (film) ν 3057, 2962, 2872, 1749, 1686,

1645, 1600, 1425, 1042, 995, 844, 619; HRMS (CI) calcd. for C35H53N2O8S2 [M + 1]: 693.3243, found: 693. 3234.

Br OCO2Me Carbonic acid 4-bromo-but-2-enyl ester methyl ester (4.59) To a solution of allylic alcohol 3.133 (15.0 g, 102.6 mmol) in DCM (300 mL) at 0 ˚C was

added NBS (18.45 g, 103.7 mmol, 100 mol%) and PPh3 (26.90 g, 102.6 mmol, 100 mol%) in DCM (100 mL). The reaction vessel was wrapped in foil and the reaction mixture slowly warmed to room temperature over 21 h at which time it was concentrated. The crude product was purified by flash column chromatography (5:1 hexanes:EtOAc) to afford allylic bromide 4.59 (16.77 g, 80.2 mmol, 78%) as a colorless oil. Spectral data matched that of the literature reference.18

OCO2Me

OEt N EtO Me Carbonic acid 4-[(2,2-diethoxy-ethyl)-(1-naphthalen-2-yl-ethyl)-amino]-but-2-enyl ester methyl ester (4.16) To a solution of (R)-(+)-1-(2-napthyl)ethylamine (4.08 g, 23.8 mmol) in MeCN (180 mL) at room temperature was added K2CO3 (4.88 g, 35.3 mmol, 150 mol%) and bromoacetaldehyde diethyl acetal (4.4 mL, 28.6 mmol, 120 mol%). The reaction mixture was heated at reflux for 18 h at which time it was cooled, filtered, and concentrated to afford the crude secondary amine (3.97 g) as a yellow oil. The crude amine was taken up in DMF (70 mL) and at room temperature were added K2CO3 (2.80 g, 20.2 mmol, 85

217 mol%) and allylic bromide 4.59 (4.14 g, 19.8 mmol, 83 mol%). The reaction mixture

stirred for 15 h at which time it was poured into water and extracted with Et2O (3x). The

combined ethereal extracts were washed with brine (1x), dried over Na2SO4, and concentrated. The crude residue was purified by flash column chromatography (20:1 hexanes:EtOAc (with 1% Et3N by volume) to 20:1, 5:1, 4:1) gave aminoacetal 4.16 (5.58 1 g, 13.3 mmol, 56%) as a yellow oil. H NMR (400 MHz, CDCl3): δ 7.82-7.77 (m, 3 H), 7.72 (s, 1 H), 7.58 (dd, 1 H, J = 8.4, 1.7 Hz), 7.45-7.42 (m, 2 H), 5.84-5.78 (m, 1 H), 5.69-5.63 (m, 1 H), 4.69-4.59 (m, 2 H), 4.47 (t, 1 H, J = 5.3 Hz), 4.12 (q, 1 H, J = 6.8 Hz), 3.76 (s, 3 H), 3.70-3.22 (m, 7 H), 2.71 (dd, 1 H, J = 14.0, 5.5 Hz), 2.62 (dd, 1 H, J = 14.0, 5.1 Hz), 1.45 (d, 3 H, J = 6.8 Hz), 1.21-1.12 (m, 6 H); 13C NMR (100 MHz,

CDCl3): δ 155.3, 141.1, 133.4, 132.9, 132.3, 127.5, 127.3, 127.1, 126.3, 125.5, 125.4, 125.1, 124.7, 102.7, 63.3, 62.0, 61.5, 59.0, 54.2, 52.3, 47.6, 15.3, 15.0, 15.0; IR (neat) ν 3056, 2974, 2878, 2246, 1742, 1633, 1601, 1506, 1443, 1373, 648, 623; HRMS (CI)

calcd. for C24H34NO5 [M + 1]: 416.2437, found: 416.2451.

OCO2Me

O

Me N

Me Carbonic acid methyl ester 4-[(1-naphthalen-2-yl-ethyl)-(4-oxo-pent-2-enyl)-amino]- but-2-enyl ester (4.17)

To a solution of aminoacetal 4.16 (0.20 g, 0.48 mmol) in DCM (9.6 mL) at -78 ˚C was added HBr (33% in AcOH, 0.19 mL, 1.1 mmol, 230 mol%). The reaction mixture stirred for 30 min at -78 ˚C at which time a second portion of HBr (33% in HOAc, 0.19 mL, 1.1 mmol, 230 mol%) was added. The resulting reaction mixture stirred for an additional 30 min at -78 ˚C at which time it was poured into water and extracted with Et2O (3x). The combined ethereal extracts were washed with brine (1x) and concentrated to give the

crude aldehyde. The crude aldehyde was taken up in DCM (4 mL) and at room temperature Wittig reagent 3.134 (0.26 g, 0.82 mmol, 170 mol%) was added. The reaction mixture stirred at room temperature for 48 h at which time it was concentrated. The crude product was purified by flash column chromatography (20:1 hexanes:EtOAc

(with 1% Et3N by volume) to 5:1, 3:1, 2:1) to give exclusively trans-enone 4.17 (0.077 g, 1 0.20 mmol, 42%) as a yellow oil. H NMR (400 MHz, CDCl3): δ 7.82-7.80 (m, 3 H),

218 7.72 (s, 1 H), 7.56 (dd, 1 H, J =8.4, 1.5 Hz), 7.49-7.44 (m, 2 H), 6.74 (dt, 1 H, J = 16.1, 5.8 Hz), 6.21 (d, 1 H, J = 16.1 Hz), 5.82-5.77 (m, 1 H), 5.73-5.69 (m, 1 H), 4.63 (d, 2 H, J = 6.5 Hz), 4.04 (q, 1 H, J = 6.6 Hz), 3.77 (s, 3 H), 3.34-3.13 (m, 4 H), 2.22 (s, 3 H), 13 1.46 (d, 3 H, J = 6.8 Hz); C NMR (100 MHz, CDCl3): δ 198.2, 155.5, 146.1, 140.7, 133.1, 132.7, 132.6, 131.8, 127.8, 127.7, 127.4, 125.8, 125.6, 125.4, 63.3, 59.3, 54.6, 51.2, 47.3, 26.7, 16.5; IR (neat) ν 3055, 2986, 1749, 1674, 1630, 1444, 1422, 1365, 1178,

860; HRMS (CI) calcd. for C23H28NO4 [M + 1]: 382.2018, found: 382.2025.

O

Me N

Me 1-[1-(1-Naphthalen-2-yl-ethyl)-3-vinyl-1,2,3,6-tetrahydro-pyridin-4-yl]-ethanone (4.18) To a degassed solution of enone 4.17 (0.084 g, 0.22 mmol) in tAmOH (2.2 mL) at room

temperature was added Pd(PPh3)4 (0.013 g, 0.01 mmol, 5 mol%) and freshly distilled

PBu3 (0.05 mL, 0.2 mmol, 90 mol%). The reaction mixture stirred at room temperature for 35 min at which time it was concentrated. The crude product was purified by flash

column chromatography (50:1 hexanes:EtOAc (with 1% Et3N by volume) to 50:1, 20:1, 10:1, 5:1) to give piperidine 4.18 (0.021 g, 0.055 mmol, 25%) as a yellow oil as a 1:1 1 mixture of inseparable diastereomers. H NMR (400 MHz, CDCl3): δ 7.84-7.80 (m, 3 H), 7.73-7.72 (m, 1 H), 7.54-7.44 (m, 3 H), 6.85-6.83 (m, 0.5 H), 6.72 (t, 0.5 H, J = 3.4 Hz), 6.00-5.85 (m, 1 H), 5.12-5.00 (m, 2 H), 3.68-3.65 (m, 1 H), 3.47-3.35 (m, 1 H), 3.30 (br s, 1 H), 3.06-2.95 (m, 2 H), 2.82 (d, 1 H, J = 10.3 Hz), 2.08 (s, 1.5 H), 2.06 (s, 1.5 H), 1.45 (d, 3 H, J = 6.5 Hz).

OEt NHTrs EtO N-(2,2-Diethoxy-ethyl)-2,4,6-triisopropyl-benzenesulfonamide (4.31) To a solution of aminoacetaldehyde diethyl acetal (11.7 mL, 80.7 mmol) in DCM (129

mL) at 0 ˚C was added Et3N (13.8 mL, 99.0 mmol, 120 mol%) and 2,4,6-triisopropylbenzenesulfonyl chloride (25 g, 82.6 mmol, 100 mol%). The reaction mixture slowly warmed to room temperature over 22 h at which time it was poured into

H2O and extracted with DCM (3x). The combined organic extracts were washed with 5%

219 aqueous Cu2SO4 (1x), brine (2x), dried over Na2SO4, and concentrated to afford pure sulfonamide 4.31 (31.89 g, 79.9 mmol, 99%) as a white solid. mp: 79-80 ˚C; 1H NMR

(400 MHz, CDCl3): δ 7.16 (s, 2 H), 4.63 (t, 1 H, J = 6.5 Hz), 4.56 (t, 1 H, J = 5.5 Hz), 4.13 (hp, 2 H, J = 6.8 Hz), 3.71-3.64 (m, 2 H), 3.53-3.46 (m, 2 H), 3.02 (t, 2 H, J = 6.0 Hz), 2.89 (hp, 1 H, J = 6.8 Hz), 1.26 (t, 18 H, J = 7.2 Hz), 1.17 (t, 6 H, J = 7.0 Hz); 13C

NMR (100 MHz, CDCl3): δ 152.7, 150.1, 131.9, 123.7, 100.8, 63.3, 45.3, 34.1, 29.6, 24.8, 23.5, 15.2; IR (film) ν 3305 (b), 2961, 2931, 2872, 1601, 1153, 1061; HRMS (CI)

calc. for C21H36NO4S [M – 1]: 398.2365, found: 398.2368.

OTs O

OEt O N EtO Trs Toluene-4-sulfonic acid 5-{[(2,2-diethoxy-ethyl)-(2,4,6-triisopropyl- benzenesulfonyl)-amino]-methyl}-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester (4.32) To a solution of KH (30% in oil, 0.11 g, 0.82 mmol, 130 mol%) in DMF (2.1 mL) at 0 ˚C was added sulfonamide 4.31 (0.25 g, 0.63 mmol). The resulting mixture was stirred at room temperature at which time bistosylate19 (0.59 g, 1.26 mmol, 200 mol%) was added. The reaction mixture was heated at 80 ˚C for 1 h. The reaction mixture was then cooled to room temperature, poured into H2O, and extracted with Et2O (3x). The combined

ethereal extracts were washed with brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (10:1 hexanes:EtOAc to 7:1, 25 5:1) to provide tosylate 4.32 (0.35 g, 0.50 mmol, 80%) as a pale yellow oil. [α]D : -22.4˚ 1 (c = 0.02 in DCM); H NMR (400 MHz, CDCl3): δ 7.79 (d, 2 H, J = 8.2 Hz), 7.34 (d, 2 H, J = 8.2 Hz), 7.15 (s, 2 H), 4.46 (t, 1 H, J = 5.3 Hz), 4.09-3.99 (m, 3 H), 3.96-3.88 (m, 2 H), 3.84-3.79 (m, 1 H), 3.65-3.51 (m, 3 H), 3.48-3.35 (m, 5 H), 2.89 (hp, 1 H, J = 6.8 13 Hz), 2.44 (s, 3 H), 1.26-1.12 (m, 30 H); C NMR (100 MHz, CDCl3): δ 153.1, 151.1, 144.8, 132.4, 131.7, 129.7, 127.9, 123.7, 110.1, 101.8, 76.4, 75.8, 68.8, 62.8, 62.7, 48.8, 48.7, 33.9, 29.2, 26.7, 26.5, 24.7, 24.6, 23.4, 21.4, 15.1; IR (neat) ν 3056, 2963, 2932, 2873, 1713, 1600, 1365, 1220, 929, 885, 844, 815, 664; HRMS (CI) calcd. for

C35H55NO9S2 [M - 1]: 697.3318, found: 697.3319.

220 I O

OEt O N EtO Trs N-(2,2-Diethoxy-ethyl)-N-(5-iodomethyl-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)- 2,4,6-triisopropyl-benzenesulfonamide (4.33) To a solution of tosylate 4.32 (0.35 g, 0.50 mmol) in acetone (5 mL) at room temperature was added NaI (0.75 g, 5.00 mmol, 1000 mol%). The reaction mixture was heated at reflux for 46 h at which time it was cooled to room temperature, filtered, and concentrated. The crude product was purified by flash column chromatography (10:1 hexanes:EtOAc to 7:1) furnished iodide 4.33 (0.26 g, 0.41 mmol, 81%) as a thick, light 25 1 yellow oil. [α]D : -21.4˚ (c = 0.1 in DCM); H NMR (400 MHz, CDCl3): δ 7.16 (s, 2 H), 4.59 (t, 1 H, J = 5.3 Hz), 4.09 (hp, 2 H, J = 6.8 Hz), 3.78 (td, 1 H, J = 7.9, 2.5 Hz), 3.71- 3.44 (m, 9 H), 3.14 (dd, 1 H, J = 10.8, 4.8), 3.05 (dd, 1 H, J = 10.4, 5.5 Hz), 2.89 (hp, 1 H, J = 6.8 Hz), 1.34 (s, 6 H), 1.28-1.23 (m, 18 H), 1.18 (q, 6 H, J = 6.7); 13C NMR (100

MHz, CDCl3): δ 153.0, 151.1, 131.7, 123.7, 109.7, 101.8, 79.9, 77.8, 62.8, 62.6, 49.0, 48.8, 34.0, 29.2, 27.1, 27.1, 24.7, 24.7, 23.5, 23.4, 15.1, 5.3; IR (neat) ν 2961, 2932,

2871, 1601, 1462, 1424, 1381, 1195, 884; HRMS (CI) calcd. for C28H47NO6SI [M -1]: 652.2169, found: 652.2170.

OEt OH N EtO Trs N-(2,2-Diethoxy-ethyl)-N-(2-hydroxy-but-3-enyl)-2,4,6-triisopropyl- benzenesulfonamide (4.34) To a solution of iodide 4.33 (0.97 g, 1.48 mmol) in THF (14.6 mL) at -78 ˚C was added dropwise nBuLi (2.5 M in hexanes, 1.5 mL, 3.7 mmol, 250 mol%). After 10 min at

-78 ˚C the reaction mixture was quenched with saturated aqueous NH4Cl and extracted

with Et2O (3x). The combined ethereal extracts were washed with brine (1x), dried over

Na2SO4, and concentrated. The crude product was purified by flash column chromatography (10:1 hexanes:EtOAc to 7:1) gave allylic alcohol 4.34 (0.67 g, 1.42 25 1 mmol, 96%) as a thick, colorless oil. [α]D : -13.3˚ (c = 0.02 in DCM); H NMR (400

MHz, CDCl3): δ 7.16 (s, 2 H), 5.68 (ddd, 1 H, J = 16.3, 10.5, 5.5 Hz), 5.22 (d, 1 H, J =

221 17.1 Hz), 5.09 (d, 1 H, J = 10.6 Hz), 4.70 (t, 1 H, J = 5.6 Hz), 4.30-4.27 (m, 1 H), 4.09 (hp, 2 H, J = 6.8 Hz), 3.76-3.64 (m, 2 H), 3.58-3.47 (m, 3 H), 3.35 (dd, 1 H, J = 15.4, 5.8 Hz), 3.29 (dd, 1 H, J = 14.8 Hz, 2.4 Hz), 3.02 (dd, 1 H, J = 14.6, 9.4 Hz), 2.88 (hp, 1 H, J 13 = 6.8 Hz), 1.26-1.17 (m, 24 H); C NMR (100 MHz, CDCl3): δ 153.5, 151.5, 137.1, 130.6, 124.0, 116.1, 101.9, 70.9, 63.9, 63.1, 55.4, 50.9, 34.0, 29.4, 24.8, 24.7, 23.5, 15.1, 15.1; IR (neat) ν 3451 (br), 2962, 2931, 2872, 1601, 1463, 1424, 1384, 1265, 884, 662;

HRMS (CI) calcd. for C25H42NO5S [M -1]: 468.2784, found: 468.2783.

OEt OCO2Me N EtO Trs Carbonic acid 1-{[(2,2-diethoxy-ethyl)-(2,4,6-triisopropyl-benzenesulfonyl)-amino]- methyl}-allyl ester methyl ester (4.35) To a solution of KH (30% in oil, 0.048 g, 0.36 mmol, 130 mol%) in THF (0.4 mL) at 0 ˚C was added allylic alcohol 4.34 (0.13 g, 0.28 mmol) in THF (1.0 mL). The resulting mixture was stirred for 1 h at which time methyl chloroformate (0.06 mL, 0.77 mmol, 280 mol%). The reaction mixture was stirred at room temperature for 30 min and 60 ˚C for 20 h at which time it was cooled to room temperature, poured into saturated aqueous

NaHCO3, and extracted with DCM (3x). The combined organic extracts were washed

with brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (10:1 hexanes:EtOAc to 7:1) to furnish allyl carbonate 25 4.35 (0.10 g, 0.20 mmol, 70%) as a white solid. mp: 61-62 ˚C; [α]D : +1.1˚ (c = 0.02 in 1 DCM); H NMR (400 MHz, CDCl3): δ 7.16 (s, 2 H), 5.75-5.67 (m, 1 H), 5.29 (dt, 1 H, J = 17.1, 1.2 Hz), 5.23 (d, 1 H, J = 10.6 Hz), 5.19-5.17 (m, 1 H), 4.47 (t, 1 H, J = 5.1 Hz), 4.07 (hp, 2 H, J = 6.8 Hz), 3.73 (s, 3 H), 3.71-3.54 (m, 4 H), 3.48-3.39 (m, 4 H), 2.90 (hp, 1 H, J = 6.8 Hz), 1.25 (d, 18 H, J = 6.8 Hz), 1.16 (t, 3 H, J = 7.0 Hz), 1.15 (t, 3 H, J = 7.0 13 Hz); C NMR (100 MHz, CDCl3): δ 154.7, 153.2, 151.2, 133.3, 131.8, 123.9, 119.0, 102.1, 76.4, 63.0, 62.9, 54.6, 49.7, 49.4, 34.1, 29.4, 24.8, 24.7, 23.5, 15.2, 15.2; IR (film) ν 2960, 2932, 2872, 2360, 2340, 1754, 1601, 1443, 1425, 1364, 1128, 1021, 791, 663;

HRMS (CI) calcd. for C27H44NO7S [M - 1]: 526.2839, found: 526.2838.

222 O

Me OCO2Me N Trs Carbonic acid methyl ester 1-{[(4-oxo-pent-2-enyl)-(2,4,6-triisopropyl- benzenesulfonyl)-amino]-methyl}-allyl ester (4.29)

To a solution of acetal 4.35 (0.77 g, 1.48 mmol) in CHCl3 (3.6 mL) and H2O (1.8 mL) at 0 ˚C was added TFA (1.8 mL, 24.50 mmol, 1660 mol%). The reaction mixture stirred for 24 h slowly warming to room temperature at which time it was poured into saturated aqueous NaHCO3 and extracted with DCM (3x). The combined organic extracts were

washed with brine (1x), dried over Na2SO4, and concentrated. The resulting oily residue was then taken up in DCM (14.8 mL) and Wittig reagent 3.134 (0.57 g, 1.78 mmol, 120 mol%) was added at room temperature. The reaction mixture stirred for 18 h at which time it was concentrated. The crude was product was purified by flash column chromatography (5:1 hexanes:EtOAc) to furnish enone 4.29 (0.42 g, 0.86 mmol, 58%) as 25 1 a white solid. mp: 74-75 ˚C; [α]D : -60.6˚ (c = 0.002 in DCM);. H NMR (400 MHz,

CDCl3): δ 7.18 (s, 2 H), 6.61 (dt, 1 H, J = 16.2, 6.3 Hz), 6.14 (d, 1 H, J = 16.1 Hz), 5.74- 5.65 (m, 1 H), 5.31 (d, 1 H, J = 17.4 Hz), 5.27 (d, 1 H, J = 10.6 Hz), 5.16 (m, 1 H), 4.10- 4.03 (m, 4 H), 3.75 (s, 3 H), 3.52 (dd, 1 H, J = 15.4, 3.4 Hz), 3.35 (dd, 1 H, J = 15.4, 8.5 Hz), 2.90 (hp, 1 H, J = 6.8 Hz), 2.22 (s, 3 H), 1.26-1.24 (m, 18 H); 13C NMR (125 MHz,

CDCl3): δ 197.7, 154.6, 153.7, 151.5, 141.1, 133.6, 132.8, 130.8, 124.2, 119.4, 54.9, 49.4, 49.3, 34.2, 29.7, 29.5, 26.9, 24.8, 24.7, 23.5; IR (film) ν 2960, 2931, 2870, 2361, 1751,

1683, 1363, 1267, 1153, 668; HRMS (CI) calcd. for C26H40NO6S [M + 1]: 494.2576, found: 494.2579.

OEt OTBDPS N EtO Trs N-[2-(tert-Butyl-diphenyl-silanyloxy)-but-3-enyl]-N-(2,2-diethoxy-ethyl)-2,4,6- triisopropyl-benzenesulfonamide (4.49) To a solution of allylic alcohol 4.34 (0.06 g, 0.13 mmol) in DMF (0.65 mL) at room temperature was added imidazole (0.027 g, 0.39 mmol, 300 mol%) and TBDPSCl (0.10 mL, 0.39 mmol, 300 mol%). The reaction mixture stirred at room temperature for 40 h

and was poured into H2O and extracted with Et2O (3x). The combined ethereal extracts

223 were washed with H2O (3x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (10:1 hexanes:EtOAc to 7:1) to give TBDPS ether 4.49 (0.079 g, 84%) as a colorless oil and recovered allylic alcohol 4.34 25 1 (0.009 g, 0.018 mmol, 14%). [α]D : +36.3˚ (c = 0.02 in DCM); H NMR (400 MHz,

CDCl3): δ 7.68-7.62 (m, 4 H), 7.41-7.31 (m, 6 H), 7.13 (s, 2 H), 5.76-5.67 (m, 1 H), 4.95 (d, 1 H, J = 17.1 Hz), 4.87 (d, 1 H, J =10.3 Hz), 4.46-4.41 (m, 1 H), 4.28-4.26 (m, 1 H), 4.01 (hp, 2 H, J = 6.7 Hz), 3.51-3.27 (m, 6 H), 3.23 (dd, 1 H, J = 15.2, 4.6 Hz), 3.11 (dd, 1 H, J = 15.2, 5.6 Hz), 2.89 (hp, 1 H, J = 6.8 Hz), 1.25-1.20 (m, 18 H), 1.09-1.05 (m, 15 13 H); C NMR (100 MHz, CDCl3): δ 152.8, 151.1, 138.1, 135.8, 133.8, 133.7, 132.4, 129.6, 129.5, 127.5, 127.4, 123.8, 116.3, 101.5, 72.5, 62.6, 62.3, 53.4, 49.7, 34.1, 29.4, 26.9, 24.9, 24.8, 23.6, 23.5, 19.2, 15.2, 15.1; IR (neat) ν 2959, 2931, 1427, 1152, 1113,

1061, 998, 740, 701, 668; HRMS (CI) calcd for C41H60NO5SiS [M - 1]: 706.3961, found: 706.3954.

O

Me OTBDPS N Trs N-[2-(tert-Butyl-diphenyl-silanyloxy)-but-3-enyl]-2,4,6-triisopropyl-N-(4-oxo-pent-2- enyl)-benzenesulfonamide (4.50)

To a solution of acetal 4.49 (0.20 g, 0.28 mmol) in CHCl3 (0.70 mL) and H2O (0.35 mL) at 0 ˚C was added TFA (0.35 mL, 4.71 mmol, 1680 mol%). The reaction mixture stirred for 24 h slowly warming to room temperature and was poured into saturated aqueous

NaHCO3 and extracted with DCM (3x). The combined organic extracts were washed with

brine (1x), dried over Na2SO4, and concentrated. The resulting oily residue was then taken up in DCM (2.7 mL) and Wittig reagent 3.134 (0.10 g, 0.32 mmol, 120 mol%) was added at room temperature. The reaction mixture stirred for 18 h at which time it was concentrated. The crude was product was purified by flash column chromatography (20:1 hexanes:EtOAc to 10:1) to furnish enone 4.50 (0.14 g, 0.21 mmol, 74%) as a colorless 25 1 oil. [α]D : +27.5˚ (c = 0.09 in DCM); H NMR (400 MHz, CDCl3): δ 7.65-7.59 (m, 4 H), 7.43-7.33 (m, 6 H), 7.13 (s, 2 H), 6.40 (dt, 1 H, J = 16.3, 6.1 Hz), 5.80 (d, 1 H, J = 16.4 Hz), 5.74-5.65 (m, 1 H), 5.02-4.95 (m, 2 H), 4.31-4.26 (m, 1 H), 3.98 (hp, 2 H, J = 6.7 Hz), 3.81 (d, 2 H, J = 6.2 Hz), 3.32 (dd, 1 H, J = 14.2, 7.7 Hz), 3.24 (dd, 1 H, J = 14.0, 4.8 Hz), 2.88 (hp, 1 H, J = 6.9 Hz), 2.08 (s, 3 H), 1.24-1.19 (m, 18 H), 1.04 (s, 9 H); 13C

224 NMR (100 MHz, CDCl3): δ 197.4, 153.3, 151.2, 141.7, 137.6, 135.8, 135.7, 133.4, 133.2, 132.7, 131.4, 129.9, 129.8, 127.7, 127.5, 123.9, 117.0, 77.2, 72.9, 52.3, 48.5, 34.1, 29.4, 26.9, 26.7, 24.8, 24.8, 23.5, 19.2; IR (neat) ν 2959, 2931, 2860, 1700, 1683, 1600, 1427,

1363, 1320, 1152, 1112, 702; HRMS (CI) calcd for C40H56NO4SiS [M + 1]: 674.3699, found: 674.3693.

OEt OTs N EtO Trs Toluene-4-sulfonic acid 1-{[(2,2-diethoxy-ethyl)-(2,4,6-triisopropyl- benzenesulfonyl)-amino]-methyl}-allyl ester (4.51) To a solution of allylic alcohol 4.34 (0.17 g, 0.35 mmol, 100 mol%) in pyridine (1.8 mL) at room temperature was added tosyl chloride (0.34 g, 1.76 mmol, 500 mol%). The

reaction mixture stirred at room temperature for 64 h at which time 3% aqueous CuSO4 was added and the resulting mixture was stirred for an additional 1 h. The resulting mixture was poured into H2O and extracted with ether (3x). The combined ethereal extracts were washed with brine (1x), dried over Na2SO4, and concentrated. Purification of the crude product by flash column chromatography (10:1 hexanes:EtOAc to 7:1) 25 provided allylic tosylate 4.51 (0.088 g, 0.14 mmol, 40%) as a colorless oil. [α]D : +4.0˚ 1 (c = 0.01 in DCM); H NMR (400 MHz, CDCl3): δ 7.76 (d, 2 H, J = 8.2 Hz), 7.29 (d, 2 H, J = 8.2 Hz), 7.16 (s, 2 H), 5.68-5.59 (m, 1 H), 5.29-5.13 (m, 3 H), 4.33 (t, 1 H, J = 5.3 Hz), 4.00 (hp, 2 H, J = 6.7 Hz), 3.64-3.61 (m, 2 H), 3.56-3.45 (m, 4 H), 3.40-3.30 (m, 3 H), 3.19 (dd, 1 H, J = 15.4, 5.8 Hz), 2.89 (hp, 1 H, J = 6.8 Hz), 2.42 (s, 3 H), 1.24 (d, 18 13 H, J = 6.8 Hz), 1.22-1.09 (m, 6 H); C NMR (100 MHz, CDCl3): δ 153.3, 151.3, 144.6, 134.1, 132.6, 131.6, 129.5, 128.0, 123.9, 120.4, 101.6, 80.6, 77.2, 62.8, 62.6, 50.4, 49.2, 34.1, 29.5, 24.8, 24.8, 23.5, 21.6, 15.2, 15.1; IR (neat) ν 2961, 2930, 2872, 1600, 1366,

1190, 1178, 1060, 668; HRMS (CI) calcd for C32 H50NO7S2 [M + 1]: 624.3031, found: 624.3029.

225 O N EtO Trs 2-Ethoxy-4-(2,4,6-triisopropyl-benzenesulfonyl)-6-vinyl-morpholine (4.53) To a solution of allylic alcohol 4.34 (0.041 g, 0.088 mmol) in acetone (1 mL) and water

(1 mL) at room temperature was added TsOH·H2O (0.017 g, 0.089 mmol, 100 mol%). The reaction mixture was heated at 50 ˚C for 46 h at which time it was cooled to room temperature, poured into H2O, and extracted with EtOAc (3x). The combined organic

extracts were washed with brine (1x), dried over Na2SO4, and evaporated to afford an oily residue. Purification of the residue by flash column chromatography (20:1 hexanes:EtOAc) furnished mixed acetal 4.53 (0.032 g, 0.075 mmol, 85%) as a colorless 1 oil and inseparable 1:1 mixture of diastereomers. H NMR (400 MHz, CDCl3): δ 7.17 (s, 2 H), 5.86-5.73 (m, 1 H), 5.40-5.31 (m, 1 H), 5.25-5.21 (m, 1 H), 4.88 (m, 0.5 H), 4.62 (dd, 0.5 H, J = 8.9, 2.4 Hz), 4.38 (m, 0.5 H), 4.20-4.07 (m, 2.5 H), 3.96 (ddd, 0.5 H, J = 14.4, 9.6, 2.4 Hz), 3.69 (dd, 0.5 H, J = 14.1, 9.6, 2.4 Hz), 3.61-3.55 (m, 0.5 H), 3.52-3.35 (m, 3 H), 3.00 (dd, 0.5 H, J = 11.6, 2.7 Hz), 2.90 (hp, 1 H, J = 6.8 Hz), 2.74 (t, 0.5 H, J = 11.1 Hz), 2.68-2.61 (m, 0.5 H), 1.27-1.25 (m, 18 H), 1.24-1.14 (m, 3 H); 13C NMR (100

MHz, CDCl3): δ 153.5, 153.4, 152.1, 151.6, 134.7, 134.0, 129.4, 128.9, 123.9, 123.8, 117.6, 117.5, 98.0, 94.4, 77.2, 74.0, 67.7, 64.7, 62.8, 47.5, 47.3, 46.3, 34.1, 29.3, 24.9, 24.8, 24.7, 24.7, 23.5, 15.1, 14.9; IR (neat) ν 2960, 2929, 2870, 1600, 1321, 1154, 1059,

942, 668; HRMS (CI) calcd for C23H38NO4S [M + 1]: 424.2522, found: 424.2520.

O N HO Trs 4-(2,4,6-Triisopropyl-benzenesulfonyl)-6-vinyl-morpholin-2-ol (4.54)

A solution of allylic alcohol 4.34 (0.056 g, 0.12 mmol) in AcOH (0.90 mL), and H2O (1.1 mL) were heated at 100 ˚C for 45 min. The reaction mixture was then cooled to room temperature and concentrated. The residue was again taken up in AcOH (0.90 mL) and

H2O (1.1 mL) and heated at 100 ˚C for 46 h at which time it was cooled to room temperature and concentrated with toluene (2x). The oily residue was purified by flash column chromatography (5:1 hexanes:EtOAc) to furnish lactol 4.54 (0.033 g, 0.084 mmol, 70%) as a colorless oil and inseparable 1:1 mixture of diastereomers. 1H NMR

226 (400 MHz, CDCl3): δ 7.18-7.17 (m, 2 H), 5.85-5.73 (m, 1 H), 5.41-5.34 (m, 1 H), 5.28- 5.23 (m, 1 H), 4.90-4.88 (m, 0.5 H), 4.60 (m, 0.5 H), 4.18-4.14 (m, 1 H), 4.10 (hp, 2 H, J = 6.8 Hz), 3.80 (d, 0.5 H, J = 7.2 Hz), 3.62-3.44 (m, 2 H), 3.32 (m, 0.5 H), 3.07 (dd, 0.5 H, J = 12.8, 2.2 Hz), 2.91 (hp, 1 H, J = 6.8 Hz), 2.76 (dd, 0.5 H, J = 12.5, 10.8 Hz), 2.68- 13 2.58 (m, 1 H), 1.27-1.24 (m, 18 H); C NMR (100 MHz, CDCl3): δ 153.3, 153.3, 151.7, 151.5, 134.5, 133.8, 129.1, 128.9, 123.8, 117.4, 117.3, 92.4, 88.8, 73.9, 67.5, 66.7, 48.3, 47.5, 46.9, 46.7, 33.9, 29.2, 29.1, 24.6, 24.6, 24.5, 24.4, 23.2; IR (neat) ν 3447 (br), 2960, 2361, 2340, 1600, 1559, 1457, 1420, 1363, 1319, 1153, 957, 668; HRMS (CI) calcd for

C21H34NO4S [M + 1]: 396.2209, found: 396.2209.

O O N Me Trs 1-[4-(2,4,6-Triisopropyl-benzenesulfonyl)-6-vinyl-morpholin-2-yl]-propan-2-one (4.56) To a solution of diethyl (2-oxopropyl)phosphonate (0.07 mL, 0.36 mmol, 520 mol%) in THF (0.35 mL) at 0 ˚C and LHMDS (1.0 M in THF, 0.11 mL, 0.11 mmol, 160 mol%) was added slowly. The resulting mixture was stirred at 0 ˚C for 1 h at which time lactol 4.54 (0.028 g, 0.070 mmol) in THF (0.35 mL) was added slowly. The reaction mixture continued to stir at 0 ˚C for 1 h, at room temperature for 20 h, and 60 ˚C for 23 h at which

time it was concentrated. The residue was taken up in EtOAc, washed with H2O (1x),

saturated aqueous NaHCO3 (1x), brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (5:1 hexanes:EtOAc) to afford morpholino ketone 4.56 (0.016 g, 0.037 mmol, 53%) as a colorless oil and 1 inseparable 1:1 mixture of diastereomers. H NMR (400 MHz, CDCl3): δ 7.17 (s, 2 H), 5.85-5.70 (m, 1 H), 5.33-5.19 (m, 2 H), 4.38-4.34 (m, 1 H), 4.16-3.99 (m, 3 H), 3.45-3.40 (m, 1 H), 3.29 (dd, 0.5 H, J = 12.0, 3.4 Hz), 3.18 (dd, 0.5 H, J = 12.0, 3.4 Hz), 3.11 (dd, 0.5 H, J = 12.0, 5.8 Hz), 3.02 (dd, 0.5 H, J = 12.0, 6.2 Hz), 2.94-2.87 (m, 1 H), 2.78-2.71 (m, 1.5 H), 2.64 (d, 0.5 H, J = 12.0 Hz), 2.59 (d, 0.5 H, 11.6 Hz), 2.44 (dd, 0.5 H, J = 16.1, 4.8 Hz), 2.18 (s, 1.5 H), 2.12 (s, 1.5 H), 1.27-1.24 (m, 18 H); 13C NMR (125 MHz,

CDCl3): δ 205.6, 205.5, 153.6, 151.9, 151.8, 134.9, 134.6, 129.4, 129.3, 124.0, 118.3, 117.5, 75.7, 71.5, 70.9, 66.5, 47.7, 47.6, 47.4, 47.1, 47.0, 45.1, 34.2, 31.1, 30.7, 29.6, 29.4, 25.1, 24.8, 24.8, 23.5, 23.5; IR (film) ν 2959, 2928, 2869, 2360, 2340, 1718, 1363,

227 1319, 1163, 1153, 668; HRMS (CI) calcd for C24H38NO4S [M + 1]: 436.2522, found: 436.2520.

O P OEt OEt O OEt N EtO Trs Phosphoric acid 1-{[(2,2-diethoxy-ethyl)-(2,4,6-triisopropyl-benzenesulfonyl)- amino]-methyl}-allyl ester diethyl ester (4.57) To a solution of KH (30% in oil, 0.037 g, 0.28 mmol, 130 mol%) in THF (0.34 mL) at 0 ˚C was added allylic alcohol 4.34 (0.097 g, 0.21 mmol) in THF (0.68 mL). The resulting mixture was stirred for 30 min at 0 ˚C and 30 min at room temperature at which time diethyl chlorophosphate (0.09 mL, 0.62 mmol, 300 mol%) was added. The reaction mixture was heated at 65 ˚C for 2 h at which time it was cooled to room temperature,

quenched with saturated aqueous NH4Cl, and extracted with Et2O (3x). The combined

organic extracts were washed with brine (1x), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (3:1 hexanes:EtOAc to 1:1) 25 to furnish allylic phosphonate 4.57 (0.10 g, 0.17 mmol, 81%) as a colorless oil. [α]D : 1 +4.3˚ (c = 0.005 in DCM); H NMR (400 MHz, CDCl3): δ 7.16 (s, 2 H), 5.85-5.76 (m, 1 H), 5.35 (d, 1 H, J = 17.1 Hz), 5.25 (d, 1 H, J = 10.6 Hz), 4.96-4.91 (m, 1 H), 4.37 (t, 1 H, J = 5.1 Hz), 4.14-4.02 (m, 6 H), 3.72 (dd, 1 H, J = 14.7, 6.8 Hz), 3.59-3.51 (m, 3 H), 3.40-3.35 (m, 4 H), 2.89 (hp, 1 H, J = 6.8 Hz), 1.32-1.23 (m, 24 H), 1.15-1.10 (m, 6 H); 13 C NMR (100 MHz, CDCl3): δ 153.1, 151.1, 134.4, 132.1, 123.9, 119.3, 101.6, 63.7, 62.7, 62.6, 48.9, 34.1, 29.4, 24.8, 24.8, 23.5, 16.0, 16.0, 15.2, 15.1; IR (film) ν 2961,

2931, 2871, 1268, 1127, 1034, 983, 668; HRMS (CI) calcd for C29H53NO8PS [M + 1]: 606.3230, found: 606.3228.

O O P OEt Me O OEt N Trs Phosphoric acid diethyl ester 1-{[(4-oxo-pent-2-enyl)-(2,4,6-triisopropyl- benzenesulfonyl)-amino]-methyl}-allyl ester (4.58)

To a solution of acetal 4.57 (1.69 g, 2.79 mmol) in CHCl3 (7.3 mL) and H2O (3.7 mL) at 0 ˚C was added TFA (3.7 mL, 49.41 mmol, 1770 mol%). The reaction mixture stirred for 24 h slowly warming to room temperature at which time it was poured into saturated

228 aqueous NaHCO3 and extracted with DCM (3x). The combined organic extracts were

washed with brine (1x), dried over Na2SO4, and concentrated. The resulting oily residue was then taken up in DCM (27.9 mL) and Wittig reagent 3.134 (1.07 g, 3.35 mmol, 120 mol%) was added at room temperature. The reaction mixture stirred for 18 h at which time it was concentrated. The crude was product was purified by flash column chromatography (3:1 hexanes:EtOAc to 2:1, 1:1) to furnish enone 4.58 (1.00 g, 1.76 25 1 mmol, 63%) as a thick, slightly yellow oil. [α]D : +3.0˚ (c = 0.1 in DCM); H NMR (400

MHz, CDCl3): δ 7.17 (s, 2 H), 6.56 (dt, 1 H, J = 16.1, 6.5 Hz), 6.11 (dt, 1 H, J = 16.1 Hz), 5.83-5.74 (m, 1 H), 5.38-5.34 (m, 1 H), 5.29-5.26 (m, 1 H), 4.91-4.86 (m, 1 H), 4.14-4.01 (m, 8 H), 3.54-3.44 (m, 2 H), 2.93-2.86 (m, 1 H), 2.19 (s, 3 H) 1.33-1.29 (m, 6 13 H), 1.27-1.21 (m, 18 H); C NMR (100 MHz, CDCl3): δ 197.1, 170.5, 153.2, 151.1, 150.9, 140.5, 133.7, 133.1, 130.9, 123.7, 123.7, 119.2, 63.6, 63.6, 63.5, 59.9, 50.2, 50.1, 48.2, 33.7, 29.1, 26.6, 24.5, 24.4, 24.4, 24.3, 23.2, 23.1, 15.7, 15.7, 15.6, 15.6; IR (film) ν 2961, 2870, 1700, 1684, 1363, 1257, 1153, 1034, 983, 668; HRMS (CI) calcd for

C28H47NO7PS [M + 1]: 572.2811, found: 572.2811.

229 4.7 1H AND 13C NMR SPECTRA

OCO2Me

O O

O N NTrs

4.11

230 OCO2Me

O

S N O O NTrs 4.13

231 OCO2Me

OEt N EtO Me 4.16

232 OCO2Me

O

Me N

Me 4.17

233 O

Me N

Me 4.18

234 OEt NHTrs EtO 4.31

235 OTs O

OEt O N EtO Trs 4.32

236 I O

OEt O N EtO Trs 4.33

237 OEt OH N EtO Trs 4.34

238 OEt OCO2Me N EtO Trs 4.35

239 O

Me OCO2Me N Trs 4.29

240 OEt OTBDPS N EtO Trs 4.49

241 O

Me OTBDPS N Trs 4.50

242 OEt OTs N EtO Trs

4.51

243 O N EtO Trs 4.53

244 O N HO Trs 4.54

245 O O N Me Trs 4.56

246 O P OEt OEt O OEt N EtO Trs 4.57

247 O O P OEt Me O OEt N Trs 4.58

248 4.8 REFERENCES

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2 Oppolzer, W.; Chapuis, C.; Bernardinelli, G. Helv. Chim. Acta 1984, 67, 1397.

3 (a) Fox, D. N. A.; Gallagher, T. Tetrahedron 1990, 46, 4697. (b) Corelli, F.; Summa, V.; Brogi, A.; Monteagudo, E.; Botta, M. J. Org. Chem. 1995, 60, 2008. (c) Davies, S. G.; Fenwick, D. R. J. Chem. Soc., Chem. Commun. 1995, 1109. (d) Takayma, Y.; Okamoto, S.; Sato, F. Tetrahedron Lett. 1997, 38, 8351.

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5 Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.

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9 Evans, D. A.; Peterson, G. S.; Johnson, J. J.; Barnes, D. M.; Campos, K. R.; Woerpel, K. A. J. Org. Chem. 1998, 63, 4541.

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249

18 Oppolzer, W.; Fuerstner, A. Helv. Chim. Acta 1993, 76, 2329.

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250 Vita

Peter Andrew Webber was born in Lakewood, Ohio on March 9, 1981 the son of Eugene

Patrick and Diane Marie Webber. After graduating from Keystone High School,

LaGrange, Ohio in May 1999, he began working for his Bachelor of Science degree in chemistry at The Ohio State University in Columbus, Ohio. He received his degree in

June 2003, and enrolled in the graduate chemistry program at the University of Texas at

Austin in August 2003.

Permanent Address: 2105 Keepsake Drive, Austin, TX 78745

This dissertation was typed by the author.

251