SYNTHETIC APPLICATIONS OF (E)-α-TRIALKYLSILYL-α,β-UNSATURATED ESTERS

by

DAVID ALLEN JOHNSON

MICHAEL P. JENNINGS, COMMITTEE CHAIR ANTHONY J. ARDUENGO III JASON A. DECARO KEVIN H. SHAUGHNESSY TIMOTHY S. SNOWDEN

A DISSERTATION

Submitted in partial fulfillment of the requirements for the Doctor of Philosophy in the Department of Chemistry in the Graduate School of The University of Alabama

TUSCALOOSA, ALABAMA

2017

Copyright David Allen Johnson 2017 ALL RIGHTS RESERVED ABSTRACT

This dissertation details the use of (E)-α-trialkylsilyl-α,β-unsaturated esters for three novel methodologies. This document is divided into four chapters.

The first chapter will relate pertinent background information about enolates and extended dienolates that will be revisited in subsequent chapters. The second chapter will recount a γ-deprotonation-α-protonation sequence resulting in (E)-α-trialkylsilyl-β,γ-unsaturated esters.

It explores potential reasons for poor a-regioselective protonations present in the literature. The intermediate extended dienolate was also trapped which allowed for confirmation of its stereochemistry.

A method to transform (Ε)-α-trialkylsilyl-α,β-unsaturated esters into chiral allyl silanes will be examined in the third chapter. This will involve a Cu(I) catalyzed conjugate addition involving Grignard reagents followed by a diastereoselective protonation. This is important because α-silyl-α,β-unsaturated esters have a scant record in the literature as Michael acceptors.

Finally, the last chapter will relate the culmination of work performed in chapter two and direct application of ideas presented in chapter one, which consists of using the extended dienolate with known sterochemistry for a tandem diastereoselective aldol-Peterson olefination process. These methodologies will provide much needed light on the synthetic utility of (E)-α- trialkylsilyl-α,β-unsaturated esters.

ii LIST OF ABBREVIATIONS AND SYMBOLS

9-BBN 9-borabicyclo[3.3.1.]nonane

Bn benzyl

CSA camphorsufonic acid

DCM dichloromethane

DIBAL-H diisobutyl aluminum hydride

DIPEA diisopropyl ethyl amine

DMAP 4-dimethyl amino pyridine

DME dimethoxyethane

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide d.r. diastereomeric ratio

E- entgegen (opposite, trans-) equiv equivalents

EWG electron withdrawing group

HMPA hexamethylphosphoramide

HRMS high resolution mass spectroscopy

Hz hertz

IR infrared

J coupling constant

KHMDS potassium hexamethyl disilazide

iii LDA lithium diisopropylamide

LiHMDS or LHMDS lithium bis(trimethylsilyl)amide

M molar

MHz megahertz mmol millimole mol mole

MTBE methyl tert-butyl ether

NA not applicable nBuLi n-butyllithium

ND not determined

NMR nuclear magnetic resonance

NOE nuclear Overhauser enhancement

NR no reaction o- ortho-

-OTf trifluoromethane sulfonate (triflate) p- para-

PTSA (TsOH) p-toluenesulfonic acid

Py (pyr) pyridine

(R)- rectus (clockwise)

RT room temperature

(S)- sinister (counterclockwise)

TBS t-butyldimethylsilyl

TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy free radical

iv TES triethylsilyl

TFA trifluoroacetic acid

THF tetrahydrofuran

THP tetrahydropyran

TMS trimethylsilyl

TMSOTf trimethylsilyl trifluoromethanesulfonate

TPS triphenylsilyl

Z- zuzammen (together, cis-)

‘

v ACKNOWLEDGEMENTS

En primera instancia quiero agradecer a mi hermosa esposa, Lina Mariana De Lorenci

Johnson, quien con su paciencia, amor, y apoyo, siempre estuvo a mi lado. Tú eres mi todo y mi gran amor! Gracias por tus palabras de aliento cuando más lo necesite.

I would like to acknowldege several people who were important to my development as synthetic chemist. I would like to thank my advisor, Dr. Michael P. Jennings for accepting me into the group and nurturing my growth as an experimentalist. I want to thank my committee members for their time, research suggestions, involvement, and challenges in my graduate studies. Thank you Dr. Michael P. Jennings, Dr. Anthony J. Arduengo III, Dr. Kevin H.

Shaughnessy, Dr. Timothy S. Snowden, Dr. Jason A. DeCaro, and Dr. Margaret Johnson. Thank you to the NMR lab manager, Dr. Ken Belmore for instructing me on how to perform various experiments. In addition, I would like to thank Dr. Qiaoli Liang for all the mass spec analysis experiments she has performed for me, particularly when I needed the silyl ketene acetals analyzed immediately.

I would like to express my sincere gratitude to my father and mother, Kenneth and

Claudine Johnson. Thank you for all the lessons you provided to me as a child and instilling in me a strong work ethic. Thank you for your support, your guidance, and for believing in me. I am truly blessed to have you as parents.

Finally, I want to thank my brother, Keith Miller, for a friendship that has lasted over a decade and will surely last a lifetime. Thank you for the support you have given me. I wish you the best when you start your PhD. studies!

vi CONTENTS

ABSTRACT...... ii

LIST OF ABBREVIATIONS AND SYMBOLS ...... iii

ACKNOWLEDGEMENTS ...... vi

LIST OF TABLES ...... x

LIST OF FIGURES ...... xii

LIST OF SCHEMES …………………………………………………………………………...xiii

CHAPTER 1: SELECTED FEATURES OF ENOLATES AND EXTENDED DIENOLATES………...... 1

1.1 Introduction ...... 1

1.2 The Aldol Reaction...... 1

1.3 Lithium Enolate Structure and Stereoselective Formation…………………………………....5

1.4 The Aldol Reaction of Extended Dienolates...... 13

1.5 The Stereoselective Production of Extended Dienolates via Deprotonation by Metallo Dialkylamides…………………………………………………………………………………....15

1.6 Deprotonations of E-α,β-Unsaturated Carbonyls by Metallo Dialkylamides……...... 17

1.7 Deprotonations of Z-α,β-Unsaturated Carbonyls by Metallo Dialkylamides…………….....20

1.8 Deprotonations of E/Z-β,γ-Unsaturated Carbonyls by Metallo Dialkylamides……………...26

1.9 Conclusion ...... 27

CHAPTER 2: DIASTEREOSELECTIVE SYNTHESES OF (E)-α-TRIALKYLSILYL-α,β- UNSATURATED ESTERS, α-SILANE SUBSTITUTED CONJUGATED SILYL KETENE ACETALS, AND α,γ-SUBSTITUTED ALLYL SILANES...... 29

2.1 Introduction ...... 29

vii 2.2 Motivation...... 29

2.3 Allylsilanes...... 34

2.4 Recent Synthetic Applications of α-Silyl-β,γ-Unsaturated Esters...... 37

2.5 Synthetic Methods for α-Silyl-β,γ-Unsaturated Esters...... 42

2.6 Synthetic Methods for (E)-α-Silyl-α,β-Unsaturated Esters...... 54

2.7 Synthesis of Starting Materials………………………………………………………………57

2.8 Lithium Extended Dienolate Protonation Studies……………………………………………59

2.9 Extended Silyl Ketene Acetal Protonation Studies…………………………………………..61

2.10 Isolation of Intermediate Silyl Ketene Acetals……………………………………………..66

2.11 Discussion…………………………………………………………………………………..70

2.12 Future Works……………………………………………………………………………….73

2.13 Conclusion ...... 75

CHAPTER 3: A TANDEM COPPER CATALYZED CONJUGATE ADDITION- DIASTEREOSELECTIVE PROTONATION PROCESS WITH (E)-α-TRIALKYLSILYL-α,β- UNSATURATED ESTERS……………………………...... 76

3.1 Introduction ...... 76

3.2 Motivation...... 76

3.3 Gilman and Kharasch Reagents: Nucleophilic Organocopper(I) Reagents...... 77

3.4 Carbocupration Chemistry...... 80

3.5 Organocuprate Conjugate Addition Chemistry ...... 81

3.6 Silylating Agents and Lithium Halide Salt Additives………………………………………..85

3.7 Conjugate Additions to α-Trialkylsilyl-α,β-Unsaturated Esters………………………….....87

3.8 Optimization Studies…………………………………………………………………………91

3.9 Me3SiOTf Accelerated Conjugate Addition Substrate Scope……………………………….92

viii 3.10 Diastereoselective Quench Studies…………………………………………………………94

3.11 Me3SiCl Accelerated Conjugate Addition Substrate Scope………………………………..95

3.12 NOE Studies………………………………………………………………………………...98

3.13 Catalytic Cycle…………………………………………………………………………….100

3.14 Conclusion ...... 101

CHAPTER 4: A NOVEL TANDEM DECONJUGATIVE ALDOL PETERSON TYPE OLEFINATION PROCESS ...... 102

4.1 Introduction ...... 102

4.2 The Tandem Process Idea and Motivation...... 102

4.3 The Peterson Olefination Reaction...... 106

4.4 Lithium Enolate Studies...... 109

4.5 Methods of Accessing Boron Enolate and Dienolates...... 113

4.6 Boron Enolate Studies...... 117

4.7 Conclusion...... 119

CONCLUSION...... 121

EXPERIMENTAL ...... 122

REFERENCES...... 149

APPENDIX...... 157

ix LIST OF TABLES

Table 1.1 The Effect of Carbonyl Substituents on Stereoselectivity...... 10

Table 1.2 Variables Affecting Stereoselectivity………………………………………………...12

Table 1.3 Isomerizations of E-α,β-Unsaturated Carbonyls to β,γ-Unsaturated Carbonyls………………………………………………………………………………………...19

Table 1.4 Silyl Ketene Acetals Derived from Deprotonations of E-α,β-Unsaturated Carbonyls………………………………………………………………………………………...20

Table 1.5 Isomerizations of Z-α,β-Unsaturated Carbonyls to β,γ-Unsaturated Carbonyls………………………………………………………………………………...... 23

Table 1.6 Silyl Ketene Acetals Derived from Deprotonations of Z-α,β-Unsaturated Carbonyls………………………………………………………………………………………...25

Table 1.7 Silyl Ketene Acetals Derived from Deprotonations of E/Z-β,γ-Unsaturated Carbonyls………………………………………………………………………………………...27

Table 2.1 Synthesis of (E)-α-Silyl-α,β-Unsaturated Esters……………………………………..58

Table 2.2 Lithium Extended Dienolate Studies with the β-Benzyl Substrate E47f……………..60

Table 2.3 Extended Silyl Ketene Acetal Protonation Studies with the β-Benzyl Substrate E47f………………………………………………………………………………………………62

Table 2.4 Extended Silyl Ketene Acetal Protonation Studies with the β-Methyl Substrate E47g……………………………………………………………………………………………...64

Table 2.5 Synthesis of (E)-α-Silyl-β,γ-Unsaturated Esters……………………………………...65

Table 2.6 Synthesis of (1E, 3E)-α-Silyl-Conjugated Silyl Ketene Acetals……………………..68

Table 3.1 Tandem Conjugate Addition Diastereoselective Protonation Process with the β- Trifluoromethylated α-Trimethylsilyl-α,β-Unsaturated Ester 160…………………………...…91

Table 3.2 Optimization Studies with the β-Ethyl Substrate E47i……………………………….92

x Table 3.3 Me3SiOTf Accelerated Conjugate Addition Substrate Scope………………………...93

Table 3.4 Temperature Compatibility Studies with EtMgBr and Me3SiCl……………………...94

Table 3.5 Diastereoselective Protonation Experiments………………………………………….95

Table 3.6 Me3SiCl Accelerated Conjugate Addition Substrate Scope…………………………..96

Table 3.7 Studies with the β-Phenyl substrate E47a……………………………………………97

Table 3.8 Methylation Attempts…………………………………………………………………98

Table 4.1 Effect of Temperature on Diastereoselectivity……………………………………...109

Table 4.2 Optimization Studies using the Lithium Enolate……………………………………112

Table 4.3 Attempt at Isolation of Aldol Adduct………………………………………………..113

Table 4.4 Boron Enolate Transmetallation Optimization……………………………………...118

Table 4.5 Substrate Scope for the Tandem Aldol-Olefination Process………………………...119

xi LIST OF FIGURES

Figure 1.1 Binding Modes of Enolates...... 5

Figure 1.2 Aggregation States of Lithium Enolates………………………………………………6

Figure 1.3 Commonly Used Amide Bases………………………………………………………..7

Figure 1.4 Lithium Amide Aggregation States…………………………………………………...8

Figure 1.5 Mixed Aggregates of LTMP and LiBr……………………………………………...12

Figure 1.6 The Electronic Structure of Extended Dienolates…………………………………...15

Figure 1.7 Calculated pKas of Saturated and Unsaturated Esters……………………………….16

Figure 1.8 Transition State Rationale for 3Z-stereoselectivity with Methoxy Group…………..24

Figure 1.9 Lithium Extended Dienolates Isolated as Crystals…………………………………..25

Figure 2.1 Activation and Stabilization Effects of Silicon……………………………………...35

Figure 2.2 Key NOE Enhancements for Unknown (E)-α-Silyl-α,β-Unsaturated Esters……………………………………………………………………………………………..58

Figure 2.3 Key NOE Enhancements for Unknown (E)-α-Silyl-β,γ-Unsaturated Esters……………………………………………………………………………………………..66

Figure 2.4 Key NOE Enhancements for (1E, 3E)-α-Silyl-Conjugated Silyl Ketene Acetals……………………………………………………………………………………………69

Figure 2.5 Natural Charges for α-Silyl Conjugated Silyl Ketene Acetals 60c, 60g, and 60i………………………………………………………………………………………………..70

Figure 3.1 Key NOE Enhancements for the β-Phenyl Saturated Product 116.1h……………....99

Figure 4.1 Key NOE Interactions for 166e…………………………………………………….109

xii LIST OF SCHEMES

Scheme 1.1 The Original Aldol Reaction……………………………...... 1

Scheme 1.2 The General Aldol Reaction…………………………………………………………2

Scheme 1.3 The Origin of Aldol Diastereoselectivity I………………………………………..…4

Scheme 1.4 The Origin of Aldol Diastereoselectivity II……………………………………….....4

Scheme 1.5 Ireland Transition State of Amide Base Deprotonation……………………………...9

Scheme 1.6 Open Transtion State Deprotonations with HMPA or DMPU…………………….10

Scheme 1.7 Regioselectivity of the Extended Dienolate Aldol Reaction……………………….13

Scheme 1.8 Vinylogous Mukaiyama Aldol Reaction (VMAR)…………………………………14

Scheme 1.9 Methods of Evaluating 1,2- and 3,4-Olefin Components………………………...... 16

Scheme 1.10 Conjugate Addition Adducts with LDA and E-α,β-Unsaturated Carbonyls………………………………………………………………………………………...17

Scheme 1.11 “Syn Effect” with Deprotonations of E-α,β-Unsaturated Carbonyls……………..18

Scheme 1.12 General CIPE with Deprotonation Reactions…………………………………..…21

Scheme 1.13 Transition States for the Deprotonation of Z-α,β-Unsaturated Carbonyls………………………………………………………………………………………...22

Scheme 2.1 Diastereoselective Allylsilane Addition……………………………………………30

Scheme 2.2 Manufacturing α-Substituted Allysilanes…………………………………………..30

Scheme 2.3 (E)-α-Silyl-α,β-Unsaturated Esters via Catalytic Carbocupration of Alkynoates in the Presence of Excess Silyl Triflates…………………………………………………………....31

Scheme 2.4 Synthesis of Cyanolide A via a Diastereoselective Mukaiyama Aldol Addition………………………………………………………………………………………….32

Scheme 2.5 γ-Deprotonation-α-Protonation Sequence………………………………………….33

xiii Scheme 2.6 Potential Application of α,γ-Substituted Allylsilanes……………………………...34

’ Scheme 2.7 SE Reactions of Allylsilanes……………………………………………………….36

Scheme 2.8 Allylsilane SEʹ Transition State……………………………………………………..37

Scheme 2.9 Asymmetric Synthesis of Cyclic Alkenes via Cyclization of Enantioenriched Allylsilanes………………………………………………………………………………………37

Scheme 2.10 Asymmetric Vinylogous Aldol Products via Chiral Crotylsilanes………………..38

Scheme 2.11 Asymmetric Crotylation via Chiral Homoallylic TBDPS Ether Crotylsilanes……………………………………………………………………………………..39

Scheme 2.12 Asymmetric Crotylaton in the Synthesis of (-)-Virginiamycin M2……………….40

Scheme 2.13 Asymmetric Syntheses of Bifunctional Homoallylic Carbamates………………..40

Scheme 2.14 Asymmetric Synthesis of Orthogonally Protected 2-Methyl-1,3-Diols…………..42

Scheme 2.15 1,3-Cycloadditions of Methyl 3-Trimethylsilylpropenoates with Diazoalkanes Leading to α-Trimethylsilyl-β,γ-Unsaturated Esters………………………………………….....43

Scheme 2.16 α-Silyl-β,γ-Unsaturated Esters via Nickel Catalyzed α-Vinylation of α-Silyl Esters………………………………………………………………………………………….….44

Scheme 2.17 α-Trimethylsilyl-β,γ-Unsaturated Esters via a γ-Deprotonation-α-Protonation Sequence with Lithium Enolates……………………………………………………………...…44

Scheme 2.18 α-Silyl-β,γ-Unsaturated Esters via Regioselective Carboxylation of Silicon Stabilized Allylic Carbanions……………………………………………………………………45

Scheme 2.19 α-Silyl-β,γ-Unsaturated Esters via a BF3ŸOEt2 mediated SN2ʹ Allylic Substitution Employing a Higher Order Silylcuprate…………………………………………………………46

Scheme 2.20 α-Trimethylsilyl-β,γ-Unsaturated Esters via an HMPA Aided γ-Deprotonation-α- Protonation Sequence with Silyl Ketene Acetals…………………………………………….…..47

Scheme 2.21 α-Silyl-β,γ-Unsaturated Esters via Rh(II)-catalyzed carbenoid Si-H Insertion with Vinyldiazoesters………………………………………………………………………………….48

Scheme 2.22 Asymmetric α-Silyl-β,γ-Unsaturated Esters via Rh(II)-Catalyzed Carbenoid Si-H Insertion with Vinyldiazoesters Containing an (R)-Pantolactone Chiral Auxiliary…...... 49

xiv Scheme 2.23 Asymmetric α-Silyl-β,γ-Unsaturated Esters via Rh(II)-Catalyzed Carbenoid Si-H insertion with Vinyldiazoesters by Employing the Chiral Ligand, (S)-N-[p-(dodecylphenyl)sulfonyl]prolinate……………………………………………………..50

Scheme 2.24 Dussault’s Report of an α-Silyl-β,γ-Unsaturated Ester via Nickel Catalyzed α- Vinylation of α-Silyl Esters……………………………………………………………………...50

Scheme 2.25 Dussault’s Report of a (Z)-α-Silyl-β,γ-Unsaturated Ester via a BF3ŸOEt2 mediated SN2ʹ Allylic Substitution Employing a Higher Order Silylcuprate……………………………....51

Scheme 2.26 Asymmetric α-Silyl-β,γ-Unsaturated Esters via Rh(II)-Catalyzed Carbenoid Si-H Insertion with a Vinyldiazoester Employing a Chiral Peptide Ligand…………………………..51

Scheme 2.27 Panek’s Report of Asymmetric Rh(II)-Catalyzed Carbenoid Si-H Insertion with Vinyldiazoesters Employing Enantiomeric N-[p-(dodecylphenyl)sulfonyl]prolinate Ligands…………………………………………………………………………………………...52

Scheme 2.28 Asymmetric α-Silyl-β,γ-Unsaturated Esters via Cu(I)-catalyzed Carbenoid Si-H Insertion………………………………………………………………………………………….52

Scheme 2.29 Fe(III) Catalyzed Diastereoselective Synthesis of (Z)-α-Trimethylsilyl-β,γ- Unsaturated Esters……………………………………………………………………………….53

Scheme 2.30 α-Trimethylsilyl-β,γ-Unsaturated Esters via Asymmetric Rh(I)-Catalyzed Carbenoid Si-H Insertion with Vinyldiazoesters Utilizing a C1-Symmetric Diene Ligand……………………………………………………………………………………………54

Scheme 2.31 (E)-α-Trimethylsilyl-α,β-Unsaturated Esters via LDA Mediated Isomerization of (Z)-α-Trimethylsilyl-α,β-Unsaturated Esters…………………………………………………....55

Scheme 2.32 Failed Isomerization of the β-Benzyl Substrate Z47e…………………………….55

Scheme 2.33 (E)-α-Trimethylsilyl-α,β-Unsaturated Esters via Ni-Catalyzed Regioselective Carboxylation of Disubstituted Alkynes………………………………………………………....56

Scheme 2.34 (E)-α-Silyl-α,β-Unsaturated Esters via Pd-Catalyzed Regio- and Stereoselective Hydrosilylations of Alkynoates…………………………………………………56

Scheme 2.35 (E)-α-Silyl-α,β-Unsaturated Esters via Pt-Catalyzed Regio- and Stereoselective Hydrosilylations of Alkynoates………………………………………………………………….57

Scheme 2.36 Regioselectivity of Extended Dienolates………………………………………….59

Scheme 2.37 Proposed Origin of Deconjugated/Desilylated Ester 106…………………………61

xv Scheme 2.38 Previously Isolated α-Silyl Extended Silyl Ketene Acetals………………………66

Scheme 2.39 Extended Silyl Ketene Acetals with Confirmed Stereochemistry………………...67

Scheme 2.40 Hydrolysis NMR Study of the Silyl Ketene Acetal 60c in CDCl3………………..70

Scheme 2.41 Enantioselective Protonations with a Cationic Au(I) Complex…………………...73

Scheme 2.42 Enantioselective Organocatalytic Protonation with Chiral Ammonium Salts………………………………………………………………………………………………74

Scheme 3.1 Asymmetric Allylations via Chiral Allyl Silanes…………………………………..77

Scheme 3.2 Chiral Allyl Silanes via a Tandem Copper Catalyzed Conjugate Addition – Diastereoselective Protonation Process………………………………………………………….77

Scheme 3.3 Gilman and Kharasch Reagents…………………………………………………….78

Scheme 3.4 General Mechanisms for Gilman and Kharasch Reagent Additions……………….79

Scheme 3.5 Types of Nucleophilic Organocopper(I) Additions with α,β-Unsaturated Carbonyls………………………………………………………………………………………...80

Scheme 3.6 Carbocupration Mechanism with Acetylenic Carbonyls…………………………...81

Scheme 3.7 Conjugate Addition Mechanism……………………………………………………82

Scheme 3.8 13C KIEs for the Conjugate Addition of Dibutylcuprate to 2-Cyclohexenone………………………………………………………………………………...83

Scheme 3.9 π-Complexes Proposed on the Basis of Rapid-Injection NMR studies……………83

Scheme 3.10 Catalytic Cycle for Conjugate Addition in the Absence of Ligands……………...84

Scheme 3.11 Catalytic Cycle for Conjugate Addition with Chiral Bidentate Phosphine Ligands…………………………………………………………………………………………...85

Scheme 3.12 Detection of a Silylated β-Cuprio(III)-Enolate Adduct…………………………...86

13 17 Scheme 3.13 C and O KIEs for the Me3SiCl-Assisted Conjugate Addition of Dibutylcuprate to 2-Cyclohexenone……………………………………………………………………………...87

Scheme 3.14 CuX3Li2 Catalyzed Conjugate Addition Reactions with Grignard Reagents……………………………………………………………………………….87

xvi Scheme 3.15 Tandem Conjugate Addition Peterson Olefination with Methyl α- Trimethylsilylacrylate……………………………………………………………………………88

Scheme 3.16 Tandem Sequential Conjugate Addition Diastereoselective Protonation Process with Methyl α-Trimethylsilylacrylate…………………………………………………………...89 Scheme 3.17 Michael Adduct Selectivity with the Tandem Sequential Conjugate Addition Diastereoselective Protonation Process……………………………………………………….....90

Scheme 3.18 Tandem Conjugate Addition Alkylation Process with Methyl α- Trimethylsilylacrylate……………………………………………………………………………90

Scheme 3.19 Stereochemical Consequences of an Eclipsed versus Bisected Conformation During the Protonation of the Silyl Ketene Acetal 115g………………………………………...99

Scheme 3.20 Assigned Stereochemistry for the Saturated Products…………………………...100

Scheme 3.21 Proposed Catalytic Cycle………………………………………………………...101

Scheme 4.1 A Novel Tandem Deconjugative Aldol Peterson Type Olefination Process………………………………………………………………………………………….103

Scheme 4.2 Aryne Diels-Alder Reactions with (2Z,3E)-α,β’-β,γ-Unsaturated Esters…………103

Scheme 4.3 Intramolecular Diels-Alder Reactions with (2Z,3E)-α,β’-β,γ-Unsaturated Esters……………………………………………………………………………………………103

Scheme 4.4 [4+1] Intramolecular Cycloadditions with (2Z,3E)-α,β’-β,γ-Unsaturated Esters……………………………………………………………………………………………104

Scheme 4.5 Cis-Z-α-Alkylidenebutyrolactones……………………………………………….104

Scheme 4.6 Trans-Z-α-Alkylidenebutyrolactones……………………………………………..105

Scheme 4.7 (E)-2-Alkenyl-2-Butenolides……………………………………………………...106

Scheme 4.8 The Peterson Olefination………………………………………………………….106

Scheme 4.9 Acid and Base Promoted Peterson Olefinations………………………………..…107

Scheme 4.10 Mechanistic Details for the Base Promoted Peterson Olefination……………….108

Scheme 4.11 Predictive Model for Olefin Stereochemistry……………………………………108

Scheme 4.12 Potential Mechanistic Pathways to Explain Temperature Dependence………….110

Scheme 4.13 Direct Enolization with Dialkylborane Reagents………………………………..114

xvii Scheme 4.14 Dicyclohexylchloroborane Mediated Deprotonations of (E)-α-Trialkylsilyl-α,β- Unsaturated Esters…………………………………………………………………..………….115

Scheme 4.15 Dicyclohexylchloroborane Mediated Deprotonations of (E)-α-Trialkylsilyl-β,γ- Unsaturated Esters……………………………………………………………………………...116

Scheme 4.16 Accessing Boron Enolates via Transmetallation………………………………...117

xviii CHAPTER 1: THE ALDOL REACTION OF MONOENOLATES AND OF EXTENDED DIENOLATES

1.1 Introduction

This chapter will present selected key features of monoenolates and extended dienolates, which will set the stage for further discussion as these concepts are applied to the individual projects of the dissertation. The topics examined will be the aldol reaction of monoenolates and of extended dienolates, as well as the stereoselective production of both classes of enolates.

1.2 The Aldol Reaction

The aldol reaction is a classical transformation used extensively in synthetic organic chemistry.1 The discovery of this reaction is attributed to both Alexander Borodin in 1864 and

Charles-Adolphe Wurtz in 1872. Their independent studies involved the condensation of acetaldehyde 1 with the use of an acid or a base (scheme 1.1).2 The name of the reaction comes from the product, 3-hydroxybutanal 2 and was coined aldol by Wurtz.

O Acid or Base OH O H H 1 2

Scheme 1.1 The Original Aldol Reaction

As illustrated this creates one new stereocenter, but if the starting material possesses at least one alkyl substituent on the α-carbon this process can create a maximum of two stereocenters. This indicates the power of the aldol reaction due to the generation of products with greater complexity both in functionality and stereochemistry from simple starting materials.

1 The reaction allows for the formation of C-C bonds in a diastereoselective and enantioselective fashion if the correct conditions are chosen. There are several different iterations of the aldol reaction, but this discussion will be limited to the aldol reaction of enolates. This will include some mention of the different metals used with enolates when necessary, but the focus will be on lithium enolates. The general aldol reaction of enolates involves a nucleophilic partner 3, which possesses at least one alpha hydrogen and is normally an ester or ketone, but can be an tertiary amide or imide, that is transformed into an enolate with the use of a strong base (scheme 1.2). It is important at this point to define how enolates will be labeled. E-enolates will be defined as those possessing a trans relationship between the oxygen bearing the metal and the highest priority group on the α-carbon. Conversely, Z-enolates will be defined as those possessing a cis relationship between the aforementioned groups.

OH O OM R1 R2 X X R1 Z-4 O O 6 1 syn-racemic R Base 2 X M = metal R H 3 5 Nucleophilic Electrophilic Partner Partner OH O OM X = R, OR, NR 2 R2 X X R1 R1 E-4 7 anti-racemic

Scheme 1.2 The General Aldol Reaction

If the enolates are furnished in a stereoselective manner, this process can be diastereoselective. Z-enolates Z-4 will preferentially react with an electrophilic partner 5, generally an aldehyde, to give a syn-β-hydroxy product 6 after an acidic workup. E-enolates E-4 will preferentially react with an aldehyde to give an anti-β-hydroxy product 7.1 The syn and anti

2 nomenclature refers to the relationship of the R1 group on the α-carbon and the hydroxyl group of the β-carbon.

The Zimmerman – Traxler model is normally invoked to explain the origin of the diastereoselectivity (scheme 1.3 and 1.4).3 The enolate and the aldehyde are believed to arrange in a six-membered ring transition state that mimics the chair conformation of cyclohexane via chelation of the oxygen of the enolate and the oxygen of the aldehyde with a metal. For the Z- enolate Z-8, the R2 group of the aldehyde can be pseudo axial as in TS1 or pseudo equatorial as in TS2. However, the strain associated with each arrangement is different. TS1 possesses A1,3 strain between X group of the enolate and R2 of the aldehyde. If a ligand is present on the metal this presents an additional A1,3 strain between the ligand and R2. Because of these inherent strains, TS2 is the preferred arrangement of enolate and aldehyde, which furnishes the syn aldol product 6. The E-enolate E-8 and the aldehyde have two different chair conformation transition states as well. Once again a preference exists for the R2 group of the aldehyde to be pseudo equatorial as in TS3, because it does not possess the A1,3 strain present in TS4. Due to this feature, E-enolates E-8 will favor providing the anti aldol product 7.

3 2 R L OH O X M 2 H R X O L H O R1 7 R1 anti-racemic TS1 OML2 R2CHO Disfavored R1 X Z-8

H L OH O X M 2 R2 R X O L H O R1 6 1 M = Metal R syn-racemic L = Ligand TS2 X = R, OR, NR2 Favored

Scheme 1.3 The Origin of Aldol Diastereoselectivity I

L H OH O X M 2 O R2 X 1 R L R O R1 7 H anti-racemic TS3 OML 2 Favored R2CHO X R1 E-8

R2 L OH O X M 2 O R X 1 H L R O R1 6 M = Metal H syn-racemic L = Ligand TS4 X = R, OR, NR2 Disfavored

Scheme 1.4 The Origin of Aldol Diastereoselectivity II

4 Diasteroselection can be optimized further by careful choice of the metal and the size of the ligands present on the metal. Alkali earth metals, such as lithium, sodium, and potassium, are commonly employed with enolates. The levels of diastereoselection observed corresponds to the level of coordination with oxygen. Consequently, lithium provides the highest diastereoselectivity and potassium gives the lowest levels of diastereoselection.4 In addition, metals such as boron1c,5 or titanium6 result in even higher levels of diastereoselectivity than that of lithium. The rationale used to explain this is that the transition states are “tighter”, or more rigid and compact, due to the shorter boron-oxygen or titanium-oxygen bond lengths. Because of this, the A1,3 strains mentioned are enhanced, which creates a higher preference for one transition state over the other. Increasing the size of the ligands on the metal also increases the A1,3 strain thereby increasing diastereoselection. The production and implementation of boron enolates will be discussed in more detail in chapter 4.

1.3 Lithium Enolate Structure and Stereoselective Formation

Enolates can exist in several different binding modes. They can be O-bound 9, C-bound 10, or η3-bound 11 (figure 1.1). The binding mode must be considered, because if an equilibrium exists between the tautomers, the stereoisomeric purity of the enolate can be eroded. The binding mode depends on the metal, with groups 1, 2, and 13, as well as

OM O M O R1 M R1 X X X 1 R2 R R2 R2 9 10 11 O-bound enolate C-bound enolate η3-bound enolate

X = R, OR, or NR2

Figure 1.1 Binding Modes of Enolates

Si, Sn, Ti, and Zr preferring the O-bound enolates 9. The C-bound enolates 10 are typical

5 for the less electropositive metals, such as the transition metals, with the late transition metals also exhibiting the η3-binding mode 11.6

Lithium enolates are normally depicted as a monomers 12, however, in solution they exist as oligomeric aggregates including, but not limited to: dimers 13, cubic tetramers 14, and prismatic hexamers 15 (figure 1.2). The aggregation state is highly influenced by the solvent used as well as other reaction conditions, such as cosolvents, additives, choice of substrate, and temperature. Convention normally treats monomeric species as more reactive, but that doesn’t necessarily mean they are the active species for a reaction. Higher order aggregates could be the active species in reactions, or release lower order units. Ascertaining which aggregates, or combinations of aggregates, are operating in a mechanism or give rise to higher stereoselectivities can only be identified with specific cases. What is known for the general case is that coordinating solvents, such as THF tend to prefer dimers 13 and cubic tetramers 14, and noncoordinating solvents, such as hydrocarbons, give nonsolvated prismatic hexamers 15.7

Ethereal Solvents Hydrocarbon Solvents X

S S S Li O X O Li X O LiSn Li S Li O Li O X Li O O O Li O S X O Li X X X Li X O Li X Li S O S S O X Li X X 12 13 14 15 Cubic Prismatic Monomer Dimer Tetramer Hexamer X = R, OR, NR ; S = Solvent ; n = 2-4 2 Figure 1.2 Aggregation States of Lithium Enolates7

6 In order to generate monoenolates in a stereoselective manner, the pKa values for the parent substrate must be considered. Due to the high pKa values of ketones, esters, and amides (26.5,

30.5, and 34.5, respectively in DMSO)8, strong nonnucleophilic amide bases must be utilized in order to achieve complete enolization. Commonly used amide bases include lithium diisopropyl amide LDA 16a, lithium hexamethyldisalizide LHMDS 16b, lithium isopropylcyclohexyl amide

LICA 16c, and lithium tetramethylpiperidide LTMP 16d (figure 1.3).6 The choice of amide base depends on the steric profile and strength of basicity required for the deprotonation.

Me3Si SiMe3 N N N N Li Li Li Li 16a LDA 16b LHMDS 16c LICA 16d LTMP

SiMe3 Ph SiMe Me2PhSi SiPhMe2 N N 3 N Li Li Li 16e 16f 16g

Figure 1.3 Commonly Used Amide Bases

Like lithium enolates, lithium amide bases are normally depicted as monomeric in nature, however, they can also exist as dimers, trimers, tetramers, and higher order oligomeric aggregates in solution. The aggregation states are highly dependent upon the reaction conditions, and can play a role in the reactivity. Solvents capable of coordination, such as ethereal solvents, tend to force the amides into solvated monomers 17 and dimers 18. Noncoordinating solvents, such as hydrocarbon solvents give rise to unsolvated dimers 19, cyclic trimers 20, cyclic tetramers 21, and other higher order oligomers (figure 1.4).7d,9

7 Ethereal Solvents S Li R R R N Li Sn N N R R Li R S 17 18 Monomer Dimer Hydrocarbon Solvents

R R R R Li N Li R Li R N N R R R Li N R N N Li Li R R Li R N N Li R Li N R R R R 19 20 21 Cyclic Cyclic Dimer Trimer Tetramer S = Solvent ; n = 2-4

Figure 1.4 Lithium Amide Aggregation States

The Ireland model is used to explain the stereoselectivity in the deprotonation of carbonyl species 9 with amide bases 10 (scheme 1.5). Proposed by Robert Ireland et. al in 197610a and supported by a body of work,10b-f this model involves two competing cyclic six membered transition states, TS5 and TS6, comprised of the metal of the amide base coordinated to the carbonyl oxygen and the nitrogen of the amide base associated with an acidic α-proton. For the same reasons discussed with the aldol addition, lithium is the metal of choice over sodium or potassium due to how tightly it coordinates to oxygen.4 Due to stereoelectronic effects, the proton abstraction is believed to occur as close to perpendicular to the plane of the carbonyl as possible in order to maximize π-orbital overlap.10e,f The prediction of enolate geometry is based on the competition of steric interactions present in TS5 and TS6. TS5 possesses A1,3 strain between R1 of the carbonyl species and the substituent of the amide base, R. TS6 possesses A1,2

8 strain between the X and R1 substituents of the carbonyl species. If the A1,3 strain is greater than the A1,2 strain, the kinetic E-enolate E-4 will preferentially form. Consequently, if the A1,2 strain is larger than the A1,3 strain, the thermodynamic Z-enolate Z-4 will favored.

R OM R1 O N R1 M R X H X H Z-4

TS5

R O Amide Base R1 O N X M R MNR2 3 16 H X

R H OM O N M R H X 1 X R1 R E-4 X = R, OR, NR2 M = Metal TS6

Scheme 1.5 Ireland Transition State of Amide Base Deprotonation

Under kinetic conditions, LDA will effectively convert esters to the E-enolate with high stereoselectivity even with larger substituents, because of the minimal A1,2 strain in TS6 (entries

1 and 2, table 1.1).11 Ketones do not generally exhibit the same level of stereoselectivity for the kinetic enolate as esters because they possess a great level of A1,2 strain in TS6. In fact, as the X substituent becomes larger, the A1,2 strain becomes so high that the thermodynamic Z-enolate is formed with near complete stereoselectivity (entries 3-6, table 1.1). This is also the case for amides (entry 7 and 8, table 1.1).12,13

9 Table 1.1 The Effect of Carbonyl Substituents on Stereoselectivity OLi O OLi LDA + X X THF X 3a E-4a Z-4a Entry X E/Z Ref.

1 OCH3 19:1 11 2 Ot-Bu 19:1 11 3 Et 2.3:1 11 4 i-Pr 1:1.5 11 5 t-Bu <1:20 11 6 Ph <1:20 11

7 N(CH2)4 <1:20 12 8 N(C H ) <1:20 13 2 5 2

In most cases, the enolate desired can be accessed by careful consideration for deprotonation conditions. Strongly coordinating cosolvents, such as hexamethylphosphoramide,

HMPA 22, or N,N’-dimethylpropyleneurea, DMPU 23, can disturb the aggregation states of the amide base by solvating the metal ion, which will force an open transition state TS7 (scheme

1.6)10f and give rise to the thermodynamic Z-enolate under kinetic conditions (entries 1-3, table

1.2).14

R R N O OM MNR2 R1 H R1 X HMPA or DMPU X X O 3 Z-4 H R1 M = Metal TS7

O O

(H3C)2N P N(CH3)2 N N N(CH3)2 22 23 HMPA DMPU

Scheme 1.6 Open Transtion State Deprotonations with HMPA or DMPU

10 Using amide bases with larger steric profiles, such as LTMP or 16e can facilitate higher stereoselectivity for the kinetic E-enolate than LDA (entries 4-6, table 1.2).11,15 The use of equimolar LiBr with LTMP can increase stereoselection for the kinetic E-enolate (entry 7, table

1.2).9d The halide additive along with LTMP creates mixed aggregate species such as mixed heterodimers 24, three rung ladder mixed heterotrimers 25, and mixed cyclic heterotrimers 26

(figure 1.5).7d,9a,e,f Computational studies suggest that donor molecules bind more strongly to heterodimers than to homodimers. This could be the origin of higher stereoselectivity, because the transition state should be tighter and would exert more stereocontrol on the enolization.9f The strength of the base can also be tailored to preferentially provide the thermodynamic Z-enolate under kinetic conditions and in some cases with higher stereoselectivity than with the use of strongly coordinating cosolvents (entries 8-11, table 1.2).10a,11,15,16 This feature is rationalized by noting the lower basicity of LHMDS, 16f, and 16g compared to the other amide bases mentioned, which should give rise to a more loose, or less compact, transition state reducing the

A1,3 strain in TS5.

11 Table 1.2 Variables Affecting Stereoselectivity

O Base OLi OLi + X X X Solvent 3a E-4a Z-4a

Entry X Base Solvent E/Z Ref. 1 OEt LDA THF 16:1 14 THF 2 OEt LDA 1:6 14 23% HMPA THF 3 OEt LDA 1:13 14 45% DMPU 4 Et LDA THF 2:1 11 5 Et LTMP THF 4:1 11 6 Et 16e THF 16:1 15 7 Et LTMP•LiBr THF >20:1 9d THF 8 Et LDA 1:19 10a 23% HMPA 9 Et LHMDS THF 1:2 11 10 Et 16f THF 1:13 15 11 Et 16g THF <1:20 16

S N Li S Li Br S 24 Mixed Heterodimer

Li N Li N N N

Li Br Li Li Br Li 25 26 Three Rung Ladder Mixed Cyclic Mixed Heterotrimer Heterotrimer S = Solvent

Figure 1.5 Mixed Aggregates of LTMP and LiBr

12 1.4 The Aldol Reaction of Extended Dienolates

Extended dienolates, such as 27, possess two potential carbon nucleophilic sites, the α- carbon and the γ-carbon (scheme 1.7). Aldol reactions at the α-carbon behave similarly to the general aldol reaction for monoenolates furnishing β’-hydroxy-β,γ-unsaturated carbonyl compounds like 28 and presumably go through the same closed transition state.17 However, aldol reactions at the γ-carbon behave differently, especially in regards to proposed transition states.

Named after Fuson’s principle of vinylogy18 whereby nucleophilic or electrophilic centers can be carried through a conjugated π-system, these reactions are called vinylogous aldol reactions.19

These reactions produce δ-hydroxy-α,β-unsaturated carbonyl compounds like 29.

OH O α-addition General Aldol R2 ∗ ∗ X

R1 OM R2CHO 28 R1 X 27 OH O ∗ γ-addition R2 ∗ X Vinylogous Aldol R1 29

M = Metal ; X = R, OR, NR2

Scheme 1.7 Regioselectivity of the Extended Dienolate Aldol Reaction

Controlling the regioselectivity of this reaction is dependent on the form of the enolate and the reaction conditions. Extended dienolates with oxygen bound metals, such as 27, will prefer α-additions. However, certain metals, such as Cd20, Zn21, Cu22 and Pd23 can present high

γ-regioselectivity. Preformed masked extended dienolates, such as silyl ketene acetals, silyl enol

13 ethers, or silyl ketene aminals 30, upon treatment with an aldehyde and a Lewis acid, will prefer

γ-additions. These reactions are referred to as the vinylogous Mukaiyama aldol reaction,VMAR

(scheme 1.8). In general, the regioselectivity can be adjusted with kinetic or thermodynamic control, with cooler temperatures and shorter reaction times favoring α-additions and warmer temperatures and longer reaction times favoring γ-additions.24

SiR OH O O 3 Lewis Acid 1 ∗ R R2 ∗ X X 2 R CHO R1 30 29

X = R, OR, NR2

Scheme 1.8 Vinylogous Mukaiyama Aldol Reaction (VMAR)

Electrophilic susceptibility and orbital coefficients have been used to rationalize the regioselective differences between metal extended dienolates and conjugated silyl ketene acetals.19 These calculations were based on the extended dienolates derived from methyl crotonate (figure 1.6). For the case of the lithium extended dienolate 27a, both the orbital coefficients and the electrophilic susceptibility are higher at the α-carbon than the γ- carbon. Conversely, orbital coefficients and electrophilic susceptibilty are higher at the γ-carbon than the α-carbon for the conjugated silyl ketene acetal 30a. It is also important to consider the sterics present in the silyl ketene acetal 30a that could promote γ-addition.

14 OMe OMe SiMe3 OLi O 27a 30a Orbital 0.289 0.311 0.302 0.230 Coefficients γ α γ α Electrophilic 0.572 0.614 0.592 0.451 Susceptibility γ α γ α

Figure 1.6 The Electronic Structure of Extended Dienolates

1.5 The Stereoselective Production of Extended Dienolates via Deprotonation by Metallo Dialkylamides

Extended dienolates 27 can be accessed through deprotonation with three classes of carbonyl species, E-α,β-unsaturated carbonyls E31, Z-α,β-unsaturated carbonyls Z31, and E- or

Z-β,γ-unsaturated carbonyls E32 and Z32 (scheme 1.9). However, the mechanism of deprotonation and the stereoselective predictions for the 1,2-olefin and the 3,4-olefin of the resultant extended dienolate are different for each class. The stereoselectivity of deprotonations in each case can be evaluated by three methods: direct observation or isolation of the extended dienolate 27, isolation of the trapped extended dienolate as a silyl ketene acetal, enol ether, or silyl ketene aminal 30, or by analysis of the protonation/alkylation products of the extended dienolate E/Z33. However, the latter only provides information for the 3,4-olefin geometry.

15 R1 O O O O R1 R1 X X X X R1 E31 Z31 E32 Z32

MNR2

OM O OSiR3 3 + R3SiCl 4 E X 1 X X 1 2 1 R1 R R E 30 27 E33 + Z33 + M = Metal ; X = R, OR, NR2 ; E = Electrophile

Scheme 1.9 Methods of Evaluating 1,2- and 3,4-Olefin Components

Deprotonations of E or Z-α,β-unsaturated carbonyls occur on the γ-carbon, which is more acidic than the α-positions of their saturated counterparts, but less acidic than the α-

positions of β,γ-unsaturated carbonyls. Calculations of pKas have been performed with methyl butyrate 34, methyl-2-butenoate 35, and methyl-3-butenoate 36 that establish this trend (figure

1.7).25

β β CO2Me CO2Me CO2Me α γ α γ α 34 35 36

pKa (H2O): 25 pKa (H2O): 20 pKa (H2O): 16

Figure 1.7 Calculated pKa Values of Saturated and Unsaturated Esters

LDA is generally a poor choice for the deprotonations of E-α,β-unsaturated carbonyls due to the formation of conjugate addition adducts like 37, but is not an issue with Z-α,β- unsaturated carbonyls.y In order to curtail this, amide bases that are less nucleophilic than LDA, such as LHMDS, or its sodium and potassium analogues, NaHMDS and KHMDS, or highly coordinating cosolvents, such as HMPA or DMPU must be used along with LDA (scheme

1.10).

16

R1 OLi O OLi LDA LDA OMe OMe HMPA or DMPU (iPr)2N OMe 27 E31a 37 LHMDS, NaHMDS, or KHMDS

Scheme 1.10 Conjugate Addition Adducts with LDA and E-α,β-Unsaturated Carbonyls

1.6 Deprotonations of E-α,β-Unsaturated Carbonyls by Metallo Dialkylamides

Under kinetic conditions, deprotonation of E-α,β-unsaturated carbonyls E31 with metallo dialkylamides will generally provide 1Z,3Z-extended dienolates 27. A model developed during studies involving isomerizations of E-α,β-unsaturated carbonyls to β,γ-unsaturated carbonyls27,28 has been used to account for the 3,4-olefin geometry29, but examination of the transition states involved can provide an explanation for the 1,2-olefin geometry as well (scheme 1.11).

17 O OM R1 THF X X MNR2 R2 R1 R2 E31 1Z/E,3Z/E 27

Electronically Favored Sterically Favored O O X X H H Base H Base H R2 R2 Base H R1 H R TS8 TS9

X X O O H H Base H Base H R2 R2 Base H R1 H R TS10 TS11

X = R, OR, NR2

Scheme 1.11 “Syn Effect” with Deprotonations of E-α,β-Unsaturated Carbonyls

The electronically favored transition states TS8 and TS10, with R1 eclipsing the alkene, is believed to have enhanced acidity due to hyperconjugation of the developing carbanion with the adjacent anti-bonding π-orbitals, and will give rise to a 3Z-alkene. This has been referred to as conformational acidity or the “syn effect”. The enhanced acidity is weighed against the steric interactions inherent in these conformations. Once the sterics involved outweigh the enhanced acidity, the transition states TS9 and TS11 will be favored and this conformation will furnish a

3E-alkene. The sterically favored transition states TS9 and TS11 also possess hyperconjugation with the adjacent π-system, but not to the same degree as TS8 and TS10.

18 Control over the 1,2-olefin geometry will depend upon the size of R2 and the carbonyl substituent X. If R2 is a hydrogen, TS8 and TS9 will possess the lowest energy conformation about the C1-C2 bond. These conformations will give rise to a 1Z-alkene. Once R2 becomes too large, the steric interactions between R2 and X will force a rotation about the C1-C2 bond to provide the conformation present in TS10 and TS11, which furnishes a 1E-alkene.

Selectivity for the 3Z-alkene erodes as the size of R1 increases from methyl to isopropyl and completely shifts to favoring the 3E-alkene when R1 is tert-butyl or phenyl (entries 1-5, table

1.3). The sterics involved with the eclipsed conformation is so tenous that if R2 is a methyl group, the stereoselectivity favors the 3E-alkene (entry 6). Stereoselectivity also appears to be unaffected by the species of dialkylamide (entries 7, 8, and 11), but erodes as the temperature of deprotonation is raised (entrie 8, 10, and 12).

Table 1.3 Isomerizations of E-α,β-Unsaturated Carbonyls to β,γ-Unsaturated Carbonyls O O THF/HMPA R1 OEt OEt MNR2 R2 R1 R2 E31 Z/E33

Entry Base Temp R1 R2 Z/E Ref 1 LHMDS -78 °C Me H 10:1 28 2 LHMDS -78 °C Et H 6:1 28 3 LHMDS -78 °C i-Pr H 2:1 28 4 LHMDS -78 °C t-Bu H <1:20 28 5 LHMDS -78 °C Ph H 1:3 28 6 LDA -78 °C Me Me <1:20 30 7 LDA -78 °C Me H 13:1 31 8 LHMDS -78 °C Me H 14:1 31 9 LTMP -78 °C Me H no rxn 31 10 LHMDS -40 °C Me H 6:1 31 11 LTMP -40 °C Me H 13:1 31 12 LHMDS 0 °C Me H 5:1 31 13 LTMP 0 °C Me H 4:1 31

19 Stereoselectivity for the 1Z-alkene is moderately high with esters, roughly 9 : 1, (entries

1-3, table 1.4), but erodes to 1:1 when R2 is a methyl group (entry 4). Ketones (entries 5 and 6) and amides with smaller alkyl groups (entry 7) provide very high stereoselectivity for the 1Z- alkene. Amides with larger alkyl groups, such as a morpholine ring, exhibit similar stereoselectivites to esters (entry 8), but express a stereoselectivity for the 1E-alkene when R2 is a methyl group or larger (entry 9).

Table 1.4 Silyl Ketene Acetals Derived from Deprotonations of E-α,β-Unsaturated Carbonyls

O THF OSiR3 R1 MNR2 X X R2 R3SiCl R1 R2 E31 1Z/E,3Z/E 30

Entry Base X R1 R2 1Z/E 3Z/E Ref 1 LDA/DMPU OEt H H 9:1 NA 32

2 LDA/HMPA OMe CH3 H 8:1 >20:1 26

3 LDA/HMPA Ot-Bu CH3 H 9:1 >20:1 33

4 LDA/HMPA OEt H CH3 1:1 NA 33 5 KHMDS t-Bu H H >20:1 NA 34 6 KHMDS Ph H H >20:1 NA 34

7 KHMDS NEt2 H H >20:1 NA 34

N 8 KHMDS CH3 H 9:1 >20:1 34 O

N 9 KHMDS H CH3 1:3 NA 34 O

1.7 Deprotonations of Z-α,β-Unsaturated Carbonyls by Metallo Dialkylamides

The complexed-induced proximity effect (CIPE) has been used to explain deprotonations/lithiations occuring at remote positions in relation to functional groups capable of coordination.35,36 The general case for a deprotonation/substitiution sequence involves association of the organolihium or lithium amide species with the substrate 38 to provide the prelithiation complex 39 (scheme 1.12). This complexation directs the

20 FG FG (LiR) FG n Li + (RLi)n R H C H C H C

38 39 TS12

FG FG E+

C E C Li

41 40 FG = Functional Group ; E+ = Electrophile

Scheme 1.12 General CIPE with Deprotonation Reactions organolithium or lithium amide species to deprotonate the remote hydrogen in TS12, to furnish the new lithated species 40 that can further undergo a transformation with an electrophile to manufacture 41.

CIPE has been cited for deprotonations of Z-α,β-unsaturated carbonyls Z31 particularly to explain the high preference for γ-Z deprotonations over γ-E deprotonations when the β- position is disubstituted (scheme 1.13).35,37 Under kinetic conditions, deprotonations of Z-α,β- unsaturated carbonyls generally provide 1Z,3E extended dienolates. Competitive eight membered transitions states TS13 and TS14 have been proposed to rationalize the stereoselectivity for both olefin components.37,38 TS13 is favored when R2 is small and will give the 1Z,3E extended dienolate. However, as R2 becomes larger, the A1,2 strain between R2 and R1 will outweigh the A1,3 strain between R1 and the carbonyl system. This will favor TS14, which furnishes the 1Z,3Z extended dienolate. The cyclic transition state ensures the high diastereoselectivity of the 1,2-olefin. Computational studies have been performed for the eight- membered transition states to see how similar the deprotonations are to the Ireland model for α-

21 37 deprotonations of carbonyl compounds. The O-C1-C2-C3 dihedral angle of 24.37° shows that the π-system is nearly planar, which maximizes conjugation. The C2-C3-C4-H dihedral angle of

89.52° reflects that the deprotonation is occuring perpendicular to the plane of the carbonyl and the olefin, which ensures conjugation with the newly forming pi system. As mentioned previously, the use of HMPA or DMPU is not required for the deprotonations of Z-α,β- unsaturated carbonyls, but their use does not always change the predictive model. With β,β- disubstituted α,β-unsaturated carbonyls it is believed to disturb the CIPE, because it tips the scales in favor of γ-E deprotonations over γ-Z deprotonations.22 Nevertheless, if they are used with mono β-substituted substrates, the preference for the 3Z-alkene remains.17b,17h,31

γ-Z R1 R1 O LDA OLi

R2 X THF R2 X γ-E Z31 1Z/E,3E/Z 27

H R1 R1 H R2 R2 X X O H O H Li Li NiPr NiPr 2 O-C-C-C dihedral 2 TS13 24.37° TS14 C-C-C-H dihedral 89.52° C-H-N angle 2 R 166.82° R2 X R1 X H OLi H OLi R1 1Z,3E 27 1Z,3Z 27 X = R, OR, NR 2 Scheme 1.13 Transition States for the Deprotonation of Z-α,β-Unsaturated Carbonyls

22 Deprotonations of β,β-disubstituted-α,β-unsaturated amides show that stereoselectivity for the 3E-alkene is high when R1 and R2 are linear alkyl chains (entries 1,2, and 3, table 1.5), but erodes to roughly 1:1 when a minorly branched substitiuent,

Table 1.5 Isomerizations of Z-α,β-Unsaturated Carbonyls to β,γ-Unsaturated Carbonyls R1 R1 THF O O MNR2 R2 X R2 X E+ E Z31 E33

Entry Base Temp X R1 R2 E/Z Ref 1 LDA RT NMe2 Me Et 4:1 37 2 LDA -78 °C NMe2 Me Et 12:1 37 3 LDA RT NMe2 Me n-Bu 4:1 37 4 LDA RT NMe2 Me s-Bu 1:1.4 37 5 LDA RT NMe2 Me t-Bu <1:20 37 6 LDA RT NMe2 i-Pr s-Bu 1:12 37 7 LDA RT NMe2 OMe n-Bu <1:20 37 8 LDA -78 °C OEt Me H >20:1 31 9 LHMDS -78 °C OEt Me H NR 31 10 LTMP -78 °C OEt Me H >20:1 31 11 LHMDS -40 °C OEt Me H 11:1 31 12 LTMP -40 °C OEt Me H 19:1 31 13 LTMP 0 C OEt Me H 10:1 31 ° such as sec-butyl is R2 (entry 4).37 Once a tert-butyl group is R2, or both R1 and R2 are minorly branched subtituents such as isopropyl and sec-butyl, the 3Z-alkene is favored (entries 5 and 6).

If R1 is a methoxy group (entry 7), the 3Z-alkene is also favored, and this is believed to arise from coordination of the methoxy group to lithium in TS15 (figure 1.8) Just like the deprotonations of E-α,β-unsaturated carbonyls, the stereoselectivity is enhanced when performed at cooler temperatures (entry 2). An examination of the lithium amide base used for the deprotonation of Z-α,β-unsaturated

23 esters shows that LTMP provides the same stereoselectivity as LDA (entries 8 and 10).31

LHMDS does not deprotonate the esters at -78 °C, but at -40 °C it exhibits reduced stereoselectivity (entries 9 and 11). This may be due to a looser transition state because of the reduced basicity of LHMDS. Stereoselectivity for the 3E-alkene is also reduced as the temperature of deprotonation is raised (entries 10, 12, and 13).

MeO H n-Bu Me2N O H Li i N Pr2 TS15

Figure 1.8 Transition State Rationale for 3Z-stereoselectivity with Methoxy Group

Stereoselectivity for the 1Z-alkene is very high (>20:1) for esters,26,39,40 ketones,41 and amides,42 but the reactions must be performed at lower temperatures (table 1.6). There are more studies of the C1-C2 alkene geometry with esters than for ketones or amides. The presence of a disubstituted β-position appears to have no effect on the C1-C2 geometry (entry 1-4, 6-11).

Substituents on the α-position also appear to have no effect on the C1-C2 or C3-C4 alkene geometry, which is in aggreement with the eight membered transition state model (entry 5). The results with the large pyrrolidine substituents as R2 are also consistent with this model and echo those reported with β,β-disubstitited α,β-unsaturated amides (entry 6 and 8). The lithium extended dienolates 1Z,3E 27a and 1Z,3E 27b for these studies have been isolated as crystals in

THF as a dimer, and in benzene as a hexamer (figure 1.9) The use of the potassium analogue of

LDA, KDA, exhibits the same level of stereoselectivity for the 1Z-alkene, but complete erosion of the stereoselectivity for the 3,4-olefin (entry 7). This shows that the counter

24 cation of the base does matter, and may hint at a looser transition state, which would possess reduced steric interactions, but still hold the carbonyl in position to lock the C1-C2 geometry.

Table 1.6 Silyl Ketene Acetals Derived from Deprotonations of Z-α,β-Unsaturated Carbonyls R1 R1 O THF OSiR3 MNR2 R2 X R2 X R3SiCl R3 R3 Z31 1Z/E,3E/Z 30

Entry Base Temp X R1 R2 R3 1Z/E 3E/Z Ref 1 LDA -78 °C OMe H Et H >20 : 1 NA 26 2 LDA -78 °C OMe Et H H >20 : 1 >20 : 1 26 3 LDA -78 °C OMe Me Pr H >20 : 1 >20 : 1 26 4 LDA -78 °C OMe Pr Et H >20 : 1 >20 : 1 26 5 LDA -78 °C OMe H H Me >20 : 1 NA 26

6 LDA -78 °C OMe Me N H >20 : 1 >20 : 1 39

7 KDA -78 °C OMe Me N H >20 : 1 1 : 1 40

8 LDA -78 °C OMe Me N H >20 : 1 >20 : 1 39

9 LDA -78 °C Ph H Me H >20 : 1 NA 41

10 LDA -78 °C Ph Me >20 : 1 >20 : 1 41

11 LDA RT NMe H Me H >20 : 1 NA 42 2

OLi OLi

N OMe N OMe

1Z,3E 27a 1Z,3E 27b

Figure 1.9 Lithium Extended Dienolates Isolated as Crystals

25 1.8 Deprotonations of E/Z-β,γ-Unsaturated Carbonyls by Metallo Dialkylamides

Deprotonations of E/Z-β,γ-unsaturated carbonyls by metallo dialkylamides are not used as commonly for accessing extended dienolates compared with their α,β-unsaturated isomers. Even if they possess enhanced acidity, they do not generally provide the same level of stereoselectivity for the 1,2-alkene (table 1.7).32, 43-47 Isomerizations of the substrate β,γ-olefin are not observed and the alkene geometry is retained (entries 1, 2, 3, 7, and 8). The cases that do exist for using

E/Z-β,γ-unsaturated carbonyls for accessing extended dienolates are typically for processes that place more emphasis on stereoisomeric purity for the 3,4-alkene, such as the vinylogous mukaiyama aldol reaction or alkylations. While these are α-deprotonations only a few examples are consistent with the predictions of the Ireland model when considering disubstituted α- positions (entries 4, 6, and 8), or very large carbonyl substituents (entry 7 and 8), but most are not and conflicting results have been reported (entries 5 and 6). Deprotonations of saturated carbonyls normally give E-enolates when performed under kinetic conditions with LDA, and Z- enolates with LHMDS or LDA paired with HMPA or DMPU, but deprotonations of E/Z-β,γ-unsaturated carbonyls favor 1Z enolates with LDA with or without

HMPA or DMPU and with NaHMDS.

26 Table 1.7 Silyl Ketene Acetals Derived from Deprotonations of E/Z-β,γ-Unsaturated Carbonyls

O THF/-78 °C OSiR3 MNR2 X X R3SiCl R1 R2 R1 R2 E/Z 32 1Z/E,3E/Z 30

Entry Base X Substrate R1 R2 1Z/E 3Z/E Ref 1 LDA OMe E Me H 2:1 1:9 32 2 LDA/DMPU OMe E Me H 2:1 <1:20 43 3 LDA OiPr E Ph Et 1:1 <1:20 44 4 LDA OEt NA H Me 2:1 NA 45 5 LDA OEt NA H H 4:1 NA 45 6 LDA OEt NA H H 1:2 NA 32

7 NaHMDS E Me H 3:1 <1:20 46

O 8 NaHMDS N Z Me Me <1:20 >20:1 47 O Bn

1.9 Conclusion

This chapter has presented selected features of monoenolates and extended dienolates that pertain to the remainder of the dissertation. Monoenolates can be generated via deprotonation of carbonyl compounds by metallo dialkylamide bases. Without the use of coordinating cosolvents, such as HMPA and DMPU, these transformations are believed to have competing cyclic six- membered transition states called the Ireland model. Overall, both E- and Z-enolates can be acquired if the correct conditions are chosen. Under kinetic conditions, strong amide bases provide E-enolates and weaker amide bases provide Z-enolates. Coordinating cosolvents utilized with strong amide bases can also provide Z-enolates.

Aldol reactions of stereoisomerically pure enolates can be diastereoselectively with Z- enolates providing syn-adducts and E-enolates furnishing anti-adducts. This transformation is

27 also believed to have competing cyclic six-membered transition states referred to as the

Zimmerman-Traxler model.

Extended dienolates can be generated from deprotonation of E- and Z-α,β-unsaturated carbonyls as well as E- and Z-β,γ-unsaturated carbonyls with metallo dialkylamides.

Deprotonations of E-α,β-unsaturated carbonyls generally provide 1Z,3Z-extended dienolates and are believed to occur through an open transtion state with a “syn effect” dictating the 3,4-olefin geometry and allylic strain determining the 1,2-olefin geometry. The 3Z-alkene is formed more stereoselectively than the 1Z-alkene. They require the use of coordinating cosolvents with LDA in order to suppress Michael additions. Deprotonations of Z-α,β-unsaturated carbonyls generally provide 1Z,3E-extended dienolates and are believed to occur through a cyclic eight-membered transition state. The stereoselectivity is incredibly high for the 1Z-alkene as well as the 3E- alkene, unless the β-position is congested, which shifts the stereoselectivity for a 3Z-alkene.

Deprotonations of E- and Z-β,γ-unsaturated carbonyls do exhibit the same level of stereoselectivity as their α,β-unsaturated isomers. The stereoselectivity for the 1,2-olefin is very poor and the 3,4-olefin geometry is retained from the original β,γ-unsaturated substrate.

Extended dienolates possess two carbon nucleophilic sites, the α-carbon and the γ-carbon.

Kinetic conditions favor additions to the α-carbon and thermodynamic condtions favor additions to the γ-carbon. For aldol reactions, the regioselectivity is highly dependent on the nature of the extended dienolate. Metal extended dienolates are prone to α-additions and masked extended dienolates, such as silyl ketene acetals, silyl enol ethers, and silyl ketene aminals, possess an inclination for γ-additions.

28 CHAPTER 2: DIASTEREOSELECTIVE SYNTHESES OF (E)-α-TRIALKYLSILYL-α,β- UNSATURATED ESTERS, α-SILANE-SUBSTITUTED CONJUGATED SILYL KETENE ACETALS, AND α,γ-SUBSTITUTED ALLYL SILANES

2.1 Introduction

This chapter will detail several methodologies centered on (E)-α-trialkylsilyl-α,β- unsaturated esters: the expansion of substrate scope for the diastereoselective syntheses (E)-α- trialkylsilyl-α,β-unsaturated esters via catalytic carbocupration of alkynoates, the diastereoselective synthesis of (E)-α,γ-substituted allylsilanes derived from (E)-α-trialkylsilyl-

α,β-unsaturated esters by a γ-deprotonation-α-protonation sequence, and the successful isolation and stereochemical assignment of α-silane substituted conjugated silyl ketene acetals derived from (E)-α-trialkylsilyl-α,β-unsaturated esters. The discussion will begin with the motivation behind the γ-deprotonation-α-protonation sequence with (E)-α-trialkylsilyl-α,β-unsaturated esters. Methods of accessing each class of substrates and the synthetic applications will be described as well.

2.2 Motivation

Dr. Jennings and former graduate student Aymara Albury have used α-substituted allylsilanes 43 for the diastereoselective synthesis of (E)-non-conjugated homoallylic alcohol 44 using the masked chiral aldehyde 42 (scheme 2.1).48 The α-substituted

29 Bn O OH Bn O O Me3Si TiCl4 + Ph 5 44 H Ph DCM 5 81% 42 43 E/Z = >20:1 anti/syn = >20:1

Scheme 2.1 Diastereoselective Allylsilane Addition allylsilane 43 was accessed over four steps from the α-trimethylsilyl-α,β-unsaturated ester 47a

(scheme 2.3). The ester was hydrogenated using Pearlman’s catalyst and submitted to a DIBAL reduction that resulted in the alcohol 45. This alcohol was then oxidized using Dess-Martin

Periodinane, furnishing an aldehyde that was converted to the α-substituted allylsilane 43 by a

Wittig olefination.

O O Me Si a) H2, Pd(OH)2 Me Si 3 OEt 3 OEt

Ph EtOH Ph 47a 46 89%

O b) DIBAL toluene O c) I OAc AcO OAc NaHCO Me Si 3 Me Si 3 DCM 3 OH

Ph d) H C PPh Ph 43 2 3 45 48% over 2 steps THF 85% 32% overall

Scheme 2.2 Manufacturing α-Substituted Allysilanes

The α-trimethylsilyl-α,β-unsaturated ester 47a was furnished via a methodology develped by Dr. Jennings and former graduate student Dr. Amanda Mueller-Hendrix. In 2010, they reported the diastereoselective synthesis of (E)-α-trialkylsilyl-α,β-unsaturated esters 47 via

30 catalytic carbocupration of alkynoates 48 in the presence of excess silyl triflates (scheme 2. ).49

Upon warming, the trialkylsilyl allenolate intermediate 49 tautomerized to the (E)-α-trialkylsilyl-

α,β-unsaturated esters. This study mainly involved aryl grignard addition, but two examples were given with alkyl grignard reagents.

SiR 2 5 mol% CuI•2LiCl 3 CO2R 2 2 O OR 3 CO2R 3.3 equiv R3SiOTf R SiR3 1.2 equiv R3MgX -78 °C to RT • R1 47 7 examples R1 THF 3 R1 Yields = 85-93 % -78 °C R 48 49 E/Z = >20:1

Scheme 2.3 (E)-α-Silyl-α,β-Unsaturated Esters via Catalytic Carbocupration of Alkynoates in the Presence of Excess Silyl Triflates

In 2012, Dr. Jennings and former undergraduate student Dr. Robert Sharpe reported the formal synthesis of (-)-cyanolide A 58, which involved a diastereoselective Mukaiyama aldol reaction utilizing the chiral masked aldehyde 50 (scheme 2.5).50 The Mukaiyama adduct 52 was transformed into the chiral pyran acid 53 over eight steps. The pyran was dimerized using

Yamaguchi macrolactonization conditions and MOM deprotected with LiBF4 in aqeuous MeCN to furnish the aglycon 56. The total synthesis of (-)-cyanolide A 58 could have been completed following the diastereoselective glycosylation of 56 with the thioacetal 57 along with TMSOTf as reported by Hong.51

31 Ph Ph OTMS BF •OEt O O OH O O O O 3 2 + OEt OEt H DCM 50 51 52 64% dr = 4:1

8 steps OMOM OH O O 54, DMAP, PhCH3 O O OH O Cl O O O OMOM 53 Cl O Cl Cl 54 OMOM 55 OMe MeO OMe LiBF4 CH3CN/H2O O O OH O O O O O O 57, TMSOTf O O O O O MeO OMe O O O PhS OMe OH 56 O MeO OMe 57 OMe 58 (-)-Cyanolide A

Scheme 2.4 Synthesis of Cyanolide A via a Diastereoselective Mukaiyama Aldol Addition

The deprotonation of (E)-α-trialkylsilyl-α,β-unsaturated esters bearing a β-alkyl substituent 47 followed by a regioselective α-protonation of the metal extended dienolate 59 or conjugated silyl ketene acetal 60 would provide the higher functionalized α,γ-substituted allylsilanes, or α-trialkylsilyl-β,γ-unsaturated esters 61 (scheme 2.4).

32 OM MNR R3 2 OR1 2 R SiR3 59 1 2 1 + 3 CO R R CO2R α-H R 2 3 2 R SiR3 R SiR3 47 61

OSiR3 R3 OR1 MNR2 2 R SiR3 R3SiCl 60

Scheme 2.5 γ-Deprotonation-α-Protonation Sequence

The pyran acid synthetic intermediate 53 used in the formal synthesis of (-)-cyanolide A could be accessed in a more concise manner via a diastereoselective allylsilane addition using a masked chiral aldehyde 62 with the α-trialkylsilyl-β,γ-unsaturated ester 61.1 (scheme 2.6). The

δ-hydroxy group on the α,β-unsaturated ester 63 adduct could be orthogonally protected and using an acid catalyst, the remaining protecting groups could be removed which would promote an intramolecular cyclization to provide the pyran ester 65. The ester functionality could then by saponified to furnish the pyran acid 53.

33 OR OR O OR OR OH CO2Et LA + CO Et H 2 SiMe3 62 61.1 63

Hydroxyl Protection OH O OEt Acid Catalyst OR OR OR1 O O Selective Deprotection OEt and Conjugate Cyclization 64 65 OR1

MeO 1. NaOH + 2. H3O /H2O MeO O O O MeO O O OH O OH

O O O O OMe O O OMe 53 OR1 OMe 58 (-)-Cyanolide A

R = Protecting Group ; LA = Lewis Acid

Scheme 2.6 Potential Application of α,γ-Substituted Allylsilanes

2.3 Allylsilanes

Allylsilanes have been heavily used in synthetic organic chemistry because of their low to non-toxicity and high regioselective and diastereoselective reactions.52 They possess a nucleophilic γ-positions because of σ-π conjugation 66 (figure 2.1). Carbocations β to a silicon group can be stabilized by this conjugation and when this occurs, it is called the β-effect 67.

Carbanions α to a silicon group can also be stabilized through σ*-π conjugation and this is referred to as the α-effect 68.

34 R Si R Si 3 3 Si C C C C C C C α β γ α β σ−π stabilization σ∗−π stabilization σ−π activation (β-effect) (α-effect) 66 67 68

Figure 2.1 Activation and Stabilization Effects of Silicon

Electrophilic additions with acyclic allylsilanes are best classfied as anti-SEʹ reactions

(scheme 2.7).52a,c The reactive conformer 69 is thought to have the smallest substituent, normally a hydrogen, eclipsing the adjacent alkene. The electron rich olefin will react with an electrophile on the opposite face housing the silane, generating a secondary carbocation TS16. This carbocation will be stabilized in a periplanar fashion with the C-Si bond through hyperconjugation with the empty p-orbital. The β-effect will also make the silane more electrophilic and a nucleophile will then promote the silane elimination which furnishes the β- substituted (E)-olefin product 70. The (Z)-olefin 72 is disfavored due to A1,3 strain in the reactive conformer 71 and the transition state TS17 resulting from the electrophilic addition.

35 Nu H H H H H + H R Si E R3Si Anti-SEʹ R 3 E Favored H H E R H R H (E)-Olefin 69 TS16 70

H H H H H H + R E H E Anti-SEʹ H H R H Disfavored SiR3 R E SiR 3 Nu (Z)-Olefin 71 TS17 72

E+ = Electrophile ; Nu = Nucleophile

Scheme 2.7 SEʹ Reactions of Allylsilanes

An anti-periplanar transition state is normally invoked to explain and predict reactions involving γ-substituted allylsilanes (E and Z), also referred to as crotyl silanes, with electrophilic carbonyl species (scheme 2.8).52 The participating π-bonds are oriented 180° away from each other. This provides an anti and coplanar relationship between the nucleophilic carbon and the activated carbonyl, an aldehyde in this example. Because this model minimizes destabilizing steric interactions, transition state TS18 for the (E)-allylsilane and transition state TS20 is favored for the (Z)-allylsilane. In these transition states the steric interactions between the γ- substituent and the aldehyde substituent are diminished and will provide the syn-homoallylic alcohol 73. Transition state TS19 for the (E)-allylsilane and transition state TS20 for the (Z)- allylsilane would provide the anti-homoallylic alcohol 74, but they are disfavored due to maximizing the steric interactions between the γ-substituent and the aldehyde substituent. In general, (E)-allylsilanes are highly selective for the syn-stereoisomer, but the (Z)-allylsilanes are only moderately selective.52c

36 LA LA O R2 O R2 H H R2 R3 Favored R1 Favored R3 R H H OH 73 R1 R1 H Syn-Homoallylic H Alcohol SiR3 SiR3 TS18 TS20 (E)-Allylsilane (Z)-Allylsilane

LA 2 LA O R O R2 H R3 H R2 Disfavored R1 Disfavored 3 OH 3 R H 74 H R R1 R1 H Anti-Homoallylic H Alcohol SiR3 SiR3 TS19 TS21 (E)-Allylsilane (Z)-Allylsilane LA = Lewis Acid

Scheme 2.8 Allylsilane SEʹ Transition State

2.4 Recent Synthetic Applications of α-Silyl-β,γ-Unsaturated Esters

In 2001, the groups of Suginome and Ito reduced the E-(R)-α-silyl-β,γ-unsaturated ester

(R)-E61.2 to the (R)-homoallylic silane 75 for an intramolecular cyclization to furnish trans- disubstituted oxacyclohexenes 76 (scheme 2.9).53a The process was highly enantioselective, moderately diastereoselective, and gave medium to high yields with both aromatic and aliphatic aldehydes.

RCHO 3 examples CO Me HO R O 2 LAH TMSOTf Yields = 56-77% Bu SiMe dr = 9:1 3 Bu SiMe DCM Bu (R)-E61.2 3 up to 99% ee 75 -78 °C 76 LAH = Lithium Aluminum Hydride ; R = Alkyl and Aryl

Scheme 2.9 Asymmetric Synthesis of Cyclic Alkenes via Cyclization of Enantioenriched Allylsilanes

In 2010, Panek reported the implementation of the (R)-α-silyl-β,γ-unsaturated esters (R)-

E61.3 and (R)-E61.4 in the preparation of syn-polypropionate building blocks (scheme 2.10).53b

37 Overall, the process provided the homo allylic ether vinylogous aldol products 77 in a diastereoselective and enantioselective fashion. The selectivity was high with deactivated aromatic aldehydes and branched aliphatic aldehydes, but low with activated aromatic aldehydes and linear aliphatic aldehydes.

1 R : Aryl OR2 5 examples CO2Me R2: Me, Bn, or Allyl Yields = 67-79% CO2Me R1 dr = 5:1-15:1 SiR3 1 77 up to 97 % ee (R)-E61.3, R: Bu R CHO (R)-E61.4, R: Ph TMSOR2 (1.1 equiv) TMSOTf (1 equiv) -60 °C OR2 6 examples CO Me Yields = 39-79% R1 2 dr = 5:1-15:1 R1: Alkyl 77 up to 85 % ee R2: Me, or Bn

Scheme 2.10 Asymmetric Vinylogous Aldol Products via Chiral Crotylsilanes

In an attempt to increase selectivity, Panek converted the (R)-α-silyl-β,γ-unsaturated ester

(R)-E61.5 to the primary TBDPS ether 78 by reducing the ester group and silylating the alcohol

(scheme 2.11). Diastereoselectivity increased across the board for both linear and branched aliphatic aldehydes, as well as for activated and deactivated aromatic aldehydes. The level of enantioselectivity was maintained and this method exhibited higher yields. The aliphatic aldehydes required a slightly different procedure with BF3ŸOEt2 replacing TMSOTf and the use of excess TMSOMe in order to suppress tetrahydrofuran byproducts.

38 1. LAH CO2Me OTBDPS 2. TBDPSCl, imidazole SiMe2Ph SiMe Ph (R)-E61.5 78 2

R1CHO R1CHO TMSOR2 (1.1 equiv) TMSOMe (3.3 equiv)

TMSOTf (1 equiv) BF3OEt2 (2 equiv) -78 °C -78 °C R1: Aryl R1: Alkyl R2: Me, Bn, or Allyl

OR2 OMe

R1 OTBDPS R1 OTBDPS 79 79a 10 examples 3 examples Yields: 51-92% Yields = 47-76% dr = 8:1->20:1 dr = 16:1->20:1 up to 97% ee up to 97% ee

Scheme 2.11 Asymmetric Crotylation via Chiral Homoallylic TBDPS Ether Crotylsilanes

In 2011, Panek utilized the (S)-α-silyl-β,γ-unsaturated ester (S)-E61.5 for an asymmetric crotylation with isobutyraldehyde 80 as a key step in the synthesis of (-)-Virginiamycin M2 82

(scheme 2.12).53c The reaction provided a modest yield with very high diastereo and enantioselectivity. The polypropionate moiety of 81 is highlighted in red in the structure of (-)-

Virginiamycin M2.

39 O OH CO2Me TiCl4 + CO Me H 2 SiMe2Ph DCM (S)-E61.5 80 81 Yield = 63% dr = >20:1 O 97% ee N O N O O O H N HO 82 O (-)-Virginiamycin M2

Scheme 2.12 Asymmetric Crotylaton in the Synthesis of (-)-Virginiamycin M2

Panek was able to access bifunctional homoallylic carbamates 83 by expanding the scope of asymmetric crotylations with the (S)-α-silyl-β,γ-unsaturated ester (S)-E61.5 in 2012 (scheme

2.13).53d In this case an in-situ N-acyl iminium ion was used as the electrophilic partner.

Aromatic imines provided modest to high yields, moderate diastereoselectivity, but high enantioselectivities. On the other hand, linear and branched aliphatic imines offered high diastereoselectivity, modest to high yields, and high enantioselectivities.

O R1CHO R2 5 examples BF3•OEt2 (2 equiv) HN O 2 Yields = 53-78% CO2Me NH2CO2R CO Me R1 2 dr = 3:1-8:1 up to 94% ee SiMe2Ph MeCN 83 (S)-E61.5 -30 °C R1 : Aryl R2 : Me or Allyl O R2 4 examples HN O -10 °C Yields = 40-71% CO Me R1 2 dr = 15:1->20:1 up to 94% ee 83 R1 : Alkyl R2 : Me

Scheme 2.13 Asymmetric Syntheses of Bifunctional Homoallylic Carbamates

40 In 2013, Han’s research group was able to combine Panek’s asymmetric aldehyde crotylation with their Ir(I)-catalyzed diastereoselective allylic etherification in order to access orthogonally protected 2-methyl-1,3-diols 86a and 86b (scheme 2.14).53e The (R)-α-silyl-β,γ- unsaturated ester (R)-E61.5 was reduced to an alcohol and acylated to provide the p- methoxyphenyl (PMP) homoallylic carbonate 84. Submitting these to the asymmetric crotylation conditions furnished the PMP allylcarbonates 85. Enantioselectivity and yield was high no matter the nature of the aldehyde, however diastereoselectivity was higher with aromatic aldehydes and branched aliphatic aldehydes. Application of an Ir(I)-catalyzed decarboxylative double diastereoselective allylic etherification to the PMP allylic carbonates 85 in the presence of a chiral phosphoramidite L1 or ent-L1 afforded the orthogonally protected 2-methyl-1,3-diols

86a and 86b. The Phosphoramidite ligand L1 provides the (1S, 2R, 3S) stereoisomer 86a and the ligand ent-L1 reverses the diastereofacial preference to provide the (1S, 2R, 3R) stereoisomer

86b. Diastereoselectivities are given for the relationship of the PMP ether and the adjacent methyl group.

41 1. LAH O CO2Me O OPMP SiMe2Ph 2. ClCO2PMP, pyridine (R)-E61.5 84 SiMe2Ph

RCHO OCH3 TMSOBn (3 equiv) TfOH (3 equiv) PMP = EtCN, -78 °C

OBn O

R O OPMP [Ir(dbcot)Cl] (2 mol %) [Ir(dbcot)Cl]2 (2 mol %) 2 L1 (4 mol %) 85 ent-L1 (4 mol %) DBU (100 mol %) DBU (100 mol %) THF, 60 °C 5 examples THF, 60 °C R: alkyl OMe Yields = 82-92% OMe dr = 4:1->25:1 ee = 94-98% O O P N P N 6 examples O R: aryl O Yields = 88-96% OMe dr = >25:1 OMe L1 ee = 95-97% ent-L1

OBn OPMP OBn OPMP

R ∗ R ∗ 86a 86b 10 examples 10 examples Yields = 36-83% Yields = 41-86% dr = 10:1->25:1 dr = 10:1->25:1

Scheme 2.14 Asymmetric Synthesis of Orthogonally Protected 2-Methyl-1,3-Diols

2.5 Synthetic Methods for α-Silyl-β,γ-Unsaturated Esters

The first reported synthesis of an α-silyl-β,γ-unsaturated ester was by the Cunico research group utilizing 1,3-cycloadditions of (E)- and (Z)-methyl 3-trimethylsilylpropenoates Z/E 87 with diazoalkanes in 1977 (scheme 2.15).54a The 1,3-cycloadditions provided 3-carbomethoxy-4- trimethylsilyl-1-pyrazolines 88 that underwent 1,2-trimethylsilyl group migrations to furnish a mixture of homolygated ester products. The α-silyl-β,γ-unsaturated esters, E61.6 and E61.7

42 ,were isolable only when diazoethane or tert-butyldiazomethane were used. Diazomethane did not promote the 1,2-trimethylsilyl migration, resulting only in the 3-carbomethoxy-4- trimethylsilyl-1-pyrazolines 88 and the use of phenyldiazomethane or ethyl diazoacetate resulted in the desilylated products 90 and 91.

CO Me CO Me CO Me SiMe 2 2 2 3 RCHN2 Me3Si + N SiMe3 CO2Me Et2O N R R R SiMe3 Z/E 87 88 89a, R = Me 89b, R = Me Ester Diazoalkane Products (%) CO2Me Z87 CH3CHN2 89a (58) 89b (2) E61f (40)

E87 CH3CHN2 89b (68) E61f (32) R SiMe3 E61.6, R = Me Z87 t-BuCHN2 E61g (97) E61.7, R = t-Bu E87 t-BuCHN2 E61g (97) CO2Me CO2Me Z87 PhCHN2 90b (97) + E87 PhCHN2 90b (97)

Z87 EtO2CCHN2 91a (18) 91b (82) R R 90a, R = Ph 90b, R = Ph E87 EtO2CCHN2 91a (18) 91b (82) 91a, R = CO2Et 91b, R = CO2Et

Scheme 2.15 1,3-Cycloadditions of Methyl 3-Trimethylsilylpropenoates with Diazoalkanes Leading to α-Trimethylsilyl-β,γ-Unsaturated Esters

In 1983, the Katzenellenbogen research group reported implementing

Ni-catalyzed α-vinylation to ethyl α-(trimethylsilyl)acetate 92 (scheme 2.16).54b Four α- trimethylsilyl-β,γ-unsaturated esters 61.8-61.11 were furnished with this method. The process gave low to moderate yields and was more selective for the E-vinyl bromides. When isomerically pure Z-vinyl bromides were used, Z61.11, the yields were extremely low. The benzyl ester E61.9 gave lower yields due to desilylation upon distillation or column chromatography.

43 1.) LDA/THF 2.) NiBr2/n-BuLi SiMe3 R1 Br, R1 = Vinyl Me3Si CO2Et 1 R CO2Et 92 -78 °C, 5 min RT, 1 - 4 hrs 61 3.) 5% HCl at -78 °C

SiMe3 SiMe3 SiMe SiMe3 3

CO2Et CO2Et CO Et Ph CO2Et 2 61.8 E61.9 E61.10 Z61.11 Yield = 62 % YIeld = 42 % Yield = 32 % Yield = 8 %

Scheme 2.16 α-Silyl-β,γ-Unsaturated Esters via Nickel-Catalyzed α-Vinylation of α-Silyl Esters

In the same report, a γ-deprotonation-α-protonation sequence with a mixture of the (E)- and (Z)-α-trimethylsilyl-α,β-unsaturated esters 47b was detailed (scheme 2.17). The deprotonation was performed without the use of HMPA and the lithium enolate was directly protonated with NH4Cl. The yield was high for this process, but possessed very low regioselectivity for the protonation (E61.12/47b = 2:1), but high diastereoselectivity with the β,γ- alkene.

SiMe3 SiMe3 1.) LDA/THF -40 C, 5.5 hrs ° CO2t-Bu CO2t-Bu E61.12 47b 2.) Sat. NH4Cl Yield = 87 % E/Z = 1:1 -40 °C E61.12/47b = 1.7 : 1.0

Scheme 2.17 α-Trimethylsilyl-β,γ-Unsaturated Esters via a γ-Deprotonation-α-Protonation Sequence with Lithium Enolates

In 1986, Uno furnished several α-silyl-β,γ-unsaturated esters, Z61.5, 61.13-61.18, via regioselective carboxylations of aluminum “ate” complexes and esterifying the resultant β,γ- unsaturated acids (scheme 2.18).54c The process began with lithiation of an allylsilane 93, which was converted to an aluminum “ate” complex because the lithium anions did not exhibit the

44 same level of regioselectivity. This provided low to moderate yields, but reasonably high diastereoselectivities when the original allylsilane possessed a γ-substituent.

1.) t-BuLi, TMEDA, -78 °C to -40 °C 1 2.) AlEt3, -78 °C R R1 3.) CO2, -78 °C to 0 °C SiR3 2 R SiR3 2 4.) NH4Cl, -10 °C R CO2Me 93 5.) CH2N2, 0 °C 61

SiMe2t-Bu SiMe2p-Tol SiMePh2 SiMe2Ph

CO2Me CO2Me CO2Me CO2Me 61.13 61.14 61.15 61.16 Yield = 20% Yield = 50% Yield = 60% Yield = 85%

SiMe2Ph SiMe2 SiMe2Ph

CO2Me CO2Me CO2Me Z61.5 61.17 61.18 Yield = 65 % Yield = 46% Yield = 75% Z/E = >10:1

Scheme 2.18 α-Silyl-β,γ-Unsaturated Esters via Regioselective Carboxylation of Silicon Stabilized Allylic Carbanions

Employing (E)-γ-bromo-α,β-unsaturated esters 94, Girard et. al were able to access two

α-silyl-β,γ-unsaturated esters, 61.19 and Z61.20, via BF3ŸOEt2 mediated SN2’ allylic

54d substitutions with a higher order silylcuprate (Me2PhSi)2Cu(CN)Li2 in 1989 (scheme 2.19).

This methodology provided moderate yields and diastereoselectivity for the (Z)-β,γ-olefin (Z/E =

5:1).

45 (Me2PhSi)2Cu(CN)Li2 Br (1.5 equiv) 1 R1 R SiMe2Ph 2 BF3•OEt2 (1.5 equiv) R CO2Et 2 R CO2Et 94 THF 61 -78 °C or -25 °C

SiMe2Ph SiMe2Ph

CO2Et CO2Et 61.19 Z61.20 Yield = 56 % Yield = 53% Z/E = 5:1

Scheme 2.19 α-Silyl-β,γ-Unsaturated Esters via a BF3ŸOEt2 mediated SN2’ Allylic Substitution Employing a Higher Order Silylcuprate

In 1990, Zweifel et. al also reported a γ-deprotonation-α-protonation sequence to access

(E)-α-trimethylsilyl-β,γ-unsaturated esters E61.22-E61.24 (scheme 2.20).54e The γ-deprotonation was performed on (Z)-α-trimethylsilyl-α,β-unsaturated esters 47c-47e with the use of LDA and

HMPA as a cosolvent. The lithium enolate was trapped as a silyl ketene acetal with the use of chlorotrimethylsilane and the authors suggest that in order to remove the HMPA before protonation, the crude reaction mixture was submitted to a saturated NH4Cl, ice, and pentane wash and extraction. Application of 5% HCl after the wash and extraction provided (E)-α- trimethylsilyl-β,γ-unsaturated esters E61.22-E61.24 with high yields, high α-regioselectivity and high diastereoselectivity for the β,γ-olefin.

46 SiMe3 1.) LDA or LHMDS HMPA/THF, -78 °C SiMe R CO2Me 2.) TMSCl, -78 °C 3 H R CO2Me 47c, R = n-propyl 3.) Sat. NH4Cl, Ice, Pentane 47d, R = Chx 4.) 5% HCl 61 47e, R = Ph

SiMe3 SiMe3 SiMe3 CO2Me CO2Me Ph CO2Me E61.21 E61.22 E61.23 Yield = 71% Yield = 84% Yield = 88% E/Z = >20:1 E/Z = >20:1 E/Z = >20:1 α/γ = >20:1 α/γ = >20:1 α/γ = >20:1

Scheme 2.20 α-Trimethylsilyl-β,γ-Unsaturated Esters via an HMPA Aided γ-Deprotonation-α- Protonation Sequence with Silyl Ketene Acetals

Rh(II)-carbenoid Si-H insertion has been shown to be an effective process for the formation of the C-Si bond.55 In 1994, the Landais research group extended this methodology to vinylcarbenoid species 96 derived from vinyldiazoesters 95 for the stereocontrolled synthesis of

α-silyl-β,γ-unsaturated esters 61.24-61.30 (scheme 2.21).54f This provided moderate to high yields, allowed for the incorporation of a range of silanes, and did not affect the geometry of the olefin in the β,γ-unsaturated esters.

47 Rh (OAc) H SiR N 2 4 Rh L 3 SiR 2 (1 mol %) (2 equiv) 3 R1 CO R 1 R1 CO R 2 DCM R CO2R 2 95 RT 96 61

S SiMe2Ph Si(TMS)3 SiMe2 Ph CO2Et Ph CO2Et Ph CO2Et E61.24 E61.25 E61.26 Yield = 70 % Yield = 72 % Yield = 45 %

SiMe2Ph SiMe2Ph SiMe2Ph

CO2Me Ph CO2Et CO2Me E61.27 Z61.27 E61.28 Yield = 73 % Yield = 75 % Yield = 80 %

S SiMe2Ph SiMe2Ph SiMe2 CO2Et CO2Et Ph CO2Et E61.29 E61.30 Z61.30 Yield = 61 % Yield = 76 % Yield = 72 % L = Ligand

Scheme 2.21 α-Silyl-β,γ-Unsaturated Esters via Rh(II)-catalyzed carbenoid Si-H Insertion with Vinyldiazoesters

Implementing an (R)-pantolactone chiral auxiliary into the vinyldiazoesters allowed for the asymmetric synthesis of α-silyl-β,γ-unsaturated esters 61.31-61.33 with moderate yields and low to modest diastereomeric excesses (scheme 2.22).

48 Rh2(OAc)4 (1 mol %) N2 SiR3 H SiR3 (2 equiv) 1 R1 CO2R R CO2R DCM 95 RT 61

SiMe2Ph SiMe2Ph O O Ph H H O O O O O O E61.31 E61.32 Yield = 67% Yield = 67% de = 32% de = 50%

SiMe2Ph Si(SiMe3)3 O O Ph H H O O O O O O Z61.32 E61.33 Yield = 75% Yield = 55% de = 70% de = 34%

Scheme 2.22 Asymmetric α-Silyl-β,γ-Unsaturated Esters via Rh(II)-Catalyzed Carbenoid Si-H Insertion with Vinyldiazoesters Containing an (R)-Pantolactone Chiral Auxiliary

In 1997, the Davies’ research group improved the asymmetric synthesis of α-silyl-β,γ- unsaturated esters 61.5,61.34-61.36 with Rh(II)-catalyzed carbenoid Si-H insertion with vinyldiazoesters by employing the chiral ligand, (S)-N-[p-(dodecylphenyl)sulfonyl]prolinate C1

(scheme 2.23).54g This methodology provided moderate yields, but very high enantioselectivities.

49 Rh2(S-DOSP)4 : Rh catalyst H N2 SiMe2Ph O Rh PhMe2Si H R1 CO R R1 CO R N O Rh 2 Pentane 2 SO Ar 95 -78 °C (R)-61 2 4 C1

SiMe2Ph SiMe2Ph

Ph CO2Me CO2Me (R)-E61.34 (R)-E61.5 Yield = 76 % Yield = 64 % ee = 91 % ee = 95 %

SiMe2Ph SiMe2Ph

CO2Me CO2Me

(R)-E61.35 (R)-E61.36 Yield = 63 % Yield = 77 % ee = 85 % ee = 92 %

Ar = p-C12H25C6H4

Scheme 2.23 Asymmetric α-Silyl-β,γ-Unsaturated Esters via Rh(II)-Catalyzed Carbenoid Si-H insertion with Vinyldiazoesters by Employing the Chiral Ligand, (S)-N-[p- (dodecylphenyl)sulfonyl]prolinate

In 1999, the Dussault research group reported utilizing the Ni(II)-catalyzed α-vinylation of methyl (α-trimethylsilyl)acetate 97 to furnish the α-trimethylsilyl-β,γ-unsaturated ester E61.2

(scheme 2.24).54h The yield was comparable to those given by Albaugh-Robertson and

Katzenellenbogen.54b

1.) LDA/THF SiMe 2.) NiBr2/n-BuLi 3 I CH CHBu Me3Si CO2Me Bu CO2Me 97 -78 °C to RT 30 min E61.2 3.) 6M HCl Yield = 60%

Scheme 2.24 Dussault’s Report of an α-Silyl-β,γ-Unsaturated Ester via Nickel-Catalyzed α- Vinylation of α-Silyl Esters

In the same report, Dussault detailed expanding the BF3ŸOEt2 mediated SN2ʹ allylic substitution of an (E)-γ-bromo-α,β-unsaturated ester 94a with a higher order silylcuprate to

50 manufacture the (Z)-α-silyl-β,γ-unsaturated ester Z61.2 (scheme 2.25).54h The yield and stereoselectivity was similar to those given by Girard et. al.54d

(Me2PhSi)2Cu(CN)Li2 Bu SiMe2Ph Br (1.5 equiv) BF3•OEt2 (1.5 equiv) CO2Et CO Et Bu 2 Z61.2 -25 °C 94a Yield = 53% Z/E = 6:1

Scheme 2.25 Dussault’s Report of a (Z)-α-Silyl-β,γ-Unsaturated Ester via a BF3ŸOEt2 mediated SN2ʹ Allylic Substitution Employing a Higher Order Silylcuprate

In 2010, the Ball research group wanted to examine the application of peptide ligand libraries to asymmetric Rh(II)-catalyzed carbenoid Si-H insertion with α-diazoesters (scheme

2.26).54i One of the carboxylate containing peptide ligands was found to furnish the (E)-α-silyl-

β,γ-unsaturated ester (S)-E61.34 in very high yield and enantiomeric excess.

0.5 mol % Rh(II) catalyst SiMe2Ph N2 Peptide Ligand PhMe2Si H Ph CO2Me Ph CO2Me (S)-E61.34 CF CH OH 95a 3 2 Yield = 97% -35 °C ee = 90%

Scheme 2.26 Asymmetric α-Silyl-β,γ-Unsaturated Esters via Rh(II)-Catalyzed Carbenoid Si-H Insertion with a Vinyldiazoester Employing a Chiral Peptide Ligand

The Panek research group reported slightly improved yields and enantiomeric excesses with Rh(II)-catalyzed carbenoid Si-H insertion with vinyldiazoesters by employing higher catalyst loadings and silane equivalents in 2011 (scheme 2.27).54j They were able to synthesize both enantiomers of E61e by using enantiomeric N-[p-(dodecylphenyl)sulfonyl]prolinate catalyst systems, C1 and C2.

51 Rh2(S-DOSP)4 : 3 mol % Rh2(S-DOSP)4 SiMe2Ph H 5 equiv PhMe2SiH O Rh CO2Me Hexane N O Rh -78 °C (R)-E61.5 SO2Ar 4 N2 Yield = 72% C1 Rh (R-DOSP) : CO2Me ee = 95-97% 2 4 H 95b O Rh 3 mol % Rh2(R-DOSP)4 SiMe2Ph O Rh 5 equiv PhMe2SiH N CO Me SO Ar Hexane 2 2 4 -78 °C (S)-E61.5 C2

Ar = p-C12H25C6H4

Scheme 2.27 Panek’s Report of Asymmetric Rh(II)-Catalyzed Carbenoid Si-H Insertion with Vinyldiazoesters Employing Enantiomeric N-[p-(dodecylphenyl)sulfonyl]prolinate Ligands

In the same report, Panek et. al. described an asymmetric Cu(I)-catalyzed carbenoid Si-H insertion with the vinyldiazoester 95b employing the chiral diimine ligand L2 to furnish the α- silyl-β,γ-unsaturated ester (R)-E61.5 in modest yield and moderately high enantiomeric excess but lower than that produced by the

Rh(II)-catalyzed methodology (scheme 2.28).

SiMe Ph 5 mol % (MeCN)4CuBF4 2 N2 8 mol % L2 CO2Me CO2Me SiMe2PhH (5 equiv) (R)-E61.5 95b Benzene, Yield = 52% 0 °C for 12 hrs ee = 78%

N N

C10H21 L2 C10H21

Scheme 2.28 Asymmetric α-Silyl-β,γ-Unsaturated Esters via Cu(I)-catalyzed Carbenoid Si-H Insertion

52 The Ma research group investigated Fe(III)-catalyzed conjugate additions of 1-

(trimethylsilyl)allene-1-carboxylates 98 with alkyl, aryl, and vinyl Grignard reagents in 2013

(scheme 2.29)54k The methodology provided (Z)-α-trimethylsilyl-β,γ-unsaturated esters 61 in high yields and high diastereoselectivities.

1 1.) R2MgX (1.1 - 3 equiv) R SiMe3

2 mol % Fe(acac)3 Me Si CO Me CO2Me 3 2 Et O, -78 °C, 0.5 - 2 hrs. 2 R2 Z61 • 2.) Sat. NH4Cl (aq.) 19 examples 1 98 R -78 °C to RT Yields = 74-95% Z/E = 32:1->99:1

R1 = Alkyl ; R2 = Alkyl, Aryl, and Vinyl

Scheme 2.29 Fe(III)-Catalyzed Diastereoselective Synthesis of (Z)-α-Trimethylsilyl-β,γ- Unsaturated Esters

The Xu research group developed an asymmetric Rh(I)-catalyzed carbenoid Si-H insertion methodology with α-diazoesters by utilizing a C1-symmetric diene ligand L3 bearing a bicyclo[2.2.2]octadiene structure in 2016 (scheme 2.30).54l Three of the substrates used were vinyldiazoesters, which provided α-silyl-β,γ-unsaturated esters 61.35-61.37 in lower yields compared to those given by the Rh(II)-catalyzed process, but comparable enantiomeric excesses.

53 1.5 equiv. R3SiH CF3 1.5 mol % [Rh(C H ) Cl] N2 2 4 2 2 SiR3 3.3 mol % L3 1 1 R CO2R R CO2R DCM CF3 95 61 40 °C, 12 hr Ph L3

MeO SiEt3 SiEt3 MeO CO2Et Si CO2Et MeO Ph CO Et MeO 2 OMe (R)-E61.35 (R)-E61.36 (R)-E61.37 Yield = 41% Yield = 36 % Yield = 28% ee = 90% ee = 89% ee = 94%

Scheme 2.30 α-Trimethylsilyl-β,γ-Unsaturated Esters via Asymmetric Rh(I)-Catalyzed Carbenoid Si-H Insertion with Vinyldiazoesters Utilizing a C1-Symmetric Diene Ligand

2.6 Synthetic Methods for (E)-α-Silyl-α,β-Unsaturated Esters

Synthetic methodologies for accessing (E)-α-silyl-α,β-unsaturated esters with high diastereoselectivity and regioisomeric purity are limited to isomerizations from (Z)-α-silyl-α,β- unsaturated esters,54e carboxylations of silylated alkynes,56a catalytic carbocuprations of alkynoates with excess TMSOTf,49 and transition metal catalyzed hydrosilylations of alkynoates.56b,c

In 1991, the Zweifel research group furnished (Z)-α-trimethylsilyl-α,β-unsaturated esters

Z47c,Z47d following carboxylations of aluminum complexes arising from DIBAL reductions of silylated alkynes 99. Submitting the (Z)-α-trimethylsilyl-α,β-unsaturated esters Z47c,Z47d to

LDA in the absence of HMPA lead to a Michael/Retro Michael addition isomerization process following a methanolic workup. This provided (E)-α-trimethylsilyl-α,β-unsaturated esters E47c,

E47d in moderate to high yield and high diastereoselectivity (scheme 2.31).54e Application of these conditions to the β-benzyl substrate Z47e did not result in the isomerized product E47e, but

54 resulted in the desilylated and deconjugated ester 102. Presumably, the γ-position of Z47e is more acidic than those of Z47c and Z47d, which precludes the Michael addition.

SiMe SiMe3 3 1. DIBAL-H CO2Me 2. CO 1. LDA/THF 2 R CO2Me R SiMe 3. 10% HCl 2. MeOH 3 H H 4. CH OH / BF •OEt Z47c, R = n-Pr 3. NH Cl/H O R 3 3 4 2 E47c, E47d Z47d, R = Chx 99 LDA - HN(iPr)2 Yields Overall = 50-82%

E/Z = 98:2 SiMe3 SiMe3 R (iPr)2N OMe MeOH H H OMe

(iPr)2N OLi R HO 100 101

Scheme 2.31 (E)-α-Trimethylsilyl-α,β-Unsaturated Esters via LDA Mediated Isomerization of (Z)-α-Trimethylsilyl-α,β-Unsaturated Esters

SiMe CO2Me 3 1. LDA/THF Ph CO2Me + Ph SiMe3 Ph CO2Me 2. MeOH 102 H E47e H 3. NH4Cl/H2O Z47e Yield = 100% 0%

Scheme 2.32 Failed Isomerization of the β-Benzyl Substrate Z47e

In 2005, the Mori research group developed a slightly regioselective and highly diastereoselective Ni-catalyzed carboxylation of silylated alkynes 99 with organozinc reagents to furnish, upon esterification of the resultant acids, β-disubstituted (E)-α-trimethylsilyl-α,β- unsaturated esters 47 (scheme 2.33).56a

55 1.) CO2 (1 atm), Ni(cod)2 (20 mol %) SiMe3 1 CO2Me DBU (10 equiv), R 2Zn (3 equiv) CO2Me α R1 2.) CH2N2 1 SiMe3 + R R β 7 examples SiMe 103 R Yields = 58-85% R 47 3 99 α/β = 3:1->20:1 α-product β-product

Scheme 2.33 (E)-α-Trimethylsilyl-α,β-Unsaturated Esters via Ni-Catalyzed Regioselective Carboxylation of Disubstituted Alkynes

In 2012, the research groups of Sumida and Hosoya reported highly regio- and diastereoselective Pd-catalyzed hydrosilylations of alkynoates 48 to provide (E)-α-silyl-α,β- unsaturated esters E47 in moderate to high yields, high regioselectivity, and high diastereoselectivity (scheme 2.34).56b

5 mol % Pd(dba)2 2 2 CO R2 CO2R 10 mol % PCy3 CO2R 2 10 examples α R1 R1 1.2 equiv HSiR3 + Yields = 42-99% SiR3 β 104 α/β = >99:1 E47 SiR3 1 Toluene E/Z = >99:1 R α-product β-product 48 RT

R1 = Alkyl ; R2 = Me or Et

Scheme 2.34 (E)-α-Silyl-α,β-Unsaturated Esters via Pd-Catalyzed Regio- and Stereoselective Hydrosilylations of Alkynoates

The Ferreira research group reported the Pt-catalyzed hydrosilylations of alkynoates 48 in

2014. This furnished (E)-α-silyl-α,β-unsaturated esters E47 in similar yield and diastereoselectivities to the Pd-catalyzed methodology, but with reduced regioselectivity in certain cases (scheme 2.35).56c

56 CO R2 2 5 mol % PtCl2 2 CO R2 CO2R 2 11 examples α 1.1 equiv HSiR 1 3 R1 R + Yields = 42-99% β SiR3 E47 α/β = 10:1->19:1 R1 DCM 104 SiR3 -product E/Z = >99:1 48 RT α β-product R1 = Alkyl ; R2 = Me or Et

Scheme 2.35 (E)-α-Silyl-α,β-Unsaturated Esters via Pt-Catalyzed Regio- and Stereoselective Hydrosilylations of Alkynoates

2.7 Synthesis of Starting Materials

In an effort to expand the scope of the chemistry developed in our lab, the catalytic carbocupration of alkynoates in the presence of excess silyl triflates was used to produce the required (E)-α-silyl-α,β-unsaturated esters 47 (table 2.1). Alkyl grignard reagent additions at –78

°C produced very thick and viscous solutions that were difficult to stir on larger scales than the ones reported. The reactions were unoptimized, but an increase in catalyst loading, using larger glassware, and increasing the reaction times at

-78 °C and at RT gave low (33% for E47h) to high yields (90% for E47l). The use of TMSOTf and TESOTf allowed for the synthesis of both (E)-α-trimethylsilyl- and (E)-α-triethylsilyl-α,β- unsaturated esters. The benzyl substrate E47f was particularly troublesome because upon warming, any remaining benzyl grignard reagent led to polymerized THF as well as the product.

The TES isopropyl ester E47o was produced in moderate yield, but was inseperable from an unidentifiable side product. Additions involving ethyl butynoate, 47p and E47q, resulted in α,β- unsaturated esters, but did not allow for the migration of the trimethylsilyl group, with one exception E47n. The key NOE enhancements establishing the stereochemistry for the unknown

(E)-α-silyl-α,β-unsaturated esters are shown in figure 2.2.

57 Table 2.1 Synthesis of (E)-α-Silyl-α,β-Unsaturated Esters

SiR3 2 15 mol% CuI•2LiCl 2 CO2R CO R2 O OR 2 3.3 equiv R3SiOTf R3 3 SiR 1.2 equiv R MgX • -78 °C to RT 3 1 R 47 THF R1 - 78 °C R3 R1 E/Z = >20:1 NOE Confirmed 48 49 Products

CO2Et CO2Et CO2Et

Ph SiMe3 SiMe3 SiEt3 E47f E47g E47h Yield = 70% Yield = 58% Yield = 33%

CO2Et CO2Et CO2Et

SiMe3 SiEt3 SiMe3 E47i E47j E47k Yield = 74% Yield = 45% Yield = 86%

CO2Et CO2Et CO2Et

Me3Si SiMe3 Me3Si SiEt3 Me3Si SiMe3 E47l E47m E47n Yield = 90% Yield = 75% Yield = 33%

CO2Et CO2Et CO2Et

SiEt3 SiMe3 SiMe3 E47o inseparable 47p E47q from side product Yield = 0% Yield = 0%

CO2Et CO2Et CO2Et

SiMe3 SiEt3 SiMe3 H H H E47i E47j E47k

CO Et CO2Et CO2Et 2

Me Si SiMe3 Me3Si SiMe3 Me3Si SiEt3 3 H H Me E47l E47m E47n

Figure 2.2 Key NOE Enhancements for Unknown (E)-α-Silyl-α,β-Unsaturated Esters

58 2.8 Lithium Extended Dienolate Protonation Studies

Predicting the regioselectivity for reactions of extended dienolates with electrophiles is not always straight forward. It depends on the nature of the extended dienolate as well as the nature of the electrophile (scheme 2.36). As discussed in chapter 1, with aldol and alkylation processes, lithium extended dienolates 27a will generally give the α-regioselective

R3 O α-E+ R5 α-E+ X 4 2 3 R R E 3 R OLi R OSiR3 33 R5 R5 X X 4 2 4 2 R R R3 O R R 30 27a E X γ-E+ R5 γ-E+ R4 R2 105 + X = R, OR, NR2 ; E = Electrophile

Scheme 2.36 Regioselectivity of Extended Dienolates product 33. Extended silyl enol ethers, silyl ketene acetals, and silyl ketene aminals 30 will generally give the γ-regioselective product 105. As previously mentioned, this has been rationalized with electron density coefficents on the α- and γ-carbons of lithium dienolates and extended silyl ketene acetals.19a However, protonations are a different story. In some cases lithium extended dienolates have provided highly regioselective α-protonations (α/γ = >20:1)57-

61 whereas in others it provides a mixture of α- and γ-protonations with some giving moderately regioselective α-protonations (α/γ = 8:1)62 and others giving poor regioselectivity (α/γ =

~2:1).54b, 63 On the other hand, extended silyl ketene acetals have exhibited highly regioselective

α-protonations.54e, 64-68

The protonation investigations in the conversion of (E)-α-silyl-α,β-unsaturated esters to

(E)-α-silyl-β,γ-unsaturated esters began with the lithium extended dienolate of the β-benzylic

59 substrate E47f (table 2.2). Surprisingly, regioselective protonation was not the only issue to contend with because a significant amount of the deconjugated and desilylated ester 106 was observed with all of the proton sources. Recalling the isomerization process developed by the

Zweifel research group, this is not unprecedented with substrates bearing a β-benzyl substituent.54e This ester could arise from desilylation

Table 2.2 Lithium Extended Dienolate Studies with the β-Benzyl Substrate E47fa

CO Et CO2Et 2 LDA/THF + Ph CO Et Ph SiMe Ph SiMe 2 3 H+ 3 E47f E61.38 106 Ratio Combined Entry H+ Temp (E47f/E61.36/106)b Yieldc 1 5 % HCl -78 °C 1:2:2 85% 2 5 % HCl -40 °C 1:10:7 85% 3 5 % HCl -20 °C 0:2:1 90% 4 TFA (2 equiv) -20 °C 1:4:20 90% 5 AcOH (2 equiv) -20 °C 1:0:10 95% 6 CSA (2 equiv) -20 °C 1:6:20 80% 7 PTSA (2 equiv) -20 °C 0:0:100 90%

8 H2SO4 conc. (2 equiv) -20 °C 1:0:10 80%

9 H3PO4 conc. (2 equiv) -20 °C 0:0:100 60%

10 NH4Cl (sat.) -20 °C 0:0:100 80% (a) Reactions ran with 1 equiv E47f and 1.2 equiv LDA for 2 hrs at -78 °C, quenched at the temperature specified, and then allowed to warm to RT for 30 min. (b) Product ratios were determined by 1H NMR spectroscopy (360 and 500 MHz) of the crude reaction mixture. (c) Isolated yields of the inseperable products. with an anion source, most likely the conjugate base of the acid, following α-protonation of the extended dienolate (scheme 2.37). Ratios are given for the γ-protonation ester E47f, the α- protonation ester E61.38, and the deconjugated/desilylated ester 106. Temperature studies showed that 5% HCl at – 20 °C (entry 3) gave the lowest amount of γ-protonation and the lowest

60 amount of the deconjugated/desilylated ester. All other proton sources gave more of the deconjugated/desilylated ester 106 than the γ- or α-protonation ester, E47f or E61.38.

CO2Et THF/LDA CO2Et

Ph SiMe3 HX Ph SiMe3 E47f E61.38 X

H+ Ph CO2Et Ph CO2Et 106 107

Scheme 2.37 Proposed Origin of Deconjugated/Desilylated Ester 106

2.9 Extended Silyl Ketene Acetal Protonation Studies

Protonations of the lithium extended dienolate gave high α-regioselectivity, but led to significant desilylation of the deconjugated ester and attempts to purify the crude mixtures via column chromatography led to complete desilylation. Investigations were continued with protonation of the silyl ketene acetal in an effort to achieve high α-regioselectivity while avoiding desilylation (table 2.3). Temperature studies indicated that colder temperatures allowed for higher α-regioselecivity and lower amounts of desilylation with 5% HCl (entries 1 and 4) but higher γ-regioselectivity with TFA (entries 3 and 5). Reverse quenches with 5% HCl resulted in higher γ-regioselectivity (entry 6). Protonating with stoichiometric amounts of acid (5% HCl) and reducing the duration of the protonation had little effect on selectivity, but slightly improved the yield (entries 4 and 8). 1.4M HBr was used as an equimolar solution to 5% HCl (w/v) and gave the highest α-regioselectivity as well as the lowest amount of desilylation in THF (entry 9).

Solvent studies revealed higher γ-regioselectivity with other ethereal solvents, such as Et2O and

MTBE (entries 10 and 11), and that hydrocarbon solvents, such as toluene or pentane showed the

61 highest α-regioselectivity and the lowest amount of desilylation (entries 12 and 13). Base studies reflected that LDA gave the highest α-regioselectivity,

Table 2.3 Extended Silyl Ketene Acetal Protonation Studies with the β-Benzyl Substrate E47fa CO Et CO2Et 1.) Base/Solvent 2 2.) TMSCl + Ph SiMe Ph CO2Et Ph SiMe3 + 3 E47f 3.) H E61.38 106

Ratiob Combined Entry Base Solvent H+ Temp (E47f/E61.38/106) Yieldc 1 LDA THF 5% HCl -20 °C 1:3:4 80%

2 LDA THF NH4Cl (sat.) -20 °C 1:2:20 60% 3 LDA THF TFA (2 equiv) -20 °C 0:2:1 90% 4 LDA THF 5% HCl -78 °C 1:10:2 85% 5 LDA THF TFA (2 equiv) -78 °C 2:3:1 80% 6 LDA THF 5% HCl reverse -78 °C 2:5:1 90% 7 LDA THF 5% HCl 2 min -78 °C 1:10:2 88% 8 LDA THF 2 equiv 5 % HCl 2 min -78 °C 1:10:2 90% 9 LDA THF 2 equiv HBr (1.4M) 2 min -78 °C 1:10:1 86%

10 LDA Et2O 2 equiv HBr (1.4M) 2 min -78 °C 1:20:4 62% 11 LDA MTBE 2 equiv HBr (1.4M) 2 min -78 °C 3:10:1 90% 12 LDA Toluene 2 equiv HBr (1.4M) 2 min -78 °C 1:20:2 92% 13 LDA Pentane 2 equiv HBr (1.4M) 2 min -78 °C 1:20:2 95% 14 LICA Toluene 2 equiv HBr (1.4M) 2 min -78 °C 0:7:1 90%

15 LHMDS Toluene 2 equiv HBr (1.4M) 2 min -78 °C 3:1:0 90%

16d LDA Toluene 2 equiv HBr (1.4M) 2 min -78 °C 1:4:4 92% (a) Reactions ran with 1 equiv E47f and 1.2 equiv LDA for 2 hrs at -78 °C, 1.2 equiv TMSCl at -78 °C, quenched at the temperature specified, stirred for 30 minutes, and then allowed to warm to RT for 30 min unless specified. (b) Product ratios were determined by 1H NMR spectroscopy (360 and 500 MHz) of the crude reaction mixture. (c) Isolated yields of the inseperable products. (d) No TMSCl present.

LICA gave slightly more of the deconjugated/desilylated product, and LHMDS was insufficient to deprotonate the starting material at – 78 °C (entries 14 and 15). After discovering the optimal acidic species, equivalence, protonation duration, and solvent, the optimal conditions were

62 applied to the lithium extended dienolate, but this resulted in similar amounts of desilylation

(entry 16).

Interestingly, application of the optimized conditions to the β-methyl substrate E47g did not result in the same level of α-regioselectivity in pentane or THF (entries 1 and 2, table 2.4).

Ratios are given for the γ-protonation ester E47g, and the α-protonation ester E61.38. None of the deconjugated/desilylated ester 108 was detected in any of the trials. The poor α- regioselectivities were much lower than those reported by Zweifel et. al for the protonation of silyl ketene acetals derived from (Z)-α-silyl-α,β-unsaturated esters (scheme 2.20).54e Their γ- deprotonation-α-protonation sequence with LDA required the use of HMPA as a cosolvent and prior to protonation with 5% HCl, a sat. NH4Cl, pentane, and ice wash and extraction step was performed to remove this cosolvent. To determine if this wash and extraction step before protonation not only removed HMPA, but allowed for higher α-regioselectivity, two trials were performed with 5% HCl. Pentane gave the same α-regioselectivity as the previous attempts, whereas THF provided very high α-regioselectivity (entries 3 and 4). To ensure that the higher

α-regioselectivity was not due to a different proton source, temperature, and reaction time, a direct 5% HCl quench at 0 °C was examined, but it provided poor α-regioselectivity (entry 5).

63 Table 2.4 Extended Silyl Ketene Acetal Protonation Studies with the β-Methyl Substrate E47ga

CO2Et LDA/Solvent CO2Et TMSCl + CO2Et SiMe SiMe 3 H+ 3 E47g E61.38 108

Ratiob Combined Entry Solvent H+ Temp (E47g/E61.38/108) Yieldc 1 Pentane 2 equiv HBr (1.4M) 2 min -78 °C 1:2:0 80% 2 THF 2 equiv HBr (1.4M) 2 min -78 °C 1:2:0 81%

NH4Cl, Pentane, Ice 3 Pentane Wash and Extraction 0 °C 1:2:0 99% then 5% HCl 15 min

NH4Cl, Pentane, Ice 4 THF Wash and Extraction 0 °C 1:15:0 80% then 5% HCl 15 min 5 THF Direct 5% HCl 15 min 0 °C 1:2 :0 99%

(a) Reactions ran with 1 equiv E47g and 1.1 equiv LDA for 2 hrs at -78 °C, then 1.2 equiv TMSCl at -78 °C, stirred for 30 minutes, and quenched under the conditions specified. (b) Regioisomeric ratios were determined by 1H NMR spectroscopy (360 and 500 MHz) of the crude reaction mixture. (c) Isolated yields of the inseperable regioisomeric isomers.

Table 2.5 delineates the scope of the methodology, which allowed for very high diastereoselectivity, α-regioselectivity, and yield. The yields given are for the crude product, but did not require purification. The sat. NH4Cl, pentane, and ice wash and extraction step prior to protonation proved to be essential to ensure high α-regioselectivity. Utilizing this step with the

β-benzyl substrate E47f furnished its regioisomer E61.38 with improved α-regioselectivity and no detectable amount of the deconjugated/desilylated ester 106. Slight changes to the procedure allowed for the incorporation of some sterically demanding subtrates. The β-isopropyl substrate

61.1 required higher temperatures (-40 °C) for the γ-deprotonation and both β- trimethylsilylmethylene subtrates E61.42 and E61.43 required longer protonation times (1 hr).

Despite several attempts, efforts to manufacture the β-methyl-β-trimethylsilylmethylene subtrate

E61.44 resulted in complex mixtures. The

64 Table 2.5 Synthesis of (E)-α-Silyl-β,γ-Unsaturated Estersa,b,c

2 LDA/THF R CO2Et 2 R CO2Et TMSCl 3 R SiR3 3 R SiR3 NH4Cl, Pentane, Ice R1 61 1 R Wash and Extraction E/Z = >20:1 47 5% HCl, 0 °C NOE Confirmed

Products

Ph CO2Et CO2Et CO2Et

SiMe3 SiMe3 SiEt3 E61.38 E61.39 E61.40 α/γ = 14:1 α/γ = 15:1 α/γ = >20:1 Yield = 99% Yield = 90% Yield = 99%

CO2Et CO2Et CO2Et

SiMe3 SiEt3 SiMe3 E61.11 E61.41 61.1 α/γ = >20:1 α/γ = >20:1 α/γ = >20:1 Yield = 80% Yield = 99% Yield = 90%

Me3Si CO2Et Me3Si CO2Et Me3Si CO2Et

SiMe3 SiEt3 SiMe3 E61.42 E61.43 E61.44 α/γ = >20:1 α/γ = >20:1 α/γ = NA Yield = 98% Yield = 98% Yield = 0% (a) Reactions ran with 1 equiv 47 and 1.1 equiv LDA for 2 hrs at -78 °C or -40 °C, then 1.2 equiv TMSCl at -78 °C, stirred for 30 minutes, poured into a sat. NH4Cl, pentane, and ice mixture and extracted in a seperatory funnel. The organic extracts were then submitted to 5% HCl at 0 °C. (b) Regioisomeric and diastereomeric ratios were determined by 1H NMR spectroscopy (360 and 500 MHz) of the crude reaction mixture. (c) Isolated yields of the crude products that did not require further purification. stereochemistry of the β,γ-olefins were assigned based on previous syntheses of the known compounds, and for the unknown (E)-α-silyl-β,γ-unsaturated esters, trans vinylic coupling constants and NOE interactions were used to assign the stereochemistry (figure 2.3).

65 H H H H H H

CO2Et CO2Et CO Et Me3Si Me3Si 2 SiMe3 SiEt3 SiEt3 H H H E61.42 E61.43 E61.41

Figure 2.3 Key NOE Enhancements for Unknown (E)-α-Silyl-β,γ-Unsaturated Esters

2.10 Isolation of Intermediate Silyl Ketene Acetals

Zweifel et. al. were able to isolate silyl ketene acetals derived from the deprotonation of

(E)-α-trimethylsilyl-α,β-unsaturated esters E47c and E47d in the absence of HMPA with a nonaqueous workup.54e Only one stereoisomer was detected and it was suggested to be 1E,3E.

An eight membered transition state like TS13 (scheme 1.13) was used to explain the origin of the stereochemistry, but at the time the 1,2-olefin geometry was assigned tentatively based on a previously reported study of an extended silyl ketene acetal 30b derived from the (E)-α,β- unsaturated ester E109 (scheme 2.39)45. As discussed in chapter 1, several extended silyl ketene acetals derived from deprotonations of (Z)-α,β-unsaturated carbonyls have been isolated and illustrate the general preference for a cis relationship between the vinyl substituent group and the silyloxy group. However, the stereochemistry of extended silyl ketene acetals derived from deprotonations of (E)-α-trimethylsilyl-α,β-unsaturated esters was not confirmed.

CO2Me OSiMe3 LDA/THF R R SiMe3 OMe H TMSCl SiMe3 E47c, R = n-Pr 1E,3E-60a, R = n-Pr E47d, R = Chx 1E,3E-60b, R = Chx

Scheme 2.38 Previously Isolated α-Silyl Extended Silyl Ketene Acetals

66 LDA/THF OSiMe3 HMPA CO2Et OEt TMSCl 30b E109 Z/E = 9:1

Scheme 2.39 Extended Silyl Ketene Acetals with Confirmed Stereochemistry

The poor α-regioselectivities with direct quenches and the very high α-regioselectivites when a wash and extraction step was implemented prior to protonation provided evidence that the intermediate silyl ketene acetal was not being hydrolyzed, or at least only partially hydrolyzed, during the wash and extraction step. This conclusion led to the successful isolation of several extended silyl ketene acetals 60c-60h in high yield by omitting treatment with 5% HCl

(table 2.6). The 1,2- and 3,4-olefin stereochemistry was assigned by NOE and confirmed the intermediates to be (1E,3E)-α-silyl-β,γ-unsaturated silyl ketene acetals (figure 2.4). This is in agreement with the stereochemistry proposed by Zweifel, provides additional support for an eight-membered transition state in the deprotonation of (Z)-α,β-unsaturated carbonyl compounds, and illustrates the geometry of the lithium extended dienolate. This (1E, 3E)-α-silyl- extended dienolate will be used for a tandem aldol-olefination process discussed in chapter 4.

67 Table 2.6 Synthesis of (1E, 3E)-α-Silyl-Conjugated Silyl Ketene Acetals

LDA/THF OSIMe3 2 TMSCl R3 R CO2Et OEt 3 1 R2 SiR1 R SiR 3 3 NH4Cl, Pentane, Ice 60 47 Wash and Extraction NOE Confirmed 1E,3E = >20:1

Products

OSIMe3 OSIMe3 OSIMe3 OEt OEt OEt

SiMe3 SiEt3 SiMe3 60c 60d 60e Yield = 93% Yield = 91% Yield = 99%

OSIMe3 OSIMe3 OSIMe3 Me Si OEt OEt 3 OEt

SiEt3 SiMe3 SiMe3 60f 60g 60h Yield = 85% Yield = 89% Yield = 91%

(a) Reactions ran with 1 equiv 47 and 1.1 equiv LDA for 2 hrs at -78 °C or -40 °C, then 1.2 equiv TMSCl at -78 °C, stirred for 30 minutes, poured into a sat. NH4Cl, pentane, and ice mixture and extracted in a seperatory funnel. The organic extracts were then concentrated. (b) Diastereomeric ratios were determined by 1H NMR spectroscopy (360 and 500 MHz) of the crude reaction mixture. (c) Isolated yields of the crude products that did not require further purification.

68 H H H H H H O O O Me3Si SiMe3 Et Si SiMe Me3Si SiMe3 O 3 O 3 O H H H H H H H H 60c 60d 60e

H H H H H H O O O Et Si SiMe Me Si SiMe Me3Si SiMe3 3 O 3 3 O 3 O H H H H H SiMe3 60f 60g 60h

Figure 2.4 Key NOE Enhancements for (1E, 3E)-α-Silyl-Conjugated Silyl Ketene Acetals

During one the syntheses of 60c, the silyl ketene acetal was left in solution in an NMR tube at room temperature and analyzed by 1H NMR every few days until complete hydrolysis from the small amount of HCl present in CDCl3 was observed (scheme 2.40). The spectra for day

1, 5, 12, 15, and 21 along with the relative ratios of the γ-protonated product E47g, the silyl ketene acetal 60c, and the α-protonated product E61.38 are shown. The spectrum for day 21 will appear slightly different because it was recorded with a different spectrometer. Under these dilute acidic conditions, the hydrolysis of the silyl ketene acetal exhibited higher α- regioselectivity (α/γ = ~5:1) at RT than a direct quench without the wash and extraction step at -

78 °C or at 0 °C (α/γ = 2:1), but lower than protonation in the organic extracts following the wash and extraction step.

69 OSiMe3 CO Et CO Et 2 γ-protonation -protonation 2 OEt α SiMe3 SiMe3 SiMe3 E47g 60c E61.38 60c E47g E61.38

Day 1

Day 5

Day 12

Day 15

Day 21

Scheme 2.40 Hydrolysis NMR Study of the Silyl Ketene Acetal 60c in CDCl3

2.11 Discussion

The natural charges of the silyl ketene acetals 60c, 60g, and 60i have been calculated by

Dr. Blackstock using AM1, and in all cases the α-positions are more electron rich than the γ- positions (figure 2.5). The regioselectivity of the

Natural Charges

OSiMe3 OSiMe3 OSiMe3 Ph OEt OEt OEt

SiMe3 SiMe3 SiMe3 60c 60g 60i γ : -0.253 α : -0.571 γ : -0.126 α : -0.570 γ : -0.172 α : -0.576

Figure 2.5 Natural Charges for α-Silyl Conjugated Silyl Ketene Acetals 60c, 60g, and 60i

70 protonation appears to be influenced by steric effects, electronic effects, and concentration, particularly of the acidic species. While there is significant support for protonations of extended silyl ketene acetals exhibiting high α-regioselectivity, it is important to note the sterically demanding α-position present in these extended silyl ketene acetals. This feature, along with the importance of dilution, is demonstrated with protonations of the γ-phenyl silyl ketene acetal 60i involving TFA and 5% HCl. TFA protonations in THF are homogenous solutions over a range of temperatures. At -78 °C, protonations with TFA have higher γ-regioselectivity than at -20 °C

(entries 3 and 5, table 2.3). At -78 °C, access to the α-position becomes slightly suppressed, and under concentrated conditions this tips the scale for higher amounts of γ-protonations than at - 20

°C. Additions of 5% HCl into THF at subzero temperatures leads to heterogenous solutions with some of the water freezing out. This dilutes the acidic species and allows for more control over regioselectivity because it slows down the rate of protonation and permits the electronic features to overcome the steric features of the α-silyl extended silyl ketene acetal. This is demonstrated with protonations using 5% HCl providing higher α-regioselectivity at -78 °C than at -20 °C or with a reverse quench at 0 °C (entries 1,4, and 6, table 2.3). The use of hydrocarbon solvents, such as toluene or pentane, suppress the SN2 like decomposition pathway leading to the deconjugated/desilylated ester 106 (scheme 2.37), and provides higher α-regioselectivities via dilution of the acidic species during the creation of a biphasic solution with 1.4M HBr additions

(entries 12 and 13, table 2.3).

For protonations of the β-methylene silyl ketene acetal 60c it is important to note the electronic differences with the γ-phenyl silyl ketene acetal 60i. The disparity of natural charges between the α- and γ-positions of the β-methylene silyl ketene acetal 60c is not as large as the disparity in the γ-phenyl silyl ketene acetal 60i. This illustrates that the γ-position in the β-

71 methylene silyl ketene acetal 60c is more electron rich and can explain why its protonation is less

α-regioselective with direct quenches compared with the γ-phenyl silyl ketene acetal 60i.

The wash and extraction step is essential to exert kinetic control over the protonation, because it acts as a method of purification and significant dilution. The components of the wash, sat. NH4Cl, pentane, and ice, creates a biphasic solution. At the conclusion of the reaction prior to protonation, the crude reaction mixture contains: THF, the silyl ketene acetal, lithium chloride, and diisopropyl amine. Once the crude reaction mixture is poured into the wash, the silyl ketene acetal, which is quite nonpolar, will be pulled into the pentane layer. THF is completely miscible in water and pentane, but pentane is immiscible in water. The THF will be partitioned into water and pentane, but will most likely favor water. Likewise, the lithium chloride and diisopropyl amine will be pulled into the water layer as well. The removal of diisopropyl amine clarifies the active acidic species as well, because its presence creates a question as to whether diisopropyl ammonium or the examined acid is the proton donor. When transferred to a separatory funnel, pentane is used for the extraction, which means the organic extracts will be a dilute solution of the silyl ketene acetal in pentane with a very small amount of THF. Upon addition of a 5% HCl solution in water, the small amounts of THF will act as a phase transfer catalyst, shuttling protons into the pentane layer allowing the protonation to be done under incredibly dilute conditions.

As can be seen with protonations of the β-methylene silyl ketene acetal 60c in pentane, simply a biphasic solution is not enough for high levels of α-regioselectivity. Additionally, during one of the syntheses of E61.42, it was found that a 15 minute protonation time at 0 °C was insufficient for complete hydrolysis. 1H NMR showed a 3:1 mixture of the silyl ketene acetal 60g and the (E)-α-silyl-β,γ-unsaturated ester E61.42. The CDCl3 solution was added to a

72 mixture of pentane and THF and stirred with 5% HCl at 0 °C. The amount of pentane was equivalent to the amount used in the wash step and the amount of THF was equal to the amount used during the deprotonation sequence. This afforded an 85% yield and very high α- regioselectivity (α/γ = >20:1). While α-protonations give the kinetic product and γ-protonations give the thermodynamic product, the α-positions sterically hindered and are less accessible at sub zero temperatures. It is believed that protonations at elevated temperatures allow for the sterics at the α-position to be overcome and at the same time, the biphasic dilute protonation conditions permits greater kinetic control by slowing down the rate of protonation.

2.12 Future Works

Future work in this area could include an enantioselective protonation of the extended silyl ketene acetals. Applicable methodologies would have to take into account the labile nature of the α-silyl group and regioselective issues. Current technology in this area is generally limited to cyclic silyl enol ethers with a few linear examples, but there appears to be no examples of extended sily enol ethers or extended silyl ketene acetals.69 Toste et. al. have used the cationic

Au(I) complex C3 as a Lewis-acid-assisted Bronsted

(R)-BINAP(AuCl) 2 O (3 mol %) R3 OSiMe3 AgBF4 (3 mol %) R1 PPh AuCl H 2 R3 C3 2 R1 110 R PPh2Au 14 examples R2 DCM, EtOH BF4 RT Yields = 82-98% C3 109 ee = 17-95%

Scheme 2.41 Enantioselective Protonations with a Cationic Au(I) Complex

73 O R2 C4 (10 mol %) 1 OSiMe3 R R2 PhCOF (1.1 equiv) H 1 EtOH (1.1equiv) X R 112 X DMF 10 examples 111 RT Yields = 70-98% ee = 30-92%

X = CH2, (CH2)2, (CH2)3, OCH2

Et Et N N O O H H H H MeO O O OMe

N N (DHQ)AQN C4

O R2 OSiMe R1 R2 3 C4 (10 mol %) Citric Acid (1.1 equiv) H 1 X R 112 X DMF -10 °C 12 examples 111 Yields = 91-98% ee = 27-75%

X = CH2, (CH2)2, OCH2

Scheme 2.42 Enantioselective Organocatalytic Protonation with Chiral Ammonium Salts

Acid (LBA) catalyst and EtOH as a proton donor to effect high levels of enantioselectivity with

α-disubstituted linear silyl enol ethers 109 with the requirement that at least one of the α- substituents be an aryl group(scheme 2.41).70 LBAs arise from complexes of a Lewis acid and a

Bronsted acid, which enhances the acidity of the Bronsted acid.69 Levacher et. al. have developed an organocatalytic version utilizing an in situ generation of a chiral ammonium salt in association with an anionic Lewis base such as acetate, phenolate, or fluoride and allows for high enantioselectivities with cyclic silyl enol ethers 111 (scheme 2.42).71,72 The chiral ammonium salt was derived from a chiral tertiary amine, such as hydroquinine anthraquinone-1,4-diyl

74 diether (DHQ)AQN C4 with a latent source of HF arise from the reaction of PhCF and EtOH or a stoichiometric amount of a proton donor like citric acid.

2.13 Conclusion

This chapter has presented an expansion of scope for the catalytic carbocupration of alkynoates in the presence of excess silyl triflates developed in the Jennings lab to include several β-alkyl substituted (E)-α-silyl-α,β-unsaturated esters. These substrates were converted to their β,γ-unsaturated regioisomers via a γ-deprotonation-α-protonation sequence. Dilute protonations of the intermediate silyl ketene acetals in a biphasic solution were required to illicit high levels of regioselectivity. The extended silyl ketene acetal intermediates were isolated and their stereochemistry was confirmed by NOE to be 1E,3E. This gives insight into the lithium extended dienolate structure resulting from these deprotonations and provides additional support for an eight-membered transition state in the deprotonation of (Z)-α,β-unsaturated carbonyls with metallo dialkylamides.

75 CHAPTER 3: A TANDEM COPPER-CATALYZED CONJUGATE ADDITION- DIASTEREOSELECTIVE PROTONATION PROCESS WITH (E)-α-TRIALKYLSILYL-α,β- UNSATURATED ESTERS

3.1 Introduction

This chapter will present a tandem process involving a Cu(I)-catalyzed conjugate addition with Grignard reagents followed by a diastereoselective protonation using (E)-α- trialkylsilyl-α,β-unsaturated esters. Nucleophilic organocopper(I) reagents, both stoichiometric and catalytic, will be discussed in terms of their current mechanistic understanding, as well as the effects of silylating agents and LiCl salts. The record of α-trialkylsilyl-α,β-unsaturated esters operating as Michael acceptors will also be presented.

3.2 Motivation

Asymmetric synthetic methodologies are among the most important transformations due to the ability to manufacture enantiopure materials.73 Enantioselective control with asymmetric allylations via chiral allylsilanes is very well understood (scheme 3.1).52 In particular, the Lewis acid mediated reactions of allylsilanes with aldehydes are believed to go through an acyclic antiperiplanar transition state TS22, and the reacting aldehyde approaches from the opposite face of the silyl group. The stereochemistry of the α-carbon in the allylsilane 113, as well as any other chiral centers, such as the βʹ-carbon, will be encoded in the homoallylic alcohol product 114, which could be a useful synthon for natural product synthesis.

76 O SiR OH R1 3 R3 β' R2 H R3 α R2 β Lewis Acid R1 113 114

H SiR O H 3 R2 LA H 1 R3 R TS22

Scheme 3.1 Asymmetric Allylations via Chiral Allyl Silanes

We envisioned (E)-α-trialkylsilyl-α,β-unsaturated esters E47 as a source for chiral allylsilanes 113 following a tandem enantioselective Cu(I)-catalyzed conjugate addition with

Grignard reagents and a diastereoselective protonation process (scheme 3.2). There are very few cases of α-trialkylsilyl-α,β-unsaturated esters, particularly β-substituted ones, acting as Michael acceptors. The first step of this long term goal was to establish α-trialkylsilyl-α,β-unsaturated esters as suitable substrates for the racemic Cu(I)-catalyzed process and to optimize the diastereoselective protonation.

1 CuI•2LiCl 1 Diastereoselective 1 R R OSiMe3 R Chiral Ligand Protonation CO Et ∗ ∗ CO Et 2 R2 OEt R2 2 Me3SiCl or Me3SiOTf ∗ 2 SiR3 R MgX SiR3 SiR3 E47 115 116

R1 ∗ 1. DIBAL R2 ∗ 2. CH2=PPh3 SiR3 113

Scheme 3.2 Chiral Allyl Silanes via a Tandem Copper-Catalyzed Conjugate Addition – Diastereoselective Protonation Process

3.3 Gilman and Kharasch Reagents: Nucleophilic Organocopper(I) Reagents

Conjugate addition via organocopper reagents with α,β-unsaturated carbonyls is one of the most important and heavily utilized methods for the C-C bond formation in organic

77 synthesis.74 Nucleophilic organocopper chemistry began in 1941 with the report by Kharasch and

Tawney of a Cu(I)-catalyzed conjugate addition of an α,β-unsaturated ketone with a Grignard reagent (scheme 3.3).75 In 1952, Gilman reported a precipitate when CuI was treated with one equivalent of MeLi, but upon an additional equivalent of MeLi a colorless solution formed.76 In

1966, House et. al demonstrated that this Gilman reagent, Me2CuLi, undergoes a conjugate addition with an enone, suggesting that the disubstituted cuprate is the active species with the

Kharasch conjugate addition as well.77

Since that time, nucleophilic organocopper(I) reagents have been extensively studied and developed. A main feature of this transformation includes generating up to two new stereogenic centers if the α,β-unsaturated carbonyl 117 is appropriately substituted and the intermediate metal enolate is treated with an electrophile. Due to the fact that the Gilman variation is stoichiometric, it can provide more control over regioselectivity, 1,2 vs. 1,4 addition, and it is more suited for sluggish substrates. However, the Kharasch variation has been shown to be quite versatile and is more attractive for an asymmetric version because it is catalytic.

Kharasch Gilman R O R2CuMgBr O R2CuLi•LiX R O Catalytic Stoichiometric 1 ∗ 1 R ∗ Y R Y R1 ∗ Y + + ∗ R2 E E R2 E R2 E 118 117 118 Y = R, OR ; X = Anion ; E+ = Electrophile

Scheme 3.3 Gilman and Kharasch Reagents

Gilman and Kharasch reagents both operate on a Cu(I)/Cu(III) redox relay that has three steps in common: transmetalation between a Cu(I) salt and an organolithium or Grignard reagent to produce a mono- or diorganocuprate species, nucleophilic attack of an electrophile with the d- orbital of the copper atom to give a organocopper(III) intermediate, which decomposes (by

78 undergoing reductive elimination) to furnish the end product and a neutral Cu(I) species (scheme

3.4).

R-M I R-M I CuIX [RCu (X)] M [R2Cu ] M

E+ E+

III III RCu (X)E R2Cu E

CuIX RCuI R-E R-E M = Li, MgX ; X = Halide

Scheme 3.4 General Mechanisms for Gilman and Kharasch Reagent Additions

Current literature suggests that oxidative additions of nucleophilic organocopper(I) reagents with unsaturated systems can occur through two different mechanistic manifolds

(scheme 3.5).74a After π-complexation of the organocopper species with the α,β-unsaturated carbonyl 119, a β-cuprio(III) enolate 120 can form through conjugate addition of the cuprate species, or a cuprio(III) cyclopropane intermediate 121 can form through carbocupration of the olefin. Following reductive elimination from either intermediate and treatment with an electrophile, both manifolds would provide the same saturated carbonyl 118.

79 R III R MX Conjugate Cu O Addition R1 Y 120 R2 R R I Cu MX β-Cuprio(III) O R O Enolate Reductive Elimination 1 1 ∗ R Y + R ∗ Y MX E 2 R2 119 O R E π-Complex 118 R1 Y Cu 2 R III R R 121 Carbocupration Cuprio(III) Cyclopropane Intermediate

Y = R, OR ; M = Metal ; X = Anion ; E+ = Electrophile

Scheme 3.5 Types of Nucleophilic Organocopper(I) Additions with α,β-Unsaturated Carbonyls

3.4 Carbocupration Chemistry

The carbocupration manifold is normally not invoked to explain additions with α,β- unsaturated carbonyl compounds, such as enone and enoates. It has more support with acetylenic carbonyl compounds, and because of this the mechanistic details of carbocupration will be discussed in the context of alkynoates and alkynones. After π-complexation of the organocuprate species 123 with the reactive partner 122, a cuprio(III)cyclopropene intermediate 124 forms, which undergoes reductive elimination through transition state TS23 to furnish an alkenyl cuprate(I) species 126. The α-alkenyl cuprate(I) species 126 can isomerize to a lithium allenolate

127. The rate of this isomerization depends on the identity of the reactive partner. With cooler temperatures the energy barrier is too high for esters and the stereochemistry is retained if it reacts with an electrophile. However, warmer temperatures will overcome the energy barrier, which will result in an erosion of stereoselectivity when reacted with an electrophile. The

80 isomerization energy barrier for ketones is much lower; therefore reactions with electrophiles at cold or warm temperatures provide reduced stereoselectivities.

X X R CuI R R I R R III R Cu Cu O Li X Li Li 123 Y H O H O Y Y 122 124 125 π-Complex Cuprio(III) Cyclopropene Intermediate

R X X R R slow (Y = OR) III I Li I X Reductive R Cu Cu fast (Y = R) R Cu Elimination Li O R Li • H O H O H Y Y Y 127 126 TS23 Lithium Allenolate Alkenyl Cuprate(I)

High Low E+ E+ Temp. Temp.

O O

R Y R Y H H E/Z-128 E-128 Y = R, OR ; X = Li-Cl, Li-RCuR ; E+ = Electrophile

Scheme 3.6 Carbocupration Mechanism with Acetylenic Carbonyls

3.5 Organocuprate Conjugate Addition Chemistry The conjugate addition manifold has more support with α,β-unsaturated carbonyls. While equilibrium processes with the cuprate cluster 123 are at play, such as aggregation/disaggregation, structural reorganization, and complexation/decomplexation, the most important steps involve oxidative addition following π-complexation 129 of the cuprate species 123 and the α,β-unsaturated carbonyl 117 to provide a β-cuprio(III) enolate 130 that undergoes reductive elimination through transition state TS24 to furnish a lithium enolate 131.

81 This enolate can further react with an electrophile providing the saturated carbonyl 118. Kinetic isotope effect experiments using the natural abundance of 13C in dibutylcuprate and 2- cyclohexenone 132 (scheme 3.8) exhibit the greatest KIEs with the β-carbon (C3) of 2- cyclohexenone and the α-carbon of the dibutylcuprate providing evidence that reductive elimination is rate determining.78 NMR studies of the intermediate complexes feature loosening of the C=C bond in the π-complex, as well as lithium coordination of the carbonyl oxygen.

Complexation of the copper and lithium is apparent, but aggregation structures of the organocuprate and reactive partner remain elusive except in a few cases, such as an experiment with rapid injection NMR leading to the proposal of two types of cuprate-enone π-complexes

135 and 136 (scheme 3.9).79

R O R R I I R R I Li Cu R Cu Cu I R1 Y Y Li S R Sn Li n Cu Li•Sn 2 O R 117 H Li R CuI R R 123 R1 R2 129 π-Complex Oxidative Addition R R R Li I R R Li CuI III Cu III Cu Cu Y Y R R R O H O Li Li H 2 1 R2 R1 R R 130 TS24 β-Cuprio(III) Enolate R Li I Reductive R Cu R O I + Elimination Cu Y R E R O R1 ∗ Y Li ∗ H R2 E R1 R2 131 118 S = Solvent ; Y = R, OR ; E+ = Electrophile

Scheme 3.7 Conjugate Addition Mechanism

82 O O C1: 0.999-1.004 1 1. Bu CuLi, THF, - 78°C 2 2 2 C : 1.005-1.006 3 3 2. aq. NH4Cl C : 1.020-1.026 Ca: 1.011-1.016 132 133 α

Scheme 3.8 13C KIEs for the Conjugate Addition of Dibutylcuprate to 2-Cyclohexenone

Li X O Li O O Li I Me Cu Me Me Me 132 Cu I + Cu I Li Li X - 100 °C Me Me 134a, X = I 135 136a, X = I 134b, X = CN 133b, X = CN

Scheme 3.9 π-Complexes Proposed on the Basis of Rapid-Injection NMR studies

Catalytic cycles for organocopper conjugate additions with Kharasch reagents depend on the presence or absence of ligands. In the absence of ligands, the mechanism mirrors that of the stoichiometric variant; π-complexation 137 of the α,β-unsaturated carbonyl 117 with a diorganocuprate species, followed by oxidative addition 138, which terminates with reductive elimination furnishing the magnesium enolate 139. The active catalyst is regenerated by treatment of the resultant neutral monoorganocuprate(I) species with an additional equivalent of a Grignard reagent.

83 O I R2Cu MgX RMgX R1 Y R2 117 π-Complexation RCuI

R Reductive R I Cu MgX Elimination O

R1 Y 2 R III R R 137 MgX Cu MgX R O O Oxidative 1 R1 Y R Y Addition 139 R2 R2 138 Y = R, OR ; X = Halide

Scheme 3.10 Catalytic Cycle for Conjugate Addition in the Absence of Ligands

Spectroscopic, structural, and kinetic experiments with the enantioselective copper- catalyzed conjugate addition with Grignard reagents utilizing chiral ferrocenyl-diphosphine ligands, L4 and L5, suggest a catalytic cycle with slight modifications.74f The active catalyst is thought to be a ligated Cu(I)/Mg(II) bimetallic complex 141, generated from a dinuclear complex

140 which follows the normal trend of π-complexation 142, oxidative addition 143, and reductive elimination. However, in this case it was shown that higher equivalents of the Grignard reagent actually promotes the reductive elimination and regenerates the catalyst.

84 P* Br P* CuI CuI PCy2 P* Br P* Ph2P Fe PPh2 140 Cy2P Fe L4 L5 RMgBr O * R Y P R CuI MgBr R1 Y 1 MgBr * Br R ∗ O P R2 117 141 R2 139 π-Complexation

RMgX P* = L4 or L5 P* Reductive Elimination P* P* P* P* III Br I Br R Cu R Cu Y MgBr Y MgBr R1 O R1 O 143 R2 R2 142

Oxidative Addition

Y = R, OR

Scheme 3.11 Catalytic Cycle for Conjugate Addition with Chiral Bidentate Phosphine Ligands

3.6 Silylating Agents and Lithium Halide Salt Additives

Silylating agents, such as chlorotrimethylsilane (Me3SiCl) and the less commonly used trimethylsilyltrifluoromethanesulfonate (Me3SiOTf) have become standard reagents for acceleration of conjugate additions. Independently discovered by Nakamura/Kuwajima80,

Corey81, and Alexakis82 in the 1980s, the mechanistic details for the acceleration effect remains in debate. Recent experiments with RI-NMR at – 100 °C allowed for the spectroscopic observation at of an intermediate in the silylative conjugate addition reaction by two different methods.83 Method A involved 2-cyclohexenone 132 reacting with the Gilman cuprate

Me2CuIŸLiI which formed the previously known π-complexes 135 and 136a. Following

85 treatment with cyanotrimethylsilane (Me3SiCN), the π-complexes were converted to a square- planar trialkylcyanocuprate(III) species 143 with silylation of the carbonyl oxygen. Warming the silyl enol ether Cu(III) complex to – 80 °C facilitated reductive elimination to furnish the conjugate addition product 144. Method B utilized the Gilman cuprate Me2CuLiŸLiCN in the presence of Me3SiCl lead to the same square-planar trialkylcyanocuprate(III) intermediate when treated with 2-cyclohexenone.

Method A Method B

Me2CuLi•LiI Me2CuLi•LiCN + Me3SiCl O - 100 °C - 100 °C 132 Li I Me2CuLi•LiCl + Me3SiCN Li O O Li Me Me O Cu I + Cu I Me Me 132 135 136a

OSiMe3 Li Me3SiCN OSiMe3

CN - 80 °C Cu Me Me Me 143 144

Scheme 3.12 Detection of a Silylated β-Cuprio(III)-Enolate Adduct

Kinetic isotope effect studies using the natural abundance of 17O and 13C with 2-

17 13 cyclohexenone and the dibutylcuprate Bu2CuLiŸLiBrŸSMe2 exhibited a higher O KIE than C

84 13 KIEs. The C KIEs were lower than those observed in the absence of Me3SiCl (scheme 3.8),

α particularly C3 and C , suggesting that the silylation of the π-complex is the rate determining step, as opposed to the reductive elimination. This is also supported by mechanistic studies involving Me3SiI and Me3SiCl showing that the magnitude of rate acceleration is proportional to the strength of the silylating agent.85

86 O O SiMe3 O : 1.018-1.019 Bu CuLi LiBr SMe 1 2 • • 2 C1: 1.003-1.007 2 Me SiCl 3 C2: 1.001-1.007 3 THF, -85 to -65 °C C3: 1.000-1.008 132 145 α Cα: 0.996-1.002

13 17 Scheme 3.13 C and O KIEs for the Me3SiCl-Assisted Conjugate Addition of Dibutylcuprate to 2-Cyclohexenone

Traditionally, the use of nonparticipating ligands, such as SMe2 have been used to increase the solubility of Cu(I) salts in ethereal medium. In 1995, Reetz and Kindler modified

Kharasch reagents with the use of LiCl salts in THF creating a homogenous catalyst (CuIŸ2LiCl or CuCl3Li2) that facilitated conjugate additions with sterically demanding substrates just as

86 effectively or slightly better than a CuBrŸSMe2 catalyst. The CuIŸ2LiCl catalyst provided high regioselectivity and moderate to high yields with or without the use of Me3SiCl.

THF Me3Si O 10 mol % CuI•2LiCl 17 Examples R1 "CuX3Li2" Y 1,4/1,2 Product >99:1 Me SiCl 2 3 R Yields = 60-96% O RMgX R 146 R1 Y THF R2 O 10 mol % CuI•2LiCl 7 Examples 117 R1 "CuX3Li2" Y 1,4/1,2 Product 2 95:5-99:1 RMgX R Yields = 47-97% R 147 Y = R, OR ; X = Halide

Scheme 3.14 CuX3Li2-Catalyzed Conjugate Addition Reactions with Grignard Reagents

3.7 Conjugate Additions to α-Trialkylsilyl-α,β-Unsaturated Esters

There are very few examples of α-trialkylsilyl-α,β-unsaturated esters acting as Michael acceptors. The examples that do exist, mainly involve methyl α-trimethylsilylacrylate 148, which does not possess a substituted β-position. The research groups of Tsuge and Tanaka

87 developed a tandem conjugate addition Peterson olefination process to afford the 1:1 and 2:1

Michael adducts 149 and 150 (scheme 3.15).87,88 The use of PhMgBr with a CuCl catalyst provided the 1:1 adduct 149 in moderate to high yields and moderate diastereoselectivities. The use organolithiums, such as PhLi, 2-lithio-

6 examples 1.1 equiv PhMgBr Yields = 40-80% 0.5 mol % CuCl E/Z = 1.5:1-1:4 SiMe3 Et O / -15 °C 2 6 examples CO Me 2 Yields = 60-85% 148 E/Z = 1:1.5-1:4 1.5 equiv PhLi CO2Me Michael Donor THF / -30 °C Nu R (Nu) 4 examples Li Yields = 57-74% 149 1 RCOR1 E/Z = 1:3-<1:20 R 1.1 equiv 151 1:1 Adduct Et2O / -78 °C 3 examples Li 1.1 equiv 152 Yields = 71-90% E/Z = 1:1->20:1 Me3S OSMe3 THF / -78 °C Nu R1 R 2 examples MeO C MeMgI or VinylMgBr Yields = 73-84% 2 Me Si CO2Me 0.5 mol % CuCl E/Z = 1:2 3 150

Et2O or THF / -15 °C 2:1 Adduct ` Scheme 3.15 Tandem Conjugate Addition Peterson Olefination with Methyl α- Trimethylsilylacrylate

1,3-butadiene 151, and methyl lithio(methylsulfinyl)methyl sulfide 152 also afforded the 1:1 adduct in moderate to high yields but higher diastereoselectivities depending on the reaction temperature and the aldehyde. In contrast to the results with PhMgBr and CuCl, MeMgI and vinylMgBr furnished the 2:1 adduct 150 in high yields and low diastereoselectivities.

A tandem conjugate addition diastereoselective protonation with α-trimethylsilylacrylate was also studied by Tanaka et. al (scheme 3.16).89,90 Alkyl grignards with a CuCl catalyst led to the 2:1 adduct 154 as a single detected stereoisomer. While i-PrMgBr did provide the 2:1 adduct

88 154 in high diastereoselectivity, the major product was the 1:1 adduct 153. Substoichiometric amounts of PhMgBr in the absence of CuCl gave the 2:1 adduct 154 in high diastereoselectivity with Et2O, but poor diastereoselectivity in THF. Substoichiometric amounts of PhLi in THF furnished the 2:1 adduct with poor diastereoselectivity. Stoichiometric amounts of a ketone enolate 156 provided the 2:1 adduct 154 in moderate diastereoselectivity, but low yield.

5 examples SiMe3 1 equiv RMgX Yields = 62-73% Me3Si CO2Me 154/155 = >20:1 CO2Me 0.5 mol % CuCl 148 Nu Et2O Yield = 87% MeO2C SiMe3 0.5 equiv 154/155 = >20:1 154 1. Michael Donor (Nu) PhMgBr

2. H2O Et2O Me3Si CO2Me Yield = 65% 0.3 equiv PhLi 154/155 = 1:1.5 Nu THF MeO2C SiMe3 OLi 155 1.5 equiv Ph Yield = 30% 2:1 Adduct 156 154/155 = 8:1 THF SiMe3 Nu 1 equiv i-PrMgBr Yield = 36% CO Me 0.5 mol % CuCl 2 153 Et2O 1:1 Adduct

Scheme 3.16 Tandem Sequential Conjugate Addition Diastereoselective Protonation Process with Methyl α-Trimethylsilylacrylate

Optimization studies were also performed with lithium enolates as the Michael donor in order to exert more control over the Michael adduct selectivity (scheme 3.17).88 The use of substoichiometric amounts of the lithium enolate 157 in THF promoted the near exclusive formation of the 2:1 adduct 154 (>20 : 1). THF proved to be a poor solvent to furnish the 1:1 adduct with comparable selectivity, but utilizing Et2O along with a large excess of the lithium enolate provided the 1:1 adduct 153 with near exclusive selectivity (>20:1). The amount of

89 excess lithium enolate could be reduced while maintaining the same level of selectivity by using a 5 : 1 Et2O/Toluene mixture.

Nu 0.5 equiv 157 SiMe3 SiMe3 MeO2C Michael Donor (Nu) THF Me Si CO2Me 3 154 CO2Me H2O 148 2:1 Adduct

OLi 3 equiv 157 SiMe3

Et2O Nu OEt CO2Me 153 157 1.5 equiv 157 Michael Donor 1:1 Adduct 5:1 Et2O/Toluene

Scheme 3.17 Michael Adduct Selectivity with the Tandem Sequential Conjugate Addition Diastereoselective Protonation Process

The final study with methyl α-trimethylsilylacrylate 148 involved a tandem conjugate addition alkylation process using lithium enolates and a range of organolithium compounds

90 (scheme 3.18). The use of excess lithium enolates 157 and 159 in Et2O and the use of stoichiometric amounts of the organolithium compounds 151, 152, and PhLi in THF furnished the 1:1 alkylated Michael adduct 158 in moderate to high yields.

2 equiv 157 or 159 R SiMe Et O 3 SiMe3 Michael Donor (Nu) 2 Nu CO2Me CO2Me RX 158 1.2 equiv 152, 151, or PhLi 148 11 Examples 1:1 Adduct Yields = 49-98% THF

OLi OLi Li Me3S Li Me3Si PhLi OEt OEt OSMe3 157 159 151 152 Michael Donors

Scheme 3.18 Tandem Conjugate Addition Alkylation Process with Methyl α- Trimethylsilylacrylate

90 The one reported case of an α-trialkylsilyl-α,β-unsaturated ester bearing a β-substituent operating as a Michael acceptor was by Yamazaki et. al.91 They performed a number of conjugate additions with E/Z mixtures of a β-trifluoromethylated α-trimethylsilyl-α,β- unsaturated ester 160 providing moderate yields and moderate to high diastereoselectivities of the saturated product 161 (table 3.1). It is important to note that a

Table 3.1 Tandem Conjugate Addition Diastereoselective Protonation Process with the β-Trifluoromethylated α-Trimethylsilyl-α,β-Unsaturated Ester 160 CO t-Bu CO t-Bu 2 THF H 2 Michael Donor (Nu) Nu SiMe3 SiMe3 + E-160 NH4Cl H CF3 CF3 E/Z-160 161 Recovered Entry E/Z Nu Yield DR E-160 1 40:60 PhMgBr 45% 3:1 88%

2 40:60 PhCH2CH2MgBr 45% >20:1 99%

EtO2C CO2Et 3 33:67 58% >20:1 29% Na OLi 4 33:67 53% >20:1 NA Ph OLi 5 33:67 71% >20:1 NA OEt copper catalyst was not required to mediate 1,4- over 1,2-addition with aryl or alkyl Grignards

(entries 1-2). This study also suggests that the Z-isomer is more reactive than the E-isomer, at least with Grignard reagents or the sodium enolate derived from diethyl malonate (entries 1-5).

3.8 Optimization Studies

The optimization studies began with the β-ethyl substrate E47i and the reaction temperatures and times were based on the carbocupration of alkynoates in the presence of excess silyl triflates previously discussed in chapter 2 (table 3.2). The catalyst loading was evaluated and 5 mol % proved to be optimal. Me3SiCl provided a similar yield to that given by Me3SiOTf,

91 but due to the lack of β-substituted α-trialkylsilyl-α,β-unsaturated esters acting as Michael

acceptors and the success of the carbocupration of alkynoates, it was decided to use Me3SiOTf as the standard silyating agent. The use of 5 mol % PPh3 provided the saturated product 116a in high yield, but did require slightly longer reaction times.

Table 3.2 Optimization Studies with the β-Ethyl Substrate E47i THF SiMe CuI 2LiCl 3 CO2Et • 1.2 TMSX, 1.2 EtMgBr CO2Et SiMe3 2 hrs -78 °C, 2 hrs warm to RT 116a E47i H2O at RT Entry % CuI•2LiCl TMSX Yield E47i/116a 1 15 TMSOTf 83% 1:>20 2 5 TMSOTf 81% 1:>20 3 2 TMSOTf 85% 1:6 4 2 (4 hrs RT) TMSOTf 85% 1:6 5 5 TMSCl 84% 1:>20 6 5 (5 % PPh ) TMSOTf 80% 1:>20 3

3.9 Me3SiOTf Accelerated Conjugate Addition Substrate Scope

The first concern for this project was to establish β-substituted α-trialkylsilyl-α,β- unsaturated esters as suitable substrates for a copper-catalyzed conjugate addition. The issue of the diastereoselective quench would be addressed once the substrate scope was evaluated.

Me3SiOTf was an effective silylating agent for several conversions (entries 1, 4, 9-12, table 3.3) but it was ultimately limiting the process. As the steric bulk of the β-position or the Grignard reagent rose, higher temperatures were required (entries 2-6, 8, 10), but this eventually led to a decrease in conversion (entry 7) most likely because of the small range of compatible temperatures that could be implemented with Grignard

92 Table 3.3 Me3SiOTf Accelerated Conjugate Addition Substrate Scope

THF SiR SiR CuI 2LiCl 3 3 CO2Et • 1 1 2 R + R R1 1.2 TMSOTf, 1.2 R MgX CO2Et CO2Et SiR 3 2 hrs -78 °C, 2 hrs warm to RT R2 R2 E47 H2O at RT 116.1 116.2

Entry SiR3 R1 Reagent R2 Yield 116/E47 Product 1 SiMe3 Et E47i Et 85% >20:1 116a

2 SiMe3 Me E47g Et 87% >20:1 116b

3 SiMe3 Et E47i iPr 83% 6:1 116c

4 SiMe3 Et E47i iPr (4 hrs RT) 90% 6:1 116c

5 SiMe3 Et E47i iPr (2 hrs -40 °C) 91% >20:1 116c

6 SiMe3 iPr E47k Et 90% 2:1 116c

7 SiMe3 iPr E47k Et (2 hrs -40 °C) 90% 14:1 116c

8 SiMe3 iPr E47k Et (2 hrs -20 °C) 90% 1:1 116c

9 SiMe3 iPr E47k Et (3 hrs -40 °C) 90% 14:1 116c

10 SiMe3 CH2SiMe3 E47l Et 90% >20:1 116d

11 SiMe3 Me E47g iPr (2 hrs -40 °C) 95% >20:1 116e

12 SiMe3 Bn E47f Et 95% >20:1 116f 13 SiEt Et E47j Et 91% >20:1 116g 3

92 reagents and Me3SiOTf. In addition, it was important to have complete consumption of the starting material, because it was inseparable from the saturated product 116 via column chromatography, as well as its volatile nature making the need for purification highly undesirable. It was decided to utilize Me3SiCl as the silylating agent because temperature studies showed that it was compatible with EtMgBr at least up to -10 °C (table 3.4).93

93 Table 3.4 Temperature Compatibility Studies with EtMgBr and Me3SiCl THF SiMe3 CO2Et 5 mol % CuI•2LiCl 1.2 TMSCl, 1.2 EtMgBr CO2Et SiMe3 H2O at RT E47i 116a Entry Temp Yield E47i/116a 2 hrs -78 C 1 ° 84% 1:>20 2 hrs warm to RT 2 hrs -40 C 2 ° 86% 1:>20 2 hrs warm to RT 2 hrs -20 C 3 ° 83% 1:>20 2 hrs warm to RT 2 hrs -10 C 4 ° 78% 1:>20 2 hrs warm to RT

3.10 Diastereoselective Quench Studies

The evaluation of acidic species for the diastereoselective quench was performed with the

β-benzyl substrate E47f. Protonations were performed at – 78 °C and allowed to warm to room temperature for thirty minutes. Both homogenous and heterogenous acids were evaluated, but sat. NH4Cl provided the highest level of diastereoselectivity (entries 1-12, table 3.5). Additional experiments with the temperature following injection of sat. NH4Cl or TFA showed no effect, which suggests that protonation occurs at – 78 °C (entries 9-13).

94 Table 3.5 Diastereoselective Protonation Experiments

THF / -40 °C Ph CO Et OTMS 2 5 mol % CuI•2LiCl H

Ph SiMe3 1.2 TMSCl OEt E47f 1.2 EtMgBr 115f SiMe3

SiMe3 SiMe3 H+ Ph CO2Et + Ph CO2Et -78 °C to RT 116.2f 116.1f

Entry H+ DR Yield

1 NH4Cl sat. 4.0:1 82% 2 Pivalic Acid 2.5:1 94% 3 PTSA 3.5:1 82% 4 (1S)-(+)-10-CSA 3.5:1 83% 5 t-butyl alcohol 2.2:1 81% 6 Menthol 3.8:1 82% 7 BHT 2.0:1 85% 8 TFA 3.7:1 81% 9 TFA (-78 °C 30 min) 3.7:1 80%

10 NH4Cl sat. (-40 °C 30 min) 4.0:1 86%

11 NH4Cl sat. (-20 °C 30 min) 4.0:1 83%

12 NH4Cl sat. (-10 °C 30 min) 4.0:1 83%

13 NH4Cl sat. (0 °C 30 min) 4.0:1 83%

3.11 Me3SiCl Accelerated Conjugate Addition Substrate Scope

Having established a compatible range of temperatures between EtMgBr and Me3SiCl, as well as the most effective proton source for diastereostereoselectivity, the substrate scope was explored (table 3.6). The Me3SiCl accelerated process required warmer temperatures overall compared with Me3SiOTf. It allowed for the incorporation of a greater range of substrates and sterically demanding Grignard reagents, albeit requiring even higher temperatures, higher

Grignard equivalents, or higher Me3SiCl equivalents. Diastereoselectivity was the highest when a large difference existed between the steric profiles of the β-substituents, i.e. Me vs iPr, Chx vs.

Et.

95

Table 3.6 Me3SiCl Accelerated Conjugate Addition Substrate Scope THF

5 mol% CuI•2LiCl SiR3 SiR3 CO2Et 1 1.2 - 1.8 Me3SiCl R R1 1 R CO2Et + CO2Et SiR 2 3 1.2 - 2.5 R MgX R2 R2 E47 Sat. NH4Cl at -78 °C 116.1 116.2

Entry SiR3 R1 Reagent Temp R2MgX Me3SiCl Product Yield DR

1 SiMe3 Et E47i -40 °C 1.2 EtMgBr 1.2 116a 86% NA

2 SiMe3 Me E47g -40 °C 1.2 EtMgBr 1.2 116b 75% 1.4:1

3 SiMe3 iPr E47k -40 °C 1.2 EtMgBr 1.8 116c 91% 15:1

4 SiMe3 Et E47i -10 °C 2.5 iPrMgCl 1.2 116c 85% 15:1

5 SiMe3 CH2SiMe3 E47l -40 °C 1.2 EtMgBr 1.2 116d 91% 4:1

6 SiMe3 Me E47g -20 °C 1.2 iPrMgCl 1.2 116e 80% 18:1

7 SiMe3 Bn E47f -40 °C 1.2 EtMgBr 1.2 116f 86% 4:1

8 SiEt3 Et E47j -40 °C 1.2 EtMgBr 1.2 116g 79% NA 9 SiMe3 Ph E47a -20 °C 1.2 EtMgBr NA 116h 80% 3.5:1 10 SiMe3 Et E47i -10 °C 1.2 PhMgBr 1.2 116h 60% 4.5:1

11 SiMe3 Me E47g -20 °C 1.2 PhMgBr 1.2 116i 84% 7:1

12 SiMe3 CH2SiMe3 E47l -10 °C 2.5 iPrMgCl 2.5 116j 75% 11:1

13 SiEt3 Et E47j -10 °C 2.5 iPrMgCl 2.5 116k 84% 13:1

14 SiMe3 Et E47i -10 °C 2.5 ChxMgCl 1.2 116l 85% >20:1

15 SiMe3 Me E47g -20 °C 1.2 ChxMgCl 1.2 116m 71% >20:1

The Me3SiCl accelerated process led to an inseperable byproduct when using the β- phenyl substrate E47a and THF as the solvent (entries 1-4, table 3.7). The use of solvents with a record of success with β-aryl substituted α,β-unsaturated esters (Et2O, DCM, and toluene) did suppress the formation of the byproduct as well as exhibit complete conversion of the starting material, however, the diastereoselectivity was completely eroded (entries 5-7). Experiments with homogenous acids showed no beneficial effect in these solvents, which suggest that the protonation is occurring at a much higher temperature, or the protonation mechanism is different

(entries 8-10). Ultimately, it was discovered that THF could be utilized for the transformation, but only

96

Table 3.7 Studies with the β-Phenyl substrate E47a

5 mol % CuI 2LiCl SiMe3 SiMe3 CO2Et • Ph Ph Me3SiCl, EtMgBr Ph CO2Et CO2Et SiMe3 + H+ at -78 °C E47a 116.1h 116.2h NA = Not Applicable ; ND = Not Determined ; BP = Byproduct

Entry Temp Me3SiCl Solvent H+ DR 116h/E347a

1 -40 °C 1.2 THF NH4Cl ND 1:2.3 + BP

2 -20 °C 1.2 THF NH4Cl ND 1.7:1 + BP

3 -10 °C 1.2 THF NH4Cl ND 3.6:1 + BP

4 0 °C 1.2 THF NH4Cl ND >20:1 + BP

5 0 °C 1.2 DCM NH4Cl 1:1 >20:1

6 0 °C 1.2 Toluene NH4Cl ND Complex Mixture

7 0 °C 1.2 Et2O NH4Cl 1.5:1 >20:1 8 0 °C 1.2 DCM Piv. Acid 1:1 >20:1 9 0 °C 1.2 DCM TFA 1:1 >20:1

10 0 °C 1.2 Et2O TFA 1:1 >20:1

11 0 °C NA THF NH4Cl 3.5:1 >20:1 + BP

12 -10 °C NA THF NH4Cl 3.5:1 >20:1 + BP

13 -20 °C NA THF NH4Cl 3.5:1 >20:1

14 -40 °C NA THF NH4Cl NA >1:20

in the absence of Me3SiCl (entry 13). The diastereoselectivity is slightly lower than that resulting from the addition of PhMgBr to E47i (entries 9 and 10, table 3.6), which may be due to the higher reactivity of the magnesium enolate intermediate.

Asymmetric methylation would be one of the greatest applications of this methodology because of the number of chiral methyl groups present in many natural products.94 Regrettably, all attempts at methylation proved unsuccessful (table 3.8). Several parameters and addition protocols were examined. The use of excess MeMgBr with the Me3SiOTf accelerated process showed conversion of starting material, but led to 1,2-additions upon warming, A reverse addition process with a large excess of MeMgBr in the absence of a silylating agent was tried,

97 but led to no conversion or a complex mixture at higher temperatures. Longer reaction times with the Me3SiOTf accelerated process never gave complete conversion even at higher catalyst loadings. The Me3SiCl accelerated process gave poor conversions even with excess MeMgBr.

Ultimately, methylation was abandoned, but this is not without precedent. Previous studies with methylation have been unsuccessful in many cases, and it has been suggested this may be due to the stronger C-Mg bond in MeMgBr when compared to EtMgBr resulting in lower reactivity.74f

Table 3.8 Methylation Attempts

THF CuI•2LiCl SiMe3 SiMe3 CO2Et Me3SiX / MeMgBr + SiMe CO2Et CO2Et 3 + E47i H 116.1b 116.2b

Entry CuI•2LiCl Conditions MeMgBr Me3SiX Solvent 116b/E47i 1 5% 2 hrs -78 °C, 2 hrs RT 1.2 OTf THF 1:3 Reverse Addition 2 5% 5 NA Et O 0:1 2 hrs -40 °C 2 Reverse Addition 3 5% 5 NA Et O 1:9.6 2 hrs - 20 °C 2 Reverse Addition Complex 4 5% 5 NA Et O 2 hrs 0 °C 2 Mixture 5 5% 8 hrs -78 °C, 2 hrs RT 1.4 OTf THF 2:1 6 10% 8 hrs -78 °C, 2 hrs RT 1.4 OTf THF 2.8:1 7 20% 4 hrs -78 °C, 2 hrs RT 1.4 OTf THF 3.4:1 8 30% 4 hrs -78 °C, 2 hrs RT 1.4 OTf THF 4.2:1 9 5% 2.5 hrs -40 °C 1.4 Cl THF 1:4.5 10 5% 2.5 hrs -20 °C 1.4 Cl THF 1:5.5 11 5% 2.5 hrs -40 C 2.5 Cl THF 1:3.8 °

3.12 NOE Studies

The coupling constants for the α- and β-protons of the β-phenyl saturated product 116h

(12 Hz) were large enough to suggest the conformation to be nearly locked into an anti- relationship between the two protons. This allowed for the use of NOE studies to establish the relative stereochemistry for the major diastereomer 116.1h (figure 3.1). The NOE experiments

98 H SiMe3 β α O H O 116.1h

Figure 3.1 Key NOE Enhancements for the β-Phenyl Saturated Product 116.1h provided evidence that the protonation of the intermediate silyl ketene acetal 115h occurs through an eclipsed conformation, rather than a bisected conformation (scheme 3.19). A1,3 strain would then direct the incoming proton from the opposite face of the largest group, which is the phenyl group in this example, furnishing the racemic diastereomer 116.1h as the major product.

By analogy this was used to assign the relative stereochemistry of the remaining products, where the diastereomer 116.1 is favored when R2 is larger than R1 and the diastereomer 116.2 is

1 2 favored when R is larger than R (scheme 3.20).

Eclipsed Conformation H A Me3Si H H SiMe3 OEt Ph Ph H Me3Si CO Et H OSiMe 2 Ph 3 O OEt H 115h Disfavored SiMe3 162.1 116.1h Approach A Bisected Conformation Disfavored A Approach Ph SiMe OEt O 3 H Ph SiMe Me3Si 3 H Me Si OSiMe3 3 Ph OEt CO2Et H H H A 115h H 162.2 116.2h

Scheme 3.19 Stereochemical Consequences of an Eclipsed versus Bisected Conformation During the Protonation of the Silyl Ketene Acetal 115h

99 Major Diastereomer SiR3 2 1 R > R R1 CO2Et 1 R R2 116.1 OSiMe3 Sat. NH4Cl R3Si H OEt -78 °C R2 SiR3 115 R1 CO2Et Major Diastereomer R2 116.2 R1 > R2

Scheme 3.20 Assigned Stereochemistry for the Saturated Products

3.13 Catalytic Cycle

The proposed catalytic cycle begins with transmetallation between the Grignard reagent and the CuIŸ2LiCl precatalyst species, which generates the active magnesiodiorganocuprate species that π-complexes with the substrate E47. Silylation of the π-complex 163 facilitates oxidative addition furnishing a silylated β-cuprio(III) enolate 164. The enolate undergoes reductive elimination providing the silyl ketene acetal 115 and the neutral Cu(I) species. Finally, the active catalytic species is regenerated with another equivalent of the Grignard reagent.

100 CuI•2LiCl 2 R2MgX

MgXI, 2 LiCl

CO2Et 1 2 R2 CuIMgX R R MgX 2 SiR3 E47

[RCuI] π - Complexation

OSiMe3 R3Si MgX OEt O SiR 2 EtO 3 R R1 R2 I H Cu 1 R2 115 OSiMe3 R 163 R Si Reductive 3 OEt Elimination Oxidative R2 CuIII R1 Addition R2 164

SiR3 SiR3 H+ 1 1 R + R CO2Et CO2Et R2 R2 116.1 116.2

Scheme 3.21 Proposed Catalytic Cycle

3.14 Conclusion This chapter presented a tandem Me3SiCl and LiCl accelerated Cu(I)-catalyzed conjugate addition diastereoselective protonation process using (E)-α-trialkylsilyl-α,β-unsaturated esters.

This is the second time a β-alkyl substituted α-silyl-α,β-unsaturated ester has been used as a

Michael acceptor. The results of this study provide a greater understanding of how to overcome the challenges involved in these transformations. Now that the racemic, but diastereoselective process has been established, future work in this area will be with the enantioselective variant, which could provide a novel method to manufacture chiral allyl silanes.

101 CHAPTER 4: A NOVEL TANDEM DECONJUGATIVE ALDOL PETERSON TYPE OLEFINATION PROCESS

4.1 Introduction

The fourth and final chapter of this dissertation will present a multi-step single pot transformation that is the culmination of concepts discussed in previous chapters. The tandem process involves a Peterson olefination and the features of this reaction will be examined. The products furnished from this transformation possess interesting strucural motifs that could allow the fabrication of a multitude of natural products which will be considered.

4.2 The Tandem Process Idea and Motivation

A tandem deconjugative aldol Peterson type olefination process was envisioned utilizing the known lithium (1E,3E)-α-trialkylsilyl extended dienolates 164, furnished by the stereoselective deprotonation of β-alkyl substituted (E)-α-trialkylsilyl-α,β- unsaturated esters E47, for an aldol addition followed by a diastereoselective Peterson olefination. The E-enolate should provide an anti-aldol product 165, which will undergo a syn-Peterson elimination to afford ((2Z,3E)-α,β’-

β,γ-unsaturated esters 166.

102 Step 1 Diastereoselective Me Si R3 R2 1 2 3 1 R OLi R CO2Et R γ-Deprotonation EtO R2 OEt R3 SiMe O H 3 LDA R3 SiMe R1 Li 3 E47 i 164 TS25 N Pr2 Step 2 R4CHO

H OEt R4 Step 3 OLi Li R4 O CO2Et Me Si CO2Et Peterson Elimination R4 3 O 1 R3 3 R SiMe3 1 R 1 R 3 R R 2 2 R 166 R2 R 165 Anti-Aldol Product TS26

Scheme 4.1 A Novel Tandem Deconjugative Aldol Peterson Type Olefination Process

The (2Z,3E)-α,β’-β,γ-unsaturated esters 166 have been recently used for pericyclic reactions such as aryne Diels-Alder reactions95 (scheme 4.2), intramolecular Diels-Alder reactions96 (scheme 4.3), and [4+1] intramolecular cycloadditions97 (scheme 4.4). The focus on the motivation of this process will be direct application to several natural products that share certain structural features.

CO2Me - CO Et CO2 2 Heat Ph + CO2Me + N2 CO2Et 166b 168 (+/-) Ph 169

Scheme 4.2 Aryne Diels-Alder Reactions with (2Z,3E)-α,β’-β,γ-Unsaturated Esters

H O 1. Heat O CO2Et 2. Epimerization 3. HCl / H O / THF 2 H 166a 167 CO2H (+/-) - Coronafacic acid

Scheme 4.3 Intramolecular Diels-Alder Reactions with (2Z,3E)-α,β’-β,γ-Unsaturated Esters

103

CO Me MeO2C MeO2C MeO 2 O Heat H H N n-Pr + n n-Pr N O OMe n-Pr O O 166c, n = 2 OMe 166d, n = 3 170c 170d

Scheme 4.4 [4+1] Intramolecular Cycloadditions with (2Z,3E)-α,β’-β,γ-Unsaturated Esters

Successful application of a Sharpless asymmetric dihydroxylation and in-situ lactonization has been used for the synthesis of the cis-Z-α-alkylidenebutyrolactone, (-)-

98 99 dihydromahubanolide B 171 and could be used for the synthesis of (-)-litsenolide D1 172

(scheme 4.5).

AD-mix α O 14 DHQ2PHAL / K2OsO4(H2O)2 14 CO2Et K Fe(CN) / K CO 3 6 2 3 O

MeSONH2 171 HO t-BuOH/H2O (1:1) 166d (-)-dihydromahubanolide B

Et Et N N O N N 10 O O H O H H H MeO OMe HO 172 N N (-)-litsenolide D1 DHQ2PHAL

Scheme 4.5 Cis-Z-α-Alkylidenebutyrolactones

100 The trans-Z-α-alkylidenebutyrolactones such as litsenolide C1 , scabrolide E, and leptocladolide A101,102 could be accessed by hydrolyzing the (2Z,3E)-α,β’-β,γ-

104 O O O R1 R1 R1 O O CO Et CO H 2 2 O O O LiOH 174

Oxone / K2CO3 HO R 166 173 R R cat. Bu4NHSO4 / Buffer 175

O O H O O O 12 O EtO OH O OH

HO O O 175b 175c 175a O O litsenolide C1 scabrolide E leptocladolide A

Scheme 4.6 Trans-Z-α-Alkylidenebutyrolactones unsaturated ester 166 and submitting the resultant acid 173 to an enantioselective Shi epoxidation with the ketone 174. (scheme 4.6).103 The epoxide generated can be opened intramolecularly with the carboxylate to furnish the trans-butyrolactone 175.

E-2-alkenyl-2-butenolide natural products 177 such as Hamabiwalactone B 177a and

Hamabiwalactone A 177b could be accessed by using an aldehyde with a masked chiral alcohol functionality (scheme 4.7).104 After the tandem process, the unsaturated ester could be hydrolyzed, the alcohol deprotected, and the butenolide formed with 2,4,6-trichlorobenzoyl chloride 176 in pyridine.105

105 Cl O O OH 1 OLi Cl R O H CO H R1 1. 2 OEt OPG Cl Cl 176 O

SiMe3 2. LiOH Pyridine 164 3. Deprotect 173a R1 177

O O

O O 8 8 177a 177b Hamabiwalactone A Hamabiwalactone B

Scheme 4.7 (E)-2-Alkenyl-2-Butenolides

4.3 The Peterson Olefination Reaction

The Peterson olefination is the silicon analogue to a Wittig reaction (scheme 4.6).106

These reactions involve α-heteroatom stabilized carbanion addition to an aldehyde or ketone.

This discussion will focus on the use of aldehydes. Once the α-silyl carbanion 178b adds to the aldehyde, an elimination can occur from the resultant β-oxidosilane intermediate 179b or a 4- membered ring intermediate 180b. The geometry of the olefin 181 or 182 depends on the diasteroselectivity of the carbanion addition, the type of Peterson reagent, and the conditions used for the elimination.

X O R1 H R2 R3 179 X 1 1 3 R3CHO Elimination R H R R + R1 R2 R2 R3 R2 H 178 X O 181 182 R1 H + 2 3 178a, X = P R3 Wittig R R 178b, X = SiR3 Peterson 180

Scheme 4.8 The Peterson Olefination

106

There are two types of Peterson reagents, nonstabilized and stabilized. Nonstabilized

Peterson reagents possess no additional stabilizing groups other than the heteroatom α to the carbanion. Stabilized Peterson reagents possess an electron withdrawing group (EWG) such as an ester or phenyl ring for R1 or R2 178, which helps to further stabilize the carbanion. These classifications have important mechanistic consequences (scheme 4.9). The β-oxidosilane intermediates of nonstabilized Peterson

Syn R Si O R Si O R1 H Base 3 Elimination 3 1 1 R H R H 2 3 R2 R3 R2 R3 R R R3Si OH 179b 180b 181 R1 H R2 R3 Bond Anti R1 OH 2 183 R Si OH Rotation 2 Elimination R H 3 2 R2 1 H Acid R H 1 3 R Si R3 A R R R2 R3 3 184 184 182

Scheme 4.9 Acid- and Base-Promoted Peterson Olefinations reagents can generally by isolated as β-hydroxysilanes 183. The isolation of these products allows for the selective use of acidic or basic conditions to promote the elimination. Acid- promoted eliminations occur through an anti elimination pathway and base-promoted eliminations are syn. This provides diastereoselective control of the olefin formed.

Mechanistic studies for the base-promoted elimination support both a concerted and stepwise process (scheme 4.10).106a,d Once the Peterson reagent 178b adds to the aldehyde and the β-oxidosilane 179b is produced, the adduct has two potential options. Path A includes the formation of a four membered ring intermediate 180b, called an oxasiletanide, that undergoes ring cleavage to furnish the olefin 181. Instead of a oxasiletanide, Path B involves a carbanion

185 produced from the forging of the Si-O bond and breaking the Si-C bond. This carbanion

107 then undergoes an E1cb elimination to deliver the olefin 182. Path B involves a possible competition between elimination and bond rotation, which has the potential to provide both olefins, 181 and 182, reducing the diastereoselectivity of the elimination.

R Si O R Si O 1 Path A 3 3 R H R1 H R1 H R2 R3 R2 R3 R2 R3 SiR3 180b 181 R3CHO 179b R1 R2 SiR 178b O 3 R1 R3 R3Si O 1 Path B 1 H R H R 2 3 R2 H R2 R3 R R 179b 185 182

Scheme 4.10 Mechanistic Details for the Base-Promoted Peterson Olefination

For Peterson reactions involving an enolate, the diastereoselectivity of the elimination can be predicted by the stereochemistry of the aldol product because the elimination is known to be syn under basic conditions (scheme 4.11). Anti-aldol products 186a will furnish Z-alkenes Z-

187. Syn-aldol products 186b will provide E-alkenes E-187.

2 H O O R2 O R O Bond Rotation H Elimination 2 R X O X X 1 R 2 R1 1 R3Si 186a R 3Si R Anti-Aldol Product 186 Z-187

O H O O Elimination R2 X R2 X 1 R 1 R3Si 186b R Syn-Aldol Product E-187

Scheme 4.11 Predictive Model for Olefin Stereochemistry

108 4.4 Lithium Enolate Studies

Investigations into reaction conditions began with the effect of temperature on the aldehyde addition (table 4.1). NOE experiments with 166e confirmed the major diastereomer to be the Z- alkene (figure 4.1). The aldol addition at -78 °C did not give the expected alkene 166e, but gave rise the deconjugated/desilylated ester 106, which was observed during the γ-deprotonation-α- protonation sequence discussed in chapter 2. It appears that deprotonation did occur, but the aldol addition did not. Quenching the reaction provided α-protonation followed by loss of the silyl group upon work up. Surprisingly, the highest diastereoselectivity was observed with - 20°

C, rather than -40 °C, which was the lowest temperature at which the reaction proceeded.

Table 4.1 Effect of Temperature on Diastereoselectivitya

1. LDA / THF / -78 C ° CO Et CO Et CO2Et 2 2 2. CH3CH2CHO + Ph SiMe + - 3 3. NH4 Cl Quench E47f 166e Ph 106 Ph

Entry Temperature Z/Eb Yieldc 1 -78 °C NA 106 (40%) 2 -40 °C 2.7:1.0 116e (80%) 3 -20 °C 3.7:1.0 116e (85%) 4 0 °C 3.5:1.0 116e (68%) 5 RT 3.4:1.0 116e (86%) (a) reactions ran with 1 equiv E47f and 1.1 equiv LDA for 2 hrs at

-78 °C and then 1.2 equiv CH3CH2CHO at the temperature specified for 1 hr. (b) Z/E ratio determined by 1H NMR spectroscopy (360 and 500 MHz) of the crude reaction mixture. (c) isolated yields of the inseperable Z/E isomers.

O H O

H O O H H H H H H Ph Z-166e Ph E-166a

Figure 4.1 Key NOE Interactions for 166e

109

Because the diasteroselectivity noticeably changed between -40° C and -20° C, but only showed a slight reduction from -20° C to room temperature, it is possible that two mechanistic pathways are operating, one at lower temperatures and one at higher temperatures (scheme 4.11).

At -40° C, the oxasiletanide 188 formed from the anti-aldol adduct 165e may have a longer lifetime. If it does, this would provide more opportunity for the ring to open and the α-stabilized carbanion 189 to form. If bond rotation occurs before the E1cB elimination this would afford more of the E-alkene E-166e. At higher temperatures, the ring may not exist as long and ring cleavage will predominate, or the α-stabilized carbanion 189 does not undergo bond rotation, both of which would furnish more of the Z-alkene Z-166e.

Li O CO Et CO Et CO Et 2 2 2 H Ph H Ph

Me3Si Li O SiMe3 O SiMe3 165e 188 165e Ph Path A Path B

CO2Et CO2Et CO2Et H Ph H Ph

O SiMe3 O SiMe3 Z-166e Ph 188 188

No Bond Rotation

CO Et SiMe3 2 CO Et O CO Et 2 2 H Ph Ph H Bond O SiMe 189 E-166e Ph 189 Rotation 3

Scheme 4.12 Potential Mechanistic Pathways to Explain Temperature Dependence

Further experimentation showed that polar solvents such as THF and THP provided the highest diasteroselectivity, but the latter gave slightly lower yields (table 4.2). Nonpolar solvents

110 such as Et2O, toluene, and 1,2-DME gave modest yields, but a sharp decline in diastereoselectivity. Hoping to expand this reaction to DCM, LHMDS was used as the base, however, it also gave poor diastereoselectivity. Implementation of LICA and LHMDS as bases exhibited similar results to LDA, but with a slightly reduced diastereoselectivity and yield.

LiTMP showed even more erosion in diastereoselectivity. Less sterically hindered bases, such as lithium diethylamide gave poor diastereoselectivity, low yield, and gave the desilylated ester 106 as a side product. LHMDS, NaHMDS, and KHMDS were used to examine if a change in the metal enolate used had an effect. NaHMDS gave a reduced yield and a lower diastereoselectivity. KHMDS gave a complex mixture of products. The quench chosen proved to be relatively unimportant. TFA, 10% HCl, and TfOH all gave similar diastereoselectivities to saturated aqueous NH4Cl but with reduced yields. This indicates that the elimination is under basic conditions and occurs before the quench is applied.

111 Table 4.2 Optimization Studies using the Lithium Enolatea

1. Base / Solvent / -78 °C CO2Et CO2Et 2. CH3CH2CHO / -20 °C Ph SiMe3 3. Quench E47f 166e Ph

Entry Solvent Base Quench Z/E Yield + - 1 THF LDA NH4 Cl 3.7:1.0 85% + - 2 Et2O LDA NH4 Cl 1.4:1.0 66% + - 3 Toluene LDA NH4 Cl 1.2:1.0 60% + - 4 THP LDA NH4 Cl 3.7:1.0 64% + - 5 1,2 DME LDA NH4 Cl 2.4:1.0 72% + - 6 DCM LHMDS NH4 Cl 1.7:1.0 61% + - 7 THF LiTMP NH4 Cl 3.1:1.0 65% + - 8 THF LICA NH4 Cl 3.6:1.0 48% - + + - 9 THF Et2N Li NH4 Cl TFA 2.4:1.0 32% + - 10 THF LHMDS NH4 Cl 3.3:1.0 74% + - 11 THF NaHMDS NH4 Cl 2.2:1.0 42% Complex 12 THF KHMDS + - NA NH4 Cl Mixture

13 THF LDA TFATFA 3.0:1.0 48% 14 THF LDA 10% HCl 3.3:1.0 63% 15 THF LDA TfOH 3.3:1.0 65% (a) reaction ran with 1 equiv E47f and 1.1 equiv amide base for 2 hrs at -78 °C and then 1.2 equiv propanal at -20 °C for 1 hr. (b) Z/E ratio determined by 1H NMR spectroscopy (360 and 500MHz) of the crude reaction mixture. (c) isolated yields of the inseperable Z/E isomers.

In order to evaluate the selectivity of the elimination and the aldol addition, efforts were made to trap the aldol adduct 165e before elimination as the acetylated β,γ-unsaturated ester 190, but proved unsuccessful (table 4.3). This is not unexpected, given that there is little support for the isolation of stabilized Peterson reagents. Acetic anhydride and pyridine were added 1 hr, 30 minutes, or 1 min after the addition of propanal. In each case, only the alkene 166e was present.

This could mean the elimination occurs faster than the acetylation process or the acetic anhydride/pyridine complex is not reactive enough to trap the aldol adduct.

112 Table 4.3 Attempt at Isolation of Aldol Adducta OAc 1. THF / LDA / -78 °C CO2Et CO2Et CO2Et 2. CH3CH2CHO / -20 °C + Me3Si Ph SiMe3 3. Ac2O / Pyridine 4. NH +Cl- Quench E47f 4 190 Ph 166e Ph

Entry Time Product

1 1 hr 166e

2 30 min 166e

3 1 min 166e (a) reaction ran with 1 equiv E47f and 1.1 equiv LDA for 2 hrs. at -78 °C and then 1.2 equiv propanal at -20 °C. 1.2 equiv Ac2O and 1.2 equiv pyridine was added at the time specified after the addtion of propanal and stirred overnight.

Given the strong support for the geometry of the intermediate enolate being that of 1E,

3E, it was believed that the low to moderate level of diastereoselectivity induced with the lithium enolate was due to poor diastereoselectivity in the aldol addition. Because of this, efforts began to implement a boron enolate, which as discussed in chapter 1, have been shown to induce much higher levels of diastereoselectivity.

4.5 Methods of Accessing Boron Enolate and Dienolates

Boron enolates derived from ketones, esters, amides, or imides are typically accessed directly with the use of a dialkylchloroborane or dialkyltriflateborane (R2BLv) along with a

2 107 107c trialkylamine (NR 3). Two competing open transition states were proposed by Evans and are normally invoked to explain or predict the stereoselectivity of the enolization. Once the carbonyl species 3 complexes with the dialkylborane the reactive conformation of this complex can be that of TS27 or TS28. TS27 provides the thermodynamic Z-enolate Z-4, but possesses steric strain between R1 of the carbonyl species and the R group of the borane. It is the preferred transition state when the dialkylborane is small, such as 9-borabicyclo[3.3.1]nonane (9-BBN-

113 Lv), or dibutylborane (Bu2BLv), and the trialkylamine is large, such as Ni-Pr2Et. TS28 provides the kinetic E-enolate E-4, but possesses steric strain between R1 and the acyl substituent X of the carbonyl species. This is the preferred transition state when the dialkylborane is

O Small R2B Large R2B R1 X 3 2 BLv Chx2BLv R2BLv / NR 3 9-BBN-Lv 2 2 NR 3 NR 3

H H BLv X O R X O R 2 H 1 B 1 R R H B (-)-Ipc BLv R Lv 2 TS27 TS28 R Lv

BR2 O BR2 O BLv R1 Bu2BLv X X 2 1 Nrb BLv Z-4 R E-4 2

2 X = R, Ar, OR, or NR2 ; Lv = Cl or OTf ; NR 3 = NEt3 or NiPr2Et

Scheme 4.13 Direct Enolization with Dialkylborane Reagents large, such as diisopinocampheylborane (Ipc2BLv), dicyclohexylborane (Chx2BLv), or bis-exo-

2-norbornylborane (Nrb2BLv) and the trialkylamine is smaller like NEt3. The leaving group (Lv) is more important when the E-enolate is desired. Triflates generally give the Z-enolate, however there are exceptions when the E-enolate can be reached.107i-o Chlorides are easier to handle and prepare107d as well as potentially deliver more control over diastereoselectivity. Once the deprotonation occurs, a trialkylammonium chloride or triflate crashes out of solution.

Boron extended dienolates have also been accessed via direct enolization of α,β- and β,γ- unsaturated esters and imides with dialkylchloroboranes or dialkyltriflateboranes.108 Following the stereochemical outcomes of those reactions and analyzing the competing open transition

114 states for those deprotonations, direct enolization of either (E)-α-trialkylsilyl-α,β-unsaturated esters or (E)-α-trialkylsilyl-β,γ-unsaturated esters with dicyclohexylchloroborane (Chx2BCl) and

Et3N should diastereoselectively

CO2Et

1 R SiR3 E47

Chx2BCl / Et3N

NEt3 NEt3 H SiR H 3 SiR H 3 Chx H R1 H OEt B Cl R1 H Chx O O EtO Chx B Cl Chx TS29 TS30

Favored Disfavored

Et3NHCl

BChx O 2 OEt 1 1 R R BChx2 OEt O

191 SiR3 192 SiR3

Scheme 4.14 Dicyclohexylchloroborane Mediated Deprotonations of (E)-α-Trialkylsilyl-α,β- Unsaturated Esters provide the boron extended dienolate 191 with the same stereochemistry as the lithium extended dienolate (1E, 3E) derived from LDA deprotonation. The transition state TS29 should be favored for the α,β-unsaturated isomer due to the large steric interactions between the α-silyl group and the cyclohexyl boron ligand in the disfavored transtion state TS30 (scheme 4.14). The β,γ- unsaturated isomer should favor transtion state TS31 because it also avoids the severe steric strain between the α-silyl group and the cyclohexyl boron ligand in the disfavored transtion state

TS32 (scheme 4.15).

115 CO2Et

1 R SiR3 E47

Chx2BCl / Et3N

R1 Et3N Chx Chx H Cl R Si Cl 3 B B EtO O EtO O Chx Chx SiR3 H TS31 R1 TS32 Et3N

Favored Et3NHCl Disfavored

BChx O 2 OEt R1 R1 BChx OEt O 2

191 SiR3 192 SiR3

Scheme 4.15 Dicyclohexylchloroborane Mediated Deprotonations of (E)-α-Trialkylsilyl-β,γ- Unsaturated Esters

Disappointly, direct enolization with Chx2BCl and Et3N was not amenable to either class of substrates. In all attempts, only the starting material was recovered. At that point, a transmetallation from the lithium extended dienolate was envisioned (scheme 4.16). While this would add an additional step to access the boron extended dienolate, it would allow for greater certainty in the enolate’s stereochemistry. This is not without precedent with many research groups using transmetallations to access both boron enolates and boron extended dienolates.109

116 R1 OLi R2 OEt LDA 3 SiR R 3 Chx BCl 164 2 2 R CO2Et

3 X BChx2 R SiR3 R1 O 1 R E47 Chx BCl R2 2 OEt NEt 3 R3 SiR 2 3 R CO2Et 191 3 R SiR3 X R1 E61

Scheme 4.16 Accessing Boron Enolates via Transmetallation

4.6 Boron Enolate Studies

Initial experiments with transmetallation furnished lower diastereoselectivities than those induced by the lithium enolate (table 4.4). Optimization of the transmetallation temperature was investigated first. Diastereoselectivity was the highest when the reaction was allowed to warm to

–20 °C, but no higher (entries 1 and 3). A basic oxidation gave a higher yield and cleaner conversion (entry 5) THF showed the greatest promise providing the highest yield while maintaining the elevated diastereoselectivity (entry 10). 11B NMR experiments with the transmetallation step in hexane at 0 °C indicated the presence of two species, one that was representative of a B-O bond (55 ppm), but another at 0 ppm that was in a 2:1 ratio. The

11 iPr2NHŸChx2BCl complex was ruled out as an option, because B NMR experiments gave a chemical shift of 33 and 45 ppm when iPr2NH was combined with Chx2BCl at 0 °C. It is believed that the boron enolate and the iPr2NH could form a complex, which would reduce the lewis acidity of the boronate. In an effort to circumvent this process, 2.2 eq. of Chx2BCl was used to soak up all remaining iPr2NH after deprotonation of E47f. This induced the greatest level of diastereoselectivity as well as providing the highest yield (entry 12).

117 Table 4.4 Boron Enolate Transmetallation Optimization

1. 1.1 LDA / Solvent / Temperature CO Et 2 2. Chx2BCl / 1 hr CO2Et

Ph SiMe3 3. CH3CH2CHO / - 78 °C to RT / 12 hrs 4. Oxidative Workup E47f 166e Ph ND = Not Determined ; CM = Complex Mixture

Entry Solvent Chx2BCl Conditions Propanal Conditions Work up Z/E Yield 1 Hexane 1.1 -78 °C to 0 °C 1 -78 °C to RT Neutral 2.5:1 ND

2 Hexane 1.1 -78 °C to RT 1 -78 °C to RT Neutral ND CM

3 Hexane 1.1 -78 °C to -20 °C 1 -78 °C to RT Neutral 2.9:1 30% 4 Hexane 1.1 -78 °C to -40 °C 1 -78 °C to RT Neutral 2.5:1 ND 5 Hexane 1.1 -78 °C to -20 °C 1 -78 °C to RT Basic 3:1 40% 6 Hexane 1.1 -78 °C to -20 °C 1 -78 °C to RT Acidic 2:1 ND

7 Et2O 1.1 -78 °C to -20 °C 1 -78 °C to RT Basic 5:1 44% 8 MTBE 1.1 -78 °C to -20 °C 1 -78 °C to RT Basic 6:1 50% 9 Toluene 1.1 -78 °C to -20 °C 1 -78 °C to RT Basic 6:1 CM 10 THF 1.1 -78 °C to -20 °C 1 -78 °C to RT Basic 6:1 60% 11 THF 1.1 -78 °C to -20 °C 1 -40 °C to RT Basic 5:1 ND 12 THF 2.2 -78 °C to -20 °C 5 -78 °C to RT Basic 15:1 80% 13 THF 3 -78 °C to -20 °C 5 -78 °C to RT Basic 15:1 ND 14 THF 2.2 -78 °C to -20 °C 5 -78 °C to 0 °C Basic 6:1 ND

The high level of diastereoselectivity and conversion was maintained when the optimized conditions were applied to different combinations of β-alkyl-substituted (E)-α-trialkylsilyl-α,β- unsaturated esters and aldehydes (table 4.5). Certain combinations required slight modifications to aldehyde addition protocol. Warmer temperatures allowed for the incorpation of sterically challenging enolates or aldehydes (entries 2 and 5). The combination of the boron enolate derived from E47f and benzaldehyde gave very poor diastereoselectivities (Z/E = 2:1). This necessitated the use of electron deficient aromatic aldehydes, such as 194, to allow the transformation to occur at lower temperatures, but only gave moderate diastereoselectivities

(entry 4). Work will be expanded to include other (E)-α-trialkylsilyl-α,β-unsaturated esters, such

118 as E47i and E47g, as well as include a masked β-hydroxy aldehyde 193.

Table 4.5 Substrate Scope for the Tandem Aldol-Olefination Process

R3 1. 1.1 equiv LDA / THF / -78 °C or -40 °C R2 CO Et 2 CO2Et 2. 2.2 equiv Chx2BCl -78 °C to -20 °C 1 R SiMe3 3. 5 equiv R3CHO R2

4. CH3OH, 3 M NaOH, 30 % H2O2 E47 166 R1

Entry R1 R2 Reagent R3CHO Conditions Product Z/Eb Yieldc

1 Ph H E47f CH3CH2CHO -78 °C to RT 166e 16:1 80%

2 (CH3)2CHO -40 °C to RT 166f 16:1 85% CHO 3 TBSO 193

4 F3C CHO -78 °C to RT 116g 3.6:1 50% 194

5 CH3 CH3 E47k CH3CH2CHO -20 °C to RT 166h 12:1 78%

6 (CH3)2CHO 7 193 8 194

9 Me H E47i CH3CH2CHO -78 °C to RT 166i 16:1 85%

10 (CH3)2CHO 11 193

12 H H E47g CH3CH2CHO

13 (CH3)2CHO 14 193

(a) Z/E ratio determined by 1H NMR spectroscopy (360 and 500 MHz) of the crude reaction mixture. (b) Isolated yields.

4.7 Conclusion

This chapter has presented a novel tandem deconjugative aldol Peterson type olefination process. This process converts β-alkyl-substituted (E)-α-trialkylsilyl-α,β-unsaturated esters into

(1E,3E)-α-trialkylsilyl extended dienolates, which undergo transmetallation with Chx2BCl to form (1E,3E)-α-trialkylsilyl extended boron dienolates. Upon treatment with an aldehyde, these dienolates facilitate an in situ Peterson elimination furnishing (2Z,3E)-α,β’-β,γ-unsaturated

119 esters, whose stereochemistry was confirmed by NOE. Four examples have been given that elicit high levels of diastereoselectivity and conversion. (2Z,3E)-α,β’-β,γ-unsaturated esters have been used and could be used to access several interesting structural motifs found in many natural products.

120 CONCLUSION

This dissertation highlights experimental efforts to expand the synthetic applications of

(E)-α-trialkylsilyl-α,β-unsaturated esters.

Chapter one delineated select features of enolates and extended dienolates that is essential to understand several findings covered in the subsequent chapters.

Chapter two presented the expansion of substrate scope and scale of

β-alkyl-substituted (E)-α-trialkylsilyl-α,β-unsaturated esters via catalytic carbocupration of alkynoates in the presence of excess trialkylsilyltriflates, the diastereoselective synthesis of (E)-

α,γ-substituted allylsilanes via a γ-deprotonation-α-protonation sequence, and the successful isolation and stereochemical assignment of the trapped intermediate extended dienolate.

Chapter three illustrated the second example of a β-alkyl-substituted (E)-α-silyl-α,β- unsaturated ester used as a Michael acceptor for a Cu(I)-catalyzed conjugate addition with

Grignard reagents followed by a diastereoselective protonation. The saturated α-silyl ester products could serve as a source for chiral allyl silanes.

Chapter four discussed the implementation of the 1E, 3E-extended dienolate derived from

β-alkyl-substituted (E)-α-trialkylsilyl-α,β-unsaturated esters for a tandem diastereoselective aldol-Peterson olefination process. The products of this transformation exhibit potential for the synthesis of several natural products.

121 EXPERIMENTAL

General Procedure All of the reactions were performed under Ar in flame-dried glassware. All starting materials, solvents, reagents, and catalysts were commercially available and used without further purification, with the exception of n-Butyllithium, which was titrated to determine concentration. The NMR spectra were recorded with either a 360 or 500 MHz Bruker

1 13 spectrometer. H and C NMR spectra were obtained using CDCl3 or C6D6 as the solvent with chloroform (CHCl3: δ = 7.26 ppm) or benzene (C6H6: δ = 7.15 ppm) as the internal standard.

High-resolution mass spectra were recorded on an EBE sector instrument using electron ionization

(EI) at 70 eV. Column chromatography was performed using 60-200 µm silica gel. Analytical thin layer chromatography was performed on silica coated glass plates with F-254 indicator.

Visualization was accomplished by UV light (254 nm) and KMnO4.

Syntheses of (E)-α-trialkylsilyl-α,β-unsaturated esters:

General Experimental Procedure for the synthesis of E47f: CuI (0.33 g, 1.7 mmol) and LiCl

(0.14 g, 3.4 mmol) were flame dried under vacuum in a 250 mL round bottom flask under Ar.

Dry THF (57.0 mL) was added and the mixture was stirred at RT for a period of 0.5 h until complete dissolution had occurred. The clear, light yellow homogeneous solution was cooled to

– 78 °C, and ethyl propiolate (1.12 g, 1.16 mL, 11.4 mmol) was added, followed by TMSOTf

(3.3 equiv, 6.81 mL, 37.62 mmol). After 10 minutes at – 78 °C, BnMgCl (1.2 equiv, 6.84 mL,

13.68 mmol) was added dropwise via syringe, and the solution was stirred at –78 °C for 2 hrs and allowed to warm to RT for 2 hrs. The reaction was quenched with H2O and the product

122 extracted with Et2O (3 X 25 mL), and the combined organic layers were washed with brine. The organic layer was separated, dried with MgSO4, and concentrated in vacuo to give the crude product, which was then analyzed by 1H NMR spectroscopy to determine diastereoselectivity. If polymerized THF was present, the crude material was dissolved in DCM, dry loaded onto a column and purified using 1% diethyl ether in hexanes. The fractions containing the product along with starting material were collected, concentrated in vacuo, and submitted to column chromatography again using a wet loading. If the non α-silylated product was present, the purified material was then further purified using a Krugelrohr (BP = 115 °C at 6 Torr).

1 E47f: H NMR (360 MHz, CDCl3) δ7.27 (m, 5H), 6.27 (t, J = 7.0 Hz, 1H), 4.24 (q, J = 7.0 Hz,

2H), 3.72 (d, J = 7.0 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H), 0.15 (s, 9H).

General Experimental Procedure for the synthesis of E47g-E47n CuI (0.11 g, 0.6 mmol) and

LiCl (0.05 g, 1.2 mmol) was flame dried under vacuum in a 100 mL round bottom flask under

Ar. Dry THF (20 mL) was added and the mixture was stirred at RT for a period of 0.5 h until complete dissolution had occurred. The clear, light yellow homogeneous solution was cooled to

– 78 °C, and ethyl propiolate (0.39 g, 0.40 mL, 4.0 mmol) was added, followed by TMSOTf (3.3 equiv, 2.4 mL, 13.2 mmol). After 10 minutes at – 78 °C, EtMgBr (1.4 equiv, 1.9 mL, 5.6 mmol) was added dropwise via syringe, and the solution was stirred at –78 °C for 2 hrs and allowed to

warm to RT for 2 hrs. The reaction was quenched with H2O and the product extracted with Et2O

(3 X 25 mL), and the combined organic layers were washed with brine. The organic layer was

separated, dried with MgSO4, and concentrated in vacuo to give the crude product, which was then analyzed by 1H NMR spectroscopy to determine diastereoselectivity. The crude material was then submitted to column chromatography and purified using 1% diethyl ether in hexane.

123

1 E47g: H NMR (360 MHz, CDCl3) δ6.30 (q, J = 6.8 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 1.97 (d, J

= 6.8 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H), 0.13 (s, 9H).

1 E47h: H NMR (360 MHz, CDCl3) δ6.22 (q, J = 6.7 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 1.94 (d, J

= 6.6 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H), 0.92 (t, J = 8.0 Hz, 9H), 0.64 (q, J = 8.0 Hz, 6H).

1 E47i: H NMR (500 MHz, CDCl3) δ6.14 (t, J = 7.1 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.37 (p, J

= 7.5 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.6 Hz, 3H), 0.13 (s, 9H). 13C NMR (125

MHZ, CDCl3) δ 170.5, 153.1, 135.5, 59.9, 25.0, 14.3, 13.5, -1.4. IR: (Pentane) 2964, 1713,

-1 + 1608, 1366, 1249, 1196, 1140, 1037, 840, 625 cm . HRMS (EI) calculated for C10H20O2Si [M] :

+ 200.1233 found:199.1161 [M-H] . Rf = 0.64, 10% EtOAc in hexanes.

1 E47j: H NMR (360 MHz, CDCl3) δ6.06 (t, J = 7.1 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 2.33 (p, J

= 7.4 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.6 Hz, 3H), 0.93 (t, J = 7.9 Hz, 9H), 0.64 (q,

13 J = 7.9 Hz, 6H). C NMR (125 MHz, CDCl3) δ170.9, 152.8, 132.6, 59.8, 25.1, 14.3, 13.7, 7.2,

3.2. IR: (Pentane) 2956, 2876, 1713, 1607, 1459, 1417, 1366, 1348, 1307, 1195, 1137, 1037,

-1 + 1006, 721 cm . HRMS (EI) calculated for C13H26O2Si [M] : 242.1702 found: 213.1311 [M-

+ C2H5] . Rf = 0.61, 10% EtOAc in hexanes.

1 E47k: H NMR (360 MHz, CDCl3) δ5.89 (d, J = 9.3 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 1.29 (t, J

13 = 7.0 Hz, 3H), 0.99 (d, J = 6.6 Hz, 6H), 0.13 (s, 9H). C NMR (90 MHz, CDCl3)

δ170.4, 157.2, 133.2, 59.6, 30.3, 22.2, 14.1, −1.6. IR: (Pentane) 2962, 2870, 1714, 1608, 1467,

124 -1 1366, 1249, 1198, 1150, 1037, 996, 841, 694, 628 cm . HRMS (EI) calculated for C11H22O2Si

+ [M] : 214.1389 found: 214.1398. Rf = 0.70, 10% EtOAc in hexanes.

1 E47l: H NMR (360 MHz, CDCl3) δ6.41 (t, J = 9.1 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 2.22 (d, J

13 = 9.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H), 0.12 (s, 9H), 0.03 (s, 9H). C NMR (90 MHz, CDCl3)

δ170.1, 152.5, 131.1, 59.4, 25.3, 14.3, -1.0, -1.7. IR: (Pentane) 2955, 2899, 1708, 1589, 1367,

-1 + 1249, 1198, 1126, 1049, 840, 751, 693, 629 cm . HRMS (EI) calculated for C12H26O2Si2 [M] :

258.1471 found: 258.1469. Rf = 0.7, 10% EtOAc in Hexanes.

1 E47m: H NMR (500 MHz, CDCl3) δ6.32 (t, J = 9.0 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 2.18 (d, J

= 8.8 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.9 Hz, 9H), 0.64 (q, J = 7.9 Hz, 6H), 0.03 (s,

13 9H). C NMR (125 MHz, CDCl3) δ170.5, 152.4, 128.3, 59.5, 25.4, 14.3, 7.3, 3.4, -1.6. IR:

(Pentane) 2954, 2875, 1706, 1588, 1460, 1416, 1366, 1349, 1249, 1195, 1127, 1047, 1006, 854,

-1 + 728cm . HRMS (EI) calculated for C15H32O2Si2 [M] : 300.1941 found: 300.1930. Rf = 0.67,

10% EtOAc in hexanes.

1 E47n: H NMR (360 MHz, CDCl3) δ4.12 (q, J = 7.1 Hz, 2H), 1.83 (s, 3H), 1.81 (s, 2H), 1.28 (t,

13 J = 7.0 Hz, 3H), 0.17 (s, 9H), 0.05 (s, 9H). C NMR (125 MHz, CDCl3) δ172.9, 153.6, 59.8,

30.3, 24.8, 14.4, 0.1, -0.8. IR: (Pentane) 2955, 1710, 1599, 1249, 1211, 1151, 1041, 841 cm-1.

+ HRMS (EI) calculated for C13H28O2Si2 [M] : 272.1628 found: 272.1629.

Rf = 0.65, 10% EtOAc in hexanes.

Syntheses of (E)-α-trialkylsilyl-β,γ-unsaturated esters:

General Experimental Procedure for the Synthesis of E61.11, E61.38-E61.41: Freshly distilled

125 diisopropylamine (0.07g, 0.1 mL, 0.65 mmol) in dry THF (1.4 mL) was placed in a 25 mL round bottom flask and cooled to 0 °C. n-Butyllithium (2.2 M, 0.29 mL, 0.65 mmol) was added to the solution dropwise via syringe and allowed stir for 30 min. The reaction was then cooled to -78

°C. E47g (0.1 g, 0.54 mmol) was placed in a vial and added to the solution dropwise. The vial was washed with dry THF (3 x 0.2 mL) and added to the reaction. The reaction was then allowed to stir for 2 hrs. TMSCl (0.07g, 0.08 mL, 0.65 mmol) was added to the reaction and allowed to stir for 30 min. The reaction was poured into an Erlenmeyer flask containing pentane (6 mL),

saturated NH4Cl (6 mL), and crushed ice (~ 20 g) and transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted with pentane (20 mL). The organic extracts were placed in an Erlenmeyer flask, lowered to 0 °C, stirred vigorously with 5%

HCl (6 mL) for 15 min. The reaction was placed into another separatory funnel, the organic layer was removed, and the aqueous layer was washed with pentane (10 mL). The organic extracts

were washed with brine, dried with MgSO4, and concentrated.

1 E61.11: H NMR: (360 MHz, CDCl3) δ 5.63 (ddq, J = 15.2, 10.2, 1.6 Hz, 1H), 5.30 (dq, J =

15.2, 6.4 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 2.82 (d, J = 10.2 Hz, 1H), 1.68 (dd, J = 6.5, 1.7 Hz,

3H), 1.24 (t, J = 7.2 Hz, 3H), 0.06 (s, 9H).

1 E61.38: H NMR: (360 MHz, CDCl3) δ 7.33 (m, 5H), 6.52 (dd, J = 15.9, 10.0 Hz, 1H), 6.34 (d, J

= 15.9 Hz, 1H), 4.24 (q, J = 7.0 Hz, 2H), 3.13 (dd, J = 10.0, 0.7 Hz, 1H), 1.35 (t, J = 7.2 Hz, 3H),

0.21 (s, 9H).

126 1 E61.39: H NMR: (360 MHz, CDCl3) δ 6.02 (ddd, J = 17.3, 10.2, 10.2 Hz, 1H), 4.95 (ddd, J =

10.2, 1.7, 0.7 Hz, 1H), 4.89 (ddd, J = 17.3, 1.7, 0.8 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 2.90 (d, J =

10.2 Hz, 1H), 1.25 (t, J = 7.2 Hz, 3H), 0.09 (s, 9H).

1 E61.40: H NMR: (360 MHz, CDCl3) δ 6.05 (ddd, 17.3 J = Hz, 10.2 Hz, 10.2 Hz, 1H), 4.89 (m,

2H), 4.10 (q, J = 7.1 Hz, 2H), 3.01 (d, J = 10.2 Hz, 1H), 1.24 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7.8

13 Hz, 9H), 0.62 (q, J = 7.5 Hz, 6H). C NMR: (125 MHz, CDCl3)

δ173.2, 133.5, 113.1, 59.9, 42.1, 14.3, 7.1, 2.4. IR: (Pentane) 2955, 2913, 2878, 1719, 1631,

1460, 1415, 1366, 1304, 1285, 1238, 1170, 1131, 1073, 1038, 1007, 900, 801, 710 cm-1. HRMS

+ (EI) calculated for C12H24O2Si [M] : 228.1546 found 228.1550. Rf = 0.67, 10% EtOAc in hexanes.

1 E61.41: H NMR: 360 MHz, CDCl3) δ 5.65 (ddq, J = 15.2, 10.4, 1.6 Hz, 1H), 5.28 (dq, J = 15.2,

6.4 Hz, 1H), 4.07 (q, J = 7.2 Hz, 2H), 2.92 (d, J = 10.4 Hz, 1H), 1.65 (dd, J = 6.4, 1.6 Hz, 3H),

1.22 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.8 Hz, 9H), 0.59 (q, J = 7.6 Hz, 6H). 13C NMR: (125 MHz,

CDCl3) δ173.7, 125.6, 123.9, 59.8, 40.4, 17.9, 14.2, 7.0, 2.4. IR: (Pentane) 2955, 2878, 1720,

-1 + 1583, 1549, 1334, 1259, 1150, 1007, 969, 731 cm . HRMS (EI) calculated for C13H26O2Si [M] :

242.1702 found 242.1695. Rf = 0.68, 10% EtOAc in hexanes.

General Experimental Procedure for the Synthesis of 61.1: Freshly distilled diisopropylamine

(0.06g, 0.08 mL, 0.56 mmol) in dry THF (1.2 mL) was placed in a 25 mL round bottom flask and cooled to 0 °C. n-Butyllithium (2.2 M, 0.25 mL, 0.56 mmol) was added to the solution dropwise via syringe and allowed stir for 30 min. The reaction was then cooled to - 40 °C. E47k

127 (0.1 g, 0.47 mmol) was placed in a vial and added to the solution dropwise. The vial was washed with dry THF (3 x 0.2 mL) and added to the reaction. The reaction was then allowed to stir for 2 hrs. TMSCl (0.06g, 0.07 mL, 0.56 mmol) was added to the reaction and allowed to stir for 30 min. The reaction was poured into an Erlenmeyer flask containing pentane (6 mL), saturated

NH4Cl (6 mL), and crushed ice (~ 20 g) and transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted with pentane (20 mL). The organic extracts were placed in an Erlenmeyer flask, lowered to 0 °C, stirred vigorously with 5% HCl (6 mL) for

15 min. The reaction was placed into another separatory funnel, the organic layer was removed, and the aqueous layer was washed with pentane (10 mL). The organic extracts were washed with

brine, dried with MgSO4, and concentrated.

1 61.1: H NMR: (360 MHz, CDCl3) δ 5.42 (dm, J = 10.9 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.07

(d, J = 10.9 Hz, 1H), 1.74 (d, J = 1.4 Hz, 3H), 1.55 (d, J = 1.1 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H),

13 0.06 (s, 9H). C NMR: (125 MHz, CDCl3) δ173.5, 129.9, 118.7, 59.8, 39.5, 25.7, 18.2, 14.4, -

2.7. IR: (Pentane) 2965, 1718, 1367, 1294, 1250, 1202, 1145, 1041, 844, 757 cm-1. HRMS (EI)

+ calculated for C11H22O2Si [M] : 214.1389 found 214.1390. Rf = 0.63, 10% EtOAc in hexanes.

General Experimental Procedure for the synthesis of E61.42: Freshly distilled diisopropylamine

(0.05g, 0.07 mL, 0.47 mmol) in dry THF (0.98 mL) was placed in a 10 mL round bottom flask and cooled to 0 °C. n-Butyllithium (2.1 M, 0.23 mL, 0.47 mmol) was added to the solution dropwise via syringe and allowed stir for 30 min. The reaction was then cooled to -78 °C. E47l

(0.1 g, 0.39 mmol) was placed in a vial and added to the solution dropwise. The vial was washed with dry THF (3 x 0.2 mL) and added to the reaction. The reaction was then allowed to stir for 2 hrs. TMSCl (0.05g, 0.06 mL, 0.47 mmol) was added to the reaction and allowed to stir for 30

128 min. The reaction was poured into an Erlenmeyer flask containing pentane (6 mL), saturated

NH4Cl (6 mL), and crushed ice (~20 g) and transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted with pentane (20 mL). The organic extracts were placed in an Erlenmeyer flask, lowered to 0 °C, stirred vigorously with 5% HCl (6 mL) for

1 hr. The reaction was placed into another separatory funnel, the organic layer was removed, and the aqueous layer was washed with pentane (10 mL). The organic extracts were washed with

brine, dried with MgSO4, and concentrated.

1 E61.42: H NMR: (500 MHz, CDCl3) δ 6.21 (dd, J = 18.7, 9.6 Hz, 1H), 5.47 (dd, J = 18.6, 0.8

Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 2.97 (dd, J = 9.5, 0.8 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H), 0.07 (s,

13 9H), 0.06 (s, 9H). C NMR: (125 MHz, CDCl3) δ 172.7, 140.8, 128.9, 59.9, 48.6, 14.4, -1.2, -

2.9. IR: (Pentane) 2956, 2926, 2854, 1719, 1604, 1367, 1323, 1300, 1249, 1217, 1180, 1137,

-1 + 1061, 996, 842, 730, 692, 641 cm . HRMS (EI) calculated for C12H26O2Si2 [M] : 258.1471 found 258.1474. Rf = 0.71, 10% EtOAc in hexanes.

General Experimental Procedure for the synthesis of E61.43: Freshly distilled diisopropylamine

(0.04g, 0.06 mL, 0.40 mmol) in dry THF (0.83 mL) was placed in a 10 mL round bottom flask and cooled to 0 °C. n-Butyllithium (2.1 M, 0.19 mL, 0.40 mmol) was added to the solution dropwise via syringe and allowed stir for 30 min. The reaction was then cooled to -78 °C. E47m

(0.1 g, 0.33 mmol) was placed in a vial and added to the solution dropwise. The vial was washed with dry THF (3 x 0.2 mL) and added to the reaction. The reaction was then allowed to stir for 2 hrs. TMSCl (0.04g, 0.05 mL, 0.40 mmol) was added to the reaction and allowed to stir for 30 min. The reaction was poured into an Erlenmeyer flask containing pentane (6 mL), saturated

129 NH4Cl (6 mL), and crushed ice (~ 20 g) and transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted with pentane (20 mL). The organic extracts were placed in an Erlenmeyer flask, lowered to 0 °C, stirred vigorously with 5% HCl (6 mL) for

1 hr. The reaction was placed into another separatory funnel, the organic layer was removed, and the aqueous layer was washed with pentane (10 mL). The organic extracts were washed with

brine, dried with MgSO4, and concentrated.

1 E61.43: H NMR: (500 MHz, CDCl3) δ 6.26 (dd, J = 18.6, 9.8 Hz, 1H), 5.48 (dd, J = 18.6, 0.9

Hz, 1H), 4.11 (J = 7.1 Hz, 2H), 3.09 (dd, J = 9.8, 0.9 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H), 0.96 (t, J

13 = 7.9 Hz, 9H), 0.62 (q, J = 7.9 Hz, 6H), 0.05 (s, 9H). C NMR: (125 MHz, CDCl3) δ 173.0,

141.1, 128.5, 59.9, 45.7, 14.3, 7.1, 2.4, -1.2. IR: (Pentane) 2954, 2878, 1719, 1603, 1414, 1367,

1322, 1300, 1248, 1216, 1179, 1137, 1005, 867, 840, 715 cm-1. HRMS (EI) calculated for

+ C15H32O2Si2 [M] : 300.1941 found: 300.1951.

Rf = 0.71, 10% EtOAc in hexanes.

Synthesis of α-silyl conjugated silyl ketene acetals:

General Experimental Procedure for the Synthesis of 60c-60f, 60h: Freshly distilled diisopropylamine (0.07g, 0.1 mL, 0.65 mmol) in dry THF (1.4 mL) was placed in a 25 mL round bottom flask and cooled to 0 °C. n-Butyllithium (2.2 M, 0.29 mL, 0.65 mmol) was added to the solution dropwise via syringe and allowed stir for 30 min. The reaction was then cooled to -78

°C. E47g (0.1 g, 0.54 mmol) was placed in a vial and added to the solution dropwise. The vial was washed with dry THF (3 x 0.2 mL) and added to the reaction. The reaction was then allowed to stir for 2 hrs. TMSCl (0.07g, 0.08 mL, 0.65 mmol) was added to the reaction and allowed to stir for 30 min. The reaction was poured into an Erlenmeyer flask containing pentane (6 mL),

130 saturated NH4Cl (6 mL), and crushed ice (~ 20 g) and transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted with pentane (20 mL). The

organic extracts were dried with MgSO4 and concentrated.

1 60c: H NMR: (360 MHz, CDCl3) δ 6.38 (dd, J = 17.9, 11.4 Hz, 1H), 4.96 (dd, J = 17.9, 2.0 Hz,

1H), 4.81 (dd, J = 11.1, 2.0 Hz, 1H), 3.83 (q, J = 7.0 Hz, 2H), 1.23 (t, J = 6.9 Hz, 3H), 0.24 (s,

13 9H), 0.15 (s, 9H). C NMR: (125 MHz, CDCl3) δ 158.7, 136.0, 111.5, 93.1, 63.4, 14.6, 0.9, 0.2.

IR: (Pentane): 2958, 1722, 1612, 1582, 1390, 1245, 1082, 845, 762, 689, 631 cm-1. HRMS (EI)

+ calculated for C12H26O2Si2 [M] : 258.1471 found 258.1481.

1 60d: H NMR: (500 MHz, CDCl3) δ 6.36 (dd, J = 18.0, 11.4 Hz, 1H), 5.00 (dd, J = 18.0, 2.2 Hz,

1H), 4.81 (dd, J = 11.2, 2.0 Hz, 1H), 3.82 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H), 0.92 (t, J

13 = 7.9 Hz, 9H), 0.66 (q, J = 7.9 Hz, 6H), 0.25 (s, 9H). C NMR: (125 MHz, CDCl3) δ 159.0,

136.5, 111.6, 89.6, 63.3, 14.6, 7.6, 4.4, 0.3. IR: (Pentane) 2954, 2874, 1612, 1580, 1389, 1254,

-1 + 1152, 1081, 1002, 876, 849, 755, 730 cm . HRMS (EI) calculated for C15H32O2Si2 [M] :

300.1941 found 300.1929.

1 60e: H NMR: (500 MHz, CDCl3) δ 5.99 (dq, J = 15.9, 1.7 Hz, 1H), 5.39 (dq, J = 16.0, 6.5 Hz,

1H), 3.80 (q, J = 7.1 Hz, 2H), 1.71 (dd, J = 6.5, 1.7 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H), 0.23 (s,

13 9H), 0.12 (s, 9H). C NMR: (125 MHz, CDCl3) δ 157.4, 129.5, 122.9, 92.4, 63.4, 19.0, 14.6,

0.9, 0.1. IR: (Pentane): 2960, 2349, 1721, 1589, 1443, 1366, 1252, 1150, 1062, 970, 846, 755,

-1 + 631 cm . HRMS (EI) calculated for C13H28O2Si2 [M] : 272.1628 found 272.1630.

131 1 60f: H NMR: (500 MHz, C6D6) δ 6.24 (dq, J = 15.8, 1.6 Hz, 1H), 5.57 (dq, J = 15.8, 6.5 Hz,

1H), 3.67 (q, J = 7.0 Hz, 2H), 1.74 (dd, J = 6.5, 1.6 Hz, 3H), 1.15 (t, J = 7.9 Hz, 9H), 1.04 (t, J =

13 7.0 Hz, 3H), 0.88 (q, J = 7.9 Hz, 6H), 0.17 (s, 9H). C NMR: (125 MHz, C6D6) δ 158.4, 130.7,

123.3, 88.8, 63.2, 19.1, 14.7, 8.1, 5.0, 0.25. IR: (Pentane) 2954, 2874, 1589, 1481, 1462, 1389,

-1 +: 1253, 1107, 1063, 1003, 967, 849, 733 cm . HRMS (EI) calculated for C16H34O2Si2 [M]

314.2097 found 314.2099.

1 60h: H NMR: (500 MHz, C6D6) δ 6.99 (d, J = 19.5 Hz, 1H), 5.88 (d, J = 19.5 Hz, 1H), 3.65 (q,

J = 7.1 Hz, 2H), 1.01 (t, J = 7.1 Hz, 3H), 0.41 (s, 9H), 0.20 (s, 9H), 0.17 (s, 9H).

13 C NMR: (500 MHz, C6D6) δ 159.4, 144.7, 126.5, 95.7, 63.4, 14.6, 1.5, 0.2, - 0.7. IR: (Pentane)

2955, 2898, 1582, 1553, 1482, 1468, 1389, 1366, 1246, 1207, 1145, 1070, 993, 841, 757, 688,

-1 + 631 cm . HRMS (EI) calculated for C15H34O2Si3 [M] : 330.1867 found 330.1872.

General Experimental Procedure for the synthesis of 60g: Freshly distilled diisopropylamine

(0.06g, 0.08 mL, 0.56 mmol) in dry THF (1.2 mL) was placed in a 25 mL round bottom flask and cooled to 0 °C. n-Butyllithium (2.2 M, 0.25 mL, 0.56 mmol) was added to the solution dropwise via syringe and allowed stir for 30 min. The reaction was then cooled to -40 °C. E47k

(0.1 g, 0.47 mmol) was placed in a vial and added to the solution dropwise. The vial was washed with dry THF (3 x 0.2 mL) and added to the reaction. The reaction was then allowed to stir for 2 hrs. TMSCl (0.06g, 0.07 mL, 0.56 mmol) was added to the reaction and allowed to stir for 30 min. The reaction was poured into an Erlenmeyer flask containing pentane (6 mL), saturated

NH4Cl (6 mL), and crushed ice (~20 g) and transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted with pentane (20 mL). The organic extracts

132 were dried with MgSO4 and concentrated.

1 60g: H NMR: (500 MHz, CDCl3) δ 5.40 (m, 1H), 3.79 (q, J = 7.1 Hz, 2H), 1.70 (d, J = 1.3 Hz,

3H), 1.51 (d, J = 1.3 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H), 0.15 (s, 9H), 0.04 (s, 9H).

13 C NMR: (125 MHz, CDCl3) δ 155.5, 131.9, 122.5, 90.2, 62.7, 25.2, 19.5, 14.7, 0.0, -0.2. IR:

(Pentane) 2960, 1722, 1612, 1252, 1218, 1077, 836, 754 cm-1. HRMS (EI) calculated for

+ C14H30O2Si2 [M] : 286.1784 found 286.1791.

Copper-Catalyzed Conjugate Addition:

General Experimental Procedure for the synthesis of E47a CuI (0.11 g, 0.6 mmol) and LiCl

(0.05 g, 1.2 mmol) was flame dried under vacuum in a 100 mL round bottom flask under Ar.

Dry THF (24 mL) was added and the mixture was stirred at RT for a period of 0.5 h until complete dissolution had occurred. The clear, light yellow homogeneous solution was cooled to

–78 °C, and ethyl propiolate (1.2 g, 1.24 mL, 12.0 mmol) was added, followed by TMSOTf (3.3 equiv, 7.2 mL, 39.6 mmol). After 10 minutes at –78 °C, PhMgBr (1.2 equiv, 5.8 mL, 14.4 mmol) was added dropwise via syringe, and the solution was stirred at –78 °C for 2 hrs and

allowed to warm to RT for 2 hrs. The reaction was quenched with H2O and the product extracted with Et2O (3 X 25 mL), and the combined organic layers were washed with brine. The organic layer was separated, dried with MgSO4, and concentrated in vacuo to give the crude product, which was then analyzed by 1H NMR spectroscopy to determine diastereoselectivity. The crude material was then submitted to column chromatography and purified using 2% diethyl ether in hexane.

133 General Experimental Procedure for the synthesis of 116a, applicable for the synthesis of 116b,

116d, 116f, and 116g using EtMgBr: CuI (0.005 g, 0.025 mmol) and LiCl (0.002 g, 0.05 mmol) were flame dried under vacuum in a 10 mL round bottom flask under Ar. Dry THF (2.0 mL) was added and the mixture was stirred at RT for a period of 0.5 h until complete dissolution had occurred. The clear, light yellow homogeneous solution was cooled to –40 °C, and E47i (0.1 g,

0.5 mmol) was placed in a vial and added to the solution dropwise. The vial was washed with dry

THF (3 x 0.2 mL) and added to the reaction. TMSCl (1.2 equiv, 0.08 mL, 0.6 mmol) was then added and allowed to stir for 10 minutes. After this time, EtMgBr (1.2 equiv, 0.22 mL, 0.6 mmol) was added dropwise via syringe, and the solution was stirred at – 40 °C for 3 hrs and then

lowered to –78 °C. The reaction was quenched with sat. NH4Cl (0.2 mL) and warmed to rt for

0.5 hrs. The product was extracted with Et2O (3 X 10 mL), and the combined organic layers were

washed with brine. The organic layer was separated, dried with MgSO4, and concentrated in vacuo to give the crude product, which was then analyzed by 1H NMR spectroscopy to determine diastereoselectivity. The crude material was then submitted to column chromatography and

purified using 2% Et2O in hexane.

1 116a: H NMR: (500 MHz, CDCl3) δ 4.1 (m, 2H), 2.1 (d, J = 9.7 Hz, 1H), 1.83 (m, 1H), 1.5 (m,

2H), 1.4 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H), 0.84 (t, J = 7.4 Hz, 3H), 0.1

13 (s, 9H) C NMR: (125 MHz, CDCl3) δ 175.5, 59.6, 41.4, 39.7, 23.8, 14.6, 10.5, 10.2, - 1.1. IR

(Et2O): 2964, 2876, 2360, 1716, 1460, 1366, 1323, 1251, 1207, 1172, 1120, 1039, 982, 844, 691

-1 + cm . HRMS (EI) calculated for C12H26O2Si [M] : 230.42 found 230.35. Rf = 0.7, 10% Et2O in hexanes.

134 1 116b: H NMR: (500 MHz, CDCl3) δ (Μajor) 4.08 (m, 2H), 1.94 (d, J = 8.8 Hz, 1H), 1.88 (m,

1H), 1.24 (t, J = 7.1 Hz, 3H), 1.05 (m, 1H), 0.99 (d, J = 6.5 Hz, 1H), 0.88 (t, J =7.4 Hz, 3H), 0.10

(s, 9H). δ (Μinor) 4.08 (m, 2H), 1.96 (m, 1H), 1.86 (d, J = 10.3 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H),

1.05 (m, 1H), 0.95 (d, J = 6.7 Hz, 1H), 0.85 (t, J = 7.4 Hz, 3H), 0.10 (s, 9H). 13C NMR: (125

MHz, CDCl3) δ (Μajor) 175.2, 59.4, 43.9, 34.3, 28.9, 18.8, 14.5, 11.3, -1.3. δ (Μinor) 175.5,

59.5, 44.9, 34.2, 29.8, 18.6, 14.4, 10.8, - 1.3. IR (Et2O): 2963, 1716, 1463, 1366, 1316, 1283,

-1 1252, 1217, 1179, 1135, 1118, 1041, 916, 845, 691 cm . HRMS (EI) calculated for C11H24O2Si

+ [M] : 216.40 found 216.34. Rf = 0.7, 10% Et2O in hexanes.

1 116d: H NMR: (500 MHz, CDCl3) δ (Μajor) 4.08 (q, J = 7.2 Hz, 2H), 2.15 (d, J = 8.1 Hz, 1H),

2.07 (m, 1H), 1.48 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H), 0.86 (dd, J = 15.0, 10.6 Hz, 1H), 0.83 (t, J =

7.2 Hz, 3H), 0.61 (dd, J = 15.0, 3.1 Hz, 1H), 0.10 (s, 9H), 0.01 (s, 9H). δ (Μinor) 4.08 (m, 2H),

2.11 (d, J = 8.7 Hz, 1H), 2.07 (m, 1H), 1.48 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H), 0.86 (dd, J = 15.0,

10.6 Hz, 1H), 0.81 (t, J = 7.2 Hz, 3H), 0.61 (dd, J = 15.0, 3.1 Hz, 1H), 0.10 (s, 9H), 0.02 (s, 9H).

13 C NMR: (125 MHz, CDCl3) δ (Μajor) 175.3, 59.6, 43.3, 35.5, 27.2, 21.0, 14.6, 10.0, - 0.33, -

1.1. δ (Μinor) 175.8, 59.5, 44.0, 35.2, 27.3, 20.7, 14.6, 9.4, - 0.42, - 0.86. IR (Et2O): 2956, 1716,

1463, 1415, 1366, 1289, 1250, 1183, 1123, 1041, 968, 928, 840, 758, 689, 654 cm-1. HRMS (EI)

+ calculated for C14H32O2Si2 [M] : 288.58 found 288.43. Rf = 0.7, 10% Et2O in hexanes.

1 116f: H NMR: (500 MHz, CDCl3) δ (Major) 7.27 (m, 2H), 7.18 (m, 3H), 4.10 (m, 2H), 2.66 (m,

2H), 2.23 (d, J = 8.71 Hz), 2.17 (m, 1H), 1.42 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H), 0.84 (t, J = 7.4

Hz, 3h), 0.15 (s, 9H). δ (Minor) 7.27 (m, 2H), 7.18 (m, 3H), 4.10 (m, 2H), 2.66 (m, 2H), 2.17 (m,

1H), 2.11 (d, J = 7.7 Hz, 1H), 1.42 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H),

13 0.13 (s, 9H). C NMR: (125 MHz, CDCl3) δ (Μajor) 175.2, 141.2, 129.4, 128.3, 125.9, 59.8,

135 40.9, 40.6, 38.9, 23.7, 14.6, 10.2, - 1.1. δ (Μinor) 175.0, 141.3, 129.2, 128.4, 126.0, 59.7, 40.8,

40.5, 38.8, 24.3, 14.6, 10.2, - 1.0. IR (Et2O): 3027, 2963, 1714, 1603, 1496, 1454, 1367, 1317,

-1 + 1252, 1129, 1034, 844, 736, 700 cm . HRMS (EI) calculated for C17H28O2Si [M] : 292.49 found

292.40. Rf = 0.7, 10% Et2O in hexanes.

1 116g: H NMR: (500 MHz, CDCl3) δ 4.07 (m, 2H), 2.20 (d, J = 9.0 Hz, 1H), 1.79 (m, 1H), 1.42

(m, 4H), 1.24 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.9 Hz, 9H), 0.83 (dt, J = 9.1, 7.5 Hz, 6H), 0.64 (m,

13 6H). C NMR: (125 MHz, CDCl3) δ 175.5, 59.6, 39.8, 38.0, 24.4, 24.2, 14.5, 11.0, 10.3, 7.6,

3.7. IR (Et2O): 2959, 2877, 2360, 1716, 1460, 1417, 1381, 1322, 1245, 1207, 1173, 1121, 1007,

-1 + 729 cm . HRMS (EI) calculated for C15H32O2Si [M] : 272.50 found 272.45. Rf = 0.7, 10% Et2O in hexanes.

General Experimental Procedure for the synthesis of 116c using E47k and EtMgBr: CuI (0.005 g, 0.025 mmol) and LiCl (0.002 g, 0.05 mmol) were flame dried under vacuum in a 10 mL round bottom flask under Ar. Dry THF (2.5 mL) was added and the mixture was stirred with at RT for a period of 0.5 h until complete dissolution had occurred. The clear, light yellow homogeneous solution was cooled to – 40 °C, and E47k (0.1 g, 0.47 mmol) was placed in a vial and added to the solution dropwise. The vial was washed with dry THF (3 x 0.2 mL) and added to the reaction. TMSCl (1.8 equiv, 0.11 mL, 0.85 mmol) was then added and allowed to stir for 10 minutes. After this time, EtMgBr (1.2 equiv, 0.21 mL, 0.56 mmol) was added dropwise via syringe, and the solution was stirred at – 40 °C for 3 hrs and then lowered to –78 °C. The

reaction was quenched with sat. NH4Cl (0.2 mL) and warmed to RT for 0.5 hrs. The product was extracted with Et2O (3 X 10 mL), and the combined organic layers were washed with brine. The organic layer was separated, dried with MgSO4, and concentrated in vacuo to give the crude

136 product, which was then analyzed by 1H NMR spectroscopy to determine diastereoselectivity.

The crude material was then submitted to column chromatography and purified using 2% Et2O in hexane.

General Experimental Procedure for the synthesis of 116c using E47i and iPrMgCl, applicable to the synthesis of 116j and 116k using iPrMgCl: CuI (0.005 g, 0.025 mmol) and LiCl (0.002 g,

0.05 mmol) was flame dried under vacuum in a 10 mL round bottom flask under Ar. Dry THF

(2.5 mL) was added and the mixture was stirred with at RT for a period of 0.5 h until complete dissolution had occurred. The clear, light yellow homogeneous solution was cooled to – 10 °C, and E47i (0.1 g, 0.5 mmol) was placed in a vial and added to the solution dropwise. The vial was washed with dry THF (3 x 0.2 mL) and added to the reaction. TMSCl (1.2 equiv, 0.08 mL, 0.6 mmol) was then added and allowed to stir for 10 minutes. After this time, iPrMgCl (2.5 equiv,

0.64 mL, 1.25 mmol) was added dropwise via syringe, and the solution was stirred at – 10 °C for

3 hrs and then lowered to – 78 °C. The reaction was quenched with sat. NH4Cl (0.4 mL) and

warmed to RT for 0.5 hrs. The product was extracted with Et2O (3 X 10 mL), and the combined

organic layers were washed with brine. The organic layer was separated, dried with MgSO4, and concentrated in vacuo to give the crude product, which was then analyzed by 1H NMR spectroscopy to determine diastereoselectivity. The crude material was then submitted to column

chromatography and purified using 2% Et2O in hexane.

1 116c: H NMR: (500 MHz, CDCl3) δ 4.08 (m, 2H), 2.16 (d, J = 6.7 Hz, 1H), 1.89 (m, 1H), 1.62

(m, 1H), 1.57 (m, 1H), 1.48 (m, 1H), 1.26 (t, J = 7.2 Hz, 3H), 0.92 (t, J = 7.5 Hz, 3H), 0.90 (d, J

13 = 6.82 Hz, 3H), 0.86 (d, J = 6.82 Hz, 3H), 0.11 (s, 9H). C NMR: (125 MHz, CDCl3) δ 175.6,

59.5, 45.4, 39.9, 30.7, 23.4, 19.9, 19.0, 14.5, 14.4, -1.4. IR (Et2O): 2960, 1716, 1466, 1388, 1368,

137 -1 1320, 1251, 1173, 1125, 1040, 993, 843, 758, 691 cm . HRMS (EI) calculated for C13H28O2Si

+ + [M] : 244.45 found 201.13 [M-C3H7] . Rf = 0.7 10% Et2O in hexanes.

1 116j: H NMR: (500 MHz, CDCl3) δ 4.05 (m, 2H), 2.13 (d, J = 4.9 Hz, 1H), 1.96 (m, 1H), 1.78

(m, 1H), 1.23 (t, J = 7.1 Hz, 3H), 0.99 (dd, J = 15.7, 5.1 Hz, 1H) 0.85 (d, J = 6.8 Hz, 3H), 0.80

(d, J = 6.8 Hz, 3H), 0.69 (dd, J = 15.7, 2.83 Hz, 1H), 0.08 (s, 9H), 0.00 (s, 9H). 13C NMR: (125

MHz, CDCl3) δ 175.4, 59.5, 39.7, 32.8, 20.0, 18.1, 18.0, 14.6, - 0.2. - 1.5. IR (Et2O): 2955, 2900,

1716, 1465, 1414, 1387, 1368, 1318, 1250, 1181, 1143, 1120, 1044, 1013, 989, 945, 839, 762,

743, 723, 689, 647, 612, 564, 551, 540, 503 cm-1.

+ HRMS (EI) calculated for C15H34O2Si2 [M] : 302.61 found 302.54. Rf = 0.8, 10% Et2O in hexanes.

1 116k: H NMR: (500 MHz, CDCl3) δ 4.04 (m, 2H), 2.26 (d, J = 5.2 Hz, 1H), 1.86 (m, 1H), 1.59

(m, 3H), 1.23 (t, J = 7.2 Hz, 3H), 0.97 (t, J = 7.9 Hz, 9H), 0.90 (t, J = 7.2 Hz, 3H), 0.84 (d, J =

13 6.9 Hz, 3 H), 0.84 (d, J = 6.9 Hz, 3 H), 0.63 (m, 6H). C NMR: (125 MHz, CDCl3) δ 175.6,

59.5, 45.4, 35.9, 30.9, 23.6, 20.0, 19.1, 14.4, 7.6, 3.5. IR (Et2O): 2957, 2877, 1718, 1465, 1417,

-1 + 1367, 1319, 1252, 1172, 1124, 1007, 729 cm . HRMS (EI) calculated for C16H34O2Si [M] :

+ 286.53 found 243.1780 [M-C3H7] . Rf = 0.8, 10% Et2O in hexanes.

General Experimental Procedure for the synthesis of 116e using E47g and iPrMgCl: CuI

(0.0026 g, 0.014 mmol) and LiCl (0.0011 g, 0.027 mmol) was flame dried under vacuum in a 10 mL round bottom flask under Ar. Dry THF (1.0 mL) was added and the mixture was stirred with at RT for a period of 0.5 h until complete dissolution had occurred. The clear, light yellow homogeneous solution was cooled to –20 °C, and E47g (0.05 g, 0.27 mmol) was placed in a vial

138 and added to the solution dropwise. The vial was washed with dry THF (3 x 0.2 mL) and added to the reaction. TMSCl (1.2 equiv, 0.04 mL, 0.32 mmol) was then added and allowed to stir for

10 minutes. After this time, iPrMgCl (1.2 equiv, 0.16 mL, 0.32 mmol) was added dropwise via syringe, and the solution was stirred at –20 °C for 3 hrs and then lowered to –78 °C. The

reaction was quenched with sat. NH4Cl (0.2 mL) and warmed to RT for 0.5 hrs. The product was

extracted with Et2O (3 X 10 mL), and the combined organic layers were washed with brine. The organic layer was separated, dried with MgSO4, and concentrated in vacuo to give the crude product, which was then analyzed by 1H NMR spectroscopy to determine diastereoselectivity.

The crude material was then submitted to column chromatography and purified using 2% Et2O in hexane.

1 116e: H NMR: (500 MHz, CDCl3) δ 4.08 (m, 2H), 2.06 (d, J = 9.3 Hz, 1H), 1.87 (m, 1H), 1.77

(m, 1H), 1.24 (t, J = 7.1 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H), 0.77 (d, J =

13 6.8 Hz, 3H), 0.09 (s, 9H). C NMR: (125 MHz, CDCl3) δ 175.5, 59.6, 42.5, 38.5, 31.1, 21.8,

16.7, 14.6, 14.0, - 1.3. IR (Et2O): 2961, 2874, 1716, 1466, 1389, 1367, 1341, 1319, 1303, 1268,

1251, 1215, 1175, 1134, 1111, 1084, 1039, 924, 891, 844, 759, 736, 692, 659 cm-1. HRMS (EI)

+ + calculated for C12H26O2Si [M] : 230.42 found 187.11 [M-C3H7] . Rf = 0.7, 10% Et2O in hexanes.

General Experimental Procedure for the synthesis of 116h using E47i and PhMgBr: CuI (0.0025 g, 0.013 mmol) and LiCl (0.0011 g, 0.025 mmol) was flame dried under vacuum in a 10 mL round bottom flask under Ar. Dry THF (1.0 mL) was added and the mixture was stirred with a at

RT for a period of 0.5 h until complete dissolution had occurred. The clear, light yellow homogeneous solution was cooled to –20 °C, and E47i (0.05 g, 0.25 mmol) was placed in a vial and added to the solution dropwise. The vial was washed with dry THF (3 x 0.2 mL) and added

139 to the reaction. TMSCl (1.2 equiv, 0.04 mL, 0.3 mmol) was then added and allowed to stir for 10 minutes. After this time, PhMgBr (1.2 equiv, 0.1 mL, 0.3 mmol) was added dropwise via syringe, and the solution was stirred at –20 °C for 3 hrs and then lowered to –78 °C. The

reaction was quenched with sat. NH4Cl (0.2 mL) and warmed to RT for 0.5 hrs. The product was extracted with Et2O (3 X 10 mL), and the combined organic layers were washed with brine. The

organic layer was separated, dried with MgSO4, and concentrated in vacuo to give the crude product, which was then analyzed by 1H NMR spectroscopy to determine diastereoselectivity.

The crude material was then submitted to column chromatography and purified using 2% Et2O in hexane.

General Experimental Procedure for the synthesis of 116h using E47r and EtMgBr: CuI (0.002 g, 0.01 mmol) and LiCl (0.0008 g, 0.02 mmol) was flame dried under vacuum in a 10 mL round bottom flask under Ar. Dry THF (1.0 mL) was added and the mixture was stirred with at RT for a period of 0.5 h until complete dissolution had occurred. The clear, light yellow homogeneous solution was cooled to –20 °C, and E47i (0.05 g, 0.20 mmol) was placed in a vial and added to the solution dropwise. The vial was washed with dry THF (3 x 0.2 mL) and added to the reaction. EtMgBr (1.2 equiv, 0.08 mL, 0.24 mmol) was added dropwise via syringe, and the solution was stirred at – 20 °C for 3 hrs and then lowered to –78 °C. The reaction was quenched

with sat. NH4Cl (0.2 mL) and warmed to RT for 0.5 hrs. The product was extracted with Et2O (3

X 10 mL), and the combined organic layers were washed with brine. The organic layer was

separated, dried with MgSO4, and concentrated in vacuo to give the crude product, which was then analyzed by 1H NMR spectroscopy to determine diastereoselectivity. The crude material

was then submitted to column chromatography and purified using 2% Et2O in hexane.

140 1 116h: H NMR: (500 MHz, CDCl3) δ 7.27 (t, J = 7.4 Hz, 2H), 7.19 (t, J = 7.4 Hz, 1H), 7.16 (d, J

= 7.1 Hz, 2H), 4.15 (m, 2H), 2.95 (dt, J = 11.5, 3.4 Hz, 1H), 2.38 (d, J = 11.9 Hz, 1H), 1.74 (m,

1H), 1.53 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 0.63 (t, J = 7.4 Hz, 3H), - 0.26 (s, 9H). 13C NMR:

(125 MHz, CDCl3) δ 175.3, 143.1, 128.8, 128.4, 126.8, 60.0, 46.8, 45.5, 30.7, 14.6, 12.0, - 2.0.

IR (Et2O): 3062, 3028, 2961, 2930, 2873, 1714, 1660, 1603, 1495, 1453, 1366, 1322, 1250,

1197, 1155, 1126, 1078, 1066, 1035, 1012, 961, 897, 845, 760, 734, 702, 621, 601, 580, 554,

-1 + 538, 510 cm . HRMS (EI) calculated for C16H26O2Si [M] : 278.47 found -----Rf = 0.7, 10% Et2O in hexanes.

General Experimental Procedure for the synthesis of 116i using E47g and PhMgBr: CuI (0.0026 g, 0.014 mmol) and LiCl (0.0011 g, 0.027 mmol) was flame dried under vacuum in a 10 mL round bottom flask under Ar. Dry THF (1.0 mL) was added and the mixture was stirred with at

RT for a period of 0.5 h until complete dissolution had occurred. The clear, light yellow homogeneous solution was cooled to – 20 °C, and E47g (0.05 g, 0.27 mmol) was placed in a vial and added to the solution dropwise. The vial was washed with dry THF (3 x 0.2 mL) and added to the reaction. TMSCl (1.2 eq., 0.04 mL, 0.32 mmol) was then added and allowed to stir for 10 minutes. After this time, PhMgBr (1.2 equiv, 0.11 mL, 0.32 mmol) was added dropwise via syringe, and the solution was stirred at – 20 °C for 3 hrs and then lowered to –78 °C. The

reaction was quenched with sat. NH4Cl (0.2 mL) and warmed to RT for 0.5 hrs. The product was extracted with Et2O (3 X 10 mL), and the combined organic layers were washed with brine. The organic layer was separated, dried with MgSO4, and concentrated in vacuo to give the crude product, which was then analyzed by 1H NMR spectroscopy to determine diastereoselectivity.

The crude material was then submitted to column chromatography and purified using 2% Et2O in hexane.

141

1 116i: H NMR: (500 MHz, CDCl3) δ (Major) 7.24 (m, 5H), 4.16 (m, 2H), 3.24 (dq, J = 11.7, 6.7

Hz, 1H), 2.34 (d, J = 11.6 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H), 1.28 (d, J = 6.8 Hz, 3H), - 0.23 (s,

9H). δ (Minor) 7.24 (m, 5H), 3.80 (m, 2H), 3.24 (dq, J = 11.7, 6.7 Hz, 1H), 2.35 (d, J = 11.7 Hz,

1H), 0.97 (d, J = 6.6 Hz, 3H), 0.96 (t, J = 7.1 Hz, 3H), 0.19 (s, 9H). 13C NMR: (125 MHz,

CDCl3) δ (Major) 175.2, 145.7, 128.6, 127.8, 126.7, 60.0, 46.1, 39.7, 24.2, 14.6, -2.0. δ (Minor)

175.2, 128.7, 128.3, 127.0, 126.2, 59.6, 46.2, 39.8, 23.0, 14.3, -1.2. IR (Et2O): 3062, 3029, 2962,

2900, 1714, 1604, 1495, 1454, 1366, 1350, 1332, 1290, 1261, 1250, 1203, 1161, 1127, 1080,

-1 + 1040, 913, 844, 766, 738, 702, 571, 539 cm . HRMS (EI) calculated for C15H24O2Si [M] :

264.44 found 264.1546. Rf = 0.6 10% Et2O in hexanes.

General Experimental Procedure for the synthesis of 116l using E47i and ChxMgCl: CuI (0.006 g, 0.03 mmol) and LiCl (0.002 g, 0.05 mmol) was flame dried under vacuum in a 10 mL round bottom flask under Ar. Dry THF (2.5 mL) was added and the mixture was stirred with at RT for a period of 0.5 h until complete dissolution had occurred. The clear, light yellow homogeneous solution was cooled to – 10 °C, and E47i (0.1 g, 0.5 mmol) was placed in a vial and added to the solution dropwise. The vial was washed with dry THF (3 x 0.2 mL) and added to the reaction.

TMSCl (1.2 equiv, 0.08 mL, 0.6 mmol) was then added and allowed to stir for 10 minutes. After this time, ChxMgCl (2.5 equiv, 0.63 mL, 1.25 mmol) was added dropwise via syringe, and the solution was stirred at – 10 °C for 3 hrs and then lowered to –78 °C. The reaction was quenched

with sat. NH4Cl (0.4 mL) and warmed to RT for 0.5 hrs. The product was extracted with Et2O (3

X 10 mL), and the combined organic layers were washed with brine. The organic layer was

separated, dried with MgSO4, and concentrated in vacuo to give the crude product, which was then analyzed by 1H NMR spectroscopy to determine diastereoselectivity. The crude material

142 was then submitted to column chromatography and purified using 2% Et2O in hexane.

1 116l: H NMR: (500 MHz, CDCl3) δ 4.06 (m, 2H), 2.18 (d, 6.7 Hz, 1H), 1.74 (m, 2H), 1.65 (m,

1H), 1.58 (m, 3H), 1.46 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H), 1.15 (m, 6H), 0.89 (t, J = 7.3 Hz, 3H),

13 0.09 (s, 9H). C NMR: (125 MHz, CDCl3) δ 175.6, 59.6, 45.3, 41.8, 40.2, 30.8, 29.5, 27.4, 26.9,

23.8, 14.5, 14.4, -1.4. IR (Et2O): 2927, 2853, 2360, 1716, 1449, 1365, 1331, 1305, 1251, 1211,

1185, 1170, 1251, 1211, 1185, 1170, 1137, 1114, 1039, 956, 891, 844, 759, 693, 661, 625, 576,

-1 + 565, 539, 527, 516, 501 cm . HRMS (EI) calculated for C16H32O2Si [M] : 284.52 found

+ 269.1937 [M-CH3] . Rf = 0.8, 10% Et2O in hexanes.

General Experimental Procedure for the synthesis of 116m using E47g and ChxMgCl: CuI

(0.0026 g, 0.014 mmol) and LiCl (0.0011 g, 0.027 mmol) was flame dried under vacuum in a 10 mL round bottom flask under Ar. Dry THF (1.0 mL) was added and the mixture was stirred with at RT for a period of 0.5 h until complete dissolution had occurred. The clear, light yellow homogeneous solution was cooled to – 20 °C, and E47g (0.05 g, 0.27 mmol) was placed in a vial and added to the solution dropwise. The vial was washed with dry THF (3 x 0.2 mL) and added to the reaction. TMSCl (1.2 equiv, 0.04 mL, 0.32 mmol) was then added and allowed to stir for

10 minutes. After this time, ChxMgCl (1.2 equiv, 0.16 mL, 0.32 mmol) was added dropwise via syringe, and the solution was stirred at – 20 °C for 3 hrs and then lowered to –78 °C. The

reaction was quenched with sat. NH4Cl (0.2 mL) and warmed to RT for 0.5 hrs. The product was extracted with Et2O (3 X 10 mL), and the combined organic layers were washed with brine. The organic layer was separated, dried with MgSO4, and concentrated in vacuo to give the crude product, which was then analyzed by 1H NMR spectroscopy to determine diastereoselectivity.

The crude material was then submitted to column chromatography and purified using 2% Et2O in hexane.

143

1 116m: H NMR: (500 MHz, CDCl3) δ 4.08 (m, 2H), 2.11 (d, J = 9.4 Hz, 1H), 1.84 (m, 1H), 1.73

(m, 2H), 1.65 (m, 1H), 1.54 (m, 2H), 1.38 (m, 1H), 1.24 (t, J = 7.1 Hz, 3H), 1.14 (m 4H), 0.96

13 (m, 1H), 0.90 (d, J = 6.9 Hz, 3H), 0.09 (s, 9H). C NMR: (500 MHz, CDCl3) δ 175.6, 59.6,

42.0, 41.7, 38.1, 32.2, 27.3, 27.2, 26.8, 26.6, 15.2, 14.6, -1.3. IR (Et2O): 2926, 2852, 2360, 1716,

1448, 1365, 1339, 1323, 1303, 1250, 1219, 1190, 1165, 1136, 1111, 1038, 892, 845, 757, 691

-1 + cm . HRMS (EI) calculated for C15H30O2Si [M] : 270.49 found 270.34. Rf = 0.9, 10% Et2O in hexanes.

Tandem Aldol-Olefination Process:

General Experimental Procedure for the synthesis of 166e: Freshly distilled diisopropylamine

(1.1 equiv, 0.06 mL, 0.42 mmol) in dry THF (1.27 mL) was placed in a flame dried 15 mL round bottom flask and cooled to 0 °C. n-Butyllithium (1.1 equiv, 0.22 mL, 0.42 mmol) was added to the solution dropwise via syringe and allowed stir for 30 min. The reaction was then cooled to -

78 °C. E47f (0.1 g, 0.38 mmol) was placed in a vial and added to the solution dropwise. The vial was washed with dry THF (3 x 0.2 mL) and added to the reaction. The reaction was then allowed

to stir for 2 hrs. Chx2BCl (2.2 equiv, 0.84 mL, 0.84 mmol) was added to the reaction dropwise at

-78 °C. The reaction was warmed to -20 °C and allowed to stir for 1 hr. The reaction was cooled to -78 °C again and propionaldehyde (5 equiv, 0.14 mL, 1.9 mmol) was added dropwise. This was allowed to stir for 3 hrs at – 78 °C and then warmed to RT over night in the ice bath. The reaction was then cooled to 0 °C and methanol (1 mL) was added, followed by 3M NaOH (0.8

mL) and 30% H2O2 (0.3 mL) dropwise. The ice bath was removed and the reaction was allowed to stir for 12 hrs. The product was extracted with Et2O (3 X 10 mL), and the combined organic

144 layers were washed with brine. The organic layer was separated, dried with MgSO4, and concentrated in vacuo to give the crude product, which was then analyzed by 1H NMR spectroscopy to determine diastereoselectivity. The crude material was then submitted to column

chromatography and purified using 2% Et2O in hexane.

1 166e: H NMR (500 MHz, CDCl3) δ (Z) 7.39 (d, J = 7.5 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.22

(t, J = 7.3 Hz, 1H), 6.73 (d, J = 16.4, 1H), 6.60 (d, J = 16.4 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H),

2.34 (quint, J = 7.6 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.09 (t, J = 7.6 Hz, 3H). 13C NMR (125

MHz, CDCl3): δ (Z) 167.9, 140.8, 137.4, 133.2, 129.6, 128.7, 127.7, 127.0, 126.7, 60.9, 23.5,

-1 14.5, 14.0. IR (Et2O): 2968, 1718, 1448, 1377, 1208, 1156, 1029, 961, 748, 692 cm . HRMS

+ (EI) calculated for C15H18O2 [M] : 230.31 found 230.14. Rf = 0.6, 10% Et2O in hexanes.

General Experimental Procedure for the synthesis of 166f: Freshly distilled diisopropylamine

(1.1 equiv, 0.06 mL, 0.42 mmol) in dry THF (1.27 mL) was placed in a flame dried 15 mL round bottom flask and cooled to 0 °C. n-Butyllithium (1.1 equiv, 0.22 mL, 0.42 mmol) was added to the solution dropwise via syringe and allowed stir for 30 min. The reaction was then cooled to -

78 °C. E47f (0.1 g, 0.38 mmol) was placed in a vial and added to the solution dropwise. The vial was washed with dry THF (3 x 0.2 mL) and added to the reaction. The reaction was then allowed

to stir for 2 hrs. Chx2BCl (2.2 equiv, 0.84 mL, 0.84 mmol) was added to the reaction dropwise at

-78 °C. The reaction was warmed to -20 °C and allowed to stir for 1 hr. The reaction was cooled to -40 °C again and isobutyraldehyde (5 equiv, 0.18 mL, 1.9 mmol) was added dropwise. This was allowed to stir for 3 hrs at –40 °C and then warmed to RT over night in the ice bath. The reaction was then cooled to 0 °C and methanol (1 mL) was added, followed by 3M NaOH (0.8

145 mL) and 30% H2O2 (0.3 mL) dropwise. The ice bath was removed and the reaction was allowed to stir for 12 hrs. The product was extracted with Et2O (3 X 10 mL), and the combined organic layers were washed with brine. The organic layer was separated, dried with MgSO4, and concentrated in vacuo to give the crude product, which was then analyzed by 1H NMR spectroscopy to determine diastereoselectivity. The crude material was then submitted to column

chromatography and purified using 2% Et2O in hexane.

1 166f: H NMR: (500 MHz, CDCl3) δ (Z) 7.39 (d, J = 7.76 Hz, 2H), 7.31 (t, J = 7.76 Hz, 2H),

7.22 (t, J = 7.20 Hz, 1H), 6.70 (dd, J = 16.27 and 0.69 Hz, 1H), 6.59 (d, J = 16.27 Hz, 1H), 5.80

(d, J = 10.0 Hz, 1H), 4.35 (q, J = 7.14 Hz, 2H), 2.78 (ds, J = 10.0, 6.6 Hz, 1H), 1.38 (t, J = 7.14

13 Hz, 3H), 1.08 (d, J = 6.64 Hz, 6H). C NMR: (125 MHz, CDCl3) δ(Z) 168.0, 145.6, 137.4,

131.6, 129.6, 128.7, 127.7, 127.6, 126.6, 60.9, 29.6, 22.9, 14.5. IR (Et2O): 2963, 1723, 1447,

1376, 1324, 1236, 1208, 1180, 1112, 1022, 959, 845, 748, 692 cm-1. HRMS (EI) calculated for

+ C16H20O2 [M] : 244.33 found 244.12. Rf = 0.7, 10% Et2O in hexanes.

General Experimental Procedure for the synthesis of 166h: Freshly distilled diisopropylamine

(1.1 equiv, 0.07 mL, 0.52 mmol) in dry THF (1.57 mL) was placed in a flame dried 15 mL round bottom flask and cooled to 0 °C. n-Butyllithium (1.1 equiv, 0.25 mL, 0.52 mmol) was added to the solution dropwise via syringe and allowed stir for 30 min. The reaction was then cooled to -

40 °C. E47k (0.1 g, 0.47 mmol) was placed in a vial and added to the solution dropwise. The vial was washed with dry THF (3 x 0.2 mL) and added to the reaction. The reaction was then allowed

to stir for 2 hrs. Chx2BCl (2.2 equiv, 1.03 mL, 1.03 mmol) was added to the reaction dropwise at

-78 °C. The reaction was warmed to -20 °C and allowed to stir for 1 hr. Propionaldehyde (5

146 equiv, 0.17 mL, 2.4 mmol) was added dropwise at -20 °C. This was allowed to stir for 3 hrs at -

20 °C and then warmed to RT over night in the ice bath. The reaction was then cooled to 0 °C

and methanol (1 mL) was added, followed by 3M NaOH (0.8 mL) and 30% H2O2 (0.3 mL) dropwise. The ice bath was removed and the reaction was allowed to stir for 12 hrs. The product

was extracted with Et2O (3 X 10 mL), and the combined organic layers were washed with brine.

The organic layer was separated, dried with MgSO4, and concentrated in vacuo to give the crude product, which was then analyzed by 1H NMR spectroscopy to determine diastereoselectivity.

The crude material was then submitted to column chromatography and purified using 2% Et2O in hexane.

1 166h: H NMR (500 MHz, CDCl3): δ (Z) 5.81 (m, 1H), 5.79 (t, J = 7.7 Hz, 1H), 4.22 (q, J = 7.1

Hz, 2H), 2.39 (quin, J = 7.5 Hz, 2H), 1.79 (d, J = 1.24 Hz, 3H), 1.68 (d, J = 1.24 Hz, 3H), 1.31

13 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.5 Hz, 3H). C NMR (125 MHz, CDCl3): δ (Z) 168.6, 143.4,

135.5, 130.4, 122.4, 60.5, 26.7, 23.1, 19.3, 14.4, 14.1. IR (Et2O): 2970, 2933, 2874, 2361, 1718,

1627, 1447, 1372, 1338, 1312, 1223, 1191, 1154, 1036, 885, 839, 795, 600, 573, 542, 526, 510

-1 + cm . HRMS (EI) calculated for C11H18O2 [M] : 182.26 found 182.14. Rf = 0.7, 10% Et2O in hexanes.

General Experimental Procedure for the synthesis of 166i: Freshly distilled diisopropylamine

(1.1 equiv, 0.08 mL, 0.55 mmol) in dry THF (1.7 mL) was placed in a flame dried 15 mL round bottom flask and cooled to 0 °C. n-Butyllithium (1.1 equiv, 0.27 mL, 0.55 mmol) was added to the solution dropwise via syringe and allowed stir for 30 min. The reaction was then cooled to -

78 °C. E47i (0.1 g, 0.5 mmol) was placed in a vial and added to the solution dropwise. The vial

147 was washed with dry THF (3 x 0.2 mL) and added to the reaction. The reaction was then allowed

to stir for 2 hrs. Chx2BCl (2.2 equiv, 1.1 mL, 1.1 mmol) was added to the reaction dropwise at -

78 °C. The reaction was warmed to -20 °C and allowed to stir for 1 hr. The reaction was cooled to -78 °C again and propionaldehyde (5 equiv., 0.19 mL, 2.5 mmol) was added dropwise. This was allowed to stir for 3 hrs at -78 °C and then warmed to RT over night in the ice bath. The reaction was then cooled to 0 °C and methanol (1 mL) was added, followed by 3M NaOH (0.8

mL) and 30% H2O2 (0.3 mL) dropwise. The ice bath was removed and the reaction was allowed to stir for 12 hrs. The product was extracted with Et2O (3 X 10 mL), and the combined organic layers were washed with brine. The organic layer was separated, dried with MgSO4, and concentrated in vacuo to give the crude product, which was then analyzed by 1H NMR spectroscopy to determine diastereoselectivity. The crude material was then submitted to column

chromatography and purified using 2% Et2O in hexane.

1 166i: H NMR (500 MHz, CDCl3): δ (Z) 6.01 (d, J = 15.7 Hz, 1H), 5.70 (m, 2H), 4.26 (q, J = 7.2

Hz, 2H), 2.39 (quin, J = 7.5 Hz, 2H), 1.75 (d, J = 6.3 Hz, 3H), 1.32 (t, J = 7.24 Hz, 3H), 1.02 (t,

J = 7.5 Hz, 3H).

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156 APPENDIX

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound E47i………………………………160

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound E47i……………………………...161

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound E47j……………………...……….162

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound E47j……………………………...163

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound E47k………………………..…….164

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound E47k……………...……………...165

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound E47l………………………………166

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound E47l……………………………...167

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound E47m…………………….……….168

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound E47m………………………..…...169

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound E47n………………………..…….170

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound E47n………………………...…...171

1 The H NMR Spectrum (360 MHz, CDCl3) of Compound 61.1……………………..………...172

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 61.1………………………………173

1 The H NMR Spectrum (360 MHz, CDCl3) of Compound E61.40……………………..…...... 174

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound E61.40…………………………...175

1 The H NMR Spectrum (360 MHz, CDCl3) of Compound E61.41……………..…………...... 176

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound E61.41…………………………...177

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound E61.42……………………..……..178

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound E61.42………………………..….179

157 1 The H NMR Spectrum (500 MHz, CDCl3) of Compound E61.43……………………...... …..180

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound E61.43……………………..…….181

1 The H NMR Spectrum (360 MHz, CDCl3) of Compound 60c………………………...... …....182

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 60c………………….……………183

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 60d……………………...... …….184

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 60d………………………….……185

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 60e……………………….....….....186

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 60e……………………….………187

1 The H NMR Spectrum (500 MHz, C6D6) of Compound 60f………...... …….…....…….188

13 The C NMR Spectrum (125 MHz, C6D6) of Compound 60f…………………………………189

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 60g……………...... …………….190

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 60g………………………….……191

1 The H NMR Spectrum (500 MHz, C6D6) of Compound 60h………...……………….....…....192

13 The C NMR Spectrum (125 MHz, C6D6) of Compound 60h……………………..……….....193

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116a……………………………....194

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116a……………………………...195

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116b……………………….……...196

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116b……………………….……..197

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116c……………………….……...198

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116c……………………….……..199

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116d………………..……………..200

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116d………………………..…….201

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116e………………………..……..202

158 13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116e………………..…………….203

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116f……………………………….204

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116f……………………………....205

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116g……………………………....206

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116g……………………………...207

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116h…………………………...... 208

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116h…………………………..….209

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116i…………………………….....210

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116i……………………………....211

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116j…………………………….....212

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116j…………………………...….213

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116k…………………………...... 214

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116k…………………………..….215

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116l…………………………...…..216

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116l……………………………....217

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116m……………………………...218

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116m…………………..……...….219

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 166e…………………………...... 220

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 166e…………………...... 221

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 166f……………………………….222

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 166f……………………………....223

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 166h………………...………….....224

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 166h……...……………………....225

159 CO2Et

SiMe3 E47i

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound E47i

160 CO2Et

SiMe3 E47i

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound E47i

161 CO2Et

SiEt3 E47j

1 The H NMR Spectrum (360 MHz, CDCl3) of Compound E47j

162 CO2Et

SiEt3 E47j

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound E47j

163 CO2Et

SiMe3 E47k

1 The H NMR Spectrum (360 MHz, CDCl3) of Compound E47k

164 CO2Et

SiMe3 E47k

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound E47k

165

CO2Et

Me3Si SiMe3 E47l

1 The H NMR Spectrum (360 MHz, CDCl3) of Compound E47l

166

CO2Et

Me3Si SiMe3 E47l

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound E47l

167

CO2Et

Me3Si SiEt3 E47m

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound E47m

168

CO2Et

Me3Si SiEt3 E47m

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound E47m

169

CO2Et

Me3Si SiMe3 E47n

1 The H NMR Spectrum (360 MHz, CDCl3) of Compound E47n

170

CO2Et

Me3Si SiMe3 E47n

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound E47n

171

CO2Et

SiMe3 61.1

1 The H NMR Spectrum (360 MHz, CDCl3) of Compound 61.1

172

CO2Et

SiMe3 61.1

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 61.1

173

CO2Et

SiEt3 E61.40

1 The H NMR Spectrum (360 MHz, CDCl3) of Compound E61.40

174 CO2Et

SiEt3 E61.40

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound E61.40

175 CO2Et

SiEt3 E61.41

1 The H NMR Spectrum (360 MHz, CDCl3) of Compound E61.41

176 CO2Et

SiEt3 E61.41

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound E61.41

177 Me3Si CO2Et

SiMe3 E61.42

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound E61.42

178 Me3Si CO2Et

SiMe3 E61.42

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound E61.42

179 Me3Si CO2Et

SiEt3 E61.43

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound E61.43

180 Me3Si CO2Et

SiEt3 E61.43

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound E61.43

181 OSIMe3 OEt

SiMe3 60c

1 The H NMR Spectrum (360 MHz, CDCl3) of Compound 60c

182 OSIMe3 OEt

SiMe3 60c

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 60c

183 OSIMe3 OEt

SiEt3 60d

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 60d

184 OSIMe3 OEt

SiEt3 60d

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 60d

185 OSIMe3 OEt

SiMe3 60e

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 60e

186 OSIMe3 OEt

SiMe3 60e

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 60e

187 OSIMe3 OEt

SiEt3 60f

1 The H NMR Spectrum (500 MHz, C6D6) of Compound 60f

188 OSIMe3 OEt

SiEt3 60f

13 The C NMR Spectrum (125 MHz, C6D6) of Compound 60f

189 OSIMe3 OEt

SiMe3 60g

The 1H

NMR Spectrum (500 MHz, CDCl3) of Compound 60g

190 OSIMe3 OEt

SiMe3 60g

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 60g

191 OSIMe3 Me Si 3 OEt

SiMe3 60h

1 The H NMR Spectrum (500 MHz, C6D6) of Compound 60h

192 OSIMe3 Me Si 3 OEt

SiMe3 60h

13 The C NMR Spectrum (125 MHz, C6D6) of Compound 60h

193 SiMe3

CO2Et 116a

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116a

194 SiMe3

CO2Et 116a

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116a

195 SiMe3

CO2Et 116b

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116b

196 SiMe3

CO2Et 116b

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116b

197 SiMe3

CO2Et 116c

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116c

198 SiMe3

CO2Et 116c

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116c

199 SiMe3

CO2Et

Me3Si 116d

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116d

200 SiMe3

CO2Et

Me3Si 116d

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116d

201 SiMe3

CO2Et 116e

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116e

202 SiMe3

CO2Et 116e

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116e

203 SiMe3

CO2Et Ph 116f

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116f

204 SiMe3

CO2Et Ph 116f

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116f

205 SiEt3

CO2Et 116g

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116g

206 SiEt3

CO2Et 116g

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116g

207

SiMe3

CO2Et Ph 116h

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116h

208 SiMe3

CO2Et Ph 116h

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116h

209 SiMe3

CO2Et Ph 116i

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116i

210 SiMe3

CO2Et Ph 116i

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116i

211 SiMe3

Me3Si CO2Et 116j

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116j

212 SiMe3

Me3Si CO2Et 116j

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116j

213

SiEt3

CO2Et 116k

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116k

214

SiEt3

CO2Et 116k

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116k

215

SiMe3

CO2Et

116l

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116l

216 SiMe3

CO2Et

116l

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116l

217 SiMe3

CO2Et 116m

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 116m

218 SiMe3

CO2Et 116m

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 116m

219 CO2Et

166e Ph

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 166e

220 CO2Et

166e Ph

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 166e

221 CO2Et

166f Ph

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 166f

222 CO2Et

166f Ph

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 166f

223 CO2Et

166h

1 The H NMR Spectrum (500 MHz, CDCl3) of Compound 166h

224 CO2Et

166h

13 The C NMR Spectrum (125 MHz, CDCl3) of Compound 166h

225