Asymmetric Synthesis of C-1 Substituted Cocaine Analogues

ASYMMETRIC SYNTHESIS OF C-1 SUBSTITUTED COCAINE ANALOGUES

USING SULFINIMINE (N-SULFINYL IMINE) CHEMISTRY AND

VINYLALUMINUM ADDITION TO SULFINIMINES

(N-SULFINYL IMINES) FOR THE ASYMMETRIC

SYNTHESIS OF α-SUBSTITUTED-β-AMINO ESTERS

A Dissertation Submitted to the Temple University Graduate Board

In Partial Fulfillment of the Requirements for the

Degree of Doctor of Philosophy

Narendra Varma Gaddiraju On August 2013 Examining Committee Members

Dr. Franklin A. Davis, Research Advisor, Department of Chemistry

Dr. Rodrigo B. Andrade, Committee Chair, Department of Chemistry

Dr. William M. Wuest, Committee Member, Department of Chemistry

Dr. Kevin C. Cannon, External Committee Member, Department of Chemistry, Penn State

Abington

DEDICATION

This dissertation is dedicated to

My mother Ramasita Gadhiraju

My brother Surender Varma Gadhiraju

And

To my friends Naresh Theddu and Lan Nguyen Theddu

ABSTRACT

ASYMMETRIC SYNTHESIS OF C-1 SUBSTITUTED COCAINE ANALOGUES USING

SULFINIMINE (N-SULFINYL IMINE) CHEMISTRY AND VINYLALUMINUM

ADDITION TO SULFINIMINES (N-SULFINYL IMINES) FOR THE

ASYMMETRIC SYNTHESIS OF α-SUBSTITUTED-

β-AMINO ESTERS

Narendra Varma Gaddiraju

Doctor of Philosophy

Temple University, 2013

Organic nitrogen containing chiral compounds are widely found in nature, and a number of them exhibit important biological and medicinal properties. The main objective of this research is to develop new methods for the asymmetric synthesis of cocaine analogues having methyl (Me), ethyl (Et), n-propyl (n-Pr), n-pentyl (n-C5H11) and phenyl (Ph) groups at the C-1 bridgehead position. The second project concerned the asymmetric synthesis of anti-α-alkyl substituted β-amino esters, a new chiral building block, utilizing chiral sulfinimine (N-sulfinyl imine) chemistry.

The easy availability and abuse of (R)-(-)-cocaine is a global problem and has resulted in many efforts aimed at the preparation of therapeutically useful cocaine analogues. However, to

iii date analogues of cocaine for the treatment of cocaine addiction have not been reported. The requirement of a cis relationship between C-2 and C-3 substituents in the cocaine tropane skeleton where C-2 carbomethoxy group occupies the thermodynamically unfavorable axial position is the main reason for the difficulty in designing efficient asymmetric syntheses of cocaine analogues.

In this study, diastereomerically pure N-sulfinyl β-amino esters were prepared by the addition of the sodium enolate of methyl acetate to masked oxo sulfinimines, novel sulfinimines having a protected carbonyl group. Reduction of the β-amino esters gave the corresponding β- amino aldehydes and a Roush-Masamune modified Horner-Wadsworth-Emmons (HWE) reaction afforded the trans-N-sulfinyl α,β-unsaturated δ-amino esters in good yield. Acid hydrolysis of the esters unmasked the carbonyl group and deprotected the amines resulting in an intramolecular cyclization to produce the key dehydropyrrolidines. Regioselective oxidation of the dehydropyrrolidines using catalytic methyl trioxorhenium and urea-hydrogen peroxide gave the corresponding pyrrolidine nitrones in excellent yield. On heating with the Lewis acid catalyst Al(O-t-Bu)3 the nitrones underwent a novel, stereospecific, intramolecular [3+2] cycloaddition reaction to give tricyclic isoxazolidines. Importantly, the isoxazolidine establishes the necessary cis relationship between C-2 and C-3 substituents in cocaine skeleton. The tricyclic isoxazolidines were readily converted to the N-Me quaternary ammonium salts on heating with methylmethanesulfonate and hydrogenolysis with Pd/C at 1 atm of H2 cleaved the

N-O bond to afford the ecgonine methyl ester, the tropane alcohol.

In contrast to other C-3 (R = Me, Et, n-Pr, Ph) isoxazolidine quaternary ammonium salts, the C-3 n-C5H11 analogue did not undergo N-O bond cleavage under the hydrogenolysis conditions. This analogue rearranged to a bridged bicyclic [4.2.1]isoxazolidine. It was found

iv that all C-3 isoxazolidine N-Me quaternary ammonium salts undergo this rearrangement on treatment with triethylamine. Fortunately, hydrogenolysis of n-C5H11 isoxazolidine quaternary ammonium salt at 4 atm of H2 cleaved the N-O bond to give the desired alcohol, ecgonine methyl ester. Benzolylation of methyl ester of ecgonine alcohols afforded the C-1 substituted cocaine analogues in 75-95% yield. This new methodology, for the first time, afforded cocaine analogues having Me, Et, n-Pr, n-C5H11 and Ph groups at the C-1 position.

In another study, new methodology was devised for the asymmetric synthesis of anti-α- alkyl-β-amino esters, valuable new chiral building blocks for the synthesis of β-amino acids β- lactams. The aza-Morita-Baylis-Hillman (aza-MBH) reaction of various vinylaluminum/NMO reagents with N-sulfinyl imines resulted in the formation of α-vinyl-β-amino esters in good yield and with 7:1 to 12:1 anti/syn selectivity. Addition of the aza-MBH reagent takes place from the least hindered direction via a nonchelation control mechanism. Hydrogenation of aza-Morita-

Baylis-Hillman adducts using a cationic rhodium (I) catalyst gave anti-α-alkyl-β-amino esters in good yield and high dr (10:1) and is a useful new method for their preparation. The absolute configurations of the anti-α-alkyl-β-amino esters were established by the oxidation of the N- sulfinyl group to a tosylate with m-CPBA, hydrolysis with LiOH and cyclization to a -lactam of known absolute configuration.

ACKNOWLEDGEMENT

Right from the first day, 20th August 2007, when I entered the United States of America, and Temple University, a great many number of people supported, advised and shaped me into the person I am today. I owe my gratitude and thank them all.

To begin, I thank from the bottom of my heart, my research advisor Professor Franklin A.

Davis. Both professionally and personally, he will inspire me for the rest of my life.

Professionally, the Heterocyclic Chemistry and Sulfur Chemistry courses he taught and the discussions I had with him during the course of my research in his laboratory, in the group meetings and personally greatly changed my understanding of chemistry. On a personal level, he lifted my spirit up and helped me to come over difficulties I faced because of some un-wanted incidents happened. I will remember his humane qualities until my last day on the earth.

I greatly appreciate my committee members Dr. Rodrigo B. Andrade, Dr. William M.

Wuest and Dr. Kevin C. Cannon for their valuable time in reading and correcting my thesis. I thank Dr. Rodrigo B. Andrade for his course in asymmetric synthesis which helped a lot in understanding mechanisms; I will be grateful to him for writing letters of recommendation.

I express thanks to Dr. Scott McN. Sieburth for his Organometallic Chemistry course and for writing letter of recommendation. I acknowledge Dr. DeBrosse for his spectroscopy course and for training and assistance in various NMR experiments. I show gratitude to Dr. Grant R.

Krow and Dr. John R. Williams for their Physical Organic Chemistry and Organic Names

Reactions courses.

I acknowledge Dr. Michael J. Zdilla and Sandeep K. Kondaveeti for their help in solving one x-ray crystal structure. I express gratitude to Dr. Maarten E. A. Reith and Dr. Ellen M.

Unterwald and their research groups for the assistance in obtaining biological data of our cocaine analogues.

I will be grateful to Department of Chemistry – Temple University, NIH and NSF for their financial support without which none of the research work would have been possible.

I express thanks to Dr. Alfred Findeisen and Dr. Michael Lawlor for their cooperation and flexible teaching assignments.

I acknowledge Chemistry Department of staff Regina Shapiro, Bobbi Johnson, Jeanette

Ford and Sharon S. Kass for their assistance and help. I recognize Christa Viola for her assistance in dealing with administrative matters. I am thankful to Lena Cherkashina and

Christopher Wise, who are responsible for Department’s storeroom. I will be grateful to Mark

Kemmerer for his help fixing computers in the lab, my laptop, and for his help in providing the necessary software. I express thanks to Beury hall manager Donald Deigh for his help in fixing the mechanical/electrical problems in the lab. I thank Dave Plasket for his help with glassware, moving equipment and chemicals from one lab to another.

I cannot imagine myself at Temple University without my friends Dr. Naresh Theddu and

Lan Nguyen Theddu. They are more than friends and they are the dearest to my heart. The memories we had are a valuable part of my life.

I am also lucky to have friends like Dr. Bharat S. Wagh, Dr. Ramakrishna Edupuganti,

Kavya Kollu Edupuganti, Dr. Gopal Sirasani who influenced me in many ways. I have a lot of respect for my present and past colleagues Dr. Paul Gaspari, Dr. Kerish A. Bowen, Dr. Hui Qui,

Dr. Peng Xu, Joshua R. Hummel, Heng Chen, Dr. Venkata Murali velvadapu, Late Dr. Thapas

Paul, Dr. Hoan Q. Duong, Dr. Svitlana Kulyk, Dr. Swapnil Singh, Kavitha Akula, Matthew

vii

Sender, Dr. Manasa mamunooru, Dr. Soujanya Singireddy Velvadapu, Dr. Rajesh Madathingal,

Dr. Goutham Kodali, Dr. Swapna Gone and many more.

Last but not least, I am grateful to my mother Ramasita Gadhiraju, to my brother

Surender Varma Gadhiraju for their unconditional love and support. I am also grateful to my uncle and aunt Kosuri Suribabu and Kosuri Vijayalaxmi, to my cousin brothers Kosuri Srinivasa

Raju (Chinni) and Kosuri Kumar Varma (Varma) for their unconditional love and support. I am also grateful to my grandma Kothapally Parvathi for her unconditional love. I am also grateful to Satyavathama garu and Maheboob Sahrif Baba (Guruvugaru) for their unconditional love and divine blessings.

viii

TABLE OF CONTENTS

Page

ABSTRACT……………………………………………………………………………………. iii

ACKNOWLEDGEMENT…………………………………………………………………….. vi

LIST OF TABLES……...…………………………………………………………………….. xiii

LIST OF FIGURES…………………………………………………………………………… xv

CHAPTER 1 SYNTHESIS OF COCAINE

1.1 Introduction

1.1.1 History……………………………………………………………………………. 1

1.1.2 Biosynthesis of cocaine…………………………………………………………... 2

1.2 Early synthesis of cocaine

1.2.1 Willstatter synthesis of cocaine from tropinone…………………………………. 4

1.3 Asymmetric synthesis of cocaine

1.3.1 Asymmetric synthesis of ()- and (+)-cocaine using chiral pyrrolidines

1.3.1.1 Enantiospecific synthesis of ()- and (+)-cocaine using chiral cis-substituted prolines…………………………………………………… 5

1.3.1.2 Total synthesis of (+)-cocaine using proline catalyzed aldol

reaction of cis-2,5-disubstituted pyrrolidines…………………………… 8

1.3.2 Asymmetric synthesis of (+)-cocaine using tropinone………………………...... 9

1.3.3 Asymmetric synthesis of (+)-and ()-cocaine using nitrone cycloaddition reactions

1.3.3.1 Synthesis of (+)-cocaine using an intramolecular [3+2] cycloaddition reaction of an in situ generated nitrone...... 10

1.3.3.2 First enantiospecific synthesis of C-6,C-7 and C-7 cocaine analogues using intramolecular nitrone-alkene cycloaddition (INAC) reaction………………………………………………………… 12

1.3.3.3 Asymmetric synthesis of ()-cocaine, (+)-cocaine and C-1 substituted cocaine using Lewis acid catalyzed intramolecular [3+2] nitrone cycloaddition reaction……………………………………. 14

CHAPTER 2 ASYMMETRIC SYNTHESIS OF C-1 SUBSTITUTED COCAINE

ANALOGUES PRESENT STUDY

2.1 Introduction……………………………………………………………………………... 16

2.2 Sulfinimine (N-Sulfinyl Imine) Chemistry……………………………………………... 17

2.3 Enantiospecific synthesis of C-1 substituted cocaine analogues

2.3.1 Retrosynthetic analysis…………………………………………………………. 20

2.3.2 Preparation of masked oxo sulfinimines………………………………………... 21

2.3.3 Preparation of masked oxo aldehydes…………………………………………... 23

2.3.4 Preparation of N-sulfinyl β-amino ester ketals…………………………………. 25

2.3.5 Preparation of N-sulfinyl β-amino aldehydes…………………...... 27

2.3.6 Olefination of N-sulfinyl β-amino aldehydes…………………………………... 30

2.3.7 Preparation of dehydropyrrolidines…………………………………………….. 33

2.3.8 Preparation of nitrones………………………………………………………….. 34

2.3.9 Intramolecular [3+2] cycloaddition reaction of nitrones……………………….. 36

2.3.10 Preparation of mesylate salt of N-Me isoxazolidines…………………………... 44

2.3.11 Hydrogenolysis of mesylate salts of N-Me isoxazolidines……………………… 45

2.3.12 Preparation of Cocaine C-1 Analogues…………………………………………. 52

2.3.13 Biological analysis of C-1 substituted cocaine analogues……………………… 53

CHAPTER 3 PREPARATION OF C-1 SUBSTITUTED 2β-CARBOMETHOXY-

3β-ARYLTROPANES

3.1 Introduction……………………………………………………………………………... 54

3.2 Early synthesis of 2-carbomethoxy-3-phenyltropanes………………………………….. 54

3.3 Synthesis of anhydroecgonine methylester…………………………………………...... 56

3.4 Present study for the synthesis of C-1 substituted-2-carbomethoxy-3-phenyltropanes

3.4.1 Preparation of (1R,5S)-C-1 methyl anhydroecgonine methylester……………... 58

CHAPTER 4 VINYLALUMINUM ADDITION TO SULFINIMINES (N-SULFINYL

Imines) ASYMMETRIC SYNTHESIS OF ANTI-α-ALKYL β-AMINO

ESTERS

4.1 Introduction……………………………………………………………………………... 64

4.2 Earlier synthesis of α-alkyl substituted β-amino acids using sulfinimine chemistry…… 64

4.3 Present study

4.3.1. Retrosynthetic analysis…………………………………………………………. 71

4.3.2 Asymmetric synthesis of aza-Morita-Baylis-Hillman adduct…………………... 72

CHAPTER 5 EXPERIMENTAL……………………………………...……………………... 80

REFERENCES……………………………………………………………………………….. 148

BIBILOGRAPHY………………………………………………………………...………….. 156

xii

LIST OF TABLES

Table 2.1 Preparation of masked oxo sulfinimines Ti(OEt)4………………………...... 22

Table 2.2 Preparation of masked oxo aldehydes 100a and e using DIBAL-H…...... 23

Table 2.3 Addition of sodium enolate of methyl acetae to (S)-(+)-101...... 26

Table 2.4 Addition of sodium enolate of methyl acetae to (S)-(+)-102…...……...... 27

Table 2.5 Reduction of N-sulfinyl β-amino esters 103a, c and e using DIBAL-H…...... 29

Table 2.6 Reduction of N-sulfinyl β-amino esters 104a, b, d and e using DIBAL-H...... 29

Table 2.7 Olefination of N-sulfinyl β-amino aldehyde (Ss,3S)-(+)-105a...... 31

Table 2.8 Olefination of N-sulfinyl β-amino aldehyde 105c, e and 106a to e...... 33

Table 2.9 Oxidation of dehydropyrrolidines 109a – e to nitrones 110a to e...... 35

Table 2.10 Intramolecular [3+2] cycloaddition reaction of nitrone 110a...... 37

Table 2.11 Intramolecular [3+2] cycloaddition reaction of nitrones 110b to e...... 38

Table 2.12 Rearrangement of oxaziridine 129c and d to lactams 128c and d...... 39

Table 2.13 Lewis acid catalyzed [3+2] cycloaddition reaction of nitrone 110d...... 42

Table 2.14 Nitrone cycloaddition of 110a to e using Al(O-t-Bu)3...... 43

Table 2.15 Preparation of mesylate salt of N-Me isoxazolidine 112a to e...... 45

Table 2.16 Hydrogenolysis of mesylate salt of N-Me isoxazolidine 122a to e...... 46

xiii

Table 2.17 Rearrangement of mesylate salt of N-Me isoxazolidine 112a, b. d. and e...... 49

Table 2.18 Hydrogenolysis of mesylate salt of N-Me isoxazolidine 112a, b and d under high pressure conditions...... 51

Table 3.1 Acid catalyzed dehydration of methyl ester of C-1 methyl ecgonine 155...... 58

Table 3.2 Rearrangement of C-3 methanesulfonyl ester of methyl ester of ecgonine 159... 61

Table 3.3 Reduction of triflate 163...... 62

Table 4.1 Addition of prochiral enolate of α-alkyl esters to sulfinimines...... 65

Table 4.2 Addition of prochiral enolate of α-alkyl Weinreb amides to sulfinimines...... 67

Table 4.3 Addition of enolate of Weinreb amides 178a to c to sulfinimine 177...... 68

Table 4.4 Aza-Morita-Baylis-Hillman reaction of sulfinimines 168a...... 73

Table 4.5 Aza-Morita-Baylis-Hillman reaction of sulfinimines 204a and b...... 77

Table 4.6 Hydrogenation of aza-Morita-Baylis-Hillman adducts 205a to f...... 78

xiv

LIST OF FIGURES

Figure 1.1 (R)-()-cocaine...... 1

Figure 2.1 Sulfinimine (N-sulfinyl imine)...... 17

Figure 2.2 Application of Sulfinimine (N-sufinyl imine) chemistry...... 20

Figure 2.3 Retrosynthetic analysis of C-1 substituted cocaine analogues...... 21

Figure 2.4 Zimmermann transition state for the addition of sodium enolate of methyl acetate to sulfinimines...... 27 Figure 2.5 Cycloaddition vs rearrangement of nitrones...... 41

Figure 2.6 Base catalyzed rearrangement of mesylate salt of N-Me isoxazolidine...... 49

Figure 3.1 2β-carbomethoxy-3β-phenyltropane...... 54

Figure 3.2 POCl3 mediated rearrangement...... 60

Figure 4.1 ()-Cispentacin and taxol...... 64

Figure 4.2 Retrosynthetic analysis of N-tosyl-β-lactams...... 72

Figure 4.3 Transition state for the addition of vinylaluminum reagent to sulfinimine...... 75

CHAPTER 1

SYNTHESIS OF COCAINE

1.1 Introduction

1.1.1 History

Cocaine or benzoylmethylecgonine is a white crystalline tropane alkaloid. Historically, for over thousand years South American indigenous people have chewed the leaves of

Erythroxylon coca, a plant that contains vital nutrients as well as numerous alkaloids, including cocaine. Although cocaine was known for a long time, its isolation was first achieved by the

German chemist Friedrich Gaedcke in 1855.1 Synthesis of (R)-()-cocaine (Figure 1.1) and its analogues has been a subject of significant focus since then. The first synthesis and elucidation of cocaine was reported in 1898 by the German scientist Richard Willstatter.2,3 In the past the intellectual challenge of accessing the cocaine skeleton and the introduction of substituents into the ring was the main reason for interest in the synthesis of cocaine and its analogues. Recently, the synthesis of therapeutically useful molecules for the treatment of cocaine abuse and addiction is the main focus.

Figure 1.1 (R)-()-cocaine

1.1.2 Biosynthesis of cocaine

Sir Robert Robinson accomplished the synthesis of tropinone (4) by the one-pot addition of succinaldehyde (1) to methylamine (2) and acetone.4 Replacement of acetone with the calcium salt of acetone dicarboxylic acid (3) at the physiological pH (pH 7.3 to 7.4) improved the yield (Scheme 1.1).4 With this observation, Robinson hypothesized that the biosynthesis of tropinone occurs via an analogues route involving an amino acid to provide the pyrrolidine ring and acetone equivalent to furnish C-2, C-3 and C-4 of tropane ring.

Scheme 1.1

The tropane alkaloids consist of the N-Me 8-azabicyclo [3.2.1] octane ring systems.

Ornithine and related amino acids (glutamic acid, proline) are important precursors for the pyrrolidine ring of tropine. The biosynthesis of cocaine in Erythroxylum coca starts with l- ornithine 5.5a,b It is now accepted that l-ornithine 5 is decarboxylated to yield putrescine 6, which is methylated to give N-methylputrescine 7. Oxidation of the primary amino group in 7 gives (4-methylamino)butanol 8 and cyclization yields 2-hydroxy-1-methylpyrrolidine 9. In the acidic medium α-hydroxyamine 9 exists as 1-methyl-pyrrolinium salt 10. Through radioactive labeling experiments, it was proposed that the iminium salt 10 reacts with acetyl coenzyme A 11

(or perhaps malonyl coenzyme A 12 with accompanying decarboxylation) to yield coenzyme A ester of 1-methylpyrrolidine-2-acetic acid 13. The reaction of ester 13 with a second molecule of acetyl coenzyme A 11 (or perhaps malonyl coenzyme A 12 with accompanying decarboxylation)

affords coenzyme A thioester of 4-(1-methyl-2-pyrrolidinyl)-3-oxobutanoic acid 14. The carbomethoxy group of cocaine is obtained by interchange of the thioester with methanol. This ester interchange could also occur at a later step in the biosynthetic process. Oxidation of pyrrolidine 14 yields carbinolamine (15). Elimination of hydroxide results in iminium salt 16, followed by a Mannich reaction to give 2-carbomethoxy-3-tropinone (17). A stereo selective reduction of tropinone 16 mediated by NADPH-dependent reductase enzyme affords methyl ecgonine 18. Cocaine (Figure 1.1) was presumably obtained by reaction of ecgonine methyl ester 18 with benzoyl coenzyme A 19 (the benzoyl coenzyme A 19 is synthesized from phenylalanine via trans-cinnamic acid) (Scheme 1.2).

Scheme 1.2

1.2 Early synthesis of cocaine

1.2.1 Willstatter synthesis of cocaine from tropinone

Willistatter’s synthesis of the tropinone skeleton and cocaine was the masterpiece of organic synthesis in 19th century. His synthesis begins with cycloheptatriene (20).2,3

Bromination of 20 followed by substitution with dimethylamine resulted in the formation of dimethylaminocycloheptadiene (22). Controlled reduction of one double bond gives dimethylaminocycloheptene 23. Bromination of 23 induces cyclization and formation of tropane

25. Interestingly this is the first reported synthesis of the tropane skeleton. Reaction of 25 with alkali resulted in the elimination of HBr giving compound 26 which subsequently resulted in the formation of 2-tropene 27. Addition of HBr to 27 resulted in the isolation of compound 28

(supposedly β-isomer) and acid treatment of compound 28 at 200 oC gave β-tropine 29.

Oxidation of 29 gave tropinone 4. Reaction of 4 with NaOEt and with carbon dioxide gives 2- carboxylic acid-3-tropinone 30, further reaction of 30 with methanol under acidic condition gave

2-carbomethoxy-3-tropinone 17. Reduction of 17 gave ecgonine methyl ester (both α and β alcohols) 18. Reaction of benzoic anhydride with 18 gave the racemic cocaine and resolution with the D-tartaric acid afforded optically pure (R)-(-)-cocaine (Scheme 1.3).

Scheme 1.3

1.3 Asymmetric synthesis of cocaine

1.3.1 Asymmetric synthesis of ()- and (+)-cocaine using chiral pyrrolidines.

1.3.1.1 Enantiospecific synthesis of ()- and (+)-cocaine using chiral cis-substituted

prolines.

Enantiospecific synthesis of natural and unnatural isomers of cocaine was demonstrated by Rapoport and co-workers using cis-5 substituted proline diesters.6,7 Here a novel Dieckmann condensation of proline diesters 32a, 32b and [3+2] dipolar cycloaddition reaction of 2-tropene

36 are the key reactions in the synthesis. The cis-5 substituted proline esters were synthesized from commercially available D-and L-glutamic acid (31).7,8

The Dieckmann condensation of (+)-32 using KHMDS resulted in the formation of N- substituted bicyclic [3.2.1] β-keto ester amines (+)-33. Hydrolysis of the methyl ester and simultaneous decarboxylation of (+)-33 resulted (+)-35. Tosylhydrazene condensation and base treatment of ketone (+)-35 afforded 2-tropene (+)-36 as the key intermediate in the synthesis

(Scheme 1.4).

Scheme 1.4

The [3+2] dipolar cycloaddition of 2-tropene (+)-36 with ethoxycarbonylformonitrile N- oxide (37) afforded isoxazole ()-38 (Scheme 1.5).9 The stereo and regioselectivity of the cycloaddition adduct was attributed to addition of 37 from the less sterically hindered exo face of the double bond in (+)-36. Hydrolysis of isoxazole ()-38 afforded carboxylic acid isoxazole

()-39 and thermal decarboxylation of ()-39 gave cis-3-β-hydroxy-2-nitrile ()-40. Hydrolysis of ()-40 with hydrogen peroxide gave cis-3-β-hydroxy-2-carboxamide ()-41 without epimerization at the C-2 position. Benzoylation of ()-41 afforded ()-42, deprotection followed by reductive amination of ()-42 gave ()-43. Nitrosation of 2-carboxamide ()-43 to 2- carboxylic acid derivative ()-44 followed by methyl esterification afforded (R)-()-cocaine in

95% yield and high enantiopurity (100% ee) (Scheme 1.5).

Scheme 1.5

Rapoport’s method, starting with D- and L-glutamic acid (31), prepared natural and unnatural cocaine in 21 steps (Scheme 1.4 and 1.5). More recently Hu and coworkers reported a ring closing metathesis (RCM) reaction of cis-2-allyl-5-vinylpyrrolidine ()-46, derived from

(+)-45, in three steps to give Rapoport’s key 2-tropene derivative (+)-36.10,11 Conversion of chiral 2-tropene (+)-36 to (R)-()-cocaine following Rapoport’s method (Scheme 1.6).7,10

Scheme 1.6

1.3.1.2 Total synthesis of (+)-cocaine using proline catalyzed aldol reaction of cis-2,5- disubstituted pyrrolidines

A proline catalyzed intramolecular asymmetric aldol reaction of meso 2,5-dialdehyde pyrrolidine 47 was used to construct aza bicyclic aldehyde 48 which was then converted to (+)- cocaine in three steps by Pearson and Mans (Scheme 1.7).12,13 The L-proline catalyzed asymmetric aldol reaction of meso-2,5-dialdehyde pyrrolidine 47 using conditions reported by

List and coworkers resulted in a 1:1 inseparable axial/equitorial isomers of N-Boc β-hydroxy aldehyde tropane 48.14 Owing to instability of the aldol adduct, the crude 48 was oxidized to a β- hydroxy acid which was treated with diazomethane to give N-Boc β-hydroxy ester 49.

Benzylation of β-hydroxy ester 49 resulted in a 1:1 mixture of C-2 epimers of N-Boc tropane 50.

Deprotection of the axial isomer of 50 followed by reductive amination gave (S)-(+)-cocaine in

74% yield (Scheme 1.7).

Scheme 1.7

1.3.2 Asymmetric synthesis of (+)-cocaine using tropinone

The enantioselective enolization of tropinone (4) with chiral base 51 in the presence lithium chloride and benzaldehyde (52) gave exo-anti adduct 53 as a single diastereomer.15,16

This transformation illustrates the preferential approach of the electrophile from the axial position (Scheme 1.8). Using this approach Cha and co-workers prepared unnatural (S)-(+)- cocaine.16 Commercially available tropinone 4 was enolized using chiral base 54 and reaction with α-silyloxy acetaldehyde 55 gave exo-aldol product (+)-56 as a single diastereomer.

Stereoselective reduction of the ketone followed by benzoate esterification of (+)-57 resulted in the formation of (+)-59 without epimerization. (S)-(+)-Cocaine was obtained in a one-pot operation by sequential treatment of (+)-59 with HF to give the vicinal diol followed by oxidation and the resulting carboxylic acid was transformed into methyl ester using TMSCHN2

(Scheme 1.9).

Scheme 1.8

Scheme 1.9

1.3.3 Asymmetric synthesis of (+)-and (-)-cocaine using nitrone cycloaddition

reactions.

1.3.3.1 Synthesis of (+)-cocaine using an intramolecular [3+2] cycloaddition reaction of an in situ generated nitrone

Tufariello and co-workers used a novel intramolecular [3+2] cycloaddition reaction of an in situ generated pyrrolidine nitrone 66 in the synthesis of racemic (+)-cocaine.17,18 This intramolecular nitrone cycloaddition controls the required cis relationship between C-2 and C-3 substituents in the cocaine tropane ring.

The cycloaddition reaction of 1-pyrrolidine-1-oxide (60) with methyl-3-butanoate (61) resulted in the formation of bicyclic isoxazolidine (+)-62. Oxidation of (+)-62 gave hydroxy nitrone 63 and protection followed by the generation of α,β-unsaturated ester in the side chain gave bicyclic isoxazolidine (+)-65 with exclusive E-geometry in the side chain (Scheme 1.10).

Scheme 1.10

The intramolecular [3+2] nitrone cycloaddition of 65 was achieved by heating isoxazolidine (+)-65 in xylene. This liberates the pyrrolidine nitrone 66 which undergoes the cycloaddition reaction to give tricyclic isoxazolidine (+)-67. Treatment with methyl iodide followed by reductive cleavage of N-O bond resulted in tropane salt 69. Racemic (+)-cocaine was obtained by benzoylation of tropane salt 69 using de Jong procedure (Scheme 1.11).18,19

Scheme 1.11

1.3.3.2 First enantiospecific synthesis of C-6,C-7 and C-7 cocaine analogues using intramolecular nitrone-alkene cycloaddition (INAC) reaction

Shing and co-workers described the first enantiospecific synthesis of cocaine and C-6,C-7 and C-7 cocaine analogues starting from D-()-ribose (70).20 A novel intramolecular nitrone- alkene cycloaddition (INAC) reaction was used to construct isoxazolidine skeleton 73 which was then transformed into various substituted cocaine analogues (Scheme 1.12,1.13).

Reaction of N-methylhydroxylamine with 7-aldehyde 71, obtained from D-()-ribose

(70)21 gave nitrone 72. The INAC reaction of nitrone 72 produced a 20:1 inseparable mixture of seven-membered endo-cycloadduct 73 and six-membered exo-cycloadduct 74.20,22 The diol ()-

75 and ()-76 were obtained by the acidic hydrolysis of cycloadducts 73 and 74. At this stage, the diols were separated and diol ()-75 was used in the synthesis of the cocaine analogues

(Scheme 1.12).

Scheme 1.12

Regioselective esterification of diol ()-75 with Tf2O followed by reaction with basic-

MeOH resulted in the formation of isoxazolidine epoxide (+)-78.20,22 Hydrogenolysis of the N-O bond gave bicyclic [4.1.1] diol (+)-80. One-pot regioselective benzoylation and mesylation of diol (+)-80 yielded (6S,7R)-6-chloro-7-benzyloxy cocaine (+)-81 (Scheme 1.13).

Scheme 1.13

Hydrogenation of 6-chloro-7-benzyloxy cocaine 81 resulted in the formation of (7S)-(-)- hydroxy cocaine 82 and reaction of 82 with methanesulfonyl chloride and triethylamine (TEA) gave (7S)-()-chloro cocaine 83 (Scheme 1.14). Hydrogenation of chloro cocaine 83 yielded

(R)-()-cocaine. Treatment of 7-hydroxy cocaine 82 with methanesulfonyl chloride, TEA and 4- dimethylamino pyridine (DMAP) gave (7S)-()-methanesulfonyloxy cocaine 84. Reaction of 84 with tetrabutylammonium iodide afforded (7S)-()-iodo cocaine 85 (Scheme 1.14).

Scheme 1.14

1.3.3.3 Asymmetric synthesis of (-)-cocaine, (+)-cocaine and C-1 substituted cocaine using Lewis acid catalyzed intramolecular [3+2] nitrone cycloaddition reaction

Cordova and co-workers developed a concise catalytic method for the preparation of pyrrolidine nitrones which were transformed into cocaine and several cocaine analogues.23

The crucial step in the synthesis was the preparation of α,β-unsaturated δ-amino ester (+)-

90 via a one-pot catalytic enantioselective three-component tandem aza-Michael/Wittig reaction

(Scheme 1.15).23,24 Reaction of dimethoxy hex-2-enal 86 with hydroxylamine 87 in the presence of chiral amine catalyst (R)-88 and with 2-(triphenylphosphoranylidene)acetate gave (S)-α,β- unsaturated δ-amino ester (+)-90 (96% ee, E:Z > 20:1, 70% yield). Nitrone 92 was generated by treatment of (S)-(+)-90 with Et3N/Et3SiH/PdCl2 and HCl (Scheme 1.15). Using the procedures introduced by Davis and co-workers the mesylate salt of N-Me isoxazolidine (+)-94 was prepared from the nitrone and converted into (R)-(-)-cocaine, (S)-(+)-cocaine and C-1 methyl cocaine analogues.23,25

Scheme 1.15

CHAPTER 2

ASYMMETRIC SYNTHESIS OF C-1 SUBSTITUTED COCAINE

ANALOGUES PRESENT STUDY

2.1 Introduction

(R)-()-Cocaine has many physiological effects including use as a local anesthetic drug, a vasoconstrictant, and use during nasal and throat surgery where control of bleeding is desired.26

A number of studies have shown that (R)-()-cocaine binds to the dopamine transporter (DAT), the norepinephrine transporter (NE) and serotonin transporter (5-HT); monoamine transporters.26,27 Cocaine abuse includes its ability to produce euphoria and reinforcing properties, where the predominant theoretical basis for these properties is the so called

“dopamine hypothesis”.28 According to this hypothesis, (R)-()-cocaine binds to DAT in a way that inhibits dopamine transport, affects the primary mechanism to remove dopamine from the synaptic cleft after its release leading to significant potentiation of dopaminergic transmission.26,29 This potentiation, which does not occur under normal conditions, is responsible for the reinforcing properties and euphorigenic effects of cocaine. Dopamine binding to DAT alters the functional state of limbic areas leading to the observed behavioral effects of (R)-()-cocaine.26 To date, the exact mechanism for cocaine addiction remains unclear.

Some structural changes to the cocaine tropane skeleton will alter its monoamine transporters (DAT, NE, 5-HT) binding functionality leading to medicinally useful properties.

Structure activity relationship (SAR) experiments suggested modifications that could lead to

increased potency and selectivity.27 To date, no therapeutically useful cocaine analogue was available.

In present day study, chiral sulfinimine chemistry is used to prepare here-to-unknown C-

1 analogues of cocaine for applications for treatment of cocaine abuse and to provide new information on the SAR’s of the new analogues.

2.2 Sulfinimine (N-Sulfinyl Imine) Chemistry

Chiral sulfinimines (N-sulfilyl imine), introduced by Davis and co-workers have evolved into a powerful tool for the asymmetric synthesis of diverse nitrogen - containing compounds.30

Compared to aliphatic imines, aliphatic sulfinimines are stable and do not undergo self- condensation. The electron withdrawing nature of chiral sulfinyl group activates imine bond for the stereoselective addition of nucleophilies. The N-sulfinyl auxiliary group stabilizes the chiral

C-N bond and acts as protecting group for the amine functionality. The sulfinyl group can be removed under mild acid conditions without epimerization to give C-N chiral center (Figure 2.1).

Figure 2.1 Sulfinimine (N-sulfinyl imine)

Enantiopure sulfinimines 94 can be prepared in one step from the commercially available

Anderson reagent ()-93 by condensation with aldehydes or ketones. Studies show that sulfinimines 94 were obtained in the best yields by condensing aldehydes or ketones with (S)-

(+)-p-toluenesulfinamide (+)-95 in the presence of titanium (IV) ethoxide or molecular sieves.

Aminolysis of Anderson reagent ()-93 gives (S)-(+)-p-toluenesulfinamide (+)-95 in excellent yields. Reviews on synthetic utility of sulfinimines are available (Scheme 2.1).30,31a-b

Scheme 2.1

An alternate sulfinamide, (S)-(-)-tert.butanesulfinamide (-)-99 introduced by Ellman and co-workers is also used in the asymmetric synthesis of diverse nitrogen containing

31a-b compounds. Commercially available di tert-butyl disulfide (96) was oxidized using H2O2,

31c VO(acac)2 and chiral ligand 97 to give (S)-(+)-tert-butyl tert-butanethiosulfinate 98. Reaction of (S)-(+)-98 with LiNH2/liq. NH3 and Fe(NO3)3.9H2O afforded (S)-(-)-99 in good yield (Scheme

2.2).31a,c

Scheme 2.2

The extensive utility of enantiopure sulfinimines in the diastereoselective synthesis of nitrogen containing compounds is shown in Figure 2.2.30 Some of the examples include asymmetric synthesis of α-amino acids,32 β-amino acids,33 syn- and anti-2,3-diamino esters,34 α- amino aldehydes and ketones,35 β-amino ketones and aldehydes,36 isoquinolines,37 α-amino phosphonates,38 aziridine carboxylates39 and aziridine 2-phosphonates.40 These examples demonstrate the reliable application of chiral sulfinimines in the preparation of chiral non- racemic amine derivatives (Figure 2.2).

Figure 2.2 Application of Sulfinimine (N-sulfinyl imine) chemistry

2.3 Enantiospecific synthesis of C-1 substituted cocaine analogues

2.3.1 Retrosynthetic analysis

The strategy for the enantiospecific synthesis of C-1 substituted cocaine analogue was inspired by Tufariello’s racemic synthesis of cocaine (Scheme 1.10 and 1.11).17,18 Optically pure

C-3 substituted tricyclic isoxazolidines can be converted to C-1 substituted cocaine analogues in three steps. Stereoselective enolate addition to masked oxo-sulfinimines will fix the necessary chirality at C-5 position in dehydropyrrolidine derivatives which can be transformed into C-3 substituted isoxazolidine derivatives in two steps (Figure 2.3).

Figure 2.3 Retrosynthetic analysis of C-1 substituted cocaine analogues

2.3.2 Preparation of masked oxo sulfinimines

The synthesis of C-1 substituted analogues of cocaine begins with the preparation of the enantiopure masked oxo sulfinimines. Condensation of masked oxo-aldehydes 100a, c and e with (S)-(+)-p-toluenesulfinamide (95) using Lewis acid Ti(OEt)4 in DCM for 48 h at rt afforded masked oxo sulfinimines (S)-(+)-101a, c and e in good yield (Scheme 2.3, Table 2.1, entries 2-

4).25 Condensation of masked oxo-aldehydes 100a, b, d and e with (S)-(-)-tert- butanesulfinamide (99) was carried out in presence of the Lewis acid Ti(OEt)4 in THF for 24 h to give corresponding masked oxo sulfinimines (S)-(+)-102a, b, d and e in good yield (Scheme 2.3,

Table 2.1, entries 5, 6, 8 and 9).25,41

Scheme 2.3

Table 2.1: Preparation of masked oxo sulfinimines using Ti(OEt)4

Entry 100 Z conditions %yield

1 a (R = Me) (S)-(+)-95 (Z = p-Tolyl) DCM, 24 h 50 (101a)

2 DCM, 48 h 70 (101a)

3 c (R = n-Pr) DCM, 48 h 70 (101c)

4 e (R = Ph) DCM, 48 h 65 (101e)

5 a (R = Me) (S)-(-)-99 (Z = t-Bu) THF, 24 h 85 (102a)

6 b (R = Et) THF, 24 h 80 (102b)

7 THF, 48 h 81 (102b)

8 d (R = n-C5H11) THF, 24 h 70 (102d)

9 e (R = Ph) THF, 24 h 85 (102e)

2.3.3 Preparation of masked oxo aldehydes

The masked oxo aldehydes 100a and 100e were prepared from commercially available keto esters 115a and 115e (Scheme 2.4).42a-c Protection of ketone in keto esters 115a and 115e using ethylene glycol and PTSA gave masked oxo esters 116a and 116e. Reduction of masked oxo esters 116a and 116e to masked oxo aldehydes 100a and 100e was accomplished using

DIBAL-H. Reaction time, number of equivalents of DIBAL-H, temperature and solvent play a critical role in the reaction (Table 2.2). To control the formation of over-reduction products, reaction was carried out using 1.05 equiv. of DIBAL-H, in toluene solvent at -78 oC for 45 min.

Using the optimized conditions, masked oxo esters 116a and 116e were converted masked oxo aldehydes 100a and 100e in good yield (Scheme 2.4, Table 2.2).

Scheme 2.4

Table2.2: Preparation of maked oxo aldehydes 100a,e using DIBAL-H at -78 oC for 45 min.

Entry 116 (R = ) solvent DIBAL-H (equiv) 100:121a %yield (100)

1 116a (R = Me) THF 1.5 1:1.5 38

2 THF 1.05 1:1 46

Table 2.2 continued 23

3 DCM 1.05 1:1 47

4 toluene 1.05 1:0 90

5 116e (R = Ph) toluene 1.05 1:0 92 aRatio was determined using 1H-NMR of crude sample.

Other masked oxo aldehydes 100b-d were prepared from corresponding commercially available lactones 117b-d (Scheme 2.5).43,41 Reaction of lactones 117b-d with magnesium N,O- dimethylhydroxyiamine gave corresponding γ-hydroxy Weinreb amides 118b-d, two singlets in

1H-NMR at δ 3.18 and 3.69, peak at δ 175.1 in 13C-NMR confirms the formation of Weinreb amide. Oxidation of hydroxyl group using 2-iodoxybenzoic acid (IBX) gave γ-oxo Weinreb amides 119b-d. Ketone protection of 119b-d using ethylene glycol and PTSA resulted in the formation of masked γ-oxo Weinreb amides 120b-d. Reduction of Weinreb amides 120b-d yielded masked oxo aldehydes 100b-d (Scheme 2.5).

Scheme 2.5

2.3.4 Preparation of N-sulfinyl β-amino ester ketals

Diastereoselective addition of enolates to sulfinimines and masked oxo sulfinimines is well documented in the Davis group.30a,44,46 The optimized conditions indicate that addition of sodium enolates to masked oxo sulfinimine at -78 oC in anhydrous diethyl ether gives best selectivity. Accordingly, masked oxo sulfinimines (S)-(+)-101a, c and e were added to the sodium enolate of methyl acetate in diethyl ether at -78 oC to give N-sulfinyl β-amino ester ketals

(Ss,3S)-(+)-103a, c and e as single diastereomer in 65-80% yield (Scheme 2.6, Table 2.3, entries

1 - 3).25,41 1H-NMR of crude samples was used to determine the diastereomeric ratio. A six membered Zimmerman-transition state (Figure 2.4) rationalizes the diastereoselectivity observed.45 Even though the desired N-sulfinyl β-amino ester ketals (+)-103a, c and e were obtained as major products, formation of N-sulfinyl δ-amino β-keto ester ketals (Ss,5S)-122a, c and e was detected. Addition of masked oxo sulfinimines (S)-(+)-102a, b, d and e to sodium enolate of methyl acetate in diethyl ether at -78 oC resulted in the formation of N-sulfinyl β- amino ester ketals (Ss,3S)-(+)-104a, b, d and e as a single diastereomer in 91-93% yield (Scheme

2.6, Table 2.4, entries 1 – 4). Here the formation of N-sulfinyl δ-amino β-keto ester ketals

(Ss,5S)-123a, b, d and e was not detected (Table 2.4, entries 1 – 4).

Scheme 2.6

Table 2.3: Addition of sodium enolate of methyl acetate to (S)-(+)-101.

Entry 101 conditions 103:122a %yield (103)

1 101a (R = Me) CH3CO2Me/NaHMDS 4:1 75

o Et2O, -78 C, 5 h

2 101c (R = n-Pr) 2:1 65

3 101e (R = Ph) 4:1 80 aRatios determined using 1H-NMR of crude sample.

Table 2.4: Addition of sodium enolate of methyl acetate to (S)-(+)-102.

Entry 102 conditions 104:123a %yield (104)

1 102a (R = Me) CH3CO2Me/NaHMDS 1:0 93

o Et2O, -78 C, 3 h

2 102b (R = Et) 1:0 91

3 102d (R = n-C5H11) 1:0 91

4 102e ( R = Ph) 1:0 93 aRatios determined using 1H-NMR of crude sample.

Figure 2.4 Zimmermann-transition state for the addition of sodium enolate of methyl acetate to sulfinimines

2.3.5 Preparation of N-sulfinyl β-amino aldehydes

Reduction of (+)-103a, c and e and (+)-104a, b, d and e using DIBAL-H in toluene afforded the corresponding N-sulfinyl β-amino aldehydes (+)-105a, c and e and (+)-106a, b, d and e in good yield.25,41 The main concern was to prevent over reduction of the β-amino

aldehyde to the β-amino alcohol. The number of equivalents of DIBAL-H, the reaction time and temperature play a critical role in controlling the over-reduction. The optimized reduction conditions were 1.8 equiv. of DIBAL-H in toluene solvent at -78 oC for 45 min. (Table 2.5, Entry

3, 4 and 5). Using the optimized reaction conditions (Scheme 2.7, Table 2.5), the reduction of

(+)-103a, c and e gave N-sulfinyl β-amino aldehydes (+)-105a, c and e in good yield (Scheme

2.7, Table 2.5, entries 3, 4 and 5). However, similar reaction conditions for the t-butylsulfinyl β- amino esters (+)-104a, b, d and e resulted in the formation of significant amounts of β-amino alcohols 125 (Scheme 2.7, Table 2.6, entries 1 and 3). Shorter reaction times reduced the formation β-amino alcohol 125 and gave β-amino aldehydes (+)-106a, b, d and e in good yields

(Scheme 2.7, Table 2.6, entries 2, 4, 5 and 6).

Scheme 2.7

Table 2.5: Reduction of N-sulfinyl β-amino esters (+)-103a, b and c using DIBAL-H at -78 oC in toluene

Entry Compound DIBAL-Ha (equiv.) time 105:124b %yield (105)

1 103a (R = Me) 2.0 1 h 70:30 64

2 2.0 45 min 85:15 81

3 1.8 45 min 97:3 95

4 103c (R = n-Pr) 1.8 45 min 93:7 91

5 103e (R = Ph) 1.8 45 min 88:12 85 a1.0 M solution of DIBAL-H in toluene was used for the reaction. bRatio determined using 1H-

NMR of the crude reaction mixture.

Table 2.6: Reduction of N-sulfinyl β-amino esters (+)-104a, b, d and e using DIBAL-H at -78 oC in toluene

Entry Compound DIBAL-Ha (equiv.) time (min) 106:125b %yield (106)

1 104a (R = Me) 1.8 45 60:40 56

2 1.8 10 89:10 85

3 104b (R = Et) 1.8 45 50:50 47

4 1.8 10 78:22 75

5 104d (R = n-C5H11) 1.8 10 76:24 72 Table 2.6 continued 29

6 104e (R = Ph) 1.8 10 85:15 85 a1.0 M solution of DIBAL-H in toluene was used for the reaction. bRatio determined using 1H-

NMR of the crude reaction mixture.

2.3.6 Olefination of N-sulfinyl β-amino aldehydes

Using the Wittig reaction and the modified Wittig reactions, olefination of N-sulfinyl β- amino aldehydes (+)-105 and (+)-106 was next explored (Scheme 2.8, Table 2.7). Reaction of

(+)-105a with methyl (triphenylphosphoranylidene) acetate gave (Ss,5S,2E)-(+)-α,β-unsaturated

N-sulfinyl δ-amino ketal ester 107a as the major product (Scheme 2.8, Table 2.7, Entry 1).47 The

E geometry of double bond was confirmed by the 16 Hz coupling constant for the olefinic protons in the 1H-NMR. The longer reaction time (10 h) and recovery of significant amount of starting material (20%) were the main limitations of this Wittig procedure (Table 2.7, Entry 1).

To address these limitations, the Roush-Masamune modification of Horner-Wadsworth-Emmons

(HWE) reaction was explored.48 Reaction of (+)-105a with trimethylphosphonoacetate and

DBU-LiCl resulted in the formation of (Ss,5S,2E)-(+)-107a and (Ss,5S,2Z)-126a as an inseparable

9:1 mixture of isomers in 80% yield within 5-6 h (Table 2.7, Entry 2). Interestingly, in the absence of LiCl, Roush-Masamune modified HWE reaction of N-sulfinyl β-amino aldehyde (+)-

105a afforded only (Ss,5S,2E)-(+)-107a (Table 2.7, Entry 3). Therefore, the presence of LiCl and prolonged reaction times are thought to be causing isomerization of olefin geometry.

Furthermore, pure (Ss,5S,2E)-(+)-107a underwent olefin isomerization to (Ss,5S,2Z)-126a when treated with LiCl under the HWE reaction conditions (Scheme 2.9). This reaction confirms the

hypothesis that presence of LiCl was causing isomerization of α,β-unsaturated δ-amino ester formed in the reation.

Scheme 2.8

Table 2.7: Olefination of N-sulfinyl β-amino aldehyde (Ss,3S)-(+)-105a

Entry conditions 107a:126aa %yield

1 208 (1.3 equiv), THF, rt, 10 h 38:1 77b [20% (+)-105a]

2 209 (1.2 equiv), DBU (1.0 equiv) 9:1 80b [20% (+)-105a]

LiCl (1.2 equiv), CH3CN, rt, 6 h

3 209 (2.0 equiv), DBU (2.0 equiv) 1:0 92c

CH3CN, rt, 1 h aRatio determined using 1H-NMR of crude sample. bcombined yield of 107a and 126a isomers. cyield of E isomer (+)-107a.

Scheme 2.9

Using the optimized conditions (Table 2.7, Entry 3), olefination of N-sulfinyl β-amino aldehydes (+)-105c and e and (+)-106a, b, d and e was explored. The Roush-Masamune modified HWE reaction of N-sulfinyl β-amino aldehydes (+)-105c, e and (+)-106a, b, d in the absence of LiCl afforded α,β-unsaturated N-sulfinyl δ-amino ketal esters (Ss,5S,2E)-107c and e and (Ss,5S,2E)-(+)-108a, b and d as single isomers (Scheme 2.10, Table 2.8, entries 1-5).

However, under the same conditions, N-sulfinyl β-amino aldehyde (+)-106e afforded α,β- unsaturated N-sulfinyl δ-amino ketal ester (Ss,5S,2E)-108e and (Ss,5S,2Z)-127e as an inseparable

95:5 mixture of isomers (Scheme 2.10, Table 2.8, entry 6).

Scheme 2.10

Table 2.8: Olefination of N-sulfinyl β-amino aldehyde (Ss,3S)-(+)-105c, e and (Ss,3S)-106a - e.

Entry compound conditions ratio of E:Z %yield

1 105c 209 (2.0 equiv), DBU (2.0 equiv) 1:0 (107c:126c) 95

CH3CN, rt, 1 h

2 105e 1:0 (107e:126e) 95

3 106a 1:0 (108a:127a) 95

4 106b 1:0 (108b:127b) 93

5 106d 1:0 (108d:127d) 89

6 106e 95:5 (108e:127e) 95a aisolated yield of mixture of E,Z isomers.

2.3.7 Preparation of dehydropyrrolidines.

Acid hydrolysis of α,β-unsaturated δ-amino ketal esters (Ss,5S,2E)-(+)-107a, c and e and

(Ss,5S,2E)-(+)-108a, b, d and e using 3 N HCl in 1:1 THF/MeOH afforded the corresponding dehydropyrrolidines (5S,2E)-109a-e in good yield (Scheme 2.11).25,41 It is noteworthy that increasing MeOH in the reaction to 3:1 MeOH/THF resulted in isomerization of α,β-unsaturated ester and using pure THF resulted in the hydrolysis of ester functionality. Interestingly, when mixture of E:Z isomers of α,β-unsaturated δ-amino ketal esters was subjected to acid hydrolysis, the dehydropyrrolidines were obtained as single isomers (E isomer).

Scheme 2.11

2.3.8 Preparation of nitrones

Selective oxidation of dehydropyrrolidines (5S,2E)-(+)-109a-e to nitrones was next explored. Reagents like m-CPBA can oxidize dehydropyrrolidines to nitrones and oxaziridines.49 Recently, a selective oxidation of imines to nitrones using urea hydrogen peroxide (UHP) catalyzed by methyltrioxorhenium (MTO) was reported by Goti and coworkers.50 Oxidation of (+)-109a using 3.3 equiv of UHP and catalytic MTO (2 mol%) in

MeOH for 1 h, however, gave none of the nitrone and starting material (+)-109a was recovered

(Scheme 2.12, Table 2.9, Entry 1). Increasing the reaction time form 1 h to 6 h resulted in formation of a 6:4 mixture of (+)-109a and 110a (Table 2.9, Entry 2). Quantitative conversion of (+)-109a to 110a was achieved by increasing the amount of catalyst from 2 to 6% and the reaction time to 16 h (Table 2.9, Entry 3). 1H-NMR and 13C-NMR data of crude reaction mixture was the main tool to confirm the conversion of dehydropyrrolidines to nitrones. The C-2 hydrogen in nitrone pyrrole ring was shifted downfield to δ 4.20 ppm as compared to δ 4.05 ppm

in dehydropyrrolidine, the C-5 carbon in nitrone pyrrole ring was shifted to upfield to δ 150.5 ppm as compared to δ 175.0 ppm in dehydropyrrolidine ring. Using the optimized conditions, dehydropyrrolidines (+)-109 b – e were converted to corresponding nitrones 110b – e in excellent yield (Scheme 2.12, Table 2.9, entries 4 – 7). Attempts to purify nitrones using silica gel column chromatography resulted in decomposition. For this reason, crude nitrones were used without additional purification in the [3 + 2] cycloaddition reactions.

Scheme 2.12

Table 2.9: Oxidation of dehydropyrrolidines (5S,2E)-(+)-109a – e to nitrones (5S,2E)-110a – e.

Entry 109 conditions ratio (109:110)a %yieldb,c

b 1 109a (R = Me) MeReO3 (2 mol%), MeOH 1:0 100 UHP (3.3 equiv.), rt, 1 h

2 MeReO3 (2 mol%), MeOH 6:4 ----- UHP (3.3 equiv.), rt, 6 h

c 3 MeReO3 (6 mol%), MeOH 0:1 100 UHP (3.3 equiv.), rt, 16 h

4 109b (R = Et) 0:1 100c

5 109c (R = n-Pr) 0:1 100c

Table 2.9 continued

c 6 109d (R = n-C5H11) 0:1 100

7 109e (R = Ph) 0:1 100c aRatio determined by 1H-NMR on crude reaction mixture. byield of dehydropyrrolodine isolated. cisolated yield of nitrone without purification.

2.3.9 Intramolecular [3+2] cycloaddition reaction of nitrones

The intramolecular [3+2] cycloaddition reaction of nitrone (5S,2E)-110a was first explored. A variety of experiments were performed to optimize the reaction conditions (Table

2.10). Heating the nitrone 110a in DCM did not result in cycloaddition and starting material was recovered (Table 2.10, entry 1, Scheme 2.13); decomposition of the nitrone was observed when high boiling solvents such as xylene were used (Table 2.10, entry 2, Scheme 2.13). The formation of desired tricyclic isoxazolidine (-)-111a was observed when the reaction was carried out in benzene and toluene (Table 2.10, entries 3 and 4, Scheme 2.13). Better results were achieved when the cycloaddition reaction was performed in toluene solvent under reflux condition for 48 h (Table 2.10, entry 5, Scheme 2.13). The structure of tricyclic isoxazolidine

(1R,2R,3R,6S)-(-)-111a was characterized by C-1 hydrogen doublet at δ 4.94 ppm and C-2 hydrogen singlet at δ 2.44 ppm in 1H-NMR spectra. Decomposition of nitrone 110a was still the main drawback in the cycloaddition reaction (Table 2.10, entries 3, 4 and 5).17,18,25,41

Scheme 2.13

Table 2.10: Intramolecular [3+2] cycloaddition reaction of nitrone (5S,2E)-110a

Entry nitrone conditions ratio (110a:111a)a %yield (111a)

1 110a (R = Me) DCM, reflux, 24 h 1:0 no reactionb

2 xylene, reflux, 24 h decomposed -----

3 benzene, reflux, 24 h 3:1 10 (decomposition observed)

4 toluene, reflux, 24 h 2:1 20 (decomposition observed)

5 toluene, reflux, 48 h 0:1 45 – 50 (decomposition observed) aRatio was determined using 1H-NMR of crude reaction mixture. bStarting material was recovered.

Using the optimized conditions the intramolecular [3+2] cycloaddition reaction of nitrones (5S,2E)-110b, c, d and e were next explored. Heating of nitrones 110b (R = Et) and

110e (R = Ph) in toluene for 48 h resulted in the formation of 1:1 and 1:3 mixtures of tricyclic isoxazolidines (1R,2R,3R,6S)-(-)-111b and e and lactams (5S,2E)-(+)-128b and e respectively

(Table 2.11, entries 1 and 4, Scheme 2.14). Nitrones 110 c (R = n-Pr) and d (R = n-C5H11) under the reaction conditions yielded exclusively lactams (5S,2E)-(+)-128c and (5S,2E)-()-128d, respectively (Table 2.11, entries 2 and 3, Scheme 2.14). Formation of the lactam was supported by presence of double bond hydrogens at δ 5.88 – 5.94, δ 6.95 – 7.04 ppm in 1H-NMR spectra and by the presence of amide C=O at δ 172.8 – 179.8 ppm in 13C-NMR spectra.25,41 These results were not unexpected, because on heating, nitrones can rearrange to oxaziridines and oxaziridines can rearrange to amides.49

Scheme 2.14

Table 2.11: Intramolecular [3+2] cycloaddition reaction of nitrones (5S,2E)-110b, c, d and e

Entry nitrone (110) conditions ratio (111:128)a %yieldb (128)

1 110b (R = Et) toluene, reflux, 48 h 1:1 32

2 110c (R = n-Pr) 0:1 40

3 110d (R = n-C5H11) 0:1 62

4 110e (R = Ph) 1:3 50 aRatio was determined using 1H-NMR of crude reaction mixture. bAttempts to isolate pure tricyclic isoxazolidine ()-111 were not successful.

To verify that the source of the lactams are oxaziridines, the corresponding oxaziridines

(5S,2E)-(+)-129c and d were prepared from dehydropyrrolidines (5S,2E)-(+)-109c and d

(Scheme 2.15). Oxidation of dehydropyrrolidines (+)-109c and d using m-CPBA resulted in the formation of 2.5:1 diastereomeric mixture of isomers of oxaziridines (+)-129c and d (Scheme

2.15). Heating of oxaziridine (+)-129c in toluene for 48 h resulted in no rearrangement (Table

2.12, entry 1, Scheme 2.15). However, in the presence of catalytic amount of peroxorhenium complex (prepared by the reaction of 2% MTO with UHP),25,41 heating of oxaziridine (+)-129c in toluene for 96 h gave lactam (+)-128c in 51% yield (Table 2.12, entry 2, Scheme 2.15). By contrast, even in the absence of peroxorhenium catalyst, heating of oxaziridine (+)-129d in toluene for 48 h yielded 68% lactam (-)-128d (Table 2.12, entry 3, Scheme 2.15).

Scheme 2.15

Table 2.12: Rearrangement of oxaziridines (5S,2E)-(+)-129c - d to lactams (5S,2E)-128c – d

Entry oxaziridine (129) conditions %yield (128)

1 129c (R = n-Pr) toluene, reflux, 48 h no reactiona

2 peroxorhenium catalyst 51 toluene, reflux, 96 h

3 129d (R = n-C5H11) toluene, reflux, 48 h 68 Table 2.12 continued 39

aStarting material was recovered.

As represented in Figure 2.5, steric repulsions between the “R” group in the nitrone ring and carbomethoxy group in the side chain may be responsible for inhibition of the intramolecular

[3+2] cycloaddition reaction thus leading to oxaziridine formation. The experimental observations support this hypothesis. As the size of “R” group increases in the nitrone, lactam formation was increased. The steric effect based on A-values is Me (1.7) < Et (1.75) < n-Pr (

51 1.8) < n-C5H11 < Ph (3.0). Heating of nitrone (5S,2E)-110a (R = Me) resulted only in the intramolecular [3+2] cycloaddition reaction (Table 2.10, entry 5, Scheme 2.13). Nitrone 110b (R

= Et) resulted in both intramolecular [3+2] cycloaddition reaction and in the lactam formation via rearrangement (Table 2.11, entry 1, Scheme 2.14). Nitrones 110c (R = n-Pr) and 110d (R = n-C5H11) gave exclusively the lactams (Table 2.11, entry 2 and 3, Scheme 2.14). However, in contrast, nitrone 110e (R = Ph) with the largest A-value (3.0) resulted in a 1:3 mixture of tricyclic isoxazolidine and lactam (Table 2.11, entry 4, Scheme 2.14). This anomaly may be the result of a favorable transition state stabilizing interaction between phenyl group and the anti- bonding orbitals of the C=O of ester group.52

Figure 2.5 cycloaddition vs rearrangement

Increasing the reactivity of α,β-unsaturated ester to promote intramolecular [3+2] nitrone cycloaddition reaction was next explored. It is known that nitrone cycloaddition reactions are favored by Lewis acids that can coordinate to α,β-unsaturated carbonyl moiety.53 Initial attempts to catalyze [3+2] cycloaddition reaction of nitrone 110d (R = n-C5H11) using 10 mol% of Lewis

o acids BF3OEt2 and Ti(iPrO)4 in toluene at 110 C resulted in decomposition (Scheme 2.16,

Table 2.13, entries 1 and 2). On the other hand, using 10 mol% of Lewis acids like La(OTf)3,

Cu(OTf)3 and Sc(OTf)3 resulted in the formation of both tricyclic isoxazolidines 111d and lactams 128d (Scheme 2.16, Table 2.13, entries 3 to 5). Attempts to improve the [3+2] cycloaddition reaction using 20 mol% of Lewis acid catalyst were unsuccessful (Table 2.13, entries 6 to 8).

Scheme 2.16

Table 2.13: Lewis acid catalyzed [3+2] cycloaddition reaction of nitrone 110d (R = n-C5H11).

Entry nitrone Lewis acid (mol %) time ratio (111d:128d)a %yield

1 110d (R = n-C5H11) BF3OEt2 (10 mol%) 24 h none decompose

2 Ti(iPrO)4 (10 mol%) 24 h none decompose

b 3 La(OTf)3 (10 mol%) 24 h 1:1 20 (128d)

b 4 Cu(OTf)3 (10 mol%) 24 h 1:1 18 (128d)

b 5 Sc(OTf)3 (10 mol%) 24 h 1:1 18 (128d)

6 La(OTf)3 (20 mol%) 24 h none decompose

7 Cu(OTf)3 (20 mol%) 24 h none decompose

8 Sc(OTf)3 (20 mol%) 24 h none decompose aRatios determined using 1H-NMR of crude sample. bAttempts to isolate 111d were not successful.

The Lewis acids can coordinate both to carbomethoxy group and to nitrone. Selective coordination to carbomethoxy group can be favored by using bulky Lewis acids. Towards this

goal, the commercially available aluminum tert-butoxide was used for the [3+2] cycloaddition reaction of nitrone 110a (R = Me) (Scheme 2.17, Table 2.14, entry 1). The optimum conditions for the cycloaddition reaction of nitrone 110a were 50 mol% aluminum tert-butoxide in toluene and heating at reflux 72 h (Table 2.14, entry 2). Using these conditions, nitrones 110b (R = Et),

110c (R = n-Pr), 110d (R = n-C5H11) afforded the corresponding tricyclic isoxazolidines without the formation of lactams, but longer reaction times (72 to 96 h) were necessary to get good yields

(Scheme 2.17, Table 2.14, entries 4, 5 and 7). However, nitrone 110e (R = Ph), under the aluminum tert-butoxide condition gave 1:1 mixture of tricyclic isoxazolidine 110e and lactam

128e (Scheme 2.17, Table 2.14, entry 8).

Scheme 2.17

Table 2.14: Nitrone cycloaddition reactions using Al(O-t-Bu)3

a Entry nitrone (110) mol% [Al(O-t-Bu)3] time (h) ratio (111:128) %yield

1 110a (R = Me) 10 24 h 1:0 25b

2 50 72 h 1:0 70b

3 100 72 h 1:0 40b

4 110b (R = Et) 50 96 h 1:0 64b

5 110c (R = n-Pr) 50 72 h 1:0 65b

Table 2.14 continued 43

6 100 72 h 1:0 40b, decompose

b 7 110d (R = n-C5H11) 50 96 h 1:0 68

8 110e (R = Ph) 50 72 h 1:1 50b, 40c aRatios determined using 1H-NMR of crude sample. bIsolated yields of corresponding isoxazolidines 111a to e. cIsolated yield of lactam 128e.

2.3.10 Preparation of mesylate salt of N-Me isoxazolidines.

Addition of 10 equiv of methyl methanesulfonate (MeSO3Me) to tricyclic isoxazolidines

111a - d in DCM and refluxing for 48 h gave the corresponding mesylate salts of N-Me isoxazolidines 112a - d in quantitative yield (Scheme 2.18, Table 2.15, entries 2 to 5). For tricyclic isoxazolidine 111e (R = Ph) heating for 72 h in DCM was necessary to get the best yields (Scheme 2.18, table 2.15, entry 7). Higher boiling solvents such as benzene resulted in decomposition (Table 2.15, entries 8 and 9).

Scheme 2.18

Table 2.15: Preparation of mesylate salt of N-Me isoxazolidine 112a to e

Entry isoxazolidine (111) conditions %yield (112)

1 111a (R = Me) DCM, reflux, 24 h 72

2 DCM, reflux, 48 h 100

3 111b (R = Et) 100

4 111c (R = n-Pr) 100

5 111d (R = n-C5H11) 100

6 111e (R = Ph) 82

7 DCM, reflux, 72 h 100

8 111a (R = Me) benzene, reflux, 24 h decompose

9 111e (R = Ph) 15

2.3.11 Hydrogenolysis of mesylate salts of N-Me isoxazolidines.

Hydrogenolysis of mesylate salts of N-Me isoxazolidines 112a (R = Me), b (R = Et), c

(R= n-Pr), and e (R = Ph) using 5% Pd-C/H2 (1 atm) afforded corresponding mesylate salts of methyl ester of ecgonine 113a, b, c and e in excellent yield (Scheme 2.19, Table 2.16). The optimal hydrogenolysis conditions were 20% w/w Pd-C/H2 (1 atms), at rt, for 48 h. Longer reaction times (48 h) are necessary for the conversion of isoxazolidines 112a, b and c to corresponding methyl esters of ecgonine 113 a, b and c (Scheme 2.19, Table 2.16, entries 2, 3

and 4). In the case of the isoxazolidine 112e, hydrogenolysis for 48 h gave a complex mixture of products (Scheme 2.19, Table 2.16, entry 6), lowering the reaction time to 10 h gave an 85% of methyl ester of ecgonine 113e (Scheme 2.19, Table 2.16, entry 7). When mesylate salt of N-Me isoxazolidine 112d (R = n-C5H11) was subjected to hydrogenolysis, a compound 130d was formed in 32% yield, the ecgonine 113d was not detected (Scheme 2.19, Table 2.16, entry 5).

Scheme 2.19

Table 2.16: Hydrogenolysis of mesylate salts of N-Me isoxazolidines 112a to e.

Entry 112 reaction time (h) ratio (112:113:130)a %yield

1 112a (R = Me) 24 h 1:1:0

2 48 h 0:1:0 100b

3 112b (R = Et) 48 h 0:1:0 100b

4 112c (R = n-Pr) 48 h 0:1:0 100b

c 5 112d (R = n-C5H11) 48 h 1:0:1 32

6 112e (R = Ph) 48 h 0:1:0 complex mixd

7 10 h 0:1:0 85b

Table 2.16 continued

aRatios are determined using 1H-NMR of crude sample. bIsolated yield of methyl ester of ecgonine 113. cIsolated yield of rearranged compound 130. dInseparable mixture of compounds.

The hydrogenolysis of mesylate salt of N-Me isoxazolidine 112d (R = n-C5H11) at 1 atm resulted in rearrangement rather than cleavage of N-O bond. The new compound was tentatively given the structure 130d. In the crude 1H-NMR new doublets at δ 5.2 ppm (J = 8.8 Hz), δ 1.8 ppm (J = 12 Hz) and in crude 13C-NMR olefinic carbons at δ 157.4 ppm and 131.8 ppm suggest formation of new compound with [4.2.1] bicyclic system. The ratio of 112d:130d determined by

1H-NMR of crude sample was 1:1 (Table 2.16, entry 5). Treatment of the mixture with satd

K2CO3 followed by extraction with DCM gave 32% isolated yield of bridged bicyclic [4.2.1] isoxazolidine (E,1S,6S)-(+)-131d (Scheme 2.20). 2D NMR analysis was used to support the bicyclic [4.2.1] isoxazolidine. Observations are as follows:-

1. Total number methylene units in the molecule are seven and their chemical shifts are δ 22.4, 27.5, 31.1, 31.8, 33.1, 37.8, 39.3 ppm 2. Total number of methine units in the molecule are two and their chemical shifts are at δ 64.4 and δ 77.0 ppm 3. Total number of methyl units in the molecule are three and their chemical shifts are δ 13.9, 46.5, 51.3 ppm 4. The methine hydrogen on C-1 can couple only with one of the two methylene hydrogens on C-9 (because of dihedral angle difference). This particular C-1 hydrogen appears as doublet at δ 5.20 ppm with J value of 8.8 Hz. The two methylene hydrogens on C-9 couple with each other (diastereotopic relationship), the C-9 hydrogen which is not coupling with C-1 hydrogen appears as doublet at around δ 1.88 ppm with J value of 12.0 Hz. 5. The methine hydrogen on C-4 which appears around δ 3.45 ppm has coupling with one of the hydrogen on C-9 and with one of the hydrogen on C-5 (because of dihedral angle

difference). This particular C-4 hydrogen was expected to appear as doublet of doublet, and instead appears as triplet with J value of 6.1 Hz.

The above data supports the bridged bicyclic [4.2.1] isoxazolidine structure 131d (Scheme 2.20).

Scheme 2.20

A reasonable mechanism for the formation of 131d is a base-catalyzed elimination of C-2 carbomethoxy proton (Figure 2.6). Treatment of 112d (R = n-C5H11), 112a (R = Me) and 112b

(R = Et) with K2CO3 and pyridine resulted in no reaction (Scheme 2.21, Table 2.17, entries 2, 3,

6, 7, 10 and 11). However, reaction of 112d with triethyl amine (TEA) resulted in the formation of 83% yield of 131d (Scheme 2.21, Table 2.17, entry 4), similar results were observed for 112a and 112e (R = Ph) (Scheme 2.21, Table 2.17, entries 8 and 14). Isoxazolidine 112e underwent similar rearrangement when treated with pyridine (Scheme 2.12, Table 2.17, entry 13). The examples of bridged bicycle [4.2.1] isoxazolidines being employed in synthesis are rare, with only a few known examples.54,55

Scheme 2.21

Figure 2.6 Base catalyzed rearrangement of mesylate salt of N-Me isoxazolidine

Table 2.17: Rearrangement of mesylate salts of N-Me isoxazolidines 112a, b, d and e.

Entry 112 conditions ratio (112:130)a %yield (131)

1 112d (R = n-C5H11) 5% Pd-C/MeOH 1:1 32

2 pyridine/MeOH 1:0 no reaction

3 K2CO3/MeOH 1:0 no reaction

4 TEA/MeOH 0:1 83

5 112a (R = Me) 5% Pd-C/MeOH 1:0 no reaction

6 pyridine/MeOH 1:0 no reaction

7 K2CO3/MeOH 1:0 no reaction

Table 2.17 continued

8 TEA/MeOH 0:1 95

9 112b (R = Et) 5% Pd-C/MeOH 1:0 no reaction

10 pyridine/MeOH 1:0 no reaction

11 K2CO3/MeOH 1:0 no reaction

12 112e (R = Ph) 5% Pd-C/MeOH 1:0 no reaction

13 pyridine/MeOH 0:1 84

14 TEA/MeOH 0:1 81 aRatios determined using 1H-NMR of crude reaction mixture.

The mesylate salt of N-Me isoxazolidine 112d (R = n-C5H11) is the only compound to undergo rearrangement under normal hydrogenolysis conditions (Table 2.16, entries 1, 5, 9 and

12). Curiously, a hydrogen atmosphere was not necessary for the rearrangement (Table 2.16, entry 1). Palladium catalyzed dehydrogenation of secondary alcohols to ketones,56 oximes to nitriles,57 amines to imines,58 and aromatization of cyclic dienes59 is well known. It is proposed that the C-3 n-C5H11 group in 122d sterically inhibits the coordination of palladium to N-O bond, in such a case the palladium may coordinate to C-2 carbomethoxy group leading to 131d.

In theory, at higher pressure of H2, Pd-C becomes completely saturated with hydrogen and coordination of Pd-C to carbomethoxy group can be inhibited. When mesylate salt of N-Me isoxazolidine 112d (R = n-C5H11) was subjected to hydrogenolysis at 4 atm of H2, cleavage of N-

O bond was observed and rearrangement was not observed (Scheme 2.22, Table 2.18, entries 1

and 2). Under the higher H2 pressure conditions (4 atm), the time for hydrogenolysis was reduced for 112a (R = Me) and 112b (R = Et) (Table 2.18, entries 4 and 5). Indeed when the Pd-

C was pre-saturated with H2 at 4 atm for 12 h, 112d underwent N-O bond cleavage using 1 atm hydrogen condition (Table 2.18, entry 3). This reaction supports the hypothesis that when Pd-C was saturated with H2, it cannot coordinate to carbomethoxy group and delivers hydrogen by coordinating to N-O bond.

Scheme 2.22

Table 2.18: Hydrogenolysis of mesylate salts of N-Me isoxazolidines 112a, b and d under high

Pressure conditions.

Entry 112 conditions %yield (113)

1 112d (R = n-C5H11) 20% W/W Pd-C/MeOH/H2 (4atms), rt, 48 h 100

2 20% W/W Pd-C/MeOH/H2 (4atms), rt, 6 h 100

3 20% W/W Pd-C/MeOH/H2 (4 atms), rt, 12 h 100

then added 112d, H2 (1 atms), rt, 6 h

4 112a (R = Me) 20% W/W Pd-C/MeOH/H2 (4atms), rt, 30 h 100

5 112b (R = Et) 20% W/W Pd-C/MeOH/H2 (4atms), rt, 15 h 100

2.3.12 Preparation of Cocaine C-1 Analogues

Benzoylation of mesylate salts of methyl ester of ecgonine 113a to e with 1.5 equivalents of benzoyl chloride in pyridine at rt for 20 h afforded the C-1 substituted cocaine analogues 114a to e as a pale yellow oils in good to excellent yields (Scheme 2.23). The free bases of C-1 substituted cocaine analogues were converted into hydrochloride salts for biological analysis

(Scheme 2.24). Addition of HCl (1.0 M solution in ether) to the ice cold solution of 114a to e in ether afforded HCl salts 132a to e as a white crystalline solid in quantitative yield.

Scheme 2.23

Scheme 2.24

2.3.13 Biological analysis of C-1 substituted cocaine analogues:

Even though a large number of cocaine-like analogues have been evaluated in efforts to develop therapeutically useful molecules for treatment of cocaine abuse, there is no information on analogues having a C-1 substituent.60 The C-1 methyl, C-1 ethyl and C-1 phenyl cocaine analogues 132a (R = Me), 132b (R = Et), 132e (R = Ph) were found to bind to the dopamine transporter (DAT) twofold, threefold and tenfold times better, respectively, than cocaine.

Significantly, in a mouse stimulatory assay, these analogues were found not to have locomotor activity; i.e. they are not stimulants in contrast cocaine.

CHAPTER 3

PREPARATION OF C-1 SUBSTITUTED, 2β-CARBOMETHOXY-3β-

ARYLTROPANES

3.1 Introduction

The important structural feature of 3-phenyltropanes is the replacement of 3β-benzoyl ester group in cocaine with 3β-phenyl ring (Figure 3.1). The goal of designing such cocaine analogues is to retain stimulant or antidepressant pharmacological properties while minimizing high toxicity and dependence liabilities. The 3-phenyltropanes, first reported by Clarke and co- workers, maintained their stimulant and antidepressant activity with reduced toxicity.

Replacement of C-3 benzoyl ester with 3-phenyl group also increased the metabolic stability of the analogues.61,62

Figure 3.1 2β-carbomethoxy-3β-phenyltropane

3.2 Synthesis of 2-carbomethoxy-3-phenyltropanes from anhydroeconine methyl esters

The C-3 phenyltropane analogues 2α-135 (2-carboxymethoxy group in axial position) and 2β-136 (2-carbomethoxy group in equatorial position) were prepared by reaction of phenylmagnesium bromide (134) with (1R,5S)-(-)-anhydroecgonine methylester (133) in 75% yield as an inseparable 3:1 mixture of isomers (Scheme 3.1).61a-b Addition of Normant-cuprates

to (1R,5S)-(-)-anhydroecgonine methylester (133) afforded 2α-135 in high yield (88%) and with a diastereomeric excess > 85%.61c Hydrolysis of benzoyl ester followed by dehydration of R- cocaine afforded (1R,5S)-anhydroecgonine methylesters (133) in good yield (85%). Acid hydrolysis of (R)-(-)-cocaine gave ecgonine (18), and heating of 18 with POCl3 followed by reaction with MeOH/H+ afforded (1R,5S)-anhydroecgonine methylesters (133) in 82% yield

(Scheme 3.2).61

Scheme 3.1

Scheme 3.2

3.3 Synthesis of anhydroecgonine methyl ester

Davies and co-workers reported a method for the preparation of (1R,5S)-(-)- anhydroecgonine methylester (133) using a tandem cyclopopanation/Cope rearrangement.63

Reaction of methyl 2-diazo-3-buteonate (139) with rhodium(II)hexanoate (140) in the presence of N-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrole (138) gave bicyclic tropane 141 in 62% yield.

Catalytic hydrogenation of 141 using Rh(PPh3)3Cl (142) and H2 at 45 psi afforded 143 in 92% yield. Deprotection of 143 using tetrabutylammonium fluoride (144) followed by reductive methylation gave anhydroecgonine methylester (133) in 90% yield in two steps (Scheme 3.3).

Scheme 3.3

Majewski et al. described a method for the preparation of (+)-anhydroecgonine methylester (152) starting from tropinone (4).64 Reaction of methyl cyanoformate (148) with the lithium enolate 147 resulted in the formation of (-)-(methoxycarbonyl)tropinone (149) in 89% yield. Hydrogenation of (-)-149 afforded (+)-(methoxycarbonyl)tropine (150) in 90% yield. The

(+)-anhydroecgonine methylester (152) was obtained in 90% yield by reaction of (+)-150 with trifluoroacetic anhydride (151) and TEA (Scheme 3.4).

Scheme 3.4

A method for the preparation of (1R,5S)-(-)-anhydroecgonine methylester (133) using the coupling reaction between aryltriflates and the tetrakis(triphenylphosphine)palladium(0) catalyst was reported by Carroll.65 Reaction of (1R,5S)-(+)-2-carbomethoxy-3-tropinone (17) with

NaHMDS and phenyl triflimide (153) gave triflate 154 in 86% yield. Reduction of triflate 154 using formic acid, triethylamine, triphenylphosphine in the presence of palladium acetate yielded

(1R,5S)-(-)-anhydroecgonine methylester (133) (Scheme 3.5)

Scheme 3.5

3.4 Present study for the synthesis of C-1 substituted-2-carbomethoxy-3-phenyltropanes

3.4.1 Preparation of (1R,5S)-C-1 methyl anhydroecgonine methylester

Efforts for the preparation of the methyl ester of C-1 methyl substituted anhydroecgonine

(1R,5S)-164 began with the methyl ester of C-1 methyl ecgonine 155 prepared from 113a

(Scheme 3.6). Acid catalyzed dehydration of 155 was next explored. The absence of a vinyl hydrogen in the 1H-NMR of the crude reaction mixture (triplet at δ 6.3), led to the conclusion that the acid catalyzed dehydration reaction of 155 did not afford expected C-1 methyl anhydroecgonine 157. Refluxing 155 with aq. HCl for 12 h resulted in a 1:1 mixture of 155 and

156 (Scheme 3.9, Table 3.1, entry 1). Increasing the reaction time to 18 h and 36 h increased the ratio of 155:156 to 1:1.5 and 1:1.9, respectively (Scheme 3.6, Table 3.1, entries 2 and 3).

Scheme 3.6

Table 3.1: Acid catalyzed dehydration reaction of methyl ester of C-1 methyl ecgonine 155

Entry starting material conditions ratio (155:156:157)a

1 (1R,2R,3S,5S)-155 aq. HCl, reflux, 12 h 1:1:0

2 aq. HCl, reflux, 18 h 1:1.5:0

3 aq. HCl, reflux, 36 h 1:1.9:0

Table 3.1 continued 58

aRatios determined using 1H-NMR of crude reaction mixture.

Reaction of 113a with POCl3 under reflux conditions did not result in the formation of methyl ester of C-1 methyl anhydroecgonine 164 (Scheme 3.7). A new compound (5S,2Z)- methyl-(N-Me-2,3-dihydro-1H-pyrrole)-but-2-enoate (158) was isolated in 58% yield (Scheme

3.7). The structure of 158 is supported by analysis of its 1H-NMR spectra. Absorptions in the alkene region at δ 6.92 ppm and δ 5.83 ppm with J = 11.3 Hz indicates the presence of a cis double bond between C-2 and C-3 carbons, and the multiplet at δ 5.98 ppm indicates the presence of a vinyl hydrogen of enemine double bond. The absence of a broad peak corresponding to bridgehead hydrogen at δ 3.82 ppm also indicates absence of the bicyclic tropane system.

A possible mechanism for the rearranged product is given in Figure 3.2. The steric strain caused by methyl substitution at C-1 position and C-2 axial carbomethoxy group may be responsible for retro Mannich reaction resulting in the opening of the bicyclic system affording

158.

Scheme 3.7

Figure 3.2 POCl3 mediated rearrangement

The reaction of methyl ester of C-1 methyl ecgonine 155 with TEA and methanesulfonyl chloride afforded the methanesulfonyl ester 159 in 62% yield (Scheme 3.8). Treatment of 159 with TEA in DCM resulted in the rearrangement dehydropyrrolidine (5S,2Z)-158 in 34% yield

(Scheme 3.9, Table 3.2, entry 1). Similar results were observed on treatment of 159 with

NaHMDS. At -78 oC no reaction was observed between NaHMDS and 159 (Scheme 3.9, Table

3.2, entry 2). At 0 oC, treatment of 159 with NaHMDS resulted in the formation of 1:1 mixture of 159 and 158 (Scheme 3.9, Table 3.2, entry 3).

Scheme 3.8

Scheme 3.9

Table 3.2: Rearrangement of methanesulfonyl ester of methyl ester of ecgonine 159

Entry Starting material conditions ratio (159:158)a %Yield (158)

1 (1R,2R,3S,5S)-159 TEA/DCM/0 oC to rt, 4 h 1:1 34

2 NaHMDS/THF/-78 oC/6 h no reaction xxx

3 NaHMDS/THF/-78 oC to 0 oC/6 h 1:1 xxx aRatios determined using 1H-NMR of crude reaction mixture.

Swern oxidation of methyl ester of C-1 methyl ecgonine 155 afforded (1R,2R,5S)-(-)-1- methyl-2-carbomethoxy-3-tropinone (160) in 78% yield (Scheme 3.10). The reaction of 160 with NaHMDS followed by phenyl triflimide (161) resulted in the formation of complex mixture of compounds. The reaction of 160 with NaHMDS and N-(5-chloro-2- pyridyl)bis(trifluoromethanesulfonamide) (Comins reagent) (162) afforded (1R,5S)-1-methyl-2- carbomethoxy-3-tropinone-3-triflate (163) in 61% yield (Scheme 3.10). Reduction of triflate

163 using formic acid, TEA, triphenylphosphine in the presence of palladium acetate resulted in decomposition (Scheme 3.11, Table 3.3, entry 1). Reduction of triflate 162 using formic acid,

TEA and tetrakis(triphenylphosphine)palladium(0) also resulted in decomposition (Scheme 3.11,

Table 3.3, entry 2).

Scheme 3.10

Scheme 3.11

Table 3.3: Reduction of triflate (1R,5S)-(-)-163

Entry starting material conditions products

1 (1R,2S)-(-)-163 PPh3/Pd(OAc)2/HCO2H/TEA/THF/reflux decomposition

2 (PPh3)4Pd(0)/HCO2H/TEA.THF/reflux decomposition

In summary, attempts to prepare the methyl ester of C-1 methyl anhydroecgonine (164) were not successful. Rearrangement of bicyclic system to dehydropyrrolidine 158 derivative occurred when methyl ester of C-1 methyl ecgonine was treated with POCl3 or base treatment of methanesulfonyl ester of methyl ester of ecgonine 159. Attempts for hydrogenation of triflate derivative 163 were also not successful.

CHAPTER 4

VINYLALUMINUM ADDITION TO SULFINIMINES (N-SULFINYL

IMINES) ASYMMETRIC SYNTHESIS OF

ANTI-α-ALKYL β-AMINO ESTERS

4.1 Introduction

Owing to their valuable biological properties and importance as chiral building blocks and as precursors for the synthesis of β-lactams, β-amino acids and their derivatives continue to be important target for enantioselective synthesis.66,67 To date, only a few methods are available for the asymmetric synthesis of acyclic α-substituted β-amino acids and their derivatives.68-70

Molecules having α-substituted β-amino acid moiety such as (-)-cispentacin and taxol (Figure

4.1) are known to possess antibiotic and antitumor activity.66

Figure 4.1 Cispentacin and taxol

4.2 Earlier synthesis of α-alkyl substituted β-amino acids using sulfinimine chemistry.

An early example of the asymmetric synthesis of α-alkyl β-amino acids using sulfinimine chemistry was reported by Ellman and co-workers.71 The addition of prochiral titanium enolates of α-alkyl substituted esters 166a to c to various N-tert-butylsulfinimes 165a to e afforded the

corresponding α-substituted β-amino esters 167a to f in good yield and diastereoselectivity

(Scheme 4.1, Table 4.1).

Scheme 4.1

Table 4.1: Addition of prochiral enolates of α-alkyl substituted esters to sulfinimines.71

Entry Sulfinimine (165) α-substituted esters (166) dra %yield (167)

1 165a (R1 = Me) 166a (R2 = H) 99:1 94 (167a)

i 2 165c (R1= Pr) 98:2 85 (167b)

3 165e (R1 = Ph) 98:2 90 (167c)

i 4 165d (R1 = Bu) 166b (R2 = Me) 95:3:2:0 81 (167d)

5 165e (R1 = Ph) 94:4:0:0 85 (167e)

6 165b (R1 = Et) 166c (R2 = Bn) 90:10:0:0 81 (167f) adr ratio was determined using HPLC analysis of crude sample.

Davis and co-workers studied the addition of prochiral enolates of Weinreb amides to sulfinimines.69 Enolates of Weinreb amides were added to various sulfinimines to generate syn

α-alkyl substituted β-amino Weinreb amides as the major isomer (Scheme 4.2, Table 4.2). The reaction of lithium enolate of 172 with sulfinimine 168a (Z = p-Tolyl, R = Ph) in THF produced an 87:13 mixture of syn:anti isomers of 173a in 99% yield, but the isomers were inseparable

(Scheme 4.2, Table 4.2, entry 1). Following the above protocol, reaction of lithium enolate of

172 with sulfinimine 168b (Z = p-Tolyl, R = Et) gave mixture of syn:anti isomers of 173b in

67% yield (Scheme 4.2, Table 4.2, entry 2). Surprisingly, sulfinimine 169a (Z = t-Bu, R = Ph) did not reacted with the lithium enolate of 172 (Scheme 4.2, Table 4.2, entry 3). Addition of lithium enolate of 172 to sulfinimines 170a (Z = 2,4,6-Me3C6H2-, R = Ph) and b (Z = 2,4,6-

Me3C6H2-, R = Et) resulted in the formation of 96:4 and 87:13 mixtures of syn:anti isomers of

175a and b respectively (Scheme 4.2, Table 4.2, entries 4 and 5). Significantly, these isomers were inseparable. Reaction of lithium enolate of 172 with sulfinimines 171a (Z = 2,4,6- i i Pr3C6H2-, R = Ph) and b (Z = 2,4,6- Pr3C6H2-, R = Et) produced a 92:5 and 4:1 mixture of syn:anti isomers of 176a and b respectively, the major syn isomer was isolated in 76% yield using column chromatography (Scheme 4.2, Table 4.2, entries 6 and 7).

Scheme 4.2

Table 4.2: Addition of prochiral enolate of α-alkyl substituted Weinreb amides to sulfinimines

Entry Sulfinimine enolate conditions dr (syn:anti)a %yield

1 168a (Z = p-Tolyl, R = Ph) LiHMDS, THF 87:13 (traces) 99b

2 168b (Z = p-Tolyl, R = Et) LiHMDS, THF 75:11:10:4 67b

3 169a (Z = t-Bu, R = Ph) LiHMDS, THF NR NR

b 4 170a (Z = 2,4,6-Me3C6H2, R = Ph) LiHMDS, THF 96:4 99

b 5 170b (Z = 2,4,6-Me3C6H2-, R = Et) LiHMDS, THF 80:17:3 72

i b c 6 171a (Z = 2,4,6- Pr3C6H2-, R = Ph) LiHMDS, THF 92:5:3 74 , 13

i b c d 7 171b (Z = 2,4,6- Pr3C6H2, R = Et) LiHMDS, THF 4:1 95 , 76 , 19 aRatio determined using 1H-NMR of crude sample. bIsolated yield of mixture of diastereomers. cIsolated yield of syn-isomer. dIsolated yield of anti-isomer.

Recently, Davis and Theddu reported a protocol for addition of prochiral unsaturated enolates of Weinreb amides, generated using LDA, to sulfinimines to exclusively yield syn α- substituted β-amino Weinreb amides.72 Addition of potassium, sodium and lithium enolates of

Weinreb amide 178a to sulfinimine 177 in THF at -78 oC produced all the four isomers (Scheme

4.3, Table 4.3, entries 1 to 3), but the reaction of lithium enolate of 178a, generated using LDA, with sulfinimine 177 resulted in the exclusive formation of syn α-substituted β-amino Weinreb amide in 89% yield (Scheme 4.3, Table 4.3, entry 4). Using these optimized reaction conditions, addition of lithium enolates of Weinreb amides 178a and c to sulfinimine 177 gave syn α-

substituted β-amino Weinreb amide 179a to c as exclusive isomer (Scheme 4.3, Table 4.3, entries 5 and 6). Oxidation of syn α-substituted β-amino Weinreb amide 179a - c yields N- tosylate derivative of α-substituted β-amino Weinreb amides 181a - c in good yield (Scheme

4.4). Ring-closing metathesis (RCM) reaction of 179a - c and of 181a - c provided five-, six- and seven-membered unsaturated cyclic cis-β-amino Weinreb amides 180a - c and 182a - c, respectively (Scheme 4.4), which can then be converted into molecules with significant biological importance.72

Scheme 4.3

Table 4.3: Addition of enolate of Weinreb amides 178a to c (n = 1, 2 and 3) to sulfinimine 17772

Entry Sulfinimine Weinreb amide (178a to c) base %yielda (dr syn:anti)b (179)

1 (S)-(+)-177 178a (n = 1) KHMDS 92 (39:34:18:9)

2 NaHMDS 90 (68:10:10:6)

3 LiHMDS 90 (77:15:8)

4 LDA 89 (>99:1) (179a)

5 178b (n = 2) LDA 90 (>99:1) (179b)

6 178c (n = 3) LDA 90 (>99:1) (179c)

Table 4.3 continued

aCombined yield of inseparable isomers. bRatios determined using 1H-NMR of crude reaction mixture.

Scheme 4.4

Aggarwal and co-workers reported the preparation of α-aminoalkyl acrylates (+)-186 and

(-)-187 (aza-Morita-Baylis-Hillman) adducts using sulfinimine chemistry (Scheme 4.5).73 These reactions offer an alternate procedure for the preparation of syn α-alkyl β-amino esters using sulfinimines.

Scheme 4.5

In 2003, Ramachandran and co-workers described a procedure for generation vinylaluminum reagents by the reaction of DIBAL-H, NMO (N-methylmorpholine N-oxide) with

α-acetylenic esters (Scheme 4.6).74 Addition of these vinylaluminum reagents to various electrophiles like aldehydes and ketones produced Morita-Baylis-Hillman (MBH) adducts in good yields (Scheme 4.7).74 Li and co-workers generated vinylcuprates by the reaction of

R2CuLi with α-acetylenic esters (Scheme 4.8). Reaction of these vinylcuprates with sulfinimines gave branched aza-MBH adducts in good yields (Scheme 4.8).75 This procedure needs careful control of reaction conditions and has limited practical applicability.

Scheme 4.6

Scheme 4.7

Scheme 4.8

4.3 Present study76

4.3.1. Retrosynthetic analysis

The aim of this project was to develop a route for the asymmetric synthesis of N-sulfinyl

α-substituted β-amino esters and ketones.76 Addition vinylaluminum esters to sulfinimines would result in the formation of aza-Morita-Baylis-Hillman adducts (aza-MBH adduct).

Stereospecific reduction of the aza-MBH adduct could result in the formation anti N-sulfinyl α- alkyl β-amino esters which can then be converted into β-lactams and other synthetically useful intermediates (Figure 4.2).76

Figure 4.2 Retrosynthetic analysis of N-tosyl-β-lactams

4.3.2 Asymmetric synthesis of aza-Morita-Baylis-Hillman adduct

The aza-Morita-Baylis-Hillman reaction of sulfinimine was performed using the

Ramachandran protocol (Scheme 4.9).74 Vinylaluminum reagent 189a was prepared by addition of solution of DIBAL-H-NMO to ethyl propiolate (188a) (Scheme 4.9). Addition of vinylaluminum reagent 189a to (S)-(+)-N-(benzylidine)-p-toluenesulfinimine (168a) resulted in the formation of aza-Morita-Baylis-Hillman adduct 195a in 17% yield (Scheme 4.9, Table 4.4, entry 1). In efforts to increase the yield, three equivalents of vinylaluminum reagent 189a were used (Scheme 4.9, Table 4.4, entry 2). Addition of Lewis acid catalyst Zn(OTf)2 had little effect on diastereoselectivity and the yield (Table 4.4, entry 3). Drastic reduction in the yield was observed when methyl propiolate (193) was used instead of ethyl propiolate (188a), (32% yield observed when methyl propiolate was used as compared to 65% yield when ethyl propiolate was used) (Scheme 4.9, Table 4.4, entries.3, 4 and 5).

Scheme 4.9

Table 4.4: Aza-Morita-Baylis-Hillman reaction of sulfinimine 168a74

Entry DIBAL-H:NMO:alkyne alkyne dra %yieldb

1 1.5:2.0:1.0 188a (R = Et) 9:1 17

2 4.5:6.0:3.0 188a (R = Et) 7:1 65

3 4.5:6.0:3.0 [Zn(OTf)2] 188a (R = Et) 8:1 63

4 4.5:6.0:3.0 193 (R = Me) 8:1 32 aRatio determined using 1H-NMR of crude reaction mixture. bIsolated yield of major isomer

To establish the absolute configuration of aza-MBH adduct (+)-195a, it was converted into β-lactam (3R,4S)-(-)-202, a compound of known absolute stereochemistry. Stereoselective catalytic hydrogenation of the Baylis-Hillman adducts preferentially gave anti selectivity.

Hydrogenation of N-acyl β-amino α-methylene esters using either Rh(II) and Rh(I) catalyst at higher pressure reaction condition (30 atm) afforded the anti α-substituted β-amino esters as

major isomers.77,78 Hydrogenation of aza-MBH adduct (+)-195a with catalytic cationic Rh(I) complex 197 resulted in an 22:1 (anti:syn) mixture of diastereoisomers. The major isomer

(Ss,2R,3S)-(+)-198 was isolated in 88% yield (Scheme 4.10).

Scheme 4.10

Oxidation of (Ss,2R,3S)-(+)-198 with m-CPBA resulted in the formation of (2R,3S)-(-)-

200 in 88% yield (Scheme 4.11). Hydrolysis of 200 gave acid (2R,3S)-(-)-201 in 87% yield which has been reported (Scheme 4.11).79,80 Reaction of the N-tosyl amino β-acid (-)-201 with dichlorohexylcarbidiimide (DCC) and 4-pyrrolidinopyridine gave known β-lactam (-)-202 in

80 80% yield (Scheme 4.11). These results confirm the absolute configuration of (Ss,R)-(+)-195a and (Ss,2R,3S)-(+)-198 and the anti-stereochemistry of the product.

Scheme 4.11

The addition of vinylaluminum reagents to the C-N double bond of sulfinimines can be explained using a chelated, chair-like transition state where the metal ion coordinates with the sulfinyl oxygen. A Yamamoto-type model transition state (Figure 4.3) predicts the addition of vinylaluminum reagents from si face of C-N double bond, and explains the results observed in this study.40c,81 The NMO acts as a ligand to aluminum and diminishes the ability of DIBAL-H to reduce either carbomethoxy and C-N double bond, and prevents complexation of aluminum with the sulfinyl group.

Figure 4.3 Transition state for the addition of vinylaluminum reagent to sulfinimine

Addition of β-substituted vinylaluminum reagents to sulfinimines was next explored.

Reaction of sulfinimine 168a with [α-(ethoxycarbonyl)-β-methylvinyl]diisobutylaluminum

(189b) resulted in 5:1 inseparable mixture of diastereoisomers of adducts 195b and 203 (Scheme

4.12).

Scheme 4.12

Reaction of α-ethoxycarbonyl vinyldiisobutylaluminum (189a) with (Rs)-(-)-N-

(benzylidene)-2-methylpropanesulfinamide (204a) at rt resulted in no reaction (Scheme 4.13,

Table 4.5, entry 1). Increasing the temperature from rt to 70 oC for 15 h gave the aza-Morita-

Baylis-Hillman adduct as a 12:1 mixture diastereoisomers (Rs,S)-205a and (Rs,R)-206a where the major isomer (Rs,S)-205a was isolated in 65% yield (Scheme 4.13, Table 4.5, entry 2).

Following the above protocol, [α-(ethoxycarbonyl)-β-methylvinyl]diisobutylaluminum (189b) and [α-(ethoxycarbonyl)-β-phenylcinyl]diisobutylaluminum (189c) were added to sulfinimine

204a to give aza-Mortia-Baylis-Hillman adducts (Rs,S)-205b and (Rs,R)-206b (Scheme 4.13,

Table 4.5, entry 3), (Rs,S)-205c and (Rs,R)-206c (Scheme 4.13, Table 4.5, entry 4), respectively.

The major diastereoisomers 205b and 205c were isolated in 71 and 73% yields, respectively

(Table 4.5, entries 3 and 4). Reaction of 189a, b and c with sulfinimine (Rs)-204b using above conditions also produced aza-Morita-Baylis-Hillman adducts (Rs,S)-205d and (Rs,R)-206d,

(Rs,S)-205e and (Rs,R)-206e, (Rs,S)-205f and (Rs,R)-206f, respectively (Scheme 4.13, Table 4.5, entries 5, 6 and 7). The diastereoisomers 205d and 206d, 205e and 206e could not be separated

(Table 4.5, entries 5 and 6), but 205f and 206f can be separated and the major diastereoisomer

205f was isolated in 35% yield (Table 4.5, entry 7).

Scheme 4.13

Table 4.5: Aza-Morita-Baylis-Hillman reaction of sulfinimines 204a and b

Entry DIBAL-H:NMO:alkyne sulfinimine temperature, time %yielda (dr)b

1 4.5:6:3 (188a) (Rs)-204a rt, 16 h no reaction

2 70 oC, 15 h 65 (12:1)

3 4.5:6:3 (188b) 70 oC, 15 h 71 (7:1)

4 4.5:6:3 (188c) 70 oC, 15 h 73 (7:1)

o c 5 4.5:6:3 (188a) (Rs)-204b 70 C, 15 h 58 (13:1)

6 4.5:6:3 (188b) 70 oC, 15 h 50c (11:1)

7 4.5:6:3 (188c) 70 oC, 15 h 35 (6.2:1) a b 1 Isolated yield of major diastereoisomer (Rs,S)-205a to f. Ratio determined using H-NMR of crude reaction mixture. cYield of inseparable diastereoisomer mixture.

Hydrogenation of aza-MBH adducts (Rs,S)-205a - f was carried out using catalytic cationic Rh(I) complex 197 (Scheme 4.14). Addition of hydrogen to double bond in (Rs,S)-205a and d was accomplished at rt and 1 atm of H2 for 48 h (Scheme 4.14, Table 4.6, entries 1 and 4).

In the case of (Rs,S)-205b, c and f, higher pressure of H2 (25 atm) and longer reaction times (72 h) were necessary for the hydrogenation of double bond (Scheme 4.14, Table 4.6, entries 2, 3 and 7). Hydrogenation of (Rs,S)-205e at 25 atm of H2 for 72 h yielded mixture of inseparable diastereoisomers contaminated with starting material (Scheme 4.14, Table 4.6, entry 5); prolonged reaction time (90 h) resulted in decomposition.(Scheme 4.14, Table 4.6, entry 6).

Scheme 4.14

Table 4.6: Hydrogentation aza-MBH adducts (Rs,S)-205a to f using cationic Rh(I) complex 197

Entry aza-MBH adduct (205) conditions solvent %yielda (dr)b

1 (Rs,S)-205a H2 (1 atm), 48 h CH2Cl2 83 (21:1)

2 (Rs,S)-205b H2 (25 atm), 72 h ClCH2CH2Cl 81 (20:1)

3 (Rs,S)-205c 79 (20:1)

4 (Rs,S)-205d H2 (1 atm), 48 h CH2Cl2 55 (10:1)

5 (Rs,S)-205e H2 (25 atm), 72 h ClCH2CH2Cl complex mix.

6 H2 (25 atm), 90 h decomposition

7 (Rs,S)-205f 79 (17:1) aIsolated yield of major diastereoisomer. bRatio determined using 1H-NMR of crude reaction mixture.

In summary, a new method for the preparation anti-α-alkyl-β-amino esters using sulfinimine chemistry was developed. The Ramachandran protocol for the Morita-Baylis-

Hillman reaction using vinylaluminum esters was applied to sulfinimine chemistry and demonstrated that aza-Morita-Baylis-Hillman reaction of sulfinimines can used for the asymmetric synthesis of anti-α-alkyl-β-amino esters.

CHAPTER-5

EXPERIMENTAL

5.1 General procedures

Reagents and solvents were purchased from Aldrich Chemical Company or Acros

Organics and used without additional purification unless otherwise noted. Glassware was oven- dried at 120 oC and cooled to ambient temperature in a desiccators prior to use. Reactions involving air sensitive materials and/or requiring anhydrous reaction conditions were performed under an argon atmosphere. Reagent grade tetrahydrofuran (THF), diethyl ether (Et2O), dichloromethane (DCM), and toluene were dried by filtration on a glass contour solvent dispensing system. Column chromatography was performed on silica gel, Merck grade 60 (230-

400 mesh). Analytical and preparative thin-layer chromatography was performed on precoated silica gel plates (250 and 1000 microns) purchased from Analtech Inc. TLC plates were visualized with UV-lamp, in an iodine chamber, or with a phosphomolybdic acid solution unless noted otherwise.

Melting points were recorded on a Mel-Temp apparatus and are uncorrected. Optical rotations were measured on a Perkin-Elmer 341 polarimeter. Infrared spectra were recorded on a

Perkin-Elmer 1600 FTIR spectrometer using NaCl plates for liquids and KBr disc for solids. 1H

13 and C NMR spectra were obtained in CDCl3 solution unless noted otherwise and were referenced to either TMS (0.00 ppm) and CDCl3 (7.26 ppm and 77.0 ppm, respectively) using

Bruker 500 MHz, Bruker 400 MHz or Varian 300 MHz NMR spectrometer. Mass spectra were collected at the Department of Chemistry, Drexel University and Department of Chemistry,

University of California-Riverside and Department of Chemistry, Hunter College-New York.

5.2 Chapter 2: Asymmetric Synthesis of C-1 Substituted Cocaine Analogues present

study

4-Hydroxy-N-methoxy-N-methylhexanamide (118b):

In a 100 mL, oven dried, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum and argon inlet, was placed N,O-dimethyl hydroxylamine hydrochloride (2.9 g, 29.8 mmol) and dihydro-5-ethyllfuran-2(3H)-one (117b) (Aldrich, 2.2 g,

19.3 mmol) in THF (96 mL), and the solution was cooled to -15 oC in an salt-ice mixture.

Isopropylmagnesuim chloride (2.0 M solution in THF, 28.8 mL, 57.6 mmol) was added slowly via syringe and the reaction mixture was stirred at -20 oC for 20 min. At this time the solution was quenched with sat. NH4Cl solution (20 mL) and extracted with EtOAc (3 x 25 mL). The combined organic phases were washed with brine (2 x 50 mL), dried (MgSO4), and concentrated.

Flash chromatography (60% EtOAc/hexanes) gave 2.87 g (85%) of a colorless oil; IR (neat)

-1 1 3418, 1648 cm ; H NMR (CDCl3) δ 0.943 (t, J = 7.2 Hz, 3H), 1.49 (m, 2H), 1.72 (m, 1H), 1.85

13 (m, 1H), 2.58 (m, 3H), 3.18 (s, 3H), 3.54 (b, 1H), 3.69 (s, 3H); C NMR (CDCl3) δ 9.9, 28.5,

30.4, 31.1, 61.2, 72.9, 82.0, 175.1. HRMS calcd for C8H18NO3 (M+H) 176.1287. Found

176.1279.

4-Hydroxy N-methoxy N-methyl heptamide (118c):

Prepared from -heptalactone (117c). Flash Chromatography (50% EtOAc in hexanes)

-1 1 afforded 87% of a colourless oil: IR (film) 3440, 1640 cm ; H NMR (CDCl3)  0.92 (t, J = 7.1

Hz, 3H), 1.45 (m, 4H), 1.72 (m, 1H), 1.84 (m, 1H), 2.57 (m, 3H), 3.18 (s, 3H), 3.64 (m, 1H),

13 3.69 (s, 3H); C NMR (CDCl3)  14.1, 18.8, 28.5, 31.6, 32.2, 39.9, 61.2, 71.3, 175.1. HRMS calcd for C9H20NO3 (M+H) 190.1443. Found 190.1436.

4-Hydroxy-N-methoxy-N-methylnonanamide (118d):

Prepared from dihydro-5-pentylfuran-2(3H)-one (117d). Flash chromatography (40%

-1 1 EtOAc/hexanes) gave 90% of a colorless oil; IR (neat) 3418, 1648 cm ; H NMR (CDCl3) δ

0.88 (t, J = 7.2 Hz, 3H), 1.31 (b, 5H), 14.3(b, 3H), 1.70 (m, 1H), 1.86 (m, 1H), 2.56 (m, 3H),

13 3.18 (s, 3H), 3.62 (b, 1H), 3.69 (s, 3H); C NMR (CDCl3) δ 14.0, 22.6, 25.3, 28.4, 31.5, 31.8,

32.1, 37.6, 175.0. HRMS calcd for C11H24NO3 (M+H) 218.1756. Found 218.1753.

N-Methoxy-N-methyl-4-oxonohexanamide (119b):

In a 250 mL, oven dried, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum and argon inlet, was placed IBX (13.44 g, 48 mmol) in dry EtOAc

(80 mL) and the mixture was cooled to 0 oC. A solution of 118b (2.8 g, 16 mmol) in EtOAc (80 mL) was added, the reaction mixture was refluxed for 5 h, cooled to rt, and filtered. The filter cake was washed with EtOAc (2 x 30 mL), and the combined organic phase combined organic phases were washed with brine (50 mL), dried (MgSO4), and concentrated. Flash chromatography (40% EtOAc/hexanes) gave 2.07 g (75%) of a colorless oil; IR (neat) 1698,

-1 1 1645 cm ; H NMR (CDCl3) δ 1.06 (t, J = 7.2 Hz, 3H), 2.50 (q, J = 7.3 Hz, 2H), 2.72 (b, 4H),

13 3.16 (s, 3H), 3.72 (s, 3H); C NMR (CDCl3) δ 7.6, 25.7, 32.0. 35.9, 36.0, 61.0, 173.1, 210.3.

HRMS calcd for C8H16NO3 (M+H) 174.1130. Found 174.1123.

N-Methoxy N-methyl 4-oxoheptamide (119c):

Flash Chromatography (50% EtOAc in hexanes) afforded 70% of a colourless oil: IR

-1 1 (film) 1715, 1640 cm ; H NMR (CDCl3)  0.88 (t, J = 7.2 Hz, 3H), 1.58 (m, 2H), 2.42 (t, J =

13 7.3 Hz, 2H), 2.71 (bm, 4H), 3.13 (s, 3H), 3.69 (s, 3H); C NMR (CDCl3)  13.6, 17.1, 25.6,

32.1, 36.3, 44.7, 61.0, 173.1, 209.8. HRMS calcd for C9H18NO3 (M+H) 188.1287. Found

188.1279.

N-Methoxy-N-methyl-4-oxononanamide (119d):

Flash chromatography (20% EtOAc/hexanes) gave 85% of a colorless oil; IR (neat) 1698,

-1 1 1645 cm ; H NMR (CDCl3) δ 0.88 (t, J = 7.2 Hz, 3H), 1.29 (m, 4H), 1.57 (m, 2H), 2.46 (t, J =

13 7.6 Hz, 2H), 2.73 (s, 4H), 3.16 (s, 3H), 3.72 (s, 3H); C NMR (CDCl3) δ 13.8, 22.4, 23.4, 25.7,

31.3, 32.1, 36.5, 42.9, 61.1, 173.2, 210.1. HRMS calcd for C11H22NO3 (M+H) 216.1600. Found

216.1595.

N-Methoxy-N-methyl-3-(2-ethyl-1,3-dioxolan-2-yl)propanamide (120b):

In a 250 mL, oven dried, single-necked round-bottom flask equipped with a magnetic stirring bar and rubber septum, was placed 119b (2.0 g, 11.56 mmol), ethylene glycol (1.07 g,

. 17.34 mmol), PTSA H2O (0.0679 g, 0.34 mmol) and benzene (140 mL). The reaction mixture was refluxed using a Dean-Stark column for 12 h, concentrated, and the residue was diluted with

EtOAc (100 mL). The organic phase was washed with sat. NaHCO3 (3 x 30 mL), H2O (2 x 20

mL), brine (2 x 25 mL), dried (MgSO4), and concentrated. Flash chromatography (40%

-1 1 EtOAc/hexanes) gave 2.00 g (80%) of a colorless oil; IR (neat) 1642 cm ; H NMR (CDCl3) δ

0.89 (t, J = 7.6 Hz, 3H), 1.63 (q, J = 7.6 Hz, 2H), 1.96 (m, 2H), 2.47 (m, 2H), 3.15 (s, 3H), 3.67

13 (s, 3H), 3.93 (s, 4H); C NMR (CDCl3) δ 7.9, 26.4, 29.8, 30.9, 32.3, 35.9, 36.1, 61.2, 64.4,

111.3, 174.4. HRMS calcd for C10H20NO4 (M+H) 218.1392. Found 218.1386.

N-Methoxy-N-methyl-3-(2-n-propyl-1,3-dioxolan-2-yl)propanamide (120c):

Flash chromatography (70% EtOAc in hexanes) afforded 85% of a colourless oil: IR

-1 1 (film) 1640 cm ; H NMR (CDCl3)  0.86 (t, J = 7.3 Hz, 3H), 1.35 (m, 2H), 1.55 (m, 2H), 1.93

13 (m, 2H), 2.44 (t, J = 7.6 Hz, 2H), 3.12 (s, 3H), 3.64 (s, 3H), 3.89 (m, 4H); C NMR (CDCl3) 

14.2, 16.9, 26.3, 31.3, 32.2, 39.3, 61.1, 64.7, 110.9, 174.3. HRMS calcd for C11H22NO4 (M+H)

232.1549. Found 232.1544.

N-Methoxy-N-methyl-3-(2-pentyl-1,3-dioxolan-2-yl)propanamide (120d):

Flash chromatography (15% EtOAc/hexanes) afforded 75% of a colorless oil; IR (neat)

-1 1 1642 cm ; H NMR (CDCl3) δ 0.87 (t, J = 7.6 Hz, 3H), 1.31 (b, 6H), 1.61 (m, 2H), 1.97 (m,

13 2H), 2.48 (m, 2H), 3.17 (s, 3H), 3.68 (s, 3H), 3.94 (s, 4H); C NMR (CDCl3) δ 13.9, 22.5, 23.3,

26.4, 31.3, 32.0, 32.2, 37.0, 61.1, 64.8, 111.1, 174.4. HRMS calcd for C13H26NO4 (M+H)

260.1862. Found 260.1860.

3-(2-ethyl-1,3-dioxalan-2-yl)propanal (100b):

In a 100 mL, oven dried, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon inlet, was placed LiAlH4 (0.525 g, 13.82 mmol) in THF

(40 mL) and the reaction mixture was cooled to -78 oC. A solution of 100b (2.0 g, 9.21 mmol) in

THF (52 mL) was added slowly, the reaction mixture was stirred at -78 oC for 1 h, quenched with H2O (50 mL), and extracted with EtOAc (3 x 75 mL). The combined organic phases were washed with H2O (2 x 50 mL), brine (2 x 30 mL), dried (MgSO4), and concentrated. Flash chromatography (25% EtOAc/hexanes) gave 1.23 g (85%) of a colorless oil; IR (neat) 1704,

-1 1 1646 cm ; H NMR (CDCl3) δ 0.87 (t, J = 7.6 Hz, 3H), 1.57 (m, 2H), 2.00 (m, 2H), 2.41 (m,

13 2H), 3.90 (s, 4H), 9.67 (t, J = 1.6, 1H); C NMR(CDCl3) δ 7.8, 29.1, 30.0, 37.9, 64.7, 110.8,

201,6. HRMS calcd for C8H15O3 (M+H) 159.1021. Found 159.1014.

3-(2-n-Pentyl-1,3-dixoalan-2-yl)propanal (100d):

Flash chromatography (10% EtOAc/hexanes) gave 91% of a colorless oil; IR(neat) 1704,

-1 1 1646 cm ; H NMR (CDCl3) δ 0.86 (t, J = 6.8 Hz, 3H), 1.26 (m, 6H), 1.56 (m, 2H), 2.01 (t, J =

13 6.8 Hz, 2H), 2.42 (m, 2H), 3.90 (m, 4H), 9.69 (t, J = 2.72 Hz, 1H); C NMR(CDCl3) δ 14.0,

22.6, 23.6, 29.8, 32.0, 37.6, 38.3, 65.0, 111.0, 202.2. HRMS calcd for C11H21O3 (M+H)

201.1491. Found 201.1482.

(S)-(+)-3-(2-n-propyl-1,3-dioxolan-2-yl)propylidine-p-toluenesulfinamide (101c):

To a 500 mL round-bottomed flask equipped with magnetic stirring bar and argon inlet was placed 100c (2.22 g, 12.88 mmol) in dry CH2Cl2 (100 mL). (S)-(+)-p-Toluenesulfinamide

(95) (1.99 g, 12.88 mmol) was added followed by Ti(OEt)4 (14.71 g, 64.45 mmol) and the reaction was stirred at rt for 24 to 48 h until complete. At this time, the reaction mixture was

o cooled to 0 C and then quenched with H2O (6 mL). After stirring for 5 min, the solids were filtered; the filter cake was washed with DCM (3 x 50 mL), the combined organic phases were washed with brine (100 mL), dried (MgSO4), and concentrated. Flash chromatography (25%

-1 20 EtOAc/hexanes) gave 2.79 g (70%) of slightly yellow oil; IR (film) 1625 cm ; []D +230.2 (c

1 0.6, CHCl3); H NMR (CDCl3)  0.89 (t, J = 7.3 Hz, 3H), 1.36 (m, 2H), 1.55 (m, 2H), 1.96 (m,

2H), 2.39 (s, 3H), 2.55 (m, 2H), 3.86 (m, 4H), 7.29 ( bd, J = 7.8 Hz, 2H), 7.56 (bd, J = 8.1 Hz,

13 2H), 8.23 (t, J = 4.4 Hz, 1H); C NMR (CDCl3)  14.3, 17.1, 30.5, 32.5, 39.7, 64.9, 65.0, 110.8,

124.6, 129.7, 141.6, 141.8, 167.3; HRMS calcd for C16H24NO3S (M+H) 310.1477. Found

310.1473.

(S)-(+)-3-(2-phenyl-1,3-dioxolan-2-yl)propylidine-p-toluenesulfinamide (101e):

Flash chromatography (12% EtOAc/hexanes) yielded 0.710 g (65%) of a slightly yellow

20 -1 1 oil; [] D +206.0 (c 1.30, CHCl3); IR (neat) 3051, 1635, 1213 cm ; H NMR (CDCl3)  2.16

(m, 2H), 2.33 (s, 3H), 2.53 (dt, J = 7.6 Hz, 4.4 Hz, 2H), 3.66 (m, 2H), 3.88 (m, 2H), 7.24 (m,

13 5H), 7.35 (m, 2H), 7.48 (d, J = 10.0 Hz, 2H), 8.18 (t, J = 5.5 Hz, 1H); C NMR (CDCl3)  21.4,

30.6, 35.9, 64.5, 109.5, 124.6, 125.6, 128.0, 128.2, 129.7, 141.5, 142.1, 167.1. HRMS calcd for

C19H21NNaO3S (M + Na) 366.1140. Found 366.1139.

(S)-(+)-3-(2-Ethyl-1,3-dioxolan-2-yl)propylidene-t-butylsulfinamide (102b):

In a 250 mL, oven dried, single-necked round bottom flask equipped with a magnetic stirring bar, rubber septum, and argon inlet, was placed 100b (1.2 g, 7.59 mmol) in THF (76 mL) and (S)-(-)-tert-butylsulfinamide (99) (0.919 g, 7.59 mmol), and Ti(OEt)4 (5.19 g, 22.78 mmol) were added. The reaction mixture was stirred at rt for 24 h, cooled to 0 oC, and quenched by addition of brine solution (75 mL). The solution was filtered through Celite, the filter cake was washed with EtOAc (2 x 75 mL), and the combined organic phases were washed with brine

(75 mL), dried (MgSO4), and concentrated. Flash chromatography (25% EtOAc/hexanes) gave

20 -1 1 1.58 g (80%) of a colorless oil; [α] D +163.4 (c 2.085, CHCl3); IR(neat) 1623 cm ; H NMR

(CDCl3) δ 0.917 (t, J = 7.6 Hz, 3H), 1.18 (s, 9H), 1.64 (m, 3H), 1.97 (m, 2H), 2.57 (m, 2H), 3.94

13 (s, 4H), 8.08 (t, J = 4.4 Hz, 1H); C NMR (CDCl3) δ 8.0, 22.1, 30.0, 30.5, 31.9, 56.3, 64.9, 65.0,

111.0, 169.3. HRMS calcd for C12H24NO3S (M+H) 262.1477. Found 262.1477.

(S)-(+)-3-(2-Methyl-1,3-dioxalan-2-yl)propylidene-t-butylsulfinamide (102a):

20 Flash chromatography (40% EtOAc/hexanes) gave 85% of a clear oil;  D +228.9 (c

1 1.59, CHCl3); H NMR (CDCl3)  1.19 (s, 9H), 1.35 (s, 3H), 2.01 (m, 2H), 2.61 (m, 2H), 3.95

13 (m, 4H), 8.09 (t, J = 4.8 Hz, 1H); C NMR (CDCl3)  22.2, 23.9, 30.7, 34.4, 56.3, 64.5, 64.6,

109.0, 169.1. HRMS calcd for C11H22NO3S (M+H) 248.3623. Found 248.3620.

(S)-(+)-3-(2-n-Pentyl-1,3-dioxolan-2-yl)propylidene-t-butylsulfinamide (102d):

20 Flash chromatography (25% EtOAc/hexanes) gave 1.59 g (70%) of a colorless oil; [α] D

-1 1 +156.6 (c 3.56, CHCl3); IR(neat) 1623 cm ; H NMR (CDCl3) δ 0.88 (t, J = 7.2 Hz, 3H), 1.18 (s,

9H), 1.31 (m, 6H), 1.59 (m, 2H), 1.98 (m, 2H), 2.57 (m, 2H), 3.94 (m, 4H), 8.08 (t, J = 4.4 Hz,

13 1H); C NMR(CDCl3) δ 13.9, 22.2, 22.4, 23.4, 30.6, 31.9, 32.4, 37.2, 56.4, 64.8, 64.9, 110.8,

169.3. HRMS calcd for C15H30NO3S (M+H) 304.1946. Found 304.1945.

(S)-(+)-3-(2-Phenyl-1,3-dioxalan-2-yl)propylidene-t-butylsulfinamide (102e):

Flash chromatography (40% EtOAc/hexanes) gave 85% of a white solid; mp 60-61 oC;

20 1  D +155.5 (c 0.55, CHCl3); H NMR (CDCl3)  1.17 (s, 3H), 2.24 (m, 2H), 2.60 (m, 2H),

3.78 (m, 2H), 4.02 (m, 2H), 7.35 (m, 3H), 7.45 (m, 2H), 8.08 (t, J = 4.4 Hz, 1H); 13C NMR

(CDCl3)  22.3, 30.7, 35.9, 56.5, 64.5, 64.6, 109.6, 125.6, 128.1, 128.2, 142.1, 169.2. HRMS calcd for C16H24NO3S (M+H) 310.1477. Found 310.1477.

(Ss,3S)-(+)-Methyl-N-(p-toluenesulfinyl)-3-amino-5-(2-methyl-1,3-dioxolan-2- yl)pentanoate (103a):

To a 500 mL round-bottomed flask equipped with magnetic stirring bar and argon inlet was placed NaHMDS (53.63 mL, 53.63 mmol, 1.0 M solution in THF) in anhydrous ether (300 mL). To this solution methyl acetate (3.61 g, 48.75 mmol) was added drop wise at -78 oC slowly via syringe and the reaction mixture was stirred at this temperature for 1 h. At this time (+)-101a

(5.48 g, 19.50 mmol) in THF (20 mL) was added to the above solution slowly via cannula. After

o stirring for 5 h at -78 C, the reaction mixture was quenched by adding sat. NH4Cl solution (30 mL) and H2O (100 mL) was added. The phases were separated and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (100 mL), dried (MgSO4) and concentrated. Flash chromatography (hexanes:EtOAc, 50:50) gave

-1 20 6.92 g (75%) of a clear oil (dr >99:1); IR (film) 3230, 1740, cm ;  D +80.4 (c 1.49, CHCl3);

1 H NMR (CDCl3) δ 1.32 (s, 3H), 1.73 (m, 3H), 1.87 (m, 1H), 2.40 (s, 3H), 2.60 (dq, J = 5.4 Hz,

J = 16.4 Hz, 2H), 3.65 (s, 3H), 3.68 (m, 1H), 3.94 (m, 4H), 4.62 (d, J = 8.8 Hz, 1H), 7.28 (bd, J =

13 8.4 Hz, 2H), 7.57 (td, J = 1.6 Hz, J = 8.0 Hz, 2H); C NMR(CDCl3) δ 21.3,23.9, 30.0, 35.4,

40.5, 51.7, 52.6, 64.6, 64.7, 109.7, 125.4, 129.5, 41.3, 142.4, 171.9. HRMS calcd for

C17H25NNaO5S (M+Na) 378.1351. Found 378.1333.

(Ss,3S)-(+)-Methyl-N-(p-toluenesulfinyl)-3-amino-5-(2-n-propyl-1,3-dioxolan-2- yl)pentanoate (103c):

Flash chromatography (hexanes:EtOAc, 50:50) gave 65% of a colourless oil (dr >99:1);

-1 20 1 IR (film) 3226, 1736, cm ;  D +66.8 (c 0.9, CHCl3); H NMR (CDCl3)  0.91 (t, J = 7.3 Hz,

3H), 1.38 (m, 2H), 1.58 (m, 2H), 1.69 (m, 3H), 1.83 (m, 1H), 2.40 (s, 3H), 2.60 (dq, J = 16.6 Hz,

J = 5.6 Hz, 2H), 3.65 (s, 3H), 3.68 (m, 1H), 3.92 (bs, 4H), 4.61 (d, J = 9.0 Hz, 1H), 7.28 (bd, J =

13 8.1 Hz, 2H), 7.58 (td, J = 8.1 Hz, J = 1.7 Hz, 2H); C NMR (CDCl3)  14.3, 17.1, 21.3, 29.8,

33.3, 39.4, 40.5, 51.6, 52.7, 64.9 (2C), 111.4, 125.4, 129.5, 141.3, 142.4, 171.9. HRMS calcd for

C19H29NNaO5S (M+Na) 406.1664. Found 406.1665.

(Ss,3S)-(+)-Methyl-N-(p-toluenesulfinyl)-3-amino-5-(2-phenyl-1,3-dioxolan-2- yl)pentanoate (103e):

Flash chromatography (hexanes:EtOAc, 50:50) gave 80% of a colourless oil (dr >99:1);

-1 20 1 IR (film) 3230, 1740 cm ;  D +62.6 (c 1.02, CHCl3); H NMR (CDCl3) δ 1.62 (m, 1H), 1.94

(m, 1H), 2.01 (m, 1H), 2.32 (s, 3H), 2.49 (m, 2H), 3.54 (s, 3H), 3.61 (m, 1H), 3.67 (m, 2H), 3.92

13 (m, 2H), 4.50 (d, J = 9.2 Hz, 1H), 7.23 (m, 5H), 7.37 (m, 3H), 7.47 (m, 2H); C NMR (CDCl3)

δ 21.3, 29.5, 36.6, 40.6, 51.5, 52.5, 64.4, 64.5, 109.9, 125.4, 125.5, 127.8, 128.1, 129.4, 141.1,

142.3, 142.4, 171.7. HRMS calcd for C22H28NO5S (M+H) 418.1688. Found 418.1687.

(Ss,3S)-(+)-Methyl-N-(t-butylsulfinyl)-3-amino-5-(2-methyl-1,3-dioxolan-2- yl)pentanoate (104a):

Flash chromatography (hexanes:EtOAc, 50:50) gave 93% of a clear oil (dr >99:1); IR

-1 20 1 (film) 3235, 1730 cm ;  D +44.0 (c 1.78, CHCl3); H NMR (CDCl3)  1.19 (s, 9H), 1.27 (s,

3H), 1.63 (m, 3H), 1.78 (m, 1H), 2.68 (m, 2H), 3.54 (m, 1H), 3.66 (s, 3H), 3.91 (m, 4H), 4.16 (d,

13 J = 8.4 Hz, 1H); C NMR (CDCl3)  22.5, 23.6, 29.9, 35.3, 40.2, 51.5, 53.8, 55.7, 64.4, 64.5,

109.5, 172.1. HRMS calcd for (M+H) C14H28NO5S 322.1688. Found 322.1682.

(Ss,3S)-(+)-Methyl-N-(t-butylsulfinyl)-3-amino-5-(2-ethyl-1,3-dioxolan-2-yl)- pentanoate (104b):

20 Flash chromatography (80% EtOAc/hexanes) gave 91% of a colorless oil; [α] D +29.2 (c

-1 1 1.60, CHCl3); IR(neat) 1741 cm ; H NMR (CDCl3) δ 0.88 (t, J = 7.6 Hz, 3H), 1.21 (s, 9H), 1.60

(m, 5H), 1.79 (m, 1H), 2.62 (dd, J = 16.0, 5.2 Hz, 1H), 2.79 (dd, J = 16.0, 5.2 Hz, 1H), 3.53 (b,

13 1H), 3.68 (s, 3H), 3.92 (s, 4H), 4.17 (d, J = 8.8 Hz, 1H); C NMR(CDCl3) δ 8.0, 22.6, 29.7,

32.8, 40.3, 51.6, 54.0, 55.8, 64.8, 64.9, 111.6, 172.2. HRMS calcd for C15H30NO5S (M+H)

336.1845. Found 336.1837.

(Ss,3S)-(+)-Methyl-N-(t-butylsulfinyl)-3-amino-5-(2-n-pentyl-1,3-dioxolan-2-yl)- pentanoate (104d):

20 Flash chromatography (70% EtOAc/hexanes) gave 91% of a colorless oil; [α] D +34.8 (c

-1 1 1.375, CHCl3); IR(neat) 1741 cm ; H NMR (CDCl3) δ 0.88 (t, J = 7.2 Hz, 3H), 1.21 (s, 9H),

1.27 (m, 6H), 1.55 (m, 3H), 1.62 (m, 1H), 2.61 (dd, J = 16.1, 5.6 Hz, 1H), 2.79 (dd, J = 16.1, 5.6

13 Hz, 1H), 3.53 (b, 1H), 3.68 (s, 3H), 3.92 (m, 4H), 4.18 (d, J = 8.8 Hz, 1H); C NMR(CDCl3) δ

13.9. 22.5, 22.6, 23.4, 29.8, 31.9, 33.2, 37.0, 40.3, 51.6, 54.0, 55.8, 64.8 (2 C’s), 111.4, 172.2.

HRMS calcd for C18H36NO5S (M+H) 378.2314. Found 378.2314.

(Ss,3S)-(+)-Methyl-N-(t-butylsulfinyl)-3-amino-5-(2-phenyl-1,3-dioxolan-2- yl)pentanoate (104e):

Flash chromatography (hexanes:EtOAc, 50:50) gave 93% of a clear oil (dr >99:1); IR

-1 20 1 (film) 3230, 1740 cm ;  D +31.3 (c 2.35, CHCl3); H NMR (CDCl3)  1.19 (s, 9H), 1.62 (m,

2H), 1.94 (m, 1H), 2.03 (m, 1H), 2.65 (m, 2H), 3.55 (m, 1H), 3.65 (s, 3H), 3.75 (m, 2H), 4.00

13 (m, 2H), 4.09 (d, J = 8.8 Hz, 1H), 7.32 (m, 3H), 7.41 (m, 2H); C NMR (CDCl3)  22.5, 29.4,

36.5, 40.2, 51.5, 53.7, 55.7, 64.3, 64.4, 109.9, 125.4, 127.7, 128.0, 142.2, 172.1. HRMS calcd for C19H30NO5S (M+H) 384.1845. Found 384.1842.

(Ss,3S)-(+)-N-(p-Toluenesulfinyl)-3-amino-5-(2-methyl-1,3-dioxolan-2-yl)pentanal

(105a):

In a 250 mL, oven-dried, single-neck round-bottomed flask equipped with magnetic stirring bar, and a rubber septum was placed (Ss,3S)-(+)-103a (2.64 g, 7.42 mmol) in toluene (75 mL). The solution was cooled to –78 oC and diisobutylaluminumhydride (13.36 mL, 13.36 mmol, 1.0 M solution in toluene) was added slowly via syringe. After stirring for 45 min, the

o reaction mixture was quenched with saturated aqueous NH4Cl (15 mL) at –78 C and warmed to rt. The reaction mixture was diluted with EtOAc (50 mL) and water (40 mL). This mixture was filtered through a Celite pad and the aqueous phase was extracted with EtOAc (3 x 60 mL). The combined organic phases were washed with brine (100 mL), dried (MgSO4) and concentrated.

Flash chromatography (80% EtOAc/hexanes) afforded 2.3 g (95%) of a clear oil; IR (film) 3424,

-1 20 1 1725 cm ;  D +78.3 (c 1.68, CHCl3); H NMR (CDCl3)  1.31 (s, 3H), 1.75 (m, 4H), 2.39 (s,

3H), 2.68 (m, 1H), 3.76 (m, 1H), 3.93 (m, 4H), 4.43 (d, J = 8.8 Hz, 1H), 7.27 (bd, J = 8.0 Hz,

13 2H), 7.54 (td, J = 2.0 Hz, J = 8.0 Hz, 2H), 9.61 (t, J = 1.2 Hz, 1H); C NMR (CDCl3)  21.3,

23.8, 30.5, 35.4, 49.9, 50.6, 64.6, 64.7, 109.6, 125.4, 129.5, 141.5, 141.9, 200.7. HRMS calcd for C16H24NO4S (M+H) 326.1426. Found 326.1424.

(Ss,3S)-(+)-N-(p-Toluenesulfinyl)-3-amino-5-(2-n-propyl-1,3-dioxolan-2-yl)pentanal

(105c):

Flash chromatography (80% EtOAc/hexanes) afforded 91% of a clear oil; IR (film) 3440,

-1 20 1 1721 cm ;  D +73.7 (c 1.56, CHCl3); H NMR (CDCl3)  0.91 (t, J = 7.3 Hz, 3H), 1.37 (m,

2H), 1.57 (m, 2H), 1.69 (m, 3H), 1.83 (m, 1H), 2.40 (s, 3H), 2.67 (m, 2H), 3.75 (m, 1H), 3.92

(bs, 4H), 4.41 (d, J = 8.8 Hz, 1H), 7.28 (bd, J = 7.8 Hz, 2H), 7.55 (td, J = 8.1 Hz, J = 1.7 Hz,

13 2H); C NMR (CDCl3)  14.3, 17.1, 21.3, 30.3, 33.2, 39.4, 49.9, 50.7, 64.9(2C), 111.3, 125.4,

129.5, 141.4, 142.0, 200.7; HRMS calcd for C18H27NNaO4S (M+Na) 376.1558. Found

376.1557.

(Ss,3S)-(+)-N-(p-Toluenesulfinyl)-3-amino-5-(2-phenyl-1,3-dioxolan-2-yl)pentanal

(105e):

-1 20 Flash chromatography afforded 85% of a clear oil; IR (film) 3430, 1730 cm ;  D

1 +69.3 (c 2.0, CHCl3); H NMR (CDCl3)  1.63 (m, 2H), 1.88 (m, 1H), 2.15 (m, 1H), 2.32 (s,

3H), 2.56 (dt, J = 5.4 Hz, J = 1.2 Hz, 2H), 3.67 (m, 3H), 3.93 (m, 2H), 4.33 (d, J = 8.8 Hz, 1H),

13 7.18 – 7.28 (m, 5H), 7.36 (m, 2H), 7.45 (m, 2H); C NMR (CDCl3)  21.3, 30.1, 36.6, 49.9,

50.5, 64.4, 64.5, 109.9, 125.4, 125.5, 127.9, 128.1, 129.5, 141.3, 141.9, 142.2, 200.7. HRMS calcd for C21H26NO4S (M+H) 388.1583. A satisfactory HRMS could not be obtained due to decomposition.

(Ss,3S)-(+)-N-(t-Butylsulfinyl)-3-amino-5-(2-ethyl-1,3-dioxolan-2yl)pentanal (106b):

In a 100 mL, oven dried, single necked round-bottom flask equipped with magnetic stirring bar and rubber septum was placed (+)-104b (1.84 g, 5.49 mmol) in toluene (55 mL) and the solution was cooled to -78 oC. DIBAL-H in toluene (1.0 M solution in toluene, 9.9 mL, 9.88 mmol) was added slowly via syringe, the solution was stirred for 10 min at -78 oC, and quenched by the addition of sat. NH4Cl (30 mL). The solution was extracted with EtOAc (3 x 30 mL), dried (MgSO4), and concentrated. Flash chromatography (90% EtOAc/hexanes) provided 1.25 g

20 -1 1 (75%) of colorless oil; [α] D +35.5 (c 1.46, CHCl3); IR (film) 3435, 1723 cm ; H NMR

(CDCl3) δ 0.89 (t, J = 7.6 Hz, 3H), 1.20 (s, 9H), 1.65 (m, 5H), 1.80 (m, 1H), 2.89 (d, J = 5.6 Hz,

13 2H), 3.62 (b, 1H), 3.75 (d, J = 8.8 Hz, 1H), 3.93 (s, 4H), 9.78 (s, 1H); C NMR(CDCl3) δ 8.0,

22.5, 29.7, 30.0, 32.7, 49.8, 52.8, 55.8, 64.8 (2 C’s), 111.5, 200.9; HRMS calcd for C14H28NO4S

(M+H) 306.1739. Found 306.1737.

(Ss,3S)-(+)-N-(t-Butylsulfinyl)-3-amino-5-(2-methyl-1,3-dioxolan-2-yl)pentanal

(106a):

Flash chromatography (80% EtOAc/hexanes) afforded 85% of a clear oil; IR (film) 3435,

-1 20 1 1725 cm ;  D +43.0 (c 1.85, CHCl3); H NMR (CDCl3)  1.18 (s, 9H), 1.28 (s, 3H), 1.67 (m,

3H), 1.81 (m, 1H), 2.86 (dd, J = 5.4 Hz, J = 1.0 Hz, 2H), 3.62 (m, 1H), 3.75 (d, J = 8.8 Hz, 1H),

13 3.91 (m, 4H), 9.76 (bs, 1H); C NMR (CDCl3)  22.6, 23.8, 30.3, 35.5, 49.9, 52.8, 55.9, 64.5,

64.6, 109.6, 200.9. HRMS calcd for C13H26NO4S (M+H) 292.1583. Found 292.1580.

(Ss,3S)-(+)-N-(t-Butylsulfinyl)-3-amino-5-(2-n-pentyl-1,3-dioxolan-2yl) pentanal

(106d):

20 Flash chromatography (90% EtOAc/hexanes) gave 72% of a colorless oil; [α] D +32.5 (c

-1 1 1.64, CHCl3); IR (film) 3435, 1723 cm ; H NMR (CDCl3) δ 0.88 (t, J = 7.2 Hz, 3H), 1.20 (s,

9H), 1.28 (m, 6H), 1.63 (b, 5H), 1.772 (b, 1H), 2.89 (d, J = 5.6 Hz, 2H), 3.62 (b, 1H), 3.75 (d, J

13 = 8.8 Hz, 1H), 3.92 (m, 4H), 9.78 (s, 1H); C NMR(CDCl3) δ 13.9, 22.6, 23.5, 30.1, 32.0, 33.3,

37.1, 50.0, 53.0, 56.0, 64.8, 64.9, 111.4, 201.0. HRMS calcd for C17H34NO4S (M+H) 348.2209.

Found 348.2208.

(Ss,3S)-(+)-N-(t-Butylsulfinyl)-3-amino-5-(2-phenyl-1,3-dioxolan-2-yl)pentanal

(106e):

20 Flash chromatography (80% EtOAc/hexanes) afforded 85% of a clear oil;  D +32.5 (c

1 1.77, CHCl3); H NMR (CDCl3)  1.18 (s, 9H), 1.66 (m, 1H), 1.93 (m, 1H), 2.06 (m, 1H), 2.83

(dd, J = 5.4 Hz, J = 1.0 Hz, 2H), 3.63 (m, 1H), 3.68 (d, J = 8.4 Hz, 1H), 3.76 (m, 2H), 3.99 (m,

13 2H), 7.33 (m, 3H), 7.41 (m, 2H), 9.74 (bs, 1H); C NMR (CDCl3)  22.6, 29.9, 36.7, 49.9, 52.7,

55.9, 64.4, 64.5, 109.9, 125.5, 127.9, 128.1, 142.2, 200.9. HRMS calcd for (M+H) C18H28NO4S

354.1739. A satisfactory HRMS could not be obtained due to decomposition.

(Ss,5S,2E)-(+)-Methyl-N-(p-toluenesulfinyl)-5-amino-7-(2-methyl-1,3-dioxolan-2- yl)hept-2-enoate (107a):

In a 50 mL, oven-dried, single-neck round-bottomed flask equipped with magnetic stirring bar, and a rubber septum was placed trimethylphosphonoacetate (2.11 g, 11.60 mmol) in anhydrous acetonitrile (20 mL) under argon. To this solution DBU (1.76 g, 11.60 mmol) was added at rt and the solution was stirred for 15 min. At this time, a solution of (+)-105a (1.89 g,

5.80 mmol) in dry acetonitrile (20 mL) was added to the mixture via cannula and the reaction mixture was monitored for completion by TLC (typically 2 h). At this time the reaction mixture was quenched by addition of water (80 mL), the phases were separated, and the aqueous phase was extracted with EtOAc (4 x 60 mL). The combined organic phases were washed with brine

(2 x 100 mL), dried (MgSO4), and concentrated. Flash chromatography (80% EtOAc/hexanes)

-1 20 afforded 2.10 g (95%) of a colorless oil; IR (film) 3440, 1720,1660 cm ;  D +34.9 (c 1.07,

1 CHCl3); H NMR (CDCl3)  1.31 (s, 3H), 1.57 (m, 1H), 1.74 (m, 2H), 1.84 (m, 1H), 2.30 (m,

1H), 2.39 (s, 3H), 3.49 (m, 1H), 3.71 (s, 3H), 3.94 (m, 4H), 4.07 (d, J = 8.0 Hz, 1H), 5.80 (td, J =

1.6 Hz, J = 15.2 Hz, 1H), 6.80 (td, J = 7.2 Hz, J = 15.6 Hz, 1H), 7.27 (bd, J = 8.0 Hz, 2H), 7.56

13 (td, J = 2.0 Hz, J = 8.4 Hz, 2H); C NMR (CDCl3)  21.2, 23.8, 29.7, 35.0, 39.0, 51.4, 53.2,

64.5, 64.6, 109.6, 123.9, 125.5, 129.4, 141.2, 141.9, 144.2, 166.4. HRMS calcd for C19H28NO5S

(M+H) 382.1683. Found 382.1695.

(Ss,5S,2E)-(+)-Methyl-N-(p-toluenesulfinyl)-5-amino-7-(2-n-propyl-1,3-dioxolan-

2yl)-hept-2-enoate (107c):

100

Flash chromatography (50% EtOAc/hexanes) afforded 95% of a colorless oil; IR (film)

-1 20 1 3431, 1722, 1657 cm ;  D +26.6 (c 2.83, CHCl3); H NMR (CDCl3)  0.90 (t, J = 7.3 Hz,

3H), 1.40 (m, 2H), 1.56 (m, 3H), 1.66 (m, 2H), 1.84 (m, 1H), 2.26 (m, 1H), 2.36 (m, 1H), 2.39

(s, 3H), 3.48 (m, 1H), 3.71 (s, 3H), 3.92 (bs, 4H), 4.07 (d, J = 8.1 Hz, 1H), 5.81 (td, J = 15.7 Hz,

J = 1.2 Hz, 1H), 6.80 (td, J = 15.7 Hz, J = 7.6 Hz, 1H), 7.27 (bd, J = 8.1 Hz, 2H), 7.56 (td, J =

13 8.1 Hz, J = 1.7 Hz, 2H); C NMR (CDCl3)  14.3, 17.1, 21.3, 29.5, 32.9, 39.1, 39.4, 51.4, 53.3,

64.8(2C), 111.3, 124.0, 125.5, 129.5, 141.3, 141.9, 144.2, 166.4. HRMS calcd for

C21H31NNaO5S (M+Na) 432.1821. Found 432.1820.

(Ss,5S,2E)-(+)-Methyl-N-(p-toluenesulfinyl)-5-amino-7-(2-phenyl-1,3-dioxolan-2- yl)hept-2-enoate (107e):

Flash chromatography (50% EtOAc/hexanes) afforded 95% of a colorless oil; IR (film)

-1 20 1 3440, 1725, 1660 cm ;  D +35.4 (c 0.87, CHCl3); H NMR (CDCl3)  1.56 (m, 1H), 1.67 (m,

1H), 1.98 (m, 1H), 2.05 (m, 1H), 2.26 (m, 1H), 2.34 (m, 1H), 2.39 (s, 3H), 3.49 (m, 1H), 3.71 (s,

3H), 3.75 (m, 2H), 4.00 (m, 2H), 4.04 (d, J = 8.0 Hz, 1H), 5.77 (td, J = 15.6 Hz, J = 1.6 Hz, 1H),

6.77 (td, J = 15.7 Hz, J = 7.6 Hz, 1H), 7.26 – 7.35 (m, 5H), 7.43 (m, 2H), 7.54 (m, 2H); 13C

NMR (CDCl3)  21.3, 29.3, 36.3, 39.1, 51.4, 53.3, 64.4, 64.5, 110.0, 123.9, 125.5, 125.6, 127.9,

128.1, 129.4, 141.3, 141.9, 142.2, 144.2, 166.4. HRMS calcd for C24H30NO5S (M+H) 444.1845.

Found 444.1841.

101

(Ss,5S,2E)-(+)-Methyl-N-(t-butylsulfinyl)-5-amino-7-(2-methyl-1,3-dioxolan-2- yl)hept-2-enoate (108a):

Flash chromatography (80% EtOAc/hexanes) afforded 95% of a clear oil; IR (film) 3430,

-1 20 1 1720, 1650 cm ;  D +20.3 (c 0.87, CHCl3); H NMR (CDCl3)  1.16 (s, 9H), 1.25 (s, 3H),

1.51 (m, 1H), 1.63 (m, 2H), 1.76 (m, 1H), 2.54 (m, 2H), 3.17 (d, J = 7.6 Hz, 1 H), 3.35 (m, 1H),

13 3.68 (s, 3H), 3.89 (m, 4H), 5.89 (bd, J = 16.0 Hz, 1H), 6.87 (m, 1H); C NMR (CDCl3)  22.5,

23.7, 29.5, 35.1, 39.2, 51.4, 55.7, 55.9, 64.5, 64.6, 109.6, 124.3, 144.0, 166.4. HRMS calcd for

(M+H) C16H30NO5S 348.1845. Found 348.1841.

(SS,5S,2E)-(+)-Methyl-N-(-t-butylsulfinyl)-5-amino-7-(2-ethyl-1,3-dioxolan-2yl)- hept-2-enoate (108b):

20 Flash chromatography (80 % EtOAc/hexanes) afforded 93% of a colorless oil; [α] D

-1 1 +20.0 (c 1.74, CHCl3); IR (film) 3428, 1716, 1651 cm ; HNMR (CDCl3) δ 0.88 (t, J = 7.6 Hz,

3H), 1.20 (s, 9H), 1.61 (m, 5H), 1.70 (b, 1H), 2.54 (m, 1H), 2.61 (m, 1H), 3.16 (d, J = 8.0 Hz,

1H), 3.39 (b, 1H), 3.73 (s, 3H), 3.92 (m, 4H), 5.94 (td, J = 1.5 Hz, 15.7 Hz, 1H), 6.82 (td, J = 7.1

13 Hz, 15.7 Hz, 1H); CNMR (CDCl3) δ 8.0, 22.5, 29.3, 29.7, 32.4, 39.2, 51.3, 55.8, 55.9, 64.8 (2

C’s), 111.5, 124.2, 144.0, 166.3. HRMS calcd for C17H32NO5S (M+H) 362.2001. Found

362.1997.

102

(Ss,5S,2E)-(+)-Methyl-N-(-t-butylsulfinyl)-5-amino-7-(2-n-pentyl-1,3-dioxolan-2yl)- hept-2-enoate (108d):

20 Flash chromatography (75 % EtOAc/hexanes) afforded 89% of a colorless oil; [α] D

-1 1 +16.9 (c 1.31, CHCl3); IR (film) 3428, 1716, 1651 cm ; HNMR (CDCl3) δ 0.88 (t, J = 7.2 Hz,

3H), 1.20 (s, 9H), 1.28 (m, 6H), 1.596 (m, 5H), 1.76 (m, 1H), 2.57 (m, 2H), 3.15 (d, J = 8.0 Hz,

1H), 3.38 (bm, 1H), 3.73 (s, 3H), 3.92 (m, 4H), 5.94 (td, J = 1.5 Hz, 15.7 Hz, 1H), 6.91 (td, J =

13 7.1 Hz, 15.7 Hz, 1H); CNMR (CDCl3) δ 13.9, 22.5, 22.6, 23.4, 29.3, 31.9, 32.9, 37.0, 39.0,

51.4, 55.8, 56.0, 64.8 (2 C’s), 111.4, 124.4, 144.0, 166.4. HRMS calcd for C20H38NO5S (M+H)

404.2471. Found 404.2470.

(Ss,5S,2E)-(+)-Methyl-N-(t-butylsulfinyl)-5-amino-7-(2-phenyl-1,3-dioxolan-2- yl)hept-2-enoate (108e):

Flash Chromatography (60% EtOAc/hexanes) afforded 95% of clear oil. The product

-1 20 was isolated as a 95:5 mixture of E:Z isomers; IR (film) 3430, 1730, 1665 cm ;  D +14.4 (c

1 2.2, CHCl3); H NMR (CDCl3)  1.10 (s, 9H), 1.42 (m, 1H), 1.58 (m, 1H), 1.87 (m, 1H), 1.95

(m, 1H), 2.40 (m, 1H), 2.51 (m, 1H), 3.03 (d, J = 7.6 Hz, 1H), 3.29 (m, 1H), 3.65 (s, 3H), 3.68

103

(m, 2H), 3.92 (m, 2H), 5.82 (td, J = 15.6 Hz, J = 1.6 Hz, 1H), 6.79 (td, J = 15.7 Hz, J = 7.1 Hz,

13 1H), 7.24 (m, 3H), 7.33 (m, 2H); C NMR (CDCl3)  22.6, 29.1, 36.3, 39.3, 51.4, 55.6, 56.0,

64.3, 64.4, 110.0, 124.3, 125.5, 127.9, 128.1, 142.2, 144.1, 166.4. HRMS calcd for (M+H)

C21H32NO5S 410.2001. Found 410.1997.

(5S,2E)-(+)-methyl-(3,4-dihydro-5-methyl-2H-pyrrol-2-yl)-but-2-enoate (109a):

In a 250 mL, oven-dried, single-neck round-bottomed flask equipped with magnetic stirring bar, and a rubber septum was placed (+)-107a (0.12 g, 0.31 mmol) in MeOH (15 mL) and THF (15 mL). To this solution was added 3.0 N HCl (1.05 mL) slowly via syringe at rt.

This reaction mixture was stirred at rt for 16 h, concentrated, and the residue was dissolved in

CH2Cl2 (50 mL) and washed with saturated aqueous NaHCO3 solution (2 x 20 mL), brine (30 mL), dried (MgSO4), and concentrated. Flash chromatography (70% EtOAc/hexanes) gave 0.55

-1 20 1 g (100%) of a clear oil; IR (film) 1720, 1655, 1650 cm ;  D +39.7 (c 1.21, CHCl3); H NMR

(CDCl3)  1.45 (m, 1H), 2.00 (d, J = 1.6 Hz, 3H), 2.02 (m, 1H), 2.33 (m, 1H), 2.45 (m, 2H), 2.58

(m, 1H), 3.69 (s, 3H), 4.05 (m, 1H), 5.87 (td, J = 1.6 Hz, J = 16.0 Hz, 1H), 6.95 (td, J = 7.2 Hz, J

13 = 15.6 Hz, 1H); C NMR (CDCl3)  19.6, 28.4, 38.9, 39.0, 51.3, 71.2, 122.6, 146.3, 166.8,

175.0. HRMS calcd for C10H16NO2 (M+H) 182.1176. Found 182.1172.

104

(5S,2E)-(+)-Methyl-(3,4-dihydro-5-ethyl-2H-pyrrol-2-yl)-but-2-enoate (109b):

20 Flash chromatography (60% EtOAc/hexanes) afforded 100% of a clear oil; [α] D +43.4

-1 1 (c 1.9, CHCl3); IR(neat) 1636, 1698 cm ; H NMR (CDCl3) δ 1.14 (t, J = 7.6 Hz, 3H), 1.46 (m,

1H), 2.04 (m, 1H), 2.33 (m, 3H), 2.49 (m, 2H), 2.65 (m, 1H), 3.72 (s, 3H), 4.09 (m, 1H), 5.89

13 (td, J = 1.6, 15.7 Hz, 1H), 6.96 (td, J = 7.6, 15.7 Hz, 1H); C NMR (CDCl3) δ 10.6, 26.7, 27.7,

36.7, 38.8, 51.1, 70.7, 122.5, 146.1, 166.6, 179.2. HRMS calcd for C11H18NO2(M+H) 196.1338.

Found 196.1334.

(5S,2E)-(+)-Methyl-(3,4-dihydro-5-n-propyl-2H-pyrrol-2-yl)-but-2-enoate (109c):

Flash chromatography (60% EtOAc/hexanes) afforded 97% of a clear oil; IR (film) 1730,

-1 20 1 1660, 1653 cm ;  D +39.1 (c 0.9, CHCl3); H NMR (CDCl3)  0.93 (t, J = 7.3 Hz, 3H), 1.46

(m, 1H), 1.59 (m, 1H), 2.03 (m, 1H), 2.33 (m, 3H), 2.46 (m, 2H), 2.65 (m, 1H), 3.70 (s, 3H),

4.09 (m, 1H), 5.88 (td, J = 15.7 Hz, J = 1.5 Hz, 1H), 6.95 (td, J = 15.7 Hz, J = 7.3 Hz, 1H); 13C

NMR (CDCl3)  13.9, 19.8, 27.9, 35.7, 37.1, 39.0, 51.4, 70.9, 122.7, 146.3, 166.8, 178.3. HRMS calcd for C12H20NO2 (M+H) 210.1494. Found 210.1489.

105

(5S,2E)-(+)-Methyl-(3,4-dihydro-5-n-pentyl-2H-pyrrol-2-yl)-but-2-enoate (109d):

20 Flash chromatography (50% EtOAc/hexanes) afforded 83% of an oil; [α] D +31.1 (c

-1 1 3.15, CHCl3); IR(neat) 1636, 1698 cm ; H NMR (CDCl3) δ 0.88 (t, J = 6.8 Hz, 3H), 1.31 (m,

4H), 1.50 (m, 3H), 2.03 (m, 1H), 2.40 (m, 5H), 2.63 (m, 1H), 3.72 (s, 3H), 4.09 (m, 1H), 5.88

13 (td, J = 1.5, 15.7 Hz, 1H), 6.96 (td, J = 7.3, 15.7 Hz, 1H); C NMR (CDCl3) δ 13.9, 22.4, 26.2,

27.9, 31.6, 33.8 37.2, 39.0, 51.3, 71.0, 122.7, 146.3, 166.8, 178.5. HRMS calcd for

C14H24NO2(M+H) 238.1807. Found 238.1805.

(5S,2E)-(+)-Methyl-(3,4-dihydro-5-phenyl-2H-pyrrol-2-yl)-but-2-enoate (109e):

Flash chromatography (30% EtOAc/hexanes) gave 90% of a clear oil; IR (film) 1735,

-1 20 1 1663, 1650 cm ;  D +27.5 (c 1.78, CHCl3); H NMR (CDCl3)  1.65 (m, 1H), 2.20 (m, 1H),

2.45 (m, 1H), 2.75 (m, 1H), 2.94 (m, 1H), 3.01 (m, 1H), 3.72 (s, 3H), 4.33 (m, 1H), 5.93 (td, J =

15.6 Hz, J = 1.6 Hz, 1H), 7.04 (td, J = 15.6 Hz, J = 7.6 Hz, 1H), 7.41 (m, 3H), 7.83 (m, 2H); 13C

NMR (CDCl3)  28.0, 35.1, 39.1, 51.4, 71.7, 122.8, 127.7, 128.4, 130.5, 134.3, 146.3, 166.8,

172.9. HRMS calcd for C15H18NO2 (M+H) 244.1338. Found 244.1329.

106

(5S,2E)-Methyl-(3,4-dihydro-5-methyl-2H-pyrrol-2-yl)-but-2-enoate-N-oxide (110a):

In a 50 mL, oven-dried, single-neck round-bottomed flask equipped with magnetic stirring bar, and a rubber septum was placed urea hydrogen peroxide (0.743 g, 7.898 mmol) in anhydrous MeOH (30 mL) under argon. Methyltrioxorhenium (0.041 g, 0.165 mmol) was added, the solution was stirred for 15 min and (S)-109a (0.440 g, 2.43 mmol) in MeOH (20 mL) was added via cannula. The yellow solution was stirred at rt for 16 h, concentrated, and the residue was dissolved in CH2Cl2 (20 mL). The suspended urea crystals were filtered; the filtrate was concentrated to give 0.47 g (98%) of a yellow oil, which was taken to the next step without further purification. The C-2 hydrogen in the nitrone was shifted down field to δ 4.20 ppm as compared to 4.06 ppm in the dehydropyrrolidine. The C-5 carbon in the nitrone was shifted up field to δ 150.5 ppm as compared to 175.0 ppm for its precursor.

General procedure for the synthesis of (1S,2R,3R,6S)-(-)-methyl-3-methyl-7-aza-8- oxatricyclo[4,2,1,0]-nonane-2-carboxylate (111a) by direct heating:

In a 500 mL, oven-dried, single-neck round-bottomed flask equipped with magnetic stirring bar, reflux condenser and a rubber septum was placed nitrone 110a (0.400 g, 2.028 mmol) in anhydrous toluene (200 mL) and the solution was refluxed (while maintaining the oil

107

bath temperature at 140 oC) for 48 h and concentrated. Purification by flash column

-1 20 chromatography gave 0.180 g (45%) of a low melting solid; IR (film) 1740 cm ;  D –56.5 (c

1 0.42, CHCl3); H NMR (CDCl3)  1.24 (s, 3H), 1.81 (m, 3H), 2.18 (m, 3H), 2.44 (s, 1H), 3.61

13 (m, 1H), 3.68 (s, 3H), 4.94 (d, J = 4.8 Hz, 1H); C NMR (CDCl3)  22.0, 26.0, 33.8, 42.0, 51.5,

61.2, 62.7, 75.7, 81.5, 171.6. HRMS calcd for C10H16NO3 (M+H) 198.1130. Found 198.1124.

General procedure for the synthesis of (1S,2R,3R,6S)-()-methyl-3-methyl-7-aza-8- oxatricyclo[4,2,1,0]-nonane-2-carboxylate (111a) using Lewis acid aluminum t-butoxide:

In a 500 mL, oven-dried, single-neck round-bottomed flask equipped with magnetic stirring bar, and a rubber septum was placed nitrone 110a (0.370 g, 1.876 mmol) in anhydrous toluene (200 mL). To this solution was added Al(O-t-Bu)3 (0.230 g, 0.938 mmol) and the solution was stirred at rt for 6 h. At this time the reaction mixture was refluxed for 72 h, cooled to rt, and extracted with aqueous 5% HCl solution (4 x 50 mL). The combined aqueous phases were carefully neutralized by slow addition of solid Na2CO3 until the solution became slightly basic (pH 8). This aqueous solution was extracted with DCM (4 x 50 mL) and the combined organic phases were washed with brine, dried (MgSO4), and concentrated. Flash

-1 20 chromatography gave 0.260 g (70%) of a low melting white solid; IR (film) 1740 cm ;  D –

1 56.47 (c 0.42, CHCl3); H NMR (CDCl3)  1.24 (s, 3H), 1.81 (m, 3H), 2.18 (m, 3H), 2.44 (s,

13 1H), 3.61 (m, 1H), 3.68 (s, 3H), 4.94 (d, J = 4.8 Hz, 1H); C NMR (CDCl3)  22.0, 26.0, 33.8,

108

42.0, 51.5, 61.2, 62.7, 75.7, 81.5, 171.6. HRMS calcd for C10H16NO3 (M+H) 198.1130. Found

198.1124.

(1S,2R,3R,6S)-()-Methyl-3-ethyl-7-aza-8-oxatricyclo[4,2,1,0]-nonane-2-carboxylate

(111b) using Lewis acid aluminum t-butoxide:

The toluene solution was extracted with 5% HCl solution (4 x 50 mL, the combined aqueous phases were neutralized by slow addition of solid Na2CO3 until the solution was slightly basic. At this time the aqueous solution was extracted with DCM (4 x 50 mL) and the combined

20 organic phases were washed with brine, dried and concentrated to give 64% of a clear oil; [α] D

-1 1 -27.3 (c 0.495, CHCl3); IR(film) 1738 cm ; H NMR (CDCl3) δ 0.95 (t, J = 7.6 Hz, 3H), 1.26

(dd, J = 11.8, 2.4 Hz, 1H), 1.57 (q, J = 7.6 Hz, 3H), 1.85 (m, 1H), 1.98 (m, 2H), 2.14 (m, 2H),

13 2.48 (s, 1H), 3.619 (m, 1H), 3.69 (s, 3H), 4.90 (d, J = 4.8 Hz, 1H); C NMR (CDCl3) δ 8.7, 25.8,

26.1, 29.3, 41.9, 51.5, 62.2, 62.8, 77.3 81.6, 171.8. HRMS calcd for C11H18NO3(M+H)

212.1287. Found 212.1282.

109

(1S,2R,3R,6S)-()-Methyl-3-n-propyl-7-aza-8-oxatricyclo[4,2,1,0]-nonane-2- carboxylate (111c) using Lewis acid aluminum t-butoxide:

-1 20 1 (film) 1738 cm ;  D -56.6 (c 0.71, CHCl3); H NMR (CDCl3)  0.88 (t, J = 7.1 Hz, 3H), 1.25

(dd, J = 11.5 Hz, J = 2.2 Hz, 1H), 1.31 (m, 1H), 1.49 (m, 3H), 1.80 (m, 1H), 1.99 (m, 2H), 2.15

13 (m, 2H), 2.46 (s, 1H), 3.60 (m, 1H), 3.68 (s, 3H); C NMR (CDCl3)  14.6, 17.7, 25.9, 30.1,

35.9, 42.0, 51.6, 62.3, 62.8, 79.0, 81.6, 171.9. HRMS calcd for C12H19NNaO3 (M+Na)

248.1263. Found 248.1260.

(1S,2R,3R,6S)-()-Methyl-3-n-pentyl-7-aza-8-oxatricyclo[4,2,1,0]-nonane-2- carboxylate (111d) using Lewis acid aluminum t-butoxide:

The toluene solution was extracted with 5% HCl solution (4 x 50 mL), the organic layer was washed sat. Na2CO3 solution (2 x 30 mL), brine (40 mL), dried (MgSO4) and concentrated

110

20 -1 1 to give 68% of clear oil; [α] D -45.6 (c 1.275, CHCl3); IR(film) 1738 cm ; H NMR (CDCl3) δ

0.86 (t, J = 6.8 Hz, 3H), 1.25 (b, 6H), 1.49 (b, 4H), 1.81 (m, 1H), 2.0 (m, 2H), 2.18 (m, 2H), 2.46

13 (s, 1H), 3.60 (m, 1H), 3.69 (s, 3H), 4.89 (d, J = 4.8 Hz, 1H); C NMR (CDCl3) δ 14.0, 22.6,

24.2, 25.9, 30.1, 32.4, 33.7, 42.0, 51.5, 62.2, 62.8, 79.1, 81.6, 171.8. HRMS calcd for

C14H24NO3(M+H) 254.1756. Found 254.1752.

(1S,2R,3R,6S)-()-Methyl-3-phenyl-7-aza-8-oxatricyclo[4,2,1,0]-nonane-2- carboxylate (111e) using Lewis acid aluminum t-butoxide:

The toluene solution was washed with H2O (3 x 20 mL) and the organic phase was dried

(MgSO4) and concentrated. Flash chromatography (35% EtOAc/hexanes) gave 50% of a white solid isoxazolidine 111e; mp 136-138 oC and 40% of lactam (5S,2E)-(+)-128e (see below); IR

-1 20 1 (film) 1750 cm ;  D –54.7 (c 0.88, CHCl3); H NMR (CDCl3)  1.38 (dd, J = 11.7 Hz, J =

2.4 Hz, 1H), 1.93 (m, 1H), 2.22 (m, 2H), 2.28 (m, 1H), 2.73 (m, 1H), 2.81 (s, 1H), 3.04 (s, 3H),

3.75 (m, 1H), 4.95 (d, J = 4.9 Hz, 1H), 7.14 (m, 1H), 7.23 (m, 2H), 7.45 (m, 2H); 13C NMR

(CDCl3)  25.4, 34.1, 42.2, 50.9, 63.0, 64.5, 80.7, 81.2, 126.6, 126.8, 127.3, 141.5, 170.6.

HRMS calcd for (M+H) C15H18NO3 260.1287. Found 260.1281.

111

(E)-(S)-(+)-Methyl-4-(5-oxo-1-ethyl-pyrrolidini-2-yl)but-2-enoate (128b):

In a 100 mL round-bottom flask equipped with magnetic stirring bar, reflux condenser and argon inlet was placed nitrone 110b (0.05 g, 0.226 mmol) in anhydrous toluene (23 mL) and solution was refluxed for 96 h. At this time, the reaction mixture was cooled to rt and concentrated. Flash chromatography (90% EtOAc/hexanes) gave 0.016 g (32%) of slightly

-1 20 1 brownish oil; IR (film) 1726, 1651, 1640 cm ; [] D +36.0 (c 0.40, CHCl3); H NMR (CDCl3) δ

1.14 (t, J = 7.6 Hz, 3H), 2.04 (m, 2H), 2.35 (m, 3H), 2.51 (m, 2H), 2.65 (m, 1H), 3.72 (s, 3H),

13 4.10 (m, 1H), 5.89 (td, J = 1.6, 15.7 Hz, 1H), 6.97 (td, J = 7.6, 15.7 Hz, 1H); C NMR (CDCl3)

δ 10.8, 26.9, 28.0, 37.0, 39.0, 51.3, 71.1, 122.8, 146.3, 166.8, 179.8. HRMS calcd for

C11H18NO3(M+H) 212.1287. Found 212.1280.

(E)-(S)-()-Methyl-4-(5-oxo-1-n-propyl-pyrrolidin-2-yl)but-2-enoate (128c):

In a 100 mL round-bottomed flask equipped with magnetic stirring bar, reflux condenser and argon inlet was placed nitrone 110c (0.100 g, 0.444 mmol) in anhydrous toluene (45.0 mL) and the solution was refluxed for 96 h. At this time, the reaction mixture was cooled to rt and concentrated. Flash chromatography (25% EtOAc/hexanes) yielded 0.04 g (40%) of slightly

112

-1 20 1 yellow oil; IR (film) 1724, 1657, 1642 cm ;  D +25.1 (c 0.45, CHCl3); H NMR (CDCl3) 

0.95 (t, J = 7.1 Hz, 3H), 1.49 (m, 1H), 1.61 (m, 2H), 2.06 (m, 1H), 2.35 (m, 3H), 2.51 (m, 2H),

2.66 (m, 1H), 3.72 (s, 3H), 4.15 (m, 1H), 5.90 (bd, J = 15.7 Hz, 1H), 6.96 (td, J = 15.7 Hz, J =

13 7.3 Hz, 1H); C NMR (CDCl3)  13.9, 19.8, 27.7, 35.6, 37.1, 38.8, 51.4, 70.6, 122.9, 146.0,

166.8, 179.5; HRMS calcd for C12H20NO3 (M+H) 226.1443. Found 226.1436.

(E)-(S)-(-)-Methyl-4-(5-oxo-1-n-pentyl-pyrrolidin-2-yl)but-2-enoate (128d):

20 Flash chromatography (50% EtOAc/hexanes) gave 62% of an oil; [α] D -33.9 (c 1.28,

-1 1 CHCl3); IR (film) 1720, 1656 cm ; H NMR (CDCl3) δ 0.88 (t, J = 6.8 Hz, 3H), 1.35 (m, 4H),

15.6 (m, 2H), 2.03 (m, 1H), 2.39 (m, 6H), 2.64 (m, 1H), 3.71 (s, 3H), 4.1 (m, 1H), 5.88 (td, J =

13 1.5, 17.7 Hz, 1H), 6.95 (td, J = 7.3, 15.7 Hz, 1H); C NMR (CDCl3) δ 13.9, 22.4, 26.2, 27. 9,

31.6, 33.7, 37.2, 39.0, 51.4, 70.8, 122.78, 146.3, 166.8, 178.7. HRMS calcd for

C14H24NO3(M+H) 254.1756. Found 254.1752.

(E)-(S)-(+)-Methyl-4-(5-oxo-1-phenyl-pyrrolidin-2-yl)but-2-enoate (128e):

113

20 Flash chromatography (35% EtOAc/hexanes) gave 50% of a brown oil;  D +27.9 (c

1 1.53, CHCl3); H NMR (CDCl3)  1.65 (m, 1H), 2.21 (m, 1H), 2.45 (m, 1H), 2.75 (m, 1H), 2.93

(m, 1H), 3.01 (m, 1H), 3.73 (s, 3H), 4.34 (m, 1H), 5.94 (td, J = 15.6 Hz, J = 1.6 Hz, 1H), 7.04

13 (td, J = 15.6 Hz, J = 7.6 Hz, 1H), 7.41 (m, 3H), 7.83 (m, 2H); C NMR (CDCl3)  28.1, 35.1,

39.1, 51.4, 71.7, 122.8, 127.7, 128.4, 130.5, 134.4, 146.3, 166.8, 172.8. HRMS calcd for (M+H)

C15H18NO3 260.1287. Found 260.1281.

(E)-Methy-4((2S)(+)-5-n-propyl-6-oxa-1-aza-bicyclo[3.1.0]hexan-2-yl)but-2-enoate

(129c):

In a 25 mL, oven-dried, single-neck round-bottomed flask equipped with magnetic stirring bar, and a rubber septum was placed (+)-109c (0.054 g, 0.259 mmol) in anhydrous dichloromethane (5.0 mL) under argon. To this solution was added m-CPBA (0.067 g, 0.388 mmol, 77%) at 0 oC, the reaction mixture was stirred for 0.5 h, and quenched by adding saturated solution of NaHCO3:Na2S2O3 (1:1) (10 mL). The aqueous phase was extracted with

EtOAc (2 x 30 mL), the combined organic phases were washed with satd. NaHCO3 solution (2 x

30 mL), brine (30 mL), dried (MgSO4) and concentrated. Flash chromatography (30% EtOAc in hexanes) afforded 0.045 g (77%) of a yellow oil as 2.5:1 mixture of isomers; IR (film) 1724,

-1 20 1 1650 cm ;  D + 60.3 (c 1.53, CHCl3); H NMR (CDCl3)  major isomer 0.93 (t, J = 7.4 Hz,

3H), 0.94 (t, J = 7.3 Hz, 3H), 1.28 (m, 3H), 1.45 (m, 3H), 1.67 (m, 4H), 1.81 (m, 4H), 2.10 –

114

2.24 (m, 2H), 2.29 (m, 1H), 2.39 (m, 1H), 2.39 (m, 1H), 2.70 (m, 1H), 3.19 (m, 1H), 3.58 (m,

1H), 3.70 (s, 3H), 3.71 (s, 3H), 5.87 (td, J = 15.6 Hz, J = 1.5 Hz, 1H), 5.92 (td, J = 15.6 Hz, J =

1.5 Hz, 1H), 6.91 (td, J = 15.6 Hz, J = 7.3 Hz, 1H), 7.01 (td, J = 15.6 Hz, J = 7.3 Hz, 1H); 13C

NMR (CDCl3)  major isomer 14.1, 14.2, 17.9, 17.9, 24.4, 25.3, 27.5, 29.3, 34.6, 34.7, 35.3,

35.3, 51.4, 51.5, 64.5, 65.8, 90.2, 90.3, 122.7, 123.3, 144.8, 145.6, 166.5, 166.7. HRMS calcd for C12H20NO3 (M+H) 226.1443. Found 226.1441.

(E)-Methyl-4((2S)(+)-5-pentyl-6-oxa-1-aza-bicyclo[3.1.0]hexan-2-yl)but-2-enoate

(129d):

Flash chromatography (50 % EtOAc/hexanes) provided a colorless oil as a 2.6:1 mixture

20 -1 1 of oxaziridines isomers; [α] D + 46.2 (c 2.03, CHCl3); IR(film): 1728, 1651 cm ; H NMR

(CDCl3) major isomer: δ 0.87 (t, J = 6.7 Hz, 3H), 1.29 (m, 5H), 1.45 (m, 2H), 1.74 (m, 1H), 2.43

(m, 6H), 2.71 (m, 1H), 3.71 (s, 3H), 4.2 (b, 1H), 5.92 (td, J = 1.5, 15.7 Hz, 1H), 7.06 (td, J = 7.6,

15.7 Hz, 1H); minor isomer δ 0.87 (t, J = 6.7 Hz, 3H), 1.29 (m, 5H), 1.74 (m, 1H), 2.39 (m, 6H),

2.71 (m, 1H), 3.72 (s, 3H), 5.86 (td, J = 1.5, 15.7 Hz, 1H), 6.92 (td, J = 7.6, 15.7 Hz, 1H); 13C

NMR (CDCl3) major isomer δ 13.9, 22.5, 22.3, 24.8, 25.3, 27.5, 29.4, 31.8, 32.6, 35.4, 51.4,

65.9, 90.3, 122.8, 145.7, 166.8; minor isomer δ 15.2, 23.3, 24.4, 24.7, 29.7, 32.5, 34.7, 51.5,

64.5, 90.5, 123.3, 144.8, 166.5. HRMS: calcd for C14H24NO3(M+H) 254.1756. Found 254.1750.

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(E)-(S)-(+)-Methyl-4-(5-oxo-1-propyl-pyrrolidin-2-yl)but-2-enoate (128c) from oxaziridine 129c:

In a 50 mL single necked round bottom flask was added MeReO3 (0.001 g, 0.005 mmol) and UHP (0.021 g, 0.224 mmol) in methanol (2.0 mL). The reaction mixture was stirred for 0.5 h under an argon atmosphere, concentrated, and the residue was dissolved in CH2Cl2 (10 mL).

The solids were removed by filtration and the filtrate was concentrated to give the methylperoxorhenium complex. The complex was dissolved in anhydrous toluene (4.0 mL) and added to a solution of (+)-129c (0.015 g, 0.069 mmol) in anhydrous toluene (4.0 mL). The solution was refluxed for 96 h, and concentrated. Flash chromatography (25% EtOAc/hexanes) gave 0.008 g (51%) of slightly yellow oil with spectral properties identical to that prepared from

20 110c; []D +27.5 (c 0.4 , CHCl3).

Methane sulfonate salt of methyl (1S,2R,3R,6S)-()-3,7-dimethyl-7-aza-8- oxatricyclo[4,2,1,0]-nonane-2-carboxylate (112a):

In a 50 mL, oven-dried, single-neck round-bottomed flask equipped with magnetic stirring bar, and a reflux condenser was placed ()-111a (0.06 g, 0.304 mmol) in anhydrous

116

dichloromethane (20 mL) under argon. Methylmethanesulfonate (0.335 g, 3.04 mmol) was added via syringe and the solution was heated at reflux for 48 h. At this time the solution was concentrated, the residue was dissolved in H2O (20 mL). The aqueous solution was extracted with CH2Cl2 (3 x 10 mL) and the aqueous phase was concentrated, acetonitrile:water (2:1) was added (20 mL) and the solution was lyophilized to give 0.92 g (98%) of a white sticky material;

-1 20 1 IR (film) 1745 cm ;  D 2.9 (c 0.7, CHCl3); H NMR (CD3OD)  1.45 (s, 3H), 2.12 (dd, J =

2.4 Hz, J = 12.7 Hz, 1H), 2.28 (m, 2H), 2.50 (m, 1H), 2.58 (m, 1H), 2.62 (s, 3H), 2.77 (m, 1H),

3.42 (s, 3H), 3.50 (s, 1H), 3.71 (s, 3H), 4.43 (tq, J = 8.6 Hz, J = 2.0 Hz, 1H), 5.36 (d, J = 5.2 Hz,

13 1H); C NMR (CD3OD)  18.2, 25.6, 34.1, 39.7, 41.6, 41.7, 53.1, 60.8, 78.3, 84.0, 88.1, 170.2.

+ HRMS calcd for C11H18NO3 (M ) 212.1281. Found 212.1279.

Methanesulfonate salt of methyl (1S,2R,3R,6S)-(+)-3-ethyl-7-methyl-7-aza-8- oxatricyclo[4,2,1,0]-nonane-2-carboxylate (112b):

20 -1 1 Sticky material of 100% yield; [α] D +10.7 (c 3.975, MeOH); IR (film) 1748 cm ; H

NMR (CD3OD) δ 0.617 (t, J = 7.6 Hz, 3H), 1.69 (m, 2H), 1.87 (dd, J = 12.8, 2.8 Hz, 1H), 2.02

(m, 2H), 2.18 (m, 1H), 2.33 (m, 1H), 2.38 (s, 3H), 2.51 (m, 1H), 3.01 (s, 1H), 3.16 (s, 3H), 3.22

13 (s, 1H), 3.41 (s, 3H), 4.14 (m, 1H), 5.02 (d, J = 4.8 Hz, 1H); C NMR (CD3OD) δ 8.98, 25.2,

25.75, 32.64, 39.65, 41.54, 42.0, 53.20, 59.8, 79.10, 84.97, 92.0, 171.0. HRMS calcd for

C12H20NO3(M+) 226.1438. Found 226. 1438.

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Methanesulfonate salt of methyl (1S,2R,3R,6S)-(+)-3-n-propyl-7-aza-8- oxatricyclo[4,2,1,0]-nonane-2-carboxylate (112c). Sticky solid of 100% yield; IR (film) 1750

-1 20 1 cm ;  D +14.3 (c 0.77, CHCl3); H NMR (CD3OD)  0.87 (t, J = 7.3 Hz, 3H), 1.13 (m, 1H),

1.28 (m, 1H), 1.82 (m, 2H), 2.08 (dd, J = 12.5 Hz, J = 2.7 Hz, 1H), 2.25 (m, 2H), 2.41 (m, 1H),

2.52 (m, 1H), 2.58 (m, 1H), 2.59 (s, 3H), 2.74 (m, 1H), 3.41 (s, 3H), 3.42 (s, 1H), 3.66 (s, 3H),

13 4.36 (m, 1H), 5.26 (d, J = 4.9 Hz, 1H); C NMR (CD3OD)  14.8, 19.0, 25.4, 32.9, 34.7, 39.6,

+ 41.7, 41.9, 53.2, 60.0, 78.9, 85.0, 91.5, 171.1. HRMS calcd for C13H22NO3 (M ) 240.1594.

Found 240.1598.

Methanesulfonate salt of methyl (1S,2R,3R,6S)-(+)- 3-n-pentyl-7-methyl-7-aza-8- oxatricyclo[4,2,1,0]-nonane-2-carboxylate (112d):

20 -1 1 Sticky material of 100% yield; [α] D +13.9 (c 1.06, MeOH); IR(film) 1748 cm ; H

NMR (CD3OD) δ 0.82 (t, J = 7.2 Hz, 3H), 1.20 (m, 6H), 1.81 (dt, J = 4.4, 12.4 Hz, 1H), 1.94 (m,

1H), 2.08 (dd, J = 2.7, 12.5 Hz, 1H), 2.23 (m, 2H), 2.39 (m, 1H), 2.55 (m, 1H), 2.60 (s, 3H), 2.73

(m, 1H), 3.41 (s, 3H), 3.42 (s, 1H), 3.66 (s, 3H), 4.36 (m, 1H), 5.26 (d, J = 5.2 Hz, 1H); 13C

NMR (CD3OD) δ 14.3, 23.4, 25.2, 25.4, 32.7, 33.0, 33.3 39.6, 41.6, 41.9, 53.2, 60.0. 78.9, 85.0,

91.6, 171.1. HRMS calcd for C15H26NO3(M+) 268.1907. Found 268.1912.

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Methanesulfonate salt of methyl (1S,2R,3R,6S)-(+)-3-phenyl-7-aza-8- oxatricyclo[4,2,1,0]-nonane-2-carboxylate (112e):

-1 20 Isolated as a white sticky material; IR (film) 1760 cm ;  D +38.9 (c 1.62, CH3OH);

1 H NMR (CD3OD)  2.21 (dd, J = 12.5 Hz, J = 1.7 Hz, 1H), 2.40 (m, 1H), 2.55 (s, 3H), 2.65 (m,

1H), 2.77 (m, 1H), 2.88 (m, 1H), 2.91 (s, 3H), 2.99 (m, 1H), 3.21 (s, 3H), 3.85 (s, 1H), 4.59 (m,

13 1H), 5.60 (d, J = 4.6 Hz, 1H), 7.36 (m, 3H), 7.45 (m, 2H); C NMR (CD3OD)  25.8, 31.3, 39.7,

42.7, 42.9, 52.7, 62.9, 80.1, 83.8, 91.8, 129.6, 130.2, 131.9, 133.5, 169.7. HRMS calcd for

+ C16H20NO3 (M ) 274.1438. Found 274.1440.

Methanesulfonate salt of methyl (1R,2R,3S,5S)-()-3-(hydroxy)-1,8-dimethyl-8- azabicyclo[3.2.1]octane-2-carboxylate (113a):

In a 50 mL, oven-dried, single-neck round-bottomed flask equipped with magnetic stirring bar, and a rubber septum was placed ()-112a (0.030 g, 0.097 mmol) in anhydrous

MeOH (10 mL), and Pd-C (0.01 g, 5% Pd on carbon) was added. A hydrogen atmosphere (1 atm) was maintained using a balloon, and the reaction mixture was stirred at rt for 48 h. At this time the solution was filtered through a short pad of Celite, and concentrated to give 0.03 g

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-1 20 1 (99%) of a white sticky solid; IR (film) 3400, 1750, cm ;  D 24.2 (c 1.17, MeOH); H NMR

(CD3OD)  1.38 (s, 3H), 1.99 (m, 1H), 2.07 (m, 4H), 2.28 (m, 1H), 2.63 (s, 3H), 2.71 (s, 3H),

3.12 (d, J = 6.8 Hz, 1H), 3.73 (s, 3H), 3.84 (m, 1H), 4.28 (td, J = 6.6 Hz, J = 11.0 Hz, 1H); 13C

NMR (CD3OD)  20.8, 25.3, 32.4, 36.4, 36.5, 39.6, 53.2, 57.0, 63.1, 66.8, 71.8, 175.7. HRMS

+ calcd for C11H20NO3 (M ) 214.1434. Found 214.1434.

Methanesulfonate salt of methyl (1R, 2R, 3S, 5S)-()-1-ethyl-3-(hydroxyl)-8-methyl-

8-azabicyclo[3.2,1]octane-2-carboxylate (113b):

20 -1 1 Sticky solid of 100% yield; [α] D 7.6 (c 4.055, MeOH); IR (film) 3380, 1749 cm ; H

NMR (CD3OD) δ 0.89 (t, J = 7.6 Hz, 3H), 1.56 (m, 1H), 1.80 (m, 1H), 1.99 (m, 3H), 2.10 (m,

2H), 2.25 (m, 1H), 2.59 (s, 3H), 2.62 (s, 3H), 3.22 (s, 1H), 3.27 (d, J = 6.8 Hz, 1H), 3.68 (s, 3H),

13 3.81 (b, 1H), 4.22 (m, 1H); C NMR (CD3OD) δ 9.4, 25.0, 28.1, 30.4, 36.4, 39.7, 52.8, 53.2,

+ 63.1, 67.0, 75.3, 175.4. HRMS calcd for C12H22NO3(M ) 228.16. Found 228.1592.

Methanesulfonate salt of methyl (1R,2R,3S,5S)-(+)-1-n-propyl-3-(hydroxy)-8- methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (113c):

120

-1 20 1 Sticky solid of 100% yield; IR (film) 3340, 1745cm ;  D +1.7 (c 0.82, MeOH); H

NMR (CD3OD)  0.85 (t, J = 7.3 Hz, 3H), 1.15 (m, 1H), 1.35 – 1.71 (m, 7H), 1.97 (m, 1H), 2.10

(m, 1H), 2.12 (s, 3H), 2.60 (s, 3H), 2.89 (d, J = 6.6 Hz, 1H), 3.17 (m, 1H), 3.57 (s, 3H), 3.88 (m,

13 1H); C NMR (CD3OD)  15.4, 19.5, 27.2, 33.7, 36.6, 37.7, 39.6, 39.9, 51.6, 55.6, 64.3, 65.7,

+ 69.1, 173.6. HRMS calcd for C13H24NO3 (M ) 242.1751. Found 242.1751.

Methanesulfonate salt of methyl (1R,2R,3S,5S)-(+)-1-n-pentyl-3-(hydroxyl)-8- methyl-8-azabicyclo[3.2,1]octane-2-carboxylate (113d):

A hydrogen atmosphere (50 atm) was applied and the reaction mixture was stirred at rt for 6 h. At this time the solution was filtered through a short pad of Celite, and the Celite

20 washed with MeOH (2 x 5 mL) and concentrated to give 0.295 g (98%) sticky solid; [α] D +3.5

(c 0.43, MeOH); IR(film) 3380, 1749 cm-1; 1H NMR (CD3OD) δ 0.82 (t, J = 7.2 Hz, 3H), 1.20

(b, 6H), 1.48 (m, 8H), 1.94 (m, 1H), 2.09 (3, 3H), 2.60 (s, 3H), 2.88 (d, J = 6.4 Hz, 1H), 3.14 (m,

13 1H), 3.24 (s, 1H), 3.55 ( (s, 3H), 3.87 (m, 1H); C NMR (CD3OD) δ 14.4, 23.6, 25.7, 27.2, 33.8,

33.9, 36.6, 36.3, 37.5, 37.7, 39.5, 51.5, 55.6, 64.2, 65.7, 68.9, 173.5. HRMS calcd for

+ C15H28NO3 (M ) 270.2064. Found 270.2066.

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Methanesulfonate salt of methyl (1R,2R,3S,5S)-()-3-(hydroxy)-1-phenyl-8-methyl-

8-azabicyclo[3.2.1]octane-2-carboxylate (113e):

In a 50 mL, oven-dried, single-neck round-bottomed flask equipped with magnetic stirring bar, and a rubber septum was placed (1S,2R,3R,6S)-(+)-112e (0.160 g, 0.433 mmol) in anhydrous MeOH (10 mL), Pd-C (0.01 g, 5% Pd on Carbon) was added. A hydrogen atmosphere (1 atm) was maintained using a balloon, and the reaction mixture was stirred at rt for

10 h. At this time the solution was filtered through a short pad of Celite, and concentrated to give 0.159 g (99%) of sticky material. This crude reaction mixture was taken further in the synthesis because it could not be purified.

Methyl (1S,6S,2E)-(+)-7-methyl-3-n-pentyl-8-oxa-7-aza-bicyclo[4.2.1]non-2-ene-2- carboxylate (131d) from palladium:

In a 25 mL, oven dried, single necked round-bottom flask equipped with magnetic stirring bar and rubber septum was placed 112d (0.030 g, 0.083 mmol) and 5% Pd/C (20% w/w) in methanol (10 mL). The reaction mixture was stirred at rt for 48 h, the solution was filtered through Celite, washed using methanol (2 x 7 mL) and concentrated. The residue was dissolved in anhydrous pyridine (5 mL) and stirred at rt for 20 h under an argon atmosphere. At this time

122

the solution was concentrated, the residue was dissolved in sat. K2CO3 (10 mL) and extracted with DCM (2 x 7 mL), the combined organic phases were washed with brine (8 mL), dried

(MgSO4) and concentrated. Flash chromatography (60% EtOAC in hexanes) yielded 0.014 g

20 -1 1 (63%) of oil. [α] D (+) 66.5 (c 0.4, CHCl3); IR (CHCl3) 1719 cm ; H NMR (CDCl3) δ 0.87 (t,

J = 6.8 Hz, 3H), 1.28 (m, 4H), 1.46 (m, 3H), 1.98 (m, 3H), 2.20 (m, 1H), 2.40 (m, 1H), 2.65 (m,

4H), 3.17 (m, 1H), 3.45 (t, J = 6.0 Hz, 1H), 3.70 (s, 3H), 5.20 (d, J = 8.8 Hz, 1H); 13C NMR

(CDCl3) δ 13.9, 22.4, 27.5, 31.1, 31.8, 33.1, 37.8, 39.3, 46.5, 51.3, 64.4, 76.8, 131.8, 157.4,

168.4. HRMS calcd for C15H26 NO3 (M+H) 268.1913. Found 268.1909.

Methyl (1S,6S,2E)-(+)-7-methyl-3-n-pentyl-8-oxa-7-aza-bicyclo[4.2.1]non-2-ene-2- carboxylate (131d) using triethylamine:

In a 25 mL, oven dried, single necked round-bottom flask equipped with magnetic stirring bar and rubber septum was placed salt 112d (0.020 gm, 0.055 mmol) in methanol (1 mL) and triethylamine was added (1 mL). The reaction mixture was stirred at rt for 12 h, and the solution was concentrated. The residue was taken into sat. K2CO3 (5 mL) and extracted with

DCM (2 x 5 mL), the combined organic phases were washed with brine (8 mL), dried (MgSO4) and concentrated. Flash chromatography (60% EtOAC in hexanes) gave 0.0132 g (90%) of oil identical to that prepared above.

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Methyl (1S,6S,2E)-(+)-7-methyl-3-methyl-8-oxa-7-aza-bicyclo[4.2.1]non-2-ene-2- carboxylate (131a):

20 Flash chromatography (70% EtOAC in hexanes) yielded 0.013 g (95%) of oil; [α] D

-1 1 +73.7 (c 2.195, CHCl3); IR (CHCl3) 1719 cm ; H NMR (CDCl3) δ 1.55 (m, 1H), 1.95 (m, 3H),

2.04 (s, 3H), 2.65 (m, 4H), 3.22 (m, 1H), 3.44 (t, J = 6.0 Hz, 1H), 3.71 (s, 3H), 5.24 (d, J = 8.8

13 Hz, 1H); C NMR (CDCl3) δ 24.7, 29.6, 32.6, 33.0, 39.1, 46.5, 51.3, 64.3, 77.2, 131.9, 154.2,

168.3. HRMS calcd for C11H18NO3 (M+H) 211.1287. Found 212.1284.

Methyl (1S,6S,2E)-(+)-7-methyl-3-phenyl-8-oxa-7-aza-bicyclo[4.2.1]non-2-ene-2- carboxylate (131e):

In a 50 mL, oven-dried, single-neck round-bottomed flask equipped with magnetic stirring bar, and a rubber septum was placed 112e (0.028 g, 0.076 mmol) in anhydrous MeOH

(1.0 mL) under argon. To this solution was added pyridine (1.0 mL) and the mixture was stirred at rt for 16 h. At this time, the solvent was removed, sat. aqueous potassium carbonate (30 mL) was added and the solution was stirred for 10 min. At this time the aqueous solution was extracted with CHCl3 (3 x 30 mL), the combined organic phases were dried (MgSO4), and concentrated. Flash chromatography (50% EtOAc/hexanes) gave 0.019 g (96%) of a syrupy oil;

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20 1  D +97.1 (c 0.38, CHCl3); H NMR (CDCl3)  1.74 (ddt, J = 13.4 Hz, J = 3.4 Hz, J = 1.0 Hz,

1H), 2.04 (m, 1H), 2.15 (d, J = 12.4 Hz, 1H), 2.33 (td, J = 16.4 Hz, J = 3.9 Hz, 1H), 2.71 (s, 3H),

2.76 (m, 1H), 3.36 (s, 3H), 3.50 (m, 2H), 5.26 (d, J = 9.2 Hz, 1H), 7.08 (m, 2H), 7.27 (m, 3H);

13 C NMR (CDCl3)  32.7, 33.2, 39.1, 46.6, 51.2, 64.5, 77.2, 126.4, 127.1, 127.9, 134.9, 144.5,

153.1, 169.2. HRMS calcd for C16H20NO3 (M+H) 274.1443. Found 274.1440.

Methyl (1R,2R,3S,5S)-()-3-(benzyloxy)-1,8-dimethyl-8-azabicyclo[3.2.1]octane-2- carboxylate (114a):

In a 25 mL, oven-dried, single-neck round-bottomed flask equipped with magnetic stirring bar, and a rubber septum was placed ()-113a (0.03 g, 0.097 mmol) in anhydrous pyridine (1.0 mL) under argon. Benzoyl chloride (0.020 g, 0.145 mmol) was slowly added and the solution was stirred at rt for 20 h. At this time the solvent was removed, sat. aqueous potassium carbonate (30 mL) was added and the solution was stirred for 10 min. At this time the mixture was extracted with CHCl3 (3 x 20 mL), the combined organic phases were dried

(MgSO4), and concentrated. Flash chromatography (1% NH4OH in 40% EtOAc/hexanes) gave

-1 20 1 0.029 g (94%) of a syrupy oil; IR (film) 1720, 1645 cm ;  D 8.3 (c 1.25, CHCl3); H NMR

(CDCl3)  1.27 (s, 3H), 1.72 (m, 1H), 1.81 (m, 2H), 1.89 (m, 1H), 2.14 (m, 1H), 2.26 (s, 3H),

2.50 (dt, J = 2.7 Hz, J = 12.0 Hz, 1H), 2.94 (d, J = 6.8 Hz, 1H), 3.36 (m, 1H), 3.64 (s, 3H), 5.36

13 (td, J = 6.4 Hz, J = 11.7 Hz, 1H), 7.40 (m, 2H), 7.54 (m, 1H), 7.95 (m, 2H); C NMR (CDCl3) 

125

22.7, 26.7, 34.2, 34.5, 36.8, 51.1, 55.5, 62.8, 64.9, 68.4, 128.3, 129.5, 130.1, 132.9, 165.9, 170.4.

HRMS calcd for C18H24NO4 (M+H) 318.1705. Found 318.1701.

Methyl (1R,2R,3S,5S)-()-1-ethyl-3-(benzoyloxy)-8-methyl-8- azabicyclo[3.2.1]octane-2-carboxylate (114b):

20 Flash chromatography (1% NH4OH+EtOAc) gave 75% of an oil; [α] D 1.8 (c 1.365,

-1 1 CHCl3); IR (film) 1721, 1646 cm ; H NMR (CDCl3) δ 0.99 (t, J = 7.6 Hz, 3H), 1.61 (m, 3H),

1.75 (m, 2H), 1.84 (m, 1H), 2.07 (m, 1H), 2.28 (s, 3H), 2.53 (td, J = 11.7, 2.7 Hz, 1H), 3.17 (d, J

= 6.4 Hz, 1H), 3.39 (m, 1H), 3.62 (s, 3H), 5.34 (m, 1H), 7.4 (m, 2H), 7.53 (m, 1H), 7.95 (m, 2H);

13 C NMR (CDCl3) δ 9.2, 26.1, 28.5, 29.6, 32.4, 33.2, 35.9, 50.7, 51.0, 62.5, 68.1, 68.5, 128.2,

129.5, 130.1, 132.9, 165.8, 170.5. HRMS calcd for C19H26NO4(M+H) 332.1862. Found

332.1858.

Methyl (1R,2R,3S,5S)-()-1-n-propyl-3-(benzoyloxy)-8-methyl-8- azabicyclo[3.2.1]octane-2-carboxylate (114c):

126

Flash chromatography (1% NH4OH in 40% EtOAc/hexanes) gave 92% of a syrupy oil;

-1 20 1 IR (film) 1719, 1641cm ;  D 3.0 (c 0.4, CHCl3); H NMR (CDCl3)  0.94 (t, J = 7.3 Hz,

3H), 1.23 (m, 1H), 1.44 (m, 1H), 1.66 (m, 2H), 1.76 (m, 1H), 1.84 (m, 1H), 2.08 (m, 1H), 2.30

(s, 3H), 2.53 (dt, J = 12.0 Hz, J = 2.4 Hz, 1H), 3.15 (d, J = 6.6 Hz, 1H), 3.39 (m, 1H), 3.63 (s,

13 3H), 5.33 (m, 1H), 7.40 (m, 2H), 7.53 (m, 1H), 7.95 (m, 1H); C NMR (CDCl3)  15.0, 18.2,

26.3, 32.9, 33.4, 36.1, 38.5, 51.1, 51.4, 62.4, 67.8, 68.6, 128.3, 129.6, 130.2, 132.9, 165.9, 170.6.

HRMS calcd for C20H28NO4 (M+H) 346.2018. Found 346.2019.

Methyl (1R,2R,3S,5S)-(+)-1-n-pentyl-3-(benzoyloxy)-8-methyl-8- azabicyclo[3.2.1]octane-2-carboxylate (114d):

20 Flash chromatography (1% NH4OH:EtOAc) gave 82% of an oil; [α] D +6.7 (c 1.2,

-1 1 CHCl3); IR (film) 1721, 1646 cm ; H NMR (CDCl3) δ 0.89 (t, J = 6.8 Hz, 3H), 1.37 (b, 4H),

1.62 (b, 5H), 1.77 (m, 2H), 1.84 (b, 1H), 2.09 (b, 1H), 2.30 (s, 3H), 2.54 (dt, J = 2.7, 12.2 Hz,

1H), 3.16 (d, J = 6.8 Hz, 1H), 3.39 (b, 1H), 3.62 (s, 3H), 5.34 (m, 1H), 7.41 (m, 2H), 7.52 (m,

13 1H), 7.96 (m, 2H); C NMR (CDCl3) δ 13.9, 22.4, 24.4, 26.2, 32.6, 32.9, 33.2, 36.0, 36.1, 51.0,

51.3, 62.4, 67.7, 68.6, 128.2, 129.5, 130.1, 132.9, 165.8, 170.5. HRMS calcd for

C22H32NO4(M+H) 374.2331. Found 374.2327.

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Methyl (1R,2R,3S,5S)-(+)-1-phenyl-3-(benzyloxy)-8-methyl-8- azabicyclo[3.2.1]octane-2-carboxylate (114e):

Flash chromatography (40% EtOAc/hexanes) gave 80% of a syrupy oil; IR (film) 1710,

-1 20 1 1635 cm ;  D +33.61 (c 1.8, CHCl3); H NMR (CDCl3)  1.81 (m, 1H), 1.97 (m, 1H), 2.09

(s, 3H), 2.21 (m, 2H), 2.34 (m, 1H), 2.58 (m, 1H), 2.98 (d, J = 6.8 Hz, 1H), 3.22 (s, 3H), 3.52 (m,

1H), 5.38 (td, J = 11.6 Hz, J = 6.3 Hz, 1H), 7.17 (m, 2H), 7.27 (m, 5H), 7.45 (m, 1H), 7.80 (m,

13 2H); C NMR (CDCl3)  25.1, 32.3, 34.3, 38.4, 50.9, 58.1, 62.9, 68.3, 73.1. 127.1, 127.7, 128.1,

128.3, 128.4, 129.5, 129.9, 133.0, 133.3, 165.7, 169.7. HRMS calcd for C23H26NO4 (M+H)

380.1862. Found 380.1859.

Hydrochloride salt of methyl (1R,2R,3S,5S)-()-3-(benzyloxy)-1,8-dimethyl-8- azabicyclo[3.2.1]octane-2-carboxylate (132a):

In a 25 mL, oven-dried, single-neck round-bottomed flask equipped with magnetic stirring bar, and a rubber septum was placed methyl (1R,2R,3S,5S)-()-3-(benzyloxy)-1,8- dimethyl-8-azabicyclo[3.2.1]octane-2-carboxylate (114a) (0.10 g, 0.31 mmol) in anhydrous ether

(10 mL) under argon. Hydrochloric acid (3.0 mL, 1.0 M solution in diethylether) was added to it

128

via syringe at 0 oC and continued stirring for 1 h. At this time, the suspension was allowed to settle and the supernatant liquid was removed using a cannula. The solid remained in the flask was washed with dry ether (3 x 15 mL) and the residue was dried to give 0.109 g (98%) of a

20 o 1 white solid;  D 28.32 (c 1.55, MeOH); M.Pt. 134 – 136 C; H NMR (CD3OD)  1.45 (s,

3H), 2.14 – 2.40 (m, 6H), 2.78 (s, 3H), 3.53 (d, J = 7.2 Hz, 1H), 3.98 (m, 1H), 5.57 (m, 1H), 7.43

13 (m, 2H), 7.57 (m, 1H), 7.86 (m, 2H); C NMR (CD3OD)  20.7, 25.1, 32.4, 33.5, 37.2, 53.3,

53.8, 66.4, 66.5, 71.8, 129.8, 130.3, 130.5, 134.9, 166.3, 174.4.

Hydrochloride salt of methyl (1R,2R,3S,5S)-()-1-n-pentyl-3-(benzoyloxy)-8-methyl-

8-azabicyclo[3.2.1]octane-2-carboxylate(132d):

o 20 1 Obtained 97% of white solid; M.Pt. 128 – 130 C; [α] D 9.263 (c 0.95, MeOH); H

NMR (CD3OD) δ 0.83 (t, J = 6.8, 3H), 1.27 (b, 6H), 1.67 (m, 1H), 1.78 (m, 1H), 2.16 (m, 2H),

2.37 (m, 4H), 2.78 (s, 3H), 3.63 (s, 3H), 3.66 (d, J = 6.8 Hz, 1H), 3.98 (m, 1H), 5.52 (m, 1H),

13 7.43 (t, J = 8.0 Hz, 2H), 7.57 (m, 1H), 7.87 (m, 2H); C NMR (CD3OD) δ 14.2, 23.3, 25.0, 25.4,

30.8, 33.0, 33.5, 34.9, 36.8, 50.1, 53.8, 66.6, 66.7, 75.0, 130.0, 130.5, 130.6, 135.0, 166.5, 174.2.

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Hydrochloride salt of methyl (1R,2R,3S,5S)-(+)-3-(benzyloxy)-1-phenyl-8-methyl-8- azabicyclo[3.2.1]octane-2-carboxylate (132e):

20 o 1 Obtained 95% of a white solid.  D +28.43 (c 1.15, MeOH); M.Pt. 135 – 137 C; H

NMR (CD3OD)  2.32 (m, 1H), 2.45 (m, 1H), 2.53 (m, 1H), 2.62 (m, 1H), 2.72 (s, 3H), 2.74 (m,

1H), 2.88 (m, 1H), 3.37 (s, 3H), 3.50 (d, J = 6.8 Hz, 1H), 4.24 (m, 1H), 5.63 (m, 1H), 7.24 (m,

13 2H), 7.40 (m, 5H), 7.53 (m, 1H), 7.80 (m, 2H); C NMR (CD3OD)  24.8, 31.8, 33.4, 39.4,

53.6, 57.1, 66.9, 67.4, 77.5, 128.5, 129.9, 130.4, 130.6, 130.8, 130.9, 135.1, 136.9, 166.3, 173.2.

5.3 Chapter 3: Preparation of C-1 substituted, 2β-carbomethoxy-3β-aryltropanes

Methyl (1R,2R,3S,5S)-()-3-hydroxy-1,8-dimethyl-8-azabicyclo[3.2.1]octane-2- carboxylate (155):

In a 25 mL, oven-dried, single-neck round bottom flask equipped with magnetic stirring bar was placed ()-113a (0.04 g, 0.13 mmol) and water (4 mL), and cooled to 0 oC. A sat. aqueous potassium carbonate (4 mL) was added and the solution was stirred for 10 min. At this time the aqueous solution was extracted with CHCl3 (3 x 30 mL), the combined organic phases

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20 were dried (MgSO4), and concentrated to give 0.022 g (80%) of oil; [α] D 7.29 (c 0.85,

1 CHCl3); H NMR (CDCl3) δ 1.26 (s, 3H), 1.96 (m, 1H), 2.01 (m, 4H), 2.28 (m, 1H), 2.63 (s, 3H),

3.12 (d, J = 6.8 Hz, 1H), 3.69 (s, 3H), 3.82 (m, 1H), 4.21 (td, J = 6.6 Hz, J = 11.0 Hz, 1H); 13C

NMR (CDCl3)  20.8, 25.3, 32.4, 36.4, 36.5, 39.6, 53.2, 57.0, 63.1, 66.8, 71.8, 175.7. HRMS for the mesyalte salt 113a (salt of 155) was available.

(5S,2Z)-()-Methyl-(N-Me-2,3-dihydro-1H-pyrrole)-but-2-enoate (158) from mesylate salt of methyl ester of C-1 methyl ecgonine (113a):

In a 25 mL, oven-dried, single-neck round bottom flask equipped with magnetic stirring bar, rubber septum and reflux condenser was placed mesylate salt of methyl ester of C-1 methyl ecgonine (113a) (0.036 g, 0.11 mmol) in anhydrous POCl3 (3 mL) under argon atmosphere and heated to reflux for 90 min. At this time, reaction mixture was cooled to rt, quenched using water (15 mL) and sat. aqueous potassium carbonate (5 mL) was added. The solution was extracted with CHCl3 (3 x 3 mL), the combined organic phases were dried (MgSO4), and concentrated. Flash chromatography (10% MeOH/DCM) gave 0.013 g (58%) of oily compound.

20 1  D 1.14 (c 0.86, CHCl3); H NMR (CDCl3)  1.90 (m, 2H), 2.14 (s, 3H), 2.67 (m, 2H), 3.00

(s, 3H), 3.46 (m, 1H) 3.69 (s, 3H), 5.84 (m, 1H), 5.91 (td, J = 1.8 Hz, J = 11.3 Hz, 1H), 6.37 (m,

13 1H); C NMR (CDCl3)  21.4, 27.3, 38.1, 39.6, 51.9, 71.2, 121.8, 131.9, 132.9, 145.9, 174.8.

HRMS calcd for C11H18NO2 (M+H) 196.1338. Found 196.1334.

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Methyl (1R,2R,3S,5S)-()-3-methanesulfonyl-1,8-dimethyl-8- azabicyclo[3.2.1]octane-2-carboxylate (159):

In a 25 mL, oven-dried, single-neck round-bottomed flask equipped with magnetic stirring bar, and a rubber septum was placed tropane alcohol ()-155 (0.034 g, 0.159 mmol) in

THF (4.0 mL) under an argon atmosphere, and cooled to 0 oC. Triethylamine (0.066 mL, 0.478 mmol) was added followed by methanesulfonyl chloride (0.034 mL, 0.438 mmol). The reaction mixture was stirred at rt for 4 h. At this time, the reaction was quenched using sat. aqueous potassium carbonate (10 mL), extracted using DCM (3 x 5 mL), the combined organic phases were dried (MgSO4), and concentrated. Flash chromatography (50% EtOAc/hexanes) gave

20 1 0.028 g (62%) of oily compound.  D 2.32 (c 0.92, CHCl3); H NMR (CDCl3)  1.27 (s,

3H), 1.72 (m, 1H), 1.81 (m, 2H), 1.87 (m, 1H), 2.13 (m, 1H), 2.21 (S, 3H), 2.27 (s, 3H), 2.52 (dt,

J = 2.7 Hz, J = 12.0 Hz, 1H), 2.96 (d, J = 6.8 Hz, 1H), 3.37 (m, 1H), 3.63 (s, 3H), 5.36 (td, J =

13 6.4 Hz, J = 11.7 Hz, 1H); C NMR (CDCl3)  22.2, 26.4, 34.6, 34.9, 36.4, 41.5, 51.3, 55.9, 62.8,

64.8, 68.3, 170.5. HRMS calcd for C12H22NO5S (M+H) 292.1219. Found 292.1217.

132

Methyl (1R,2R,5S)-()-1,8-dimethyl-8-azabicyclo[3.2.1]octan-3-one-2-carboxylate (160):

In a 25 mL, oven-dried, single-neck round-bottomed flask equipped with magnetic stirring bar, and a rubber septum was placed anhydrous DCM (3 mL), oxalyl chloride (0.024 mL,

0.28 mmol) under argon atmosphere, and cooled to 0 oC. Dimethyl sulfoxide (0.025 mL, 0.35 mmol) was added and the solution was stirred at 0 oC for 15 min. To the reaction mixture was added tropane alcohol ()-155 (0.030 g, 0.14 mmol) in anhydrous DCM (2.0 mL), the solution was stirred at 0 oC for 30 min and triethylamine (0.118 mL, 0.84 mmol) was added. After stirring for 30 min the reaction mixture was quenched using sat. aqueous potassium carbonate

(10 mL), extracted with DCM (3 x 5 mL), the combined organic phases were dried (MgSO4), and concentrated. Flash chromatography (40% EtOAc/hexanes) gave 0.023 g (78%) of oily

20 1 compound.  D 3.11 (c 0.85, CHCl3); H NMR (CDCl3)  1.24 (s, 3H), 1.52 (m, 2H), 2.02

(m, 1H), 2.16 (dd, J = 1.6, 15.2 Hz, 1H), 2.52 (s, 3H), 2.66(m, 2H), 3.49 (s, 1H), 3.59 (m, 1H),

13 3.73 (s, 3H); C NMR (CDCl3) δ 22.8, 27.6, 30.6, 32.6, 38.7, 42.1, 51.7, 60.8, 61.9, 169.4,

203.1. HRMS calcd for C11H18NO3 (M+H) 212.1287. Found 212.1285.

(1R,5S)-()-2-carbomethoxy-1,8-dimethyl-3-trifluoromethanesulfonyloxy-8- azabicyclo[3.2.1]oct-2-ene (163):

133

In a 25 mL, oven-dried, single-neck round-bottomed flask equipped with magnetic stirring bar, and a rubber septum was placed tropane ()-160 (0.025 g, 0.11 mmol) in THF (5 mL) under an argon atmosphere. The solution was cooled to -78 oC, NaHMDS (0.18 mL, 1.0 M solution in THF, 0.18 mmol) was added and stirred at -78 oC for 20 min. At this time, N-(5- chloro-2-pyridyl)bis(trifluoromethanesulfonimide) (0.055 g, 0.14 mmol) in THF (5 mL) was added, the solution was warm to 0 oC and stirred for 1 h. During this time, solvent was removed under vacuum and quenched using water (20 mL), extracted using DCM (3 x 4 mL), combined organic phases were washed with water (10 mL), brine washed (2 x 4 mL), dried (MgSO4) and concentrated. Flash chromatography using alumina (20% EA in hexanes) afforded 0.025 g

20 1 (61%) of oily compound.  D 9.2 (c 0.89, CHCl3); H NMR (CDCl3) δ 1.52 (s, 3H), 1.75 (m,

2H), 1.91 (d, J = 17.65 Hz, 1H), 2.17 (m, 1H), 2.34 (s, 3H), 2.44 (dt, J = 2.4, 10.9 Hz, 1H), 2.83

13 (dd, J = 4.5, 17.67 Hz, 1H), 3.55 (m, 1H), 3.81 (s, 3H); C NMR (CDCl3) δ 11.1, 22.7, 27.6,

29.6, 36.5, 42.2, 51.8, 53.4, 61.2, 65.9, 118.3, 169.4. HRMS calcd for C12H17F3NO5S (M+H)

344.0780. Found 212.0773.

5.4 Chapter 4: Vinylaluminum Addition to Sulfinimines (N-Sulfinyl Imines)

Asymmetric Synthesis of anti-α-Alkyl β-Amino Esters

(Ss,R)-(+)-Ethyl 2-[phenyl(p-toluenesulfinylamino)methyl]acrylate (195a):

134

In a 5 mL, oven dried, single-necked round bottom flask equipped with a magnetic stirring bar and rubber septum was placed NMO (0.174 g, 1.48 mmol) in anhydrous THF (2 mL), cooled to 0 oC. To the solution was added DIBAL-H (1.12 mL, 1.0 M in THF) and the mixture was stirred at this temperature for 1 h. Added ethyl propiolate (188a) (0.076 mL, 0.74 mmol) and stirred for 2 h at 0 oC. Added the solution of (S)-(+)-N-benzylidene-p-toluenesulfinamide

(168a) (0.060g, 0.246 mmol) in THF (2 mL), the mixture was warmed up to rt, stirred for 4 h.

Reaction was quenched using aqueous NaKC4H4O6. H2O (6 mL), diluted with EtOAc (5 mL), vigorously stirred for 30 min and extracted with EtOAc (3 X 5 mL). The combined organic layers were washed with brine (2 x 10 mL), dried (MgSO4) and concentrated. Prep. TLC (50% hexane/ethyl acetate) provided 0.55 g (65%) of colorless oil as a major isomer. (dr >20:1).

20 -1 1 [] D +30.0 (c 0.28, CHCl3); IR (neat): 3204, 1711, 1053 cm ; H NMR (CDCl3)  1.20 (t, J =

6.8 Hz, 3H), 2.39 (s, 3H), 4.13 (qt, J = 7.2 Hz, 2H), 4.93 (d, J = 7.2 Hz, 1H), 5.35 (d, J = 7.2 Hz,

2H), 6.03 (d, J = 0.8 Hz, 1H), 6.47 (s, 1H), 7.20-7.28 (m, 7H), 7.61 (d, J = 6.4 Hz, 2H); 13C

NMR (CDCl3) δ 14.5, 21.7, 58.4, 61.3, 126.0, 127.2, 127.4, 128.0, 128.9, 129.9, 140.5, 141.6,

141.8, 166.0 (one carbon can’t be identified due to overlap). HRMS calcd. for

C19H22NO3S(M+H): 344.1320. Found 344.1327.

(Ss,R)-(+)-Methyl 2-[phenyl(p-toluenesulfinylamino)methyl]acrylate (196):

Prep. TLC (50% hexane/ethyl acetate) provided 0.0195 mg (32%) of colorless oil as a

20 -1 1 major isomer. (dr >28:1); [] D +32.5 (c 0.415, CHCl3); IR (neat): 3228, 1720, 1053 cm ; H

135

NMR (CDCl3)  2.39 (s, 3H), 3.70 (s, 3H), 4.95 (d, J = 6.8 Hz, 1H), 5.35 (d, J = 7.2 Hz, 2H),

6.04 (s, 1H), 6.47 (s, 1H), 7.20 - 7.28 (m, 7H), 7.61 (d, J = 6.4 Hz, 2H); 13C NMR δ 21.7, 52.3,

58.3, 126.0, 127.3, 127.5, 128.0, 128.9, 129.9, 140.3, 141.3, 141.7, 141.8, 166.5. HRMS calcd. for C18H19NaNO3S (M+Na) 352.0983. Found 352.0990.

Ethyl (Rs,2S)-()-2-[phenyl-(2-methylpropanesulfinylamino)methyl]acrylate (205a):

In a 50 mL, flame-dried, single-necked round-bottomed flask equipped with a magnetic stirring bar, rubber septum, a reflux condenser, and argon balloon was placed NMO (0.606 g,

5.16 mmol) in THF (6 mL). To the solution was added DIBAL-H (3.9 mL, 1.0 M solution in

THF) at 0 °C and the mixture was stirred for 30 min. Ethyl propiolate (188a) (0.264 mL, 2.59 mmol) was added via syringe, and the mixture was stirred for 1 h at 0 °C, and (R)-()-204a

(0.180 g, 0.864 mmol) in anhydrous THF (6 mL) was added. The mixture was heated to 70 °C and stirred for 15 h, cooled to rt, quenched by addition of sat. aqueous Rochelle salt (10 mL), diluted with EtOAc (15 mL), and stirred vigorously for 0.5 h. The organic phase was washed with brine (5 mL), dried (MgSO4), and concentrated. Flash chromatography (25%

20 EtOAc/hexanes) provided 0.174 g (65%) of a colorless oil; [] D 1.40 (c 0.93, CHCl3); IR

-1 1 (KBr) 3233, 2980, 1717, 1061 cm ; H NMR (CDCl3)  7.26 (m, 5H), 6.45 (s, 1H), 5.99 (s, 1H),

5.49 (d, J = 4.8 Hz, 1H), 4.12 (m, 2H), 3.76 (d, J = 4.8 Hz, 1H), 1.25 (s, 9H), 1.20 (t, J = 7.2 Hz,

136

13 3H); C NMR (CDCl3)  166.0, 141.6, 140.7, 129.1, 128.3, 127.9, 126.8, 61.3, 59.8, 56.5, 23.0,

14.4. HRMS calcd. for C16H24NO3S (M+H) 310.1477. Found 310.1472.

(Z)-Ethyl (Rs,2S)-()-2-[phenyl-(2-methylpropanesulfinylamino)methyl] but-2- enoate (205b):

In a 50 mL, flame-dried, single-necked round-bottomed flask equipped with a magnetic stirring bar, rubber septum, a reflux condenser, and argon balloon was placed NMO (0.606 g,

5.16 mmol) in THF (6 mL). The solution was cooled to 0 oC, DIBAL-H (3.9 mL, 1.0 M solution in THF) was added, and the reaction mixture was stirred for 30 min at which time ethyl but-2- ynoate (188b) (0.300 mL, 2.59 mmol) was added via syringe. After stirring for 4 h at rt (R)-(-)-

204a (0.180 g, 0.864 mmol) in THF (6 mL) was added. The reaction mixture was heated to 70

°C, stirred for 15 h, cooled to rt and quenched by addition of sat. aqueous Rochelle salt (10 mL).

The solution was diluted with EtOAc (15 mL), vigorously stirred, and the organic phase was washed with brine (5 mL), dried (MgSO4), and concentrated. Flash chromatography (33%

20 EtOAc/hexanes) provided 0.329 g (71%) of a colorless oil; [] D 24.8 (c 0.29, CHCl3); IR

-1 1 (KBr) 3214, 3030, 2959, 2869, 1717 cm ; H NMR (CDCl3) major isomer  7.25 (m, 5H), 6.35

(q, J = 7.2 Hz, 1H), 5.34 (d, J = 6.4 Hz, 1H), 4.09 (m, 2H), 3.85 (d, J = 6.4 Hz, 1H), 2.05 (dd, J =

13 0.8, 7.2 Hz, 3H), 1.23 (s, 9H), 1.15 (t, J = 7.0 Hz, 3H); C NMR (CDCl3)  166.7, 141.0, 138.8,

137

133.8, 128.7, 127.8, 127.4, 61.9, 60.5, 56.2, 22.8, 15.7, 14.2. HRMS calcd for C17H26NO3S

(M+H) 324.1633. Found 324.1649.

(Z)-Ethyl (Rs,2R)-()-2-[phenyl(2-methylpropanesulfinylamino)methyl]-3- phenylacrylate (205c):

20 Flash chromatography (25% EtOAc/hexanes) provided 73% of a colorless oil; [] D

-1 1 41.0 (c 1.05, CHCl3); IR (KBr) 3211, 1734, 1225 cm ; H NMR (CDCl3)  7.46 (m, 2H), 7.36

(m, 3H), 7.28 (m, 5H), 6.94 (s, 1H), 5.45 (d, J = 6.0 Hz, 1H), 4.00 (m, 2H), 3.91 (d, J = 6.0 Hz,

13 1H), 1.27 (s, 9H), 0.97 (t, J = 7.0 Hz, 3H); C NMR (CDCl3)  168.1, 139.9, 135.7, 135.4,

134.9, 128.8, 128.6, 128.5, 128.3, 128.2, 127.7, 62.7, 60.9, 56.4, 22.8 (3C), 13.7. HRMS calcd for C22H28NO3S (M+H) 386.1790. Found 386.1805.

(RS,3S)-()-Ethyl 3-(1,1-dimethylethylsulfinamido)-2-methylenepentanoate (205d):

Flash chromatography (40% EtOAc/hexanes) provided 55% of a colorless oil; IR (neat)

-1 20 1 3212, 1718 cm ; [] D 39.6 (c 1.26, CHCl3); H NMR (CDCl3)  6.26 (s, 1H), 5.27 (s, 1H),

138

4.22 (m, 2H), 4.04 (dt, J = 6.8 Hz, 1H), 3.68 (d, J = 6.8 Hz, 1H), 1.86 (m, 2H), 1.31 (t, J = 6.8

13 Hz, 3H), 1.19 (s, 9H), 0.93 (t, J = 7.6 Hz, 3H); C NMR (CDCl3)  166.4, 141.3, 126.3, 61.2,

60.1, 56.1, 29.1, 22.9, 14.5, 11.3. HRMS calcd for C12H24NO3S (M+H) 262.1477. Found

262.1455.

(Z)-(RS,3S)-()-Ethyl 3-(1,1-dimethylethylsulfinamido)-2-ethylidenepentanoate

(205e):

20 Flash chromatography (40% EtOAc/hexanes) provided 50% of a colorless oil; [] D

-1 1 51.5 (c 1.20, CHCl3); IR (neat,) 3224, 1714, 1454, cm ; H NMR (CDCl3)  6.11 (m, 1H), 4.21

(m, 2H), 3.87 (q, J = 6.8 Hz, 1H), 3.58 (d, J = 6.0 Hz, 1H), 1.97 (d, J = 6.8 Hz, 3H), 1.79 (m,

13 2H), 1.31 (t, J = 7.2 Hz, 3H), 1.17 (s, 9H), 0.90 (t, J = 7.2 Hz, 3H); C NMR (CDCl3)  167.5,

137.7, 133.8, 62.6, 60.7, 55.9, 29.4, 22.9, 15.8, 14.6, 11.3. HRMS calcd for C13H26NO3S (M+H)

276.1633. Found 276.1635.

139

Ethyl (Z)-(Rs,2S)-()-2-[ethyl(2-methylpropanesulfinylamino)methyl]-3- phenylacrylate (205f):

20 Flash chromatography (50% EtOAc/hexanes) provided 35% of a colorless oil; [] D

-1 1 36.3 (c 0.84, CHCl3); IR (KBr) 3211, 1722, 1225, 1061 cm ; H NMR (CDCl3)  7.22 (m, 5H),

6.77 (s, 1H), 4.07 (m, 3H), 3.47 (d, J = 5.2 Hz, 1H), 1.98 (m, 1H), 1.83 (m, 1H), 1.20 (s, 9H),

13 1.06 (t, J = 7.2 Hz, 3H), 1.02 (t, J = 7.6 Hz, 3H); C NMR (CDCl3)  168.7, 135.7, 135.3, 134.8,

128.7, 128.6 128.5, 62.7, 61.1, 56.1, 29.3, 22.9, 14.0, 11.4. HRMS calcd for C18H28NO3S

(M+H) 338.1790. Found 338.1781.

(SS,2R,3S)-(+)-Ethyl 2-methyl-3-(4-methylphenylsulfinamido)-3-phenyl-propanoate

(198):

In an oven-dried, 25 mL one neck round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and an H2 balloon was placed (+)-195a (0.200 g, 0.585 mmol) and cationic rhodium complex 197 (0.031 g, 0.044 mmol) in anhydrous DCM (5.0 mL). The solution was evacuated and filled with H2, and this sequence was repeated 5 times. The reaction mixture was stirred for 48 h at rt, and concentrated. Flash chromatography (50%

140

20 EtOAc/hexanes) afforded 0.180 g (88%) of a colorless oil; [] D +33.6 (c 0.65, CHCl3); IR

-1 1 (neat) 3206, 1730, 1090, 1053 cm ; H NMR (CDCl3) δ 7.43 (d, J = 8.0 Hz, 2H), 7.21 (m, 3H),

7.11 (m, 4H), 5.06 (d, J = 7.2 Hz, 1H), 4.50 (dd, J = 7.2, 8.0 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H),

2.88 (dq, J = 6.8, 8.0 Hz, 1H), 2.32 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H), 1.46 (d, J = 6.8 Hz, 3H);13C

NMR δ 175.0, 142.0, 141.4, 141.1, 129.5, 129.0, 127.9, 127.3, 126.1, 61.1, 60.4, 46.9, 21.6, 15.8,

14.5. HRMS calcd for C19H23NaNO3S (M+Na) 368.1296. Found 368.1304.

(RS,2S,3R)-()-Ethyl 2-methyl-3-(4-methylphenylsulfinamido)-3-phenyl propanoate

(207a):

20 Flash chromatograpy (50% EtOAc/hexanes) afforded 83% of a colorless oil; [] D -20.6

-1 1 (c 0.18, CHCl3); IR (neat) 3584, 3256, 1734 cm ; H NMR (CDCl3)  7.32 (m, 5H), 4.46 (dd, J

= 8.4, 8.4 Hz, 1H), 4.12 (q, J = 7.3 Hz, 2H), 3.96 (d, J = 8.4 Hz, 1H), 2.92 (dq, J = 7.2, 8.4 Hz,

13 1H), 1.24 (t, J = 7.2 Hz, 3H), 1.11 (s, 9H), 0.99 (d, J = 6.8 Hz, 3H); C NMR (CDCl3)  174.9,

140.4, 128.9, 128.2, 127.4, 63.1, 60.8, 56.4, 46.8, 22.7, 15.2, 14.3. HRMS calcd for C16H26NO3S

(M+H) 312.1633. Found 312.1625.

141

(RS,2S,3R)()-Ethyl-2-[(R)-(1,1-dimethylethylsulfinamido)(phenyl)methyl]butanoate

(207b):

In an oven-dried, 25 mL one necked, round-bottomed flask equipped with a magnetic stirring bar was placed ()-205b (0.0302 g, 0.093 mmol) and cationic rhodium complex 197

(0.005 g, 0.007 mmol) in 1,2-dichloroethane (4.5 mL). The solution was placed in a high- pressure vessel (Series 4650 2.50 Inch Inside Diameter HP/HT from Parr Instrument Company).

The vessel was tightly closed and was filled with H2 until the inner pressure reached 25 atm at which time it was evacuated and refilled with H2 to 25 atm. This sequence was repeated 3 times.

The reaction mixture was stirred at 25 atm of H2 for 72 h at rt, at which time the solution was concentrated. Preparative TLC (50% EtOAc/hexanes) afforded 0.0241 g (81%) of a colorless

20 -1 1 oil; [] D 44.4 (c 0.41, CHCl3); IR (neat): 3216, 1732, 1052 cm ; H NMR (CDCl3)  7.30 (m,

5H), 4.60 (dd, J = 7.6, 7.6 Hz, 1H), 3.95 (q, J = 7.2 Hz, 2H), 3.66 (d, J = 7.6 Hz, 1H), 2.80 (m,

1H), 1.63 (m, 2H), 1.20 (s, 9H), 1.04 (t, J = 7.2 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR

(CDCl3)  173.0, 140.6, 128.6, 128.0, 127.3, 61.7, 60.4, 56.5, 54.2, 22.7, 22.1, 14.0, 11.9.

HRMS calcd for C17H28NO3S (M+H) 326.1790. Found 326.1782.

142

(RS,2S,3R)-()-Ethyl 2-benzyl-3-(1,1-dimethylethylsulfinamido)-3-phenylpropanoate (207c):

20 Preparative TLC (50% EtOAc/hexanes) afforded 79% of a colorless oil; [] D 19.5 (c

-1 1 0.57, CHCl3); IR (neat) 3221, 1730, 1052 cm ; H NMR (CDCl3)  7.30 (m, 10H), 4.66 (dd, J =

7.2, 7.2 Hz, 1H), 3.81 (m, 3H), 3.20 (m, 1H), 3.06 (m, 1H), 2.92 (m, 1H), 1.23(s, 9H), 0.89 (t, J

13 = 7.2 Hz, 3H); C NMR (CDCl3)  172.3, 140.0, 138.8, 128.8, 128.6, 128.4, 128.1, 127.3,

126.4, 61.9, 60.3, 56.5, 54.6, 35.0, 22.6, 13.7. HRMS calcd for C22H29NaNO3S (M+Na)

410.1766. Found 410.1766.

(Rs,2S,3S)-()-Ethyl-2-methyl-3-(tert-butylsulfinylamino)pentanoate (207d). In a 50 mL, dry, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and an H2 balloon was placed ()-205d (0.05 g, 0.17 mmol) and cationic rhodium complex 197

(0.009 g, 0.013 mmol) in anhydrous DCM (5 mL). The solution was evacuated and filled with

H2, and this sequence was repeated 5 times. The reaction mixture was stirred at rt for 48 h.

20 Preparative TLC (50% EtOAc/hexane) afforded 0.0255 g (55%) of a colorless oil; [α] D 31.46

-1 1 (c 0.06, CHCl3); IR (neat) 3280, 1732, 1462, cm ; H NMR (CDCl3) δ 4.06 (m, 2H), 3.62 (d, J =

143

12 Hz, 1H), 3.29 (m, 1H), 2.69 (m, 1H), 1.72 (m, 1H), 1.26 (t, J = 7.2 Hz, 3H) 1.23 (s, 9H), 1.19

13 (d, J = 7.2 Hz, 3H) 0.99 (t, J = 7.6 Hz, 3H); C NMR (CDCl3) δ 174.9, 61.3, 60.4, 56.2, 43.4,

27.37, 22.7, 14.7, 14.2, 10.0. HRMS calcd for C12H26NO3S (M+H) 264.1633. Found 264.1613.

(Rs,2S,3S)-()-Ethyl 2-benzyl-3-(1,1-dimethylethylsulfinamido)pentanoate (207f).

20 Preparative TLC (50% EtOAc/hexanes) afforded 77% of a colorless oil; [] D 27.7 (c 0.51,

-1 1 CHCl3); IR (neat) 3228, 1731, 1053 cm ; H NMR (CDCl3) major isomer  7.19 (m, 5H), 4.00

(q, J = 7.6 Hz, 2H), 3.66 (m, 1H), 3.23 (d, J = 7.6 Hz, 1H), 2.96 (m, 2H), 2.85 (m, 1H), 1.77 (m,

1H), 1.62 (m, 1H), 1.20 (s, 9H), 1.10 (t, J = 8.1 Hz, 3H), 0.97 (t, J = 7.6 Hz, 3H) ; 13C NMR

(CDCl3)  173.2, 139.2, 128.8, 128.5, 126.4, 60.4, 59.8, 56.2, 52.0, 34.1, 26.8, 22.9, 14.1, 10.4.

HRMS calcd for C18H29NaNO3S (M+Na) 362.1766. Found 362.1761.

(2R,3S)-()-Ethyl 2-methyl-3-(4-methylphenylsulfonamido)-3-phenylpropanoate

(200) from (+)-198:

In an oven-dried, 10 mL one neck, round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (+)-198 (0.168 g, 0.486 mmol) in

144

DCM (18.0 mL). The solution was cooled to 0 oC, m-CPBA (0.336 g, 1.458 mmol, 75% wt) was added in one portion, the reaction mixture was warmed to rt, stirred for 1.5 h, and quenched by addition of sat. Na2S2O3 solution (10 mL). The solution was extracted with DCM (2 x 5 mL), the combined organic phases were washed with sat. NaHCO3 solution (2 x 5 mL), brine (5 mL), dried (MgSO4), and concentrated. Flash chromatography (50% EtOAc/hexanes) afforded 0.145

20 -1 1 g (88%) of a colorless oil; [] D 43.0 (c 1.09, CHCl3); IR (neat) 3279, 1733, 1161 cm ; H

NMR (CDCl3)  7.48 (d, J = 8.0 Hz, 2H), 7.12 (m, 3H), 7.05 (d, J = 8.4 Hz, 2H), 7.00 (m, 2H),

5.96 (d, J = 8.8 Hz, 1H), 4.50 (dd, J = 6.0, 8.4 Hz, 1H), 4.01 (q, J = 7.2 Hz, 2H), 2.79 (quint, J =

13 6.4 Hz, 1H), 2.31 (s, 3H), 1.13 (m, 6H); C NMR (CDCl3) δ 174.9, 143.1, 139.4, 138.4, 129.5,

128.6, 127.7, 127.3, 126.9, 61.2, 60.5, 46.3, 21.7, 15.8, 14.3. Spectral properties were consistent with literature values.82

(2R,3S)-()-2-Methyl-3-(4-methylphenylsulfonamido)-3-phenylpropanoic acid (201):

In an oven-dried, 10 mL one necked, round-bottomed flask equipped with a magnetic stirring bar, reflux condenser, and rubber septum was placed ()-200 (0.0435 g, 0.120 mmol) and

LiOH monohydrate (0.0435 g, 0.120 mmol) in THF (9 mL) and H2O (0.33 mL). The reaction mixture was refluxed for 16 h at 67 oC, cooled to rt, and concentrated. The residue was diluted with DCM (10 mL), and 1 N HCl was added until the solution reached pH >2. The solution was stirred for 10 min, and extracted with DCM (3 x 5 mL). The combined organic phases were

145

washed with brine (4 mL), dried (MgSO4), and concentrated. Preparative TLC (50%

EtOAc/hexanes) afforded 0.0363 g (91%) of white solid, mp 131-133 oC; [lit79 mp 135-136 oC];

20 79 20 80 20 [] D -23.6 (c 0.49, EtOAc), [lit [] D -25.6 (c 0.06, EtOAc), lit [] D 28.1 (c 1.0,

-1 1 EtOAc)]; IR (neat) 3263, 1712, 1160 cm ; H NMR (CDCl3) δ 7.47 (m, 2H), 7.11 (m, 3H), 7.02

(m, 4H), 6.20 (d, J = 9.2 Hz, 1H), 4.50 (dd, J = 7.2, 8.8 Hz, 1H), 2.87 (quint, J = 6.8 Hz, 1H),

13 2.29(s, 3H), 1.17(d, J = 6.8 Hz, 3H); C NMR (CDCl3) δ 178.6, 143.3, 138.9, 138.0, 129.5,

128.7, 127.9, 127.3, 127.1, 60.5, 46.1, 21.7, 15.7. HRMS calcd for C17H20NO4S(M+H)

334.1113. Found 334.1126. Spectral properties were consistent with literature values.79,80

(3R,4S)-()-3-Methyl-4-phenyl-1-tosylazetidin-2-one (202):

In an oven-dried, 10 mL one necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (-)-201 (0.0224 g, 0.067 mmol), DCC

(0.017 mg, 0.0804 mmol), and 4-pyrrolidinopyridine (3.7 mg) in DCM (2.5 mL). The reaction mixture was stirred for 16 h at rt, filtered through celite and the filtrate was washed with water

(3.0 mL), 5% aqueous HOAc (3 mL), and water (3 mL). The combined organic phases were washed with brine (3.5 mL), dried (MgSO4), and concentrated. Preparative TLC (25%

EtOAc/hexanes) afforded 0.0165 g (80%) of a white solid, mp 133-135 oC [lit80 mp 134-135 oC;

20 80 20 -1 [] D 103 (c 0.58, EtOAc), lit [] D -114 (c 1.05, EtOAc)]; IR (neat) 1794, 1361, 1168 cm ;

1 H NMR (CDCl3) δ 7.62 (dd, J = 3.2, 6.4 Hz, 2H), 7.26 (m, 7H), 4.60 (d, J = 3.2 Hz, 1H), 3.16

146

(m, 1H), 2.42 (s, 3H), 1.34 (d, J = 7.6 Hz, 3H); 13C NMR δ 167.9, 145.4, 136.5, 136.1, 130.1,

129.3, 129.2, 127.8, 126.9, 65.4, 55.0, 22.0, 12.8. HRMS calcd for C17H18NO3S [M+H]

316.1007. Found 316.1013. Spectra properties were consistent with literature values.79,80

147

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