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DEVELOPMENT OF NOVEL METHODS AND APPLICATIONS IN OF NATURAL PRODUCTS

A Dissertation Submitted to the Temple University Graduate Board

in Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY

by Gopal Sirasani January, 2012

Examining Committee Members:

Prof. Rodrigo B. Andrade, Department of Chemistry, Temple University Prof. Franklin A. Davis, Department of Chemistry, Temple University Prof. Magid Abou-Gharbia, Department of Chemistry, Temple University Prof. David R. Dalton, Department of Chemistry, Temple University Prof. Kevin C. Cannon, External Examiner, Pennsylvania State University

! "!

©

by

Gopal Sirasani

2012

All Rights Reserved

! ""! ABSTRACT

DEVELOPMENT OF NOVEL METHODS AND APPLICATIONS IN

TOTAL SYNTHESIS OF NATURAL PRODUCTS

Gopal Sirasani

Doctor of Philosophy

Temple University, 2012

The olefin cross metathesis reaction has been sequenced with four common organic transformations in a one-pot manner to rapidly access useful building blocks.

Those reactions are: (1) phosphorus-based olefination (e.g., Wittig and Horner-

Wadsworth-Emmons); (2) reduction; (3) Evans propionate ; and (4)

Brown allyl- and Roush crotylboration. The products of these reactions include stereodefined 2,4-dienoates, trans allylic , syn-propionate aldols and chiral non- racemic homoallylic alcohols, respectively, which can be carried further in the context of .

Two approaches toward the total synthesis of cytotoxic

(+)-crocacin C have been accomplished. The first-generation approach used a Crimmins aldol reaction and reagent-controlled double asymmetric crotylboration (Brown and

Roush) reaction, which was not selective. The first-generation approach was replaced altogether with a second that afforded (+)-crocacin C in 10 steps from commercially available Evans’ chiral propionimide (5% overall yield).

! """! The key reactions in the second-generation approach included an Evans dipropionamide aldol reaction, 1,3-anti reduction and a vinylogous Horner-Wadsworth-

Emmons olefination. No protecting groups were utilized in the total synthesis of (+)- crocacin C.

A novel method to access the ABCE tetracyclic framework of the Strychnos has been developed. Five different strategies were utilized toward this goal, out of which the first four were unsuccessful. The fifth-generation strategy featured a novel sequential one-pot bis-cyclization method. Specifically, the AgOTf-mediated spirocyclization of an appropriately functionalized 3-carbinamide afforded a stable spiroindolenine intermediate; subsequent addition of DBU to the reaction mixture effected an unprecedented intramolecular aza-Baylis-Hillman reaction, delivering tetracyclic product in 70% isolated yield.

The bis-cyclization was showcased in concise racemic total syntheses of akuammicine and in six and thirteen operations, respectively. Key steps include (1) the vinylogous ; (2) our sequential one-pot spirocyclization/intramolecular aza-Baylis-Hillman reaction; and (3) a Heck cyclization.

The synthesis of strychnine proceeded via the Wieland-Gumlich . We have also utilized our method to prepare other biologically active Strychnos alkaloids (-)- akuammicine, (-)-leuconicines A and B, (-)-norfluorocurarine, (-)-dehydrotubifoline, (-)- dihydroakuammicine, (-)-tubifoline and (-)-valparicine in a concise, asymmetric manner.

! "#!

Dedication

I dedicate this dissertation to all my wonderful family members whose support and

encouragement throughout my graduate school journey made it possible

! #! ACKNOWLEDGMENTS

This is by far the most important part of my thesis. Synthetic organic chemists often define their achievements in terms of the number of natural products they made or the number of novel reactions they developed. Yet, I realize that my greatest achievements have been the professional and personal relationships I have developed that have gotten me to this stage in life. It is with tremendous gratitude that I write these acknowledgements to show my appreciation to the people who have helped me throughout the years.

First and foremost, I would like to thank my advisor Rodrigo B. Andrade for his unwavering support, enthusiasm and general concern for my development as an organic chemist. The excitement with which Rod approaches synthesis and his dedication to the goal of producing “good science” is inspiring. Rod’s teaching style, both in the classroom and the laboratory with all of the historical background, motivated me to join the group, and his willingness and openness to discussion are what kept me excited. It has been a privilege to work under his tutelage and an even greater pleasure to be one of his first

Ph.Ds. Rod has had a tremendous influence on how I think of chemistry and I hope to continue to learn from him in the future. Rod’s persistent enthusiasm is a great source of inspiration. As an advisor, he has always encouraged me to explore my ideas and he has always guided me in the right direction. Whenever I was losing motivation for a project, I knew that a five-minute conversation with him would be enough to inspire me.

The other members of my thesis committee have been a true pleasure to interact with. Prof. Davis, the chair of my committee is the most well organized person I have ever met. I would like to thank him for providing me with many scientific insights.

! #"! I am grateful for all the scientific and career advice Prof. Dalton has provided me over the years. He was like a living library for me throughout these years and I will never forget the conversations I had with him. Prof. Magid Abou-Garbia may be the most down-to-earth genius I know. I am grateful for all the opportunities he provided to interact with him. In addition to serving as an external examiner on my thesis committee

Prof. Cannon was one of the great teachers I had.

Although Prof. Wuest is the newest member in the department, I have already gotten to know him quite well. Sitting in his organic class this past semester was a great learning experience for me. Most of all, I value his highly interactive teaching style and I would like to thank him for providing me with some good career plans. I would like to thank our collaborators Drs. Abou-Gharbia, Wayne, Krynestsky, Kiss, Frederick, Shrome and Roger for their valuable suggestions and support in biological activity testing. I am grateful for the support and friendship of the wonderful staff at Temple Chemistry

Department: Bobbi, Regina, Sharon, Leena, Lia, Jenette and Dave Plasket. They do the behind the scenes work that makes it possible for us to conduct our research. For facilities, I would like to thank Dr. Debrosse in the NMR lab and for helping with some

2D analysis. I would also like to thank Dr. Shivaiah and Sandeep from Dr. Zdilla’s lab for solving several crystal structures for the Melotenine and Sungucine projects (not included in this thesis). During my graduate career I have had the privilege of working with a number of interesting and exceptional people and I would like to take the opportunity to thank them individually.

! #""! I would like to thank the first group members of the Andrade group; we all had a part in turning this young lab into a chemical powerhouse. I convey my special thanks to

Dr. Tapas Paul, the first post doc in the Andrade lab for teaching me some techniques and helping me with the end games in crocacin and strychnine projects.

I want to especially thank Justin Kaplan who kindly and patiently took the time to proofread my thesis. He deserves credit for any coherence in the following pages. I would like to thank the other gang (Chary, Praveen, Senzhi) for taking up these projects and progressing with shining glitters. I thank rest of the current Andrade gang (Bharat,

Ian, Justin, Miseon, Vijay and Gary) for their friendship and support throughout the years. I also want to thank the Andrade group alumni Venkat, Sharon, Natalie for providing me a good experience working with them. Being a part of the Andrade group has been a great honor. The science comes and goes as I hope my contributions here are quickly overshadowed by even greater advances. However, the experiences from the people here is the most valuable part of my education. Although I am sad to be leaving, I am looking forward to the future and will enjoy watching the lab develop during the upcoming years.

I convey my special thanks to my best friend Manasa for all her support throughout the years. At Temple I have learned some of my most valuable lessons from my peers. I would like to express my gratitude to the entire chemistry class that arrived at

Temple chemistry department in the fall of 2006. I would like to specially thank Naresh,

Svitlana and Bo for having good discussions while we were taking courses. I want to thank Goutham Kodali for proving a great deal of guidance during the early years. The lunch club has made last couple of years at Temple my happiest years.

! #"""! I also want to thank my friends Rao, Kavita, Nagesh, Andrew, Gopee, Riley,

Varma, Peng, Hoan, Paul, Conrad, and Matt for their friendship at Temple. I would like to thank the Sieburth and Schafmeister groups for their generosity with reagents, equipment and discussions.

This thesis certainly would not have been possible without the love and encouragement of my family and friends. I must thank the most important people in my life, my family. I am nothing without them. My desire to seek answers for unanswered questions, which eventually drove me to pursue graduate studies in chemistry, was developed when I was very young. I would like to take this opportunity to thank all my childhood teachers. I had the pleasure of attending JNTU for masters and Loyola

Academy for bachelors. Prof. Dubey has encouraged and inspired me in getting a doctoral degree through his lectures on alkaloids chemistry and exciting discussions.

Before I came to Temple, I was fortunate enough to develop some amazing friendships that have withstood the test of time. I would like to thank my best friends Mahesh,

Santosh, Ravi, Pradeep and the crew from Loyola. Over the years, they have always been there to support me, and they have taught me the true meaning of friendship. I would like to thank the Swern fellowship and the Case fellowship committees at department of chemistry, Temple University for selecting me as the award winner for 2009 and 2011 respectively. I would like to thank CST, Temple University for awarding me the 2010 outstanding research by a graduate student award. I also want to thank Cephalon Inc. for awarding me the 2010 Horst Witzel Fellowship and NSF (1111558) for funding our alkaloids project.

! "$! TABLE OF CONTENTS

ABSTRACT...... iii

DEDICATION…………...... v

ACKNOWLEDGMENTS...... vi

LIST OF TABLES...... xv

LIST OF FIGURES...... xvii

LIST OF SCHEMES...... xviii

LIST OF ABBREVIATIONS...... xxiii

CHAPTER

1. SEQUENCING CROSS-METATHESIS (CM) AND NON-METATHESIS REACTIONS TO RAPIDLY ACCESS BUILDING BLOCKS FOR SYNTHESIS

1.1 Introduction...... 1

1.2 Background on tandem CM/non-metathesis reactions ...... 3

1.2.1 CM/...... 5

1.2.2 CM/Allylboration...... 8

1.2.3 CM/Isomerization...... 9

1.2.4 CM/Dihydroxylation...... 10

1.2.5 CM/!-Keto ...... 13

1.2.6 CM/Wittig...... 14

1.2.7 CM/Hydroarylation...... 16

! $! 1.3 Present Study...... 18

1.4 Conclusion……………………….………………………………………….…..…30

2. CONCISE ASYMMETRIC SYNTHESIS OF (+)-CROCACIN C

2.1 Introduction…………………………………………………………...……….....31

2.2 Previous asymmetric syntheses…………………………………..………………32

2.2.1 Rizzacasa’s First and Second-Generation Approaches….….…….……...... 32

2.2.2 Chakraborty’s Approach………………………………………….……...... 36

2.2.3 Dias’s Approach………………………………..…………………..…...….38

2.2.4 Burke’s Approach…………………………………………………...….….41

2.3 Present Study……………………………………………………………….……42

2.4 Conclusion………………………………………………………………………..51

3. CONCISE SYNTHESIS OF THE ABCE TETRACYCLIC FRAMEWORK OF STRYCHNOS ALKALOIDS 3.1 Introduction………………………………………………………………..………52

3.2 Previous approaches……………….………………………….………...…………54

3.2.1 Wenkert’s Approach…………………………..……………………………..55

3.2.2 Natsume’s Approach………………………………………………………...55

3.2.3 Rubiralta’s Approach………………………..……………………………….57

3.2.4 Woodward’s Approach ……………………………….……………………..57

3.2.5 Magnus’s Approach …………………………………….…………………...59

3.2.6 Stork’s Approach ……………………………………………………………59

3.2.7 Overman’s Approach ………………………………………....……………..60

3.2.8 Kuehne’s Approach ………………………………..…..……………………61

! $"! 3.2.9 Rawal’s Approach ……………………….…………………………….……62

3.2.10 Martin’s Approach ……………………………..…………………………..63

3.2.11 Bonjoch and Bosch’s Approach ……………………….…..………………64

3.2.12 Vollhardt’s Approach …………………..………………………………….65

3.2.13 Mori’s Approach …………………………………………………………...67

3.2.14 Bodwell’s Approach ……………………………………………………….68

3.2.15 Shibasaki’s Approach ……………………………………………………...69

3.2.16 Fukuyama’s Approach ……………………………………………………..70

3.2.17 Padwa’s Approach …………………………………………………………71

3.2.18 Vanderwal’s Approach …………………………………………………….72

3.2.19 Reissig’s Approach ………………………………………………………...73

3.2.20 MacMillan’s Approach……………………………………………………..74

3.3 Present Study…………………………….…………………..…………………….75

3.3.1 First Generation……………………………………….….………………….78

3.3.2 Second Generation…………………………………………………………...80

3.3.3 Third Generation……………………………………………………………..82

3.3.4 Fourth Generation……………………………………...…………………….84

3.3.5 Fifth Generation………………………………..…………………………….86

3.4 Conclusion…………………………………………………..…..…………………94

4. CONCISE TOTAL SYNTHESES OF STRYCHNOS ALKALOIDS

4.1 Introduction...... ………………….95

4.2 Background………...... ………………100

! $""! 4.2.1 Akuammicine Total Syntheses…………………………….…………...…..100

4.2.1.1 Overman’s Approach………………………………...…………….100

4.2.1.2 Kuehne’s Approach………………………………...………...…….101

4.2.1.3 Martin’s Approach ………………………………...……...……….103

4.2.1.4 MacMillan’s Approach………………………………...…….…….104

4.2.2 Strychnine Total Synthesis………………………………...…………….....105

4.2.2.1 Woodward’s Approach…………………….. ……………………...105

4.2.2.2 Magnus’s Approach …………………………………….…………108

4.2.2.3 Stork’s Approach ………………………………………………….111

4.2.2.4 Overman’s Approach ………………………………………...... 112

4.2.2.5 Kuehne’s Approach ………………………………..………………114

4.2.2.6 Rawal’s Approach …………………………………………………116

4.2.2.7 Martin’s Approach ………………………………………………...118

4.2.2.8 Bonjoch and Bosch’s Approach ……………….……….………….119

4.2.2.9 Padwa’s Approach …………………………………………………121

4.2.2.10 Vanderwal’s Approach …………………………………………...123

4.2.2.11 MacMillan’s Approach…………………………………………...124

4.3 Present Study...... 126

4.3.1 Akuammicine (racemic)……………………………………………………126

4.3.2 Strychnine (racemic)………………………………………………………..129

4.3.3 (-)-Akuammicine and Leuconicines A and B……………………………...133

4.3.4 (-)-Norfluorocurarine, (-)-dehydrotubifolene, (-)-Dihydroakuammicine, (-)-

tubifolene and (-)-Valparicine……………………………..……………………..140

! $"""! 4.4 Conclusion………………………………………………………………………..143

5. EXPERIMENTAL SECTION…………………………………………………144

REFERENCES………………………………………………………………………...201

BIBLIOGRAPHY……………………………………………………………………..215

APPENDIX…………………………………………………………………………….228

! $"#! LIST OF TABLES

Table 1.1 Tandem CM/Hydrogenation…………………………………………..…..6

Table 1.2 Tandem CM/Hydrogenation/Cyclization, Synthesis of ……..….7

Table 1.3 Tandem CM/Allylboration with various …………………….....8

Table 1.4 Tandem CM/Isomerization for the preparation of methyl ……....10

Table 1.5 Tandem CM/Dihydroxylation by Blechert to prepare vicinal

………………………………………………………………………11

Table 1.6 Tandem CM-Dihydroxylation, Synthesis of Vicinal Diols

(Snapper)………………………………………………………………....12

Table 1.7 Tandem CM/-!Ketohydroxylation to prepare !-Hydroxy

Carbonyls………………………………………………………………...14

Table 1.8 Tandem CM/Wittig for the Synthesis of Dienoic ………….……..15

Table 1.9 CM/Intramolecular Hydroarylation for the Synthesis of

Tetrahydrocarbazoles...... 17

Table 1.10 One-Pot CM/Wittig olefination for the Stereoselective Synthesis of

(2E,4E)- dienoates………………………………………………………..19

Table 1.11 Tandem CM/HWE Olefination for the Stereoselective Synthesis of

(2E,4E)- or (2Z,4E)-dienoates……………………………………..……..21

Table 1.12 One-pot sequential CM/hydride reduction method for the stereoselective

synthesis of primary (E)-allylic alcohols with the Grubbs-II catalyst

(2)……………………………………………………………………...…24

! $#! Table 1.13 One-pot sequential CM/hydride reduction method for the stereoselective

synthesis of primary (E)-allylic alcohols with the Hoveyda-Grubbs-II

Catalyst (4)……………………………………………………………….25

Table 1.14 Sequential CM/Evans aldol reaction for the asymmetric synthesis of

unsaturated propionate aldols with 5 mol% Grubbs-II catalyst (2)……...27

Table 1.15 Sequential CM/Brown allyl- or Roush (E)-crotylation reactions for the

asymmetric synthesis of homoallylic alcohols with 5 mol% Grubbs-II

catalyst (2)………………………………………………………………..29

Table 4.2 Summary of strychnine syntheses………………………………………..98

Table 4.3 Summary of akuammicine syntheses………………………………….…99

Table A1 Summary of Structure Determination of Compound 363………………230

Table A2 Refined Positional Parameters for Compound 363……………………..232

Table A3 Positional Parameters for in Compound 363……………….233

Table A4 Refined Thermal Parameters for Compound 363………………………234

Table A5 Bond Distances in Compound 363……………………………………..236

Table A6 Bond Angles in Compound 363………………………………………...237

Table A7 Crystal data and structure refinement for 352…………………………..241

Table A8 Atomic coordinates and equivalent isotropic displacement parameters for

352………………………………………………………………………242

Table A9 Bond lengths [Å] and angles [°] for 352………………………………..244

Table A10 Anisotropic displacement parameters for 352………………………….247

Table A11 Coordinates and isotropic displacement parameters for 352…………..249

Table A12 bonds for 352………………………………………………..251

! $#"! LIST OF FIGURES

Figure 1.1 Catalysts used for Metathesis Reactions in common…………………...…2

Figure 1.2 Grubbs Classification of the Olefins for Cross-Metathesis Reaction……..4

Figure 2.1. Structures of (+)-Crocacins A-D………………………………………....31

Figure 3.1 Selected representative Strychnos alkaloids……………………………..53

Figure 3.2 Degradation of strychnine………………………………………………..75

Figure 4.1 Structures of Strychnine and Akuammicine……………………………..95

Figure A1 ORTEP drawing of title compound with 30% probability thermal

ellipsoids……………………………………………………………….230

! $#""! LIST OF SCHEMES

Scheme 1.1 Routes to primary (E)-allylic alcohols: (a) traditional; (b) CM………….23

Scheme 2.1 Rizzacasa’s First-generation Synthesis of (+)-Crocacin C (142)……….34

Scheme 2.2 Rizzacasa’s Second-generation Synthesis of (+)-Crocacin C (142)…….36

Scheme 2.3 Chakraborty’s Synthesis of (+)-Crocacin C (142)……………………….37

Scheme 2.4 Dias’s Synthesis of (+)-Crocacin C (142)………………………………..40

Scheme 2.5 Burke’s Synthesis of (+)-Crocacin C (142)……………………………...41

Scheme 2.6 First-generation retrosynthesis of 142…………………………………...43

Scheme 2.7 Synthesis of aldehyde 196…………………………………………...…..44

Scheme 2.8 Double asymmetric crotylboration reaction with aldehyde 196…………45

Scheme 2.9 Structural assignment of 199 and 200 via 13C acetonide

analysis…………………………………………………………………...46

Scheme 2.10 Second-generation retrosynthesis of 142………………………...………47

Scheme 2.11 Evans Dipropionate Aldol Reaction with 194……………………….…..48

Scheme 2.12. 13C NMR acetonide analysis of 204…………………………….…..49

Scheme 2.13 Synthesis of 155…………………………………………………49

Scheme 2.14 Completion of the Synthesis………………………………………….….50

Scheme 3.1 Wenkert’s cyclization of "-acyl derivative…………………..…55

Scheme 3.2 Natsume’s bis-cyclization strategy for Aspidosperma alkaloids………...56

Scheme 3.3 Rubiralta’s cyclization in Aspidospermidine synthesis………………….57

Scheme 3.4 Woodward’s Pictet-Spengler Approach…………………………………58

Scheme 3.5 Magnus’ transannular oxidative cyclization……………………………..59

Scheme 3.6 Stork’s skeletal rearrangement polycyclization……………………….…60

! $#"""! Scheme 3.7 Overman’s aza-Cope-Mannich rearrangement…………………………..61

Scheme 3.8 Kuehne’s Mannich-[3,3]sigmatropic rearrangement…………………….62

Scheme 3.9 Rawal’s Diels-Alder approach for the ABCE tetracycle……………..….63

Scheme 3.10 Martin’s skeletal rearrangement…………………………………………64

Scheme 3.11 Bonjoch-Bosch reductive Heck cyclization………………………….…..65

Scheme 3.12 Vollhardt’s Co-mediated [2+2+2] ………………………...66

Scheme 3.13 Mori’s catalyzed key cyclizations…………………………….67

Scheme 3.14 Bodwell’s IEDDA reaction strategy………………………………….….68

Scheme 3.15 Shibasaki’s transannular cyclization strategy………………………...….69

Scheme 3.16 Fukuyama’s transannular cyclization by deprotection of Ns group……..70

Scheme 3.17 Padwa’s intramolecular Diels-Alder rearrangement…………………..…71

Scheme 3.18 Vanderwal’s formal cyclo addition of Zincke aldehyde………………....72

Scheme 3.19 Reissig’s samarium diiodide mediated cascade strategy……………...…73

Scheme 3.20 MacMillan’s cascade strategy……………………………….…74

Scheme 3.21 Conversion of isostrychnie to strychnine…………………………….…..75

Scheme 3.22 Conversion of Wieland-Gumlich aldehyde to strychnine………………..76

Scheme 3.23 Rawal’s intramolecular Heck cyclization for D-ring closure……………77

Scheme 3.24 Corey’s inspiring polycyclization strategies……………………………..78

Scheme 3.25 Proposed mechanism for Corey’s cyclization…………………………....78

Scheme 3.26 First-generation retrosynthesis…………………………………………...79

Scheme 3.27 First-generation forward synthesis……………………………………....79

Scheme 3.28 Second-generation retrosynthesis………………………………………..80

Scheme 3.29 Second-generation forward synthesis………………………………...….81

! $"$! Scheme 3.30 Jacobsen activation of the using ………………….82

Scheme 3.31 Weinreb’s intramolecular spirocyclization via tethered allyl

trimethylsilane…………………………………………………………....83

Scheme 3.32 Third-generation retrosynthesis…………………………………...……..83

Scheme 3.33 Third-generation forward synthesis…………………………………...…84

Scheme 3.34 Nakagawa’s usage of nitrone in the cyclization…………………………85

Scheme 3.35 Fourth-generation retrosynthesis………………………………………...85

Scheme 3.36 Fourth-generation forward synthesis………………………………...…..86

Scheme 3.37 Magnus and Heathcock spirocyclizations………………………………..87

Scheme 3.38 Fifth-generation retrosynthesis…………………………………………..88

Scheme 3.39 Fifth-generation synthesis of spiroindolinine…………………………....89

Scheme 3.40 Synthesis of enoate-tethered spiroindolinine…………………………….91

Scheme 3.41 Novel intramolecular aza-Baylis-Hillman reaction to close the E-ring….91

Scheme 3.42 Sequential One-Pot Synthesis of Tetracycle 363………………………...93

Scheme 4.1 Proposed of strychnine……………………………………..97

Scheme 4.2 Overman’s synthesis of akuammicine……………………………….…100

Scheme 4.3 Kuehne’s synthesis of akuammicine……………………………………102

Scheme 4.4 Martin’s biomimetic synthesis of akuammicine………………………..103

Scheme 4.5 MacMillan’s organocascade approach to akuammicine………………..105

Scheme 4.7 Woodward’s landmark synthesis of strychnine………………………...106

Scheme 4.7 Second reported total synthesis of strychnine by Magnus……………...109

Scheme 4.8 Total synthesis of strychnine by Magnus……………………………….110

Scheme 4.9 Stork’s total synthesis of strychnine…………………………………....111

! $$! Scheme 4.10 Overman’s first enantioselective total synthesis of (-)-strychnine……..113

Scheme 4.11 Kuehne’s asymmetric total synthesis of strychnine………………….....115

Scheme 4.12 Rawal’s total synthesis of strychnine…………………………………...117

Scheme 4.13 Martin’s biomimetic formal synthesis of strychnine…………………...118

Scheme 4.14 Bonjoch and Bosch’s total synthesis of strychnine…………………..…120

Scheme 4.15 Padwa’s total synthesis of strychnine…………………………………..122

Scheme 4.16 Vanderwal’s concise total synthesis of strychnine………………..……123

Scheme 4.17 MacMillan’s catalytic asymmetric total synthesis of

strychnine…………………………………………………………….…124

Scheme 4.18 Retrosynthetic analysis of racemic akuammicine…………………...….126

Scheme 4.19 Synthesis of tetracycle using vinylogous Mannich reaction……………127

Scheme 4.20 Endgame for racemic total synthesis of akuammicine………………....128

Scheme 4.21 Retrosynthetic analysis for total synthesis racemic strychnine………....130

Scheme 4.22 Tetracycle 462 from vinylogous Mannich and bis-cyclization

reactions………………………………………………………………...131

Scheme 4.23 Endgame for strychnine via Wieland-Gumlich aldehyde……………....132

Scheme 4.24 Retrosynthetic analysis for total synthesis of (-)- akuammicine………..134

Scheme 4.25 Synthesis of chiral bromoacetamide using asymmetric allylation……...135

Scheme 4.26 Endgame for total synthesis of (-)-akuammicine……………………….136

Scheme 4.27 Retrosynthetic analysis of leuconicines………………………………..137

Scheme 4.28 Total synthesis of (-)-leuconicines………………………………….....138

Scheme 4.29 Total synthesis of (-)-norfluorocurarine and (-)-dehydrotubifoline…….140

Scheme 4.30 Total synthesis of (-)-dihydroakuammicine and (-)-tubifoline………....141

! $$"! Scheme 4.31 Total synthesis of (-)-valparicine……………………………………….142

! $$""! LIST OF ABBREVIATIONS

9-BBN 9-Borabicyclo(3.3.1)nonane

Å Angstrom

Ac Acetyl

Ac2O

Acac acetylacetonate

AcCl Acetyl chloride

ACECl 1-Chloroethyl

AcOH Acetic

AgOTf trifluoromethanesulfonate aq aqueous

BF3.OEt2 trifluoride etherate

Bn benzyl

Boc tert-Butoxycarbonyl

Bu3P Tributylphosphine

BuLi Butllithium

Bz benzoyl

Calc’d calculated

CbzCl benzyloxycarbonyl chloride

CDCl3 -d

CH2Cl2 Chloride

CHCl3 Chloroform

! $$"""! CM cross-metathesis

CO carbonmonoxide

CO2 dioxide

CSA camphorsufonic acid

CuCl2 chloride d doublet

D2O deuterium oxide

DABCO 1,4-diazabicyclo[2.2.2]octane

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCE 1,1-dichloroethane

DCM dd doublet of doublet

DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DIBAL-H diisobutylaluminum hydride

DIPT diisopropyl tartrate

DMAP N,N-4-dimethylaminopyridine

DMB m-dimethoxybenzene

DMF N,N-

DMPU N,N-dimethyl propylene

DMSO dimethylsulfoxide dppp 1,3-bis(diphenylphosphino)propane dr diastereomeric ratio

DTBMP 2,6-di-tert-butyl-4-methylpyridine

! $$"#! EDA ethyl diazoacetate ee

EM ethoxymethyl

Equiv equivalent

Et2O diethyl

Et3N

EtOAc ethyl acetate

EtOH

FAB fast atomic bombardment

FTIR fourier transform infrared g gram

G-I Grubbs-I

G-II Grubbs-II h hours (length of reaction time)

H2 hydrogen

H2O water

H2O2

H2SO4

HBr hydrobromic acid

HCl hydrochloric acid

HF hydrofluoric acid

HG Hoveyda-Grubbs

HI hydroiodic acid

! $$#! HMPA hexamethylphosphoramide

HR-MS high resolution mass spectrometry

HWE Horner-Wadsworth-Emmons

Hz hertz

IABH intra-molecular aza Baylis Hillman

IEDDA inverse electron demand diels alder

Ipc isopinocamphenyl

IR infrared spectroscopy

J coupling constant

KH potassium hydride

KHMDS potassium bis()

KOH potassium

LC-MS liquid chromatography mass spectrometry

LDA diisopropylamide

LHMDS lithium bis(trimethylsilyl)amide mmol milli mol

LiCl lithium chloride

LiOH lithium hydroxide

M molar m-CPBA meta chloroperbenzoic acid

Me methyl

MeCN

MeI methyl iodide

! $$#"! MeOH mg milli gram

MgSO4 sulfate

MHz mega hertz min minutes mL milli liters mmol milli moles

MnCl2 manganese chloride mol moles

MOM methoxymethyl m.p

MsCl methanesulfonyl chloride

MVK methyl vinyl

N normal

Na

Na2SO4 sodium sulfate

NaBH4 sodium

NaH

NaHCO3 sodium bicarbonate

NaOMe sodium methoxide

NH3

NH4Cl chloride

Ni

! $$#""! NiCl2 nickel chloride

NMP N-methyl-2-pyrrolidinone

NMR nuclear magnetic

Ns 2-nitrobenzenesulfony

O3

P phosphorus

Pd palladium

Ph phenyl

PMB p-methoxybenzyl

PPh3 triphenyl ppm parts per million

PPTS pyridinium p-toluenesulfonate

RCM ring closing metathesis rf retention factor

ROM ring opening metathesis

ROMP ring opening metathesis rt room temperature

S singlet

SN2 secondary nucleophilic substitution t triplet

TBA tribromo

TBAF tetra-n-butylammonium fluoride

TBAI tetra-n-butylammonium iodide

! $$#"""! TBDMS t-butyldimethylsilyl

TBDPS t-butyldiphenylsilyl

TBS t-butyldimethylsilyl

Tf2O trifluoromethanesulfonyl anhydride

TFA trifluoroacetic acid

TFAA trifluoroacetic anhydride

TfOH trifluoromethanesulfonic acid

TFP tris(2-furyl)phosphine

THF

TiCl4

TIPS triisopropylsilyl

TLC thin layer chromatography

TMS trimethylsilyl

TPAP tetra-n-propylammonium perruthenate

TsCl p-toluenesulfonyl chloride

W-G Weiland Gumlich

Zn zinc

! $$"$! CHAPTER 1: SEQUENCING CROSS-METATHESIS (CM) AND NON-

METATHESIS REACTIONS TO RAPIDLY ACCESS BUILDING BLOCKS FOR

SYNTHESIS.

1.1 Introduction

Current and synthetic methodology are driven by the need to maximize the efficiency (i.e., atom,1 step,2 redox3 economy) and selectivity (e.g., chemo-, regio-, stereo-)4 by which are prepared. Syntheses that employ tandem

(sequential, ideally one-pot) operations5 or domino (cascade) reactions6 address this need.

Tandem reactions encompass those reactions that occur in a specific order or involve sequential addition of reagents to give specified products. Many selective methods have been developed which allow preparation of complex molecules with excellent regio-, chemo-, diastereo-, and enantioselectivity. In the current age of organic synthesis, it is not only a question of what we can synthesize, but also how we do it. A major issue in chemical production is waste handling; thus, the development of procedures that are environmentally friendly and that increase efficiency are highly sought.

Solutions to these problems would not only be favorable to the environment, but also reduces the production cost. Organic molecules are typically prepared by the stepwise formation of individual bonds. Naturally, it would be more efficient to form multiple bonds in a single sequence without isolating intermediates, changing the reaction conditions or adding the next reagents. We call this type of transformation a “domino reaction”. These reactions are powerful due to the bond forming efficiency (atom

1 economy), increase in structure complexity (structure economy) and suitablity for general applications.

The advent of defined metal catalysts in the 1990’s (Figure 1.1) for the efficient metathesis of olefinic bonds revolutionized the way synthetic organic chemists think about assembling the . For this reason, the 2005 Nobel Prize in Chemistry was awarded to Professors Yves Chauvin, Robert H. Grubbs, and Richard Schrock.

MesN NMes PCy3 Cl Cl Ru Ru Cl Ph Cl Ph PCy3 PCy3 Grubbs-I (1) Grubbs-II (2)

MesN NMes PCy3 MesN NMes Cl Cl Ru Ru Cl Cl Cl Ru Me Cl O O PCy3 i-Pr i-Pr Me Hoveyda-Grubbs-I (3) Hoveyda-Grubbs-II (4) Vinylidine Grubbs-II (5)

Figure 1.1 Catalysts used for Metathesis Reactions in common

While a greater part of the 1990’s was characterized by the robust !,"- ring- closing metathesis (RCM) reaction, the less-often used intermolecular variant of the reaction, namely olefin cross-metathesis (CM), lay dormant until the introduction of more powerful catalysts in the late 1990’s. Consequently, the current decade has been characterized by the abundant application of CM in various contexts, including complex total synthesis.7

Throughout this chapter, the term “tandem” refers to two or more reactions (i.e., one after the other) combined in a single synthetic operation without isolating intermediates.6

2 This chapter covers the relevant tandem CM/non metathesis reactions developed to date and will discuss the methods developed in the Andrade laboratory in which I was involved.

1.2 Background on tandem CM/non-metathesis reactions

Olefin cross metathesis has emerged as a powerful, operationally simple method for the stereo selective preparation of carbon-carbon double bonds in high yield, particularly when coupling terminal (!-olefins) and electron-deficient or sterically bulky olefins. The realization of this method is due in large part to catalysts such as Grubbs 2nd generation catalyst (2) and the Hoveyda-Grubbs 2nd generation catalyst (4) (Figure 1.1).

In 2003, Grubbs and co-workers systematically classified the various olefinic substrates into four different types according to the catalyst used (Figure 1.2).9 In order to avoid a statistical mixture of coupled products, it is best to react a Type I with either a Type II or

III in order to achieve maximum synthetic efficiency.

The geometry of the double bond is typically trans (>20:1 E/Z) when electron- deficient olefins (e.g., crotonaldehyde, MVK, ) are used as Type II partners. Bulky Type II olefins in addition can be coupled with Type I partners and also approach high E:Z selectivities. These classifications have served to guide the development of novel applications of CM and broaden the scope of this powerful technology. The development of sequential one-pot or tandem reaction sequences is driven by the need to streamline linear synthetic processes.10

3 This often translates into an increase in overall product yield resulting from the elimination of intermediary purification steps, which are both time-consuming and expensive, particularly when chromatography is required.

Various types of olefins that react with and their substrates. Olefin Type Substrates

!-olefins; 1o allylic Type I alcohols; ; allyl (fast homodimerization) silanes &

and derivatives; Type II vinyl ketones/; (slow homodimerization) 2o/3o unprotected allylic alcohols

1,1-disubstituted olefins; Type III non-bulky trisubstituted olefins; (no homodimerization) 4o allylic substrates

Type IV vinyl nitro olefins; (spectator) 3o protected allylic alcohols

Figure 1.2 Grubbs Classification of the Olefins for Cross-Metathesis Reaction

In order to maximize chemical yield, all reactions in the tandem (or one-pot) sequence should ideally be clean and efficient with an emphasis on the first. CM under the aforementioned regime (Type I plus Type II or III) fulfills this requirement.

4 In the area of metathesis chemistry, the recently developed tandem catalysis links metathesis steps (CM, ROM, RCM, EM, ROMP) with one another or with various non- metathetical transformations aiming at constructing a diversity of structural motifs in a one pot procedure and in the presence of only metathesis catalyst.6 The exceptional achievements in coupled with non-metathesis reactions during the last decade include hydrogenation, isomerization, cycloisomerization, , atom transfer addition, atom transfer radical polymerization among others. Grubbs and co-workers launched the first sequential CM/non-CM method in 2001.11 The Andrade lab and others have focused efforts on sequencing CM with other non-CM reactions in order to maximize efficiency.6 Modern synthetic has matured to a point that virtually any complex molecular structure can be synthesized given enough time, effort and personnel. Currently, there is a high premium placed on the efficiency of a synthesis. Tactics such as avoiding steps (i.e., interconversion) and protecting groups altogether are gaining popularity. Metathesis in this regard is an enabling method for achieving such goals.

1.2.1 CM/Hydrogenation

The first tandem CM/non-CM method was reported in 2001 by Grubbs and

Bielawski wherein olefin metathesis was followed by hydrogenation, which was effected by a single catalyst.11 The tandem process mediated by one catalyst, termed tandem catalysis, was a testament to the efficiency of these -mediated processes (Table

1.1). Addition of H2 to Grubbs I (1) catalyst afforded the hydride complex

RuCl(H2)(PCy3)2 quantitatively, an effective hydrogenation catalyst.

5 The same Ru hydride complex was observed upon introducing the hydrogen gas following a CM reaction. The CM reaction was performed at 40 °C in dichloroethane

(DCE) using catalyst 1 or 2. Upon completion of CM, the reaction vessel was pressurized with H2 gas and then heated to 70 °C. The yields were synthetically useful and in addition, the catalyst did not facilitate the dehydrohalogenation of halides (entry 4), which is a common drawback in many hydrogenation reactions.

Table 1.1 Tandem CM/Hydrogenation

Grubbs-I (1) or Grubbs-II (2) (3 mol%) Hydrogen Gas R R R + 2 R2 2 1 R1 R1 (2 equiv.) ClCH2CH2Cl ClCH2CH2Cl reflux, 40 °C not isolated reflux, 70 °C

Entry Substrates Metathesis Product Tandem Product (% Conversion)a (% Yield)b

O 1 AcO AcO AcO 3 3 O O 6 7 8 (85%) 9 (77%)

AcO AcO 2 AcO OAc Ph Ph Ph 10 11 12 (90%) 13 (82%) O O O

3

14 7 15 (85%) 16 (80%) O O O

4 Cl Cl Cl 17 7 18 (92%) 19 (69%)

a Determined by GC. b Isolated yield based on starting material.

6 Overall, this one-pot tandem Ru-catalyzed CM/hydrogenation approach is much more convenient than the standard procedures where Pd- or Rh-catalyzed hydrogenation are employed after isolating the CM product. In 2003, Cossy and co-workers disclosed a tandem CM/Hydrogenation/Cyclization method using compatible catalysts (Table 1.2).12

Table 1.2 Tandem CM/Hydrogenation/Cyclization, Synthesis of Lactones

Hoveyda O O O OH O Grubbs II OH PtO /H (4) OH R 2 2 OH R O O R1 + R R R or 1 1 R R2 n R n n 1 R1 2 R2 n R2 R2 n R = H or OH

Entry Unsaturated Alcohol Saturated alcohol (% Yield) (% Yield)

O OH OH 1 O n-Hex n-Hex n-Hex 20 21 (66%) 22 (-) OH OH OH O 2 Ph Ph Ph 23 24 (56%) 25 (-) O OH OH O 3

26 27 (57%) 28 (6%) OH OH OH O 4

29 30 (42%) 31 (-)

The CM reaction was effected in presence of Hoveyda-Grubbs II catalyst (4); once the CM reaction was completed, catalytic Pt2O was added in addition to an H2 balloon.

7 Table 1.2 shows the preparation of both #- and $-lactones from allylic and homoallylic alcohols respectively in modest to good yields.12

1.2.2 CM/Allylboration

The allylation of aldehydes with allylboron reagents is an excellent method for the stereoselective synthesis of homo-allylic alcohols and is widely used in synthesis.13

Pioneering research from Hoffmann and later Brown and Roush on the asymmetric allyl- and crotylboration of aldehydes provided a robust alternative to the acetate and propionate aldol reaction.

Table 1.3 Tandem CM/Allylboration with various aldehydes

Hoveyda O Grubbs-II (4) O OH B (5 mol%) B PhCHO + R1 Ph O CH Cl O 2 2 R 32 reflux, 40 °C R1 Allylboration 1 not isolated

Entry Substrates Product Yield (anti:syn)a

OH 60% (4.7:1) 1 BnO OBn Ph

33 B n O 34 OH

Ph 2 68% (>20:1) O O 35 36 OH

Ph 3 60% (>20:1) Br Br 37 38 OH

Ph 58% (>20:1) 4 OH OH 39 40

a Determined by means of 1H NMR spectroscopy 8

These reactions are often high-yielding, in addition to being enantio- and diastereoselective, resulting in stereodefined homoallylic alcohols.14 The availability of functionalized allylboron reagents, however, has remained limited for decades. With the advent of CM reactions, a novel route to functionalized allyl boronates was realized. In this context, Goldberg and Grubbs reported15 a one-pot CM/allylboration sequence that affords densely functionalized homoallylic alcohols (Table 1.3). Pinacol allylboronate

(32) was subjected to the CM reaction with Hoveyda-Grubbs II (4) catalyst and styrenyl or hindered terminal olefins in refluxing CH2Cl2. Once the CM reaction was completed, the aldehyde was added at room temperature. The yields were good and anti:syn diastereoselectivities excellent for this process.

1.2.3 CM/Isomerization

In 2006, Snapper and co-workers reported a tandem process in which a single ruthenium complex was used to achieve olefin CM then heated to catalyze olefin isomerization/tautomerization.16 Using (Z)-hex-3-ene-2,5-diol (41) as the coupling partner, the CM/isomerization method resulted in the formation of various methyl ketones in a single pot operation. The sequence first results in an E-allylic alcohol from the CM reaction, which is further isomerized to the that tautomerizes to the ketone.

To avoid oligomerization during the CM process with 41, slow addition of catalyst was necessary.16

9 Table 1.4 Tandem CM/Isomerization for the preparation of methyl ketones

Hoveyda Grubbs-II (4) OH O (0.5 mol%) 200 °C HO OH + R 1 R Me R Me CH2Cl2, rt 1 6.5 h 1 41 (3 equiv) not isolated

Entry Substrates Product %Yield

O 1 BnO BnO 57 5 5 Me 42 43

OTBS OTBS O 2 69 Ph Ph Me 44 45 O O Me 3 51 O 46 47

O O O 69 N N Me 4 3 3 O 48 O 49

1.2.4 CM/Dihydroxylation

A variety of Ru sources, such as RuCl3, RuO2, RuCl2(dppp)2, Ru(acac)3, TPAP and

Ru/C have been used for making the oxidative species RuO4 in different oxidation reactions17. The method of choice for dihydroxylating the olefins is in situ generation

18 from a catalytic amount of RuCl3 H2O using NaIO4 as the stoichiometric oxidant . In

2006, Blechert and co-workers employed a ruthenium for the first time to effect the tandem CM/Dihydroxylation process.19

10 Table 1.5 Tandem CM/Dihydroxylation by Blechert to prepare vicinal diols

Hoveyda Grubbs-II (4) NaIO4 OH YbCl .6H O (3 mol%) 3 2 R + R R2 2 R1 2 R R1 CH Cl EtOAc, 2 2 OH (2 equiv) reflux not isolated MeCN, H2O

Entry Olefin 1 Olefin 2 Product % Yield

OH O O 50 1 NsHN NsHN OMe OEt 50 51 52 OH

OH 2 AcO CN AcO CN 46 4 4 OH 53 54 55

O OH O AcO 56 3 AcO OMe 4 OEt 4 53 51 56 OH

The choice of solvent for dihydroxylation reaction was critical and when a 3:3:1 mixture of MeCN/EtOAc/H2O was used, a rapid cis-dihydroxylation of olefins was observed. Brønsted and particularly Lewis acids were found to further accelerate the rate of and minimize side reactions such as over-oxidation. A typical tandem procedure for CM/dihydroxylation starts with refluxing the CM partners in

CH2Cl2 with 3 mol% of Hoveyda-Grubbs II (4) catalyst. Once the CM reaction was over, the solvent was evaporated and was treated with the dihydroxylating reagents in a suitable mixture of solvents to give the appropriate cis-dihydroxylated product in a synthetically useful yield.19

11 20 Pleitker and co-workers have recently described a RuCl3 catalyzed dihydroxylation of double bonds. The treatment of an olefin with RuCl3 and NaIO4 in the presence of either a Brønsted or Lewis acid realized the desired cis-diols in good yields.

Inspired by these findings, Snapper and co-workers developed a tandem

21 CM/Dihydroxylation in 2006. The olefin partners were stirred in refluxing CH2Cl2 with

5 mol% of Grubbs II (2) catalyst until the CM reaction was finished.

Table 1.6 Tandem CM-Dihydroxylation, Synthesis of Vicinal Diols (Snapper)

Grubbs-II (1) OH CeCl , NaIO (5 mol%) 3 4 R + R R2 2 R1 2 R R1 CH Cl EtOAc, 2 2 OH (2 equiv) reflux not isolated MeCN, H2O

Entry Olefin 1 Olefin 2 Product % Yield

OH O O 77 1 OMe OMe OH 57 58 59 OH

Cl Cl 42 2 Cl OH 14 60 61

O OH O AcO 76 3 AcO OMe 4 OMe 4 HO 53 M e 62 63

At this stage the solvent was removed by evaporation and the CM product was added to a freshly prepared dihydroxylating reagent mix in another reaction vessel.

12 The above table shows the scope of this method. Cyclic, acyclic, aromatic olefins were treated with electron deficient and sequenced with the dihydroxylation reaction. Entries from Table 1.6 shows some representative examples covered in this method.

1.2.5 CM/!-Keto Hydroxylation

Plietker and co-workers reported RuCl3-catalyzed oxidations of olefins to produce

!-hydroxy ketones.20 Using this transformation, Snapper and co-workers developed a tandem CM-!-ketohydroxylation reaction in 2006.21 CM reaction partners were stirred at room temperature using 10 mol% of Grubbs II (2) catalyst until the CM is finished, then the solvent and the excess CM partner were removed in vacuo and was treated with the oxidants in an appropriate mixture of solvents to access the relevant !-ketohydroxylation products in good yields.

The of the oxidation was generally low and it was proposed that the mixtures were observed due to a selective oxidation followed by an isomerization of the resulting %-keto esters under these reaction conditions. This hypothesis was supported by a control experiment wherein purified %-keto was shown to equilibrate with the corresponding regioisomer under the basic oxidation conditions. On the other hand, the trisubstituted olefins afford the !-hydroxy ketone products with high selectivity.21

13

Table 1.7 Tandem CM/!-Ketohydroxylation to prepare !-Hydroxy Carbonyls

Oxone, Grubbs-II (1) O OH (10 mol%) NaHCO3 R R2 R R + R2 2 + 2 1 R R1 R1 CH2Cl2 EtOAc, OH O (2 equiv) not isolated MeCN, H2O

Entry Olefin 1 Olefin 2 Product % Yield (regioselectivity)

O O O AcO 1 AcO OMe 56 (1.5:1) 4 OMe 4 53 58 64 OH O O O OMe 2 OMe 56 (2:1) OH 57 58 65 O O O OMe 3 OMe 49 HO Me Me 57 62 66 O

4 Cl Cl Cl 47 OH 14 60 67

1.2.6 CM/

Over the past decade, metal-catalyzed or “-free” Wittig olefination reactions have gained interest as an alternative approach to classic -mediated Wittig olefinations.22 In 1998, Fujimura and Honma, who used Ru catalyzed version of Wittig

23 reaction, demonstrated that ethyl diazoacetate (EDA) and PPh3 in the presence of substoichiometric amouts of RuCl2(PPh3)3 couple to give a phosphonium , capable of olefinating aldehydes. Since then, several alternative Ru catalysts have been developed to carry out this kind of transformation.

14 Table 1.8 Tandem CM/Wittig for the Synthesis of Dienoic Esters

Catalyst (4 or 5) (5 mol%) PPh3 (2 equiv) CO Et R + CHO CHO 2 R R CH Cl R 2 2 Ethyl Diazoacetate R1 1 reflux R1 not isolated (3 equiv)

Entry Olefin 1 Olefin 2 Product % Yield

1 TBSO CHO TBSO CO2Et 8 75 8 68 M e 69 M e 70

BnO CHO 2 BnO CO2Et 72 5 5 71 M e 69 M e 72

3 CHO CO t-Bu 59 n-Hex n-Hex 2 73 74 75

CHO 4 CO2Et 65 76 74 77

Snapper and co-workers22 disclosed the tandem CM/Wittig reaction in 2007 using

Ru-metathesis catalyst (5). Synthetically useful !,%,#,$-unsaturated carbonyl compounds were prepared using their method. The terminal olefins were subjected to the CM conditions in refluxing CH2Cl2 with catalysts either 4 or 5 to access precursor to the

Wittig reaction. Then the solvent and the excess olefinic starting material were evaporated and the product was subjected to Wittig olefination conditions with ethyl diazoacetate (EDC) to access the !,%,#,$-dienoic esters in synthetically useful yields and good selectivity. Along these lines, a related Horner-Wadsworth-Emmons olefination has also been developed in a one-pot operation.

15

1.2.7 CM/Hydroarylation

In 2008, a one-pot CM/intramolecular hydroarylation reaction was developed by

Xiao and co-workers.23 The CM and hydroarylation reactions were catalyzed by a single

Ru catalyst to access diverse and structurally complex tetrahydrocarbazoles. These heterocycles constitute an important class of alkaloid natural products. The Ru alkylidine catalyzed the CM reaction of "-indolyl alkenes with electron-deficient olefins to produce the -fused . The authors propose that the Ru species derived from the catalyst would catalyze not only the CM reaction, but also the intramolecular hydroarylation due to its Lewis acidity.

The authors provided experimental evidence with a control experiment23 wherein they perform the reaction with the CM product and starting material having the Ru catalyst and no catalyst. The reaction worked only when it had the catalyst, suggesting the generation of Lewis acid Ru complex within the reaction. A typical procedure involves stirring the indole containing olefin and an electron deficient CM reaction partner in refluxing dichloroethane with 5 mol% of Hoveyda-Grubbs II (4) catalyst for

30-90 min, evaporate the solvent and purify the product using column purification.

The table 1.9 shows the scope of this one-pot protocol to access the complex tetrahydrocarbazoles with synthetically useful yields.23

16

Table 1.9 CM/Intramolecular Hydroarylation for the Synthesis of Tetrahydrocarbazoles

Hoveda EWG EWG Grubbs-II (4) (5 mol%) R R2 + EWG 2 R2 N (5 equiv) ClCH2CH2Cl N N reflux R R1 not isolated 1 R1

Entry Olefin 1 Olefin 2 Product % Yield

CHO

1 CHO 82 N H 77 78 N 79 H CHO Cl 2 Cl

CHO 86 N 80 78 N 81 Me Me COMe

O 3 98 N 82 7 N 83 Me Me CO2Et

O 4 95 N OEt N Me 82 51 84 Me

17 1.3 Present Study

1.3.1 Sequential one-pot CM/Phosphorus-based olefination

The synthesis of stereodefined 2,4-dienoates generally involves the repetitive olefination of aldehydes using stabilized Wittig24 or Horner-Wadsworth-Emmons

(HWE)25 reaction conditions. Due to the inefficient redox manipulations in this process to access key 2-enal intermediates for couplings, it is not the best way to consider. While vinylogous phosphonates26 and the chemoselective CM reaction between terminal olefins and 2,4-dienoates27,28 address synthetic inefficiency to a certain extent, these reagents must be prepared in a stepwise manner with intermediary purification.

We reported a convenient and efficient alternative method that employs only commercially available reagents for the rapid assembly of either (2E,4E)- or (2Z,4E)- dienoates by modifying the second olefination step. The one-pot CM/Wittig olefination sequence is summarized in Table 1.10. A variety of terminal alkenes were prepared and subjected to CM using 5 mol% Grubbs-II (2) and crotonaldehyde in refluxing dichloromethane to effect the first cross-metathesis step. It was determined that refluxing the olefin with an excess (3.0 equiv) of crotonaldehyde for 3 h was the optimal protocol.

18 Table 1.10 One-Pot CM/Wittig olefination for the Stereoselective Synthesis of (2E,4E)- dienoates

R1

2 Ph3P CO2R Grubbs-II (2) 85: R1=H; R2=Me 1 2 2 + CHO (5 mol%) CHO 86: R =Me; R =Et CO2R R Me R R CH Cl CH Cl 1 (3 equiv.) 2 2 2 2 R reflux, 3 h not isolated 0 °C!rt!reflux >20/1 E/Z

a,b Entry Olefin Phosphorane Product Yield (ratio: 2E/2Z)c

1 TBSO 85 TBSO CO2Me 77% (9:1)

87 88

2 CO2Me 57% (9:1) MeO2C 85 MeO2C 89 90

BzO CO Me 60% (8:1) 3 BzO 85 2

91 92

73% (9:1) 4 85 CO2Me

93 94

CO2Me 48% (11:1) 5 85 95 14

CO2Et 50% (5:1) 6 MeO2C 86 MeO2C 96 97 Me

a Yields refer to the average of two runs. b Isolated yield of separable E/Z mixture. c Ratio determined by 1H NMR.

The reaction mixture was then cooled to 0 °C, reacted with a slight excess of phosphorane 85 and subsequently warmed to room temperature. While screening conditions for the second step, it was found that equimolar phosphorane (3.0 equiv) did not result in higher product yields and 1.2 equivalents of either 85 or 86 would be sufficient.

19 The hypothesis that excess crotonaldehyde had decomposed over the course of the reaction was supported by the fact that very little methyl sorbate (the byproduct of the

Wittig reaction and crotonaldehyde) was isolated from the reaction mixture when three equivalents of 85 were used. Yields as high as 77% (entry 1) were realized with this procedure, corresponding to an average of 88% per step. Upon adding phosphorane 85, the solution was warmed to room temperature and stirred overnight (12 h). Entry 6 in

Table 1.10 required reflux due to the hindered nature of phosphorane 86.

All reactions delivered good yields of dienoates 88-97 with entry 6 affording a trisubstituted (2E,4E)-dienoate. The E/Z geometric isomers were separable by chromatography. Since it is known that stabilized phosphoranes are stereoselective for the E isomer in the Wittig reaction, we turned our attention to the Horner-Wadsworth-

Emmons (HWE) reaction in order to (1) increase the of the olefination step and (2) access the Z-enoate by recruiting the Still-Gennari29 100 (vide infra). Toward this end, we repeated the CM sequence with the olefin substrates albeit in a tandem fashion as HWE reactions are performed in ethereal solvents (e.g., THF or ). The results are summarized in Table 1.11. Operationally, the reaction mixtures were concentrated following the CM step and added to phosphonate anions corresponding to 98-100 at –78 °C. The yields were ranged from 55% (entry 3) to 83%

(entry 1), showing the synthetic viability of this tandem sequence.

20

Table 1.11 Tandem CM/HWE Olefination for the Stereoselective Synthesis of (2E,4E)- or (2Z,4E)-dienoates

R3

5 4 (R O)2(O)P CO2R 3 4 5 CHO 98: R =H; R =R =Me Me 99: R3=Me; R4=R5=Et 3 4 78 Grubbs II 2 100: R =H;R =Me; or 5 4 + (5 mol%) CHO R =CH2CF3 CO2R R R R CHO 2 3 CH2Cl2 R2 THF or diglyme R R -78 °C!rt 68 reflux, 3 h R2=H or Me Me >20/1 E/Z not isolated

a,b Entry Olefin Aldehyde Phosphonate Product Yield c (3 equiv.) (ratio: 2E/2Z)

1 TBSO CHO TBSO CO2Et 83% (20:1) Me 99 78 101 Me 87

2 CHO 81% (20:1) TBSO TBSO CO2Me 98 Me Me 87 68 102 3 CHO CO Me 55% (18:1) Me 2 98 14 78 95

4 CHO 63% (1:6.5) Me 100 103 CO2Me 14 78 69% (5:1) 5 CHO CO2Et MeO2C Me 99 MeO2C 104 78 97 Me

a Yields refer to the average of two runs. b Isolated yield of separable E/Z mixture. c Ratio determined by 1H NMR.

The Still-Gennari olefination with phosphonate 100 realized (2Z,2E)-dienoate 103 in 63% yield with a satisfactory Z/E ratio (6.5:1). In order to expand the scope of this method, we wanted to study what other !,%-unsaturated aldehydes could be used in the sequence.

21

While (E)-2-methyl-2-butenal failed to react after 12 h under refluxing condition, recourse to methacrolein (3.0 equiv) resulted in a favorable reaction (entry 2). Olefination with trimethyl phosphonoacetate (98) yielded 81% of dienoate 102 with excellent 2E,2Z selectivity (20:1). Finally, tandem CM/HWE with phosphonopropionate 99 afforded dienedioate 97 in 69% with good 2E,2Z selectivity (5:1). Compound 97 was also prepared via one-pot CM/Wittig (see Table 1.10, entry 6) albeit in lower yield (50%).

1.3.2 Sequential CM/hydride Reduction

Primary (E)-allylic alcohols are excellent substrates for a variety of transformations such as the Sharpless asymmetric epoxidation reaction,30 which has been heavily utilized in the iterative synthesis of polyketide natural products.31,32 These substrates are typically prepared in the following three-step sequence procedure due to the need for redox manipulation: (1) oxidation of a or terminal olefin to the aldehyde; (2) olefination of the resulting aldehyde with a phosphorus-based reagent

(e.g., phosphorane, phosphonate); and (3) 1,2-reduction of the enoate to the primary (E)- allylic alcohol (Scheme 1a). A shorter alternative route using CM between a terminal olefin and allyl alcohol (Scheme 1b) was considered. While the short route is attractive, the stereoselectivity of the transformation is highly dependent on the nature of ‘R’ such that an increase in steric hindrance favors the (E) geometric isomer.33,34

22 Scheme 1. Routes to primary (E)-allylic alcohols: (a) traditional; (b) CM

1,2- R OH oxidation olefination CO2R' reduction (a) or R O R R OH R (E) only

CM (b) R + OH R OH

E/Z mixture

dr highly dependent on nature of R

By sequencing (1) the highly (E)-selective CM reaction of an electron-rich terminal olefin and an electron-poor olefin (i.e., , acrylate, etc.) with (2) a hydride reduction step, the stereochemical fidelity of the product is preserved. Table 1.12 shows a variety of terminal alkenes that were subjected to this one-pot CM-Reduction method.

Styrene (14) and a series of TBS-protected terminal alkenols were treated with 3.0 equivalents of either crotonaldehyde or methacrolein and 5 mol% Grubbs-II (2) in refluxing CH2Cl2 for 3 h to afford intermediary !,%-enals in high yield and high dr

(>20:1 E/Z by 1H NMR)35.

As these reactions progressed well and in high yield (Important requirements for efficient one-pot procedures), the reaction mixtures were subsequently cooled to -78 °C and reacted with excess DIBAL-H (commercially available solution in hexanes), affording exclusively primary (E)-allylic alcohols 105-112 in synthetically useful yields

(59%-74%). The temperature regime was necessary to avoid the undesired 1,4 reduction products. The substitution of the double bond is controlled by choice of either crotonaldehyde or methacrolein.

23

Table 1.12 One-pot sequential CM/hydride reduction method for the stereoselective synthesis of primary (E)-allylic alcohols with the Grubbs-II catalyst (2)

Grubbs-II (2) (5 mol%) DIBAL-H + CHO CHO R R1 R R OH CH2Cl2 R2 R2 CH2Cl2 R2 reflux, 3 h -78 °C, 2 h 1 2 not isolated R =Me; R =H >20/1 E/Z >20/1 E/Z R1=H; R2=Me

Yielda Entry Olefin Coupling Partner Product dr > 20:1 (E/Z)b ( 3 equiv.)

CHO OH 1 Me 70% 78 14 105

TBSO CHO TBSO 2 Me OH 74% 87 78 106

CHO 3 TBSO Me TBSO OH 72% 107 78 108

CHO 4 TBSO TBSO OH 56% 107 Me 109 Me 68 TBSO CHO TBSO 5 OH 69% 87 68 Me 110 Me

CHO 6 TBSO TBSO OH 59% 68 111 Me 112 Me

a Yields refer to the average of two runs. b Ratio determined by 1H NMR.

With these results in hand, we turned our attention to more synthetically useful terminal olefins 113-123 (Table 1.13). The allylation and crotylation reaction of aldehydes represent formidable alternatives to the acetate and propionate aldol reactions, respectively. These methods have been leveraged in the stereoselective total synthesis of natural products, such as those of polyketide origin36.

24 Table 1.13 One-pot sequential CM/hydride reduction method for the stereoselective synthesis of primary (E)-allylic alcohols with the Hoveyda-Grubbs-II Catalyst (4)

Hoveyda- Grubbs-II (4) (10 mol%) DIBAL-H CO Me R + CO2Me R 2 R OH CH Cl CH2Cl2 2 2 58 not isolated -78 °C (3 equiv.) reflux, 3 h >20/1 E/Z then -45 °C, 2 h >20/1 E/Z Yielda Entry Olefin Product dr > 20:1 (E/Z)b

OBn OBn 1 59% Me Me OH

113 114 OTBS OTBS 2 56% Ph Ph OH 115 116 OTBS OTBS 3 54% Ph Ph OH 117 118 OTBS OTBS Me Me 4 OH 64% 119Me 120 Me

OTBS OTBS 5 57% Ph Ph OH 121 Me 122 Me OTBS OTBS 6 Ph Ph OH 74% 123 Me 124 Me

a Yields refer to the average of two runs. b Ratio determined by 1H NMR.

As the products of these reactions are terminal olefins, they represent excellent substrates for our method. Toward this goal, a variety of protected homoallylic alcohols

30-32 were prepared by the addition of allylmagnesium bromide to the corresponding aldehyde whereas 113-117 were prepared in an asymmetric manner by the addition of

Roush’s tartrate-functionalized (E)-crotylboronate to the corresponding aldehyde37.

25

For these substrates, we found that the combination of 10 mol% Hoveyda-

Grubbs-II catalyst (4) and 3.0 equivalents of methyl acrylate as a coupling partner gave the best results38. Following the addition of DIBAL-H at -78 °C, the reaction mixture was allowed to -45 °C and continued stirring for 2 h. Noteworthy are chemoselective CM entries 3 and 6 from Table 1.13, which afford alcohols 118 and 124 due to the bulky TBS that sterically shields the allylic position39. Synthetically useful yields

(54%-74%) were obtained for both allylated (entries 1-3) and crotylated (entries 4-6) substrates, shown in the Table 1.13.

1.3.3 Sequential CM/Evans aldol reactions

The Evans aldol reaction is arguably the most powerful and versatile means of preparing propionate aldol subunits in a stoichiometric asymmetric manner.40 The levels of diastereoselectivity enjoyed by the robust N-acyl oxazolidinones (in both single and double asymmetric synthesis) and flexible nature of their manipulation have made the

Evans aldol method popular in the synthesis of complex natural products, particularly . As the products of CM reactions of terminal olefins and crotonaldehyde (or methacrolein) led to (E)-2-enals, which are substrates for the Evans aldol reaction, we investigated sequencing our method with the Evans propionate aldol reaction to rapidly access building blocks for total synthesis of natural products. To substantiate the utility in synthesis, we deliberately chose substrates that had been previously prepared in a stepwise manner and subsequently employed in total synthesis.

26 Table 1.14 Sequential CM/Evans aldol reaction for the asymmetric synthesis of unsaturated propionate aldols with 5 mol% Grubbs-II catalyst (2)

O O Me N O

Grubbs-II (2) Bn OH O O (5 mol%) 125 or ent-125 + CHO CHO R Me R R N O CH Cl Et3N, Bu2BuOTf 78 2 2 Me reflux, 3 h not isolated CH2Cl2 (3 equiv.) Bn >20/1 E/Z -78 °C

Entry Olefin Evans reagent Product Yield (dr>20:1)a,b

HO O O

1 125 N O 60% Me 14 126 Bn HO O O TBSO TBSO 2 125 N O 48% 127 128 Me Bn HO O O BnO BnO 3 ent-125 N O 52% 129 130 Me Bn HO O O PMBO PMBO 4 125 N O 64% 131 132 Me Bn a Yields refer to the average of two runs. b Aldol diastereoselectivity ratio (dr) determined by 1H NMR.

Table 1.14 shows four examples of this method. Styrene (14) and a series of protected allyl were treated with 3.0 equivalents of crotonaldehyde and 5 mol%

Hoveyda-Grubbs-II (4) in refluxing CH2Cl2 for 12 h to afford intermediary !,%-enals in high yield and high dr (>20:1 E/Z by 1H NMR)41. In a separate reaction vessel, Evans propionimide 125 (or ent-125 for entry 3) was enolized under the standard reaction conditions (Bu2BOTf, Et3N or i-Pr2NEt, CH2Cl2 at -78 °C).

27 To this was added a solution of enal derived from the CM reaction, and the corresponding aldol products 126-132 were isolated in good yields (48%-64%) with excellent diastereoselectivities (dr>20:1).

1.3.4 Sequential CM/Brown allyl- and Roush crotylboration reactions

The allyl- and crotylmetallation of aldehydes represent powerful alternatives for the acetate and propionate aldol reactions, respectively42. Thus, they have found widespread use in the total synthesis of polyketide43 natural products synthesis. Brown and Roush have both developed some of most utilized stoichiometric allyl- and crotylboration methods37. As we had shown the utility of sequencing CM with the Evans aldol reaction (vide supra), we opted to employ Brown’s Ipc-controlled allylboration and

Roush’s tartrate-derived crotylboration reactions in a tandem manner.

Table 1.15 shows six examples whose products are known intermediates previously employed in natural product total syntheses. Styrene (14) and a series of other olefins were subjected to the standard CM sequence with crotonaldehyde. Following concentration and solvent exchange, the solution of enal was transferred to another reaction vessel containing Brown’s allylborane 133 or Roush’s (E)-crotylboronate 134 at

-78 0C to afford the corresponding allylated and crotylated enantioenriched homoallylic alcohols 135-141 in high yields (71-82%) and good selectivity (67-88 %ee).

28

Table 1.15 Sequential CM/Brown allyl- or Roush (E)-crotylation reactions for the asymmetric synthesis of homoallylic alcohols with 5 mol% Grubbs-II catalyst (2)

O Me B 134 CO2i-Pr or Grubbs-II (2) O B(-)-Ipc2 OH (5 mol%) 133 CO2i-Pr + CHO CHO R Me R R CH Cl PhMe 78 2 2 R' reflux, 3 h -78 °C (3 equiv.) not isolated R'=H or Me >20/1 E/Z then NaOH

Entry Olefin Reagent Product Yielda,b

HO 1 133 74% (83% ee)

14 135

HO 2 133 75% (88% ee) C6H13 H13C6 72 136 HO

3 133 72% (82% ee) 137 57 HO

4 133 71% (83% ee) F F 139 138 HO

5 134 80% (dr>20:1) 1 4 0 M e (67% ee) 14 HO

C6H13 134 H C 82% (dr>20:1) 6 1 3 6 (86% ee) 72 141 Me

a Enantiomeric excess (% ee) determined by Mosher ester analysis. b Crotylation anti:syn ratio (dr) determined by 1H NMR.

29

1.11 Conclusion

In conclusion, this chapter demonstrated the wide utility of sequencing olefin cross-metathesis with various non-metathesis reactions. The scope of this method includes the Wittig and Horner-Wadsworth-Emmons44a olefination reactions to access stereodefined dienoates, hydride (DIBAL-H)-mediated reduction44b to furnish trans allylic alcohols, the Evans aldol reaction to prepare diastereomerically pure syn- propionate aldols and finally the Brown allyl- and Roush crotylboration reactions44c to furnish enantioenriched homoallylic alcohols. Most of the products of these reactions have been employed in total synthesis, thus validating the utility of this method in telescoping linear total synthesis and enabling greener, more efficient routes to complex targets (i.e., natural products).

30 CHAPTER 2: CONCISE ASYMMETRIC SYNTHESIS OF (+)-CROCACIN C

2.1 Introduction

In 1994, Jansen and co-workers reported the isolation and structure determination of a group of electron transport inhibitors from the myxobacterium Chondromyces crocatus, named Crocacins.45 These (+)-Crocacin family of compounds showed to inhibit Gram-positive bacterial growth moderately, in addition to antifungal and cytotoxic activity.45 In 1999, the same group disclosed the relative of parent crocacin C (142) and its congeners (+)-Crocacins A (143), B (144) and D (145) (Figure

2.1).46

MeO OMe Me O 21 15 18 11 NH2 Me Me (+)-Crocacin C (142) MeO OMe Me O 21 15 H 1 18 O N CO2R 11 NH 4 Me Me 9 6 (+)-Crocacin A (143); R = Me (+)-Crocacin B (144); R = H

MeO OMe Me O 21 15 H 1 18 O N CO2Me 11 NH 4 Me Me 9 6 (+)-Crocacin D (145)

Figure 2.1. Structures of (+)-Crocacins A-D

31 The (+)-Crocacins, recently have been identified as novel agricultural pesticide leads.47 By inspection, crocacin C (142) is composed of a polyketide fragment possessing the challenging anti-anti-syn stereotetrad (C16-C19) in addition to a conjugated (E,E)- dienamide system (C11-C15). (+)-Crocacins A (143), B (144) and D (145) are further characterized by an acid-sensitive (Z)-N-acylenamine motif (C7-C11) tethered to a residue. These structural features coupled with an interesting biological activity profile have made these natural products attractive targets for synthesis. This chapter covers the total syntheses of (+)-Crocacin C, a biologically active polyketide-derived natural product, reported in the period of 2000-2009.

The first enantioselective total synthesis of (+)-crocacin C (142) was reported in

2000 by Rizzacasa,48 which was quickly followed by both Chakraborty49 and Dias50 in

2001. In 2008, we reported51 a concise synthesis of 142, which was shortly followed by

Burke.52 In addition, there are five formal synthesis of 142 by Gurjar, Raghavan, Furstner and Yadav (two approaches). Recently, all syntheses of the crocacins were reviewed by

Andrade. 53 The order of approaches toward total syntheses of (+)-Crocacin C are presented chronologically.

2.2 Previous Asymmetric Syntheses of (+)-Crocacin C

2.2.1 Rizzacasa’s First and Second Generation Approaches

In 2000, the first enantioselective total synthesis of (+)-crocacin C was reported by Rizzacasa’s group (Scheme 2.1).48 The synthesis starts with the application of

Paterson’s dipropionate synthon54 146, which was prepared in three steps from the commercially available Roche ester [Methyl (S)-(+)-3-hydroxy-2-methylpropionate].55

32 Using this strategy, the homochiral methyl from the propionate reagent 146 enables high !-facial selectivity in the Sn(II) syn-aldol manifold and becomes incorporated into the target molecule (i.e., C-16 methyl). The C-18 methyl was resulted from the ethyl ketone. The Sn(II) aldol reaction between ethylketone 146 and (E)- cinnamaldehyde realized syn-aldol 147 in 86% yield (97% ds). Substrate-based anti- selective hydride delivery was accomplished with Me4NHB(OAc)3 to access the 1,3-anti diol and concisely synthesize the challenging anti-anti-syn stereotetrad.56 The relative stereochemistry of the reduced product was confirmed by 13C analysis of the acetonide derived from 148.57 of both hydroxyl groups in 148 using KH, MeI delivered

149.

At this juction, removal of the p-methoxybenzyl (PMB) ether with 2,3-dichloro-

5,6-dicyanobenzoquinone (DDQ) was found to be complicated by the unwanted oxidation of the electron-rich allylic ether at C-19 to the enone 150 in 72% yield. To address this problem, electronically deactivating protecting groups were recruited. In the event, of diol 148 using Ac2O, pyridine furnished diacetate 151 that when treated with DDQ successfully delivered alcohol 152 in 81% yield. Protection of the primary alcohol as its tert-butyldimethylsilyl (TBDMS) ether, reductive removal of the acetates with diisobutylaluminum hydride (DIBAL-H), and methylation of the resulting diol 154 using KH, MeI resulted in intermediate 206.

33

Scheme 2.1 Rizzacasa’s First-generation Synthesis of (+)-Crocacin C (142)

Sn(OTf)2 Me NHB(OAc) Me i-Pr2NEt Me Me 4 3 (E)-cinnamaldehyde AcOH/MeCN OPMB OPMB Me 96% O CH2Cl2, -78 °C OH O ds 97% 146 86% 147 ds 97%

Me Me DDQ Me Me OPMB OPMB CH2Cl2/H2O OR OR O OMe KH, MeI 148: R = H 72% 150 70% 149: R = Me

Me Me Me Me DDQ DIBAL-H OPMB OR CH Cl /H O CH Cl , -78 °C OR OR 2 2 2 OAc OAc 2 2 Ac O 2 148: R = H 81% TBDPSCl 88% pyridine 152: R = H 151: R = Ac 153: R = TBDPS 84% 87%

1.) Dess-Martin Me Me Me Me TBAF Periodinane OTBDPS OH THF 2.) Bu SnCHI , OR OR OMe OMe 3 2 100% CrCl2, DMF KH, MeI 154: R = H 155 97% 206: R = Me 75%

Me Me

SnBu3 OMe OMe 156

1.) HI, 90 °C AlMe , NH Cl I OMe 3 4 I NH2 Me CO2H 2.) 135 °C Me O 52% Me O 3.) CH N 157 2 2 158 159 51% Me Me Me Me 159, Pd2(dba)3, TFP NH2 SnBu 3 NMP, 50 °C OMe OMe OMe OMe Me O 160 51% (+)-Crocacin C (142)

34 Removal of the silyl-protecting group with tetrabutylammonium fluoride (TBAF) quantitatively delivered alcohol 155. Oxidation with the Dess-Martin Periodinane58 and application of Hodgson’s Cr-mediated vinylstannation59 delivered 156, thus completing the synthesis of C14-C21 fragment of (+)-Crocacin C. The C11-C14 fragment commenced with tetrolic acid (157). The addition of HI resulted initially mostly the (Z)- acid, which after was heated to 135 oC for 16 h to give a 70:30 mixture of E:Z isomers, respectively.60 Methylation using diazomethane and chromatographic separation yielded known ester 158.61 Weinreb amidation produced 159.62

The synthesis of (+)-crocacin C (142) was finished by a Stille coupling63 wherein vinylstannane 156 and iodide 159 were heated in N-methyl-2-pyrrolidone (NMP) at 50 o C with catalytic Pd2dba3 and trifurylphosphine (TFP), which proceeded in 51% yield.

Due to the difficulties associated with the PMB protecting group and the need for a streamlined route to an advanced intermediate for the synthesis of the crocacins, recourse to the triisopropylsilyl (TIPS) protecting group was made (Scheme 2.2).48,64 The Sn(II)- mediated aldol reaction, using ethylketone 161 and (E)-cinnamaldehyde delivered syn- aldol 162 in 84% yield (93% ds). Anti-reduction (83% yield, 96% ds), methylation, and

TBAF-mediated desilylation (76% for both steps) realized alcohol 155, which was transformed into stannane 156 utilized in the first-generation approach. The coupling of

156 and 159 was optimized by exchanging the on palladium (i.e., trifurylphosphine to triphenylarsine)65, resulting (+)-Crocacin C in 66% yield.

35

Scheme 2.2 Rizzacasa’s Second-generation Synthesis of (+)-Crocacin C (142)

Sn(OTf)2 i-Pr2NEt Me4NHB(OAc)3 Me (E)-cinnamaldehyde Me Me AcOH/MeCN OTIPS OTIPS Me CH2Cl2, -78 °C 83% O OH O ds 96% 161 84% 162 ds 93%

1.) KH, MeI Me Me 2.) TBAF Me Me OTIPS OH 76% OH OH OMeOMe 163 155

1.) Dess-Martin 159, Pd2(dba)3 Periodinane AsPh3 156 (+)-Crocacin C (142) 2.) Bu3SnCHI2, NMP CrCl2, DMF 66% 88%

2.2.2 Chakraborty’s Approach

The asymmetric synthesis of 142 by Chakraborty quickly followed Rizzacasa’s

(Scheme 2.3).49 Chakraborty and co-workers synthesis of Crocacin C began with a

Crimmins66 aldol reaction between N-acylthiazolidinethione 164 and (E)-cinnamaldehyde to set the first two in 165 (89%, dr > 95:5). Reductive removal of the auxiliary with DIBAL-H and a Wittig olefination resulted in the enoate 166 in 70% yield.

Further reduction of the enoate intermediate yielded diol 167 (85%). Regioselective protection of the primary alcohol as its TBS ether 168 (89%) enabled methylation of the remaining secondary alcohol to access methyl ether 169 (88%).

36

Scheme 2.3. Chakraborty’s Synthesis of (+)-Crocacin C (142)

TiCl , i-Pr NEt S O 4 2 S 1.) DIBAL-H CH Cl -78 °C O OH Me 2 2, THF, -78 °C S N S N then Me 2.) Ph3P=CHCO2Et Bn (E)-cinnamaldehyde Bn 164 165 70% 89% dr > 95:5 OH OH DIBAL-H TBSCl, imidazole EtO2C HO THF, 0 °C - rt Me CH2Cl2, -78 °C Me 166 167 82% 85%

OMe OR CSA TBSO HO Me CH2Cl2/MeOH (2:1) Me 0 °C - rt NaH, MeI, 168: R = H 170 TBAI (cat), THF 169: R = Me 88% 89%

Ti(O-i-Pr)4, (-)-DIPT OMe OH OMe O TBHP, 4 Å MS Me2CuLi HO HO Me Et O Me Me CH2Cl2, -20 °C 2 171 172 86% 93% 1.) TBSCl, imidazole OMeOMe OMeOMe 2.) NaH, MeI, TBAI (cat.) SO pyr, Et N 3 3 OHC HO 3.) CSA, CH2Cl2/MeOH Me Me DMSO, CH2Cl2 Me Me

155 173 60% 96%

O Me O O Me OMeOMe P LDA, DMPU EtO OEt EtO OEt THF, - 78 °C 174 then 173 Me Me 48% 175

MeO OMe Me O 1.) LiOH, THF/MeOH/H2O NH2 2.) Et3N, ClCO2Et, THF, Me Me 25% NH4OH -20 °C - 0 °C (+)-Crocacin C (142) 66%

37 Deprotection of the (89%) with camphorsulfonic acid (CSA) set the stage for a Sharpless asymmetric epoxidation, which proceeded in 93% yield to produce epoxy alcohol 171 as a single .67 Regioselective -opening with

Me2CuLi gave mostly 1,3-diol 172 in 86% yield. Reiteration of the three-step diol differentiation protocol used before (regioselective silylation, methylation, desilylation) realized alcohol 155 in 60% overall yield. Parikh-Doering oxidation68 of the primary alcohol 155 delivered an aldehyde 173, which set the stage for the key vinylogous

Horner-Wadsworth-Emmons69 reaction with known phosphonate 174.70 In the event, of 174 with LDA and DMPU followed by the addition of aldehyde 173 at -

78 oC afforded 48% isolated yield of the E,E dienoate. Saponification using LiOH, activation of the resulting acid with isobutyl chloroformate and amidation with ammonium hydroxide delivered Crocacin C 142 in 66%, thus completing their total synthesis.

2.2.3 Dias’s Approach

The synthesis of crocacin C 142 by the Dias group shortly followed and began with an Evans aldol reaction between commercially available N-propionyl oxazolidinone

125 and (E)-cinnamaldehyde to access the aldol 176 in 85% yield (dr>95:5).50 Silyl protection of the aldol and reductive removal of the auxiliary with LiBH4 afforded alcohol 177 in 70% overall yield. Homologation by the three-step reaction sequence

(Swern oxidation, 71 Horner-Wadsworth-Emmons olefination,69 reduction) delivered allylic alcohol 178 in 82% overall yield (Scheme 2.4).

38

Oxidation of 178 using MCPBA proceeded with high regio- and diastereoselectivity (dr=92:8) to furnish anti-epoxy alcohol 179 in 94% yield. Epoxide ring-opening with Me2CuCNLi2 yielded diol 180 thus securing the anti-anti-syn stereotetrad of target 142.72 Removal of the TBS ether with TBAF furnished a triol, which was treated with TBDPSCl to selectively protect the primary alcohol and realize the intermediate 154. Carbon-13 NMR analysis of acetonides derived from both 180 and

154 confirmed the 1,3-anti relative stereochemistry.57 Methylation of both secondary alcohols using KH, MeI followed by desilylation with TBAF afforded alcohol 155, converging on an intermediate previously prepared by both Rizzacasa and Chakraborty.

The Endgame of Dias’s route began with oxidation of 155 and

73 (CHI3, CrCl2) to afford vinyl iodide 181 (67% over two steps). To forge the dienoate portion of crocacin C (142), methodology developed by Piers74 was recruited. Ethyl 2- butynoate (182) was treated with Bu3SnLi and CuBr•Me2S to result in the intermediate vinyl stannane 183 (70% yield, E/Z = 87:13). Amidation of 183 under the agency of

AlMe3 furnished amide 184 in 72% yield. Stille coupling of vinyl iodide 181 and vinyl

o stannane 184 in the presence of catalytic Pd2dba3 and AsPh3 in NMP at 60 C resulted in

(+)-crocacin C (142) in 69% yield. 63

39

Scheme 2.4 Dias’s Synthesis of (+)-Crocacin C (142)

O O Bu2BOTf, Et3N O O OH 1.) TBSOTf (E)-cinnamaldehyde 2,6-lutidine, CH Cl Me 2 2 O N O N CH2Cl2 Me 2.) LiBH4, THF/MeOH Bn -78 °C - 0 °C Bn 0 °C 125 85% 176 70% dr > 95:5

1.) (COCl)2, DMSO, Et3N 2.) NaH, THF, methyl OTBS diethylphosphono- OTBS HO acetate, 0 °C - rt HO Me Me 3.) DIBAL-H, CH Cl , 177 2 2 -15 °C 178 82% (E/Z > 95:5)

OTBS OH OTBS MCPBA O Me2CuCNLi2 HO HO THF CH2Cl2, 0 °C Me Me Me -78 °C - 20 °C 85% 179 180 dr = 92:8 90%

1.) TBAF, THF OH OH 2.) TBDPSCl, DMAP, 1.) KH, MeI TBDPSO imidazole, CH2Cl2, -5 °C Me Me 2.) TBAF, THF 96% 80% 154

OMeOMe 1.) Dess-Martin OMeOMe Periodinane I HO Me Me 2.) CrCl2, CHI3 Me Me 155 THF, 0 °C 181 67%

1.) Bu3SnLi, THF -100 °C - -78 °C O Me AlMe3, NH4Cl O Me EtO2C Me EtO SnBu3 H2N SnBu3 2.) CuBr.SMe2 PhMe, 50 °C 182 1.7 equiv MeOH 183 72% 184 70% (E/Z = 87:13)

OMeOMe 184, Pd2(dba)3 AsPh3 I (+)-Crocacin C (142) Me Me NMP, 60 °C 181 69%

40 2.5 Burke’s Approach

Burke has mastered the use of N-methyliminodiacetic acid (MIDA) boronates as robust vinylboronic acid surrogates.75 These compounds are found to be bench stable, can withstand a wide variety of reaction conditions, and can be purified by standard silica gel chromatography. To demonstrate their utility in natural product synthesis, the Burke lab employed these MIDA boronates for the synthesis of Crocacin C 142 (Scheme 2.5).52

Scheme 2.5 Burke’s Synthesis of (+)-Crocacin C (142)

Me NHB(OAc) MeN MeN 4 3 146, Sn(OTf)2, Et3N Me Me AcOH/MeCN H B O O PMBO B O O O O CH2Cl2, -78 °C O O -30 °C, 6 h O 70% O OH 71% 185 186

MeN MeN Me Me DDQ Me Me PMBO B O O HO B O O O O CH2Cl2/H2O O O OR OR 81% OMeOMe Me OBF 3 4 187: R = H 189 proton sponge 188: R = Me 82%

1.) Dess-Martin MeN 45, Pd(PPh3)4 Periodinane Me Me CsF, CuI B O O I O O 2.) CrCl2, CHI3 OMeOMe DMF THF/dioxane 69% 72% 190

MeN PhBr, Pd(OAc) , Me Me 2 SPhos, K3PO4 H2N B O O (+)-Crocacin C (142) O O O Me OMeOMe THF/H2O, 60 °C 77% 191

The first portion of Burke’s synthesis follows the Rizzacasa protocol.48 A

Paterson aldol reaction with 146 resulted aldol 186 in 70% yield.

41 Selective anti reduction furnished diol intermediate 187 in 71% yield. of both the hydroxyls using Meerwein’s salt and proton sponge resulted in dimethyl ether

188 in 82% yield. Removal of the PMB ether using DDQ, oxidation with the Dess-Martin

Periodinane,58 and Takai olefination73 secured vinyl iodide 190 in 52% over three steps.

Stille coupling of 190 with Dias’s stannane 184 in the presence of Pd(PPh3)4, CsF, and

CuI realized the dienamide 191 in 69% yield.76 A final Suzuki coupling of MIDA

77 boronate and bromobenzene in the presence of Pd(OAc)2 and SPhos (Pd/SPhos) resulted in crocacin C (142) in 77% yield.

2.3 Present Study

2.3.1 First Generation Retrosynthesis

The first generation retrosynthetic analysis of crocacin C (142) is shown in

Scheme 2.6. To maximize convergence a chemoselective cross-metathesis reaction between known diene 19278 and dienamide 193 using a suitable catalyst was selected. In order to achieve a successful proposed chemoselective cross-metathesis step, it is important to note that the presence of a cyclic protecting group (i.e., acetonide) would be essential. In its absence, the 1,7-diene system would certainly cyclize under the conditions to form a cyclohexene derivative and styrene via a ring-closing metathesis

(RCM) pathway.

As such, we hypothesized an acetonide (or related cyclic protecting group) would avoid the undesired RCM and enable a cross-metathesis pathway by eliminating conformational isomers capable of cyclizing.

42

Scheme 2.6 First-generation retrosynthesis of 142

Crotylboration MeO OMe Me O 15 NH 14 2 Me Me Chemoselective Crimmins Aldol Cross-Metathesis (+)-crocacin C (142)

Me Me

O O Me O + NH2 Me Me 193 192

S CHO O + Me + N S BR2 Me 194 164 195; R = (-)-Ipc Bn 139 ; R = (+)-DIPT

A survey of the literature showed Crimmins had employed this cross metathesis tactic to effect a reaction between diene 208 and (209), isolating dienoate

210 in near quantitative yield and validating our hypothesis (Eq. 1).79

PMP PMP

O O CO2Et O O 209 CO Et 2 (Eq. 1) Me Me 208 210

Preparation of diene 192 can be achieved via a reagent-controlled asymmetric crotylboration reaction utilizing Brown’s14 reagent 195 or Roush’s37 reagent 139 and an aldehyde derived from the Crimmins aldol reaction80 of propionate 164 and trans-cinnamaldehyde (194).

43

2.3.2 Attempted Synthesis of Crocacin C (142)

The first generation forward synthesis began with a Crimmins aldol reaction of commercially available thiazolidinethione propionimide 164 and trans-cinnamaldehyde

(194). Enolization of the propionamide 164 with TiCl4 and Hunig’s base in dichloromethane afforded non-Evans syn aldol product 165 in 50% isolated yield (dr >

20:1). Protection of the free aldol as its TBS ether with TBSOTf and 2,6-lutidine proceeded in 75% yield. Reductive removal of the auxiliary with diisobutylaluminium hydride (DIBAL-H) at -78 °C furnished requisite aldehyde 196 in 82% yield (Scheme

2.7).

Scheme 2.7 Synthesis of aldehyde 196

O S TiCl4, i-Pr2NEt HO O S 1.) TBSOTf, 2,6-lutidine then, 194 Me 75% N S Ph N S CH2Cl2 Me 2.) DIBAL-H, CH2Cl2, Bn 50% (dr>20:1) Bn -78 °C, 82% 164 165

TBSO CHO Ph Me 196

At this stage, options for executing the asymmetric crotoylboration reaction with aldehyde 196 were considered. Mindful of the fact the desired product was the anti-

Felkin diastereomer, 196 was subjected to two well-known asymmetric crotylboration reagents well known for their ability to override substrate-derived bias in double asymmetric reactions.81

44

In the event, reaction with Brown’s reagent 195 resulted in a 61% yield of two inseparable diastereomers 197 and 198 (3:1 ratio by 1H NMR spectroscopy) (Scheme 2.8) and Roush’s reagent 139 was also used similarly in the crotylboration reaction, albeit in

60% yield (dr = 4:1).

Scheme 2.8 Double asymmetric crotylboration reaction with aldehyde 196

1,3-syn 1,3-anti BIpc2-(-) Me 195 TBSO TBSO OH TBSO OH 61% (16:17 = 3:1) CHO + Ph Ph Ph (+)-DIPT2B Me Me Me Me Me Me 139 196 197 198 60% (16:17 = 4:1) undesired (major) desired (minor)

Structural assignment of diastereomers 197 and 198 was realized by well- developed 13C acetonide analysis.57 Toward this goal, the inseparable isomers were treated with TBAF in THF to remove the silyl ether, affording the mixture of diols in

88% yield, which were carried forward. Isopropylidenation with dimethoxypropane and

PPTS afforded chromatographically separable acetonide diastereomers 199 and 200 in

76% and 19% yields, respectively.

Analysis of the 13C NMR spectra of 199 and 200 revealed that major isomer 199 was the 1,3-syn diastereomer with the ketal carbon resonating at 99.2 and methyls at 19.6

(axial Me) and 30.0 (equatorial Me), which are consistent with the chair-like conformation adopted by 1,3-syn acetonides. Anti-diastereomer 200, on the other hand, possessed a ketal carbon at 100.6 ppm and acetonide methyls at 25.5 and 23.6, which are characteristic of the twist-boat conformation of 1,3-anti acetonides (Scheme 2.9). 57

45 Scheme 2.9 Structural assignment of diastereomers 199 and 200 via 13C acetonide analysis

19.6 (ax) and 30.0 (eq) 25.5 and 23.6

Me Me 99.2 Me Me 100.6 TBSO OH O O O O 1.) TBAF, THF (88%) Ph Ph + Ph 2.) DMP, PPTS Me Me Me Me Me Me syn-199 anti-200 197, 198 undesired (major) (76%) (19%) desired (minor)

The results clearly indicated chiral reagents 195 and 139 were unable to overcome the stereochemical bias of aldehyde 196 to result in the desired anti-Felkin diastereomer.

In light of these unfortunate results, recourse was made to an entirely different synthetic plan.

2.3.3 Second Generation Retrosynthesis

The second approach to (+)-crocacin C (142) wanted to retain the high levels of convergence from the first; hence, the disconnection at the C14-C15 olefin was maintained (Scheme 2.10). Chakraborty employed the vinylogous Horner-Wadsworth-

Emmons olefination with phosphonate 17470 to efficiently make this bond, so our challenge lied in the concise synthesis of aldehyde 173. Access to homochiral 173 was thought to proceed from Evans’ dipropionate synthon 202 and commercially available trans-cinnamaldehyde (194).82

46 Scheme 2.10 Second-generation retrosynthesis of 142

1,3-anti reduction

MeO MeO Me O 15 NH 14 2 Me Me Vinylogous Evans Dipropionate Horner-Wadsworth- Aldol Emmons (+)-crocacin C (142)

MeO MeO Me O CHO +(EtO) (O)P 2 OEt Me Me 174 173

O O O CHO + Me N O Me 194 Bn 202

The power of this method lies in its ability to (1) accomplish stereocontrol in the aldol reaction to access either syn aldol diastereomer; and (2) utilize the newly formed hydroxyl to direct the stereochemical course of the reduction by proper reagent selection, leading to either a 1,3-syn or 1,3-anti diol.56

2.3.4 Total Synthesis of Crocacin C (142)

The synthesis commenced with the preparation of ketoimide 202 by an Evans aldol reaction 83 of oxazolidinone 125 and propionaldehyde (dr > 20:1) in dichloromethane, followed by Parikh-Doering oxidation68 reaction, which proceeded in

71% overall yield.

47 Enolization of 202 with TiCl4 and i-Pr2NEt and subsequent addition of trans- cinnamaldehyde (194) realized the desired aldol 203 (dr > 20:1) in 75% yield (Scheme

2.11).

Scheme 2.11 Evans Dipropionate Aldol Reaction with 194

O O HO O O n-Bu2BOTf, Et3N Me EtCHO Me N O N O CH Cl , -78 °C Me Bn 2 2 Bn 125 75% 201 dr > 20:1 O O O SO Pyr, Et N 3 3 Me TiCl4, i-Pr2NEt, 194 N O DMSO/CH2Cl2, 0 °C Me CH2Cl2, -78 °C 95% 75% 202 Bn dr > 20:1 HO O O O

N O Me Me Bn 203

Stereoselective substrate-based reduction of the C17 ketone in a mixture of acetonitrile and acetic acid with NMe4BH(OAc)3 afforded desired 1,3-anti diol 204 in

88% yield as a single diastereomer.56 To confirm the relative 1,3-anti stereochemistry, diol 204 was converted into acetonide 205 following standard conditions of treatment with dimethoxy propane and PPTS, followed by 13C NMR analysis. Resonances from the

13C NMR of 205 (23.5 and 25.8 ppm for the methyls; 100.8 ppm for the ketal carbon) were consistent with those found in a twist-boat conformation, which is indicative of a

1,3-anti diol disposition (Scheme 2.12).57

48 Scheme 2.12. 13C NMR acetonide analysis of diol 204

HO HO O O NMe4BH(OAc)3 203 N O MeCN/AcOH, -40 °C 88% Me Me Bn dr > 20:1 204 25.8 and 23.5

Me Me 100.8 O O O O Me2C(OMe)2, PPTS N O 73% Me Me Bn 205

Having 204 in hand, we turned our attention to installing the methyl ethers in the final natural product 142. Toward this end, we reductively cleaved the oxazolidinone auxiliary using LiBH4 (66% yield) and differentiated the primary from the secondary alcohols by protecting with the bulky TBDPS group (90% yield) using imidazole and

TBDPSCl. Rizzacasa and Dias had utilized the latter tactic.

Scheme 2.13 Synthesis of alcohol 155

OH OH O O OH OH TBDPSCl, LiBH4 imidazole Ph N O Ph OH MeOH Me Me Me Me 90% Bn 66% 204 205

OH OH MeO OMe KH, MeI Ph OTBDPS Ph OTBDPS Me Me 97% Me Me 154 206 MeO OMe TBAF Ph OH THF 95% Me Me 155

49 After some consideration, we opted for a shorter route to access the alcohol 155 that avoided protecting groups, such as silyl ethers, altogether. Methylation of diol 204 resulting from the anti-reduction reaction would directly accomplish our goal. Thus, various methylation protocols were screened to install both requisite methyl ethers69 in a single step. Ultimately, the combination of MeOTf and 2,6-di-tert-butyl-4- methylpyridine at 0 oC provided 207 in 49% yield with unproductive elimination accounting for the remaining mass balance (Scheme 2.14).

Scheme 2.14 Completion of the Synthesis

MeOTf MeO MeO O O 2,6-di-t-Bu-4-Me-Pyr 204 N O

CHCl3, 0 °C Me Me Bn 49% 207

MeO MeO 1.) LiBH4, THF/MeOH LDA, 174 CHO 2.) Dess-Martin THF/DMPU Me Me periodinane -78 °C 59% 173 57%

MeO MeO Me O 1.) LiOH OEt 142 Me Me 2.) ClCO2Me, Et3N then NH4OH 175 63% overall

Reductive removal of the in 207 using LiBH4 in a mixture of methanol and THF, and subsequent oxidation of the intermediary primary alcohol with the Dess-Martin periodinane provided aldehyde 173 in 59% yield over two steps.

Endgame began with a stereoselective, vinylogous Horner-Wadsworth-Emmons reaction with a known phosphonate 174 to prepare conjugated E,E-dienoate 175 in 57% yield as one diastereomer.

50 Saponification of the ester, followed by activation of the intermediary acid with methyl chloroformate and treatment with aqueous ammonia delivered crocacin C (142) in

63% yield from 175.49

2.4 Conclusion

Two synthetic strategies for the concise asymmetric synthesis of (+)-crocacin C

(142) have been presented.51 The first was unsuccessful due to undesired substrate control in the asymmetric crotylboration reaction, which resulted in an undesired diastereomer. The second-generation strategy, based on a well precedented Evans’ dipropionate synthon methodology, enabled a concise total synthesis of 142 in ten steps from commercially available Evans’ propionimide 202 and cinnamaldehyde (194) in 5% overall yield without recourse to protecting groups.

51 CHAPTER 3: CONCISE SYNTHESIS OF THE ABCE TETRACYCLIC

FRAMEWORK OF STRYCHNOS ALKALOIDS

3.1 Introduction

The genus Strychnos is numerically the most important of the Loganiaceae family and consists of approximately 190 species of trees and lianas growing in the warm regions of Asia, America, and Africa.84 The toxicity of Strychnos was well known in

South-Eastern Asia and India from centuries. Seeds of Strychnos nux vomica, which are the source of the notorious poison strychnine, were used as a traditional poison and as a pesticide, particularly for killing small vertebrates such as rodents. Strychnine was first isolated in 1818 from the seeds and bark of Strychnos nux vomica by Caventou and

Pelletier,85 its elemental composition was established 20 years later by Regnault.86

Before the advent of modern spectroscopic techniques, strychnine was the subject of a very large number of degradative studies. The elucidation of its structure represented one of the major achievements of classical organic chemistry. The degradative studies of strychnine started in the 1880s with Woodward and Brehm87 published the finishing touches in 1948. Leuchs and Robinson88 made major contributions along with their collaborators in the degradation studies. The relative configuration of strychnine was provided via two independent X-ray crystallographic analyses done by Robertson, Bevers and Bijvoet. 89 The absolute stereochemistry of strychnine was established by

Peerdeman90 with X-ray and was later confirmed by Schmid and his collaborators91 utilizing a chemical method.

! "#! The numbering system and ring labeling was based on the biogenetic interrelationship of monoterpene indole alkaloids, as proposed by Le Men and Taylor.92

A year later, Woodward independently suggested the same structure.

Strychnine ranks as one of the most complex natural products of its size

(C21H22N2O5, molecular weight of 334) – only twenty-four skeletal atoms are assembled in seven rings, resulting in six contiguous stereogenic centers (five of them in the core cyclohexane E ring), hence strychnine is recognized as the flagship of Strychnos alkaloids (Figure 3.1).93 Meanwhile, various other Strychnos alkaloids84 were isolated and identified, all containing an important group of architecturally complex system with a common tetracyclic (ABCE) skeleton.

5 4

6 N N N 9 21 C 8 D 10 3 14 MeO E 7 A 2 H 15 20 B 11 1 H 13 N 16 19 MeO N 12 H N H H F H H H Me G 18 CO Me O 24 17 O 2 O O 23 strychnine akuammicine brucine

N N N H OH N H N H N H H H Me H Me Me CO2Me tubifolidine echitamidine tubifoline

Figure 3.1 Selected representative Strychnos alkaloids

The classical total synthesis of strychnine by Woodward94 remained the only synthesis for nearly 40 years, and was a benchmark for the evaluation of synthetic strategies. Later on a number of other researchers reported successful syntheses of racemic and enantiopure strychnine.

! "$! Each synthesis featured a novel strategy and methods that were employed showed increased synthetic efficacy; however, the Strychnos alkaloids remain excellent substrates for showcasing methodologies aimed at rapidly assembling polycyclic structures in both atom and step-economical fashion. The Strychnos alkaloids possess a compact, ABCDE pentacyclic core that harbors three distinct synthetic challenges: (1) the C7 spirocyclic quaternary , (2) the bridged CDE framework, and (3) the alkylidene side chain. This chapter will discuss the general strategies aimed at preparing the tetracyclic

ABCE core of the Strychnos alkaloids, in addition to the closely related Aspidosperma alkaloids. The work goes to 2011 and features work done in the Andrade laboratory.

3.2 Previous Approaches

Over the past six decades, many strategies aimed at accessing the polycyclic core of the Strychnos alkaloids have been developed. Woodward94 reported the first successful synthesis of strychnine in 1954 and to this day, new strategies continue to be reported.

This chapter will begin with work on tetracyclic ABCE core of the Aspidosperma alkaloids, which are closely related to the Strychnos family, and move to the Strychnos alkaloids. Each approach is presented in chronological order. Work in this area has been reviewed by Bonjoch and Sole (up to 2001), and Shibasaki has reviewed the work up to

2007.95

! "%! 3.2.1 Wenkert’s Approach

In 1983, Wenkert and co-workers96 reported a concise key cyclization strategy to access the alkaloids 20-epipseudoaspidospermidine (209), 20-epidehydro- pseudoaspidospermidine (210) and 20-epipseudovincadifformine intermediate (211).

Scheme 3.1 Wenkert’s cyclization of !-acyl pyridine derivative

O H O N Et H BF3 OEt2 N N H Et N O H H 208 O 209 O O H H N N Et Et H H

N O N O H H H H 4:4:1 ratio 210 211

The N-acyl derivative 208 was prepared in few steps from commercially available materials and was heated in diethyl etherate for 30 min and resulted in stereoisomeric, pentacyclic keto lactams 209, 210, and 211 in a 4:4:1 ratio.

3.2.2 Natsume’s Approach

Natsume and co-workers97 have disclosed a high yielding, one-pot bis-cyclization reaction strategy to concisely access the Aspidosperma family of alkaloids in 1984. The authors showcased their powerful method by synthesizing racemic vindorosine.97a

! ""! The key reaction involves treatment of the methyl keto aminol 212 with methanesulfonyl chloride and potassium carbonate to realize the chloride 213, which upon reacting with KHMDS in THF resulted in the key pentacyclic intermediate in 60% overall yield.

Scheme 3.2 Natsume’s bis-cyclization strategy for Aspidosperma alkaloids

HO Cl N N MsCl N KHMDS K2CO3 60% N O N O N O H H H H 212 213 214

HO Cl N N MsCl N t-BuOK K2CO3 H H H N O 81% N O 91% N O H H CO Me MeO2C CO2Me MeO2C CO2Me 2 215 216 217

The same authors have also extended this method to !-keto esters in synthesizing racemic kopsinine97b and its related alkaloids. In the event, activation of the hydroxyl group in the beta keto ester 215 using methanesulfonyl chloride and potassium carbonate resulted in chloride 216 in 81%. With the chloride in hand, it was subjected to a t-BuOK mediated hydrolysis of the methyl ester at indole to generate 1-indolyl anion, which initiates the spirocyclization. The spirocyclic imine undergoes another cyclization in situ from the of the !-keto ester to access the pentacyclic core of kopsinine.

! "&! 3.2.3 Rubiralta’s Approach

In 1996, Rubiralta and co-workers98 utilized a similar approach as Natsume, but with a different activating reagent in the synthesis of aspidospermidine (221).

Scheme 3.3 Rubiralta’s cyclization in Aspidospermidine synthesis

HO N N H t-BuOK TsCl Et Et N N H S S S S 218 219

N N W2, Raney-Ni dioxane + Et Et 65% N N H 1.2:1.0 H 220 221

Ethyloxyamine 218 was treated with TsCl and excess of t-BuOK in THF to effect the desired spirocyclization. The dithiane functionality in spirocycle 219 was removed with W-2 Raney nickel to afford a 1.2:1.0 ratio of dehydroaspidospermidine 220 and aspidospermidine 221, which resulted from additional reduction of the imine moiety in

220.

3.2.4 Woodward’s Approach

In 1954, the Woodward group94 reported the first total synthesis of strychnine and the key spirocyclization reaction was achieved via a Pictet-Spengler reaction. 2- veratryltryptamine 222 was condensed with ethyl glyoxalate to afford the corresponding

Schiff base 223, which upon treatment with p-toluenesulfonyl chloride and pyridine gave the spiroindolinine compound 224 in 64% yield.

! "'!

Scheme 3.4 Woodward’s Pictet-Spengler Approach

Cl

SO2p-Tol Ts NH2 O N N 1. H CO2Et CO2Et CO2Et OMe OMe OMe N 2. p-TsCl N N H H OMe 64% OMe OMe 222 223 224

Ts O3 Ts Ts N N N AcOH MeOH 1. NaBH4 CO Et H O CO Et HCl 2 2 2 CO2Et OMe 2. Ac O N N CO Me 75% 2 29% 2 N CO2Me 84% Ac Ac CO2Me OMe O 225 226 227

Ac 1. HI, red P Ac Ac N N N O H 2. Ac2O NaOMe OH 3. CH2N2 CO Me 2 OMe N CO2Me 57% Overall N CO2Me N CO2Me 88% O O O 228 229 230

The spiroimine was reduced using and the inoline nitrogen was acylated with acetic anhydride. The highly electron-rich veratryl group in 225 was selectively cleaved by ozone at the double bond between two methoxy groups and was cyclized to furnish pyridone 227. Next, the was cleaved using hydroiodic acid and red phosphorus. N-acylation and esterification using diazomethane yielded Dieckman condensation precursor 228 in 57% overall. Treatment of 228 with sodium methoxide in methanol resulted in epimerization followed by the Dieckman cyclization to realize the pentacyclic core skeleton 230 of strychnine in 88% yield.

! "(! 3.2.5 Magnus’ Approach

Nearly 40 years after Woodward’s synthesis of strychnine, Magnus and co- workers99 reported the second total synthesis of strychnine in 1992. The key cyclization in Magnus’ synthesis featured a mercuric acetate-mediated transannular oxidative

Mannich cyclization. Intermediate 231 was prepared in 15 steps from commercially available tryptamine and was subjected to the transannular oxidative cyclization originally developed by Harley-Mason100 for the synthesis of tubifoline.

Scheme 3.5 Magnus’ transannular oxidative cyclization

N N N Hg(OAc)2 O AcOH O O O N HO N H 65% N HO H CO2Me H CO2Me H CO2Me 231 232 233

Although the oxidation of tertiary 231 could yield three different , treatment with Hg(OAc)2 in acetic acid resulted largely in iminium 232, which gave desired pentacyclic core 233 of strychnine in 65% yield.

3.2.6 Stork’s Approach

In 1992 Stork and co-workers101 reported a synthesis of strychnine using a skeletal rearrangement of tetrahydro !-carboline to hexahydropyrrolocarbazole, which was previously reported by Massiot.102

! ")! Scheme 3.6 Stork’s skeletal rearrangement polycyclization

Cl Cl Cl NaH N N N N Bn N Bn N Bn

MeO2C CO2Me

MeO2C CO2Me MeO2HC CO2Me 234 235 236

Bn Bn N N

N N MeO2C CO2Me H CO2Me 237 238

Key substrate 234 was prepared using the Pictet-Spengler reaction of N-benzyl tryptamine and an aldehyde, followed by chlorination at the C-3 position. Intermediate

234 was subjected to a skeletal rearrangement by reaction with sodium hydride. During the course of the rearrangement, the initially formed malonate anion 235 does an intramolecular nucleophilic attack on to the imine and a skeletal rearrangement with the simultaneous expulsion of chloride, followed by Krapcho-like to access

ABCE tetracycle 238.

3.2.7 Overman’s Approach

Overman103 reported the first enantioselective total synthesis of strychnine in

1993. The optically pure starting material for the synthesis was achieved by an enzymatic reaction. The key polycyclization strategy they used was an aza-Cope-Mannich rearrangement,104 which was developed by his group and employed in the total syntheses of other alkaloids.

! &*!

Scheme 3.7 Overman’s aza-Cope-Mannich rearrangement

Ot-Bu Ot-Bu Ot-Bu

aza-Cope Mannich N N cyclization N (CH2O)n rearrangement

HO HO O 98% H NR NR2 NR2 2

239 240 241

Ot-Bu

N N 1. LDA, N NCCO2Me O 2. HCl, MeOH N H O H R2N H CO Me OH NR2 O-t-Bu 2 242 7 0 % 243

Heating allylic alcohol 239 with excess gave iminium species 240, which underwent an aza-Cope-rearrangement followed by intramolecular Mannich cyclization to produce the azatricyclic ketone 242 in near quantitative yield. The lithium enolate of 242 was treated with Mander’s reagent then refluxed in methanolic HCl to furnish ABCDE pentacyclic core 243 in 70% overall yield.

3.2.8 Kuehne’s Approach

In 1993, Kuehne and Xu 105 discovered a novel domino condensation/Mannich/sigmatropic rearrangement/Mannich sequence to concisely assemble the ABCE framework of the Strychnos alkaloids.

! &+! Scheme 3.8 Kuehne’s Mannich-[3,3]sigmatropic rearrangement

Bn Bn O N N OMe H HN OMe CO Me CO Me N Bn N 2 N 2 CO2Me CO2Me H CO2Me BF3 Et2O H CO2Me H CO2Me 244 245 246

Bn Bn N N H OMe OMe N N OMe OMe H H CO2Me H CO2Me 247 248

Key precursor 244 was prepared in 5 steps from commercially available tryptamine. Condensation of tryptamine derivative 244 with 4,4-dimethoxy-2-butenal in the presence of a catalytic boron trifluoride diethyl etherate provided tetracycle 248 in a single operation. Although alternative pathways can be considered, this multistep reaction presumably goes through an initial Mannich condensation to result in iminium 245 followed by an aza-spirocyclization and [3,3]-sigmatropic rearrangement to result in the tetracyclic 248. This strategy is one of the shortest ways of making the ABCE core of the Strychnos framework and using this method, Kuehne and co-workers105 reported concise syntheses of strychnine and related alkaloids.106

3.2.9 Rawal’s Approach

In 1994, Rawal and co-workers disclosed a powerful intramolecular Diels-Alder reaction for the construction of the ABCE ring system of the Strychnos alkaloids.107 They showcased this method by accomplishing the total synthesis of strychnine in 15 steps.

Intermediate 249 was prepared in 7 steps from commercially available starting materials.

! &#! Compound 249, in which both the diene and the dienophile are electron rich, underwent an intramolecular Diels-Alder reaction upon heating in a seal tube at high temperature using as solvent to afford pyrrolo carbazole 252 in excellent yield with a complete stereocontrol; the diastereomer obtained was from the exo-transition state 250 in which the non-bonding interactions are minimized.

Scheme 3.9 Rawal’s Diels-Alder approach for the ABCE tetracycle

CO Me CO2Me 2 CO2Me CO2Me N N N 185 °C vs N C6H6 N N CO Me MeO2C CO2Me CO2Me 2 Exo (favored) Endo 249 250 251

CO2Me N

252 99% N H MeO2C CO2Me

Rawal’s approach is also one of the most concise ways of accessing the tetracyclic core of the Strychnos alkaloids.

3.2.10 Martin’s Approach

In 1996, Martin and group108 employed a biomimetic approach to Strychnos alkaloids akuammicine and strychnine using a skeletal rearrangement, reminiscent of

Stork’s approach. They published two reports108 using this key skeletal rearrangement in

1996 and 2001. The precursor to the skeletal rearrangement was prepared in 11 steps from the commercial tryptamine.

! &$! When 253 was treated with LiHMDS at cold temperature, it produced the pentacyclic core intermediate 256 in modest yield.

Scheme 3.10 Martin’s skeletal rearrangement

Cl Cl

N LiHMDS N N N H H 253 H 254 H

MeO2C OTBS OTBS CO2Me

N N Cl H

N H N H H H CO2Me OTBS H CO2Me OTBS 255 256

The mechanism for this transformation was not fully established but probably involves the nucleophilic attack of the lithium enolate 254 onto the imine carbon to give pentacyclic intermediate 255, which subsequently undergoes a skeletal rearrangement with a concominant expulsion of chloride to afford pentacyclic intermediate 256.

3.2.11 Bonjoch-Bosch Approach

Bonjoch and Bosch109 reported a total synthesis of strychnine in 1999 using a few key strategies, out of which reductive Heck cyclization followed by zinc mediated reductive cyclization produced the ABCDE pentacycle. The key intermediate 257 was prepared in 9 steps from commercially available material via a Claisen rearrangement and a diastereoselective double reductive .

! &%! The secondary amine 257 was alkylated with a known allyl bromide 258 and potassium carbonate in acetonitrile to yield the hexahydroindolone 259.

Scheme 3.11 Bonjoch-Bosch reductive Heck cyclization

OTBS OTBS Br N NH N Pd(OAc)2 I 258 I PPh3, Et3N

NO2 NO K2CO3, MeCN NO O H 2 O 2 O 50% OTBS 257 7 4 % 259 260 N N LiHMDS 1. Zn, H2SO4 NCCO2Me 2. CH3ONa NO N H 67% 2 O 26% H H H CO Me OH 261 262 2 CO2Me OTBS

The reductive Heck cyclization of 259 was achieved using Pd(OAc)2, PPh3 and

Et3N to access tricyclic ketone 260 in 50% yield. Stereoselective methoxycarbonylation with LHMDS and Mander’s reagent provided !-keto ester 261, which was subjected to reductive cyclization using sulfuric acid and zinc dust. The methyl ester was equilibrated using sodium methoxide in refluxing methanol to produce the pentacyclic alcohol 262.

3.2.12 Vollhardt’s Approach

In the 1970s, Vollhardt and co-workers110 discovered a mediated [2+2+2] cycloaddition. This reaction was showcased in 2000 by synthesizing the pentacyclic ring system of Strychnos framework in a concise manner. Vollhardt’s synthesis of strychnine starts began with commercially available tryptamine.

! &"! Starting material 263 for the cycloaddition reaction was prepared in 6 steps. The key [2+2+2] cycloaddition reaction of 263 proceeded well to give the tetracyclic cobalt complex 265 in 46% and a side product in 20-30% yield.

Scheme 3.12 Vollhardt’s Co-mediated [2+2+2] cycloaddition

Ac Ac NHAc NHAc N N H (I) H CoCp (C2H4)2 + M N N N HC CH N H CoCp O O O O 46% 20-30% 263 264 265 266

NHAc NH NH Aq KOH 2 MeOH, reflux Fe(NO3)3 9H2O

N 93% N 77% N H CoCp H CoCp H O O O 265 267 268

This reaction may proceed as follows: (i) two ligands of low valent

CpCo(I)(C2H4)2 are displaced by the terminal in 263; (ii) oxidative coupling gives

Co(III) metallocypentadiene intermediate 264; and (iii) either an alkyne insertion or a

Diels-Alder type cyclization results in tetracycle 265. Hydrolysis of the 265 using aqueous KOH in refluxing methanol resulted the primary amine 267, which was subjected to an oxidative demetalation protocol with Fe(III), led to a formal 1,8-conjugate addition of the amine onto the unsaturated lactam, affording pentacyclic intermediate 268 in 77% yield.

! &&! 3.2.13 Mori’s Approach

In 2001, Mori and co-workers111 reported a total synthesis of strychnine, which consists of five palladium-catalyzed reactions. The palladium-mediated intramolecular

Heck cyclization of aryl bromide 269 onto the olefin resulted in the ABE ring system 270 in 87 % yield.

Scheme 3.13 Mori’s palladium catalyzed key cyclizations

CN CN NHBoc Cat. Pd(OAc)2 1. LiAlH Br 4 Cat. Me2PPh 2. Boc2O

N Ag2CO3 N N H H 74% H Ts DMSO, 90 °C Ts Ts 87% 269 270 271

Boc Boc Boc Cat. Pd(OAc)2 N N 1. 9-BBN, N 1. KHMDS Cat. Benzoquinone PhNTf2 H2O2 MnO2 N 2. Swern 2. Cat. Pd(OAc)2 N AcOH, 50 °C H N O H Ts Oxidation H Cat. PPh3 Ts 77% Ts 70% HCO2H, i-Pr2NEt 272 273 6 4 % 274

The reduction of the functionality in 270 to an amine using lithium aluminum hydride, followed by Boc protection realized the amine 271 in 74% yield over two steps. The palladium catalyzed allylic oxidation of 271 resulted in the teracycle 272, which may proceed through a nucleophilic attack of the amine onto the Pd-coordinated double bond and !-elimination. A regioselective oxidative of 272 using 9-

BBN gave the alcohol, which was oxidized using Swern conditions to realize the ketone

273 in 70% overall yield. The ketone was converted to the double bond functionality using regioselective formation of enol and Pd-catalyzed reduction to access the proper tetracyclic core 274 of the Strychnos framework.

! &'! 3.2.14 Bodwell’s Approach

Bodwell and co-workers112 reported a very concise formal synthesis of strychnine in 2002. The key strategy in their synthesis is the transannular inverse electron demand

Diels-Alder reaction (IEDDA). Bodwell utilized the “doubly tethered” arrangement of diene in 275 to facilitate the IEDDA reaction due to the two aromatic systems held closely in a specific orientation with respect to one another.

Scheme 3.14 Bodwell’s IEDDA reaction strategy

CO Me 2 CO2Me CO2Me N N N N,N-diethylaniline N reflux N N N N N N 100% N N H

275 276 277

CO2Me CO2Me N N NaBH4 CF3CO2H

N 100% N H H

278 279

Intermediate 275 was prepared in 5 steps from the commercially available tryptamine. The substrate 275 was heated in N,N-dimethylaniline to induce the transannular IEDDA reaction to afford the intermediate 276, following expulsion of

N2 produced pentacyclic product in quantitative yield. The chemo- and stereoselective reduction of 278 with NaBH4/CF3COOH resulted a quantitative yield of intermediate

279, which was also reported by Rawal and group. Bodwell’s short formal synthesis of strychnine was achieved in 12 steps starting with the commercially available tryptamine.

! &(! 3.2.15 Shibasaki’s Approach

In 2002, Shibasaki and group113 published a total synthesis of enantioselective strychnine using an asymmetric and a novel domino cyclization. The key starting material enone 280 was prepared in 16 steps from commercially available cyclohexenone using a catalytic asymmetric Michael reaction developed in their lab.

Scheme 3.15 Shibasaki’s transannular cyclization strategy

1. Tf O, i-Pr NEt EtS 2 2 SEt then, EtS EtS EtS N NH HO 2 H H SEt N DMTSF

O2N O 2. Zn dust. H N N H 86% H 2 O 77% H H OPMB OSEM OPMB OSEM 280 281 O S E M O P M B 282

1. NaBH3CN, TiCl4 N N N EtS 2. HCl EtS 1. TIPSCl, Im 3. Ac2O, Pyridine 2. NiCl2, NaBH4

N H N H 4. NaOMe, 35% N H 61% H H Ac OTIPS OPMB Ac OH OH OSEM OH 283 284 285

After introduction of the amine moiety using Tf2O and Hunig’s base, zinc dust mediated cyclization afforded tetracycle 282 in 77% yield. This tetracycle domino cyclization includes: (i) reduction of the nitro group to amine 281 by Zn dust; (ii) formation of the indole; (iii) 1,4-addition of the amine. The spirocyclization was achieved by the intramolecular electrophilic attack on to the thionium ion. Imine 283 was reduced using NaBH3CN and TiCl4. After some protecting group modifications, the desulfurization was achieved using nickel borite generated from NiCl2 and NaBH4 to produce the pentacyclic framework of Strychnos alkaloids.

! &)!

3.2.16 Fukuyama’s Approach

Fukuyama and co-workers114 reported an asymmetric synthesis of strychnine in

2004 demonstrating the uniqueness of 2-nitrobenzenesulfonamide (NsNH2) in the construction of cyclic . One of the key reactions used in this synthesis was similar to Magnus’ approach99 but the polycyclic iminium ion was selectively obtained by the removal of the Ns functional group.

Scheme 3.16 Fukuyama’s transannular cyclization by deprotection of Ns group

Ns N N N PhSH CO Me Cs CO H 2 2 3 CHO then N N H 84% N H CO Me CO2Me CF3CO2H 2 H CO Me Boc CO2Me H CO2Me 2 Me2S 286 287 288

The key starting material for the transannular cyclization was prepared asymmetrically in 19 steps. Aldehyde 286 bearing an ", !-unsaturated ester was subjected to a Ns deprotection protocol using and cesium carbonate. Treatment with trifluoroacetic acid and dimethyl induces a smooth transannular cyclization via requisite iminium ion 287 to prepare the tetracyclic skeleton of strychnine. In fact, intermediate 288 was also reported by Kuehne and group.105 Finally, by following

Kuehne’s procedure, this intermediate was converted to strychnine in an asymmetric fashion within 5 steps.

! '*! 3.2.17 Padwa’s Approach

In 2007, Padwa and co-workers115 published a synthesis of strychnine based on an intramolecular Diels-Alder reaction/rearrangement cascade, which was previously developed in his group. Due to the higher reactivity and greater stereocontrol, intramolecular cycloaddition reactions are powerful than the intermolecular versions.

Scheme 3.17 Padwa’s intramolecular Diels-Alder rearrangement

O O O Ar N Ar N Ar N

Cat MgI2 O O O N N N H Ac 289 A c 290 A c 291

O O Ar Ar N N

N N H H H 292 A c O H 293 Ac O

Tethered indolyl 289 was prepared in 4 steps from known starting materials.

The large on the amido nitrogen was expected to cause the reactive s-trans rotamer to be highly populated and therefore promote the intramolecular Diels-Alder reaction. Indeed, heating 289 in a microwave reactor with a catalytic amount of magnesium iodide yielded quantitative amounts of ABCE tetracycle 293. This domino sequence may proceed through: (i) nitrogen assisted ring opening of cycloadduct 291; (ii) subsequent deprotonation; and (iii) tautomerization of the enol to ketone 293.

! '+! 3.2.18 Vanderwal’s Approach

Over the past few years, Vanderwal and co-workers116 have pioneered the Zincke aldehyde chemistry. In 2009, they disclosed a concise strategy117 to access the ABCE tetracyclic core of the Strychnos and Aspidosperma alkaloids. A formal cycloaddition of the diene derived from the ring opening of pyridinium salts with the tryptamine moiety realized the tetracycle in good yields.

Scheme 3.18 Vanderwal’s formal cyclo addition of Zincke aldehyde

N N Ph t-BuOK, THF Ph N N Sealed tube, 80 °C H H 294 295 CHO CHO

N Ph N Ph formal [4+2]

N N H H H H CHO 296 C H O 297

N-benzyl tryptamine ring opening of the pyridinium salt realized the key Zincke aldehyde, which was subjected to a cycloaddition or stepwise bis-cyclization reaction.

Upon heating 294 with potassium tert-butoxide in a seal tube, cyclization followed by an isomerization process yielded the ABCE tetracyclic core. They also showcased this method by synthesizing norfluorocurarine and strychnine.117

! '#! 3.2.19 Reissig’s Approach

In 2010, Reissig and co-workers118 reported a formal total synthesis of strychnine using a samarium diiodide induced cascade reaction as the key step.

Scheme 3.19 Reissig’s samarium diiodide mediated cascade strategy

NC O N CN SmI2 Raney Ni HMPA H2

N O 76% N 97% N H OH H OH O OEt O O O 298 299 300

One of the highlights in this approach is that all the required atomic skeleton for the formation of the tetracycle are already present in the starting material, which was prepared in multigram scale by acylation of commercially available 3-indolylacetonitrile with 4-oxopimlic acid monoester. The key cyclization should be followed by an intramolecular acylation reaction, thus forming the two new rings and three stereogenic centers, including a quarternary carbon in a single step. In the event, the starting material

298 was treated with samarium diiodide in the presence of HMPA, the cyclization and the subsequent acylation readily occurred and the desired tetracycle 300 was isolated.

The cascade reaction was claimed to proceed within seconds due to the decolorization of

SmI2. Hydrogenation of the nitrile functionality in the presence of Raney nickel produced the primary amine, which was instantaneously converted into the pentacyclic imine 300 in a very good yield. This imine was subjected to a few more steps to intercept a strychnine intermediate prepared by Rawal.

! '$! 3.2.20 MacMillan’s Approach

In 2011, MacMillan and co-workers119 published an elegant strategy using an organocatalytic cascade approach to concisely access the tetracyclic framework of

Strychnos and other related family of natural products. This synthetic method was inspired by cascade catalysis in biosynthesis.

Scheme 3.20 MacMillan’s cascade catalysis strategy

O Boc 302 N NHBoc CHO 20 mol% Cat TBA

N SeMe 82%, 97%e.e. N 301 P M B P M B 303

1. (Ph3P)3RhCl NH Me O PhCN N 2. COCl2, Et3N 1-Nap t-Bu N then MeOH N H H Catalyst 3. DIBAL-H, TFA PMB CO2Me 61% 304 305

The key starting material 301 for the cascade catalysis was prepared in 3 steps from a known compound. With the required 2-vinyl indole 301 in hand, the crucial organo-cascade process was accomplished with the use of 1-naphthyl substituted imidazolidinone catalyst 305 in the presence of 20 mol% tribromoacetic acid (TBA) as co-catalyst to furnish tetracycle 303 in 82% and with excellent levels of enantioselectivity. Wilkinson’s catalyst-mediated decarboxylation and subsequent treatment with served to introduce a methoxycarbonyl group at the dienamine position. On exposure to DIBAL-H, the enamine unsaturation was reduced to access the indoline tertiary stereocenter with the isomeric mixture of the enoate 304 in 61% overall yield.

! '%! 3.3 Present Study

The extensive studies on degradation of strychnine120 started in the early 1880s, revealed that isostrychnine and Wieland-Gumlich aldehyde are the degradation products of strychnine.

N

H N H strychnine H O O 306

N N N

H H N N H N H H H H H H H CHO O HO HO O 307 O H 308 Isostrychnine Wieland-Gumlich Aldehyde

Figure 3.2 Degradation of strychnine

Synthetic studies to convert the degradation products back to strychnine were conducted independently in the Prelog and Robinson laboratories. Prelog, Anet and co- workers121 have shown that the conversion of isostrychnine to strychnine can be achieved in a single step by treating with alcoholic .

Scheme 3.21 Conversion of isostrychnie to strychnine

N N N

KOH H H N EtOH N 20% N H H H H H 85 °C H O HO O O O O Isostrychnine strychnine 307 309 306

! '"!

Hydroxide treatment induces olefin isomerization to form an ", !-unsaturated lactam with simultaneous creation of a stereocenter; conjugate addition of the pendant allylic provides strychnine in 20% yield.

Scheme 3.22 Conversion of Wieland-Gumlich aldehyde to strychnine

N N

H H N H N H H H H H N CH (CO H) 310 311 O 2 2 2 OH H NaOAC, Ac O 2 CO2H CO2H H isostrychninc acid N H AcOH H H 110 °C N HO O N

Wieland-Gumlich Aldehyde H H 308 N H N H H H H H O 312 O H 313 H CO2H CO2H strychninc acid

N N

H H N N H H 68% H H H O O O O H AcO strychnine 306 314

Robinson and co-workers122 transformed Wieland-Gumlich aldehyde (308) to strychnine (306) using a two-step protocol in 68% overall yield. This procedure involves treatment of 308 with a mixture of , sodium acetate and acetic anhydride in acetic acid as a solvent.

! '&!

The proposed transformation involves an equilibrium of strychnic and isostrychnic acids (Scheme 3.22). Enabled by these precedents, all synthetic approaches to strychnine reported thus far have targeted either isostrychnine or the Wieland-Gumlich aldehyde. As conversion of the latter is higher in yield, the Wieland-Gumlich route was selected.

Scheme 3.23 Rawal’s intramolecular Heck cyclization for D-ring closure

N N I OTBS Intramolecular Heck N N H high yielding H H O O OTBS 315 316

An extensive survey of the literature for D-ring closure of the Strychnos alkaloids suggested that Rawal’s intramolecular Heck cyclization107 is the best strategy. The ease of side-chain preparation, introduction and most importantly selectivity and high yield in the event made it an ideal target. Thus opted for this brilliant tactic.

Following this retrosynthetic analysis, the main aim of the project becomes constructing the ABCE tetracyclic core in the most concise manner possible. All different approaches toward this goal are presented in this chapter of which the first four were unsuccessful.

! ''! 3.3.1 First-generation Approach.

This approach was inspired by the total synthesis of aspidophytine reported by the

Corey lab.123 The authors have cleverly utilized the beta stabilization from .

Scheme 3.24 Corey’s inspiring polycyclization strategies

CHO TFAA N NaBH3CN NH2 OHC CO2iPr N + CO2iPr 66% MeO N Me SiMe3 H MeO Me 317 318 319

Na-Methyltrptamine 317 and dialdehyde 318 were reacted together in presence of trifluoroacetic anhydride (TFAA) and to furnish pentacycle

319 in 66% yield. The proposed mechanism is shown in Scheme 3.25.

Scheme 3.25 Proposed mechanism for Corey’s cyclization

N N H 317 + CO2iPr CO2iPr 318 MeO N MeO N MeO Me TMS MeO Me TMS 320 321 N N H H H CO2iPr 319 CO2iPr MeO N MeO N H H MeO Me MeO Me 322 323

Condensation of 318 with tryptamine 317 produces iminium ion 320, which can be trapped by the pendant allylsilane to access tetracycle 322.

! '(! Under the acidic conditions employed, the transiently formed enamine moiety isomerizes to iminium ion 323, which is reduced by the NaCNBH3 to secure pentacycle

319 in a single one-pot operation. With Corey’s elegant strategy123 as an inspiration, the first-generation retrosynthesis is shown in the following scheme.

Scheme 3.26 First-generation retrosynthesis

Bn Bn N N 325 NHBn N TMS N Me N Me3Si CHO Me 324 Me 327 326

Retrosynthetically, one can access the tetracycle 327 from iminium spirocycle

326 bearing a pendant vinyl silane moiety. The vinyl silane functionality is nucleophilic enough to cyclize onto the iminium spirocycle to access the six-membered E ring.

124 Spirocycle 326 in turn can be prepared by condensing aldehyde 324 with known Nb- benzyl tryptamine (325).125 To test the feasibility of our plan, the requisite intermediates were prepared from commercially available starting materials.125

Scheme 3.27 First-generation Forward synthesis

Me Si CHO 3 Bn Bn 324 N N

TMS N N Me 326 Me 327 NHBn N

Me Condition 1. PhCO2H, MgSO4, C6H6. (rt and reflux) 325 Condition 2. PPTS, MgSO4, C6H6. (rt and reflux)

Condition 3. 4 A0 Mol.Sieves, TFA, MeCN. (rt and reflux)

! ')! Vinyl silane aldehyde 324 was freshly prepared and used without chromatography purification. Stirring aldehyde 324 with tryptamine 325 in benzene with magnesium sulfate as a desiccant and a catalytic amount of or pyridinium para- toluenesulfonate (PPTS) to result in the condensation, followed by the addition of vinyl silane cyclization to produce the tetracycle. Unfortunately, starting material 325 was recovered and no trace of product was observed. This reaction was also performed with

4Å molecular sieves as desiccant and catalytic trifluoroacetic acid (TFA) in acetonitrile.

No product was observed in either case, and starting material 325 was recovered. In both reactions, the aldehyde portion decomposed and not stable to the reaction conditions or chromatography. With these failures and knowing the unstable nature of the vinyl silane aldehyde, attention was turned to the second-generation approach.

3.3.2 Second-generation Approach

The second-generation approach focused on a stepwise formation of the spirocycle with the goal of trapping the incipient spiroindolenium ion 328 with a (e.g., hydride or an allyl trimethylsilane. From this intermediate, the tetracycle could be prepared via ring-closing metathesis (RCM) or another tactic. The retrosynthesis for the second-generation approach is shown below.

Scheme 3.28 Second-generation retrosynthesis

Bn Bn N N PhCOOH SiMe3 325 MgSO NHBn 4 N or Me CHO N R N 328 330 Et SiH Me 3 329 Me

! (*!

In the second-generation strategy, the goal was to isolate the spirocyclic intermediate 329 and proceed to the next cyclization. The spirocyclization can be realized by condensation of Nb-benzyl protected tryptamine derivative and crotonaldehyde with a catalytic amount of benzoic acid and a desiccant. As discussed above, the resulting spiroindolenium ion 328 could, in principle, be trapped with an external nucleophile namely a hydride source from triethylsilane or an allyl trimethylsilane. The forward synthesis for the second-generation strategy is as shown in Scheme 3.29 and starts with a literature known tryptamine derivative 325.125 Addition of crotonaldehyde to a solution of

325 in benzene with magnesium sulfate presumably formed the iminium ion. Addition of triethylsilane or allyl silane, however, resulted in only the recovery of starting material.

Scheme 3.29 Second-generation forward synthesis

Bn Bn N N NHBn N Me 325 328 N R 329 N Me R = Allyl / H Me

Condition 1. PhCOOH, MgSO4, Crotonaldehyde, Et3SiH in C6H6. (rt and reflux)

Condition 2. PhCOOH, MgSO4, Crotonaldehyde, Allylsilane in C6H6. (rt and reflux)

The reaction was also performed with the nucleophile in solution. Unfortunately, starting material 325 was recovered in all of the reaction conditions.

! (+! 3.3.3 Third-generation Approach

As the vinyl silane aldehyde route from the first-generation and the intermolecular trapping of the spiroindolenium ion from the second-generation strategies failed, we decided to employ a pendant allyl as opposed to vinyl trimethylsilane. Allyl silanes are more nucleophilic than their vinyl counterparts.126 This tactic was featured in Corey’s precedent of intramolecular trapping an N-methyl spiroindolenium ion 321 with a pendant allyl trimethylsilane (Schemes 3.24 and 3.25).123 Other key reactions inspired this approach are from Jacobsen127 and Weinreb128 laboratories. In 2004, Jacobsen and co-workers127 published a highly enantioselectiove acyl Pictet-Spengler reaction, shown in Scheme 3.30. The imine was formed by condensing tryptamine and an aldehyde, which was activated using acetyl chloride and accessed the Pictet-Spengler products 333 in good yields and enantioselectivities. was achieved by using a chiral catalyst developed in the Jacobsen laboratory.

Scheme 3.30 Jacobsen activation of the imine using acetyl chloride

AcCl RCHO 2,6-lutidine NH2 N N N N 5-10 mol% N Ac H Na2SO4 H H R Chiral Catalyst R 331 332 333

In 2001, Weinreb and co-workers128 utilized the beta-carbocation stabilization by a trimethylsilyl group to cyclize N-acyl iminium ion 337 and obtain spirocycle 338 in good yield.

! (#! Scheme 3.31 Weinreb’s intramolecular spirocyclization via tethered allyl trimethylsilane

Me3Si N Me3Si 1. LDA, THF TFA 334 Me Si 2. o-NO PhCOCl N N 3 2 CH2Cl2 NEt3 O O Ar I O2N 335 336 337

N 58% 338 O Ar

The third-generation retrosynthesis is shown in Scheme 3.32. Tetracycle 343 would be formed by trapping of N-methyl spiroiminium ion 342 with the pendant allyl trimethylsilane, which in turn would arise from the union of 341 and 339.

Scheme 3.32 Third-generation retrosynthesis

R R N N 341 NH N 2 Me N N TMS 339 Me Me CHO (E or Z) 343 342 SiMe3

129 130 The Na-methyl tryptamine and the corresponding aldehyde were stirred in the presence of sodium sulfate as a desiccant to provide the imine (Scheme 3.33). This imine was activated using different acyl chlorides to facilitate the spirocyclization. Assuming the formation of spirocylic iminium ion 342, the allyl silane was treated with trifluoroacetic acid (TFA) to trigger the cyclization at the beta position on to the iminium ion and result in the tetracycle.

! ($! Scheme 3.33 Third-generation forward synthesis

Me Si 3 R R CHO N N 339 NH2 (E or Z) N Me 341 CHO N N Me 343 Me 340 342

SiMe3

Condition 1. Na2SO4, CbzCl, TFA, CH2Cl2 Condition 2. Na2SO4, AcCl, TFA, CH2Cl2

Condition 3. Na2SO4, TFAA, CH2Cl2 Condition 4. Na2SO4, TFA + TFAA, CH2Cl2

Condition 5. Na2SO4, TFAA, MeCN.

Acetyl chloride (AcCl), benzyloxy chloroformate (CbzCl), trifluoroacetic anhydride (TFAA) were used as the activating reagents for the spiroimine formation, where as TFAA and TFA were used for the allyl silane cyclization. Both E and Z olefin aldehydes were screened to see if there is any difference in the reactivity of allyl silanes.

Unfortunately, none of the reaction conditions were successful for the formation of tetracycle. In all cases, the tetrahydro-!-carbolines derived from the Pictet-Spengler reaction127 were isolated.

3.3.4 Fourth-generation Approach

In 1989, Nakagawa and co-workers131 have used nitrones in the Pictet-Spengler kind of reaction. The following reaction scheme shows a very good example of generation and usage of the nitrone system to access the spiroimine followed by trapping it in an intramolecular fashion.

! (%!

Scheme 3.34 Nakagawa’s usage of nitrone in the cyclization

CHO r.t., 5 min + NHOH SR2 N N R1HN TFA N O Me Me CH2Cl2 344 345 346 R1HN SR2 OH N H H

N N SR2 H R Me 2 347

The fourth-generation strategy was inspired by this nitrone strategy131 and the goal was to apply in accessing the Strychnos framework. The retrosynthetic analysis for this route is shown below.

Scheme 3.35 Fourth-generation retrosynthesis

OH OH N N NHOH 348 N N R N TMS 339 R R CHO 350 349 E or Z SiMe3

The spiroimine 349 can be envisioned from the condensation of the hydroxyl- tryptamine131 (348) and aldehyde 339.130 As discussed before, spiroindolenium ion 349 can be trapped with a pendant allyl trimethylsilane moiety to quickly access tetracycle

350.

! ("!

Scheme 3.36 Fourth-generation forward synthesis

NHOH N 348 TMS R N CHO N O R = H, Me R E or Z 349 339 TMS OH N

TFA, CH2Cl2 (or) 350 N TFAA, CH2Cl2 R

The fourth generation forward synthesis started with known hydroxytryptamine

(348) and aldehyde 339. Following Nakagawa’s conditions131, nitrone 349 was prepared from the corresponding aldehyde and hydroxytryptamine (348), which was subjected to the spirocyclization followed by allyl silane ring closure onto the spiroiminium ion. Both,

N-methylated and unprotected versions of tryptamine and (E) or (Z) aldehydes 339 were screened. The nitrone was treated with both trifluoroacetic acid (TFA) and trifluoroacetic anhydride (TFAA) in dichloromethane. Unfortunately, none of the reactions and gave us tetracycle 350. Instead, only isolated Pictet-Spengler products.127

3.3.5 Fifth-generation Approach

Having the failures from all the previous four generations, we wanted to follow a route that would avoid (or attenuate) the 1,2-Wagner-Meerwein shift required in the

Pictet-Spengler . Toward this end, we recruited a next to the nitrogen of the spirocycle.

! (&! The electron-withdrawing nature of the carbonyl group should slow down or completely block the 1,2 shift as the migrating group (the basic amine or Nb) is electron- deficient.

Inspiration for the fifth generation approach came from work in the Aspidosperma family of alkaloids from the Magnus 132 and Heathcock 133 groups, in addition to

Woodward’s landmark synthesis of strychnine where a spirocycle was prepared early in the synthesis (Scheme 3.4).94 Both spirocyclization reactions from Magnus and

Heathcock are shown in Scheme 3.37.

Scheme 3.37 Magnus and Heathcock spirocyclizations

O O Ph(O)S N N PhS TFAA Et Et N 91% N Ts 351 T s 352

O O N Cl N N 1. NaI, LAH Et Et 2. AgOTf Et 82% N H H N N H 84% 353 354 221

In 1983, Magnus and co-workers reported a clever spirocyclization strategy for assembling Aspidosperma alkaloids. The key step featured a Pummerer reaction using

TFAA to activate 351, which was followed by the removal of functional group.

In 2001, Heathcock and co-workers133 published a smooth spirocyclization reaction using silver trifluoromethane sulfonate (AgOTf) and a pendant iodoacetamide.

! ('! Chloroacetamide 351 was first converted to the iodide under Finkelstein conditions; subsequent treatment with silver triflate produced the spirocycle 354, which was converted to the natural product aspidospermidine (221) by reducing both the lactam and imine with lithium hydride.

A major advantage in these spirocyclizations is the stability and rigid nature of the molecule in the tetracycle. In the Strychnos system, where the goal was to access ABCE framework, the D and E rings are not present and are not rigid. The retrosynthesis for the fifth-generation strategy is as shown in the following scheme.

Scheme 3.38 Fifth-generation retrosynthsis

O O O R R X = Cl, Br, I X R N N N

N N N H H H CO2Me CO2Me CO2Me 363 362 361

In a retrosynthetic analogy, the tetracycle can be accessed from the spiroimine intermediate with an enolate already present in the molecule. An intramolecular aza-

Baylis-Hillman reaction134 can achieve this transformation. This spiroimine 362 indeed can be prepared from haloacetamide precursor 361 using similar conditions followed by

Heathcock.133 The forward synthesis begins with Scheme 3.39.

! ((! Scheme 3.39 Fifth-generation synthesis of spiroindolinine

NHBn ClAcCl CHO 1.) BnNH2 Et3N

N 2.) allylMgBr N 95% H H 355 9 0 % 356

O NOE O R AgOTf NBn 2,6-di-t-butyl- H NBn H 4-methylpyridine

PhMe H H N N H rt, 1.5 h H NOE 357: R = Cl NaI 359 358: R = I acetone 94% from 357

The fifth-generation strategy began with condensation of commercially available indole 3-carboxaldehyde (355) and using magnesium sulfate as a desiccant to produce the corresponding imine. The imine, in turn, was treated with allyl magnesium bromide to furnish the allylated product 356. Secondary amine 356 was acylated using and triethylamine in dichloromethane as solvent to afford chloroacetamide 357 in 95% yield. The chloroacetamide was then subjected to the spirocyclization conditions reported by Heathcock and co-workers. Unfortunately, the reaction did not proceed and decomposition of the starting material was observed.

Conversion of chloroacetamide 357 to iodoacetamide 358 using Finklestein conditions133set the stage for critical spirocyclization. Examination of molecular models suggested the cyclization would procede stereoselectively to furnish an intermediate mapping onto the C-ring of the Strychnos alkaloids.

! ()! When the iodoacetamide 358 was treated with freshly activated silver triflate

(AgOTf), regrettably it did not undergo the spirocyclization. The use of silver triflate in the reaction can generate (TfOH), which could decompose the starting material. To rectify this, a non-nucleophilic base was employed to scavenge the TfOH produced from the reaction. As such, a variety of bases were screened including pyridine, 2,6-lutidine, triethylamine, diisopropylethylamine (Hunig’s base) and 2,6-di- tert-butyl-4-methyl pyridine (DTBMP). The reaction worked well with the iodoacetamide substrate; however, of all the bases screened in the reaction with silver triflate, DTBMP was found to be the best base. Next, various solvents: THF, toluene, dichloromethane and methanol were screened.

The spirocyclization worked well in both THF and toluene. Stronger bases (e.g.,

NaH and t-BuOK) also cyclized 358 in the absence of AgOTf albeit at the expense of both yield and diastereoselectivity. 135 Finally, the relative stereochemistry of spiroindolenine 359 was secured from an NOE analysis of select hydrogens (C9-C3 and

C2-C4) in the 1H NMR spectrum. With the C7 stereocenter and C-ring in place, attention was directed at closing the E-ring. Keeping the electrophilicity of the spiroimine and need for a methoxycarbolate to access the ABCE tetracycle, we envisioned the use of an intramolecular aza-Morita or aza-Baylis-Hillman134 (IABH) reaction. To the best of our knowledge, this specific transformation was unprecedented.136 Furthermore we wanted to consolidate a step by utilizing a bromoacetamide in place of a chloroacetamide as the latter did not cyclize when subjected to our optimized reaction condition.

! )*! Scheme 3.40 Synthesis of enoate-tethered spiroindolinine

O Br CO Me NHBn BrAcCl NBn 2 10 mol% HG-II Et3N

N CH2Cl2 N CH2Cl2 H 94% H reflux, 3h 356 360 90% (dr = 12:1)

O O AgOTf Br NBn NBn 2,6-di-t-butyl- 4-methylpyridine

PhMe N N H rt, 1.5 h CO Me CO2Me 361 2 362 95% (dr = 13:1)

To realize this goal, acylation of the secondary benzylamine 356 with bromoacetyl chloride furnished the bromoacetamide 360 in 94% yield. A cross-metathesis reaction was utilized to install the enoate functionality.137 Phosphine-free Hoveyda-Grubbs II catalyst (HG-II)138 proved effective for this transformation, affording enoate 361 in 90% yield (dr = 12:1 by LC-MS). Gratifyingly, the key spirocyclization also proceeded well with bromoacetamide 361, accessing the spiroindolinine 362 in 95% yield (dr = 13:1).

Scheme 3.41 Novel intramolecular aza-Baylis-Hillman reaction to close the E-ring

O O NBn NBn H DBU CO2Me N THF N rt, 12 h H H CO2Me 362 363 90%

! )+! With the spiroindolinine 362 in hand, we turned our attention in cyclizing the E- ring. A variety of conditions were screened to effect either the intramolecular aza-Morita or IABH reaction. There was no reaction of the spiroindolinine 362 with tributyl phosphine (Bu3P), triethylamine (Et3N), Hunig’s base (i-Pr2NEt), (4-

Dimethylamino)pyridine (DMAP), or 1,4-Diazabicyclo[2.2.2]octane (DABCO) regardless of solvents used (e.g., CH2Cl2, THF, PhMe). However, treatment of the spiroindolinine 362 with 2 equivalents of 1,8-diazabicycloundec-7-ene (DBU) in toluene at room temperature for 12 h cleanly afforded ABCE tetracycle 363 in 90% yield. The use of less DBU translated into longer reaction times. Performing the reaction in THF gave 363 in slightly lower yield (83%).

As the more traditional Baylis-Hillman bases did not effect the cyclization irrespective of loading (0.1-2.0 equiv), an alternative mechanistic hypotheses emerged, namely, #-deprotonation of the enoate by DBU, cyclization, and olefin isomerization.139

To test this hypothesis we carried out the same reaction in PhMe that had been saturated with D2O. If the DBU-promoted deprotonation and attendant cyclization/isomerization sequence was operative, a fraction of deuterium incorporation at gamma-position should be observed in the 1H NMR spectrum of the tetracycle 363. In the event, however, no such evidence of this taking place was found. While this experiment does not disprove the alternate mechanistic hypothesis, it does strengthen the IABH argument. Currently some other experiments are in progress from our laboratory to validate the mechanism.

! )#! Figure 3.2 ORTEP of ABCE tetracycle 363.

O N Ph

N H H CO2Me 363

Recrystallization of the tetracycle 363 from EtOAc afforded material suitable for single crystal X-ray analysis. The ORTEP representation of 363 is shown in Figure 3.2, confirming the structural assignment of the ABCE Strychnos tetracycle.

Our laboratory has had a longstanding interest in maximizing synthetic efficiency in the context of natural product total synthesis51 either by deliberately avoiding protecting groups (shown in Chapter 2) or sequencing reactions in a one-pot (tandem) manner44 to rapidly access useful building blocks (shown in Chapter 1).

Scheme 3.42 Sequential One-Pot Synthesis of Tetracycle 363.

O O O Br AgOTf NBn NBn 2,6-di-t-butyl- NBn C 4-methylpyridine H DBU CO2Me N A B E THF rt, 12 h N N H rt, 1.5 h CO Me H H 361 2 362 363 CO2Me dr = 9:1 not isolated 74% overall

By not isolating the spiroindolinine 362, a sequential one-pot version could be achieved, thus streamlining the synthesis.

! )$! In the event, treatment of the bromoacetamide 361 with AgOTf and DTBMP in toluene at room temperature for 1.5 h followed by the addition of DBU and additional stirring for 12 h afforded the tetracycle 363 in 70% isolated yield after flash silica gel chromatography.140

3.4 Conclusions

In conclusion, a concise and efficient route to the ABCE tetracyclic scaffold 363 of Strychnos alkaloids (five steps from commercially available indole-3-carboxaldehyde,

53% overall yield) 140 was developed. This route features a novel sequential one-pot spirocyclization/intramolecular aza-Baylis-Hillman reaction that proceeds in 70% overall yield. This novel method was utilized in synthesizing various Strychnos alkaloids, which are discussed in the next chapter.

! )%! CHAPTER 4: CONCISE TOTAL SYNTHESES OF STRYCHNOS ALKALOIDS

4.1 Introduction

Among the monoterpenoid indole alkaloids, Strychnos alkaloids are the most famous and have attracted considerable attention from the synthetic community.

Representative alkaloids strychnine (306) and akuammicine (352) are shown below with numbering and ring labeling based on the biogenetic interrelationship of monoterpene indole alkaloids.92 Strychnine was isolated in 1818 by French pharmacists Pelletier and

Caventou from Strychnos nux vomica85 and is famous for its poisonous nature. The structure of strychnine was determined by Robinson88 and Woodward87 in 1948.

5 4

6 N N N 9 21 C 8 D 10 3 14 E 7 A 2 H 15 20 B 11 1 H 13 N 16 19 N N 12 H H H F H H H G 18 CO2Me O 24 17 O O O 23 strychnine (306) akuammicine (352) strychnine (306)

Figure 4.1 Structures of Strychnine and Akuammicine

There was more than hundred years of research work done on the structure elucidation of strychnine through many number of publications. A comprehensive review on the 150 years of historical work on the chemistry of strychnine was written in 1964 by

Smith.141 The landmark synthesis of strychnine by Woodward and group94 has been the inspiration for many organic chemists and has proven the power of synthesis in preparing complex architectural molecules.

! "#! Because of its complex architecture, Sir Robert Robinson made the famous remark “For its molecular size, strychnine is the most complex substance known.”142

Woodward further commented “The tangled skein of atoms which constitutes its molecule provided a fascinating structural problem” in 1954.94 Since the first synthesis in

1954, around twenty total syntheses of strychnine are reported in asymmetric and racemic form from different research groups. The Andrade group published a racemic synthesis of strychnine using a novel one-pot bis-cyclization strategy developed in our laboratory.143

Some of the most relevant syntheses of strychnine to our approach are discussed in this chapter. The introduction and background of strychnine was discussed in length in the third chapter and recently excellent reviews on syntheses of strychnine were published from Bonjoch and Shibasaki laboratories.95

Before we look into any synthetic details of strychnine, it is very important to discuss the biosynthesis 144 of strychnine, which is shown in Scheme 4.1. The enzymatically catalyzed Pictet-Spengler condensation of tryptamine with secologanin

365 provides , which is converted to geissoschizine 367, the common biogenetic intermediate for all monoterpenoid Strychnos alkaloids. An oxidative cyclization followed by a skeletal rearrangement of geissoschizine results in the characteristic Strychnos framework dehydropreakuammicine. The loss of a carbomethoxy functional group results in norfluorocurarine, which upon oxidation at the allylic position in the ethylidene moiety and reduction of the vinylogous furnishes the

Wieland-Gumlich (W-G) aldehyde (308).

! "$! Scheme 4.1 Proposed biosynthesis of strychnine

H OGlu OHC NH N O H NH2 H N H OGlu strictosidine H CO Me H 2 O tryptamine 331 secologanin 365 366 MeO2C

N N H N N H H N H N H CHO H MeO2C H CHO 367 dehydropreakuammicine 368 norfluorocurarine 369 MeO2C OH geissoschizine

N N N

H N H N H N H H H H H H CHO OH OH O O HO2C OH Wieland-Gumlich aldehyde 308 prestrychnine 340 strychnine 306

The W-G aldehyde was also shown to be one of the degradation products of strychnine (306).120 In order to complete the strychnine backbone, two additional are required and Robinson suggested that they come from an acetate and was proved in

1969 by Schlatter,145 and possibly occurs through prestrychnine (340), which is formed from an involving acetyl-CoA. Figure 4.2 shows an overview of all the syntheses of strychnine until 2011.

! "%! Table 4.2 Summary of strychnine syntheses

Year Group Steps

1954 Woodward Relay 28

1992 Magnus Relay 28

1992 Stork Racemic 17

1993 Overman Resolution 24

1993 Kuehne Racemic 20

1994 Rawal Racemic 12

1998 Kuehne Chiral pool (L-) 19

1999 Bonjoch/Bosch (S)-phenylethylamine 16

2000 Vollhardt Racemic 14

2001 Martin Racemic 16

2002 Bodwell Racemic 12

2002 Shibasaki Catalytic Asymmetric Michael 31 reaction 2004 Mori Asymmetric allylic amination 23

2007 Fukuyama Resolution 25

2010 Padwa Racemic 16

2010 Andrade Racemic 13

2010 Reissig Racemic 11

2011 Vanderwal Racemic 6

2011 MacMillan Organocatalytic 12

! "&! Akuammicine was first isolated in 1927 from the seeds of Picralima klaineana and has subsequently been found in various genera of . 146 It is also found in several plant species in both optically active (levorotatory) and racemic forms. The structure of akuammicine was first proposed by Robinson147 and later was confirmed by

Smith and coworker148 by establishing a correlation with strychnine. Overman and co- workers149 reported the first total synthesis of akuammicine in 1993. The Andrade lab published a concise total synthesis of akuammicine in 2010 and there are altogether six reports on total synthesis of akuammicine to date.143 In this chapter, all of the relevant syntheses of akuammicine are discussed in chronological order. The following Figure shows an overview of all the syntheses of akuammicine until 2011.

Table 4.3 Summary of akuammicine syntheses

Year Group Chirality Steps

1993 Overman Racemic 13

1994 Kuehne Racemic 9

1996 Bonjoch/Bosch Racemic 15

1996 Martin Racemic 10

2010 Andrade Racemic 6

2011 MacMillan Organocatalytic 10

2011 Andrade Chiral Auxiliary 9

! ""! 4.2 Background

4.2.1 Akuammicine Total Syntheses

4.2.1.1 Overman’s Approach.

In 1993, Overman and co-workers149 reported the first total synthesis of akuammicine in racemic form. Enol triflate 342 was prepared in 3 steps from commercially available 2-cyclopentenone in 35% overall yield. Palladium-catalyzed coupling of vinyltriflate 342 with hexamethylditin produced vinylstannane 343, which was carbonylatively cross coupled with the triazone protected 2-iodoaniline 344 to furnish enone 345.

Scheme 4.2 Overman’s synthesis of akuammicine

O Me Me N N O TIPSO TIPSO 344 3 steps N I 35% X 341 Me O Pd(PPh ) 342 X = OTf Pd (dba) 3 4 2 3 N (Me3Sn)2 AsPh3, CO N = Ar 343 X = SnMe O LiCl 90% 3 N LiCl 85% Me 345 R

N t-BuO2H Triton B NaH, PhH N 1. (CH2O)n O Ar R X 87% HO 2. LDA O H Ar NCCO Me Ar 2 CO2Me 346 X = O, R = OTIPS Ph3PCH3Br 351 KHMDS, 91% 349 R = COCF3 347 X = CH2, R = OTIPS KOH TBAF, MsCl 75% 350 R = H LiCl, NaH 348 X = CH2, R = NHCOCF3 NH2COCF3 60% O Me Me N N N

HCl, MeOH Ar = N 82% from 350 N H H CO2Me 352

! '((! Enone 345 was epoxidized with Triton B and t-BuOOH to afford epoxide 346 in

87% yield. Wittig of the aromatic ketone provided styrenenyl derivative

347, which was readily converted to the allylic trifluoroacetamide 348 via displacement of an allylic chloride intermediate with sodium trifluoroacetamide. Treatment of 348 with sodium hydride triggered the cyclization to provide the bicyclic amide 349, which upon deacylation using potassium hydroxide resulted in the desired rearrangement substrate

350 in 75% yield. Treatment of 350 with paraformaldehyde allowed the aza-Cope-

Mannich rearrangement,103 yielding the azatricycloundecane, which was carbomethoxylated using methyl cyanoformate to afford 351. Upon treatment with 1N

HCl, the triazone protecting group was cleaved. Condensation of the with the proximal ketone and attendant tautomerization produced akuammicine (352) in 82% overall yield from 350.

4.2.1.2 Kuehne’s Approach

In 1994, Kuehne and co-workers106a published a racemic total synthesis of akuammicine using a Mannich [3,3]-sigmatropic rearrangement strategy. Formylacetone ketal 353 was subjected to a Wittig reaction and extended to its vinylogue 355 in 86% yield. This unsaturated aldehyde upon heating with N-benzyl-2-

((methoxycarbonyl)methyl)tryptamine (244) in presence of borontrifluoride diethyl etherate triggered the Mannich [3,3]-sigmatropic rearrangement affording tetracyclic ketal 356 as a single diastereomer.

! '('! Debenzylation by with ammonium-formate and Pd/C provided the secondary amine, which upon condensation with formaldehyde afforded iminium intermediate 357. After treatment with HCl, the iminium-ketal underwent cyclization.

Scheme 4.3 Kuehne’s synthesis of akuammicine

Bn HN N Ph3P=CHCHO N Bn 354 O 244 H CO Me O O 2 O O O O O H H CHCl3, 60 °C BF3 Et2O N 353 8 6 % 355 356 H CO2Me

CH2 1. 10% Pd-C, N N 1. HCl, Reflux HCOONH4 O O O 2. HCl-H O Me 2. HCHO, MeOH N 2 N 83% H CO2Me H CO2Me 357 358

N H N BF3 Et2O / AcOH BnSH SBn Raney Ni HMe 63% N Me 83% N H CO2Me H CO2Me 359 352

The ketal protecting group was hydrolyzed to access ketone 358 in 83% yield from tetracycle 356. The ketone was converted to a thioenol ether with benzyl mercaptan and borontrifluoride diethyl etherate. Reduction with Raney nickel secured akuammicine

352 in 83% yield.

! '()! 4.2.1.3 Martin’s Approach

Martin and co-workers108 disclosed a 10 steps biomimetic synthesis of akuammicine in 1996. Imine 360 was prepared in 2 steps from commercially available tryptamine and was treated with 1-((trimethylsilyl)oxy)butadiene (361) in the presence of crotonyl chloride (362) to undergo a vinylogous Mannich reaction to furnish enal 363 in

79% yield. The enal was cyclized upon heating to give the pentacycle 364. With 364 in hand, hydration of the moiety followed by oxidation of the intermediate afforded lactone 366 in 79% yield. When this lactone was treated with sodium methoxide, !-elimination gave an acid, which was esterified in situ to produce the deformylgeissoschizine 367.

Scheme 4.4 Martin’s biomimetic synthesis of akuammicine

OTMS 361 N O N O N N N H N COCl H 80% H H H H 362 360 363 364 H 79% O O

Me3OBF4, DBPy; 1. p-TsOH N O NaOMe, MeOH N O then NaBH N N 4 H H H H H 2. (Ph3P)3RuCl2 then (COCl)2 91% Et3N 366 H 9 2 % 367 H O 79% O MeO2C Ph O 365 N

N 1. t-BuOCl N H H 2. LHMDS N H

H H CO2Me 368 7 0 % 352 MeO2C

! '(*! Having intermediate 367, selective reduction of the amide moiety using Borch’s conditions154 furnished the substrate 368 for key cyclization in 91% yield. Treatment of

368 with tert-butylhypochlorite effected an oxidation leading to a mixture of epimeric chloroindolenines that were subsequently treated with with lithium hexamethyldisilazide.

The pendant enolate generated from this reaction cyclized onto the sprioindolenine affording akuammicine 352 in 70% yield from b-tetrahydrocarboline 368.

4.2.1.4 MacMillan’s Approach

In 2011, MacMillan and co-workers119 published the first asymmetric synthesis of akuammicine in 10 steps using organocascade catalysis. The key starting material 301 for the cascade catalysis was prepared in 3 steps from a known compound. With the required

2-vinyl indole 301 in hand, the crucial organocascade addition/cyclization was accomplished with the use of 1-naphthyl substituted imidazolidinone catalyst 305 in the presence of 20 mol% tribromoacetic acid (TBA) as co-catalyst to furnish the spiroindoline 303 in 82% and with excellent levels of enantioselectivity. Wilkinson’s catalyst-mediated decarboxylation and subsequent treatment with phosgene served to introduce a methoxycarbonyl group at the dienamine position. Upon exposure to DIBAL-

H, the enamine was reduced to furnish the indoline tertiary stereocenter with an isomeric mixture of enoate 304 in 61% overall yield. Treatment of the PMB-protected spiroindoline 304 with TFA and thiophenol realized the deprotection of the PMB group as well as the isomerization of the into conjugation with the carbomethoxy functional group to afford the diamine 369 in 91% yield.

! '(+! Scheme 4.5 MacMillan’s organocascade approach to akuammicine

O Boc 1. (Ph P) RhCl 302 N 3 3 NH NHBoc PhCN CHO 20 mol% 305 TBA 2. COCl2, Et3N

N SeMe 82%, 97%e.e. N N then MeOH H PMB PMB 3. DIBAL-H, TFA PMB CO2Me 301 303 304 61%

NH N N Br H TFA I Pd(OAc)2 PhSH 370 I NaHCO3 H K2CO3 N Me 91% N H N H Bu NCl H 76% H 4 H CO2Me CO2Me CO2Me 47% 369 371 (-)-Akuammicine 352 10 steps, 10% overall yield

The nitrogen was selectively alkylated with the bromide 370151 to furnish the vinyl iodide 371, which is the precursor to the intramolecular Heck cyclization. After subjection of the vinyl iodide to modified Heck cyclization conditions produced akuammicine in 47% yield.

4.2.2 Strychnine Total Syntheses

4.2.2.1 Woodward’s Approach

After six years of structural elucidation of strychnine, Woodward and group94 reported the first total synthesis of strychnine in 1954, which is a historical landmark in organic synthesis. Woodward employed his biogenetic proposal featuring the oxidative cleavage of an aromatic ring and the subsequent recombination of the fragments to build up the core skeleton of strychnine. The synthesis is as shown in Scheme 4.7. The starting material, 2-veratryltryptamine (222), was prepared in 5 steps from commercially available acetoveratrone.

! '(#! Condensation of ethyl glyoxylate with 222 produced the corresponding , which was treated with TsCl to increase the electrophilicity of the imine and trigger the Mannich reaction, in addition to stabilizing the spirocycle.

Scheme 4.7 Woodward’s landmark synthesis of strychnine

Ts Ts NH2 O N N 1. H CO Et 1. NaBH4 2 CO2Et CO2Et OMe OMe OMe N 2. p-TsCl N 2. Ac2O N H 84% Ac OMe 64% OMe OMe 222 224 225 Ts 1. HI, red P Ac O3 Ts N N N 2. Ac2O AcOH MeOH 3. CH2N2 H O CO Et HCl CO2Me 2 2 CO2Et N CO Me 75% 57% Overall N CO2Me 29% 2 N CO2Me Ac CO2Me O O 226 227 228 Ac Ac 1. Raney-Ni Ac N N N H 2. H , Pd/C H H 1. TsCl SCH Ph 2 NaOMe OH 2 3. KOH 2. PhCH2SNa

N CO2Me N CO2H 88% N CO2 M e 77% 53% O O O 230 372 1st relay compound 373

H N N N SeO O 1.HC CNa O H 2 1. Ac2O, Py 8% 2. H2-Lindlar OH 2. Aq HCl CH3 N O 46% N N H H AcOH O O O O 374 2nd relay compound 375 376 N N 1. LiAlH 4 KOH, EtOH 2. HBr, AcOH H N H N H 3. Aq H2SO4 H H 4% O HO O O Isostrychnine 307 Strychnine 306

! '($! The spiroindolenine was reduced with NaBH4, which occurred from the most accessible !-face to give spiroindoline intermediate. Protecting of the amine with Ac2O afforded amide 225. The veratryl functionality was then subjected to to cleave at the most electron rich double bond position, followed by treatment with methanolic

HCl to give pyridone 227. The N-tosyl group was removed using HI in the presence of red phosphorus to afford an intermediate. Reprotection of the amine and treatment with diazomethane furnished 228. Treatment of 228 with sodium methoxide in methanol epimerized the stereogenic center, and Dieckman condensation furnished !- keto ester 230 in 88% yield. Treatment of 230 with tosyl chloride resulted the corresponding tosylate, which upon reacting with sodium benzylmercaptide gave the sulfide 372 in 77% yield via an addition-elimination process. Reduction of 372 using

Raney nickel followed by hydrogenation of the resulting unsaturated olefin and hydrolysis of methyl ester afforded first relay compound 373 in 53%. This relay compound was also prepared by degradation150 of strychnine; hence at this stage it was possible not only to verify that the synthesis had followed its projected course but also to gain access to sufficient quantities of the relay compound from degradation to complete the total synthesis. 373 was treated with acetic anhydride and pyridine to make an enol acetate, which upon in situ hydrolysis produced methyl ketone 374.

Selenium dioxide-mediated oxidation of methyl ketone 374 gave the second relay compound,150 which is also called dehydrostrychnine (375). Reaction of 375 with sodium acetylide, followed by the hydrogenation in the presence of Lindlar’s catalyst produced allyl alcohol 376 in 46% yield.

! '(%! Treatment of 376 with lithium not only removed the amide carbonyl but also reduced the alpha-pyridone to the desired dihydro structure. The tertiary cabinol was reacted with hydrogen bromide in acetic acid followed by hydrolysis of the resulting allylic halide with boiling sulfuric acid to produce the isostrychnine

(307), which was converted to strychnine (306) by following Prelog’s protocol of refluxing 307 with potassium hydroxide in ethanol.121

4.2.2.2 Magnus’ Approach

After the first total synthesis of strychnine by Woodward, many novel methods were developed to access Strychnos alkaloids. Magnus and co-workers99 successfully reported the second total synthesis of strychnine in 1992, which was 40 years later. The base-promoted conversion of isostrychnine to strychnine from Woodward synthesis was low-yielding, hence Magnus undertook an alternative route and directed their efforts toward preparing the Wieland-Gumlich aldehyde, which Robinson had converted to strychnine in high yield.122 Tryptamine (331) was subjected to Pictet-Spengler condensation with 2-ketoglutarate 377 to give lactam 378, which upon reduction through its corresponding thiolactam accessed 379. Subsequent treatment with !,!,!- trichloroethyl chloroformate and sodium methoxide resulted in ",!-unsaturated ester 380 in 63% overall yield. The indole nitrogen was protected with methyl chloroformate, and the trichloroethyl carbamate was deprotected followed by acylation of the resulting amine using phenylthio acetic acid and oxidation of it by m-CPBA provided the sulfoxide 381 in

48% yield.

! '(&! Scheme 4.7 Second reported total synthesis of strychnine by Magnus

NH 2 1. Lawesson 1. ClCO2CH2CCl3 N N 331 N H + N O N O 2. Raney Ni 2. NaOMe H H MeO C 63% MeO2C 2 MeO2C CO2Me 377 378 379

O O N N N O 1. ClCO2Me O CCl3 2. Zn, AcOH S NaH O Ph S N N 3. PhSCH2CO2H N 97% H Ph 4. MCPBA MeO2C CO2Me H CO2Me MeO2C CO2Me 380 4 8 % 381 382 1. BrCH CH OH N 2 2 N N O O DBU

TFAA OCOCF3 HgO 2. BH3 O SPh O 41% N 99% N 3. NaHCO N O H H 3, H H MeO2C CO2Me MeO2C CO2Me MeOH CO2Me 383 384 7 2 % 231 N N N 1. Zn, H2SO4 Hg(OAc)2 O 1. LiBH O 2. NaOMe 4 OH AcOH O N H O N H 2. HClO4 N HO 3. p-MeOPhSO2Cl 55% 37% R H 71% R CO2Me H CO2Me 233 385 relay compound 386

At this stage, sodium hydride-mediated cyclization resulted in the tetracycle 382.

Sulfoxide 382 underwent a Pummerer rearrangement to furnish an "-phenylthio trifluoro- acetate, which upon mercuric ion-mediated hydrolysis afforded an "-keto lactam 384 in a very good yield. This keto lactam was converted to 231 by sequential ketalization, amide and removal of methylcarbamate protecting group on indole nitrogen.

Having this key intermediate in hand, 231 was subjected to a transannular cyclization using mercuric acetate to afford the pentacycle 233.100 The !-anilino acrylate moiety of

233 was reduced with zinc dust and sulfuric acid, which upon treatment with sodium methoxide effected epimerization.

! '("! Sulfonylation of the indoline nitrogen furnished 385. Reduction of the ester with and acidic hydrolysis of the ketal afforded relay compound 386 in

37% yield.

Scheme 4.8 Total synthesis of strychnine by Magnus

N N N 1.DIBAL-H 1. TIPSOTf OH 2. NaBH4 2. N H O O N H N H H EtO H C N 31% H R H P CN R R OH EtO OTIPS OTIPS relay compound 386 5 0 % 388 389

1. SO3-Py N 2. HF-Py N N

1. HCl 3. Na CH2(CO2H)2 H H 2. TBSOTf N H 38% N 70% N H H H H H 49% R OTBS H OH HO O O O 390 Wieland-Gumlich aldehyde 308 Strychnine 306

Relay compound 386 was accessed in large quantities from the degradation of strychnine120 via the Wieland-Gumlich aldehyde. Hemikatal 386 was opened with

TIPSOTf followed by Horner-Wadsworth-Emmons olefination of the ketone to prepare vinyl nitrile 388. DIBAL-H mediated reduction of the nitrile followed by treatment with sodium borohydride afforded allyl alcohol 389. Removal of the TIPS protecting group followed by the selective silylation of the primary allylic alcohol using TBSOTf furnished 390 in 49% yield. Oxidation of the remaining alcohol with Parekh-Doering conditions followed by desilylation and removal of the sulfonyl protecting group on the indoline nitrogen afforded the Wieland-Gumlich aldehyde (308).

! ''(! Converting Wieland-Gumlich aldehyde to strychnine (306) using Robinson’s conditions122 completed the synthesis of strychnine. In summary, Magnus and co-workers published the first total synthesis of strychnine via the Wieland-Gumlich aldehyde.

4.2.2.3 Stork’s Approach

In 1992, Stork and coworkers101 contributed a new synthesis of strychnine via the

Wieland-Gumlich aldehyde. The synthesis starts with a Pictet-Spengler reaction of Nb- benzyltryptamine with aldehyde 392 to provide the tetrahydro-!-carboline, which was converted to chloroindolenine 234 by treatment with t-BuOCl.

Scheme 4.9 Stork’s total synthesis of strychnine

CHO Bn Cl N MeO2C CO2Me 392 NaH NHBn N N N Bn H t-BuOCl N Et N 391 3 234 238 H CO2Me

MeO2C CO2Me

1. NaCNBH NH NH OTBS 3 1. LDA TsO 2. ClCO Me PhSeBr 2 I 395 3. H , Pd/C 2. MCPBA 2 N H N H MeO2C CO2Me MeO2C CO2Me 393 394

N N 1. LiBH4 OTBS ( NCON)2 I 1. t-BuLi

N H N H 2. MnCl2, CuCl2 H MeO2C CO2Me MeO2C CO2Me OTBS 396 397

N 1. HF N 2. CH2(CO2H)2 H N N H H H H H CHO O OTBS O 398 strychnine 306

! '''! Addition of sodium hydride to the reaction mitxure triggered the skeletal rarrangement followed by Krapcho-type decarboxylation to afford tetracycle 238.

Sodium cyanoborohydride was used to reduce vinylogous carbamate 238, and the indoline nitrogen was protected as a methyl carbonate. The Nb-benzyl group was removed by hydrogenation to afford tetracyclic amine 393. To install a double bond at the ",!-positions, 393 was subjected to LDA, PhSeCl and MCPBA. Alkylation of Nb- with tosylate 395 afforded key intermediate 396. At this stage, the piperidine D-ring was prepared using an intramolecular conjugate addition to the ",!-unsaturated moiety.

Intermediate 396 was treated with tert-BuLi followed by the addition of MnCl2 and

CuCl2 to give the pentacyclic compound 397. Reduction of the methyl ester to the alcohol, -mediated oxidation to the aldehyde and removal of the silyl protecting group afforded the Wieland-Gumlich aldehyde. Conversion of the Wieland-

Gumlich aldehyde to strychnine was performed using Robinson’s malonic acid conditions.122

4.2.2.4 Overman’s Approach

Overman and co-workers103 published the first enantioselective total synthesis of natural (-)-strychnine in 1993. Two years later, he published the the total synthesis of the unnatural antipode, (+)-strychnine. Vinyl stannane 399 was prepared in a few synthetic operations from commercially available materials and was coupled with triazone- protected 2-iodoaniline 344 using a palladium-catalyzed carbonylative cross-. Nucleophilic epoxidation of the enone 400 with tert-butyl stereoselectively provided epoxide 401 in 87% yield.

! '')! Then, 401 was subjected to Wittig methylenation and deprotection of the silyl protecting group, followed by activation of the allylic alcohol with MsCl and then LiCl.

Scheme 4.10 Overman’s first enantioselective total synthesis of (-)-strychnine

O TIPSO TIPSO Me Me TIPSO t-BuO H N N Pd2(dba)3 2 AsPh3, CO O Triton B N O Me Sn Ar 87% Ot-Bu 3 I 80% O 399 O t - B u 344 400 O t - B u A r 401

Ar-I Ot-Bu

1. Ph3P=CH2 H N N 2. TBAF F3COC 1. NaH 3. MsCl 2. KOH N 1. (CH2O)n H 4. LiCl O 75% HO 2. LDA R2N HO H Ot-Bu 5. NH COCF NCCO2Me CO Me O-t-Bu 2 3 402 239 A r 403 2 NaH, 67% Ar

N N 1. DIBAL-H N 1. Zn, H SO HCl 2 4 2. CH (CO H) 2. NaOMe 2 2 2 MeOH H 50% 67% N N H N H H 68% H H from xx H CO2Me OH H CO2Me OH O O 243 404 (-)-strychnine 306

Treatment of the allylic chloride with sodium trifluoroacetamididate afforded 402 in 67% overall yield. The addition of NaH to 402 triggered an intramolecular SN2 opening of the epoxide to close the piperidine D-ring. Removal of the trifluoroacetyl group with KOH furnished amine 239 in 75% yield. With key intermediate 239 in hand, addition of excess formaldehyde effected the aza--Mannich cyclization104 process to afford an azatricyclic ketone intermediate. Cabomethoxylation using methyl cyano-formate (i.e., Mander’s reagent) furnished keto ester 403.

! ''*! Removal of both the tert-butyl and triazone protecting groups was achieved by treating 403 with refluxing methanolic HCl to provide pentacyclic intermediate 243 in

67% yield. Reduction of the vinylogous carbamate using zinc dust in methanol and sulfuric acid, followed by equilibration of the methoxy carbonyl group gave ester 404.

Finally, the was adjusted with DIBAL-H, which furnished the Wieland-

Gumlich aldehyde in situ. Following Robinson’s method, the W-G aldehyde was converted to (-)-strychnine.122

4.2.2.5 Kuehne’s Approach

In 1993, Kuehne and co-workers105 published a racemic synthesis of strychnine via isostrycnine and an enantioselective total synthesis in 1998 via the Wieland-Gumlich aldehyde. The asymmetric synthesis of strychnine starts with L-tryptophan, which upon protection with a Boc and benzyl functional groups on the Nb-postion. Oxidation of 406 produced the chloroindolenine, which was trapped with dimethyl malonate followed by monodecarboxylation and the removal of Nb-Boc protecting group to afford

407 in 85% yield. Amino ester 407 was reacted with 2,4-hexadienal to undergo a condensation followed by sigmatropic rearrangement tandem process to give the tetracyclic diester 409 in 84% yield with complete stereocontrol.

The tryptophanyl ester functional group was converted to an amide by treatment with ammonia and dehydrated to the nitrile. Reduction with potassium borohydride afforded tetracyclic intermediate 410 in 66% overall yield. The exocyclic double bond was subjected to Johnson-Lemieux conditions to access enantiopure aldehyde 411.

! ''+! Scheme 4.11 Kuehne’s asymmetric total synthesis of strychnine

1. t-BuOCl 1. PhCHO 2. LiCH(CO2Me)2 CO2Me CO2Me CO2Me 2. NaBH4

NH2 N 3. LiCl, DMA HN N N Bn Boc N Bn 3. (Boc)2O 4. TMSOTf H CO Me H 405 8 9 % H 406 8 5 % 407 2

MeO2C O Bn Bn N 1. NH3 N K2OsO4 H 2. TFAA, Et3N 408 HIO4

PhCOOH N 3. KBH4 N 84% 62% 409 6 6 % 410 H CO2Me H CO2Me

Bn N 1. BuLi Bn N N 1. p-TSA Bu3Sn O O O 2. Ts2O O N CHO 3. H2/Pd N H 2. NCS, DMS, Et3N N 411 H C O 2 M e 412 O E E 7 5 % 413 H CO2Me 69% H CO2Me

O 1. DIBAL-H EtO 1. DIBAL-H N 2. NaBH3CN N P CO2Me 2. Robinson EtO 3. NaOMe conditions (-)-Strychnine 64% N H 84% N H 47% CO2Me H E/Z = 17/1 414 404 O H 306 H CO2Me H CO2Me

The piperidine D-ring was prepared by first reacting 411 with the lithium anion derived from an ethoxyethyl-protcted stannyl . Oxidation of the diastereomeric alcohols under Corey-Kim conditions furnished ketone 412. Removal of the ethoxyethyl

(EE) group in 412, tosylation of the alcohol, and hydrogenation of the N-benzyl ether enabled an intramolecular cyclization to afford the pentacyclic ketone 413 in 75% yield.

Homologation of pentacyclic ketone 413 was achieved by subjecting to a Horner-

Wadsworth-Emmons25 condensation with methyl 2-(diethylphosphono)acetate to furnish the pentacyclic ester 414.

! ''#! Chemoselective reduction of the methyl enoate using DIBAL-H, reduction of the vinylogous carbamate with NaCNBH3 in acetic acid followed by an epimerization of the resulting saturated ester using sodium methoxide afforded pentacyclic alcohol 404 in

84% yield. This intermediate had been previously prepared by Overman, and endgame thus featured partial reduction of the methyl ester using DIBAL-H. The Wieland-

Gumlich aldehyde was subjected to Robinson’s conditions122 to access (-)-strychnine.

4.2.2.6 Rawal’s Approach

Rawal and co-workers107 disclosed a synthesis of strychnine in 1994 via isostrychnine as the precursor to strychnine. The synthesis starts with a commercially available o-nitrophenylacetonitrile 415, which was reacted with 1,2-dibromoethane and under phase-transfer conditions followed by a chemoselective reduction of the nitrile functionality using DIBAL-H to produce the nitroaldehyde 416 in

96%. This aldehyde was condensed with benzylamine to afford the corresponding Schiff base. Addition of TMSCl and resulted in a cyclopropyliminium ion, which subsequently rearranged to pyrroline 418 in excellent yield. Treatment of 418 with methyl chloroformate removed the N-benzyl group, and reduction of the nitro group was accomplished by catalytic hydrogenation to yield aniline 419. Condensation of 419 with an unsaturated aldehyde to give the corresponding imine, and activation with methyl chloroformate gave dieneamide 249 in 85% yield. Heating a solution of 249 in benzene

(sealed tube) furnished tetracycle 252 in quantitative yield and with complete stereocontrol.

! ''$! Scheme 4.12 Rawal’s total synthesis of strychnine

1. BrCH2CH2Br TMSCl CN n-Bu4NBr, NaOH BnNH N CHO 2 Bn NaI NO2 2. DIBAL-H NO2 NO2 96% 415 9 6 % 416 417

CO2Me OHC CO2Me N N 1. ClCO2Me Bn N CO2Me 2. HCO2NH4 249 NO2 Pd/C NH2 N ClCO2Me 418 8 6 % 419 85% MeO2C CO2Me

CO2Me N NH OTBS 1. TMSI Br 185 °C 2. MeOH I 258 C H , 99% 6 6 N 90% N 83% H H MeO2C CO2Me 252 O 421 N N 1. Pd(OAc)2, TBACl OTBS K CO , DMF I 2 3 H 2. HCl N H N H H 3. KOH, 20% O O O 422 strychnine 306

Both methyl in 252 were removed by treatment with iodotrimethylsilane; subsequent heating in methanol afforded pentacyclic lactam 421 in

90% overall yield. The secondary amine was then alkylated with allylic bromide 258 to give 422. At this stage, Rawal and group closed the bridged piperidine D-ring by using a novel intramolecular Heck cyclization. Thus, vinyl iodide 422 was reacted with

Pd(OAc)2 and tetrabutylammonium chloride in DMF, which promoted the intramolecular

Heck cyclization to produce a hexacyclic intermediate. Removal of the TBS group under acidic conditions yielded isostrychnine, which was converted to strychnine using Prelog’s conditions (heating with potassium hydroxide in ethanol).121

! ''%! 4.2.2.7 Martin’s Approach

In 1996, Martin and co-workers108 developed a novel biomimetic strategy toward a formal synthesis of strychnine. Dihydrocarboline 360, prepared by the Bischler-

Napieralski condensation of tryptamine and formic acid, was engaged in a vinylogous

Mannich reaction developed in the Martin laboratory. In the event, reaction of an appropriate with trimethylsilyloxybutadiene 361 produced enal 423, which upon heating underwent a smooth intramolecular hetero-Diels-Alder cyclization to afford pentacycle 424. Hydration of the enol ether followed by oxidation gave the lactone, which upon hydrogenolysis afforded lactone 425 in 79% yield. Sodium methoxide- mediated elimination of lactone 425 produced an acid intermediate, which was esterified in situ to afford 426.

Scheme 4.13 Martin’s biomimetic formal synthesis of strychnine

OTMS 361 N O N O N N N H H H H N BnO COCl H 85% H OBn H 360 8 0 % 423 424 O OBn O 1. p-TsOH 1. TBSCl 2.Me3OBF4 2. (Ph3P)3RuCl2 NaOMe, MeOH Et N N O N O 3.NaBH4 3 N N H H H then p-TsOH H H O 50% OH 365 425 H 426 H Ph O MeO C OH 3. H2, Pd/C 2 79% O N N 1. t-BuOCl HCl N N 2. KHMDS 30% H H N H N H H H CO2Me OTBS H CO2Me OH 427 256 243 MeO2C OTBS

! ''&!

The allylic alcohol was protected with TBSCl followed by Borch reduction of the lactam using Meerwein’s salt and sodium borohydride in a single pot operation to access key intermediate 427 in 50% overall yield. Oxidation of 427 with tert- butylhydroperchlorite afforded an epimeric mixture of chloroindolenines, which were directly treated with KHMDS to first generate an enolate that closed onto the imine.

Skeletal rearrangement and subsequent expulsion of the chloride ion gave the pentacyclic core 256 of strychnine.

Acidic removal of the silyl protecting group secured intermediate 243, which was previously converted to strychnine by Overman103 in four steps; hence, a formal synthesis of strychnine was accomplished.

4.2.2.8 Bonjoch and Bosch’s Approach

In the 1990s, Bonjoch and Bosch109 developed a highly efficient and flexible strategy for the synthesis of various Strychnos alkaloids, which allowed them to finish an enantioselective total synthesis of strychnine in 1999. The synthesis started with 1,3- cyclohexanedione 428, which upon nucleophilic aromatic substitution gave the arylated product 429. Protection of the alcohol as an allyl ether 429 was followed by a Claisen rearrangement afforded prochiral dione 430 in 80% yield. Ozonolysis of the double bond produced an aldehyde, which was subjected to a double reaction using a chiral auxiliary and NaCNBH3. The use of (S)- methylbenzylamine as the aminocyclization agent in this multistep sequence yielded the octahydroindolone 431.

! ''"! The auxiliary was converted to a carbamate by heating with a-chloroethyl chloroformat (ACECl) and an enone moiety was generated via a phenylselanyl ketone intermediate. The carbamate protecting group was removed in refluxing methanol to yield secondary amine 257, which was alkylated using known allyl bromide 258 to access key intermediate 259.

Scheme 4.14 Bonjoch and Bosch’s total synthesis of strychnine

OH O 1. o-IPhNO , K CO O 2 2 3 PhMe

O 2. BrCH2CH=CH2 NO 190 °C 2 O NO2 K2CO3 80% O 428 6 1 % 429 430 O Ph Cl 1. ACE-Cl Me O N 2. TMSI, HMDS N MeOH 1. Ozonolysis H CH 3. PhSeCl 3 reflux 2. Cl Ph NO NO2 35% from 430 Me 2 O 4. Ozonolysis O H3N 5. i-Pr NH H 431 2 432 NaCNBH3 OTBS OTBS N Br N NH Pd(OAc)2 I 258 I PPh3, Et3N

NO2 NO K2CO3, MeCN NO O H 2 O 2 O 50% OTBS 257 7 4 % 259 260

1. DIBAL-H N N LiHMDS 1. Zn, H2SO4 2. Robinson 2. CH ONa NCCO2Me 3 protocol (-)-Strychnine NO 2 26% N H 67% O H H H CO Me OH 261 C O 2 M e O T B S 262 2 306

With 259 in hand, a reductive intramolecular delivered tricyclic ketone 260, which was subjected to a carbomethoxylation using LHMDS and methyl cyanoformate to afford keto ester 261 in 67% yield.

! ')(! Zinc dust in methanolic sulfuric acid removed the silyl ether and promoted the reductive cyclization of the nitrophenyl moiety to produce an epimeric mixture of esters.

Equilibration with sodium methoxide in methanol to afforded 262, which had been prepared previously by Overman and co-workers,103 and accordingly transformed to strychnine with Robinson’s protocol.122

4.2.2.9 Padwa’s Approach

Padwa and co-workers115 developed a novel cascade intramolecular Diels-Alder reaction/rearrangement to access the tetracyclic core of the Strychnos alkaloids, and in

2007 they applied this to the total synthesis of strychnine. The synthesis began by acylating Na-protected carboxylic acid 433 followed by deprotection of the Boc group in

387. Subsequent N-alkylation with 2-methylbenzyl bromide produced key intermediate

289 in 55% yield. Heating a solution of amidofuran 289 and with catalytic magnesium iodide in a microwave effected the cascade intramolecular Diels-Alder reaction/rearrangement to produce tetracycle 293. Stereoselective reduction of the ketone using NaBH4, N-deacylation with NaOMe, lactam reduction with LiAlH4 and finally enamine reduction with NaBH(OAc)3 furnished 434. Removal of Nb-benzyl protecting group was achieved by catalytic hydrogenation to access the secondary diamine, which was chemoselectively alkylated with allylic bromide 435 to furnish vinyl iodide 436 in

56% yield.

! ')'! Scheme 4.15 Padwa’s total synthesis of strychnine

1. ClCO iBu O 2 O 2. Li N Ar Ar O NBoc N CO H 2 387 Cat MgI O 2 N 3. Mg(ClO4)2 N N 4. ArCH Br, NaH H Ac 433 2 A c 289 293 55% Ac O N Ar 1. ArCHO 1. NaBH4 N 2. NaOMe 1. H2/Pd(OH)2 I NaBH(OAc)3 OMOM

2. K2CO3 N 2. TPAP, NMO 3. LiAlH4 N OMOM H H H H Br OH 69% 4. NaBH(OAc)3 OH 65% 434 5 6 % I 435 436 O N N P OMe Pd(PPh3)4 I Ph2 OMOM PhOK Li N N H 72% H 56% H Ar O 437 A r O 438 OMOM

N N 1. HCl 2. CH2(CO2H)2 H N H N H 43% H H Ar OMOM O O OMe 439 strychnine 306

Protection of the indoline nitrogen with the dimethoxybenzyl group (DMB) was accomplished by reductive amination, and the secondary alcohol was oxidized to ketone

437. At this stage, a palladium-catalyzed intramolecular a-vinylation reaction,109 which went smoothly in 56% yield to secure the D-ring and furnish 438. Horner-Wittig olefination of the ketone followed by the deprotection of both the MOM and DMB protecting groups under acidic conditions produced the Wieland-Gumlich aldehyde in a single operation. Conversion of the W-G aldehyde into using Robinson’s method gave strychnine (306).122

! '))!

4.2.2.10 Vanderwal’s Approach

In 2009, Vanderwal and co-workers117a developed an excellent route to access the

Strychnos tetracyclic framework using an anionic bis-cyclization reaction of tryptamine- functionalized Zinke aldehydes. This approach was inspired by elegant studies of Marko and co-workers. Recently, Vanderwal reported a concise total synthesis of strychnine using this approach.117b The synthesis commenced with N-allyl tryptamine (440), which was prepared in one step from tryptophanyl bromide. Amine 440 was converted to

Zincke aldehyde 442 under standard conditions, which was subjected to the anionic bis- cyclization with potassium tert-butoxide to afford tetracycle 443 in 64% yield. Catalytic

Pd-mediated deallylation of 443 gave diamine 444, which was subseqnetly alkylated with allyl bromide 447 to produce vinyl silane 446 in good yields.

Scheme 4.16 Vanderwal’s concise total synthesis of strychnine

O N 2 441 N N N NO2 Pd(PPh3)4 Cl t-BuOK, THF EtOH HN Sealed tube N aq. NaOH N N O O H H 80 °C H H 81% CHO CHO 440 442 6 4 % 443 O O

OH N N NH OH 1. NHMDS, NMP Br SiMe3 CuBr SMe2, 5-10% H 447 SiMe 3 N H H N i-Pr2NEt N H 2. CH2(CO2H)2 H H H O CHO 69% CHO O strychnine 306 444 446

! ')*! The free hydroxyl present in 446 was engaged in a Brook rearrangement by treatment with NHMDS. The use of Cu(I) in this transformation enabled a transmetallation reaction with attendant intramolecular conjugate (Michael) addition to prepare the Wieland-Gumlich aldehyde in a single operation. Unfortunately, yields for this process were low (5-10%). With the W-G aldehyde, Robinson’s method was employed to access strychnine 306.122

4.2.2.11 MacMillan’s Approach

In 2011, MacMillan and co-workers119 developed an organocascade catalysis strategy to access various indole alkaloids. A catalytic enantioselective synthesis of strychnine was achieved in 12 steps. The synthesis began with 2-vinyl indole 301, which was prepared in few steps from commercially available materials.

Scheme 4.17 MacMillan’s catalytic asymmetric total synthesis of strychnine

O Boc 302 1. (Ph3P)3RhCl N NH NHBoc PhCN CHO 20 mol% 305 TBA 2. COCl2, Et3N

N SeMe 82%, 97%e.e. N N 3. DIBAL-H, TFA H PMB PMB 301 303 61% PMB CO2Me 304

OH N OAc 1. Pd(OAc) , Bu NCl Br N 2 4 I NaHCO3, EtOAc 447 H I 2. PhSH, TFA N 1. DBU, K CO H 2 3 N H 2. DIBAL-H H 3. CH2(CO2H)2 O PMB O 76% OH 26% 448 (-)-strychnine 306

! ')+! The key organo- cascade addition/cyclization was achieved using 1-naphthyl substituted imidazolidine catalyst 305 in presence of tribromoacetic acid as co-catalyst to produce the spiroindoline 303 in 82% yield and 97% enantiomeric excess. Wilkinson’s catalyst-mediated decarboxylation of tetracycle 303 followed by treatment with phosgene and methanol introduced the carbomethoxy functional group at the "-position of the dienamine. Unsaturation in the enamine was reduced by treatment with DIBAL-H to realize the tertiary indoline stereocenter, and an isomeric mixture of enoates 304 was isolated in 61% yield.

At this stage, the secondary amine was alkylated with allylic bromide 447. DBU- mediated olefin isomerization and reduction of both the esters to their corresponding primary alcohols was effected with DIBAL-H. A cascade Jeffery-Heck cyclization/tautomerization/lactol formation sequence was achieved with Pd(OAc)2 and tetrabutylammonium chloride. The Na-PMB protecting group was removed with TFA and thiophenol to afford the Wieland-Gumlich aldehyde, which was converted to strychnine

306 using Robinson’s conditions.122

! ')#! 4.3 Present Study

4.3.1 Akuammicine (racemic)

A novel sequential one-pot spirocyclization/intramolecular aza-Baylis-Hillman

(IABH) protocol for efficiently assembling the ABCE tetracyclic framework of Strychnos alkaloids140 (Chapter 3) was disclosed. Sequential (tandem) one-pot reactions, much like domino (cascade) methods, enable a marked rise in both molecular complexity and synthetic efficiency in a single operation,44 which was discussed in Chapter 1. With these findings in hand, we streamlined a route to the ABCE tetracyclic core of akuammicine

(352), in addition to concise racemic total synthesis thereof. The retrosynthesis of 352 is as shown in Scheme 4.18.

Scheme 4.18 Retrosynthetic analysis of racemic akuammicine

O lactam H N intramolecular Heck H N reduction N cyclization Me H Me H I I H H N Me H CO2Me N N H CO Me 352 371 2 457 H CO2Me

O O one-pot Br vinylogous N Me Br biscyclization Mannich reaction Cl I H N Me CHO + 2 I N OTMS H N CO2Me H 455 355 OMe

Retrosynthetically, one can access the D-ring by employing using Rawal’s intramolecular Heck-cyclization protocol107 from tetracycle 371. This, in turn, can be prepared from lactam reduction of tetracycle 457. Novel one-pot bis-cyclization protocol from bromoacetamide 455 was employed to prepare the ABCE core of akuammicine.

! ')$! The key precursor for the novel bis-cyclization was achieved by a vinylogous

Mannich reaction of commercially available N-Boc indole 3-carboxaldehyde (449). The synthesis of akuammicine began with condensation of aldehyde 449 with known allylic amine 450 in dichloromethane and magnesium sulfate as a desiccant afforded the corresponding Schiff base 451. Allylic amine152 450 was prepared in one step from the commercially available bromide precursor, which was also synthesized using a published protocol151 from crotonaldehyde on large scale. Treatment of imine 451 with vinyl silyl acetal 452 and bromoacetyl chloride 453 effected a vinylogous Mannich reaction via the intermediary N-acyliminium species 454.153

Scheme 4.19 Synthesis of tetracycle using vinylogous Mannich reaction

OTMS N H2N Me CHO I OMe 450 I 452 MgSO4 N N O CH2Cl2 449 B o c 451 Boc Br Cl 453

O O Cl Br then N Me Br N Me TFA I I CH2Cl2 N H N 80% over CO Me 454 2 Boc two steps 455

O O Me N N AgOTf I H Me DTBMP H DBU CO2Me H I N PhMe rt N rt 12 h H CO2Me 63% 456 457

! ')%! Termination of the reaction with TFA also removed the N-Boc protecting group, furnishing bromoacetamide 455 in 80% yield over two steps. The corresponding vinylogous Mannich reaction with indole 3-carboxaldehyde was not successful, indicating protection of the indole nitrogen with an electron withdrawing was crucial. With required bromoacetamide 455 in hand, we subjected it to our sequential one-pot spirocyclization/IABH protocol: (1) AgOTf and 2,6-di-tert-butyl-4- methylpyridine (DTBMP) generated spiroindolenine 456 bearing the C-ring; and (2) subsequent addition of 3 equivalents of DBU triggered an intramolecular aza-Baylis-

Hillman reaction, delivering ABCE tetracycle 457 in 63% yield.140 At this juncture, readjustment of the C ring oxidation state was in order. The presence of the vinyl iodide and conjugated ester moieties precluded reduction with LiAlH4 or similar reducing agents.

As the classical Borch protocol154 for amide reduction was ineffective, recourse to the

Raucher variant155 (i.e., thia-Borch) was made.

Scheme 4.20 Endgame for racemic total synthesis of akuammicine

! ')&! To this end, thionation of 457 with Lawesson’s reagent afforded thiolactam 458 in

76% yield. Alkylation of 458 with ethyl Meerwein’s salt and reduction of the intermediary thioimidate with NaBH4 and methanol furnished tetracycle 371 in a single operation and 75% yield. When the Raucher protocol was performed using methyl

Meerwein’s salt, undesired alkylation at the Na-position was observed. To address this, we employed triethyloxonium tetrafluoroborate, which is bulkier. With 371 in hand, endgame inspired by Rawal’s highly efficient, intramolecular Heck reaction107 was pursued. In the event, heating a solution of 371, catalytic Pd(OAc)2 and PPh3 in Et3N at

90 °C for 3.5 h secured akuammicine 352 in 71% yield. Treatment of akuammicine with ethereal HCl and slow evaporation of the salt from dichloromethane afforded material suitable for single-crystal X-ray analysis, which heretofore had not been reported and un- ambiguously confirmed the natural product’s structure. Thus, the total synthesis of akuammicine 352 was accomplished143 in six steps (20% overall yield) from commercially available N-Boc indole 3-carboxaldehyde 449.

4.3.2 Strychnine (racemic)

Having developed a novel sequential one-pot spirocyclization/intramolecular aza-

Baylis-Hillman (IABH) protocol for efficiently assembling the ABCE tetracyclic framework of Strychnos alkaloids and achieving a concise total synthesis of racemic akuammicine, we turned our attention in preparing racemic strychnine in a concise manner. In order to maximize synthetic convergence to strychnine 306, we employed the

N-benzyl protecting group and postponed side-chain installation to later in the synthesis.

! ')"! Scheme 4.21 Retrosynthetic analysis for total synthesis racemic strychnine

N N N Robinson intramolecular conditions Heck cyclization H H H N N N H H H H H H H H CHO O O OH HO O

strychnine 306 Wieland-Gumlich aldehyde 308 O OPG H Br Bn H Bn N N N bis-cyclization deprotection I and reduction and alkylation N N N H H H H H CO2Me CO2Me CO2Me key intermediate 361 pentacycle precursor 463 tetracycle 462

CHO vinylogous O OTMS Mannich reaction Br N + BnNH Cl 2 OMe 449 Boc

Retrosynthetically, we wanted to synthesize strychnine via the Wieland-Gumlich aldehyde 308, which is accomplished by following Robinson’s protocol.122 As in akuammicine, D-ring cyclization would involve Rawal’s intramolecular Heck reaction,107 which leads to known intermediate 463 from the akuammicine synthesis (Scheme 4.20).

The total synthesis of strychnine began with commercially available N-Boc indole

3-carboxaldehyde (449) and benzylamine. In order to maximize the synthetic efficiency, the side chain was introduced later in the synthesis. In the event, benzylamine and N-Boc indole 3-carboxaldehyde (449) were condensed in dichloromethane using magnesium sulphate as a desiccant to furnish the corresponding Schiff base, which was subjected to our vinylogous Mannich reaction conditions. Treatment of imine 459 with vinyl silyl ketene acetal 452 and bromoacetyl chloride 453 effected the vinylogous Mannich reaction via the intermediary N-acyliminium species 460. ! '*(! Termination of the reaction with TFA removed the N-Boc protecting group, furnishing the bromoacetamide 361 in 78% yield over two steps.

Scheme 4.22 Tetracycle 462 from vinylogous Mannich and bis-cyclization reactions

OTMS O Cl Bn N Br Bn BnNH2 N CHO OMe MgSO4 452

O N CH2Cl2 N Br N 449 B o c 459 B o c 460 Cl Boc 453 O O O Br Bn Bn Bn then N N N AgOTf H TFA DTBMP H DBU CO2Me H N rt CH2Cl2 N PhMe N 12 h 78% over H rt H CO2Me CO2Me 70% two steps 361 362 363

O S Bn Bn Bn N Et3OBF4 N H N Lawesson's H H then H reagent H H NaBH , N 81% N 4 N H MeOH H H CO2Me CO2Me CO2Me 363 461 7 4 % 462

With required bromoacetamide 361 in hand, we subjected it to our sequential one- pot spirocyclization/IABH protocol: (1) AgOTf and 2,6-di-tert-butyl-4-methylpyridine

(DTBMP) generated spiroindolenine 362 bearing the C-ring; and (2) subsequent addition of 3 equiv of DBU triggered an intramolecular aza-Baylis-Hillman reaction, delivering

ABCE tetracycle 363 in 70% yield.140 At this juncture, readjustment of the C ring oxidation state was achieved using Raucher variant (i.e., thia-Borch). To this end, thionation of 363 with Lawesson’s reagent afforded thiolactam 461 in 81% yield.

! '*'! Alkylation of 461 with ethyl Meerwein’s salt and reduction of the intermediary thioimidate with NaBH4 and methanol furnished tetracycle 462 in a single operation and

74% yield. At this stage, various methods for N-debenzylation were screened to achieve the diamine 369.

Scheme 4.23 Endgame for strychnine via Wieland-Gumlich aldehyde

Bn ACE-Cl N NH N H 135 °C, 48 h H Br H 258 I OTBS H H H I OTBS then K CO , MeCN N MeOH N 2 3 N H CO Me 75% H CO Me 63% H CO Me 462 2 369 2 463 2

N Pd(OAc)2 H 1.) NaBH3CN H N PPh3 AcOH DIBAL-H H H OTBS H OH PhMe Et3N N 2.) NaOMe, N CO Me H 90 °C, 1.5 h H 2 MeOH H CO2Me 85% 256 8 0 % 262

CH2(CO2H)2 N H N H Ac2O H NaOAc H H H O N O N H H H AcOH H HO H 49% O W-G aldehyde 308 (±)-strychnine 306

Optimal conditions for the debenzylation included stepwise treatment of 462 with

(1) "-chloroethyl chloroformate (ACE-Cl) and Proton Sponge to protect the indoline nitrogen; and, (2) heating in neat ACE-Cl at 135 °C for 48 h followed by methanolysis, which furnished 369 in 75% yield from 462.109a With key intermediate 369 in hand, it was subjected to a chemoselective alkylation using known bromide 258. Bromide 258 was prepared according to the literature protocol reported by Rawal and co-workers.107

The alkylation of 369 secured 463 in 63% yield, which set the stage for the intramolecular Heck cyclization.

! '*)! In the event, 463 was subjected to previously shown (Scheme 4.20) Heck conditions to obtain pentacyclic intermediate 256 in 85% yield. Both Martin and Rawal groups107,108 have previously prepared 256 in their syntheses of strychnine.

Reduction of the vinylogous carbamate with NaBH3CN in AcOH followed by base-mediated epimerization of the methyl ester yielded 262, which had been prepared by

Overman,103 Kuehne,105 Bonjoch-Bosch109 and Fukuyama114 in their syntheses of strychnine. Reduction of the methyl ester functionality in 262 with DIBAL-H afforded

Wieland-Gumlich aldehyde (308), which was converted into strychnine 306 using

Robinson’s protocol122 in 49% yield over two steps. Thus, the total synthesis of strychnine was accomplished143 in thirteen steps (5% overall yield) from commercially available N-Boc indole 3-carboxaldehyde (449).

4.3.3 (-)-Akuammicine and (-)-Leuconicines A and B

4.3.3.1 (-)-Akuammicine

The only asymmetric total synthesis of (-)-akuammicine reported in the literature is by MacMillan and group119 in 2011. Having developed a novel one-pot bis-cyclization method to quickly access the tetracycle of the Strychnos alkaloids and completed the total synthesis of racemic akuammicine and strychnine,143 we turned our attention in preparing the Strychnos alkaloids in an asymmetric manner. To realize this goal, we first targeted

(-)-akuammicine. The retrosynthetic analysis is as shown in Scheme 4.24.

! '**! Having reported a concise and efficient total synthesis of racemic akuammicine, we wanted to utilize the same end game, namely intramolecular Heck cyclization for accessing the D-ring, two step lactam reduction and a key bis-cyclization from asymmetric bromoacetamide 455. The chiral center can be set using an asymmetric allylation using a chiral auxiliary and extension can realize the bromoacetamide 455.

Scheme 4.24 Retrosynthetic analysis for total synthesis of (-)- akuammicine

H O H lactam N H H N N intramolecular Heck Me reduction H Me cyclization I H H I H Me N N N H CO2Me H CO Me 2 H CO2Me (-)- Akuammicine 352 371 457 O O Br S one-pot N Me HN t-Bu asymmetric CHO biscyclization I extension allylation

N N N H H Ts CO2Me 455 464 465

In order to render our current synthesis asymmetric, we employed a method recently reported by Yus and co-workers156 wherein N-tert-butane-sulfinimines157 are prepared and allylated in situ to afford homoallylic amines in high yields and diastereoselectivity. To this end, commercially available N-tosyl indole-3- carboxaldehyde (465) was treated with (R)-N-tert-butanesulfinamide 466, Ti(OEt)4 and indium metal in THF for 2 h followed by addition of allylbromide and refluxing at 60 °C for 12 h to furnish homoallylic amine 467 in 87% yield (dr=10:1). Removal of the chiral auxiliary was realized by treating 467 with HCl in methanol for 12 h, and the N-tosyl group was deprotected by stirring with magnesium in methanol at 0 °C for 2 h.

! '*+! Alternatively, the removal of protecting groups158 was also accomplished by sequential treatment with 4N HCl in dioxane followed by magnesium in MeOH to afford

468 in 75% yield (one-pot) to access the enantiopure intermediate 468.

Scheme 4.25 Synthesis of chiral bromoacetamide using asymmetric allylation

O O 466 S S HN t-Bu NH2 CHO H2N t-Bu In, Ti(OEt)4 4 N HCl, then N Br N Mg, MeOH N Ts 75% H 465 T H F , 6 0 ° C 467 T s 468 87% (dr=10:1)

O Br Me O HG-II Br I Br N Me 1.) Cs2CO3 N Me methyl THF + DMF I acrylate I

2.) BrAcCl, Et N CH Cl 40 °C N 3 N 2 2 H CH2Cl2 H 80% CO2Me 469 455 overall 83%

Alkylation of primary amine 468 with known (Z)-2-iodobutenyl bromide151 and cesium carbonate followed by acylation with bromoacetyl chloride furnished bromoacetamide 469 in 83% yield over two steps. Chemoselective cross-metathesis between 469 and methyl acrylate was accomplished with 10 mol% of Hoveyda-Grubbs

2nd generation catalyst,159 affording bis-cyclization substrate 455 in 80% yield. Having the key bromoacetamide 455 in hand, it was subjected to spirocyclization by reacting with AgOTf and DTBMP in toluene followed by IABH reaction promoted by DBU to furnish tetracycle in 60% yield.140

! '*#! The oxidation state in 457 was adjusted by the two step thia-Borch protocol: 1) treatment with Lawesson’s reagent in refluxing toluene afforded 87% of the thiolactam; and, 2) alkylation of 458 with Meerwein’s salt (ethyl variant) and reduction of the intermediary thioimidate with NaBH4 in methanol furnished tetracycle 371 in a single operation and 92% yield.143

Scheme 4.26 Endgame for total synthesis of (-)-akuammicine

O O Br AgOTf N N Me H Me Lawesson's DTBMP reagent I H I then Toluene 110 °C N DBU N H CO Me 87% H 60% 2 455 C O 2 M e 457 S

N N H N H Me H Me I H Et3OBF4 H I Pd(OAc)2 H N N Me NaBH4, N PPh3, Et3N H CO Me H H CO2Me 2 92% CO2Me 90 °C, 3.5 h 458 371 (-)-akuammicine 352 87%

With 371 in hand, we proceeded to the intramolecular Heck cyclization. In the event, treatment of 371 with catalytic Pd(OAc)2 and PPh3 in refluxing triethylamine for

3.5 h produced (-)-akuammicine in 87% yield.

! '*$! 4.3.3.2 (-)-Leuconicines A and B

In 2009, Kam and co-workers isolated novel hexacyclic Strychnos alkaloids (-)- leuconicine A 470 and B 471 from extracts of the Malaysian plant Leuconotis

(Apocynaceae) maingayi (Figure 4.4).160 The leuconicines are structurally related to known Strychnos alkaloids (-)-akuammicine and (-)-strychnine yet distinguish themselves by the presence of a 3-acyl-2-pyridone F-ring and an ethyl, as opposed to ethylidene, substituent on the D-ring.

Retrosynthetically, leuconicine A (470) can be prepared from leuconicine B (471) by amidation with ammonia, and 471 can be synthesized from hexacycle 477 by means of a chemo- and stereoselective hydrogenation reaction. Hexacycle 477 will be assembled from an intramolecular Heck reaction, which was used in our akuammicine and strychnine synthesis.143

Scheme 4.27 Retrosynthetic analysis of Leuconicines

H N N N H H H H Et Et H H H N trans N chemoselective N intramolecular amidation hydrogenation Heck O NH2 O OMe O OMe O O O leuconicine A 470 leuconicine B 471 477

O N Br H N Me Me H N I Me H I H I N intramolecular N Knoevanagel N biscyclization H CO Me H O 2 lactam reduction CO2Me OMe 371 455 Lactamization O 476

! '*%!

An acylation followed by intramolecular Knoevanagel condensation of the tetracycle 371 can realize pentacycle 476. Following the asymmetric total synthesis of (-

)-akuammicine shown in Scheme 4.26, tetracycle 371 can be prepared. Tetracycle 371 was prepared from commercially available N-Ts indole 3-carboxaldehyde. Asymmetric aminoallylation using tert-butyl sulfonamide chiral auxiliary156 and extension of the amine by alkylation, acylation and chemoselective cross metathesis furnished the bromoacetamide 455 as shown in Scheme 4.25. The bromoacetamide was converted to tetracycle 371 as shown in Scheme 4.26. Functional group interconversion between methyl ester 371 and aldehyde 475 was best realized by stepwise Weinreb amidation161 of 371 on treatment with LiN(OMe)Me in THF to access 374 and DIBAL-H reduction of the amide 374 provided enal 475 in 97% and 92% yields respectively.

It was envisioned that the F-ring could be prepared by installing a malonyl linchpin between the indoline nitrogen and aldehyde moieties of 475. This approach calls for (1) acylation of the indoline with a methyl malonyl and (2) an intramolecular . Moreover, the operation could be effected in a sequential one-pot manner. To test this hypothesis, we heated a solution of 475, methyl and Et3N in CH2Cl2 for 3 h and isolated pentacycle 476 in 82% yield.

Endgame for (-)-leuconicine A (470) and B (471) began with Rawal’s elegant solution to preparing the D-ring of Strychnos alkaloids, which was also utilized in our syntheses of akuammicine and strychnine.

! '*&! Scheme 4.28 Total synthesis of (-)-Leuconicines

N N H Me H Me H I LiNMe(OMe) H I DIBAL-H THF, 97% N N CH2Cl2 H H OMe CO2Me N 92% O 371 474 Me

N O O H Me N H Me I Pd(OAc) Cl OMe H 2 H I N PPh3, Et3N N Et3N, CH2Cl2 82% H CHO 82% O OMe 475 476 O

N H N H H Raney Ni Et H THF, 82% H N Me N 477 O OMe O R O O

Me3Al, NH3 471: R = OMe = (-)-leuconicine B 80% 470: R = NH2 = (-)-leuconicine A

In the event, the intramolecular Heck reaction was effected by treatment of 476 with catalytic Pd(OAc)2, PPh3 in Et3N to furnish dehydroleuconicine B (477) in 81% yield.143 Chemoselective reduction of the ethylidene moiety with Raney Nickel afforded

(-)-leuconicine B (471) in 82% yield.162 Weinreb aminolysis of 471 with dimethylaluminum amide163 in dichloromethane secured (-)-leuconicine A (470) in 91% yield. Spectral data for 470 and 471 (e.g., 1H and 13C NMR, IR, optical rotation)164 were in agreement with those reported by Kam.160

In summary, we have completed concise total syntheses of Strychnos alkaloids

(-)-akuammicine (352, 9 steps, 17% overall yield), (-)-leuconicine A (470, 14 steps, 9% overall yield) and B (471, 13 steps, 10% overall yield) from commercially available starting materials.

! '*"! Key steps include (1) asymmetric allylation using a chiral auxiliary set the stereochemistry (2) our one-pot, sequential spirocyclization/intramolecular aza-Baylis-

Hillman method to assemble the ABCE framework; (3) a domino acylation/Knoevenagel cyclization to prepare the F-ring; and (4) an intramolecular Heck cyclization to access the

D-ring.

4.3.4 (-)-Norfluorocurarine, (-)-Dehydrotubifolene, (-)-Dihydroakuammicine,

(-)-Tubifoline and (-)-Valparicine.

Along with asymmetric total syntheses of (-)-akuammicine and the (-)- leuconicines, we have also synthesized other Strychnos alkaloids (-)-norfluorocurarine,

(-)-dehydrotubifoline, (-)-dihydroakuammicine, (-)-tubifolene and (-)-valparicine in a concise manner. The same intermediates employed in the asymmetric syntheses of akuammicine and leuconicines were utilized to access these natural products.

Norfluorocurarine and dehydrotubifoline are Strychnos alkaloids, which have been synthesized by different research groups.165

Scheme 4.29 Total synthesis of (-)-norfluorocurarine and (-)-dehydrotubifoline

N H N H Me Pd(OAc)2 H I H PPh3, Et3N N Me N CHO H CHO 90 °C, 3.5 h H 475 86% (-)-norfluorocuraine 369

N N 2N HCl Sealed tube N H N H H Me 85 % Me CO2Me (-)- akuammicine 352 (-)- dehydrotubifoline 479

! '+(! Enal 475 was subjected to intramolecular Heck cyclization conditions that included catalytic Pd(OAc)2 and PPh3 in refluxing triethylamine to furnish (-)- norfluorocurarine (369) in 86% yield.

Following the protocol of Karrer and co-workers166 featuring hydrolysis followed by decarboxylation in a sealed tube, (-)-akuammicine was converted to (-)- dehydrotubifoline in 85% yield (Scheme 4.30).

Scheme 4.30 Total synthesis of (-)-dihydroakuammicine and (-)-tubifoline

N N N PtO2, H2 2N HCl MeOH Sealed tube N N N H H 70 % H Me 95 % H Me Me H CO2Me CO2Me (-)- tubifoline 481 (-)- akuammicine 352 (-)-19,20-dihydroakuammicine 480

Hydrogenation of akuammicine (352) in presence of PtO2 (Adam’s catalyst) produced (-)-dihydroakuammicine (480) in 95% yield, which was also subjected to hydrolysis and decarboxylation using 2N HCl in a sealed tube to prepare (-)-tubifoline

(481) in 70% yield.166

In 2006, Kam and co-workers167 reported the isolation of (-)-valparicine from the stem-bark extracts of Kopsia arborea, a member of the Kopsia family and the initial studies showed that (-)-valparicine has some pronounced cytotoxic effects against KB and Jurkat cells. Having access to akuammicine precursor 371 in an asymmetric manner, we wanted to convert this to (-)-valparicine. Toward this end, ester 371 was reduced to alcohol168 481 using DIBAL-H in 75% yield (Scheme 4.30).

! '+'!

Scheme 4.31 Total synthesis of (-)-valparicine

N N I I Pd(OAc)2, PPh3 DIBAL-H Et3N, 50 % N N H H CH2Cl2 H H CO2Me CH2OH 371 8 4 % 482 N N

TFA N H N H Me Me CH2Cl2 CH2OH 70% 483 (-)- valparicine 484

With vinyl iodide 482 in hand, we subjected it to the intramolecular Heck cyclization.

In the event, refluxing 482 with catalytic Pd(OAc)2 and PPh3 in triethylamine produced pentacycle 483, which had been previously prepared by Rawal.168 Various dehydration conditions were screened with 483 to install the requisite methylidene unit (e.g., HCl,

AcOH, MsCl/DBU, Martin sulfurane, TFAA and TFA). Of these conditions, the use of trifluoroacetic acid in dichloromethane at 0 °C for 2 h was found to be superior, delivering 70% of (-)-valparicine 484 after chromatography. This natural product was unstable on flash silica gel chromatography. However, the use of basic alumina chromatography, and storing in freezer was found to be the workable condition.

! '+)! 4.4 Conclusion

A novel one-pot spirocyclization/intramolecular aza-Baylis-Hillman protocol to access the ABCE tetracyclic framework of Strychnos alkaloids was utilized and racemic total synthesis of akuammicine, and strychnine was achieved. In addition, we have accomplished asymmetric total synthesis of Strychnos alkaloids (-)-akuammicine, (-)- leuconicines A and B, (-)-norfluorocurarine, (-)-dehydrotubifoline, (-)- dihydroakuammicine, (-)-tubifoline and (-)-valparicine in a concise manner.

! '+*! CHAPTER 5. Experimental Section

5.1. General

All reactions containing moisture or air sensitive reagents were performed in oven-dried glassware under nitrogen or Argon. , tetrahydrofuran, dimethylformamide and dichloromethane were passed through two columns of neutral alumina. Toluene was passed through one column of neutral alumina and one column of

Q5 reactant. Diglyme, i-Pr2NEt, CHCl3, 2,6-lutidine, pyridine, acetone and Et3N were distilled from CaH2 prior to use. Molecular sieves (4Å) and MgSO4 were activated by flame drying under vacuum prior to use. Crotonaldehyde, methyl acrylate and methacrolein were freshly distilled prior to use. AgOTf was azeotroped with dry toluene prior to use. Evans propionimides (125, ent-125) and Brown allylborane 133 and Roush crotylboronates 134 were prepared according to literature procedures respectively.14, 37

Silyl ketene acetal 452 was prepared according the procedure of Hoffman.171 All other reagents were purchased from commercial sources and used without further purification.

All solvents for work-up procedures were used as received. Flash column chromatography was performed according to the procedure of Still172 using ICN Silitech

32-63 D 60Å silica gel with the indicated solvents. For all reactions involving cross- metathesis, CH2Cl2 was deaerated by bubbling Argon through the solution (1 min/mL).

Enantiomeric excess (% ee) for Brown allylation and Roush crotylboration reactions was determined by the Mosher method.173 Thin layer chromatography was performed on

Analtech 60F254 silica gel plates. Detection was performed using UV light, KMnO4 stain,

PMA stain and subsequent heating.

144 1 13 H and C NMR spectra were recorded at the indicated field strength in CDCl3 at rt.

Chemical shifts are indicated in parts per million (ppm) downfield from tetramethylsilane

(TMS, d = 0.00) and referenced to the CDCl3. Splitting patterns are abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet) and m (multiplet).

Melting points were recorded on a Mel-Temp apparatus. 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 ATR-FTIR spectra were taken on a single bounce smart orbit diamond ATR accessory mounted in a Nicolet

Magna 750 FTIR spectrometer Thermo Scientific that was equipped with a deuterium tryglycine sulfate (DTGS) detector. High resolution mass spectrometry was collected at

Department of Chemistry, University of Pennsylvania and Ohio State University Mass

Spectrometry Facilities. X-ray analysis was performed at Department of

Chemistry, University of Pennsylvania.

145 5.2 CHAPTER 1: Sequencing Cross-Metathesis (CM) and Non-Metathesis

Reactions to Rapidly Access Building Blocks for Synthesis.

General procedure for sequential one-pot CM/Wittig reactions (Table 1.10).

Crotonaldehyde (101 mg, 1.45 mmol) dissolved in deaerated CH2Cl2 (2.2 mL) was added to a solution of olefin (0.48 mmol) in deaerated CH2Cl2 (1.0 mL). Grubbs’ second- generation catalyst 2 (20 mg, 5 mol%) was added, and the reaction mixture was heated to

40 °C under an Ar atmosphere for 3 h. The reaction mixture was cooled to 0 °C, and phosphorane (194 mg, 0.58 mmol) was added. The reaction was stirred at rt for 15 h (for entries 2 and 6, reaction was refluxed for 1 h), concentrated under reduced pressure and purified by flash column chromatography eluting with 2-10% ethyl acetate/hexanes.

General procedure for sequential one-pot CM/HWE reactions (Table 1.11 – Entries

1,2,5).

Sodium hydride (28 mg, 0.69 mmol) was added to a solution of phosphonate (0.69 mmol) in THF or diglyme (5.0 mL) at 0 °C. The reaction mixture was stirred for 30 min. The crude enal (0.48 mmol) derived from the cross-metathesis step (see above experimental) was dissolved in THF or diglyme (3.0 mL) and added to the phosphonate solution. The reaction mixture was warmed to rt and stirred for 15 h. Diethyl ether (10 mL) was added, and the reaction was quenched with saturated aqueous NH4Cl (5 mL). The aqueous phase was extracted with diethyl ether (2 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), brine (2 x 10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with

2-10% EtOAc/hexanes.

146 General procedure for sequential one-pot CM/HWE reactions (Table 1.11 – Entries

3,4).

KHMDS (1.06 mL, 0.5 M in toluene, 0.53 mmol) was added to a solution of phosphonate

(0.53 mmol) in THF (5.0 mL) at -78 °C. The reaction mixture was stirred for 30 min.

The crude enal (0.48 mmol) derived from the cross-metathesis step (see above experimental) was dissolved in THF (3.0 mL) and added to the phosphonate solution.

The reaction mixture was stirred at -78 °C for 4 h. Et2O (10 mL) was added, and the reaction was quenched with saturated aqueous NH4Cl (5 mL). The aqueous phase was extracted with diethyl ether (2 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), brine (2 x 10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with

2-10% ethyl acetate/hexanes.

General procedure for sequential one-pot CM/hydride reduction reactions (Tables

1.12 & 1.13).

To a solution of olefin (0.48 mmol) and a,b-unsaturated carbonyl partner (1.45 mmol) in deaerated CH2Cl2 (3.0 mL) was added catalyst 2 or 4 (5-10 mol%). The reaction mixture was heated to 40 °C under an Ar atmosphere and stirred for 3 h. The reaction mixture was cooled to -78 °C, and DIBAL-H (1M in hexanes, 1.8 mL, 1.80 mmol) was added dropwise. The reaction mixture was stirred at -78 °C for 2 h and quenched by the slow addition of MeOH (1.8 mL) followed by a saturated solution of Rochelle’s salt (1.8 mL).

The reaction mixture was warmed to room temperature and filtered through a cotton plug.

The residue was washed thoroughly with CH2Cl2 (3 x 10 mL).

147 The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with 20% EtOAc/hexanes.

Experimental procedures for sequential CM/Evans aldol reactions (Table 1.14).

HO O O Aldol 126. Grubbs II (2) (15 mg, 0.024 mmol) was

N O added to a mixture of styrene (14) (50 mg, 0.480 mmol) Me Bn and crotonaldehyde (67 mg, 0.96 mmol) in deaerated

CH2Cl2 (3.2 mL). The reaction mixture was heated to 40 °C under an Ar atmosphere for

12 h and cooled to rt. The solvent was concentrated under reduced pressure and the residue was dried for 10 min. To propionimide 125 (112 mg, 0.481 mmol) in CH2Cl2 (2 mL) was added a 1.0 M solution of Bu2BOTf (0.53 mL, 0.53 mmol) at 0 °C over 5 min followed by Et3N (68 mg, 0.674 mmol) and stirred for 30 min. After cooling the reaction mixture to -78 °C, the metathesis product from the previous step in CH2Cl2 (2 mL) was added dropwise. The reaction mixture was stirred for 1 h, warmed to 0 °C and stirred an additional hour. The reaction was quenched by dropwise addition of pH 7 phosphate buffer/MeOH (1 mL:1.5 mL) and MeOH/30% aq. H2O2 (1 mL:0.5 mL). The reaction mixture was stirred for additional hour at 10 °C, extracted with CH2Cl2 (3 x 10 mL), washed with NaHCO3 (10 mL), brine (10 mL) and dried over Na2SO4. The residue was purified by flash column chromatography eluting with EtOAc/hexanes (3:7) to give 105 mg (60%) of 126 as a colorless oil. NMR spectra (1H and 13C) were identical with reported literature values.

148

O HO O Aldol 128. Grubbs II (2) (9 mg, 0.0145 mmol) was TBSO N O Me added to a mixture of TBS ether 127 (50 mg, 0.29 Bn mmol) and crotonaldehyde (41 mg, 0.96 mmol) in deaerated CH2Cl2 (2 mL). The reaction mixture was heated to 40 °C under an Ar atmosphere for 12 h and cooled to rt. The solvent was concentrated under reduced pressure, and the residue was dried for 10 min under vacuum. To a solution of propionimide 125 (68 mg, 0.29 mmol) in CH2Cl2 (3 mL) was added a 1.0 M solution of

Bu2BOTf (0.34 mL, 0.34 mmol) at 0 °C over 5 min followed by freshly distilled i-Pr2NEt

(50 mg, 0.383 mmol) over 5 min and the reaction mixture was cooled to -78 °C. The above metathesis product dissolved in CH2Cl2 (2 mL) was added to the reaction mixture and stirred for 30 min after which the reaction vessel was transferred to a -20 °C freezer for 12 h. The solution was placed in an ice bath and quenched with of pH 7 phosphate buffer (1 mL) followed by MeOH (3 mL). A mixture of MeOH (3 mL) and 30% H2O2 (1 mL) was added over 15 min and stirring was continued for 30 min at 0 °C. The mixture was extracted with CH2Cl2 (3 x 10 mL), washed with NaHCO3 (10 mL), brine (10 mL) and dried over Na2SO4. After concentrating the organics, the residue was purified by flash column chromatography eluting with EtOAc/hexanes (3:7) to give 60 mg (48% yield) of 128 as a colorless liquid. NMR spectra (1H and 13C) were identical with reported literature values.

149 HO O O Aldol 130. Grubbs II (2) (11 mg, 0.017 mmol) was BnO N O added to a mixture of benzyl ether 129 (50 mg, 0.337 Me Bn mmol) and crotonaldehyde (47 mg, 0.674 mmol) in deaerated CH2Cl2 (2.2 mL). The reaction mixture was heated to 40 °C under an Ar atmosphere for 12 h and cooled to rt. The solvent was concentrated under reduced pressure and the residue was dried under vacuum for 10 min. To a solution of ent-125 (79 mg, 0.337 mmol) in CH2Cl2 (2 mL) was added a 1.0 M solution of Bu2BOTf (0.41 mL,

0.405 mmol) at -10 °C over 2 min followed by Et3N (44 mg, 0.438 mmol) making sure that the internal temperature is below 0 °C and stirred for 30 min at 0 oC. The reaction mixture was cooled to -78 °C and the metathesis product was added slowly using CH2Cl2

(2 mL) and stirred for 45 min, warmed to 0 °C and stirred for additional 3 h. The yellow orange solution was recooled to -10 oC and quenched by adding pH 7 buffer (2 mL),

MeOH (2 mL) and a mixture of MeOH, 30% H2O2 (1 + 0.5 mL). The reaction extracted with CH2Cl2 (3x10 mL), washed with NaHCO3 (10 mL), Brine (10 mL) and dried over

Na2SO4, Purified by flash column chromatography eluting with EtOAc/Hexanes (3:7) to give 71 mg (52.0 %) of 130 as a colorless liquid. NMR spectra (1H and 13C) were identical with reported literature values.

HO O O Aldol 132. Grubbs II (2) (9 mg, 0.014 mmol) was PMBO N O added to a mixture of PMB ether 131 (50 mg, 0.281 Me Bn mmol) and crotonaldehyde (40 mg, 0.562 mmol) in

CH2Cl2 (2.0 mL) and deaerated for 5 min. The reaction mixture was heated to 40 °C under an Ar atmosphere for 12 h and cooled to rt, the solvent was concentrated under reduced pressure and the residue was dried for 10 min.

150 To a solution of propionimide 125 (66 mg, 0.281 mmol) in CH2Cl2 (2 mL) was added 1.0

M solution of Bu2BOTf (0.51 mL, 0.506 mmol) at 0 °C over 2 min followed by Et3N (57 mg, 0.562 mmol) and stirred for 1 h at 0 °C and the metathesis product was added slowly using CH2Cl2 (2 mL) and cooled to -45 °C, stirred for 12 h and quenched by adding pH 7 buffer (2 mL), MeOH (2 mL) and a mixture of MeOH, 30% H2O2 (1 + 0.5 mL). The reaction was stirred for 30 min at RT and extracted with CH2Cl2 (3 x 10 mL), washed with NaHCO3 (10 mL), Brine (10 mL) and dried over Na2SO4, Purified by flash column chromatography eluting with EtOAc/Hexanes (3:7) to give 79 mg (64% yield) of 132 as a colorless liquid. NMR spectra (1H and 13C) were identical with reported literature values.

4.7. General procedure for sequential CM/Roush allyation reactions (Table 1.15).

Grubbs II (2) (5 mol%) was added to a mixture of CM partner (1 equiv) and crotonaldehyde (2 equiv) in CH2Cl2 (0.15 M) and deaerated for 5 min. The reaction mixture was heated to 40 °C under an Ar atmosphere for 12 h and cooled to rt, the solvent was concentrated under reduced pressure, and the residue was filtered through a plug of silica eluting with Et2O. The solvent was concentrated under reduced pressure and dried for 10 min. To a solution of (-)-DIPCl (2 equiv) in Et2O (2 mL) at 0 °C was added a 1.0 M solution of allylmagnesium bromide in Et2O (1.92 equiv). The reaction mixture was warmed to rt and stirred for 1 h. After cooling the reaction mixture to -78

°C, a solution of enal from the CM was slowly added over a period of 10 min using little ether (1 mL) and stirred for 70 min. The reaction was quenched by adding MeOH and allowed to rt, extracted with 1N aq HCl solution. The combined organic layers were basified using 30% NaOH solution to a pH of 12-13 and extracted with CH2Cl2 (3 x 10 mL), washed with NaHCO3 (10 mL), Brine (10 mL) and dried over Na2SO4.

151 Concentration of the organics and purification of the residue by flash column chromatography eluting with Et2O/toluene (1:9) gave the corresponding homoallylic alcohols, whose NMR spectra (1H and 13C) were identical with reported literature values.

Mosher esters were prepared from the homoallylic alcohols to determine %ee.

4.7.1. General procedure for sequential CM/Roush crotylation reactions (Table

1.15).

Grubbs 2nd generation catalyst (5 mol%) was added to a mixture of the terminal olefin (1 equiv) and crotonaldehyde (2 equiv) in deaerated CH2Cl2 (0.15 M). The reaction mixture was heated to 40 °C under an Ar atmosphere for 12 h and cooled to rt. The solvent was concentrated under reduced pressure, and the residue was filtered through a plug of silica eluting with Et2O. The solvent was concentrated under reduced pressure and dried for 10 min. To an oven-dried round-bottomed flask equipped with magnetic stirbar and 4 Å molecular sieves (100 mg per 1 mmol of the reagent) was added a 1.0 M solution of

Roush’s reagent 134 (1.5 equiv) in toluene. The mixture was cooled to -78 °C. The enal from the CM reaction was added to the reagent and rinsed with toluene (1 mL). The reaction mixture was stirred at -78 °C for 5 h. The reaction was quenched with dropwise addition of 2 N aq. NaOH (1 mL), and the mixture was warmed to 0 °C. After stirring an additional 20 min at 0 °C, the mixture was extracted with Et2O (3 x 10 mL), washed with brine (10 mL) and dried over K2CO3. Concentration of the organics and purification of the residue by flash column chromatography eluting with EtOAc/Hexanes (1:4) gave the corresponding homoallylic alcohols, whose NMR spectra (1H and 13C) were identical with reported literature values. Mosher esters were prepared from the homoallylic alcohols to determine %ee.

152 1 Compound 97. H NMR (400 MHz, CDCl3): ! 7.13

CO2Et MeO2C (d, J = 11.2 Hz, 1 H), 6.42-6.35 (m, 1H), 6.07-6.00 Me (m, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.67 (s, 3H), 2.50 (t,

13 J = 6.4 Hz, 2H), 2.47-2.43 (m, 2H), 1.91(s, 3H); C NMR (100 MHz, CDCl3): ! 173.0,

168.4, 139.7, 137.8, 127.0, 126.2, 60.4, 51.6, 33.3, 28.3, 14.2, 12.5.; IR (neat): 2982,

-1 + 2953, 1739, 1703 cm ; HRMS (FAB) calcd for C12H18O4+H = 227.1283, found

227.1277.

1 Compound 101. H NMR (400 MHz, CDCl3): !

TBSO CO2Et 7.15 (d, J = 11.2 Hz, 1H), 6.38-6.31 (m, 1H), 6.10- Me 6.00 (m, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.61 (t, J =

6.0 Hz, 2H), 2.25 (q, J = 7.2 Hz, 2H), 1.91 (s, 3H), 1.68-1.61 (m, 2H), 1.29 (t, J = 7.2 Hz,

13 3H), 0.89 (s, 9H), 0.04 (s, 6H); C NMR (100 MHz, CDCl3): ! 168.6, 142.4, 138.4,

126.3, 125.2, 62.2, 60.4, 32.0, 29.6, 25.9, 18.3, 14.3, 12.5, -5.3. IR (neat): 2953, 2930,

-1 + 1706 cm ; HRMS (FAB) calcd for C17H32O3Si+H = 313.2199, found 313.2210.

1 Compound 102. H NMR (400 MHz, CDCl3) !

TBSO CO2Me 7.31 (d, J = 15.6 Hz, 1H), 5.89 (t, J = 7.2 Hz, 1H), Me 5.78 (d, J = 15.6, 1H), 3.73 (s, 3H), 3.58 (t, J = 6.8

Hz, 2H), 2.26 (q, J = 8.0 Hz, 2H), 1.76 (s, 3H) 1.65-1.58 (m, 3H), 0.88 (s, 9H), 0.34 (m,

13 6H). C NMR (100 MHz, CDCl3) ! 168.0, 149.8, 141.8, 133.1, 115.1, 62.3, 51.4, 32.1,

25.9, 25.2, 18.3, 12.0, -5.3; IR (neat): 2952, 2930, 1726 cm-1; HRMS (FAB) calcd for

+ C16H30O3Si+H = 299.2043, found 299.2056.

153 1 Compound 117. H NMR (400 MHz, CDCl3): ! 7.46-7.44 (m, 2 OTBS

Ph H), 7.40-7.37 (m, 2H), 7.32-7.29 (m, 1H), 6.61 (d, J = 16.0 Hz,

1H), 6.31 (dd, J = 16.0, 6.0 Hz, 1H), 5.99-5.89 (m, 1H), 5.20-

5.13 (m, 2H), 4.44-4.39 (m, 1H), 2.51-2.37 (m, 2H), 1.03 (s, 9 H), 0.19 (s, 3H), 0.16 (s,

13 3H); C NMR (100 MHz, CDCl3): ! 137.1, 134.8, 132.8, 129.2, 128.5, 127.3, 126.4,

117.0, 73.3, 43.2, 25.9, 18.3, -4.3, -4.7; IR (neat): 2955, 2930, 2895, 2856, 1472, 1361,

-1 + 1254, 1071, 966, 910 cm ; HRMS (FAB) calc’d for C18H28OSi-H = 287.1831, found

287.1826.

1 OTBS Compound 121. H NMR (400 MHz, CDCl3): ! 7.30-7.21 (m, 5 H),

Ph 5.88-5.79 (m, 1H), 4.98-4.89 (m, 2H), 4.45 (d, J = 6.0 Hz, 2H), 2.43- Me 2.41 (m, 1H), 0.89 (s, 3H), 0.87 (s, 9H), -0.02 (s, 3H), -0.22 (s, 3H);

13 C NMR (100 MHz, CDCl3): ! 143.7, 141.1, 127.6, 126.9, 126.9, 114.4, 79.1, 46.4, 25.8,

18.2, 16.1, -4.6, -5.1; IR (neat): 2957, 2930, 2886, 2858, 1454, 1362, 1254, 1086, 1065,

-1 + 910 cm ; HRMS (FAB) calc’d for C17H28OSi-H = 275.1831, found 275.1830.

1 Compound 123. H NMR (400 MHz, CDCl3): ! 7.53-7.51 (m, 2 OTBS H), 7.47-7.43 (m, 2H), 7.38-7.34 (m, 1H), 6.66 (d, J = 16.0 Hz, Ph Me 1H), 6.33 (dd, J = 16.0, 6.5, 16 Hz, 1H), 6.07-5.99 (m, 1H), 5.23-

5.18 (m, 2H), 4.19 (t, J = 5.2, 1.2 Hz, 1H), 2.53 (m, 1H), 1.20 (d, J = 6.8 Hz, 1H), 1.11 (s,

13 9 H), 0.24 (s, 6H); C NMR (100 MHz, CDCl3): ! 140.8, 137.2, 131.4, 130.2, 128.5,

127.3, 126.4, 114.6, 45.1, 25.9, 18.3, 15.4, -4.1, -4.8;

154 IR (neat): 2957, 2929, 2886, 2857, 1252, 1065, 967 cm-1; HRMS (FAB) calc’d for

+ C19H30OSi-H = 301.1989, found 301.1996.

1 Compound 114. H NMR (400 MHz, CDCl3): ! 7.35-7.26 OBn Me (m, 5 H), 5.76-5.65 (m, 2H), 4.54, 4.52 (ABq, J = 12.0 Hz, OH 2H), 4.08 (br s, 2H), 3.41-3.35 (m, 1H), 2.33-2.30 (m, 2H)

13 1.59-1.55 (m, 3 H), 0.93 (t, J = 7.4 Hz, 3H); C NMR (100 MHz, CDCl3): ! 138.9,

131.4, 129.0, 128.3 (2C), 127.7 (2C), 127.5, 79.8, 70.9, 63.6, 36.1, 26.4, 9.6; IR (neat):

3384, 2964, 2932, 2872, 1454, 1349, 1090, 1064, 1027, 1005, 972, 910 cm-1; HRMS

(FAB) calc’d for C14H20O2+Na = 243.1361, found 243.1351.

1 Compound 116. H NMR (400 MHz, CDCl3): ! 7.37-7.20 (m, OTBS

Ph OH 5 H), 5.70-5.58 (m, 2H), 4.68 (dd, J = 7.0, 5.0 Hz, 1H), 4.05-

4.04 (m, 2H), 2.50-2.35 (m, 2H), 1.39 (bs, 1 H), 0.88 (s, 9H),

13 0.02 (s, 3H), -0.13 (s, 3H); C NMR (100 MHz, CDCl3): ! 144.9, 131.5, 129.4, 128.0

(2C), 127.0, 125.8 (2C), 74.9, 63.7, 43.8, 25.8, 18.2 -4.7, -4.9; IR (neat): 3363, 2953,

2930, 2885, 2857, 1471, 1362, 1255, 1091, 1005, 909, 836 cm-1; HRMS (FAB) calc’d for

C17H28O2Si+Na =315.1756, found 315.1750.

1 Compound 118. H NMR (400 MHz, CDCl3): ! 7.39- OTBS

Ph OH 7.30 (m, 4 H), 7.26-7.23 (m, 1H), 6.52 (d, J = 16.0 Hz,

1H), 6.20 (dd, J = 16.0, 6.4 Hz, 1H), 5.74-5.71 (m, 2H),

4.36 (q, J = 6.0 Hz, 1H), 4.16-4.12 (m, 2H), 2.38-2.35 (m, 2H), 1.50 (bs, 1 H), 0.95 (s,

155 13 9H), 0.12 (s, 3H), 0.10 (s, 3H); C NMR (100 MHz, CDCl3): ! 137.0, 132.7, 131.7,

129.3, 128.8, 128.5 (2C), 127.4, 126.4 (2C), 73.3, 63.6, 41.5, 25.9, 18.3, -4.3, -4.7; IR

(neat): 3356 cm-1; IR (neat): 3356, 2953, 2929, 2893, 2856, 1471, 1253, 1071, 968 cm-1;

HRMS (FAB) calc’d for C19H30O2Si+Na = 341.1913, found 341.1904.

1 Compound 122. H NMR (400 MHz, CDCl3): ! 7.29-7.21 (m, OTBS 5 H), 5.72-5.50 (m, 2H), 4.43 (d, J = 6.0 Hz 1H), 4.06 (bs, 2H), Ph OH Me 2.45-2.40 (m, 1H), 1.16 (bs, 1 H), 0.89 (d, J = 3.6 Hz, 3H),

13 0.87 (s, 9H), 0.01 (s, 3H), -0.22 (s, 3H); C NMR (100 MHz, CDCl3): ! 143.6, 135.3,

129.2, 127.6, 127.0, 126.9, 126.8, 79.1, 63.9, 45.1, 25.8, 18.2, 16.5, -4.6, -5.1; IR (neat):

3333, 2955, 2929, 2885, 2856, 1471, 1455, 1253, 1088, 1064 cm-1; HRMS (FAB) calc’d for C18H30O2Si+Na = 329.1913, found 329.1923.

1 Compound 124. H NMR (400 MHz, CDCl3): ! 7.42- OTBS

Ph OH 7.34 (m, 4 H), 7.30-7.26 (m, 1H), 6.53 (d, J = 16.0 Hz, Me 1H), 6.19 (dd, J = 16.0, 6.8 Hz, 1H), 5.80-5.68 (m, 2H),

4.19-4.16 (m, 3H), 2.44-2.38 (m, 1H), 1.43 (bs, 1H), 1.07 (d, J = 6.8 Hz, 3H), 0.96 (s, 9

13 H), 0.12 (s, 3H), 0.08 (s, 3H); C NMR (100 MHz, CDCl3): ! 137.1, 135.0, 131.4, 130.3,

129.3, 128.5 (2C), 127.4, 126.4 (2C), 77.3, 63.8, 43.6, 25.9, 18.2, 15.8, -4.2, -4.8; IR

(neat): 3357, 2956, 2929, 2884, 2856, 1471, 1461, 1362, 1253, 1070, 969, 909 cm-1;

HRMS (FAB) calc’d for C20H32O2Si+Na = 355.2069, found 355.2079.

156 5.3 CHAPTER 2: Experimental Procedures

Aldol 165. To a solution of propionimide 164 (507 mg, HO O S o 1.91 mmol) in CH2Cl2 (12 mL) at 0 C was added TiCl4 Ph N S Me (725 mg, 3.82 mmol) and the yellow slurry was stirred for 5 Bn

min. Freshly distilled i-Pr2NEt (271 mg, 2.10 mmol) was slowly added at 0 oC to give a red solution, which was stirred for an additional 20 min at

0 oC. The reaction mixture was cooled to -78 oC, and freshly distilled trans- cinnamaldehyde 194 (278 mg, 2.10 mmol) was added dropwise. After stirring at -78 oC for 1 h, the mixture was warmed to 0 oC over 3 h. The reaction mixture was quenched by

o the addition of sat’d NH4Cl (12 mL) and stirred for 5 min at 0 C. The reaction mixture was extracted with CH2Cl2 (2 x 30 mL). The combined organic layers were washed with brine solution (20 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with

EtOAc/hexanes (1:9) to afford 380 mg (50%) of 165 as a yellow oil. 1H and 13C NMR consistent with literature values. (Crimmins et. al. Org. Lett. 2000, 66, 894).

Aldol 165 O-TBS ether. To a solution of aldol 165 (225 S TBSO O o mg, 0.57 mmol) in CH2Cl2 (6.0 mL) at -78 C were added Ph N S Me distilled 2,6-lutidine (152 mg, 1.42 mmol) and TBSOTf Bn (164 mg, 0.62 mmol). After stirring the reaction mixture for

1 h at -78 oC, water (3.0 mL) was added. The reaction mixture was stirred an additional 5 min at rt and extracted with CH2Cl2 (2 x 20 mL).

157 The combined organic layers were washed with aqueous NaHCO3 (10 mL), brine solution (15 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with

20 EtOAc/hexanes (0.4:9.6) to afford 217 mg (75%) of product as a yellow oil. [a]D +63.2

(c 0.5, CH2Cl2); IR (neat) 3154, 2930, 2857, 2360, 2254, 1793, 1694, 1471, 1376, 1259

-1 1 cm ; H NMR (400 MHz, CDCl3) ! 7.41-7.23 (m, 10H), 6.56 (d, J = 16.0 Hz, 1H), 6.18

(dd, J = 15.6, 7.6 Hz, 1H), 5.42-5.37 (m, 1H), 5.20-4.89 (m, 1H), 4.70 (t, J = 8.0 Hz, 1H),

3.33 (dd, J = 11.2, 7.2 Hz, 1H), 3.24 (dd, J = 13.2, 3.2 Hz, 1H), 3.05 (dd, J = 13.2, 10.8

Hz, 1H), 2.85 (d, J = 11.6 Hz, 1H), 1.12 (d, J = 6.8 Hz, 3H), 0.87 (s, 9H), 0.10 (s, 3H),

13 0.04 (s, 3H); C NMR (100 MHz, CDCl3) ! 201.0, 176.3, 136.8, 136.7, 132.1, 130.4,

129.4, 128.9, 128.6, 127.7, 127.2, 126.5, 75.9, 69.1, 45.3, 37.1, 31.3, 25.9, 25.7, 18.1,

+ 14.4, -3.8, -4.6; HRMS (FAB) calc’d for C28H37NS2SiO2+Na = 534.1933, found

534.1945.

Aldehyde 196. To a solution of TBS-protected aldol 165 (205 TBSO CHO o Ph mg, 0.40 mmol) in CH2Cl2 (4.0 mL) at -78 C was added Me DIBAL-H (0.8 mL, 1.0 M in Hexanes, 0.8 mmol) and stirred for 30 min. Additional DIBAL-H (0.4 mL, 1.0 M in Hexanes, 0.4 mmol) was added at -

78 oC and stirred for another 20 min, and the reaction was quenched with saturated aq.

Rochelle’s salt soution (4.0 mL) and stirred for 45 min at rt. The reaction mixture was extracted with CH2Cl2 (2 x 15 mL). The combined organic layers were washed brine solution (10 mL), dried (Na2SO4) and filtered.

158 The solvent was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc/hexanes (0.3:9.7) to afford 100 mg (82%) of aldehyde 196 as a yellow oil. 1H and 13C NMR consistent with literature values.

Homoallylic alcohols 197 and 198. A solution of (E)- TBSO OH crotylboronate 139 (0.49 mL, 1.0 M solution in toluene, 0.49 Ph Me Me mmol) in toluene (1.0 mL) was treated with powdered 4 Å molecular sieves and then cooled to -78 oC. A solution of freshly prepared aldehyde 196

(100 mg, 0.33 mmol) in toluene (1.0 mL) was slowly added over a period of 10 min.

After stirring the reaction mixture for 20 h, at -78 oC, it was treated with 2 N NaOH (3.0 mL) to hydrolyze DIPT. The biphasic mixture was warmed to 0 oC and stirred for 20 min at 0 oC, the reaction mixture was extracted with ether (2 x 20 mL). The combined organic layers were washed brine solution (10 mL), dried (K2CO3) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc/hexanes (0.3:9.7) to afford 70 mg (60%) of alcohols

197 and 198 as a colorless foam. IR (neat) 3155, 2958, 2931, 2250, 1471, 1383, 1257 cm-

1 1 ; H NMR (400 MHz, CDCl3): ! 7.27-7.09 (m, 5H), 6.39 (d, J = 16.0 Hz, 1H), 6.10 (dd,

J=16.0, 7.2 Hz, 1H), 5.69-5.60 (m, 1H), 5.0-4.91 (m, 2H), 4.24 (t, J = 6.4 Hz, 1H), 3.38

(d, J = 7.6, 1H), 2.20-2.14 (m, 1H), 2.10 (bs, 1H), 0.88 (d, J = 6.8 Hz, 3H), 0.83 (d, J =

13 5.2 Hz, 3H), 0.79 (s, 9H), -0.03 (s, 3H), -0.09 (s, 3H); C NMR (100 MHz, CDCl3) !

141.9, 139.4, 136.9, 136.8, 131.8, 131.4, 130.4, 128.7, 128.6, 127.6, 127.5, 126.5, 126.4,

115.5, 114.9, 78.8, 77.9, 75.7, 42.1, 41.6, 40.6, 25.6, 25.8, 18.1, 18.0, 16.6, 12.7, 7.7, -

3.0, -3.6, -4.0, -4.4; HRMS (FAB) calc’d for C22H36SiO2-H = 359.2406, found 359.2393.

159 Me Me Acetonides 199 and 200. TBAF · 3H2O (92 mg, 0.29 O O mmol) was added to a solution of alcohols 197 and 198 (70 Ph mg, 0.19 mmol) in THF (2.0 mL) at 0 oC. The reaction was Me Me warmed to rt and stirred for 12 h, diluted with water (4 mL) and extracted with CH2Cl2 (2 x 10 mL). The combined organic layers were washed brine solution (10 mL), dried

(Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc/hexanes (2:8) to afford

42 mg (88%) of intermediary diols. The crude diols were dissolved in 2,2- dimethoxypropane (15 mL) and a catalytic amount of PPTS was added. The reaction mixture was stirred for 3 h then filtered through a plug of cotton. The solvent was concentrated under reduced pressure, and the residue was purified by preparative TLC eluting with EtOAc/hexanes (1:9) to afford 32 mg (76%) 199 as a colorless foam and 8 mg (19%) of minor acetonide 200 as a colorless foam.

Major Acetonide 199. ["] 20 + 29.5 (c 0.5, CH Cl ); IR Me Me D 2 2 O O (neat) 3154, 3082, 2977, 2938, 2360, 2253, 1605, 1452,

Ph -1 1 Me Me 1382, 1201 cm ; H NMR (500 MHz, CDCl3) ! 7.41-7.39 (m, 2H), 7.33-7.30 (m, 2H), 7.25-7.21 (m, 1H), 6.61 (dd, J = 16.0, 1.5 Hz, 1H), 6.20 (dd,

J=16.0, 5.5 Hz, 1H), 5.98-5.91 (m, 1H), 5.09-5.01 (m, 2H), 4.63-4.61 (m, 1H), 3.64 (dd,

J = 10.0, 2.0 Hz, 1H), 2.34-2.29 (m, 1H), 1.68-1.64 (m, 1H), 1.48 (s, 3H), 1.47 (s, 3H),

13 0.95 (d, J = 1.5 Hz, 3H), 0.94 (d, J = 1.0 Hz, 3H); C NMR (100 MHz, CDCl3) ! 142.0,

137.0, 130.2, 129.2, 128.5, 127.4, 126.4, 113.4, 99.2, 74.3, 38.2, 34.6, 30.0, 19.6, 14.5,

+ 5.3; HRMS (CI) calc’d for C19H26O2+H = 287.2011, found 287.2000.

160 20 Me Me Minor Acetonide 200. ["]D + 50.0 (c 0.2, CH2Cl2); IR O O (neat) 3155, 2986, 2930, 2200, 1458, 1380, 1224, 1172,

Ph -1 1 Me Me 1096 cm ; H NMR (500 MHz, CDCl3) ! 7.38 (d, J = 7.0 Hz, 2H), 7.30 (t, J = 7.5 Hz, 2H), 7.22 (t, J = 7.3 Hz, 1H), 6.57 (d, J = 15.5 Hz, 1H), 6.18

(dd, J = 15.8, 6.3 Hz, 1H), 5.94-5.87 (m, 1H), 5.07-5.02 (m, 2H), 4.50 (dt, J = 6.5, 1.5

Hz, 1H), 3.29 (dd, J = 8.0, 3.5 Hz, 1H), 2.36-2.29 (m, 1H), 2.00-1.93 (m, 1H), 1.40 (s,

3H), 1.39 (s, 3H), 1.10 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz,

CDCl3) ! 140.3, 137.0, 130.4, 128.4, 127.6, 127.3, 126.3, 115.0, 100.6, 77.8, 70.7, 41.2,

+ 37.9, 25.5, 23.6, 17.1, 13.1; HRMS (CI) calc’d for C19H26O2+H = 287.2011, found

287.2021.

Aldol 203. To a solution of dipropionimide 202 HO O O O

N O (1.38 g, 4.77 mmol) in CH2Cl2 (19 mL) at -10 °C Me Me Bn was added TiCl4 (1.00 g, 5.25 mmol) then freshly distilled i-Pr2NEt (0.68 g, 5.25 mmol). After stirring for 1 h, the reaction mixture was cooled to -78 °C and freshly distilled aldehyde 194 (0.69 g, 5.25 mmol) was added drop wise. The reaction mixture was stirred at -78 °C for 30 min then warmed to -40 °C over a period of 1 h. The reaction mixture was warmed to 0 °C and quenched by the addition of phosphate buffer (7.6 mL, pH = 7) and stirred an additional 5 min. The reaction mixture was extracted with CH2Cl2 (2 x 20 mL). The combined organic layers were washed with aqueous NaHCO3 (15 mL), brine solution (15 mL), dried (Na2SO4) and filtered.

161 The solvent was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc/hexanes (1:5) to afford 1.50 g (75%) of 203 as

20 a yellow oil. ["]D -165.0 (c 1.0, CH2Cl2); IR (neat) 3524, 2252, 1774, 1713, 1391, 1358,

-1 1 1215, 909, 731 cm ; H NMR (400 MHz, CDCl3) d 7.35-7.13 (m, 10H), 6.63 (dd, J =

16.0, 1.2 Hz, 1H), 6.13 (dd, J = 16.0, 5.6 Hz, 1H), 4.84 (q, J = 7.2 Hz, 1H), 4.78 (bs, 1H),

4.73-4.68 (m, 1H), 4.22-4.12 (m, 2H), 3.24 (dd, J = 13.6, 3.2 Hz, 1H), 3.02-3.00 (m, 2H),

2.74 (dd, J = 13.6, 9.6 Hz, 1H), 1.45 (d, J = 7.6 Hz, 3H), 1.13 (d, J = 7.2 Hz, 3H); 13C

NMR (100 MHz, CDCl3) d 211.1, 170.0, 153.9, 136.7, 134.9, 130.9, 129.3, 128.9, 128.5,

127.5, 127.4, 126.5, 71.9, 66.6, 55.3, 52.3, 49.7, 37.8, 13.0, 10.5; HRMS (FAB) calc’d

+ for C25H27NO5+Na 444.1786, found 444.1778.

Diol 204. To a stirred solution of Me4NBH(OAc)3 HO HO O O

N O (5.63 g, 21.40 mmol) in MeCN (10 mL) was added Me Me Bn glacial AcOH (10 mL). After stirring for 30 min, the reaction mixture was cooled to -40 °C and a solution of 203 (1.50 g, 3.57 mmol) in

MeCN (10 mL) was added via cannula. After stirring for 6 h at this same temperature, the reaction mixture was transferred to a refrigerator and allowed to age for 16 h at -20

°C. Aqueous sodium tartrate (0.5 M, 25 mL) was added. The reaction mixture was warmed to rt over 1 h then diluted with additional sodium tartrate (0.5 M, 25 mL) and

CH2Cl2 (50 mL). The organic layer was separated, and the aqueous layer was back- extracted with CH2Cl2 (2 x 25 mL). The combined organic layers were washed with aqueous NaHCO3 (30 mL), brine solution (30 mL), dried (Na2SO4) and filtered.

162 The solvent was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc/hexanes (2:3) to afford 1.32 g (88%) of 204 as

20 a yellow oil. ["]D -80.8 (c 1.0, CH2Cl2); IR (neat) 3460, 3028, 2976, 2360, 2341, 2252,

1 1779, 1698, 1455, 1385, 1209, 908, 732; H NMR (400 MHz, CDCl3) ! 7.40-7.20 (m,

10H), 6.64 (dd, J = 16.0, 1.2 Hz, 1H), 6.26 (dd, J =16.0, 5.6 Hz, 1H), 4.77-4.75 (m, 2H),

4.26-4.16 (m, 3H), 3.98 (d, J = 8.4 Hz, 1H), 3.73 (q, J = 6.9 Hz, 1H), 3.31 (bs, 1H), 3.25

(dd, J = 13.2, 3.4 Hz, 1H), 2.81 (dd, J = 13.2, 9.6 Hz, 1H), 1.97-1.90 (m, 1H), 1.31 (d, J =

13 7.2 Hz, 3H), 1.04 (d, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) ! 177.1, 153.3,

136.8, 135.0, 130.5, 130.3, 129.4, 129.0, 128.5, 127.5, 127.4, 126.4, 78.4, 72.8, 66.2,

+ 55.5, 40.3, 39.8, 37.9,15.0, 11.6; HRMS (FAB) calc’d for C25H29 NO5+Na 446.1943, found 446.1945.

Acetonide 205. To a stirred solution of diol 204 Me Me O O O O (80.0 mg, 0.19 mmol) in dimethoxypropane (19

N O mL) was added a catalytic amount of PPTS. The Me Me Bn reaction mixture was stirred for 3 h. The solvent was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc/hexanes (1:4) to afford 65.0 mg (73%) of 205 as a

20 yellow oil. ["]D -50.2 (c 1.0, CH2Cl2); IR (neat) 3154, 3029, 2986, 2253, 1780, 1698,

-1 1 1455, 1383, 1263, 1222, 1107, 1022, 969, 909, 650 cm ; H NMR (400 MHz, CDCl3) !

7.34-7.14 (m, 10H), 6.54 (dd, J = 15.8, 0.8 Hz, 1H), 6.09 (dd, J = 15.8, 6.0 Hz, 1H), 4.66-

4.54 (m, 1H), 4.57-4.54 (m, 1H), 4.12-4.11 (m, 2H), 4.04-3.96 (m, 1H), 3.67 (dd, J = 9.2,

6.8 Hz, 1H), 3.20 (dd, J = 13.2, 3.2 Hz, 1H), 2.74 (dd, J = 13.2, 9.6 Hz, 1H), 1.93-1.85

163 (m, 1H), 1.35 (s, 3H), 1.26 (s, 3H), 1.18 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H); 13C

NMR (100 MHz, CDCl3) ! 175.1, 153.2, 137.0, 135.3, 130.5, 129.5, 129.0,128.5, 127.4,

127.3, 127.2, 126.4, 100.8, 76.2, 70.0, 66.0, 55.4, 42.9, 38.9, 38.0, 25.8, 23.5, 14.0, 12.8;

+ HRMS (FAB) calc’d for C28H33NO5+Na 486.2256, found 486.2254.

Imide 207. To a stirred solution of the diol 204 MeO MeO O O (70.0 mg, 0.17 mmol) in CHCl3 (1.5 mL) at 0 °C, N O Me Me was added 2,6-di-t-butyl-4-methylpyridine (1.19 g, Bn 5.81 mmol) followed by the addition of MeOTf

(0.82 g, 4.98 mmol). The reaction mixture was stirred for 28 h at 0 °C, quenched with

MeOH (2 mL) and extracted with CH2Cl2 (3 x 5 mL), washed with brine solution (5 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc/hexanes (1:4) to

20 afford 37.0 mg (49%) of 207 as a yellow oil. ["]D -74.5 (c 1.0, CH2Cl2); IR (neat) 3154,

2983, 2253, 1780, 1698, 1470, 1383, 1264, 1094, 907, 733, 650 cm-1; 1H NMR (300

MHz, CDCl3) ! 7.36-7.14 (m, 10H), 6.50 (d, J = 21.2, Hz, 1H), 6.08 (dd, J = 21.2, 9.6

Hz, 1H), 4.57-4.56 (m, 1H), 4.13-4.08 (m, 3H), 3.94 (dd, J = 9.6, 4.8 Hz, 1H), 3.41-3.36

(m, 4H), 3.25-3.20 (m, 4H), 2.69 (dd, J = 17.6, 13.0 Hz, 1H), 1.90-1.88 (m, 1H), 1.20 (d,

13 J = 6.4 Hz, 3H), 0.90 (d, J = 9.2 Hz, 3H); C NMR (100 MHz, CDCl3) ! 175.2, 153.1,

136.8, 135.4, 132.3, 129.5, 129.2, 128.9, 128.6, 127.6, 127.3, 126.5, 84.9, 81.8, 66.0,

+ 60.1, 56.5, 55.7, 41.6, 40.7, 37.9, 14.1, 11.0; HRMS (FAB) calc’d for C27H33NO5+Na =

474.2256, found 474.2228.

164 Aldehyde 173.To a stirred solution of 207 (40.0 MeO MeO CHO mg, 0.09 mmol) in THF (2 mL), were added MeOH Me Me (1.26 mg, 0.20 mmol) and LiBH4 (5.0 mg, 0.20 mmol) at

0 oC. After stirred for 1.5 h at this temperature reaction mixture was quenched with 1 M

NaOH solution (0.5 mL) and stirred for additional 5 min. The reaction mixture was extracted with (3 x 5 mL) of CH2Cl2, washed with brine solution (5 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc/hexanes (1:4) to afford 0.159 g

(64%) of alcohol as a yellow oil. The nmr data was matching with the literature values.

To a stirred solution of the alcohol (15.9 mg, 0.057 mmol) in CH2Cl2 (1.5 mL), was added the Dess Martin reagent and stirred for 20 min. Saturated aqueous NaHCO3 (1.0 mL), and aqueous Na2S2O3 (1.5 M, 1.0 mL) and Et2O (3 mL) were added and stirring was continued for additional 15 min. The aqueous layer was extracted with Et2O (3x2 mL), washed with brine solution (4 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc/hexanes (1:4) to afford 14.5 mg g (92%) of aldehyde 173 as a yellow oil. The nmr data was matching with the literature values.

Dienoate 15. To a solution of MeO MeO Me O diisopropylamine (32.0 mg, 0.08 mmol) in OEt Me Me dry THF (1 mL) at -78 oC, n-BuLi (2.04 M in hexane, 1.8 mL, 0.36 mmol) was added dropwise and stirred at the same tempetature for 30 min.

165 Then DMPU (0.27 mL, 1.5 mL/mmol) was added to the reaction mixture and stirred for 5 min. Next diethylphosphonate 174 (96 mg, 0.36 mmol) in dry THF (0.2 mL) was added to the reaction mixture followed immediately by the addition of freshly prepared aldehyde 173 (50.0 mg, 0.18 mmol) in dry THF (0.2 mL). The stirring was continued at -

78 oC for 8 h. The reaction mixture was quenched by the addition of saturated aqueous

NH4Cl solution (1.5 mL) and warmed to room temperature. Then it was diluted with

EtOAc (25 mL), washed with brine (10 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc/hexanes (1:19) to afford 40.0 mg (57%) of dienoate

175 as a colorless oil. The nmr data was matching with the literature values.

Crocacin C 142. To a stirred solution of MeO MeO Me O dienoate 175 (32.0 mg, 0.09 mmol) in NH2 Me Me o THF/MeOH/H2O (3:1:1, 1.0 mL) at 0 C,

LiOH.H2O (67.0 g, 1.59 mmol) was added in one portion and stirred at room temperature for 15 h. It was then acidified with 1 M HCl at 0 oC up to pH 2 and diluted with EtOAc

(10 mL) and washed with brine (5 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the crude acid was used directly in the next reaction. To the crude acid (30.0 mg, 0.08 mmol) in dry THF (0.7 mL) at -20 oC, triethylamine (0.013 ml, 0.09 mmol) was added and stirred for 5 min. Ethyl chloroformate (10.0 mg, 0.09 mmol) was added next to the reaction mixture and stirring continued at -20 oC for 0.5 h. This was followed by the dropwise addition of 25% aqueous NH4OH solution (0.035 mL, 0.5 mmol).

166 After stirring at 0 oC for 20 min, the reaction mixture was quenched by the addition of saturated NH4Cl solution (5 mL), extracted with EtOAc (10 mL), washed with brine (5 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc/hexanes (1:1)

D to afford 18.7 mg (63%) of crocacin C 142 as a colorless semi solid. ["] 20 +59.8 (c 0.31,

D 1 MeOH), lit. ["] 20 +52.2 (c 0.3, MeOH); H NMR (400 MHz, CDCl3): ! 7.52-7.50 (m,

2H), 7.38-7.34 (m, 2H), 7.29-7.27 (m, 1H), 6.72 (br s, 1H), 6.57 (d, J = 16.0, Hz, 1H),

6.29 (dd, J=16.4, 7.6 Hz, 1H), 6.14-6.11 (m, 3H), 5.84 (s, 1H), 4.14-4.11 (m, 1H), 3.56

(s, 3H), 3.33 (s, 3H), 3.21 (dd, J=9.6, 2.0 Hz, 1H), 2.58-2.67 (m, 1H), 2.26 (d, J = 1.6 Hz,

3H), 1.62-1.57 (m, 1H), 1.21 (d, J = 6.8, 3H), 0.89 (d, J = 6.8, 3H).; 13C NMR (100

MHz, CDCl3) : ! 169.4, 148.5, 138.3, 137.5, 135.5, 133.0, 130.9, 129.8, 129.7, 128.7,

127.7, 122.4, 87.6, 82.2, 61.9, 56.9, 43.9, 41.2, 19.7, 13.9, 10.5.

5.4 CHAPTER 3: Experimental Procedures

NHBn Amine 356. Benzylamine (886 mg, 8.27 mmol) and MgSO4

(1.24 g) were added to a stirred solution of indole 3- N H carboxaldehyde 355 (1.00 g, 6.89 mmol) in CH2Cl2 (15 mL).

The reaction mixture was refluxed for 16 h, cooled to rt, filtered through a bed of Celite, and washed with ether (50 mL). The solvent was evaporated under reduced pressure to give an imine as a pale yellow solid. The imine was dried, dissolved in anhydrous THF

(60 mL), and a solution of allylmagnesium bromide (13.8 mL, 1M in THF, 13.8 mmol) was added at 0 °C.

167 The reaction mixture was stirred for 30 min at 0 °C, 3 h at rt, and quenched with saturated NH4Cl (40 mL). The organic solvent was concentrated under reduced pressure, and the remaining aqueous layer was extracted with EtOAc (2 x 60 mL). The combined organic layers were washed with brine solution (30 mL), dried (Na2SO4) and filtered.

The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with EtOAc/hexanes (1:1) to afford 1.72 g (90%) of amine 356 as a yellow oil. IR (neat) 3411, 3137, 3058, 2975, 2916, 2827, 1453; 1H

NMR (400 MHz, CDCl3) ä 8.23 (bs, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.29-7.05 (m, 9H),

5.82-5.72 (m, 1H), 5.10-5.00 (m, 2H), 4.09 (t, J = 6.8 Hz, 1H), 3.80 (d, J = 13.2 Hz, 1H)

13 3.67 (d, J = 13.6 Hz, 1H), 2.67-2.60 (m, 2H), 1.82 (bs, 1H); C NMR (100 MHz, CDCl3)

ä 140.7, 136.5, 136.0, 128.3, 128.2, 126.7, 126.5, 121.9, 121.9, 119.5, 119.2, 118.2,

+ 117.1, 111.2, 54.2, 51.5, 41.5; HRMS (FAB) calc’d for C19H20N2+H = 277.1705, found

277.1704.

Chloroacetamide 357. Chloroacetyl chloride (462 mg, 4.09 O Cl NBn mmol) was added to a stirred solution of triethylamine (621

mg, 6.14 mmol) and amine 356 (1.13 g, 4.09 mmol) in N H CH2Cl2 (40 mL) 0 °C over a period of 10 min. The reaction mixture was stirred for 15 min at 0 °C, 15 min at room temperature and diluted with water. The aqueous layer was extracted with CH2Cl2 (2 x 15 mL). The combined organic layers were washed with aqueous NaHCO3 (20 mL), brine solution (20 mL), dried

(Na2SO4) and filtered.

168 The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with EtOAc/hexanes (1:3) to afford 1.37 g (95%) of chloroacetamide 357 as a yellow oil. IR (neat) 3410, 3290, 3061, 2943, 1633, 1495,

-1 1 1454, 1417 cm ; H NMR (400 MHz, CDCl3) (Major rotamer) ä 9.04 (bs, 1H), 7.84 (d, J

= 8.0 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.36-7.00 (m, 8H), 6.60 (t, J = 7.6 Hz, 1H), 6.04-

5.97 (m, 1H), 5.27 (d, J = 17.2 Hz, 1H), 5.19 (d, J = 10.4 Hz, 1H), 4.63-4.50 (m, 2H),

13 4.11-4.02 (m, 2H), 2.86 (t, J = 7.2 Hz, 2H); C NMR (100 MHz, CDCl3) ä 167.8, 137.2,

136.2, 134.8, 128.5, 128.0, 127.8, 127.2, 126.8, 125.9, 123.8, 122.5, 119.9, 119.3, 117.4,

+ 113.3, 111.4, 50.8, 46.5, 42.6, 36.3; HRMS (FAB) calc’d for C21H21N2OCl+Na =

375.1240 found 375.1238.

Spiroindolenine 359. Sodium iodide (1.41 g, 9.40 mmol) O NBn was added to a stirred solution of chloroacetamide 357 (330

H H mg, 0.94 mmol) in acetone (10 mL). The reaction mixture N H was heated at reflux for 2 h. The solution was cooled to rt, poured into EtOAc (30 mL), washed with H2O (15 mL), dried (Na2SO4) and concentrated. The residue was immediately dissolved in toluene (10 mL) followed by the addition of AgOTf (483 mg, 1.88 mmol) and 2,6-di-tert-butyl-4-methylpyridine (386 mg,

1.88 mmol). The reaction mixture was stirred for 1.5 h and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with

MeOH/CH2Cl2 (1:15) containing 50 mL Et3N to afford 286 mg (96%) of spiroindolenine

359 as a light brown oil. IR (neat) 3353, 3068, 2926, 2854, 1683, 1415 cm-1; 1H NMR

(400 MHz, CDCl3) ä 8.26 (bs, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.41-7.29 (m, 6H), 7.13 (t, J

169 = 7.4 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 5.50-5.43 (m, 1H), 5.15 (d, J = 14.8 Hz, 1H),

5.09-5.01 (m, 2H), 4.14 (d, J = 14.8 Hz, 1H), 3.72 (dd, J = 7.0, 4.6 Hz, 1H), 2.98 (d, J =

13 16.8 Hz, 1H), 2.47 (d, J = 17.2 Hz, 1H), 2.43-2.38 (m, 2H); C NMR (100 MHz, CDCl3)

ä 172.2, 172.1, 154.1, 141.4, 135.8, 132.0, 128.8, 128.7, 128.7, 128.5, 128.0, 126.9,

121.4, 120.7, 119.3, 62.2, 59.7, 45.0, 36.5, 35.2; HRMS (FAB) calc’d for

+ C21H20N2O+Na = 477.0792, found 477.0798.

O Bromoacetamide 360. Bromoacetyl chloride (353 mg, 2.24 Br NBn mmol) was added to a stirred solution of triethylamine (340 mg,

3.36 mmol) and 356 (620 mg, 2.24 mmol) in CH2Cl2 (20 mL) at N H 0 °C over a period of 10 min. The reaction mixture was stirred for 15 min at 0 °C, 30 min at rt, then diluted with water. The aqueous layer was extracted with CH2Cl2 (2 x 15 mL). The combined organic layers were washed with aqueous

NaHCO3 (20 mL), brine solution (20 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with EtOAc/hexanes (1:3) to afford 837 mg (94%) of bromoacetamide 360 as a yellow oil. IR (neat) 3474, 3309, 3069, 1631, 1463, 1419 cm-1;

1 H NMR (400 MHz, CDCl3) (Major rotamer) ä 8.76 (bs, 1H), 7.86 (d, J = 7.6 Hz, 1H),

7.50 (d, J = 8.0 Hz, 1H), 7.38-7.01 (m, 8H), 6.57 (t, J = 7.8 Hz, 1H), 6.01-5.98 (m, 1H),

5.30-5.19 (m, 2H), 4.61-4.42 (m, 2H), 3.86 (s, 2H), 2.87 (t, J = 7.2 Hz, 2H); 13C NMR

(100 MHz, CDCl3) ä 167.9, 137.5, 136.2, 134.8, 128.6, 128.0, 127.8, 127.2, 126.9, 125.8,

123.6, 122.6, 120.0, 119.6, 117.4, 113.7, 111.2, 50.6, 47.0, 36.4, 28.0; HRMS (FAB)

+ calc’d for C21H21N2OBr+Na = 419.0735, found 419.0737.

170 Enoate 361. Grubbs-Hoveyda 2nd generation catalyst (63 mg, O Br NBn 0.10 mmol) was added to a stirred solution of the

bromoacetamide 360 (400 mg, 1.01 mmol) and methyl acrylate N H (231 mg, 3.03 mmol) in deaerated CH2Cl2 (7 mL). The reaction CO2Me mixture was stirred at 45 °C for 3 h and cooled to rt. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with EtOAc/hexanes (2:4) to afford 414 mg (90%) of enoate 361

(E:Z = 12:1, from LC–MS trace) as an oil. HPLC–MS: MeCN (0.05 % formic acid)/water (0.1 % formic acid), 5% to 95% MeCN over 30 min; flow rate 0.80 mL/min;

UV detection at 301 nm; tR for 361, 22.60, 23.25 min; ES-LRMS m/z (ion), calculated

477.1 (M+Na+), observed 477.9; Ratio of the areas found to be 12:1. IR (neat) 3469,

-1 1 3315, 3069, 2953, 1715, 1637, 1436 cm ; H NMR (400 MHz, CDCl3) ! 9.04 (bs, 1H),

7.79 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.36-6.99 (m, 9H), 6.54 (t, J = 7.8 Hz,

1H), 6.01 (d, J = 15.6 Hz, 1H), 4.59-4.46 (m, 2H), 3.83 (s, 2H), 3.77 (s, 3H), 2.97-2.92

13 (m, 2H); C NMR (100 MHz, CDCl3) ! 167.9, 166.6, 145.0, 137.1, 136.2, 128.6, 127.3,

126.6, 125.8, 123.7, 123.3, 122.7, 120.0, 119.3, 112.8, 111.4, 51.4, 50.1, 47.1, 34.8, 27.6;

+ HRMS (FAB) calc’d for C23H23N2O3Br+Na = 477.0792, found 477.0798.

O Spiroindolenine 362. AgOTf (113 mg, 0.44 mmol) and 2,6-di- NBn tert-butyl-4-methylpyridine (90 mg, 0.44 mmol) were added to

a stirred solution of the enoate 361 (100 mg, 0.22 mmol) in N CO2Me toluene (3 mL), were added activated stirred for 1.5 h and the reaction mixture was filtered through Celite, washed with CH2Cl2 (15 mL).

171 The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography, eluting with MeOH/CH2Cl2 (1:15) containing 50 mL of Et3N to afford 78 mg (95%) of spiroindolenine 362 as a light brown oil. IR (neat) 3666, 3359,

-1 1 3069, 2943, 2258, 1689, 1436 cm ; H NMR (400 MHz, CDCl3) ! 8.13 (bs, 1H), 7.52 (d,

J = 7.6 Hz, 1H), 7.33-7.21 (m, 6H), 7.11 (t, J = 7.4 Hz, 1H), 7.03 (d, J = 6.8 Hz, 1H),

6.39-6.33 (m,1H), 5.61, (d, J = 15.6 Hz, 1H), 5.04 (d, J = 14.8 Hz, 1H), 4.01 (d, J = 15.2

Hz, 1H), 3.77 (dd, J = 7.6, 4.8 Hz, 1H), 3.58 (s, 3H), 2.82 (d, J = 17.2 Hz, 1H), 2.53 (d, J

13 = 17.2 Hz, 1H), 2.50-2.43 (m, 1H), 2.33-2.27 (m, 1H); C NMR (100 MHz, CDCl3) !

172.1, 171.8, 165.6, 154.4, 141.6, 139.9, 135.6, 129.0, 128.2, 128.1, 127.9, 127.1, 124.3,

+ 121.6, 121.0, 61.7, 59.8, 51.5, 45.1, 36.4, 33.3; HRMS (FAB) calc’d for C23H22N2O3+H

= 375.1709, found 375.1709.

O ABCE tetracycle 363. DBU (323 mg, 2.12 mmol) was added NBn to a stirred solution of 362 (397 mg, 1.06 mmol) in toluene (11

mL) and stirred for 12 h. The solvent was evaporated and the N H H CO2Me residue was purified by flash column chromatography eluting with EtOAc/hexanes (1:2) to afford 357 mg (90%) of tetracycle 363 as a colorless oil, which was recrystallized from EtOAc to give light brown crystals (mp = 152-155 °C); IR

(neat) 3660, 3375, 3041, 2943, 2904, 1680, 1606, 1485, 1437, 1413, 1251, 905, 722, 646

-1 1 cm ; H NMR (400 MHz, CDCl3) ! 7.29-7.19 (m, 5H), 7.04-6.99 (m, 2H), 6.83 (t, J =

4.2 Hz, 1H), 6.66 (t, J = 7.6 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), 4.77 (d, J = 15.2 Hz, 1H),

4.48 (bs, 1H), 4.44 (bs, H), 4.11 (d, J = 15.2 Hz, 1H), 3.76 (s, 3H), 3.65 (t, J = 5.0 Hz,

1H), 2.78 (d, J = 16.4 Hz, 1H), 2.69 (d, J = 16.8 Hz, 1H), 2.38-2.31 (m, 2H);

172 13 C NMR (100 MHz, CDCl3) ! 173.2, 166.5, 149.8, 136.9, 136.0, 131.1, 131.0, 128.9,

128.7, 128.2, 127.7, 122.7, 119.1, 109.4, 60.8, 59.4, 52.0, 48.5, 44.9, 26.7; HRMS (FAB)

+ calc’d for C23H22N2O3+Na = 375.1709, found 375.1716.

O Sequential one-pot procedure for tetracycle 363. AgOTf NBn (124 mg, 0.484 mmol) and 2,6-di-tert-butyl-4-methylpyridine

(99 mg, 0.484 mmol) were added to a stirred solution of the N H H CO2Me enoate 361 (110 mg, 0.242 mmol) in toluene (3 mL) and stirred for 1.5 h at rt. After TLC had shown full consumption of starting material, DBU (111 mg,

0.726 mmol) was added dropwise, and the reaction mixture was stirred an additional 12 h. The reaction mixture was diluted with water (5 mL), extracted with EtOAc (2 x 10 mL), washed with brine solution (15 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with EtOAc/hexanes (1:2) to afford 63 mg (70%) of 363 as a colorless oil, which was recrystallized from EtOAc.

5.5 CHAPTER 4. Experimental Procedures

O Amide 455. Amine 450 (442 mg, 2.24 mmol) and Br N Me MgSO4 (2.5 g) were added to a stirred solution of I

aldehyde 449 (500 mg, 2.04 mmol) in CH2Cl2 (20 mL). N H CO2Me The reaction mixture was stirred for 16 h at rt, filtered through a bed of Celite, and washed with ether (50 mL).

173 The solvent was evaporated under reduced pressure to give the imine 451 as pale yellow solid. After drying under vacuum for 30 min, 451 was dissolved in CH2Cl2 (20 mL) and cooled to -78 °C. Vinyl silyl ketene acetal 452 (1.05 g, 6.12 mmol) was added to the reaction mixture followed by bromoacetyl chloride 453 (386 mg, 2.45 mmol). After stirring for 30 min at -78 °C, the cooling bath was removed and the reaction mixture stirred an additional 2 h. Trifluoroacetic acid (60 equiv) was added at 0 °C. After removing the cooling bath, the reaction mixture was stirred an additional 3 h. The reaction was quenched by slowly pouring the reaction mixture in to a beaker containing ice-cold NH4OH (20 mL) and sat’d aq. NaHCO3 (10 mL). The reaction vessel was rinsed with EtOAc (2 x 10 mL). The mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4) and filtered.

The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with EtOAc/hexanes (1:1) to afford 893 mg (80%) of 455 as a pale yellow oil. IR (neat) 3321, 3056, 2948, 1715, 1639, 1458, 1434, 1273,

1208, 1173 cm-1; 1H NMR (400 MHz) ä 8.61 (bs, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.37 (d, J

= 8.0 Hz, 1H), 7.20 (t, J = 7.2 Hz, 1H), 7.15 (d, J = 1.6 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H),

6.99-6.92 (m, 1H), 6.22 (t, J = 7.6 Hz, 1H), 5.94 (d, J = 16.0 Hz, 1H), 5.38 (q, J = 6.4 Hz,

1H), 4.04 (bs, 1H), 3.94 (d, J = 10.8 Hz, 1H) 3.86 (d, J = 10.8 Hz, 1H), 3.67 (s, 3H), 2.92

(t, J = 7.6 Hz, 2H), 1.42 (d, J = 6.0 Hz, 1H); 13C NMR (100 MHz) ä 167.6, 166.6, 145.0,

136.1, 130.9, 126.8, 123.5, 123.4, 122.8, 120.2, 119.2, 112.6, 111.3, 104.0, 55.6, 51.5,

+ 49.9, 34.7, 27.2, 21.2; HRMS (FAB) calc’d for C20H22N2O3BrI + Na = 566.9756, found

566.9744.

174 O Tetracycle 457. AgOTf (566 mg, 2.20 mmol) and 2,6-

N H Me di-tert-butyl-4-methylpyridine (452 mg, 2.20 mmol) H I were added to a stirred solution of the amide 455 (600 N H CO Me 2 mg, 1.10 mmol) in toluene (11 mL). The reaction mixture was stirred for 2 h at rt. TLC monitoring showed full consumption of starting material after which DBU (503 mg, 3.30 mmol) was added dropwise. The reaction mixture was stirred for an additional 12 h, quenched with water (15 mL), extracted with

EtOAc (2 x 20 mL), washed with brine (15 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with EtOAc/hexanes (1:1) to afford 322 mg (63%) of 457 as a colorless foam. IR (neat) 3367, 1699, 1608, 1485, 1466, 1436, 1254 cm-1; 1H NMR (400

MHz) ! 7.19 (d, J = 7.6 Hz, 1H), 7.08 (dt, J = 7.6, 1.2 Hz, 1H), 7.02 (dd, J = 5.6, 2.0 Hz,

1H), 6.76 (t, J = 7.4 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 5.89 (q, J = 6.4 Hz, 1H), 4.67 (dt,

J = 15.2, 1.4 Hz, 1H), 4.48 (s, 1H), 3.88 (t, J = 4.4 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 1H),

2.87 (d, J = 16.8 Hz, 1H), 2.70 (d, J = 16.8 Hz, 1H), 2.48 (qt, J = 18.4, 4.6 Hz, 2H), 1.75

(d, J = 5.6 Hz, 1H); 13C NMR (100 MHz) 173.2, 166.3, 149.9, 137.2, 134.4, 131.4, 130.7,

129.0, 123.3, 119.3, 109.6, 103.0, 61.1, 59.4, 52.0, 51.9, 48.6, 45.4, 25.9, 21.7; HRMS

+ (FAB) calc’d for C20H21N2O3I + H = 465.0675, found 465.0663.

S Thiolactam 458. Lawesson’s reagent (370 mg, 0.92

N H Me mmol) was added to a stirred solution of 457 (425 mg, H I 0.92 mmol) in toluene (10 mL). The reaction mixture was N H CO Me 2 stirred for 1 h at 100 °C (bath temp) after which TLC

175 showed no more starting material. The reaction mixture was cooled and purified by flash column chromatography eluting with EtOAc/hexanes (1:3) to afford 317 mg (72%) of

458 as a colorless oil. IR (neat) 3369, 1709, 1607, 1485, 1466, 1437, 1306, 1264, 907,

932 cm-1; 1H NMR (400 MHz) ! 7.16 (d, J = 7.2 Hz, 1H), 7.09 (t, J = 7.6, Hz, 1H), 7.02

(t, J = 4.4 Hz, 1H), 6.74 (t, J = 7.4 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 5.99 (q, J = 6.4 Hz,

1H), 5.36 (d, J = 15.2 Hz, 1H), 4.46 (s, 1H), 4.26 (d, J = 15.2 Hz, 1H), 4.11 (t, J = 5.4 Hz,

1H), 3.79 (s, 3H), 3.34 (d, J = 13.6 Hz, 1H), 3.20 (d, J = 13.6 Hz, 1H), 2.68 (dt, J = 19.0,

5.0 Hz, 1H), 2.48 (dt, J = 19.4, 4.8 Hz, 1H), 1.75 (d, J = 6.4 Hz, 1H); 13C NMR (100

MHz) 201.5, 166.2, 149.3, 136.4, 135.9, 131.1, 130.5, 129.1, 123.5, 119.4, 109.6, 99.1,

+ 65.4, 59.9, 56.7, 56.6, 52.1, 49.8, 26.7, 21.8; HRMS (FAB) calc’d for C20H22N2O2SI + H

= 481.0447, found 481.0455.

Tetracycle 371. Triethyloxonium tetrafluoroborate (0.44 N H Me H I mL, 1M in CH2Cl2, 0.44 mmol) was added to a solution of

N 458 (190 mg, 0.40 mmol) in CH2Cl2 (4 mL) at 0 °C and H CO2Me stirred for 20 min. The mixture was then warmed to rt and stirred for an additional 45 min. The reaction mixture was recooled to 0 °C and additional triethyloxonium tetrafluoroborate (0.44 mL, 1M in CH2Cl2, 0.44 mmol) was added and stirred for 15 min.

The mixture was warmed to rt and stirred an additional 30 min. The solvent was concentrated under reduced pressure, dissolved in MeOH (5 mL), and excess NaBH4 (90 mg, 2.38 mmol) was added at 0 °C. After stirring for 10 min, the reaction mixture was warmed to rt and stirred an additional 2 h. The reaction mixture was diluted with water

(10 mL) and extracted with CH2Cl2 (2 x 20 mL).

176 The combined organic layers were washed with brine (15 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with EtOAc/hexanes (1:9) to afford 135 mg (75%) of 371 as colorless foam. IR (neat) 3350, 1704, 1422, 1264, 908, 730 cm-1; 1H

NMR (500 MHz) ! 7.11 (dd, J = 7.3, 0.8 Hz, 1H), 7.04–7.01 (m, 2H), 6.71 (td, J = 7.5,

1.0 Hz, 1H), 6.57 (d, J = 7.5 Hz, 1H), 5.86 (bq, J = 6.0 Hz, 1H), 4.55 (bs, 1H), 4.31 (s,

1H), 3.78 (s, 3H), 3.58 (d, J = 14.3 Hz, 1H), 3.30 (d, J = 14.3 Hz, 1H), 3.15 (s, 1H), 3.10

(q, J = 8.2, Hz, 1H ), 2.71-2.67 (m, 1H), 2.39 (bd, J = 14.3 Hz, 1H), 2.25 (bd, J = 14.3

Hz, 1H), 2.18-2.13 (m, 1H), 2.00-1.94 (m, 1H), 1.77 (d, J = 6.5 Hz, 3H); 13C NMR (125

MHz) 167.4, 150.1, 139.4, 132.6, 130.7, 130.0, 128.1, 123.2, 118.5, 109.2, 109.1, 65.3,

+ 62.4, 61.1, 53.5, 51.7, 50.3, 37.6, 25.2, 21.7; HRMS (FAB) calc’d for C20H23N2O2I + H

= 451.0883, found 451.0882.

Akuammicine 352. Palladium(II) acetate (7.0 mg, 0.0313 H N mmol) and PPh3 (16.4 mg, 0.0626 mmol) were added to a H N Me solution of 371 (47 mg, 0.1044 mmol) in Et3N (5 mL). The H CO2Me reaction mixture was purged with argon for 10 min, heated to 90 °C (oil bath) and stirred for 3.5 h. After cooling to rt, the mixture was diluted with

CH2Cl2 (25 mL), washed with brine (10 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with MeOH/CH2Cl2 (0.4:9.6!1:9).

177 Purified 352 was washed with a solution of 25% aq. NaOH (10 mL), which afforded 24 mg (71%) of 352 as white solid whose NMR spectra (1H and 13C) were identical with reported literature values (see references 19-22, 9a).

Thiolactam 461. Lawesson’s reagent (2.84 g, 7.02 mmol) was S Bn added to a stirred solution of 363 (2.63 g, 7.02 mmol) in H N H toluene (70 mL) and stirred for 1h at 100 °C after which TLC N H CO2Me showed full consumption of starting material. The reaction mixture was cooled to rt, concentrated to ~10 mL and purified by flash column chromatography eluting with EtOAc/hexanes (1:3) to afford 2.14 g (78%) of 461 as a pale yellow oil. IR (neat) 3386, 1708, 1606, 1484, 1466, 1437, 1264, 907 cm-1; 1H NMR

(400 MHz) ! 7.30-7.24 (m, 5H), 7.02 (td, J = 7.5, 1.2 Hz, 1H), 6.95 (d, J = 7.2 Hz, 1H),

6.84 (t, J = 4.4 Hz, 1H), 6.65 (t, J = 7.4 Hz, 1H), 6.54 (d, J = 7.6 Hz, 1H), 5.36 (d, J =

14.6 Hz, 1H), 4.62 (d, J = 14.6 Hz, 1H), 4.42 (s, 1H), 3.85 (t, J = 5.8 Hz, 1H), 3.76 (s,

3H), 3.32 (d, J = 17.6 Hz, 1H), 3.21 (d, J = 17.6 Hz, 1H), 2.47 (dt, J = 19.2, 5.4 Hz, 1H),

2.30 (dt, J = 19.2, 4.7 Hz, 1H); 13C NMR (100 MHz) 200.3, 166.2, 149.1, 136.2, 134.5,

130.8, 130.6, 129.0, 128.7, 128.4, 128.2, 128.1, 122.6, 119.2, 109.5, 65.3, 59.4, 56.2,

+ 52.0, 50.0, 49.7, 27.1; HRMS (FAB) calc’d for C23H22N2O2S + H = 391.1480, found

391.1466.

Bn Tetracycle 462. Triethyloxonium tetrafluoroborate (5.56 mL, H N H 1M in CH2Cl2, 5.56 mmol) was added to a solution of 461 (1.97

N g, 5.07 mmol) in 50 mL CH2Cl2 at 0 °C and stirred for 20 min. H CO2Me The reaction mixture was warmed to rt and stirred for 45 min.

178

The reaction mixture was recooled to 0 °C and additional triethyloxonium tetrafluoroborate (5.56 mL, 1M in CH2Cl2, 5.56 mmol) was added. The reaction mixture was stirred for 15 min, warmed to rt, and stirred for an additional 30 min. The solvent was evaporated under reduced pressure, and the residue was dissolved in 50 mL of dry

MeOH. After cooling the mixture to 0 °C, excess NaBH4 (1.15 g, 30.27 mmol) was added, and the reaction was stirred for 10 min. After warming to rt, the mixture was stirred an additional 2.0 h. The solvent was evaporated under reduced pressure; the mixture was diluted with water (20 mL) and extracted with CH2Cl2 (2 x 60 mL). The combined organic layers were washed with brine (25 mL), dried (Na2SO4) and filtered.

The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with EtOAc/hexanes (1:9) to afford 1.35 g (74%) of 462 as a colorless foam. IR (neat) 3409, 3029, 2950, 2800, 1704, 1656, 1464, 1453,

1399, 1264, 1099 cm-1; 1H NMR (500 MHz) ! 7.27-7.19 (m, 5H), 7.05 (dd, J = 7.3, 0.8

Hz, 1H), 7.01–6.98 (m, 2H), 6.69 (td, J = 7.5, 1.2 Hz, 1H), 6.54 (d, J = 8.0 Hz, 1H), 4.52

(bs, 1H), 4.31 (s, 1H), 3.93 (d, J = 13.3 Hz, 1H), 3.76 (s, 3H), 3.45 (d, J = 13.3 Hz, 1H),

3.04 (t, J = 3.5, Hz, 1H), 3.02-2.97 (m, 1H), 2.61-2.56 (m, 1H), 2.43-2.38 (m, 1H), 2.28-

2.23 (m, 1H), 2.14-2.08 (m, 1H), 1.94-1.88 (m, 1H); 13C NMR (125 MHz) 167.4, 150.1,

139.4, 139.2, 132.9, 130.1, 128.4, 128.2, 128.0, 126.8, 122.9, 118.5, 109.0, 63.6, 61.4,

+ 57.6, 53.5, 51.7, 50.9, 37.8, 25.1; HRMS (FAB) calc’d for C23H24N2O2 + H = 361.1916, found 361.1908.

179

Diamine 369. ACE-Cl (625 mg, 4.37 mmol) and Proton H NH Sponge (375 mg, 1.75 mmol) were added to a solution of 462 H

N (315 mg, 0.85 mmol) in DCE (8 mL) at 0 °C. The reaction H CO2Me mixture was heated to 90 °C and stirred for 16 h at that temperature. The reaction mixture was cooled to rt and diluted with CH2Cl2 (50 mL). The organic layers were washed with 1N aq. HCl (15 mL), sat’d aq. NaHCO3 (20 mL), and brine (20 mL). The organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was dissolved in ACE-Cl (1.5 mL), and the reaction mixture was heated to 135 °C (bath temp) and stirred for 48 h at that temperature. The reaction mixture was cooled to rt and concentrated. The crude product was dissolved in MeOH

(10 mL) and heated to 70 °C (bath temp) for 3 h. The reaction mixture was cooled, concentrated and the residue was purified by flash column chromatography eluting with

CH2Cl2/MeOH/NH4OH (8.9:1:0.1) to afford 173 mg (75%) of 369 as a foam. IR (neat)

3409, 3053, 2952,1706, 1607, 1484, 1264, 906 cm-1; 1H NMR (400 MHz) ! 7.08-7.01

(m, 3H), 6.72 (td, J = 7.6, 0.9 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 4.63 (bs, 1H), 4.37 (s,

1H), 4.08 (bs, 1H), 3.78 (s, 3H), 3.62 (t, J = 4.4 Hz, 1H), 3.38-3.23 (m, 2H), 2.50 (t, J =

4.4 Hz, 1H), 2.31-2.24 (m, 1H), 2.14-2.07 (m, 1H); 13C NMR (100 MHz) ! 167.0, 150.0,

138.2, 131.0, 130.3, 128.5, 122.3, 118.7, 109.3, 59.9, 58.3, 53.4, 51.9, 43.5, 39.2, 26.9;

+ HRMS (FAB) calc’d for C160H18N2O2+H = 271.1447, found 271.1443.

180 Vinyl iodide 463. Allyl bromide 258 (121 mg, 0.31 H N H I OTBS mmol) and K2CO3 (58 mg, 0.42 mmol) were added to a

N solution of 369 (76 mg, 0.28 mmol) in MeCN (3 mL) at H CO2Me 0 °C. The reaction mixture was stirred for 16 h at 0 °C, quenched with water (5 mL), extracted with CH2Cl2 (2 x 20 mL), and washed with brine

(10 mL). The solvent was dried (Na2SO4), concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with EtOAc/hexanes

(1.2:8.8) to afford 102 mg (63%) of 463 as colorless oil. IR (neat) 3053, 2985, 1706,

1422, 1264, 906 cm-1; 1H NMR (400 MHz) ! 7.10 (dd, J = 7.2, 0.8 Hz, 1H), 7.05–7.01

(m, 2H), 6.70 (td, J = 7.4, 0.7 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 6.08 (t, J = 5.2 Hz, 1H),

4.58 (bs, 1H), 4.31 (s, 1H), 4.26 (d, J = 5.2 Hz, 2H), 3.78 (s, 3H), 3.57 (dd, J = 14.8, 1.6,

Hz, 1H), 3.29 (d, J = 14.8 Hz, 1H), 3.17(t, J = 3.8 Hz, 1H), 3.14-3.09 (m, 1H), 2.69 (td, J

= 9.6, 4.4 Hz, 1H), 2.37 (dt, J = 14.8, 3.6 Hz, 1H), 2.29-2.22 (m, 1H), 2.20-2.14 (m, 1H),

2.01-1.95 (m, 1H), 0.91 (s, 9H), 0.89 (s, 6H); 13C NMR (100 MHz) 167.3, 150.0, 139.1,

135.9, 132.4, 130.0, 128.1, 123.1, 118.4, 109.0, 105.4, 68.0, 65.1, 62.4, 61.1, 53.4, 51.7,

+ 50.4, 37.6, 25.9, 25.2, 18.2, -5.2; HRMS (FAB) calc’d for C26H37N2O3SiI + H =

581.1696, found 581.1694.

Pentacycle 256. Palladium(II) acetate (10.4 mg, H N 0.0465 mmol) and PPh3 (24.4 mg, 0.0930 mmol) were H OTBS N added to a solution of 463 (90 mg, 0.155 mmol) in H CO2Me

Et3N (7.3 mL). The reaction mixture was purged with argon for 10 min, heated to 90 °C

(bath temp) and stirred for 2 h.

181 After cooling to rt, the mixture was diluted with EtOAc (25 mL). The combined organic layers were washed with 25 % aq. NaOH (10 mL), brine (10 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with MeOH/CH2Cl2 (0.2:9.8!1:9) to afford 60 mg (85%) of 256 as a colorless oil whose NMR spectra (1H and 13C) were identical with reported literature values.

Ester 262. To a solution of 256 (60 mg, 0.133 mmol) in H N glacial AcOH (1.4 mL) at 10 °C was added NaCNBH3 H H OH N (42 mg, 0.663 mmol). The reaction mixture was stirred H H CO2Me

for 1 h, cooled to 0 °C and basified with 30 % NH4OH solution to pH 10. The mixture was extracted with CH2Cl2 (3 x 15 mL), washed with brine (10 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure and dried under vacuum for 1 h. The crude residue was dissolved in MeOH/THF

(1:1, 4.8 mL) and treated dropwise with NaOMe (90 mL, 25% in MeOH, 0.399 mmol).

After stirring for 5 h, the reaction mixture was cooled to 0 °C, quenched with 2N aq. HCl

(5 mL) solution, and stirred an additional 3 h. The pH was adjusted to 10 by the addition of 30 % NH4OH. The mixture was extracted with CH2Cl2 (3 x 20 mL), washed with brine

(10 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the crude product was purified by flash column chromatography eluting with CH2Cl2/MeOH/NH4OH (8.4:1.5:0.1) to afford 36 mg (80%) of 262 as a white powder whose NMR spectra (1H and 13C) were identical with reported literature values.

182 Strychnine 306. To a solution of 262 (36 mg, 0.106 mmol) in H N

H CH2Cl2 (2 mL) cooled to -78 °C was slowly added DIBAL-H H N O H (0.32 mL, 1M in cyclohexane, 0.32 mmol). After 45 min, H O additional DIBAL-H (0.15 mL, 1M in cyclohexane, 0.15 mmol) was added, and the reaction mixture was stirred for an additional 15 min. The reaction was quenched with MeOH (1 mL) followed by 30 % Rochelle’s salt (5 mL) then warmed to rt. The reaction mixture was extracted with CH2Cl2 (3 x 15 mL), washed with brine (10 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure to afford crude Wieland-Gumlich aldehyde (308). To 308 was added glacial AcOH (1.4 mL), NaOAc (174 mg, 2.12 mmol), malonic acid (183 mg, 1.68 mmol) and Ac2O (36 mg,

0.353 mmol). The reaction mixture was heated to 110 °C (bath temp) and stirred for 2 h, after which it was cooled to rt, diluted with water (12 mL), washed with 50% aq. NaOH

(10 mL) and extracted with CH2Cl2 (3 x 15 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography eluting with

CHCl3/MeOH (8.8:1.2) to afford 17 mg (49%) of strychnine 306 as a white powder whose NMR spectra (1H and 13C) were identical with natural 306 purchased from the

Aldrich Chemical Company (vide infra).

Sulfinamide 467. A mixture of indium powder (1.64 g, O S 14.27 mmol), (R)-N-tert-butanesulfinamide 466 (1.15 g, HN t-Bu

9.52 mmol), N1-Ts indole 3-carboxaldehyde 465 (3.28 g,

N 10.94 mmol) and Ti(OEt)4 (4.34 g, 19.03 mmol) in THF (40 Ts

183 mL) was stirred under argon for 2 h. At this time allyl bromide (1.73 g, 14.27 mmol) was added and the reaction mixture was refluxed for 12 h at 60 °C. The reaction mixture was cooled to rt, quenched with brine (10 mL), and diluted with EtOAc (100 mL). The suspension was filtered through a short pad of celite and the solvent was concentrated under reduced pressure, the residue was purified by flash column chromatography eluting with EtOAc/hexanes (1:1) to afford 3.67 g (87%) of sulfinamide 467 (10:1, separable) as

20 a yellow foam. ["] D -88.6 (c 1.0, CHCl3); IR (neat) 3450, 3280, 3050, 2920, 2810,

1 1740, 1590, 1420, 1250; H NMR (400 MHz, CDCl3) ! 8.08 (d, J = 8.4 Hz, 1H), 7.82 (d,

J = 8.0 Hz, 2H), 7.70 (d, J = 7.6 Hz, 1H), 7.65 (s, 1H), 7.42-7.25 (m, 4H), 5.83-5.76 (m,

1H), 5.25-5.20 (m, 1H), 4.81 (td, J = 6.6 Hz, 2.7 Hz, 1H), 3.90 (d, J = 3.2 Hz, 1H), 2.82-

13 2.75 (m, 1H), 2.36 (s, 3H), 1.25 (s, 9H); C NMR (100 MHz, CDCl3) ! 144.6, 135.4,

134.7, 133.4, 129.5, 128.7, 126.4, 124.5, 124.5, 122.8, 122.6, 120.2, 119.0, 113.6, 55.2,

50.4, 40.6, 22.3, 21.1; HRMS (FAB) calc’d for C23H28N2O3S2+Na = 467.1439, found

467.1428.

NH2 Amine 468. Method A (One pot): To a 0.05 M solution of

sulfinamide 467 (450 mg, 1.01 mmol) in anhydrous MeOH (20 N H mL), was added HCl (0.38 mL, 4 M in dioxane, 1.52 mmol). After stirring the mixture for 1.5 h, the reaction mixture was cooled to 0 °C and flame-dried

Mg0 powder (246 mg, 10.12 mmol) was added in portions and stirring was continued for additional 2 h. The reaction mixture was diluted with CHCl3 (15 mL), quenched with

NH4OH (8 mL), The suspension was filtered through a short pad of celite and washed with additional CHCl3 (60 mL).

184 The combined organic layers were washed with water (20 mL) and brine (25 mL), dried over Na2SO4, solvent was concentrated under reduced pressure to afford 141 mg (75%) of amine 468 as a white solid, which was used in the next reaction without any further purification.

Method B (stepwise): To a solution of sulfinamide 467 (5.78 g, 12.10 mmol) in anhydrous MeOH (80 mL), was added Conc HCl (3.0 mL, 36.29 mmol) at 0 °C and stirred overnight at rt. The solvent was evaporated under reduced pressure, diluted with

NH4OH (10 mL) and extracted with CHCl3 (3 X 100 mL), washed with brine (50 mL), dried over Na2SO4. The solvent was concentrated under reduced pressure and dried. The crude product was dissolved in anhydrous MeOH (80 mL), flame-dried Mg0 powder (246 mg, 10.12 mmol) was added in portions at 0 °C and stirring was contimued for additional

2 h. The reaction mixture was diluted with CHCl3 (25 mL), quenched with NH4OH (8 mL), The suspension was filtered through a short pad of celite and washed with additional CHCl3 (90 mL). The combined organic layers were washed with water (30 mL) and brine (35 mL), dried over Na2SO4. The solvent was concentrated under reduced pressure to afford 1.92 g (85% over two steps) of homo chiral amine 468 as a white solid,

20 which was used in the next reaction without any further purification. ["] D -47.8 (c 1.0,

1 CHCl3); M.P 91 °C; IR (neat) 3400, 3050, 2900, 2750, 1700, 1300; H NMR (400 MHz,

CDCl3) ! 8.93 (bs, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.23-7.13 (m,

2H), 7.05 (s, 1H), 5.88-5.79 (m, 1H), 5.20-5.11 (m, 2H), 4.38-4.35 (m, 1H), 2.76-2.71

13 (m, 1H), 2.56-2.48 (m, 1H), 2.23 (bs, 2H); C NMR (100 MHz, CDCl3) ! 136.5, 125.8,

121.7, 120.7, 120.3, 119.1, 119.0, 117.4, 111.3, 47.9, 43.0; HRMS (FAB) calc’d for

+ C12H14N2+H = 187.1235, found 187.1228.

185 Alkylated 468. To a mixture of the amine 468 (1.65 g, HN Me I 8.86 mmol) and activated 4 Å molecular sieves (2.5 g) in

N THF and DMF (15 + 15 mL), was added the side chain H allyl bromide (2.43 g, 1.05 mmol) in THF (4 mL) followed by Cs2Co3 (3.18 g, 1.10 mmol) at 0°C and the reaction was stirred for 16 h. The reaction was diluted with water

(15 mL) and extracted with EtOAc (3 X 30 mL), the combined organic layers were washed with brine (25 mL), dried over Na2SO4, solvent was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with

20 EtOAc/hexanes (1:3) to afford 3.08 g (95%) of alkylated 468 as a yellow foam. ["] D -

1 1.7 (c 0.5, CH2Cl2); IR (neat) 3400, 3250, 3050, 2900, 1600, 1400; H NMR (400 MHz,

CDCl3) ! 8.29 (bs, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.26-7.11 (m,

3H), 5.88-5.82 (m, 1H), 5.58 (q, J = 6.4 Hz, 1H), 5.19-5.07 (m, 2H), 4.08-4.05 (m, 1H),

3.50 (d, J = 14.4 Hz, 1H), 3.40 (d, J = 14.4 Hz, 1H), 2.66-2.58 (m, 2H), 2.30 (bs, 1H),

13 1.76 (d, J = 6.4 Hz, 3H); C NMR (100 MHz, CDCl3) ! 136.4, 135.8, 131.9, 126.5,

122.1, 121.9, 119.5, 119.2, 117.5, 117.4, 111.7, 11.2, 58.4, 51.7, 41.8, 21.7; HRMS

(FAB) calc’d for C16H19IN2+Na = 389.0491, found 389.0481.

O Bromoacetamide 469. Bromoacetyl chloride (589 mg, Br N Me 3.74 mmol) was added to a stirred solution of I

triethylamine (568 mg, 5.61 mmol) and alkylated 468 N H (1.37 g, 3.74 mmol) in CH2Cl2 (150 mL) at 0 °C over a period of 10 min. The reaction mixture was stirred for 15 min at 0 °C, 40 min at rt, then diluted with water. The aqueous layer was extracted with CH2Cl2 (2 x 35 mL).

186 The combined organic layers were washed with sat. NaHCO3 (30 mL), brine solution (40 mL), dried (Na2SO4). The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with EtOAc/hexanes (1:3)

20 to afford 1.59 g (87%) of bromoacetamide 469 as a yellow oil. ["] D -30.3 (c 1.0,

-1 1 CH2Cl2); IR (neat) 3400, 3300, 3050, 2900, 1720 cm ; H NMR (400 MHz, CDCl3) !

8.56 (bs, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.26-7.09 (m, 3H), 6.25

(t, J = 7.8 Hz, 1H), 5.89-5.82 (m, 1H), 5.36 (q, J = 6.3 Hz, 1H), 5.16 (dd, J = 17.2 Hz, 1.6

Hz, 1H), 5.05 (dd, J = 10.0 Hz, 1.2 Hz, 1H), 4.11-4.04 (m, 2H), 3.93 (d, J = 10.8 Hz,

1H), 3.86 (d, J = 10.8 Hz, 1H), 2.80-2.75 (m, 2H), 1.37 (d, J = 6.0 Hz, 3H); 13C NMR

(100 MHz, CDCl3) ! 167.6, 136.0, 134.7, 130.3, 127.0, 123.4, 122.6, 120.0, 119.3, 117.5,

113.4, 111.1, 103.6, 55.4, 50.2, 36.2, 27.4, 21.1; HRMS (FAB) calc’d for

+ C18H20N2OIBr+Na = 508.9701, found 508.9692.

Enoate 455. Hoveyda-Grubbs 2nd generation catalyst (121 O Br mg, 0.10 mmol) was added to a stirred solution of the N Me I bromoacetamide 469 (940 mg, 1.93 mmol) and methyl

N H acrylate (441 mg, 5.79 mmol) in deaerated CH2Cl2 (13 CO2Me mL). The reaction mixture was stirred at 40 °C for 2.5 h and cooled to rt. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with EtOAc/hexanes (2:4) to afford

20 842 mg (80%) of enoate 455 (E:Z = 12:1, from LC–MS trace) as a foam. ["] D -51.4 (c

-1 1.0, CHCl3); IR (neat) 3323, 3055, 2948, 1716, 1640, 1460, 1435, 1275, 1210, 1173 cm ;

1 H NMR (400 MHz, CDCl3) ! 8.68 (bs, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0

187 Hz, 1H), 7.22-7.09 (m, 3H), 7.00-6.92 (m, 1H), 6.22 (t, J = 7.8 Hz, 1H), 5.94 (d, J = 16.0

Hz, 1H), 5.38 (q, J = 6.3 Hz, 1H), 4.04 (bs, 2H), 3.95 (d, J = 10.8 Hz, 1H), 3.85 (d, J =

10.4 Hz, 1H)3.67 (s, 3H), 2.93 (t, J = 6.8 Hz, 1H), 1.42 (d, J = 6.4 Hz, 3H); 13C NMR

(100 MHz, CDCl3) ! 167.6, 166.6, 145.0, 136.1, 130.9, 126.8, 123.6, 126.3, 122.8, 120.1,

119.2, 112.5, 111.3, 104.0, 55.6, 51.5, 49.9, 34.7, 27.2, 21.1.

O Tetracycle 457. AgOTf (547 mg, 2.13 mmol) and 2,6-di- N H Me tert-butyl-4-methylpyridine (437 mg, 2.13 mmol) were H I added to a stirred solution of the enoate 455 (580 mg, 1.06 N H CO2Me mmol) in toluene (11 mL). The reaction mixture was stirred for 2.5 h at rt. TLC monitoring showed full consumption of starting material after which DBU (404 mg, 2.65 mmol) was added dropwise. The reaction mixture was stirred for an additional 12 h, quenched with water (15 mL), extracted with EtOAc (2 x 20 mL), washed with brine (15 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with EtOAc/hexanes (1:1) to afford 296 mg (60%) of tetracycle 457 as a colorless

20 foam. ["] D -89.0 (c 1.0, CH2Cl2); IR (neat) 3370, 1670, 1610, 1480, 1466, 1435, 1255 cm-1; 1H NMR (400 MHz) ! 7.17 (d, J = 7.6 Hz, 1H), 7.06 (td, J = 7.7 Hz, 1.3 Hz, 1H),

7.00 (dd, J = 5.6 Hz, 2.0 Hz, 1H), 6.74 (t, J = 7.4 Hz, 1H), 6.57 (d, J = 7.6 Hz, 1H), 5.88

(q, J = 6.4 Hz, 1H), 4.66 (dt, J = 15.2 Hz, 1.4, 1H), 4.51(bs, 1H), 4.46 (s, 1H), 3.86 (t, J =

4.6 Hz, 1H), 3.77 (s, 3H), 3.75 (s, 1H), 2.85 (d, J = 16.8 Hz, 1H), 2.68 (d, J = 16.8 Hz,

1H), 2.54-2.39 (m, 2H), 1.74 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz) ! 173.2, 166.3,

188 150.1, 137.0, 134.3, 131.5, 130.5, 128.9, 123.2, 119.0, 109.3, 103.0, 61.1, 59.3, 52.0,

51.8, 48.5, 45.4, 25.8, 21.6.

S Thiolactam (-)-458. Lawesson’s reagent (275 mg, 0.68 N H Me mmol) was added to a stirred solution of tetracycle (-)-457 H I (630 mg, 1.36 mmol) in toluene (14 mL). The reaction N H CO2Me mixture was stirred for 1 h at 100 °C (bath temp) after which TLC showed full consumption of the starting material. The reaction mixture was cooled and purified by flash column chromatography eluting with EtOAc/hexanes (1:3)

20 to afford 568 mg (87%) of thiolactam (-)-458 as an yellow oil. ["] D -65.1 (c 1.0,

-1 1 CH2Cl2); IR (neat) 3370, 1710, 1610, 1485, 1467, 1440, 1306, 1264, 930, 910 cm ; H

NMR (400 MHz) ! 7.16 (d, J = 7.2 Hz, 1H), 7.09 (td, J = 7.6 Hz, 1.2 Hz, 1H), 7.02 (t, J =

4.6 Hz, 1H), 6.74 (td, J = 7.4 Hz, 0.8 Hz, 1H), 6.60 (d, J = 7.2 Hz, 1H), 6.01-5.97 (m,

1H), 5.37 (dt, J = 15.2 Hz, 1.3 Hz, 1H), 4.55 (bs, 1H), 4.46 (s, 1H), 4.26 (d, J = 14.8 Hz,

1H), 4.11 (t, J = 5.4 Hz, 1H), 3.80 (s, 3H), 3.35 (d, J = 17.6 Hz, 1H), 3.21 (d, J = 17.6 Hz,

1H), 2.71-2.64 (m, 1H), 2.52-2.44 (m, 1H), 1.76 (d, J = 6.4 Hz, 3H); 13C NMR (100

MHz) ! 201.6, 166.3, 149.6, 136.3, 136.0, 131.2, 130.5, 129.1, 123.5, 119.3, 109.5, 99.2,

65.4, 60.0, 56.8, 56.6, 52.1, 49.9, 26.7, 21.8.

Pyrrolidine 371. Triethyloxonium tetrafluoroborate (1.50 N H Me mL, 1M in CH Cl , 1.51 mmol) was added to a solution of H I 2 2

N 458 (484 mg, 1.01 mmol) in CH2Cl2 (10 mL) at 0 °C and H CO2Me stirred for 20 min.

189 The mixture was then warmed to rt and stirred for an additional 45 min. The reaction mixture was recooled to 0 °C and additional triethyloxonium tetrafluoroborate (1.00 mL,

1M in CH2Cl2, 1.01 mmol) was added and stirred for 15 min. The mixture was warmed to rt and stirred for additional 30 min. The solvent was concentrated under reduced pressure, dissolved in MeOH (15 mL), and excess NaBH4 (229 mg, 6.05 mmol) was added at 0 °C. After stirring for 10 min, the reaction mixture was warmed to rt and stirred for additional 2 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (15 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with EtOAc/hexanes

20 (1:9) to afford 415 mg (92%) of pyrrolidine 371 as colorless foam. ["] D -86.0 (c 1.0,

-1 1 CH2Cl2); IR (neat) 3351, 1705, 1422, 1265, 910, 730 cm ; H NMR (400 MHz) ! 7.11

(d, J = 8.0 Hz, 1H), 7.04–7.00 (m, 2H), 6.70 (td, J = 7.5 Hz, 0.7 Hz, 1H), 6.57 (d, J = 7.6

Hz, 1H), 5.84 (q, J = 6.3 Hz, 1H), 4.56 (bs, 1H), 4.31 (s, 1H), 3.78 (s, 3H), 3.60-3.56 (m,

1H), 3.30 (d, J = 14.0 Hz, 1H), 3.15-3.06 (m, 2H), 2.68 (td, J = 9.8 Hz, 4.7 Hz, 1H), 2.40-

2.35 (m, 1H), 2.28-2.12 (m, 2H), 2.00-1.93 (m, 1H), 1.77 (d, J = 6.4 Hz, 3H); 13C NMR

(100 MHz) ! 167.4, 150.1, 139.4, 132.6, 130.7, 130.0, 128.1, 123.2, 118.5, 109.2, 109.0,

65.3, 62.4, 61.2, 53.5, 51.7, 50.3, 37.6, 25.2, 21.7.

Akuammicine (-)-352. Palladium(II) acetate (7.0 mg, 0.0313 H N mmol) and PPh3 (16.4 mg, 0.0626 mmol) were added to a H N Me solution of 371 (47 mg, 0.1044 mmol) in Et3N (5 mL). The H CO2Me reaction mixture was purged with argon for 10 min, heated to

190 90 °C (oil bath) and stirred for 3.5 h. After cooling to rt, the mixture was diluted with

CH2Cl2 (25 mL), washed with brine (10 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with MeOH/CH2Cl2 (0.4:9.6!1:9). Purified 352 was washed with a solution of 25% aq. NaOH (10 mL), which afforded 24 mg (71%) of 352 as white solid whose NMR spectra (1H and 13C) were identical with reported literature values (see references MacMillan).

Weinreb Amide 474. To a stirred solution of N, O- N H Me H I dimethyl hydroxylamine hydrochloride (352 mg, 3.61

N H OMe mmol) in THF (15 mL) at -78 °C was added a solution of N O Me n-BuLi (3.07 mL, 2.35 M in hexane, 7.22 mmol) and stirred at rt for 20 min. This lithium N,O- dimethylhydroxalamine solution was cooled to

-78 °C and a solution of the pyrrolidine 371 (325 mg, 0.72 mmol) in THF (7 mL) at -78

°C was added using a cannula. After 20 min, TLC showed the consumption of starting material and the reaction was quenched at -78 °C using sat. NH4Cl (10 mL), and extracted with EtOAc (3 X 25 mL). The combined organic layers were washed with brine

(15 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with

EtOAc/hexanes (1:1) to afford 334 mg (97%) of weinreb amide 474 as colorless foam.

20 -1 1 ["] D -41.1 (c 1.0, CH2Cl2); IR (neat) 3350, 3040, 2900, 2800, 1420 cm ; H NMR (400

MHz) ! 7.09 (d, J = 7.2 Hz, 1H), 7.02 (td, J = 7.8 Hz, 1.2 Hz, 1H), 6.71 (td, J = 7.3 Hz,

0.9 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 6.42 (dd, J = 5.6 Hz, 3.6 Hz, 1H), 5.88 (q, J = 6.4

191 Hz, 1H), 4.63 (bs, 1H), 4.27 (s, 1H), 3.66 (s, 3H), 3.61 (d, J = 14.0 Hz, 1H), 3.32 (s, 3H),

3.22 (d, J = 14.0 Hz, 1H), 3.14-3.08 (m, 1H), 2.97 (t, J = 3.6 Hz, 1H), 2.60-2.54 (m, 1H),

2.37-2.23 (m, 2H), 2.10-2.02 (m, 2H), 1.78 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHz) !

169.7, 150.4, 133.9, 132.9, 132.4, 131.0, 128.0, 123.1, 118.7, 109.4, 66.2, 65.3, 62.7,

61.3, 54.0, 51.4, 38.6, 34.7, 25.3, 21.6; HRMS (FAB) calc’d for C21H26N3O2I + H =

480.1148, found 480.1158.

Aldehyde 475. To a stirred solution of the amide 474 (440 N H Me H I mg, 0.92 mmol) in CH2Cl2 (10 mL) at -78 °C was added a

N H CHO solution of DIBAL-H (1.9 mL, 1 M in hexane, 1.84 mmol) and stirred for 30 min at -78 °C. As TLC showed starting material, another portion of

DIBAL-H (0.92 mL, 1 M in hexane, 0.92 mmol) was added and stirring was continued for additional 20 min. The reaction was quenched with sat. sodium potassium tartarate solution (10 mL), and extracted with EtOAc (3 X 15 mL). The combined organic layers were washed with brine (15 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with EtOAc/hexanes (1:3) to afford 387 mg (92%) of aldehyde

20 475 as colorless foam. ["] D -148.1 (c 0.5, CHCl3); IR (neat) 3400, 3050, 2925, 2810,

2715, 1680, 1650, 1610, 1490, 1465, 1190, 750 cm-1; 1H NMR (400 MHz) ! 9.49 (s, 1H),

7.08 (d, J = 7.6 Hz, 1H), 7.03 (td, J = 7.6 Hz, 1.3 Hz, 1H), 6.82 (dd, J = 5.4 Hz, 2.6 Hz,

1H), 6.70 (td, J = 7.5 Hz, 0.9 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 5.85 (q, J = 12.8 Hz, 1H),

4.51 (bs, 1H), 4.31 (s, 1H), 3.61 (dt, J = 14.0 Hz, 1.6 Hz, 1H), 3.28 (s, 1H), 3.25(bs, 1H),

3.17-3.11 (m, 1H), 2.65-2.58 (m, 1H), 2.54-2.53 (m, 1H), 2.42-2.34 (m, 1H), 2.23-2.16

192 (m, 1H), 1.98-1.90 (m, 1H), 1.78 (d, J = 6.4 Hz, 1H); 13C NMR (100 MHz) ! 194.8,

150.4, 150.4, 140.8, 131.6, 130.9, 128.3, 122.9, 118.5, 109.4, 109.2, 65.5, 62.9, 59.5,

53.5, 40.5, 37.5, 29.7, 26.0, 21.7.

Pentacycle 476. Triethylamine (246 mg, 2.43 mmol) and N H Me I H methyl malonyl chloride (91 mg, 0.67 mmol) were added N to a stirred solution of aldehyde 475 (255 mg, 0.61 mmol)

O OMe O in CH2Cl2 (14 mL) at 0 °C and the reaction mixture was heated to 45 °C. After stirring for 3 h the TLC showed complete consumption of starting material. The reaction mixture was cooled and diluted with sat. NaHCO3 and extracted with CH2Cl2 (3 X 15 mL). The combined organic layers were washed with brine (15 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with

20 EtOAc/hexanes (1:1) to afford 251 mg (82%) of pentacycle 476 as an yellow oil. ["] D -

-1 1 346.2 (c 1.0, CH2Cl2); IR (neat) 2950, 2900, 2800, 1730, 1460, 1420, 1290 cm ; H

NMR (400 MHz) ! 8.10 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.58 (s, 1H), 7.19-

7.15 (m, 1H), 7.01 (td, J = 7.5 Hz, 0.9 Hz, 1H), 6.29-6.27 (m, 1H), 5.80 (q, J = 6.3 Hz,

1H), 4.52 (t, J = 2.8 Hz, 1H), 3.81 (s, 3H), 3.50 (d, J = 13.6 Hz, 1H), 3.36 (d, J = 13.6 Hz,

1H), 3.21-3.15 (m, 1H), 2.79 (d, J = 9.6 Hz, 5.2 Hz, 1H), 2.56 (td, J = 10.3 Hz, 3.9 Hz,

1H), 2.41-2.33 (m, 1H), 2.24-2.12 (m, 2H), 2.03-1.95 (m, 1H), 1.69 (d, J = 6.4 Hz, 3H);

13C NMR (100 MHz) ! 164.9, 158.1, 143.6, 140.2, 138.9, 134.8, 131.6, 130.4, 128.2,

126.8, 126.1, 124.3, 115.2, 108.9, 63.0, 62.7, 60.4, 52.4, 51.6, 46.9, 37.4, 23.8, 26.1;

HRMS (FAB) calc’d for C23H23N2O3I + Na = 525.0651, found 525.0665.

193

Dehydroleuconicine B 477. Palladium(II) acetate (22 mg, H N

0.10 mmol) and PPh3 (52 mg, 0.20 mmol) were added to a H N Me solution of pentacycle 476 (165 mg, 0.33 mmol) in Et3N (17 O OMe O mL). The reaction mixture was purged with argon for 15 min, heated to 90 °C (oil bath) and stirred for 2.5 h. After cooling to rt, the solvent was evaporated under reduced pressure, diluted with CHCl3 (50 mL), washed with water (15 mL), brine (10 mL), dried (Na2SO4). The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with

MeOH/CH2Cl2 (0.2:9.8!0.5:9.5), to give 100 mg (81%) of dehydroleuconicine B 477 as

20 white foam. ["] D -431.4 (c 0.5, CHCl3); IR (neat) 2950, 2920, 2830, 1720, 1600, 1530,

1380 cm-1; 1H NMR (500 MHz) ! 8.67 (d, J = 8.0 Hz, 1H), 8.24 (s, 1H), 7.43-7.39 (m,

2H), 7.30 (td, J = 7.5 Hz, 1.0 Hz, 1H), 5.23-5.50 (m, 1H), 4.20 (t, J = 1.5 Hz, 1H), 4.07

(dd, J = 15.5 Hz, 2.0 Hz, 1H), 3.96 (s, 3H), 3.73 (d, J = 1.0 Hz, 1H), 3.39 (td, J = 12.6

Hz, 5.3 Hz, 1H), 3.17 (dd, J = 12.3 Hz, 6.0 Hz, 1H), 3.01 (d, J = 15.5 Hz, 1H), 2.69-2.65

(m, 1H), 2.40 (td, J = 12.5 Hz, 6.5 Hz, 1H), 1.90 (dd, J = 12.3 Hz, 5.3 Hz, 1H), 1.64 (dt, J

= 7.0 Hz, 2.0 Hz, 3H), 1.29-1.25 (m, 1H); 13C NMR (125 MHz) ! 166.3, 160.0, 158.5,

144.7, 140.5, 139.8, 137.4, 128.6, 126.9, 122.6, 120.9, 118.4, 118.1, 117.7, 62.5, 57.3,

56.7, 56.5, 52.4, 46.7, 34.6, 31.2, 13.6; HRMS (FAB) calc’d for C23H22N2O3 + Na =

397.1528, found 397.1509.

194 Leuconicine B 471. Excess Raney Ni (50% in water) was N H H added to a solution of dehydroleuconicine B 477 (67 mg, 0.18 Et H N mmol) in THF (6 mL). The reaction mixture was refluxed for

O OMe 45 min and cooled to rt. The reaction mixture was filtered O through a short bed of celite (Pre wet with MeOH) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with MeOH/CH2Cl2 (0.5:9.5), to give 55 mg (82%) of

20 20 Leuconicine B 471 as light yellowish oil. ["] D -670.0 (c 0.5, CHCl3); lit. ["] D -720.0 (c

-1 1 1.55, CHCl3); IR (neat) 3690, 3610, 3450, 3260, 1740, 1700 cm ; H NMR (400 MHz) !

8.55 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 7.89 (s, 1H), 7.35-7.31 (m, 2H), 7.26-7.22 (m, 1H),

4.05 (t, J = 2.4 Hz, 1H), 3.94 (s, 3H), 3.14-3.08 (m, 1H), 3.00 (dd, J = 11.0 Hz, 3.8 Hz,

1H), 2.91-2.83 (m, 3H), 2.17 (dt, J = 13.2 Hz, 2.8 Hz, 1H), 1.98-1.85 (m, 3H), 1.46-1.34

(m, 2H), 1.29-1.22 (m, 1H), 1.03 (t, J = 7.4 Hz, 1H); 13C NMR (100 MHz) ! 166.0,

162.2, 158.9, 146.0, 140.9, 139.5, 128.2, 126.6, 120.0, 119.9, 117.7, 114.0, 62.2, 55.7,

54.5, 52.4, 51.5, 44.9, 38.7, 36.1, 31.3, 26.4, 11.5; HRMS (FAB) calc’d for C23H24N2O3 +

Na = 399.1685, found 399.1661.

Leuconicine A 470. To a stirred solution of Me3Al (0.53 mL, N H H 2 M in toluene, 1.06 mmol) in CH2Cl2 (3 mL) at -15 °C was Et H N added freshly condensed NH3 (3 mL) and stirred for 20 min.

O NH2 Then it was warmed to rt and stirring was continued for an O additional 45 min. Leuconicine B 471 (40 mg, 0.11 mmol) in

CH2Cl2 (2 mL) was added to the reaction mixture and refluxed for 2 h.

195 The reaction was cooled to rt and quenched with aq HCl (2 mL, 0.5M, 1.06 mmol), stirred for an additional 20 min and extracted with CHCl3 (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with MeOH/CH2Cl2 (1.0:9.0), to give 35 mg (91%) of

20 20 Leuconicine A 470 as white foam. ["] D -443.4 (c 0.5, CHCl3); lit. ["] D -473.0 (c 0.24,

-1 1 CHCl3); IR (neat) 3350, 2940, 1670, 1610, 1530, 1420, 730 cm ; H NMR (500 MHz) !

9.45 (d, J = 3.5, 1H), 8.49 (d, J = 8.0 Hz, 1H), 8.27 (s, 1H), 7.38-7.34 (m, 2H), 7.30-7.27

(m, 1H), 4.10 (s, 1H), 3.19-3.13 (m, 1H), 3.03 (dd, J = 11.0 Hz, 4.0 Hz, 1H), 2.93-2.85

(m, 3H), 2.20 (dt, J = 13.5 Hz, 2.6 Hz, 1H), 2.02-1.84 (m, 1H), 1.52-1.45 (m, 1H), 1.36

(dt, J = 13.0 Hz, 3.0 Hz, 1H), 1.30-1.22 (m,1H), 1.40 (t, J = 7.6 Hz, 3H); 13C NMR (125

MHz) ! 165.8, 161.6, 161.0, 145.4, 140.6, 139.9, 128.2, 127.0, 120.3, 120.2, 117.5,

115.7, 62.2, 55.5, 54.4, 51.4, 44.8, 38.7, 36.3, 31.3, 26.5, 11.5; HRMS (FAB) calc’d for

C22H23N2O3 + H = 362.1868, found 362.1861.

Norfluorocurarine (-)-369. Palladium(II) acetate (24.1 mg, H N

0.107 mmol) and PPh3 (56.2 mg, 0.214 mmol) were added to a H N Me H CHO solution of 371 (150 mg, 0.357 mmol) in Et3N (18 mL). The reaction mixture was purged with argon for 20 min, heated to 90 °C (oil bath) and stirred for 3.0 h. After cooling to rt, the mixture was diluted with CH2Cl2 (25 mL), washed with brine (10 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with

MeOH/CH2Cl2 (0.4:9.6!1:9).

196 Purified 359 was washed with a solution of 25% aq. NaOH (10 mL), which afforded 90 mg (86%) of 352 as yellow liquid whose NMR spectra (1H and 13C) were identical with

117a 20 20 reported literature values. ["] D -1184.0 (c 0.5, CHCl3); lit. ["] D -1230.0 (c 0.5,

CHCl3).

Dehydrotubifoline (-)-479. Aqueous HCl (8 mL, 2.0 N) was N added to akuammicine (-)-352 (12.0 mg, 0.0372 mmol) and

N H Me stirred in a sealed tube at 120 °C for 2.5 h. The reaction mixture was cooled to rt and basified using ammonium hydroxide, extracted with CHCl3

(25 mL), washed with brine (10 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with MeOH/CH2Cl2 (0.4:9.6!1:9 to afford 8.4 mg (85%) of (-)-

479 as yellow oil whose NMR spectra (1H and 13C) were identical with reported literature values.111b

N 19,20-Dihydroakuammicine (-)-480. Excess PtO2 (10 mg)

was added to a solution of akuammicine (-)-352 (11 mg, N H H Me 0.0341 mmol) in CH OH (4 mL). The reaction mixture was CO2Me 3 stirred for 12 h under H2 atmosphere, filtered through a short bed of celite (Pre wet with

MeOH) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with MeOH/CH2Cl2 (0.5:9.5), to give 10.5 mg

(95%) of 19,20-dihydroakuammicine (-)-480 as light yellowish oil whose NMR spectra

(1H and 13C) were identical with reported literature values.169

197

N Tubifoline (-)-481. Aqueous HCl (15 mL, 2.0 N) was added

to 19,20-dihydroakuammicine (-)-480 (20.0 mg, 0.0617 N H Me mmol) and stirred in a sealed tube at 120 °C for 2.5 h. The reaction mixture was cooled to rt and basified using ammonium hydroxide, extracted with CHCl3 (35 mL), washed with brine (10 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with MeOH/CH2Cl2 (0.4:9.6!1:9 to afford 11.5 mg

(70%) of (-)-481 as yellow oil whose NMR spectra (1H and 13C) were identical with reported literature values. 169

Alcohol (-)-482. To a stirred solution of the ester 371 (280 N I mg, 0.622 mmol) in CH2Cl2 (10 mL) at -78 °C was added a

solution of DIBAL-H (2.5 mL, 1 M in hexane, 2.49 mmol) N H CH OH 2 and stirred for 2.0 h at -78 °C. The reaction was quenched with sat. sodium potassium tartarate solution (10 mL), and extracted with EtOAc (3 X 15 mL). The combined organic layers were washed with brine (15 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with EtOAc/hexanes (3:1) to afford 220 mg (84%) of alcohol 482 as colorless foam whose NMR spectra (1H and 13C) were

168a 20 identical with reported literature values. ["] D -41.25 (c 1.0, CH2Cl2).

198 N Pentacycle (-)-483. Palladium(II) acetate (35.0 mg, 0.156

mmol) and PPh3 (82.0 mg, 0.313 mmol) were added to a

N H Me solution of 482 (220 mg, 0.521 mmol) in Et3N (26 mL). The CH2OH reaction mixture was purged with argon for 20 min, heated to

90 °C (oil bath) and stirred for 3.0 h. After cooling to rt, the mixture was diluted with

CH2Cl2 (50 mL), washed with brine (10 mL), dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography eluting with MeOH/CH2Cl2 (0.4:9.6!1:9). Purified 483 was washed with a solution of 25% aq. NaOH (10 mL), which afforded 63 mg (50%) of 483 as yellow liquid whose NMR spectra (1H and 13C) were identical with reported literature values.

168a, 170

N Valparicine (-)-484. Trifluoroacetic acid (0.1 mL) was

added to a stirred solution of the alcohol (-)-483 (30.0 mg,

N H Me 0.1019 mmol) in CH2Cl2 (5 mL) at 0 °C and stirred for 2.0 h.

The temperature of the bath was maintained below 4 °C through out the period and was basified using NH4OH, extracted with CHCl3 (30 mL), washed with brine (10 mL), dried

(Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography with basic Al2O3 eluting with

MeOH/CH2Cl2 (0.4:9.6!1:9). This afforded 19.7 mg (50%) of (-)-484 as yellow liquid.

20 20 This compound was found to be not very stable. ["] D -79.40 (c 0.5, CHCl3); lit. ["] D -

1 40.00 (c 0.22, CHCl3); H NMR (500 MHz) ! 7.61 (dq, J = 7.5 Hz, 0.5 Hz, 1H), 7.36-

7.31 (m, 2H), 7.21 (td, J = 7.5 Hz, 1.0 Hz, 1H), 6.00 (s, 1H), 5.49 (qd, J = 6.8 Hz, 1.5 Hz,

199 1H), 5.37 (t, J = 1.2 Hz, 1H), 4.05-4.04 (m, 1H), 3.83 (m, 1H), 3.73 (dt, J = 15.0 Hz, 1.5

Hz, 1H), 3.35-3.29 (m, 1H), 3.26 (d, J = 15.0 Hz, 1H), 3.23-3.19 (m, 1H), 2.44-2.39 (m,

1H), 1.99 (dt, J = 14.3 Hz, 3.3 Hz, 1H), 1.95-1.91 (m, 1H), 1.77 (d, J = 7.0, 3H), 1.36 (dt,

J = 14.2 Hz, 2.8 Hz, 1H); 13C NMR (125 MHz) ! 186.7, 154.5, 144.8, 139.6, 128.0,

125.8, 121.1, 120.9, 119.7, 116.4, 65.4, 65.3, 56.3, 36.8, 27.1, 13.7.

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227 APPENDIX - A

X-ray Structure Determination of Compound 363

O N H

N H H CO2Me

Compound 363, C23H22N2O3, crystallizes in the monoclinic space group P21/c

(systematic absences 0k0: k=odd, and h0l: l=odd) with a=8.0163(7)Å, b=9.4598(8)Å, c=25.816(2)Å, b=93.688(2)°, V=1953.7(3)Å3, Z=4,and dcalc=1.273 g/cm3. X-ray intensity data were collected on a Rigaku CCD area detector employing graphite-monochromated Mo-Ka radiation (l=0.71073 Å) at a temperature of 143(1)K.

Preliminary indexing was performed from a series of twelve 0.5° rotation images with exposures of 30 seconds. A total of 642 rotation images were collected with a crystal to detector distance of 35 mm, a 2q swing angle of -12°, rotation widths of 0.5° and exposures of 50 seconds: scan no. 1 was a f-scan from 262.5° to 472.5° at w = 10° and c

= 20°; scan no. 2 was an w-scan from -10° to 15° at c = -90° and f = 0°; scan no. 3 was an w-scan from -20° to 4° at c = -90° and f = 225°; scan no. 4 was an w-scan from -20° to

2° at c = -90° and f = 45°; scan no. 5 was an w-scan from -20° to 20° at c = -90° and f =

135°.

228 Rotation images were processed using CrystalClear1, producing a listing of unaveraged

F2 and s(F2) values which were then passed to the CrystalStructure2 program package for further processing and structure solution on a Dell Pentium 4 computer. A total of 15485 reflections were measured over the ranges 2.55 £ q £ 25.04°, -9 £ h £ 9, -10 £ k £ 11, -30

£ l £ 30 yielding 3458 unique reflections (Rint = 0.0214). The intensity data were corrected for Lorentz and polarization effects and for absorption using REQAB3

(minimum and maximum transmission 0.8566, 1.0000).

The structure was solved by direct methods (SIR974). Refinement was by full-matrix least squares based on F2 using SHELXL-97.5 All reflections were used during refinement. The weighting scheme used was w=1/[s2(Fo2 )+ 0.0602P2 + 0.6233P P = (Fo

2 + 2Fc2)/3. Non-hydrogen atoms were refined anisotropically and hydrogen atoms were refined isotropically. Refinement converged to R1=0.0410 and wR2=0.1018 for 3049 observed reflections for which F > 4s(F) and R1=0.0468 and wR2=0.1075 and GOF

=1.004 for all 3458 unique, non-zero reflections and 342 variables.6 The maximum D/s in the final cycle of least squares was 0.010 and the two most prominent peaks in the final difference Fourier were +0.162 and -0.180 e/Å3.

Table A1. lists cell information, data collection parameters, and refinement data. Final positional and equivalent isotropic thermal parameters are given in Table A2.

Anisotropic thermal parameters are in Table A3. Tables A4. and A5. list bond distances and bond angles. Figure A1. is an ORTEP7 representation of the molecule with 30% probability thermal ellipsoids displayed.

229

Figure A1. ORTEP drawing of title compound with 30% probability thermal ellipsoids.

Table A1. Summary of Structure Determination of Compound 363

Empirical formula C23H22N2O3

Formula weight 374.43

Temperature 143(1) K

Wavelength 0.71073 Å

Crystal system monoclinic

Space group P21/c

Unit cell dimensions a = 8.0163(7) Å

230 b = 9.4598(8) Å

c = 25.816(2) Å

b= 93.688(2)°

Volume 1953.7(3) Å3

Z 4

Density (calculated) 1.273 Mg/m3

Absorption coefficient 0.085 mm-1

F(000) 792

Crystal size 0.25 x 0.22 x 0.15 mm3

Theta range for data collection 2.55 to 25.04°.

Index ranges -9 £ h £ 9, -10 £ k £ 11, -30 £ l £ 30

Reflections collected 15485

Independent reflections 3458 [R(int) = 0.0214]

Completeness to theta = 25.04° 99.6 %

Absorption correction Semi-empirical from equivalents

Max. and min. transmission 1.0000 and 0.8566

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 3458 / 0 / 342

Goodness-of-fit on F2 1.004

Final R indices [I>2sigma(I)] R1 = 0.0410, wR2 = 0.1018

R indices (all data) R1 = 0.0468, wR2 = 0.1075

Largest diff. peak and hole 0.162 and -0.180 e.Å-3

231

Table A2. Refined Positional Parameters for Compound 363

2 Atom x y z Ueq,Å

C1 0.35905(17) 0.80712(15) 0.30685(6) 0.0320(3)

C2 0.22895(19) 0.82037(18) 0.26869(6) 0.0401(4)

C3 0.2467(2) 0.75447(19) 0.22117(7) 0.0457(4)

C4 0.3883(2) 0.67744(18) 0.21162(6) 0.0451(4)

C5 0.5162(2) 0.66319(16) 0.25033(6) 0.0381(4)

C6 0.50134(17) 0.72917(15) 0.29754(5) 0.0305(3)

C7 0.62306(16) 0.73753(15) 0.34456(5) 0.0290(3)

C8 0.77952(18) 0.82934(16) 0.33821(6) 0.0341(3)

C9 0.90148(16) 0.77631(15) 0.38126(6) 0.0318(3)

C10 0.70522(16) 0.59657(15) 0.36152(6) 0.0295(3)

C11 0.59135(18) 0.49431(16) 0.38751(6) 0.0329(3)

C12 0.48850(17) 0.56391(16) 0.42608(6) 0.0332(3)

C13 0.45654(16) 0.70189(16) 0.42648(5) 0.0315(3)

C14 0.51534(17) 0.80499(15) 0.38660(5) 0.0305(3)

C15 0.94986(18) 0.55349(16) 0.42938(6) 0.0315(3)

C16 1.03362(16) 0.43831(15) 0.39985(5) 0.0301(3)

C17 1.0291(2) 0.29955(17) 0.41691(6) 0.0415(4)

C18 1.1078(2) 0.19296(19) 0.39085(7) 0.0505(4)

C19 1.1914(2) 0.22417(19) 0.34741(7) 0.0471(4)

C20 1.19544(19) 0.36201(18) 0.32925(7) 0.0410(4)

232 C21 1.11637(18) 0.46845(17) 0.35529(6) 0.0350(3)

C22 0.35832(17) 0.75850(17) 0.46889(6) 0.0348(3)

C23 0.2505(2) 0.9638(2) 0.50623(7) 0.0498(4)

N1 0.37344(16) 0.87032(13) 0.35571(5) 0.0357(3)

N2 0.84822(14) 0.64714(12) 0.39560(5) 0.0299(3)

O1 1.02747(12) 0.83661(11) 0.39954(4) 0.0405(3)

O2 0.29290(13) 0.68743(13) 0.50112(4) 0.0454(3)

O3 0.35174(13) 0.90051(11) 0.46804(4) 0.0397(3)

1 2 2 2 Ueq= /3[U11(aa*) +U22(bb*) +U33(cc*) +2U12aa*bb*cosg+2U13aa*cc*cosb+2U23bb*cc*cosa]

Table A3. Positional Parameters for Hydrogens in Compound 363

2 Atom x y z Uiso,Å

H1 0.279(3) 0.8752(19) 0.3723(7) 0.053(5)

H2 0.133(2) 0.8721(19) 0.2752(7) 0.046(5)

H3 0.157(2) 0.762(2) 0.1937(7) 0.054(5)

H4 0.399(2) 0.631(2) 0.1771(8) 0.059(5)

H5 0.615(2) 0.6063(18) 0.2444(6) 0.043(4)

H8a 0.830(2) 0.8083(17) 0.3029(7) 0.039(4)

H8b 0.762(2) 0.929(2) 0.3409(6) 0.046(5)

H10 0.7473(18) 0.5509(15) 0.3309(6) 0.027(4)

H11a 0.519(2) 0.4508(17) 0.3606(6) 0.039(4)

H11b 0.659(2) 0.4148(19) 0.4030(6) 0.043(4)

233 H12 0.4397(19) 0.5056(17) 0.4517(6) 0.035(4)

H14 0.579(2) 0.8820(18) 0.4054(6) 0.040(4)

H15a 0.8778(19) 0.5100(16) 0.4544(6) 0.033(4)

H15b 1.033(2) 0.6127(17) 0.4473(6) 0.032(4)

H17 0.966(2) 0.278(2) 0.4465(8) 0.055(5)

H18 1.100(3) 0.094(2) 0.4029(8) 0.067(6)

H19 1.249(3) 0.153(2) 0.3286(8) 0.062(6)

H20 1.251(2) 0.3831(19) 0.2981(7) 0.050(5)

H21 1.118(2) 0.564(2) 0.3432(7) 0.046(5)

H23a 0.136(3) 0.934(2) 0.4998(7) 0.054(5)

H23b 0.264(2) 1.069(2) 0.5005(7) 0.059(5)

H23c 0.292(2) 0.929(2) 0.5430(8) 0.061(6)

Table A4. Refined Thermal Parameters (U's) for Compound 363

Atom U11 U22 U33 U23 U13 U12

C1 0.0264(7) 0.0316(7) 0.0381(8) 0.0060(6) 0.0033(6) -

0.0018(6)

C2 0.0253(7) 0.0455(9) 0.0492(9) 0.0140(7) -0.0010(6) -

0.0003(7)

C3 0.0384(9) 0.0530(10) 0.0441(9) 0.0102(8) -0.0108(7) -

0.0109(8)

C4 0.0505(10) 0.0465(9) 0.0373(9) 0.0000(7) -0.0040(7) -

234 0.0076(8)

C5 0.0392(8) 0.0380(8) 0.0372(8) 0.0006(6) 0.0039(6) 0.0011(7)

C6 0.0265(7) 0.0307(7) 0.0342(7) 0.0046(6) 0.0008(6) -

0.0011(6)

C7 0.0232(7) 0.0301(7) 0.0337(7) 0.0021(6) 0.0017(5) 0.0002(5)

C8 0.0265(7) 0.0319(8) 0.0442(9) 0.0053(6) 0.0037(6) -

0.0004(6)

C9 0.0243(7) 0.0305(7) 0.0410(8) - 0.0049(6) 0.0009(6)

0.0011(6)

C10 0.0234(7) 0.0294(7) 0.0353(7) - 0.0002(6) 0.0009(5)

0.0008(6)

C11 0.0290(7) 0.0289(7) 0.0403(8) 0.0013(6) -0.0014(6) -

0.0019(6)

C12 0.0274(7) 0.0373(8) 0.0347(7) 0.0055(6) -0.0005(6) -

0.0044(6)

C13 0.0234(7) 0.0386(8) 0.0322(7) 0.0009(6) 0.0003(5) -

0.0010(6)

C14 0.0266(7) 0.0304(7) 0.0345(7) - 0.0011(6) 0.0004(6)

0.0006(6)

C15 0.0278(7) 0.0329(8) 0.0334(7) 0.0014(6) -0.0027(6) 0.0019(6)

C16 0.0220(6) 0.0330(7) 0.0347(7) 0.0003(6) -0.0031(5) 0.0009(5)

C17 0.0453(9) 0.0373(9) 0.0426(9) 0.0060(7) 0.0088(7) 0.0068(7)

C18 0.0590(11) 0.0359(9) 0.0574(11) 0.0050(8) 0.0110(8) 0.0110(8)

235 C19 0.0420(9) 0.0435(9) 0.0562(10) - 0.0066(8) 0.0094(7)

0.0076(8)

C20 0.0296(8) 0.0520(10) 0.0420(9) - 0.0064(7) 0.0002(7)

0.0038(7)

C21 0.0274(7) 0.0366(8) 0.0408(8) 0.0021(7) 0.0017(6) -

0.0022(6)

C22 0.0249(7) 0.0448(9) 0.0343(7) 0.0002(7) -0.0016(6) 0.0001(6)

C23 0.0443(10) 0.0571(12) 0.0491(10) - 0.0112(8) 0.0015(9)

0.0171(9)

N1 0.0305(7) 0.0368(7) 0.0400(7) 0.0033(5) 0.0049(6) 0.0087(5)

N2 0.0241(6) 0.0282(6) 0.0369(6) 0.0001(5) -0.0013(5) 0.0010(5)

O1 0.0287(5) 0.0365(6) 0.0557(7) - -0.0018(5) -

0.0011(5) 0.0059(4)

O2 0.0408(6) 0.0577(7) 0.0386(6) 0.0077(5) 0.0100(5) 0.0027(5)

O3 0.0352(6) 0.0430(6) 0.0413(6) - 0.0059(4) -

0.0091(5) 0.0003(5)

The form of the anisotropic displacement parameter is:

2 2 2 2 2 2 2 exp[-2p (a* U11h +b* U22k +c* U33l + 2b*c*U23kl+2a*c*U13hl+2a*b*U12hk)].

Table A5. Bond Distances in Compound 363, Å

C1-C6 1.392(2) C1-C2 1.393(2) C1-N1 1.394(2)

C2-C3 1.391(2) C2-H2 0.936(18) C3-C4 1.384(3)

236 C3-H3 0.979(19) C4-C5 1.392(2) C4-H4 1.00(2)

C5-C6 1.381(2) C5-H5 0.976(18) C6-C7 1.5099(19)

C7-C10 1.5383(19) C7-C8 1.5429(19) C7-C14 1.5657(19)

C8-C9 1.518(2) C8-H8a 1.042(17) C8-H8b 0.959(18)

C9-O1 1.2275(17) C9-N2 1.3538(18) C10-N2 1.4791(17)

C10-C11 1.516(2) C10-H10 0.980(15) C11-C12 1.487(2)

C11-H11a 0.970(17) C11-H11b 0.995(18) C12-C13 1.330(2)

C12-H12 0.964(16) C13-C22 1.489(2) C13-C14 1.515(2)

C14-N1 1.4815(18) C14-H14 0.996(17) C15-N2 1.4552(18)

C15-C16 1.512(2) C15-H15a 0.984(16) C15-H15b 0.968(17)

C16-C17 1.386(2) C16-C21 1.394(2) C17-C18 1.386(2)

C17-H17 0.96(2) C18-C19 1.375(3) C18-H18 0.99(2)

C19-C20 1.387(3) C19-H19 0.96(2) C20-C21 1.386(2)

C20-H20 0.96(2) C21-H21 0.953(19) C22-O2 1.2147(18)

C22-O3 1.3446(19) C23-O3 1.4464(19) C23-H23a 0.96(2)

C23-H23b 1.02(2) C23-H23c 1.04(2) N1-H1 0.90(2)

Table A6. Bond Angles in Compound 363, °

C6-C1-C2 120.65(14) C6-C1-N1 111.25(12) C2-C1-N1 128.01(14)

C3-C2-C1 117.96(15) C3-C2-H2 121.7(11) C1-C2-H2 120.4(11)

C4-C3-C2 121.62(15) C4-C3-H3 118.7(11) C2-C3-H3 119.7(11)

C3-C4-C5 119.88(16) C3-C4-H4 120.6(11) C5-C4-H4 119.5(11)

237 C6-C5-C4 119.22(15) C6-C5-H5 120.3(10) C4-C5-H5 120.5(10)

C5-C6-C1 120.66(13) C5-C6-C7 130.17(13) C1-C6-C7 109.13(12)

C6-C7-C10 115.22(11) C6-C7-C8 115.58(12) C10-C7-C8 100.49(11)

C6-C7-C14 102.82(10) C10-C7-C14 113.65(11) C8-C7-C14 109.42(12)

C9-C8-C7 103.06(11) C9-C8-H8a 108.0(9) C7-C8-H8a 110.6(9)

C9-C8-H8b 111.4(10) C7-C8-H8b 114.9(10) H8a-C8-H8b 108.7(14)

O1-C9-N2 125.48(13) O1-C9-C8 127.11(13) N2-C9-C8 107.40(12)

N2-C10-C11 114.13(12) N2-C10-C7 100.96(10) C11-C10-C7 114.84(11)

N2-C10- 109.2(8) C11-C10- 108.9(9) C7-C10-H10 108.4(8)

H10 H10

C12-C11- 112.92(12) C12-C11- 109.5(10) C10-C11- 107.8(10)

C10 H11a H11a

C12-C11- 112.0(10) C10-C11- 109.6(10) H11a-C11- 104.7(13)

H11b H11b H11b

C13-C12- 123.72(13) C13-C12- 118.0(9) C11-C12-H12 118.2(9)

C11 H12

C12-C13- 118.03(13) C12-C13-C14 123.90(13) C22-C13-C14 118.07(12)

C22

N1-C14-C13 111.88(11) N1-C14-C7 103.62(11) C13-C14-C7 114.72(11)

N1-C14- 107.9(9) C13-C14- 108.1(9) C7-C14-H14 110.5(10)

H14 H14

N2-C15-C16 112.73(12) N2-C15- 108.5(9) C16-C15- 109.2(9)

H15a H15a

238 N2-C15- 106.1(9) C16-C15- 110.0(9) H15a-C15- 110.3(12)

H15b H15b H15b

C17-C16- 118.66(14) C17-C16-C15 120.06(13) C21-C16-C15 121.28(13)

C21

C18-C17- 120.83(16) C18-C17- 120.5(12) C16-C17-H17 118.7(11)

C16 H17

C19-C18- 120.04(17) C19-C18- 120.4(12) C17-C18-H18 119.5(12)

C17 H18

C18-C19- 120.06(16) C18-C19- 122.2(12) C20-C19-H19 117.7(12)

C20 H19

C19-C20- 119.84(16) C19-C20- 119.9(11) C21-C20-H20 120.2(11)

C21 H20

C20-C21- 120.55(15) C20-C21- 120.8(11) C16-C21-H21 118.7(11)

C16 H21

O2-C22-O3 123.10(14) O2-C22-C13 125.22(14) O3-C22-C13 111.68(12)

O3-C23- 109.2(11) O3-C23- 103.7(11) H23a-C23- 112.0(16)

H23a H23b H23b

O3-C23- 109.4(11) H23a-C23- 107.9(16) H23b-C23- 114.5(16)

H23c H23c H23c

C1-N1-C14 108.91(12) C1-N1-H1 115.5(12) C14-N1-H1 114.1(12)

C9-N2-C15 122.63(12) C9-N2-C10 112.04(11) C15-N2-C10 122.83(11)

C22-O3-C23 115.19(13)

239

1 CrystalClear: Rigaku Corporation, 1999.

2 CrystalStructure: Crystal Structure Analysis Package, Rigaku Corp. Rigaku/MSC (2002).

3 REQAB4: R.A. Jacobsen, (1994). Private Communication.

4 SIR97: Altomare, A., M. Burla, M. Camalli, G. Cascarano, C. Giacovazzo, A. Guagliardi, A. Moliterni, G. Polidori & R. Spagna (1999). J. Appl. Cryst., 32, 115-119.

5 SHELXL-97: Sheldrick, G.M. (2008) Acta Cryst., A64,112-122.

6 R1 = !||Fo| - |Fc|| / ! |Fo| 2 2 2 2 2 ! wR2 = [!w(Fo - Fc ) /!w(Fo ) ] 2 2 2 ! GOF = [!w(Fo - Fc ) /(n - p)] where n = the number of reflections and p = the number of parameters refined.

7 “ORTEP-II: A Fortran Thermal Ellipsoid Plot Program for Crystal Structure Illustrations”. C.K. Johnson (1976) ORNL-5138.

APPENDIX - B

X-ray Structure Determination of Compound 352

N H

H Me N H CO2Me

Akuammicine HCl

240

Table A7. Crystal data and structure refinement for 352.

Identification code andr001

Empirical formula C21 H25 Cl3 N2 O2

Formula weight 443.78

Temperature 100(2) K

Wavelength 0.71073 Å

Crystal system Triclinic

Space group P-1

Unit cell dimensions a = 10.1157(19) Å a= 88.025(4)°.

b = 10.700(2) Å b= 78.525(4)°.

c = 11.006(2) Å g = 62.262(3)°.

Volume 1030.9(3) Å3

Z 2

Density (calculated) 1.430 Mg/m3

Absorption coefficient 0.465 mm-1

F(000) 464

Crystal size 0.16 x 0.13 x 0.13 mm3

Theta range for data collection 2.16 to 33.36°.

Index ranges -15<=h<=15, -16<=k<=11, -16<=l<=17

Reflections collected 17124

Independent reflections 7832 [R(int) = 0.0368]

Completeness to theta = 25.00° 99.8 %

Absorption correction Semi-empirical from equivalents 241

Max. and min. transmission 0.9421 and 0.9294

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 7832 / 7 / 270

Goodness-of-fit on F2 1.040

Final R indices [I>2sigma(I)] R1 = 0.0625, wR2 = 0.1565

R indices (all data) R1 = 0.1035, wR2 = 0.1788

Largest diff. peak and hole 1.059 and -0.880 e.Å-3

Table A8. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 352. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

______

x y z U(eq)

______

Cl(1) 9704(1) 800(1) 2491(1) 29(1)

C(21) 837(4) 1711(3) 9532(3) 45(1)

Cl(2) -95(19) 3486(11) 10040(30) 48(2)

Cl(3) 2698(3) 854(3) 9450(4) 54(1)

242

C(21') 837(4) 1711(3) 9532(3) 45(1)

Cl(2') -40(20) 3530(13) 9930(30) 48(2)

Cl(3') 2760(4) 1011(4) 9980(4) 54(1)

N(1) 3327(2) 5712(2) 7395(2) 18(1)

N(2) 7825(2) 1391(2) 6347(2) 18(1)

O(1) 1352(2) 3192(2) 6511(2) 30(1)

O(2) 1149(2) 5376(2) 6660(2) 25(1)

C(1) 4065(2) 4311(2) 6990(2) 16(1)

C(2) 6495(2) 2186(2) 7423(2) 17(1)

C(3) 8240(2) 2477(2) 5753(2) 20(1)

C(4) 6696(2) 3747(2) 5777(2) 18(1)

C(5) 5728(2) 3745(2) 7075(2) 16(1)

C(6) 5627(2) 4842(2) 7965(2) 18(1)

C(7) 6691(2) 4871(2) 8568(2) 21(1)

C(8) 6308(3) 6103(2) 9256(2) 23(1)

C(9) 4897(3) 7277(2) 9314(2) 23(1)

C(10) 3800(2) 7262(2) 8729(2) 20(1)

C(11) 4199(2) 6023(2) 8058(2) 17(1)

C(12) 5422(2) 1534(2) 7602(2) 19(1)

C(13) 4623(2) 1873(2) 6491(2) 18(1)

C(14) 1936(2) 3947(2) 6589(2) 21(1)

C(15) 3541(2) 3459(2) 6617(2) 18(1)

C(16) 4053(2) 2027(2) 3830(2) 21(1)

243

C(17) 5589(2) 1422(2) 4152(2) 20(1)

C(18) 5850(2) 1334(2) 5298(2) 18(1)

C(19) 7476(2) 588(2) 5465(2) 21(1)

C(20) -470(3) 5991(3) 6736(3) 34(1)

Table A9. Bond lengths [Å] and angles [°] for 352.

______

C(21)-Cl(3) 1.650(4)

C(21)-Cl(2) 1.733(9)

N(1)-C(1) 1.370(3)

N(1)-C(11) 1.402(3)

N(2)-C(3) 1.499(3)

N(2)-C(19) 1.509(3)

N(2)-C(2) 1.519(3)

O(1)-C(14) 1.216(3)

O(2)-C(14) 1.352(3)

O(2)-C(20) 1.439(3)

C(1)-C(15) 1.357(3)

C(1)-C(5) 1.522(3)

C(2)-C(12) 1.521(3)

C(2)-C(5) 1.550(3)

C(3)-C(4) 1.515(3)

C(4)-C(5) 1.564(3)

244

C(5)-C(6) 1.508(3)

C(6)-C(7) 1.384(3)

C(6)-C(11) 1.395(3)

C(7)-C(8) 1.392(3)

C(8)-C(9) 1.386(3)

C(9)-C(10) 1.396(3)

C(10)-C(11) 1.385(3)

C(12)-C(13) 1.539(3)

C(13)-C(15) 1.524(3)

C(13)-C(18) 1.528(3)

C(14)-C(15) 1.462(3)

C(16)-C(17) 1.493(3)

C(17)-C(18) 1.330(3)

C(18)-C(19) 1.505(3)

Cl(3)-C(21)-Cl(2) 117.0(7)

C(1)-N(1)-C(11) 110.71(16)

C(3)-N(2)-C(19) 114.12(16)

C(3)-N(2)-C(2) 105.53(16)

C(19)-N(2)-C(2) 112.98(16)

C(14)-O(2)-C(20) 116.74(19)

C(15)-C(1)-N(1) 131.40(18)

C(15)-C(1)-C(5) 121.67(18)

245

N(1)-C(1)-C(5) 106.86(17)

N(2)-C(2)-C(12) 109.63(17)

N(2)-C(2)-C(5) 105.63(15)

C(12)-C(2)-C(5) 112.84(16)

N(2)-C(3)-C(4) 102.81(16)

C(3)-C(4)-C(5) 103.79(16)

C(6)-C(5)-C(1) 101.75(15)

C(6)-C(5)-C(2) 116.87(16)

C(1)-C(5)-C(2) 113.88(16)

C(6)-C(5)-C(4) 109.84(16)

C(1)-C(5)-C(4) 109.85(15)

C(2)-C(5)-C(4) 104.67(15)

C(7)-C(6)-C(11) 120.35(19)

C(7)-C(6)-C(5) 131.64(19)

C(11)-C(6)-C(5) 107.83(17)

C(6)-C(7)-C(8) 118.6(2)

C(9)-C(8)-C(7) 120.2(2)

C(8)-C(9)-C(10) 122.0(2)

C(11)-C(10)-C(9) 116.81(19)

C(10)-C(11)-C(6) 121.93(19)

C(10)-C(11)-N(1) 128.86(18)

C(6)-C(11)-N(1) 109.20(18)

C(2)-C(12)-C(13) 108.06(16)

246

C(15)-C(13)-C(18) 115.54(16)

C(15)-C(13)-C(12) 106.91(16)

C(18)-C(13)-C(12) 108.25(16)

O(1)-C(14)-O(2) 122.97(19)

O(1)-C(14)-C(15) 125.7(2)

O(2)-C(14)-C(15) 111.35(19)

C(1)-C(15)-C(14) 123.15(19)

C(1)-C(15)-C(13) 116.75(17)

C(14)-C(15)-C(13) 118.80(18)

C(18)-C(17)-C(16) 125.41(19)

C(17)-C(18)-C(19) 118.58(19)

C(17)-C(18)-C(13) 125.40(18)

C(19)-C(18)-C(13) 115.96(17)

C(18)-C(19)-N(2) 113.57(17)

______

Symmetry transformations used to generate equivalent atoms:

Table A10. Anisotropic displacement parameters (Å2x 103) for 352. The anisotropic displacement factor exponent takes the form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12 ]

______

U11 U22 U33 U23 U13 U12

______

Cl(1) 21(1) 31(1) 27(1) 6(1) -6(1) -5(1)

247

C(21) 51(2) 44(2) 43(2) -8(1) 3(1) -29(2)

Cl(2) 41(1) 39(1) 48(4) -2(1) -20(2) -1(1)

Cl(3) 30(1) 31(1) 86(2) 4(1) 7(1) -8(1)

C(21') 51(2) 44(2) 43(2) -8(1) 3(1) -29(2)

Cl(2') 41(1) 39(1) 48(4) -2(1) -20(2) -1(1)

Cl(3') 30(1) 31(1) 86(2) 4(1) 7(1) -8(1)

N(1) 14(1) 18(1) 21(1) 0(1) -5(1) -5(1)

N(2) 15(1) 16(1) 22(1) 1(1) -6(1) -5(1)

O(1) 21(1) 36(1) 38(1) -2(1) -6(1) -17(1)

O(2) 13(1) 27(1) 31(1) 0(1) -6(1) -6(1)

C(1) 14(1) 17(1) 16(1) 1(1) -2(1) -6(1)

C(2) 16(1) 16(1) 19(1) 1(1) -4(1) -5(1)

C(3) 14(1) 20(1) 25(1) 0(1) -2(1) -6(1)

C(4) 16(1) 17(1) 19(1) 2(1) -3(1) -7(1)

C(5) 13(1) 15(1) 17(1) 0(1) -4(1) -5(1)

C(6) 18(1) 17(1) 18(1) 2(1) -4(1) -8(1)

C(7) 21(1) 21(1) 21(1) 2(1) -8(1) -10(1)

C(8) 27(1) 24(1) 22(1) 0(1) -9(1) -14(1)

C(9) 31(1) 20(1) 19(1) 0(1) -6(1) -13(1)

C(10) 22(1) 17(1) 17(1) 0(1) -4(1) -6(1)

C(11) 17(1) 17(1) 17(1) 2(1) -4(1) -7(1)

C(12) 21(1) 19(1) 19(1) 2(1) -4(1) -10(1)

C(13) 18(1) 20(1) 19(1) 1(1) -5(1) -11(1)

248

C(14) 18(1) 27(1) 19(1) -2(1) -2(1) -10(1)

C(15) 15(1) 20(1) 17(1) 1(1) -3(1) -8(1)

C(16) 24(1) 19(1) 23(1) 1(1) -7(1) -11(1)

C(17) 21(1) 16(1) 21(1) -2(1) -3(1) -9(1)

C(18) 18(1) 14(1) 21(1) 1(1) -4(1) -7(1)

C(19) 20(1) 16(1) 23(1) -2(1) -5(1) -6(1)

C(20) 13(1) 40(1) 42(1) -4(1) -7(1) -6(1)

Table A11. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x

10 3) for 352.

______

x y z U(eq)

______

H(21A) 365 1220 10095 54

H(21B) 646 1634 8697 54

H(21C) 959 1525 8631 54

H(21D) 236 1272 10000 54

249

H(1A) 2480(30) 6160(30) 7390(30) 26(7)

H(2A) 8550(40) 810(30) 6670(30) 33(8)

H(2B) 6888 2129 8199 21

H(3A) 8828 2155 4890 25

H(3B) 8843 2695 6235 25

H(4A) 6237 3645 5097 21

H(4B) 6784 4631 5698 21

H(7A) 7662 4066 8514 25

H(8A) 7017 6139 9687 28

H(9A) 4669 8118 9767 27

H(10A) 2826 8065 8787 24

H(12A) 4655 1932 8387 23

H(12B) 6004 497 7645 23

H(13A) 4007 1357 6549 21

H(16A) 4101 1465 3123 32

H(16B) 3736 3007 3609 32

H(16C) 3312 2009 4545 32

H(17A) 6452 1069 3484 24

H(19A) 8166 433 4645 25

H(19B) 7693 -351 5780 25

H(20A) -949 7007 6968 51

H(20B) -901 5535 7363 51

H(20C) -664 5851 5926 51

250

______

Table A12. Hydrogen bonds for 352 [Å and °].

______

D-H...A d(D-H) d(H...A) d(D...A) <(DHA)

______

N(1)-H(1A)...O(2) 0.76(3) 2.17(3) 2.665(2) 123(3)

N(1)-H(1A)...Cl(1)#1 0.76(3) 2.95(3) 3.5460(19) 137(3)

N(2)-H(2A)...Cl(1)#2 0.84(3) 2.16(3) 2.9985(18) 174(3)

______

Symmetry transformations used to generate equivalent atoms:

#1 -x+1,-y+1,-z+1 #2 -x+2,-y,-z+1

251