Methodological Developments and Synthetic Applications of Strained Rings and Allylic C-H Functionalization of Hindered Substrates

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METHODOLOGICAL DEVELOPMENTS AND SYNTHETIC APPLICATIONS OF

STRAINED RINGS

AND

ALLYLIC C–H FUNCTIONALIZATION OF HINDERED SUBSTRATES

Thesis by

Nicholas R. O’Connor

In Partial Fulfillment of the Requirements

for the Degree of

Doctor of Philosophy

CALIFORNIA INSTITUTE OF TECHNOLOGY

Pasadena, California

2017

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Nicholas R. O’Connor

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ACKNOWLEDGEMENTS

I should begin by acknowledging my doctoral advisor, Professor Brian Stoltz, for his

constant support over the past five years. Every project I worked on benefitted directly

from his chemical knowledge, creativity, and enthusisam. Most importantly, however,

Brian is extremely understanding, down-to-earth, and relatable, and his treatment of

students as people, not simply workers, significantly increased my enjoyment of graduate

school.

The members of my dissertation committee, Professors Greg Fu, Theo Agapie, and

Sarah Reisman, have all provided valuable advice and insightful questions on my

research and proposals. I am indebted to Sarah for teaching me more chemistry than I’ve

ever learned in three months during Ch 242a in Fall 2011, and for allowing me to TA the

same course the following year. I also wish to thank Dr. Scott Virgil for his constant

assistance with instrumentation and NMR analysis and his (along with his wife Silva’s)

regular invitations to attend performances of the LA Opera.

This thesis would not be possible without the help of Caltech’s fantastic scientific

staff, including Dr. David VanderVelde, Dr. Mona Shahgholi, Naseem Torian, Dr. Mike

Takase, and Larry Henling. I am also grateful to Rick Gerhart and Jeff Groseth for

repairing crucial glassware and instruments, respectively. I also wish to thank the

administrative staff of the Division of Chemistry and Chemical Engineering, particularly

Agnes Tong, Joe Drew, and Alison Ross, for maintining a very well-run department.

I would not have arrived at Caltech without the support and encouragement of my

previous mentors in chemistry. Specifially, I wish to thank Professor Rebecca Hoye, Dr.

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laboratories as an undergraduate student. I am indebted to my undergraduate and

graduate student mentors during these experiences, including Dr. Zach Wickens, Dr.

Suttipol Radomkit, and Pakornwit Sarnpitak, for teaching me many of the most basic

techniques in organic chemistry. I also wish to thank Professor Ronald Brisbois for

teaching my first course in organic chemistry and subsequently providing much advice

and encouragement when I chose to pursue graduate studies in the field.

My time in the Stoltz lab has been made unbelievebly educational and (surprisingly?)

entertaining by the graduate students, postdoctoral scholars, visiting scholars, and

undergraduates with whom I have overlapped the past five years. I want to particularly

acknowledge Professor Hosea Nelson, Dr. Kun-Liang Wu, Dr. Allen Hong, Dr.

Guillaume Lapointe, Dr. Jeff Holder, and Professor Wen-Bo Liu for generously spending

their time to help me get started in the lab and for showing me many fundamental aspects

of lab technique and chemical thinking. I must also thank Dr. Christopher Haley, Dr.

Doug Duquette, Dr. Seojung Han, Dr. Gerit Pototschnig, Beau Pritchett, Sam Shockely,

David Schuman, Austin Wright, Lukas Hilpert, and Nina Vrielink for their friendship.

I had the pleasure of overlapping with Dr. Kelly Kim for almost my entire time at

Caltech. Her low-key personality, willingness to listen to me complain, and preference

for a late night schedule all contributed to the rapid formation of our friendship. Despite

the appearance of her desk and fume hood, Kelly is one of the most organized people I’ve

ever known, and I benefitted tremendously from this as she underwent the candidacy

exam, fourth-year meeting, postdoc application, exit proposals exam, and thesis writing

slightly ahead of me. Kelly is also an incredibly easy person to talk to about any issue,

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Much of the work presented in this thesis has been conducted with other members of

the Stoltz laboratory, from whom I learned how to conceive and execute plans for

research projects in synthetic organic chemistry. I wish to thank Dr. Alex Goldberg and

Dr. Rob Craig for their significant contributions to the cyclopropane and aziridine

cycloaddition projects, and Dr. Xiangyou Xing for inviting me to join the allylic C–H

oxidation project. None of this work would be possible without their efforts.

I have been extremely fortunate to serve as a mentor to three undergraduates during

my time in the Stoltz lab. These experiences helped me gain teaching and mentoring

techniques and solidified my desire to pursue a career in undergraduate teaching. I

sincerely thank Stephanie Wong, Péter Bolgár, and Moriam Masha for working with me.

Throughout my time at Caltech, I have been lucky to have friends outside the Stoltz

lab, including Dr. Matt Rienzo, Dr. Zach Wickens, Dr. Maddi Kieffer, Dr. Haoxuan

Wang, Professor Raul Navarro, and Dr. Kangway Chuang.

I must thank my family for their encouragement, support, and patience over the past

five years. My decision to pursue a career in a scientific field was likely guided by

interactions with my grandfather, Professor Carl Shiffman, who supported my early

interests in science and later provided useful advice and amusing stories about many

aspects of scientific careers. Finally, I would not have made it through graduate school

without the unwavering support of my mom, who was always willing to provide advice

or encouragement, or simply listen to anything I wanted to talk about.

The work presented in this thesis would not have been possible without the

contributions and assistance of all those listed above. To each of them, as well as to

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ABSTRACT

Formal dipolar cycloadditions of cyclopropanes and aziridines are useful methods for

the formation of carbo- and heterocycles. Given our group’s previous interest in this

area, we sought to expand the scope of strained ring cycloadditions by employing

heterocumulenes as dipolarophiles. This thesis describes our development of Lewis acid

catalyzed formal (3 + 2) cycloadditions between donor–acceptor cyclopropanes and

isocyanates, isothiocyanates, and carbodiimides to furnish various five-membered

heterocycles. Enantioenriched cycloadducts can be accessed through a stereospecific

reaction if enantiopure substrates are employed. We also present a method to access

more highly nitrogenated heterocycles by replacing donor–acceptor cyclopropanes with

activated aziridines. These aziridines react smoothly with isothiocyanates and

carbodiimides in the presence of zinc Lewis acids to afford iminothiazolidine and

iminoimidazolidine products in good yields. Our efforts to apply a cyclopropane

cycloaddition toward the total synthesis of the indole alkaloid calophyline A are also

described

In addition, a method for the activation of sterically hindered allylic C–H bonds is

presented. Despite numerous recent advances in the functionalization of allylic C–H

bonds and the general utility of these transformations, reactions of sterically hindered

substrates remain challenging. In this thesis we describe the development of a novel

system for the palladium(II)-catalyzed allylic C–H acetoxylation of

α

-allyl lactams. We

believe the lactam moiety may act as a directing group to aid in the palladation of these

generally unreactive substrates. During optimization, we also discovered enal products

were formed if water was added. These conditions represent the first example of a

transition metal catalyzed C–H oxidation system with tunable selectivity over the extent

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PUBLISHED CONTENT AND CONTRIBUTIONS

Craig, R. A., II; O’Connor, N. R.; Goldberg, A. F. G.; Stoltz, B. M. “Stereoselective

Lewis Acid Mediated (3 + 2) Cycloadditions of

N-

H- and

N

-Sulfonylaziridines with

Heterocumulenes”.

Chem. Eur. J. 2014

,

20

, 4806–4813. DOI:

10.1002/chem.201303699

N.R.O. assisted in planning and executing experiements and writing the

manuscript.

Goldberg, A. F. G.; O’Connor, N. R.; Craig, R. A., II; Stoltz, B. M. “Lewis Acid

Mediated (3 + 2) Cycloadditions of Donor–Acceptor Cyclopropanes with

Heterocumulenes”.

Org. Lett.

2012

,

14

, 5314–5317. DOI: 10.1021/ol302494n

manuscript.

O’Connor, N. R.; Wood, J. L.; Stoltz, B. M. “Synthetic Applications and Methodological

Developments of Donor–Acceptor Cyclopropanes and Related Compounds”.

Isr. J.

Chem. 2016

,

56

, 431–444. DOI:

10.1002/ijch.201500089

N.R.O. discussed the contents of this perspective review with the other authors

and wrote the manuscript with their input.

O’Connor, N. R.; Xing, X.; Stoltz, B. M. “Palladium(II)-Catalyzed Allylic C–H

Oxidation of Hindered Substrates Featuring Tunable Selectivity Over Extent of

Oxidation”.

Angew. Chem., Int. Ed.

2015

,

54

, 11186–11190. DOI:

10.1002/anie.201504007

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TABLE OF CONTENTS

Acknowledgements ... iii

Abstract ... vi

Published Content and Contributions ... vii

Table of Contents ... viii

List of Figures ... xv

List of Schemes ... xxix

List of Tables ... xxxiv

List of Abbreviations ... xxxviii

CHAPTER 1

1

Synthetic Applications and Methodological Developments of Donor–Acceptor

Cyclopropanes and Related Compounds in the Stoltz Laboratory

1.1 Introduction ... 1

1.2 Use of Donor–Acceptor Cyclopropanes as Intermediates in Natural Products Synthesis ... 3

1.2.1 Total Synthesis of K252a ... 3

1.2.2 Synthesis of the Welwitindolinone Carbon Skeleton ... 6

1.2.3 Approach toward the Synthesis of Bielschowskysin………….. ... 8

1.2.4 Synthesis of the Core of the Gagunin Diterpenoids………….. ... 11

1.2.5 Synthesis of ABCD Ring System of Scandine……… ... 13

1.3 Development of Novel Reactions of Transient Donor–Acceptor Cyclopropanes and Cyclobutanes ... 15

1.3.1 Synthesis of Fused Carbocycles by a Tandem Wolff–Cope Rearrangement…… 16

1.3.2 The Acyl-Alkylation of Arynes with β-Ketoesters ... 19

1.4 Summary ... 22

1.5 Notes and References ... 23

CHAPTER 2

31

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2.2 Initial Efforts: Reactions of Donor–Acceptor Cyclopropanes with Isocyanates ... 34

2.2.1 Cycloadditions of Donor–Acceptor Cyclopropanes with Potassium Cyanate and Trimethylsilyl Isocyanate ... 34

2.2.2 Cycloadditions of Donor–Acceptor Cyclopropanes with Alkyl Isocyanates ... 36

2.3 Reactions of Donor–Acceptor Cyclopropanes with Isothiocyanates ... 37

2.3.1 Initial Reactivity and Structural Reassignment ... 38

2.3.2 Optimization and Scope of Cycloadditions with Isothiocyanates ... 39

2.4 Reactions of Donor–Acceptor Cyclopropanes with Carbodiimides ... 41

2.5 Investigations into the Reaction Stereochemistry ... 42

2.6 Proposed Mechanism ... 44

2.7 Conclusions and Future Directions ... 45

2.8 Experimental Section ... 45

2.8.1 Materials and Methods ... 45

2.8.2 General and Miscellaneous Experimental Procedures ... 47

2.8.3 Cyclopropane Characterization Data ... 52

2.8.4 Lactam Characterization Data ... 57

2.8.5 Cyclopropane Characterization Data ... 52

2.8.6 Thioimidate Characterization Data ... 61

2.8.7 Amidine Characterization Data ... 70

APPENDIX 1

83

Supplementary Synthetic Information for Chapter 2

A1.1 Introduction ... 83

A1.2 Unreactive Cyclopropanes ... 83

A1.3 Problematic Heterocumulenes ... 84

A1.4 Testing for Product Inhibition ... 85

A1.5 Product Derivatizations ... 85

A1.6 Experimental Section ... 85

A1.6.1 Materials and Methods ... 86

A1.6.2 Synthesis of Unreactive Cyclopropanes ... 88

A1.6.3 Synthesis of Mixed Carbodiimide 220 ... 91

A1.6.4 Investigation of Product Inhibition ... 93

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A1.4 Notes and References ... 95

APPENDIX 2

97

Application of Cyclopropane Cycloadditions toward the Synthesis of

Tetrahydroisoquinoline Alkaloids and Discovery of a Novel Route to Isoindolines

A2.1 Introduction and Retrosynthetic Analysis ... 97

A2.2 Toward the Synthesis of an Intramolecular Cycloaddition Substrate ... 99

A2.3 Revised Retrosynthetic Analysis ... 100

A2.4 Attempted Intermolecular Cycloaddition ... 101

A2.5 Investigation of the Isoindolone Formation ... 103

A2.6 Future Directions ... 106

A2.6.1 THIQ Alkaloid Synthesis ... 106

A2.6.2 Synthesis of Isoindolones ... 106

A2.7 Experimental Section ... 107

A2.7.1 Materials and Methods ... 107

A2.7.2 Preparation of Aryl Halides and Cyclopropanes ... 108

A2.7.3 Synthesis of Styrene 250 via Stille Coupling ... 114

A2.7.4 Proceedure for Attempted Reactions with 2-(chloroethyl)isocyanate ... 115

A2.7.5 Control Reactions with Cyclopropane 252 ... 116

A2.7.6 Reaction of Cyclopropane 264 with Benzyl Isocyanate ... 118

A2.8 Notes and References ... 119

APPENDIX 3

123

Spectra Relevant to Chapter 2

APPENDIX 4

184

X-Ray Crystallography Reports Relevant to Chapter 2

CHAPTER 3

246

Stereoselective Lewis Acid Mediated (3 + 2) Cycloadditions of H- and

N-Sulfonylaziridines with Heterocumulenes

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3.2.1 Optimization of the Reaction Conditions ... 248

3.2.2 Exploration of 2-Aziridine and Heterocumulene Substitution ... 249

3.2.3 Effect of Aziridine N-Substitution ... 251

3.2.4 Extension of Heterocumulene Scope ... 252

3.2.5 Cycloaddition of Disubstituted N-Sulfonylaziridines ... 253

3.3 Development of the Stereoselective (3 + 2) Cycloaddition ... 255

3.3.1 Development of a Stereoselective (3 + 2) Cycloaddition ... 255

3.3.2 Exploration of Isothiocyanate Substitution ... 256

3.3.3 Effect of Aziridine N-Substitution of the Transfer of Chiral Information ... 258

3.3.4 Proposed Mechanism of Stereoselective (3 + 2) Cycloaddition ... 258

3.4 Cycloaddition of an Aziridine Dicarboxylate ... 260

3.5 Deprotection of Iminothiazolidine Products ... 260

3.6 Conclusions ... 262

3.7 Experimental Section………….. ... 262

3.7.1 Materials and Methods. ... 262

3.7.2 General Experimental Procedures ... 264

3.7.3 Aziridine Synthesis and Characterization Data ... 268

3.7.4 Iminothiazolidine Synthesis and Characterization Data ... 283

3.7.5 Iminoimidazolidine Synthesis and Characterization Data ... 305

3.7.6 Preparation of Thioxoimidazolidine 343 ... 311

3.7.7 Stereoselective (3 + 2) Cycloaddition with Diphenylcarbodiimide ... 313

3.7.8 Characterization of (3 + 2) Cycloaddition Byproducts ... 313

3.7.9 Deprotection of Iminothiazolidines (S)-292 and (S)-315 ... 314

3.7.10 Experimental Procedures for Control Reactions ... 317

3.7.10.1 Reaction in the Absence of Lewis Acid ... 317

3.7.10.2 Isomerization of Disubstituted Aziridine 333 ... 318

3.7.10.3 Isomerization of Disubstituted Aziridine 330 ... 319

3.7.10.4 Racemization of Aziridine Starting Material (R)-291 ... 320

3.7.10.5 Racemization of Product (S)-292 ... 321

3.7.10.6 Isomerization of trans-Disubstituted Thiazolidine 334 ... 322

3.7.10.7 Isomerization of cis-Disubstituted Thiazolidine 335 ... 322

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APPENDIX 5

336

APPENDIX 6

426

CHAPTER 4

522

Progress toward the Total Synthesis of Calophyline A

4.1.1 Isolation and Properties of Calophyline A ... 522

4.1.2 Tantillo’s Biosynthetic Proposal ... 523

4.1.3 Zu’s Total Synthesis ... 524

4.2 Investigation of a Cyclopropane Cycloaddition Route toward the Synthesis of Calophyline A ... 526

4.2.1 Retrosynthetic Analysis ... 526

4.2.2 Attempts to Synthesize Cyclopropanated Indoles ... 527

4.2.3 Discovery of a (3 + 2) Cycloaddition Result and the Design of a New Synthetic Strategy ... 529

4.2.4 Attempts to Form the Calophyline Core by a (3 + 2)/Cyclopropanation/Fragmentation Strategy ... 530

4.3 Investigation of a [4 + 2] Cycloaddition Route toward the Synthesis of Calophyine A ... 534

4.3.1 Retrosynthetic Analysis ... 534

4.3.2 Attempts to Achieve the Desired [4 + 2] Cycloaddition ... 537

4.4 Investigation of a [2 + 2 + 2] Cycloaddition Route toward the Synthesis of Calophyline A ... 542

4.4.1 Synthetic Precedent and Retrosynthetic Analysis ... 543

4.4.2 Exploration of a [2 + 2 + 2] Strategy ... 544

4.5 Future Direction: Consideration of a Bromooxindole Alkylation Route toward the Synthesis of Calophyline A ... 545

4.6 Conclusions ... 547

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APPENDIX 7

574

Synthetic Summary toward the Total Synthesis of Calophyline A

APPENDIX 8

578

APPENDIX 9

604

CHAPTER 5

618

Palladium(II)-Catalyzed Allylic C–H Oxidation of Hindered Substrates Featuring

Tunable Selectivity Over Extent of Oxidation

5.1.1 Enantioselective Synthesis of Quaternary α-Allyl Lactams and Attempted Allylic Functionalization ... 619

5.2 Development of a Novel Palladium(II)-Catalyzed Allylic Acetoxylation Reaction ... 620

5.2.1 Optimization of the Allylic Acetoxylation ... 621

5.2.2 Substrate Scope of the Allylic Acetoxylation ... 622

5.2.3 Synthetic Utility of Allylic Acetates ... 624

5.3 Development of the Allylic Oxidation Reaction to form Enal Products ... 625

5.3.1 Optimization of the Enal Formation ... 625

5.3.2 Substrate Scope of the Enal Formation ... 626

5.3.3 Synthetic Utility of an Enal Product ... 627

5.4 Conclusions and Future Directions ... 628

5.5.2 General Experimental Proceedures ... 631

5.5.3 Substrate Synthesis and Characterization Data ... 635

5.5.4 Procedures for Unsuccessful Allylic Oxidations ... 654

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5.5.6 Enal Characterization Data ... 671

5.5.7 Allylic Acetate Derivatization Procedures and Characterization Data ... 677

5.5.8 Enal Derivatization Procedures and Characterization Data ... 683

5.5.9 Mechanistic Investigation Experiments ... 687

APPENDIX 10

699

Supplementary Synthetic Information Relevant to Chapter 5

A10.1 Introduction ... 699

A10.2 Unsuccessful Substrates in the Allylic Acetoxylation Reaction ... 699

A10.3 Unsuccessful Substrates in the Enal Formation Reaction ... 700

A10.4 Conclusions ... 701

APPENDIX 11

702

APPENDIX 12

813

Comprehensive Bibliography ... 828

Index ... 859

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LIST OF FIGURES

CHAPTER 2

Figure 2.1 Absolute configuration of an amidine product determined by X-ray

crystallography ... 44

APPENDIX 1

Figure A1.1 Unreactive cyclopropanes ... 84

Figure A1.2 Problematic heterocumulenes ... 85

APPENDIX 2

Figure A2.1 A) Tetrahydroisoquinoline alkaloids previously synthesized in our laboratory. B) Tetrahydroisoquinoline alkaloids targeted for application of a cyclopropane-isocyanate cycloaddition ... 98

Figure A2.2 Cross-coupling partners prepared ... 100

Figure A2.3 Cyclopropanes bearing slightly more electron-withdrawing acceptor groups 107

APPENDIX 3

Figure A3.1 1_{H NMR (500 MHz, CDCl3) of compound 195 ... 124}

Figure A3.2 Infrared spectrum (thin film/NaCl) of compound 195 ... 125

Figure A3.3 13_{C NMR (126 MHz, CDCl3) of compound 195 ... 125}

Figure A3.10 1_{H NMR (500 MHz, CDCl} 3) of compound 145 ... 130

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Figure A3.13 1_{H NMR (500 MHz, CDCl}

3) of compound 146 ... 132

Figure A3.14 Infrared spectrum (thin film/NaCl) of compound 146. ... 133

Figure A3.42 13_{C NMR (126 MHz, CDCl} 3) of compound 162 ... 151

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Figure A3.48 13_{C NMR (126 MHz, CDCl}

3) of compound 155 ... 155

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Figure A3.88 1_{H NMR (400 MHz, DMSO-}_d_{6, 80 °C) of compound 177 ... 182}

Figure A3.90 13_{C NMR (101 MHz, DMSO-}_d_{6, 100 °C) of compound 177 ... 183}

APPENDIX 4

Figure A4.1.1 X-ray crystal structure of thioimidate 155 ... 185

Figure A4.2.1 X-ray crystal structure of amidine (R)-170•HBr ... 196

APPENDIX 5

Figure A5.7 1_{H NMR (500 MHz, CDCl3) of compound 360. ... 341}

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3) of compound 333 ... 350

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Figure A5.69 1_{H NMR (500 MHz, CDCl3) of compound (}_S_{)-338 ... 383}

Figure A5.70 Infrared spectrum (Thin Film, NaCl) of compound (S)-338 ... 384

Figure A5.71 13_{C NMR (126 MHz, CDCl3) of compound (}_S_{)-338 ... 384}

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3) of compound 323•HCl ... 397

Figure A5.91 Infrared spectrum (Thin Film, NaCl) of compound 323•HCl ... 398

Figure A5.92 13_{C NMR (126 MHz, CDCl3) of compound 323•HCl ... 398}

Figure A5.120 1_{H NMR (500 MHz, CDCl3) of compound 374•HCl ... 417}

Figure A5.121 Infrared spectrum (Thin Film, NaCl) of compound 374•HCl ... 418

Figure A5.122 13_{C NMR (126 MHz, CDCl3) of compound 374•HCl ... 418}

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3) of compound 343 ... 420 Figure A5.126 Infrared spectrum (thin film/NaCl) of compound 376 ... 421 Figure A5.127 1_{H NMR (500 MHz, CDCl3) of compound 377 ... 422} Figure A5.128 Infrared spectrum (thin film/NaCl) of compound 377 ... 423 Figure A5.129 13_{C NMR (126 MHz, CDCl3) of compound 377 ... 423} Figure A5.130 1_{H NMR (500 MHz, CDCl3) of compound (}_S_{)-344 ... 424} Figure A5.131 Infrared spectrum (Thin Film, NaCl) of compound (S)-344 ... 425 Figure A5.132 13_{C NMR (126 MHz, CDCl}

3) of compound (S)-344 ... 425

APPENDIX 6

Figure A6.1.1 X-ray crystal structure of thiazolidine (S)-315 ... 427 Figure A6.2.1 X-ray crystal structure of thiazolidine 329 ... 450 Figure A6.3.1 X-ray crystal structure of imidazolidinium 374•(ZnBr3•MeOH) ... 466

Figure A6.4.1 X-ray crystal structure of imidazolidine 343 ... 485 Figure A6.5.1 X-ray crystal structure of oxazolidine 375 ... 503

CHAPTER 4

Figure 4.1 Structure of calophyline A ... 523 Figure 4.2 Crystal structure of tetracycle 429 ... 531

APPENDIX 8

Figure A8.1 1_{H NMR (400 MHz, CDCl3) of compound 411 ... 579} Figure A8.2 ATR-IR (CDCl3 solution) of compound 411 ... 580 Figure A8.3 13_{C NMR (101 MHz, CDCl3) of compound 411 ... 580} Figure A8.4 1_{H NMR (500 MHz, CDCl3) of compound 412 ... 581} Figure A8.5 ATR-IR (CDCl3 solution) of compound 412 ... 582 Figure A8.6 13_{C NMR (126 MHz, CDCl3) of compound 412 ... 582} Figure A8.7 1_{H NMR (300 MHz, CDCl}

3) of compound 415 ... 583 Figure A8.8 1_{H NMR (500 MHz, CDCl3) of compound 416 ... 584} Figure A8.9 ATR-IR (CDCl3 solution) of compound 416 ... 585 Figure A8.10 13_{C NMR (126 MHz, CDCl}

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Figure A8.12 ATR-IR (neat oil) of compound 419 ... 587 Figure A8.13 13_{C NMR (126 MHz, CDCl3) of compound 419 ... 587} Figure A8.14 1_{H NMR (300 MHz, CDCl3) of compound 428 ... 588} Figure A8.15 1_{H NMR (500 MHz, CDCl3) of compound 429 ... 589} Figure A8.16 ATR-IR (neat solid) of compound 429 ... 590 Figure A8.17 13_{C NMR (126 MHz, CDCl3) of compound 429 ... 590} Figure A8.18 1_{H NMR (300 MHz, CDCl3) of compound 457 ... 591} Figure A8.19 1_{H NMR (300 MHz, CDCl3) of compound 460 ... 592} Figure A8.20 1_{H NMR (500 MHz, CDCl3) of compound 461 ... 593} Figure A8.21 ATR-IR (neat solid) of compound 461 ... 594 Figure A8.22 13_{C NMR (126 MHz, CDCl3) of compound 461 ... 594} Figure A8.23 1_{H NMR (300 MHz, CDCl3) of compound 465 ... 595} Figure A8.24 1_{H NMR (300 MHz, CDCl3) of compound 488 ... 596} Figure A8.25 13_{C NMR (126 MHz, CDCl}

3) of compound 488 ... 597 Figure A8.26 1_{H NMR (500 MHz, CDCl3) of compound 500 ... 598} Figure A8.27 ATR-IR (CDCl3 solution) of compound 500 ... 599 Figure A8.28 13_{C NMR (126 MHz, CDCl3) of compound 500 ... 599} Figure A8.29 1_{H NMR (500 MHz, CDCl3) of compound 501 ... 600} Figure A8.30 Infrared spectrum (thin film/NaCl) of compound 501 ... 601 Figure A8.31 13_{C NMR (126 MHz, CDCl3) of compound 501 ... 601} Figure A8.32 1_{H NMR (500 MHz, CDCl3) of compound 502 ... 602} Figure A8.33 ATR-IR (C6H6 solution) of compound 502 ... 603 Figure A8.34 13_{C NMR (126 MHz, CDCl3) of compound 502 ... 603}

APPENDIX 9

Figure A9.1.1 X-ray crystal structure of tetracycle 429 ... 605

APPENDIX 10

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APPENDIX 11

Figure A11.1 1_{H NMR (500 MHz, CDCl3) of compound 586 ... 703} Figure A11.2 Infrared spectrum (thin film/NaCl) of compound 586 ... 704 Figure A11.3 13_{C NMR (126 MHz, CDCl3) of compound 586 ... 704} Figure A11.4 1_{H NMR (500 MHz, CDCl3) of compound 587 ... 705} Figure A11.5 Infrared spectrum (thin film/NaCl) of compound 587 ... 706 Figure A11.6 13_{C NMR (126 MHz, CDCl3) of compound 587 ... 706} Figure A11.7 1_{H NMR (500 MHz, CDCl}

3) of compound 588 ... 707 Figure A11.8 Infrared spectrum (thin film/NaCl) of compound 588 ... 708 Figure A11.9 13_{C NMR (126 MHz, CDCl3) of compound 588 ... 708} Figure A11.10 1_{H NMR (500 MHz, CDCl}

3) of compound 589 ... 709 Figure A11.11 Infrared spectrum (thin film/NaCl) of compound 589 ... 710 Figure A11.12 13_{C NMR (126 MHz, CDCl3) of compound 589 ... 710} Figure A11.13 1_{H NMR (500 MHz, CDCl3) of compound 590 ... 711} Figure A11.14 Infrared spectrum (thin film/NaCl) of compound 590 ... 712 Figure A11.15 13_{C NMR (126 MHz, CDCl3) of compound 590 ... 712} Figure A11.16 1_{H NMR (500 MHz, CDCl3) of compound 592 ... 713} Figure A11.17 Infrared spectrum (thin film/NaCl) of compound 592 ... 714 Figure A11.18 13_{C NMR (126 MHz, CDCl3) of compound 592 ... 714} Figure A11.19 1_{H NMR (500 MHz, CDCl}

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3) of compound 604 ... 731 Figure A11.44 Infrared spectrum (thin film/NaCl) of compound 604 ... 732 Figure A11.45 13_{C NMR (126 MHz, CDCl3) of compound 604 ... 732} Figure A11.46 1_{H NMR (500 MHz, CDCl3) of compound 531 ... 733} Figure A11.47 Infrared spectrum (thin film/NaCl) of compound 531 ... 734 Figure A11.48 13_{C NMR (126 MHz, CDCl3) of compound 531 ... 734} Figure A11.49 1_{H NMR (500 MHz, CDCl3) of compound 537 ... 735} Figure A11.50 Infrared spectrum (thin film/NaCl) of compound 537 ... 736 Figure A11.51 13_{C NMR (126 MHz, CDCl3) of compound 537 ... 736} Figure A11.52 1_{H NMR (500 MHz, CDCl3) of compound 538 ... 737} Figure A11.53 Infrared spectrum (thin film/NaCl) of compound 538 ... 738 Figure A11.54 13_{C NMR (126 MHz, CDCl3) of compound 538 ... 738} Figure A11.55 1_{H NMR (500 MHz, CDCl3) of compound 539 ... 739} Figure A11.56 Infrared spectrum (thin film/NaCl) of compound 539 ... 740 Figure A11.57 13_{C NMR (126 MHz, CDCl3) of compound 539 ... 740} Figure A11.58 1_{H NMR (500 MHz, CDCl3) of compound 540 ... 741} Figure A11.59 Infrared spectrum (thin film/NaCl) of compound 540 ... 742 Figure A11.60 13_{C NMR (126 MHz, CDCl3) of compound 540 ... 742} Figure A11.61 1_{H NMR (500 MHz, CDCl3) of compound 541 ... 743} Figure A11.62 Infrared spectrum (thin film/NaCl) of compound 541 ... 744 Figure A11.63 13_{C NMR (126 MHz, CDCl}

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3) of compound 543 ... 748 Figure A11.70 1_{H NMR (400 MHz, CDCl3) of compound 544 ... 749} Figure A11.71 Infrared spectrum (thin film/NaCl) of compound 544 ... 750 Figure A11.72 13_{C NMR (101 MHz, CDCl3) of compound 544 ... 750} Figure A11.73 1_{H NMR (500 MHz, CDCl3) of compound 545 ... 751} Figure A11.74 Infrared spectrum (thin film/NaCl) of compound 545 ... 752 Figure A11.75 13_{C NMR (126 MHz, CDCl3) of compound 545 ... 752} Figure A11.76 1_{H NMR (500 MHz, CDCl3) of compound 546 ... 753} Figure A11.77 Infrared spectrum (thin film/NaCl) of compound 546 ... 754 Figure A11.78 13_{C NMR (126 MHz, CDCl}

3) of compound 546 ... 754 Figure A11.79 1_{H NMR (500 MHz, CDCl3) of compound 547 ... 755} Figure A11.80 Infrared spectrum (thin film/NaCl) of compound 547 ... 756 Figure A11.81 13_{C NMR (126 MHz, CDCl3) of compound 547 ... 756} Figure A11.82 1_{H NMR (500 MHz, CDCl}

3) of compound 548 ... 757 Figure A11.83 Infrared spectrum (thin film/NaCl) of compound 548 ... 758 Figure A11.84 13_{C NMR (126 MHz, CDCl3) of compound 548 ... 758} Figure A11.85 1_{H NMR (500 MHz, CDCl3) of compound 549 ... 759} Figure A11.86 Infrared spectrum (thin film/NaCl) of compound 549 ... 760 Figure A11.87 13_{C NMR (126 MHz, CDCl3) of compound 549 ... 760} Figure A11.88 1_{H NMR (400 MHz, CDCl3) of compound 550 ... 761} Figure A11.89 Infrared spectrum (thin film/NaCl) of compound 550 ... 762 Figure A11.90 13_{C NMR (101 MHz, CDCl3) of compound 550 ... 762} Figure A11.91 1_{H NMR (500 MHz, CDCl3) of compound 551 ... 763} Figure A11.92 Infrared spectrum (thin film/NaCl) of compound 551 ... 764 Figure A11.93 13_{C NMR (126 MHz, CDCl3) of compound 551 ... 764} Figure A11.94 1_{H NMR (500 MHz, CDCl}

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Figure A11.104 Infrared spectrum (thin film/NaCl) of compound 555 ... 772 Figure A11.105 13_{C NMR (126 MHz, CDCl3) of compound 555 ... 772} Figure A11.106 1_{H NMR (500 MHz, CDCl3) of compound 556 ... 773} Figure A11.107 Infrared spectrum (thin film/NaCl) of compound 556 ... 774 Figure A11.108 13_{C NMR (126 MHz, CDCl3) of compound 556 ... 774} Figure A11.109 1_{H NMR (500 MHz, CDCl3) of compound 557 ... 775} Figure A11.110 Infrared spectrum (thin film/NaCl) of compound 557 ... 776 Figure A11.111 13_{C NMR (126 MHz, CDCl3) of compound 557 ... 776} Figure A11.112 1_{H NMR (500 MHz, CDCl3) of compound 558 ... 777} Figure A11.113 Infrared spectrum (thin film/NaCl) of compound 558 ... 778 Figure A11.114 13_{C NMR (126 MHz, CDCl3) of compound 558 ... 778} Figure A11.115 1_{H NMR (500 MHz, CDCl3) of compound 559 ... 779} Figure A11.116 Infrared spectrum (thin film/NaCl) of compound 559 ... 780 Figure A11.117 13_{C NMR (126 MHz, CDCl}

3) of compound 559 ... 780 Figure A11.118 1_{H NMR (500 MHz, CDCl3) of compound 560 ... 781} Figure A11.119 Infrared spectrum (thin film/NaCl) of compound 560 ... 782 Figure A11.120 13_{C NMR (126 MHz, CDCl3) of compound 560 ... 782} Figure A11.121 1_{H NMR (500 MHz, CDCl3) of compound 561 ... 783} Figure A11.122 Infrared spectrum (thin film/NaCl) of compound 561 ... 784 Figure A11.123 13_{C NMR (126 MHz, CDCl3) of compound 561 ... 784} Figure A11.124 1_{H NMR (500 MHz, CDCl3) of compound 562 ... 785} Figure A11.125 Infrared spectrum (thin film/NaCl) of compound 562 ... 786 Figure A11.126 13_{C NMR (126 MHz, CDCl3) of compound 562 ... 786} Figure A11.127 1_{H NMR (500 MHz, CDCl3) of compound 563 ... 787} Figure A11.128 Infrared spectrum (thin film/NaCl) of compound 563 ... 788 Figure A11.129 13_{C NMR (126 MHz, CDCl}

3) of compound 563 ... 788 Figure A11.130 1_{H NMR (500 MHz, CDCl3) of compound 564 ... 789} Figure A11.131 Infrared spectrum (thin film/NaCl) of compound 564 ... 790 Figure A11.132 13_{C NMR (126 MHz, CDCl3) of compound 564 ... 790} Figure A11.133 1_{H NMR (500 MHz, CDCl}

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3) of compound 570 ... 801 Figure A11.149 Infrared spectrum (thin film/NaCl) of compound 570 ... 802 Figure A11.150 13_{C NMR (126 MHz, CDCl3) of compound 570 ... 802} Figure A11.151 1_{H NMR (500 MHz, CDCl3) of compound 571 ... 803} Figure A11.152 Infrared spectrum (thin film/NaCl) of compound 571 ... 804 Figure A11.153 13_{C NMR (126 MHz, CDCl3) of compound 571 ... 804} Figure A11.154 1_{H NMR (500 MHz, CDCl3) of compound 572 ... 805} Figure A11.155 Infrared spectrum (thin film/NaCl) of compound 572 ... 806 Figure A11.156 13_{C NMR (126 MHz, CDCl3) of compound 572 ... 806} Figure A11.157 1_{H NMR (500 MHz, CDCl3) of compound 573 ... 807} Figure A11.158 Infrared spectrum (thin film/NaCl) of compound 573 ... 808 Figure A11.159 13_{C NMR (126 MHz, CDCl3) of compound 573 ... 808} Figure A11.160 1_{H NMR (500 MHz, CDCl3) of compound 574 ... 809} Figure A11.161 Infrared spectrum (thin film/NaCl) of compound 574 ... 810 Figure A11.162 13_{C NMR (126 MHz, CDCl3) of compound 574 ... 810} Figure A11.163 1_{H NMR (500 MHz, CDCl3) of compound 576 ... 811} Figure A11.164 Infrared spectrum (thin film/NaCl) of compound 576 ... 812 Figure A11.165 13_{C NMR (126 MHz, CDCl3) of compound 576 ... 812}

APPENDIX 12

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LIST OF SCHEMES

CHAPTER 1

Scheme 1.1 Basic reactivity modes of donor–acceptor cyclopropanes ... 2 Scheme 1.2 Retrosynthetic analysis of K252a ... 4 Scheme 1.3 Total synthesis of K252a ... 5 Scheme 1.4 Retrosynthetic analysis of N-methylwelwitindolinone C isothiocyanate ... 6 Scheme 1.5 Synthesis of the carbon skeleton of N-methylwelwitindolinone C

isothiocyanate ... 7 Scheme 1.6 A) Bielschowskysin and a simplified scaffold and B) Retrosynthetic analysis of

bielschowskysin ... 9 Scheme 1.7 Synthesis of donor–acceptor cyclopropane 37 ... 10 Scheme 1.8 Cyclopropane fragmentation ... 11 Scheme 1.9 Retrosynthetic analysis of gagunin E ... 12 Scheme 1.10 Synthesis of the gagunin core ... 13 Scheme 1.11 Retrosynthetic analysis of scandine ... 14 Scheme 1.12 Synthesis of the ABCD ring system of scandine ... 15 Scheme 1.13 Synthetic inspiration for the tandem Wolff–Cope rearrangement ... 16 Scheme 1.14 Selected scope of the tandem Wolff–Cope rearrangement ... 17 Scheme 1.15 Selected scope of the tandem Wolff–Cope–1,3-acyl shift reaction ... 19 Scheme 1.16 16 Unexpected aryne C–C insertion and mechanistic proposal ... 20 Scheme 1.17 Scope of the acyl-alkylation of arynes ... 21

CHAPTER 2

Scheme 2.1 Basic reactivity modes of donor–acceptor cyclopropanes ... 32 Scheme 2.2 Mechanistic rationale for the stereospecific cycloadditions of donor–

acceptor cyclopropanes with aryl donor groups ... 33 Scheme 2.3 A) Proposed reactions of donor–acceptor cyclopropanes with

heterocumulenes and B) Potential synthetic targets containing the 5-aryl

(30)

Scheme 2.6 Scope of the iron-mediated cycloadditions of donor–acceptor cyclopropanes with isocyanates ... 37 Scheme 2.7 Initial observation of desired reactivity with allyl isothiocyanate ... 38 Scheme 2.8 Structural reassignment of Li’s products ... 39

Scheme 2.9 Scope of the tin-mediated cycloadditions of donor–acceptor cyclopropanes with isothiocyanates ... 41 Scheme 2.10 Scope of the tin-mediated cycloadditions of donor–acceptor cyclopropanes with

carbodiimides ... 42 Scheme 2.11 Stereochemical investigations of the reaction of enantioenriched cyclopropane

(S)-152 with A) isocyanates, B) isothiocyanates, and C) carbodiimides ... 43 Scheme 2.12 Proposed mechanism of reactions of donor–acceptor cyclopropanes with

isothiocyanates and carbodiimides ... 45

APPENDIX 1

Scheme A1.1 Testing for product inhibition ... 85 Scheme A1.2 Derivatization of the cycloadducts ... 86

APPENDIX 2

Scheme A2.1 Retrosynthetic analysis of 136, 238, and 137 ... 99 Scheme A2.2 Successful cross-coupling of aryl bromide 246 with vinyltributylstannane ... 100 Scheme A2.3 Revised retrosynthetic analysis ... 101 Scheme A2.4 A) Unsuccessful intramolecular cycloadditions. B) A control experiment

with a competent cyclopropane. ... 102 Scheme A2.5 Control experiments with competent dipolarophiles ... 103 Scheme A2.6 Proposed mechanism for the formation of 5-aryl γ-lactam 257 and

isoindolone 258 ... 104 Scheme A2.7 Attempts at isoindolone formation from cyclopropanes with strongly

electron-donating groups ... 105 Scheme A2.8 Proposed synthetic route utilizing a cyclopropane-carbodiimide

(31)

CHAPTER 3

Scheme 3.1 Optimization of the reaction conditions ... 249 Scheme 3.2 Substrate scope of the isothiocyanate (3 + 2) cycloaddition ... 250 Scheme 3.3 (3 + 2) cycloaddition with 2-alkylaziridine 310 ... 251 Scheme 3.4 Scope of N-substitution in the isothiocyanate (3 + 2) cycloaddition

reaction ... 252 Scheme 3.5 Substrate scope of carbodiimide (3 + 2) cycloaddition ... 253 Scheme 3.6 Diastereoselective (3 + 2) cycloaddition with aziridine 328 ... 254 Scheme 3.7 Diastereoselective (3 + 2) cycloaddition with aziridine 330 ... 254 Scheme 3.8 (3 + 2) Cycloaddition with aziridine 333 ... 255 Scheme 3.9 Optimization of the stereoselective reaction conditions ... 256 Scheme 3.10 Substrate scope of stereoselective isothiocyanate (3 + 2) cycloaddition ... 257 Scheme 3.11 Scope of N-Substitution in the stereoselective isothiocyanate (3 + 2) ... 258 Scheme 3.12 Proposed general reaction mechanism for the stereoselective (3 + 2)

cycloaddition ... 258 Scheme 3.13 (3 + 2) Cycloaddition with aziridine dicarboxylate 342 ... 260 Scheme 3.14 Desulfonylation and deallylation of iminothiazolidine products 261

CHAPTER 4

Scheme 4.1 Tantillo’s proposal for the biosynthesis of calophyline A ... 524 Scheme 4.2 Zu’s retrosynthesis of calophyline A ... 525 Scheme 4.3 Zu’s total synthesis of calophyline A ... 526 Scheme 4.4 Initial retrosynthetic analysis ... 527 Scheme 4.5 Attempted syntheses of cyclopropanated indoles with two acceptor

groups ... 528 Scheme 4.6 Attempted syntheses of cyclopropanated indoles with one acceptor group .. 529 Scheme 4.7 A) General classes of diazo compounds. B) Qin’s use of a donor–acceptor diazo

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Scheme 4.13 Reaction of pyrones (A), pyridazines (B), and thiophene-1,1-dioxides (C) in [4 + 2]/retro [4 + 2] sequences ... 536 Scheme 4.14 Reaction of a cyclobutadienyliron complex in a [4 + 2]/electrocyclic ring

opening sequence ... 537 Scheme 4.15 Attempts to apply an indole-pyridazine [4 +2]/retro-[4 + 2] cycloaddition

toward the synthesis of calophyline A ... 538 Scheme 4.16 A) An attempt to apply an ester-linked indole-thiophene-1,1-dioxide

[4 +2]/retro-[4 + 2] cycloaddition toward the synthesis of calophyline A. B) Attempts to oxidize thiopene-2-carboxylic esters. ... 539 Scheme 4.17 Attempted synthesis of an ether-linked indole-thiophene-1,1-dioxide

cycloaddition substrate ... 540 Scheme 4.18 Unsuccessful intermolecular cycloadditions with 2,5-dibromothiophene-

1,1-dioxide ... 541 Scheme 4.19 Unsuccessful intermolecular cycloadditions with a pyrone diene ... 541 Scheme 4.20 Exploration of an indole-cyclobutadiene [4 + 2]/electrocyclic ring opening

sequence ... 542 Scheme 4.21 An example of a [2 + 2 + 2] cycloaddition engaging the indole C2–C3 bond543 Scheme 4.22 (Retrosynthetic analysis employing a [2 + 2 + 2] cycloaddition ... 544 Scheme 4.23 Investigation of an intramolecular [2 + 2 + 2] cycloaddition toward the

total synthesis of calophyline A ... 545 Scheme 4.24 Reactions of 3-bromooxindoles with malonate nucleophiles ... 546 Scheme 4.25 A potential oxindole alkylation route to calophyline A ... 547

APPENDIX 7

Scheme A7.1 Initial retrosynthetic analysis ... 574 Scheme A7.2 Formation of tetracycle 429 ... 574 Scheme A7.3 Revised synthetic plan ... 575 Scheme A7.4 Attempted (3 + 2) cycloadditions ... 575 Scheme A7.5 Retrosynthesis incorporating a [4 + 2] cycloaddition ... 576 Scheme A7.6 Retrosynthetic analysis employing a [2 + 2 + 2] cycloaddition ... 576 Scheme A7.7 Investigation of an intramolecular [2 + 2 + 2] cycloaddition ... 577 Scheme A7.8 Proposed synthetic route procceing via bromoxindole alkylation product

(33)

CHAPTER 5

Scheme 5.1 Enantioselective synthesis of α-quaternary lactams by palladium-

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LIST OF TABLES

APPENDIX 4

Table A4.1.1 Crystal data and structure refinement for thioimidate 155 ... 186 Table A4.1.2 Atomic coordinates (x 104_{) and equivalent isotropic displacement}

parameters (Å2_{x 10}3_{) for thioimidate 155. U(eq) is defined as one third} of the trace of the orthogonalized Uij_{tensor. ... 188} Table A4.1.3 Bond lengths [Å] and angles [°] for thioimidate 155 ... 189 Table A4.1.4 Anisotropic displacement parameters (Å2_x103_{) for thioimidate 155. The}

anisotropic displacement factor exponent takes the form: -2p2_{[ h}2_a*2_U11_{+ ... +} 2hka*b*U12_{]. ... 194} Table A4.1.3 Hydrogen coordinates (x103_{) and isotropic displacement parameters (Å}2_x103₎

for thioimidate 155 ... 195 Table A4.2.1 Crystal data and structure refinement for amidine (R)-170•HBr ... 197 Table A4.2.2 Atomic coordinates (x 104_{) and equivalent isotropic displacement parameters}

(Å2_{x 10}3_{) for amidine (R)-170•HBr. U(eq) is defined as one third of the trace of} the orthogonalized Uij_{tensor. ... 199} Table A4.2.3 Bond lengths [Å] and angles [°] for amidine (R)-170•HBr ... 205 Table A4.2.4 Anisotropic displacement parameters (Å2_x103_{) for amidine (R)-170•HBr. The}

for amidine (R)-170•HBr ... 240

APPENDIX 6

Table A6.1.1 Experimental details for X-ray structure determination of thiazolidine (S)-315 ... 428 Table A6.1.2 Crystal data and structure refinement for thiazolidine (S)-315 ... 428 Table A6.1.3 Atomic coordinates (x 104_{) and equivalent isotropic displacement parameters}

(35)

Table A6.1.5 Anisotropic displacement parameters (Å2_x103_{) for thiazolidine (S)-315. The} anisotropic displacement factor exponent takes the form: -2p2_{[ h}2_a*2_U11_{+ ... +} 2hka*b*U12_{]. ... 445} Table A6.1.6 Hydrogen coordinates (x103_{) and isotropic displacement parameters (Å}2_x103₎

for thiazolidine (S)-315 ... 448 Table A6.2.1 Experimental details for X-ray structure determination of thiazolidine 329 ... 451 Table A6.2.2 Crystal data and structure refinement for thiazolidine 329 ... 452 Table A6.2.3 Atomic coordinates (x 104_{) and equivalent isotropic displacement} parameters (Å2_{x 10}3_{) for thiazolidine 329. U(eq) is defined as one third of the trace} of the orthogonalized Uij_{tensor. ... 453} Table A6.2.4 Bond lengths [Å] and angles [°] for thiazolidine 329 ... 455 Table A6.2.5 Anisotropic displacement parameters (Å2_x103_{) for thiazolidine 329. The}

for thiazolidine 329 ... 464 Table A6.3.1 Experimental details for X-ray structure determination of imidazolidinium

374•(ZnBr3•MeOH) ... 467

Table A6.3.2 Crystal data and structure refinement for imidazolidinium

374•(ZnBr3•MeOH) ... 469

Table A6.3.3 Atomic coordinates (x 104_{) and equivalent isotropic displacement parameters (Å}2_x 103_{) for imidazolidinium 374•(ZnBr}

3•MeOH). U(eq) is defined as one third of the

trace of the orthogonalized Uij_{tensor. ... 470} Table A6.3.4 Bond lengths [Å] and angles [°] for imidazolidinium 374•(ZnBr3•MeOH) ... 472

Table A6.3.5 Anisotropic displacement parameters (Å2_x103_{) for imidazolidinium}

374•(ZnBr3•MeOH). The anisotropic displacement factor exponent takes the

form: -2p2_{[ h}2_a*2_U11_{+ ... + 2hka*b*U}12_{]. ... 480} Table A6.3.6 Hydrogen coordinates (x104_{) and isotropic displacement parameters (Å}2_x103₎

for imidazolidinium 374•(ZnBr3•MeOH) ... 482

Table A6.4.1 Experimental details for X-ray structure determination of imidazolidine 343. .. 486 Table A6.4.2 Crystal data and structure refinement for imidazolidine 343 ... 487 Table A6.4.3 Atomic coordinates (x 104_{) and equivalent isotropic displacement parameters (Å}2_x

(36)

Table A6.4.5 Anisotropic displacement parameters (Å2_x103_{) for imidazolidine 343. The} anisotropic displacement factor exponent takes the form: -2p2_{[ h}2_a*2_U11_{+ ... +} 2hka*b*U12_{]. ... 499} Table A6.4.6 Hydrogen coordinates (x104_{) and isotropic displacement parameters (Å}2_x103_{) for}

imidazolidine 343 ... 504 Table A6.5.1 Experimental details for X-ray structure determination of oxazolidine 375 ... 504 Table A6.5.2 Crystal data and structure refinement for oxazolidine 375 ... 505 Table A6.5.3 Atomic coordinates (x 104_{) and equivalent isotropic displacement parameters (Å}2_x

103_{) for oxazolidine 375. U(eq) is defined as one third of the trace of the}

orthogonalized Uij_{tensor. ... 507} Table A6.5.4 Bond lengths [Å] and angles [°] for oxazolidine 375 ... 509 Table A6.5.5 Anisotropic displacement parameters (Å2_x103_{) for oxazolidine 375. The}

anisotropic displacement factor exponent takes the form: -2p2_{[ h}2_a*2_U11_{+ ... +} 2hka*b*U12_{]. ... 518} Table A6.5.6 Hydrogen coordinates (x104_{) and isotropic displacement parameters (Å}2_x103_{) for}

oxazolidine 375 ... 520

APPENDIX 9

Table A9.1.1 Experimental details for X-ray structure determination of tetracycle 429 ... 606 Table A9.1.2 Crystal data and structure refinement for tetracycle 429 ... 606 Table A9.1.3 Atomic coordinates (x 104_{) and equivalent isotropic displacement parameters (Å}2_x

103_{) for tetracycle 429. U(eq) is defined as one third of the trace of the}

orthogonalized Uij_{tensor. ... 608} Table A9.1.4 Bond lengths [Å] and angles [°] for tetracycle 429 ... 609 Table A9.1.5 Anisotropic displacement parameters (Å2_x103_{) for tetracycle 429. The anisotropic}

displacement factor exponent takes the form: -2p2_{[ h}2_a*2_U11_{+ ... + 2hka*b*U}12_]. ... 613 Table A9.1.6 Hydrogen coordinates (x103_{) and isotropic displacement parameters (Å}2_x103_{) for}

tetracycle 429 ... 614 Table A9.1.7 Torsion angles [°] for tetracycle 429 ... 615

APPENDIX 12

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Table A12.1.2 Crystal data and structure refinement for diol 555 ... 815 Table A12.1.3 Atomic coordinates (x 104_{) and equivalent isotropic displacement parameters}

(Å2_{x 10}3_{) for diol 555. U(eq) is defined as one third of the trace of the}

orthogonalized Uij_{tensor. ... 817} Table A12.1.4 Bond lengths [Å] and angles [°] for diol 555 ... 818 Table A12.1.5 Anisotropic displacement parameters (Å2_x103_{) for diol 555. The anisotropic}

displacement factor exponent takes the form: -2p2_{[ h}2_a*2_U11_{+ ... +}

2hka*b*U12_{]. ... 823} Table A12.1.6 Hydrogen coordinates (x103_{) and isotropic displacement parameters (Å}2_x103₎

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LIST OF ABBREVIATIONS

[

α

]D

angle of optical rotation of plane-polarized light

Å

angstrom(s)

Ac

acetyl

APCI

atmospheric pressure chemical ionization

app

apparent

aq

aqueous

Ar

aryl group

atm

atmosphere(s)

Bn

benzyl

Boc

tert

-butoxycarbonyl

bp

boiling point

br

broad

Bu

butyl

i

-Bu

iso

-butyl

n

-Bu

butyl or

norm

-butyl

t

-Bu

tert

-butyl

Bn

benzyl

Bz

benzoyl

c

concentration of sample for measurement of optical rotation

13

C

carbon-13 isotope

/C

supported on activated carbon charcoal

(39)

calc’d

calculated

CAN

ceric ammonium nitrate

Cbz

benzyloxycarbonyl

CCDC

Cambridge Crystallographic Data Centre

CDI

1,1’-carbonyldiimidazole

cf.

consult or compare to (Latin:

confer

)

cm

–1

wavenumber(s)

COD

1,5-cyclooctadiene

comp

complex

conc.

concentrated

d

doublet

D

dextrorotatory

dba

dibenzylideneacetone

pmdba

bis(4-methoxybenzylidene)acetone

dmdba

bis(3,5-dimethoxybenzylidene)acetone

DBU

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

DCC

dicyclohexylcarbodiimide

DCE

1,2-dichloroethane

de

diastereomeric excess

DIAD

diisopropyl azodicarboxylate

DMAD

dimethyl acetylenedicarboxylate

DMAP

4-dimethylaminopyridine

(40)

DMF

N

,

N

-dimethylformamide

DMSO

dimethylsulfoxide

dppp

1,3-bis(diphenylphosphino)propane

dr

diastereomeric ratio

ee

enantiomeric excess

E

trans (entgegen) olefin geometry

EC50

median effective concentration (50%)

e.g.

for example (Latin:

exempli gratia

)

EI

electron impact

ESI

electrospray ionization

Et

ethyl

et al

.

and others (Latin:

et alii

)

FAB

fast atom bombardment

g

gram(s)

h

hour(s)

1

H

proton

HMDS

hexamethyldisilamide or hexamethyldisilazide

h

ν

light

HPLC

high performance liquid chromatography

HRMS

high resolution mass spectrometry

Hz

hertz

IC50

half maximal inhibitory concentration (50%)

(41)

IR

infrared spectroscopy

J

coupling constant

k

rate constant

kcal

kilocalorie(s)

kg

kilogram(s)

L

liter or neutral ligand

L

levorotatory

LA

Lewis acid

LD50

median lethal dose (50%)

LDA

lithium diisopropylamide

m

multiplet

M

molar or molecular ion

m

milliliter(s)

mol

mole(s)

(42)

mp

melting point

Ms

methanesulfonyl (mesyl)

MS

molecular sieves

m/z

mass-to-charge ratio

N

normal or molar

NBS

N

-bromosuccinimide

nm

nanometer(s)

NMR

nuclear magnetic resonance

NOE

nuclear Overhauser effect

NOESY

nuclear Overhauser enhancement spectroscopy

o

ortho

[O]

oxidation

p

para

p

-ABSA

para

-acetamidobenzenesulfonyl azide

PCC

pyridinium chlorochromate

PDC

pyridinium dichromate

Ph

phenyl

pH

hydrogen ion concentration in aqueous solution