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Proquest Dissertations The synthesis of highly substituted indoles via isonitriles Item Type text; Dissertation-Reproduction (electronic) Authors Kennedy, Abigail Rose Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 26/09/2021 04:52:53 Link to Item http://hdl.handle.net/10150/290368 INFORMATION TO USERS This manuscript has l)een reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be firom any type of computer printer. The quality of this raproduction is dependent upon the quality of the copy submitted. 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Ann Arbor, Ml 48106-1346 USA 800-S21-0600 THE SYNTHESIS OF HIGHLY SUBSTITUTED INDOLES VIA ISONTTRILES By Abigail Rose Kennedy A Dissertation Submitted to the Faculty of the DEPARTMENT OF CHEMISTRY In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSTTY OF ARIZONA 2001 UMI Number. 3023479 UMI' UMI Microfomt 3023479 Copyright 2001 by Bell & Howell Infomiation and Learning Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. Bell & Howell Information and Learning Company 300 North Zeeb Road P.O. Box 1346 Ann Arbor, Ml 48106-1346 2 THE UNIVERSITY OF ARIZONA « GRADUATE COLLEGE As members of the Final Examination Committee, we certify that we have read the dissertation prepared by Abigail Rose Kennedy entitled The Synthesis of Highly Substituted Indoles via IsnnifWIpg and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy Dr. Rqbect B.iBates Date S'Xi-ol Enemark Date C Dr. David F. O'Brien Date I Dr. Victo Final approval and acceptance of this dissertation is contingent upon the candidate's submission of the final copy of the dissertation to the Graduate College. I hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation requirement. Diaeeftation Director 3 STATEMENT BY AUTHOR This dissertation has been submitted in partial fulfillment of the requirements for an advanced degree at the University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library. Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgements of source are made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the head of the major department or the Dean of the Graduate College when in his or her judgement the proposed used of material is in the interests of scholarship. In all other instances, permission must be obtained from the author. SIGNED: 4 ACKNOWLEDGEMENTS I would like to thank my advisor Dr. Jon Rainier for training me in organic synthesis, and for his enthusiastic support of my chemistry and my career. He challenged me to become the chenust that I am today. I would also like to acknowledge my committee; Dr. Robert Bates, Dr. John Enemark, Dr. David O'Brien, and Dr. Victor Hruby for critiquing this dissertation. They have been wonderful teachers both inside and outside of the classroom. Furthermore, I would like to acknowledge my labmates; Dr. Shawn Allwein, Jason Cox, Jason Imbriglio, and Qing Xu for creating a fiin workplace and for all of their support. I wish the best of chemistry to the youngest Rainier group members, as well as the undergraduates that have worked with me on this project (Eric Chase and Michael Taday.) I would like to especially thank good friends that have supported me throughout this ride; Dr. Michele Cosper, Anne McElhaney, Danielle Wehle, Rachel and Danny LaBell and Brooke Schilling. Also, thanks to Dr. Jeffrey Anthis who has shown me the definition of true friendship. I wouldn't have made it this far without all of you. Finally, I would like to thank my parents, Sarah, Dougie, Ruthie and Molly for their unconditional support and for being my biggest cheering section over the past 28 years. DEDICATION For Liebehaber, I love you. 6 TABLE OF CONTENTS Page LIST OF ABBREVUTIONS 11 LISTOFnGURES 13 LIST OF SCHEMES 14 LIST OF TABLES 19 ABSTRACT 20 CHAPTER 1. THE SYNTHESIS OF 2^-DISUBSTITUTED INDOLES 1.1. Indole Containing Products; A Rationale for Indole Synthesis 21 1.2. An Overview of the Synthesis of 2,3-Disubstituted Indoles 22 1.3. The Synthesis of 2,3-Disubstituted Indoles 25 1.3.1. Functionalization of C-2 and C-3 During Indole Assembly 25 1.3.1.1. Baccolini's Indole Synthesis 25 1.3.1.2. Gassman's Indole Synthesis 26 1.3.1.3. Suzuki's Indole Synthesis 27 1.3.1.4. Blechert's Indole Synthesis 28 1.3.1.5. Larock's Indole Synthesis 29 1.3.1.6. Smith's Indole Synthesis 30 1.3.L7. Cacchi's Indole Synthesis 31 1.3.1.8. Edmondson's Indole Synthesis 32 1.3.1.9. Yamanaka's Indole Synthesis 33 7 TABLE OF COmEmS-CotiHnued 1.3.1.10. Yamamoto's Indole Synthesis 34 1.3.1.11. Suh's Indole Synthesis 35 1.3.1.12. Sundberg's Indole Synthesis 36 1.3.1.13. Soderberg's Indole Synthesis 37 1.3.1.14. FQrstner's Indole Synthesis 38 1.3.1.15. Thyagarajan's Indole Synthesis 39 1.3.1.16. Ito's Indole Synthesis 40 1.3.1.17. Fukuyama's Indole Syntheses 41 1.3.2. Functionalization of C-2 and C-3 After Indole Assembly 43 1.3.2.1. Smith's Indole Synthesis 43 1.3.2.2. M^debielle's Indole Synthesis 44 1.3.2.3. Knight's Indole Synthesis 45 1.3.2.4. Cribble's Indole Synthesis 45 1.3.2.5. Jackson's bidole Synthesis 47 1.3.2.6. Greci's Indole Synthesis 48 1.3.2.7. Anthony's Indole Synthesis 49 1.3.2.8. Nakazaki's Indole Synthesis 49 1.3.2.9. Raucher's Indole Synthesis 50 1.4. Conclusions 51 8 TABLE OF CONTENTS-Cottiinued CHAPTER 2. THE SYNTHESIS OF SUBSTITUTED INDOLES VIA ISONTTRILE RADICALS 2.1. Introduction 52 2.2. Isonitriles as Geminal Radical Donors/Acceptors 52 2.3. Bergman Cycloaromatization Approach to Substituted Quinolines 54 2.4. Tin-Mediated konitrile-Alkyne Cascade to Substituted Indoles 58 2.5. Sulfiir-Mediated Isonitrile-Alkyne Cascade to Substituted Indoles 65 2.6. Conclusions 67 CHAPTER 3. 2,10-DITHIOINDOLES AS VERSATILE INDOLE INTERMEDUTES 3.1. Genera] Approaches to Functionalization of 2,10-Dithioindoles 69 3.2. Addition of Carbon Nucleophiles at C-IO 70 3.3. Addition of Sulftir Nucleophiles at C-10 82 3.4. Addition of Cyanide Ion as a Nucleophile at C-10 83 3.5. Addition of an Amine Nucleophile at C-10 84 3.6. Elimination of the C-10 Thioether Exclusively 84 3.7. Conclusions 85 TABLE OF COmEmS-Continued CHAPTER 4. PROGRESS IN THE SYNTHESIS OF SPIROTRYPROSTATIN A 4.1. Biological Activity of Spirotryprostatin A 4.2. Danishefsky's Synthesis of Spirotryprostatin A 4.3. Reported Syntheses of Spirotryprostatin B 4.3.1. Danishefsky's Synthesis of Spirotryprostatin B 4.3.2. Ganesan's Synthesis of Spirotryprostatin B 4.3.3. Overman's Synthesis of Spirotryprostatin B 4.3.4. William's Synthesis of Spirotryprostatin B 4.3. Our First General Approach to the Core of Spirotryprostatins A 4.3.1. An "Interrupted" Pictet-Spengler Cyclization 4.3.2. Elaboration of the Thioimidates 4.4. N-Acyl Iminium Ion Approach to Spirotryprostatin A 4.5. Conclusions CHAPTER 5. DERIVATIZATION OF 2,10-DITHIOINDOLES VU SULFUR YLIDES 5.1. Formation and Structure of Sulfur Ylides 5.2. Common Reactions of Sulfur Ylides 5.3. Intramolecular Sulfur Ylide Reactions 5.3.1. Proposal for an Asymmetric Gramine Reactions via Sulfiir Ylides 10 TABLE OF CONTENTS-Coimnueif 5.3.2. Synthesis of an Intramolecular Sulfur Ylide Precursor 110 5.3.3. fotramolecular Sulfur Ylide Results 111 5.4. Intermolecular Sulfur Ylide Reactions 113 5.4.1. Sulfur Ylides from C-10 Thioindoles 113 5.4.2. Sulfur Ylides from 2,10-Dithioindoles 115 5.4.3. Sulfur Ylides from 2-Thioindoles 117 5.4.4 Attempted Sulfur Ylide Formation from Vinyl Carbenes 119 5.5. Conclusions 123 CHAPTER 6. CONCLUSIONS 124 CHAPTER 7. EXPERIMENTAL 7.1. General Methods 125 7.2. Experimental Procedures 126 APPENDICES 1. Permissions 162 2. Spectra 163 REFERENCES 356 11 LIST OF ABBREVUTIONS AIBN 2,2'-Azobisisobutyronitrile BocjO Di-reit-butyl dicaibonate t-BuOH ferr-Butyl alcohol 18-C-6 l8-Crown-6 DCC 1,3-Dicyclohexylcarbodiimide DMAP 4,-Diinethylaininopyridine DMDO Dimethyl dioxirane DMF MiV-Dimethylformamide DMSO Methyl
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