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The Synthesis of Tryptophan Derivatives, 2 Graduate Theses, Dissertations, and Problem Reports 2009 The synthesis of tryptophan derivatives, 2- and/or 3-substituted indoles, progress toward dilemmaones A-C, and synthetic studies towards fistulosin via palladium-catalyzed reductive N- heteroannulation Christopher Andrew Dacko West Virginia University Follow this and additional works at: https://researchrepository.wvu.edu/etd Recommended Citation Dacko, Christopher Andrew, "The synthesis of tryptophan derivatives, 2- and/or 3-substituted indoles, progress toward dilemmaones A-C, and synthetic studies towards fistulosin via palladium-catalyzed reductive N-heteroannulation" (2009). Graduate Theses, Dissertations, and Problem Reports. 4454. https://researchrepository.wvu.edu/etd/4454 This Dissertation is protected by copyright and/or related rights. It has been brought to you by the The Research Repository @ WVU with permission from the rights-holder(s). You are free to use this Dissertation in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you must obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Dissertation has been accepted for inclusion in WVU Graduate Theses, Dissertations, and Problem Reports collection by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. The Synthesis of Tryptophan Derivatives, 2- and/or 3- Substituted Indoles, Progress Toward Dilemmaones A-C, and Synthetic Studies Towards Fistulosin via Palladium-Catalyzed Reductive N-Heteroannulation Christopher Andrew Dacko Dissertation submitted to the Eberly College of Arts and Sciences at West Virginia University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry Björn C. G. Söderberg, Ph. D., Chair Robert K. Griffith, Ph. D. George A. O’Doherty, Ph. D. Jeffrey L. Petersen, Ph. D. Kung K. Wang, Ph. D. C. Eugene Bennett Department of Chemistry, Morgantown, West Virginia 2009 Keywords: indole, tryptophan, dilemmaone, fistulosin, palladium-catalyzed, N- heteroannulation Abstract The Synthesis of Tryptophan Derivatives, 2- and/or 3-Substituted Indoles, Progress Toward Dilemmaones A-C, and Synthetic Studies Towards Fistulosin via Palladium- Catalyzed Reductive N-Heteroannulation Christopher Andrew Dacko Palladium-catalyzed carbon monoxide-mediated reductive N-heteroannulation of o-nitrostyrenes has emerged as a very powerful method for constructing the corresponding indole core. The Söderberg variety of this methodology has been utilized to synthesize several asymmetric tryptophan derivatives along with a collection of 2- and/or 3-substituted indoles. The same protocol has also been employed to make synthetic progress toward the construction of the marine indole alkaloids Dilemmaones A-C. Finally, this versatile cyclization was implemented in studies designed to determine the true structure of the compound isolated by Tomita et. al. and given the name “fistulosin”. Acknowledgments This work is dedicated to my grandparents, Andrew and Helen Dacko, and also to my good friend Jon Murt, all of whom passed away during my time as a graduate student at West Virginia University. I miss them all very dearly and wish they could have been here to witness my accomplishments. I would like to thank my advisor, Dr. Björn Söderberg, for his constant guidance, patience, and friendship during my graduate studies. I owe my development as a chemist to his counseling and support. I would also like to thank the faculty members in the C. Eugene Bennett Department of Chemistry for all their assistance over the years, especially Dr. George O’Doherty, Dr. Jeffrey Petersen, and Dr. Kung Wang for serving on my doctoral defense committee. In addition, I would like to thank Dr. Robert Griffith for his role on the aforementioned committee. Appreciation is also directed towards Albert Taylor, Jr. and Barbara Foster for their constant help in the past. A special thanks to Dr. Novruz Akhmedov for all his NMR assistance. I have relied on his help and expertise in composing a large part of my dissertation. Most importantly, I would like to thank my family for their endless love and encouragement through all the years of my graduate career. To my parents, Greg and Kathy, I love you two very much. Without your support, both emotionally and financially, I would not have been able to make it to where I am today. Words cannot express my gratitude towards your generosity. Also, a huge thanks goes to my girlfriend, Christina, for all of her love and support during my last three years at WVU. Finally, thanks to all my research group members, past and present, for all of their advice, guidance, and companionship. iii Table of Contents Title Page i Abstract ii Acknowledgment iii Table of Contents iv List of Figures ix List of Schemes xx List of Tables xxvi Chapter 1 Introduction to Indole, Indole History and Classic Routes to the Indole Core 1.1 Indole Background and Notable Indoles 2 1.2 Classic Routes to the Indole Core 7 1.2.1 Fischer Indole Synthesis 7 1.2.2 Madelung Indole Synthesis 10 1.2.3 Bartoli Indole Synthesis 11 1.2.4 Gassman Indole Synthesis 12 1.2.5 Leimgruber-Batcho Indole Synthesis 13 1.2.6 Nenitzescu Indole Synthesis 15 iv Chapter 2 Indole Formation via Palladium-Catalyzed N- Heteroannulation 2.1 Introduction 18 2.2 Indole Formation via o-Alkynylanilides and o-Alkynylanilines 18 2.3 Indole Formation via Intermolecular Cycloaddition with Alkynes 20 2.4 Indole Formation via o-Allylanilines 21 2.5 Indole Formation via o-Vinylanilines 22 2.6 Indole Formation via Buchwald/Hartwig N-Arylation Processes 22 2.7 Indole Formation via Nitrenes 24 Chapter 3 Synthesis of Tryptophan Derivatives via Palladium-Catalyzed N-Heteroannulation 3.1 Introduction to Tryptophan/Tryptophan Skeleton in Natural Products 42 3.2 Previous Enantioselective Syntheses of α-Amino Acid Derivatives 44 3.3 Tryptophan Derivatives via Palladium-Catalyzed N-Heteroannulation 54 3.3.1 Retrosynthetic Analysis 54 3.3.2 Results and Discussion 55 3.3.3 Conclusions 79 v Chapter 4 Synthesis of 2- and/or 3-Substituted Indoles Utilizing Palladium-Catalyzed Reductive N-Heteroannulation 4.1 Attempted Synthesis of 3-Silylindoles 81 4.2 Synthesis of 2-Substituted Indoles via Hydrosilylation 82 4.3 Synthesis of 2,3- and 3-Substituted Indoles via Hydrostannylation 85 4.4 Conclusions 92 Chapter 5 Synthetic Progress Toward the Construction of Dilemmaones A-C 5.1 Introduction & Background 94 5.2 Retrosynthetic Analysis 96 5.3 Attempted Synthesis of Dilemmaone B 97 5.4 Conclusions 104 Chapter 6 Synthetic Studies Towards Fistulosin Utilizing Palladium- Catalyzed Reductive N-Heteroannulation 6.1 Fistulosin Background 106 6.2 Synthetic Studies Towards Fistulosin by Clawson et. al. 107 vi 6.3 Synthetic Studies Towards Fistulosin by Nishida et. al. 115 6.4 Dimer Synthesis and Analysis via Palladium-Catalyzed N-Heteroannulation 123 6.5 Conclusions 129 Chapter 7 Miscellaneous Reactions Forming Novel Heterocycles 7.1 Synthesis of 3-(Halomethyl)benzo[c]isoxazole-N-oxides 131 7.2 Incorporation of Additives into N-Heteroannulations 134 7.3 Conclusions 136 Chapter 8 Supporting Information: Experimental Procedures 8.1 Supporting Information Chapter 3: Tryptophan Derivatives 139 8.2 Supporting Information Chapter 4: 2- and/or 3-Substituted Indoles 165 8.3 Supporting Information Chapter 5: Dilemmaones A-C 175 8.4 Supporting Information Chapter 6: Fistulosin 179 8.5 Supporting Information Chapter 7: Miscellaneous Reactions 184 vii Appendix 1H and 13C NMR Spectra ● 1H and 13C NMR for Chapter 3: Tryptophan Derivatives 200 ● 1H and 13C NMR for Chapter 4: 2- and/or 3-Substituted Indoles 256 ● 1H and 13C NMR for Chapter 5: Dilemmaones A-C 279 ● 1H and 13C NMR for Chapter 6: Fistulosin 291 ● 1H and 13C NMR for Chapter 7: Miscellaneous Reactions 317 viii List of Figures Figure 1: Structure and Numbering of Indole 2 Figure 2: Structures of L-Tryptophan, Serotonin, Melatonin, and Sumatriptan 4 Figure 3: Structures of Ergoline, LSD, and Lisuride 5 Figure 4: Structures of Yohimbine, Ellipticine, and Strychnine 5 Figure 5: Structures of Eudistomin L, Dragmacidin, and Dihydroflustramine C 6 Figure 6: Typical Singlet and Triplet Nitrenes 24 Figure 7: Structures of L-Tryptophan and D-Tryptophan 42 Figure 8: Structures of Brevicompanine C and Fiscalin B 43 Figure 9: Structures of Echinulan, Fuchsiaefoline, and Alstophylline 43 Figure 10: General Structure of Tryptophan Target Molecule 54 Figure 11: Structures of Dilemmaones A-C 94 Figure 12: Structures of the Trikentrins 95 Figure 13: Structures of the Herbindoles 95 Figure 14: Tomita’s Proposed Structure of Fistulosin 106 Figure 15: Naturally-Occurring Dimeric Indolinone Alkaloids 107 Figure 16: Antifungal Natural Products Containing Long Aliphatic Chains 109 Figure 17: Comparison of 13C NMR Shifts of Heterocycles at C-3 122 Figure 18: 1H NMR of (2R,5S)-2,5-Dihydro-3,6-dimethoxy-5-(1-methylethyl)- 2-(2-trimethylstannyl-2-propen-1-yl)pyrazine (238) 200 Figure 19: 13C NMR of (2R,5S)-2,5-Dihydro-3,6-dimethoxy-5-(1-methylethyl)- 2-(2-trimethylstannyl-2-propen-1-yl)pyrazine (238) 201 ix Figure 20: 1H NMR of (2R,5S)-2,5-Dihydro-3,6-dimethoxy-5-(1-methylethyl)- 2-(2-(2-nitrophenyl)-2-propen-1-yl)pyrazine (239) 202 Figure 21: 13C NMR of (2R,5S)-2,5-Dihydro-3,6-dimethoxy-5-(1-methylethyl)- 2-(2-(2-nitrophenyl)-2-propen-1-yl)pyrazine (239) 203 Figure 22: 1H NMR of (2R,5S)-2,5-Dihydro-2-(2-(4-methoxy-2-nitrophenyl)-
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