Synthetic Studies for Heterocycle Synthesis Part I: Intra/intermolecular Olefin Diamination for the Stereoselective Synthesis of 3-Aminopiperidines Part II: Total Synthesis of Malagashanine and Synthetic Studies Toward Related Alkaloids Open Access

Abstract

Nitrogen heterocycles are prevalent motifs in biologically active compounds as well as in important functional materials. This dissertation outlines our efforts toward the synthetic studies of various heterocyclic compounds. Part one provides a general method for a metal free intra/intermolecular olefin diamination to synthesize 3-aminopiperidines with high regio- and diastereoselectivity. Mechanistic studies were conducted systematically (Chapter one). Part two reports the total synthesis of malagashanine and synthetic studies toward related alkaloids. The first total synthesis of malagashanine is described, and mainly focuses on addressing challenges in the construction of the syn relationship between the C(19) and C(20) stereocenters. A late-stage Raney nickel catalyzed hydrogenation of the tetrasubstituted double bond successfully constructed the correct stereochemistry (Chapter two). Several cascade cyclization reactions of oxocarbenium analogs to synthesize the core of mattogrossine are outlined. The stereoselectivity of the oxocarbenium ion cascade reaction was found to be inferior to that of the previously reported iminium ion cascade reaction. Substrate substitution, the geometry of the olefin, and the nature of the Lewis acid were found to influence the stereochemical outcome of this reaction (Chapter three). Studies toward asymmetric nucleophilic addition to iminium ions using chiral ion-pair catalysts are described. Several chiral Lewis-acid complexes were explored, but failed to provide results better than 12 % ee. BINOL-derived phosphoric acid derivatives catalyzed the cascade cyclization reaction to provide the desired product in up to 25 % ee (Chapter four).

Table of Contents

Chapter One: Intra/intermolecular Olefin Diamination for the Stereoselective Synthesis of 3-Aminopiperidines. 1
1.1 Introduction. 1
1.2 Background and Significance. 1
1.2.1 Intermolecular Alkene Diamination Reactions. 1
1.2.2 Intramolecular Alkene Diamination Reactions. 5
1.2.3 Intra/intermolecular Alkene Diamination Reactions. 6
1.2.4 Significance. 8
1.3 Results and Discussion. 11
1.3.1 Initial Studies and Reaction Discovery. 11
1.3.1.1 Initial Studies. 11
1.3.1.2 New Strategies and NMR Study. 13
1.3.1.3 Metal-Free 6-endo Diamination. 16
1.3.2 Optimizations of Metal-Free 6-endo Diamination. 17
1.3.3 Substrate Scope of Metal-Free 6-endo Diamination. 19
1.3.4 Product Structure and Stereochemistry Determination. 23
1.3.5 Deprotection of Metal-Free 6-endo Diamination Product 26
1.3.6 Mechanistic Study of Metal-Free 6-endo Diamination. 30
1.3.6.1 Deuterium-labeling Experiments. 30
1.3.6.2 Exploring the Possibility of the Rearrangement from 5-exo-cyclized products to 6-endo-cyclized products. 33
1.3.6.3 Mass Spectroscopy Study. 34
1.3.6.4 X-Ray Study of the Crystals of the Mixture of PhI=O and HN(SO2CF3)2 40
1.3.7 Proposed Mechanism of Metal-Free 6-endo Diamination. 42
1.3.8 Byproduct Identification and Optimization of gem-Diphenyl Substituted Substrate 18. 44
1.3.9 Catalytic Metal-Free 6-endo Diamination. 48
1.4 Conclusion. 49
1.5 Experimental 49
1.6 References. 102
Chapter Two: Total Synthesis of (±)-Malagashanine. 104
2.1 Introduction. 104
2.1.1 Isolation and Biological Activity. 104
2.1.2 Structure Determination and Numbering. 105
2.2 Literature Precedent for the Synthesis of 3-epi-Malagashanine Analogues. 107
2.3 Synthesis Design and Retrosynthetic Analysis. 109
2.3.1 Synthesis Design. 109
2.3.2 Retrosynthetic Analysis. 110
2.4 Results and Discussion. 112
2.4.1 Substrate Synthesis. 112
2.4.2 Stereospecific Cyclization. 114
2.4.3 Formal Olefin Hydroacylation. 115
2.4.4 Dihydropyran Formation. 117
2.4.5 Synthesis of α,β-Unsaturated Ester 90. 119
2.4.5.1 Synthesis of Trifluoromethylketone 110. 119
2.4.5.2 Synthesis of α,β-Unsaturated Ester 90. 119
2.4.6 Ionic Reduction. 122
2.4.6.1 Previous Studies on Ionic Reduction. 122
2.4.6.2 Epimerization. 123
2.4.6.3 Proposed Mechanism of Ionic Reduction and New Design. 124
2.4.6.4 New Attempts on Model Substrates. 126
2.4.6.5 Reactions with the advanced intermediate. 128
2.4.7 Hydrogenation Reactions. 132
2.4.7.1 Previous Studies of Hydrogenation Reactions. 132
2.4.7.2 Literature Precedent for Homogenous Hydrogenation. 133
2.4.7.3 Homogenous Hydrogenation of Advance Intermediate 90. 134
2.4.7.4 Reanalysis of Previous Results about Hydrogenation Reactions. 135
2.4.7.5 Synthesis of Nb-methyl Ester 145 and Structure Confirmation. 137
2.4.7.6 Homogenous Hydrogenation of Nb-methyl ester 145. 139
2.4.8 Structure Determination and Minor Peaks Identification. 142
2.4.8.1 Structure Determination. 142
2.4.8.2 Minor peaks Identification. 147
2.5 Conclusions. 148
2.6 Experimental 150
2.7 References. 177
Chapter Three: Studies Toward the Synthesis of Mattogrossine. 179
3.1 Introduction. 179
3.2 Retrosynthetic Analysis of Mattogrossine. 181
3.2.1 Intermolecular Cyclization as the Key Step. 181
3.2.2 Intramolecular Cyclization as the Key Step. 182
3.3 Results and Discussion. 185
3.3.1 Intermolecular Cyclization as the Key Step. 185
3.3.1.1 Oxonium as the Intermediate. 185
3.3.1.2 Iminium as the Intermediate. 186
3.3.2 Intramolecular Cyclization as the Key Step. 193
3.3.2.1 Synthesis of O-TMS-Acetal Substrates. 194
3.3.2.2 Cyclization of O-TMS-Acetal Substrates. 196
3.3.2.3 Determination of the Structures of the Cyclization Products. 199
3.5 Experimental 202
3.6 References. 229
Chapter Four: Studies Toward Asymmetric Nucleophilic Addition to Iminium Ions Using Chiral Ion-pair Catalysts. 230
4.1 Introduction. 230
4.2 Literature Background. 231
4.3 Results and Discussion. 235
4.3.1 Titanium(IV) Complex Catalyzed Reactions. 235
4.3.2 SnCl4 Catalyzed Reactions. 238
4.3.3 Bifunctional Catalysis. 243
4.3.4 Intramolecular Cyclization. 247
4.3.4.1 Attempted designs of new intramolecular reactions. 247
4.3.4.2 Utilization of known an intramolecular reaction as the model to investigate asymmetric catalyses. 250
4.3.4.3 Syntheses of phosphoric acid derivatives and examination of their reactivity in cascade cyclization reactions. 254
4.4 Conclusions. 261
4.5 Experimental 263
4.6 References 294

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School	Laney Graduate School
Department	Chemistry
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Keyword	diamination malagashanine 3-aminopiperidines
Committee Chair / Thesis Advisor	Blakey, Simon, Emory University
Committee Members	McDonald, Frank, Emory University Liebeskind, Lanny S, Emory University

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