Metallonitrene/Alkyne Cascade Reactions: Development of a Versatile Process for Organic Synthesis Public
Thornton, Aaron Robert (2010)
Published
Abstract
Metallonitrene/Alkyne Cascade Reactions:
Development of a Versatile Process for Organic Synthesis
By Aaron R. Thornton
This dissertation outlines our efforts towards the discovery,
development, and appliciation of a novel Rh(II)-catalyzed
metallonitrene/alkyne cascade reaction. Chapter 1 provides an
introduction and background to the field of metallonitrene
chemistry, focusing on the development and application of
aziridination and C-H amination reactions. Following this, Chapter
2 outlines our efforts towards the discovery and development of a
novel metallonitrene/alkyne cascade reaction. In this chapter we
first discuss the initial concept for catalyst selection and
substrate design, followed by the examination of various substrates
in an attempt to better understand this new cascade process.
Additionally, experiments designed to elucidate a potential
mechanism for this transformation are presented. These studies have
led to the successful development of four different cascade
termination processes, with each providing access to a range of
densely functionalized N-containing molecules from
remarkably simple starting materials.
Chapter 3 outlines our efforts towards the synthesis of the
Securinega alkaloids. A brief background discussing the history,
biological importance, and prior syntheses of these natural
products is presented. This is followed by our efforts towards the
construction of (+)-allonorsecurine and
(+)-allosecurinine through the use of our newly developed
cascade reaction. Lastly, the studies that have evolved from this
endeavor, including the development of conditions for the
intermolecular termination of this cascade process, are
highlighted.
Table of Contents
Chapter 1: Introduction and Background: The Development and
Application of Transition Metal Catalyzed Nitrene Transfer
Reactions
1.1. Prevalence of Nitrogen-Containing Molecules 2
1.2. Aziridination Reactions 3
1.3. C-H Amination Reactions 8
1.4. Future Directions 15
1.5. Metallonitrene/Alkyne Metathesis Reaction 16
References 20
Chapter 2: The Discovery and Development of a Metallonitrene/Alkyne
Cascade Reaction
2.1. Design of a Metallonitrene/Alkyne Metathesis Reaction 24
2.1.1. Potential Catalysts 24
2.1.2. Substrate Design 26
2.2. Reaction Discovery and Initial Studies 28
2.2.1. Reaction Discovery 28
2.2.2. Control Experiments and Mechanistic Hypothesis 31
2.2.3. Metallonitrene/Alkyne Cascade Reaction Optimization 34
2.2.4. Substrate Scope for Metallonitrene/Alkyne Cascade
Reaction
Termination Through Ylide Formation/Group Migration 36
2.3. Alternate Cascade Terminations and Mechanistic Insight
42
2.3.1. Reactivity Studies and the Discovery of
Metallonitrene/Alkyne Cascade Reaction Termination Through
Friedel-Crafts Reaction 42
2.3.2. Substrate Scope for Cascade Termination Through
Friedel-Crafts Reaction 45
2.3.3. Discovery of and Substrate Scope for Cascade Termination
Through Cyclopropanation 53
2.3.4. Revised Mechanistic Hypothesis Based on Reactivity Patterns
54
2.4. Conclusions and Future Directions 56
Experimental Procedures and Compound Characterization 57
X-Ray Crystallographic Data 95
References 132
Chapter 3: Application of Metallonitrene/Alkyne Cascade Reactions:
Towards the Synthesis of the Securinega Alkaloids and the
Development of Intermolecular Cascade Termination
3.1. The Securinega Alkaloids 136
3.1.1. Introduction 136
3.1.2. History and Biological Importance 137
3.1.3. Recent Syntheses of The Securinega Alkaloids 138
3.1.4. Metallonitrene/Alkyne Cascade Reactions to Streamline
Synthesis 143
3.2. Synthetic Utility of Cyclic Sulfamidates 144
3.2.1. Previous Methods for the Use of 1,2- and 1,3-Cyclic
Sulfamidates 144
3.2.2. Seven-Membered Oxathiazepane Ring-Opening 145
3.3. First Generation Approach Towards (+)-Allonorsecurinine
146
3.3.1. Retrosynthetic Analysis of (+)-Allonorsecurinine 146
3.3.2. Towards the Synthesis of (+)-Allonorsecurinine Through Allyl
Acetal Tethered Alkynyl Sulfamate Ester 37 149
3.4. Intermolecular Metallonitrene/Alkyne Cascade Reaction
Termination 153
3.4.1. Concept and Preliminary Results 153
3.4.2. Retrosynthetic Analysis for (+)-Allosecurinine Through
Intermolecular Cascade Termination 156
3.4.3. Towards the Synthesis of Allosecurinine Through
Intermolecular Cascade Termination 160
3.5. Re-evaluation of Cascade Termination Through Intermolecular
Ylide Fomation/Allyl Migration 168
3.5.1. Examination of Etheral Traps 168
3.5.2. Examination of Alkyne Substitution 169
3.5.3. Utility of Intermolecular Cascade Termination Cyclization
Adducts 171
3.6. Conclusions and Future Directions 178
Experimental Procedures and Compound Characterization 180
References 215
Appendix: Copper-Catalyzed Olefin Aminoacetoxylation
A.1. Background and Previous Studies on Olefin Aminoacetoxylation
219
A.1.1. Introduction and Background 219
A.1.2. Previous Studies Within the Blakey Group 222
A.2. Results and Discussion 225
A.2.1. Intramolecular Olefin Aminoacetoxylation 225
A.3. Conclusions 231
Experimental Procedures and Compound Characterization 232
X-Ray Crystallographic Data 247
References 282
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