Metallonitrene/Alkyne Cascade Reactions: Development of a Versatile Process for Organic Synthesis Open Access

Thornton, Aaron Robert (2010)

Permanent URL:


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

About this Dissertation

Rights statement
  • Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.
  • English
Research field
Committee Chair / Thesis Advisor
Committee Members
Last modified

Primary PDF

Supplemental Files