Intercepting Photochemically Generated Aminoalkyl and Aryl Radical Intermediates to Access Complexity Quickly Open Access

Pratt, Cameron (Summer 2021)

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By using radicals generated by photoredox catalysts, three carbon to carbon bond forming reactions have been developed. These methods are robust and operate under mild conditions. The first method showcases a simple and scalable approach to synthesizing a large range of unnatural amino acids which could modulate cell permeability and in vivo stability. A key discovery in this process was the significant effect amine loading had on restricting product formation to the desired mono-functionalized products. This method was also shown to work in increasingly complex amines including on the active ingredient of cough medicine: dextromethorphan. Using a similar redox neutral mechanistic pathway, the second method showcases a unique way to install cyclobutanes on a carbon alpha to the nitrogen in tertiary anilines. These cyclobutanes, which are often difficult to install, can act as phenyl ring isosteres. In this case, a breakthrough was made with the electrophilic strain- releasing coupling partner. It was found that electron poor rings in the phenyl sulfone led to the desired reactivity. The final chapter highlights how spirocyclic compounds can be formed via a radical hydroarylation pathway that is a metal-free alternative to existing radical methods. Access to these types of scaffolds is already valuable thanks to their presence in a wide selection of biologically relevant molecules. Overcoming the need for a metal photoredox catalyst was achieved by using a cyanoarene catalyst.

Table of Contents

Light: A Historic Reagent 1 

Light and Life 2

Brief History of Photochemistry 3

Introduction to Photoredox Catalysis 5

Photoredox Catalysis for Synthesis 8

Chapter One References 9

Synthesis of Unnatural Amino Acids and Peptides using Aminoalkyl Radicals 11

Introduction 12

Results and Discussion 14

Conclusion 21

Supporting Information 21

Chapter Two References 74

Radical α (alpha) C‒H Cyclobutylation of Aniline Derivatives 77 

Introduction 78

Results and Discussion 79

Conclusion 83

Supporting Information 84

Chapter Three References 104

Synthesis of Spirocyclic Piperidines by Radical Hydroarylation 107

Introduction 108

Results and Discussion 111

Conclusion 114

Supporting Information 114

Chapter Three References 135

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