Reductive Processes Enabled by Photoredox for the Synthesis and Modification of Pharmaceutically Relevant Molecules Open Access

Abstract

The generation and use of open shell species (radicals) has broadened reactivity and enabled novel disconnections repeatedly throughout history—often displaying orthogonal selectivity to their polar counterparts. Photoredox presents an ideal platform for studying and using these species as radicals can be generated in a catalytically and controlled fashion. Abstraction and radical chain mechanisms are rapid and uncontrolled and often limit the utility of the species being generated. Our group focuses on generating radical species via substrate reduction. Single electron transfer from a catalyst to the substrate results in a buildup of charge that then drives heterolytic cleavage of even strong bonds. A number of methods, including our own, utilize halogenated species for this reason; the weaker C–X bond allows for regiospecific cleavage and radical formation on a programmed atom upon halide expulsion.

We’ve developed a number of methods that focus on novel formation and reactivity of radicals. Detailed in Chapter 2 is the radical conjugate addition of heteroaryl radicals to an amino acid backbone for the practical and scalable synthesis of enantiopure unnatural amino acids. We later expanded the applicability of these radical additions to include neutral and rich olefins—uncovering along the way, important mechanistic principles that dictate the reactivity of heteroaryl radicals. Notably, we’ve also found that, under highly reducing photoredox conditions, that breaking and restoring aromaticity through the reduction of arenes, is a driving force strong enough to break benzylic C–F bonds. We’ve taken advantage of this cleavage mechanism to optimize conditions for alkylating trifluoromethyl aromatics—again through alkene addition. Lastly, we’ve explored these same conditions as a viable method for mineralizing (defluorinating) perfluorinated waste materials. 

Table of Contents

CHAPTER 1 INTRODUCTION TO PHOTOREDOX ................................. 1 1.1

DRIVING CHEMICAL REACTIONS WITH LIGHT ....................................................................... 2 1.2

PHOTOREDOX CATALYSIS .....................................................................................................3

1.2.1 Mechanisms of Catalysis.......................................................................................3

1.2.2 Catalyst Structures................................................................................................5 1.2.3

The Photoredox Regime........................................................................................9

CHAPTER 2 A PRACTICAL AND SCALABLE SYSTEM FOR HETEROARYL AMINO ACID SYNTHESIS ............................................. 11

2.1 INTRODUCTION....................................................................................................................12

2.2 RESULTS AND DISCUSSION..................................................................................................15

2.3 CONCLUSIONS ..................................................................................................................... 22

2.4 SUPPORTING INFORMATION.................................................................................................23

2.4.1 General Information ...........................................................................................23

2.4.2 General Procedure..............................................................................................24

2.4.3 Optimization Details...........................................................................................25

2.4.4 Preparation of Starting Materials ......................................................................28

2.4.5 Procedures and Characterization Data..............................................................45

2.4.6 Deprotection Procedures and Characterization Data........................................78

2.4.7 Chiral HPLC Data..............................................................................................84

2.4.8 Stern Volmer Fluorescence Quenching Experiments .........................................86

2.4.9 Deuterium Incorporation Studies .......................................................................88

CHAPTER 3 : RADICAL HYDROARYLATION OF FUNCTIONALIZED OLEFINS AND MECHANISTIC INVESTIGATION OF PHOTOCATALYTIC PYRIDYL RADICAL REACTIONS............... 89

3.1 INTRODUCTION....................................................................................................................90

3.2 RESULTS AND DISCUSSION..................................................................................................93

3.2.1 Radical Hydroarylation of Olefinic Substrates...................................................93

3.2.2 Mechanistic Investigation...................................................................................99

3.3 CONCLUSIONS ................................................................................................................... 109

3.4 SUPPORTING INFORMATION...............................................................................................110

3.4.1 General Information .........................................................................................110

3.4.2 General Procedures ..........................................................................................111

3.4.3 Optimization Table............................................................................................113

3.4.4 Preparation of Starting Materials ....................................................................115

3.4.5 Procedures and Characterization Data............................................................121

3.4.6 Scale-up Procedures.........................................................................................155

3.4.7 Mechanistic Investigation.................................................................................157

3.4.8 Computational Details......................................................................................177

3.4.9 Troubleshooting and Reaction Limitations.......................................................191

CHAPTER 4 : SELECTIVE C–F FUNCTIONALIZATION OF UNACTIVATED TRIFLUOROMETHYLARENES................................. 194

4.1 INTRODUCTION..................................................................................................................195

4.1.1 A Different Mode of Activation.........................................................................195

4.1.2 Modification of Trifluoromethylaromatics .......................................................196

4.2 RESULTS AND DISCUSSION................................................................................................200

4.3 CONCLUSIONS ................................................................................................................... 211

4.4 SUPPORTING INFORMATION...............................................................................................212

4.4.1 General Information .........................................................................................212

4.4.2 General Procedures..........................................................................................213

4.4.3 Optimization Details.........................................................................................215

4.4.4 Preparation of Trifluoromethylarenes..............................................................219

4.4.5 Procedures and Characterization Data............................................................231

4.4.6 Computational Details......................................................................................281

4.4.7 Fluorescence Quenching and Stern-Volmer Plots............................................285

CHAPTER 5 : REDUCTIVE MINERALIZATION OF PERFLUOROALKYL SUBSTANCES USING VISIBLE LIGHT .......... 289

5.1 INTRODUCTION..................................................................................................................290

5.2 RESULTS AND DISCUSSION................................................................................................293

5.3 CONCLUSIONS ................................................................................................................... 295

5.4 SUPPORTING INFORMATION...............................................................................................296

5.4.1 General Information .........................................................................................296

5.4.2 General Analytical Information........................................................................296

5.4.3 Procedures and Characterization Data............................................................296 

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School	Laney Graduate School
Department	Chemistry
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Keyword	Defluorination Hydroarylation PFOA Trifluoromethylarenes
Committee Chair / Thesis Advisor	Jui, Nathan, Emory University
Committee Members	Liotta, Dennis, Emory University Blakey, Simon, Emory University

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