Radical Conjugate Addition of N-Heterocycles and Tertiary Amines Public

Abstract

The direct addition of pyridine and diazine units to electron-poor alkenes has been achieved via a redox radical mechanism that is enabled by limiting the effective concentration of the hydrogen-atom source. The described method is tolerant of acidic functional groups and is generally applicable to the union of a wide range of Michael acceptors and 6-membered heterocyclic halides. This technology was advanced to the preparation of a β-heteroaryl α-amino acids by the union of heteroaryl radicals with protected dehydroalanine derivatives. This process was conducted with good efficiency on large scale, the application of these conditions to amino ketone synthesis is shown, and a simple protocol is given for enantioenriched amino acid synthesis from a number of radical precursors. Replacement of terminal reductant, Hantzsch ester, with trialkylamines revealed an unexpected reactive pathway: α-amino radical conjugate addition to dehydroalanine via a C–H functionalization mechanism. This protocol, driven by visible light, is highly chemoselective, redox- and proton-neutral, and effectively activates highly complex amine structures for coupling with a range of Dha substrates to furnish unnatural amino acids and peptide conjugates. This mechanistic manifold was advanced to the cyclobutylation of aniline derivatives by the direct addition to electrophilic strain-activated bicyclobutanes. 

Table of Contents

Chapter 1. Introduction to photoredox catalysis. 1

1.1 Photoredox Catalysis in the Context of Radical Chemistry. 2

1.2 Photoredox Catalysis. 2

1.3 Probing Photoredox Mechanism.. 7

1.4 Synthetic Utility of Photoredox Catalysis. 9

Chapter 2. A mild catalytic system for radical conjug-ate addition of nitrogen heterocycles. 11

2.1 Abstract. 12

2.2 Introduction. 12

2.3 Results and discussion. 16

2.4 Conclusions. 23

2.5 Experimental Information. 24

Chapter 3. A practical and scalable system for hetero-aryl amino acid synthesis. 68

3.1 Abstract. 69

3.2 Introduction. 69

3.3 Results and discussion. 72

3.4 Conclusions. 81

3.5 Experimental Information. 82

Chapter 4. Aminoalkyl Radicals as Powerful Intermed-iates for the Synthesis of Unnatural Amino Acids and Peptides. 165

4.1 Abstract. 166

4.2 Introduction. 166

4.3 Results and discussion. 170

4.4 Conclusion. 175

4.5 Experimental Information. 176

Chapter 5. Radical α-C‒H Cyclobutylation of Aniline Derivities 235

5.1 Abstract. 236

5.2 Introduction. 236

5.3 Results and discussion. 239

5.4 Conclusion. 243

5.5 Experimental Information. 245

Appendix. Site-selective modification of jessenipeptin via Alpha-amino radical conjugate addition.. 269

A-I Introduction. 270

A-II Results and Discussion. 274

A-III Conclusion. 275

A-IV Experimental Information. 276

About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Mot-clé	peptide radical photoredox amino acid conjugate addition antibiotic
Committee Chair / Thesis Advisor	Nathan Jui, Emory University
Committee Members	Lanny Liebeskind, Emory University Simon Blakey, Emory University

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