Mild Amide and Peptide Constructions by the Condensation of O-Silylthionoesters with Amines and Metal Mediated Cross-Coupling Reactions for Carbon-Carbon Bond Formation Open Access

Abstract

A novel, pH-neutral method for in situ activation of thiol acids for room-temperature amide and peptide bonds construction is described. The unique carboxyl activation relies upon the known spontaneous formation of O-silylthionoesters from their S-silylthiol ester by a tautomerization of the triorganosilicon group from sulfur to oxygen. O-silylthionoesters were in situ generated from a trimethylsilylation protocol using bistrimethylsilylacetamide (BSA) and thiol acids. The efficient reaction of O-silylthionoesters with amines to generate amide rather than thioamide linkages and peptides with stereoretention is unknown.

The syntheses and characterization of the new dicopper(I) 2,6-dihydroxybenzoate complexes are reported. The reactivity of copper(I) 2,6-dihydroxybenzoate (CuDHB) showed mild improvement over CuTC, CuMeSal and CuDPP in cross-coupling reactions. CuDHB mediated Suzuki cross-coupling reaction under pH-neutral and mild condition has been explored. This CuDHB mediated coupling of vinyliodides with vinylboronic acids and arylboronic acids with ortho coordination groups gives 1,3-dienes and aryl-alkenes in moderate to good yields.

A novel system modeled from a biochemical process of metallothioneins (MT-mimic) was developed for the construction of C-C bonds through Pd-catalyzed desulfitative cross-coupling reaction. Peptidyl thiol esters bearing MT-mimic pendant reacted with a variety of boronic acids to produce peptidyl ketones in good to excellent yields with complete retention of configuration under palladium catalyzed desulfitative conditions. The application of the desulfitative reaction was also extended to thiol ethers. Thiol ethers with O-acetyl oxime pendant coupled with boronic acids to generate heteroaryls and biaryls under Pd-catalyzed cross-coupling condition.

Table of Contents

Chapter 1.

In Situ Carboxyl Activation Using a Silatropic Switch: A New Approach to Amide and Peptide Constructions........ 1

1.1 Introduction and Background....................................................................................... 2

1.1.1 Brief History of Peptides Synthesis....................................................................... 2

1.1.2 Amide and Peptide Generation from Thiol Acids................................................. 6

1.2 Results and Discussion............................................................................................... 10

1.2.1 Preliminary Study................................................................................................ 10

1.2.2 BSA Mediated Simple Amide Formation............................................................ 14

1.2.3 BSA Mediated Peptides Formation..................................................................... 17

1.3 Conclusion.................................................................................................................. 25

1.4 Experimental............................................................................................................... 25

1.4.1 General Experimental.......................................................................................... 25

1.4.2 Starting Materials................................................................................................. 26

1.5 Reference.................................................................................................................... 58

Chapter 2.

Structural Characterization of Dicopper(I) 2,6-dihydroxybenzoate (CuDHB) Complexes and CuDHB-Mediated Suzuki Cross-Coupling Reaction......................... 63

2.1 Introduction and Background..................................................................................... 64

2.1.1 Copper Carboxylate Mediated Stille Cross-Coupling Reaction......................... 64

2.1.2 Structure of Copper Carboxylate Complexes...................................................... 68

2.2 Results and Discussion............................................................................................... 69

2.2.1 Synthesis of CuDHB and Structure of CuDHB Complexes................................ 69

2.2.2 The Reactivity of CuDHB and CuDHB Mediated Suzuki Cross-Coupling Reaction....................................................................................................................................... 75

2.3 Conclusion.................................................................................................................. 81

2.4 Experimental............................................................................................................... 82

2.4.1 General Experimental.......................................................................................... 82

2.4.2 Starting Material.................................................................................................. 82

2.5 Reference.................................................................................................................. 131

Chapter 3.

Palladium-Catalyzed Desulfitative Cross-Coupling Reactions of Peptidyl Thiol Esters and Thiol Ethers with Boronic Acids................................................................................... 135

3.1 Introduction and Background................................................................................... 136

3.1.1 History of Desulfitative Cross-Coupling Reaction........................................... 136

3.1.2 Synthesis of High Enantiopurity N-Protected α-Amino Ketones..................... 142

3.2 Results and Discussion............................................................................................. 145

3.2.1 Pd-Catalyzed MT-mimic Cross-Coupling of Peptidyl Thiol Esters with Boronic Acids............................................................................................................................ 145

3.2.2 Pd-Catalyzed MT-mimic Desulfitative Cross-Coupling of Heteroaromatic Thiol Ethers........................................................................................................................... 154

3.2.3 Pd-Catalyzed MT-mimic Desulfitative Cross-Coupling of Simple Aromatic Thiol Ethers........................................................................................................................... 160

3.2.4 Control Experiments and Mechanistic Hypothesis for Thiol Ether Cross-Coupling..................................................................................................................................... 162

3.3 Conclusion................................................................................................................ 166

3.4 Experimental............................................................................................................. 167

3.4.1 General Experimental........................................................................................ 167

3.4.2 Starting Materials............................................................................................... 167

3.5 Reference.................................................................................................................. 220

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School	Laney Graduate School
Department	Chemistry
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Keyword	amides/peptides O-silylthionoester peptidyl ketones palladium cross-coupling reaction
Committee Chair / Thesis Advisor	Liebeskind, Lanny S, Emory University
Committee Members	McDonald, Frank, Emory University Blakey, Simon, Emory University

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