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Access Type

WSU Access

Date of Award

1-1-2011

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

DAVID CRICH

Abstract

This dissertation describes investigations toward the development of a new chemistry for the block synthesis of peptides and peptidyl thioesters. A direct approach for the Fmoc-SPPS of peptidyl thioesters is also delineated in this thesis.

In the first part of chapter one, the difficulty and importance of chemical synthesis of peptides is explained, and a brief survey of available methods is given. The second part of chapter one presents the challenges inherent in the synthesis of peptidyl thioesters by Fmoc-SPPS.

The second chapter outlines the investigations conducted towards the development of a new chemistry for epimerization-free block synthesis of peptides from thioacids and amines by a process involving the in situ formation of highly active thioesters by nucleophilic aromatic substitution of C-terminal thioacids on electron-deficient halogenoarenes. The superiority of this new chemistry over available methods is illustrated through direct comparisons in the block synthesis of an octapeptide.

In chapter three, studies carried out to probe the reactivity of N-terminal sulfonamides towards peptidyl thioacids are presented. Studies directed at determining the optimal sulfonamide for use in convergent multiple peptide fragment ligation are presented as is the application of these sulfonamides in both left to right and right to left block synthesis of peptides.. Model studies on the development of an intramolecular variant of the thioacid/sulfonamide coupling are also presented in this chapter.

Continuing the theme, Chapter 4 presents studies undertaken with the goal of developing a direct method for the efficient synthesis of peptidyl thioesters by the widely used Fmoc-SPPS chemistry. A method to construct the thioester functionality from thioamides is described based on alkylation to give an intermediate thioimide and its subsequent hydrolysis. The application of this methodology to the synthesis of functionality diverse oligo-peptide thioesters is also presented.

In chapter five, the overall conclusions of the dissertation are presented, while in chapter six, the experimental procedures and characterization data for the synthesized compounds are documented.