Date of Award

2025

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Chemistry

Department

Chemistry

First Advisor

Fang Wang

Abstract

Functional group conversion is a cornerstone of small-molecule organic synthesis. It has been widely applied to organic reactions to access a variety of complicated structures that are otherwise inaccessible. Despite its widespread use in the small molecule chemical space, it has seldom been applied to biomolecules such as peptides and proteins. Many of the established methods for the modification of proteins and peptides are limited to simple addition reactions rather than direct functional group conversion.

The lack of reaction variety for biological targets is largely due to synthetic challenges present in such substrates. Out of the 20 canonical amino acids, 14 are potentially nucleophilic. As a result, protein and peptides frequently contain multiple reactive sites with different nucleophiles, which can participate in undesired reactions, introducing site- and chemoselectivity issues. More importantly, there are no canonical amino acid side chains that possess electrophilic character, limiting the design of new reactions to electrophiles that are compatible with naturally occurring nucleophiles.

To address the limited available toolkit for biomolecular modification, we developed a unique method for directly converting the nucleophilic side chain thiol of cysteine residues in unprotected peptides to electrophilic alkyl iodides under mild conditions. By following a three-step, one-pot protocol, we were able to introduce an electrophilic moiety capable of undergoing further reactions, including transition metal-mediated coupling reactions. We expect the inclusion of one the most ubiquitous synthetic precursors into the biomolecular chemical space will enable the molecular editing of biomolecules.

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Available for download on Tuesday, September 07, 2027

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