Date of Award
Fall 2025
Language
English
Embargo Period
12-17-2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
College/School/Department
Department of Chemistry
Program
Chemistry
First Advisor
Qiang Zhang
Committee Members
Pan Li, Maksim Royzen, Alexander Shekhtman, Ting Wang, Qiang Zhang
Keywords
Peptide chemistry, Transition Metal catalysis
Subject Categories
Life Sciences
Abstract
This dissertation explores two intersecting themes in modern chemical biology: (1) the design of novel ligands for transition-metal catalysis, and (2) the development of thiolactone-mediated strategies for protein synthesis and modification in aqueous media. Together, these studies advance chemical methods for precise molecular transformations under mild, biocompatible conditions.
In the first chapter, a geometrically constrained bicyclic [3.3.1] sulfoxide framework was developed as a new class of bissulfoxide ligands for palladium-catalyzed C–H functionalization. The ligand was synthesized concisely from thiophenol through a three-step sequence and shown to promote allylic C–H amination and alkylation reactions with high efficiency. The catalytic system tolerated diverse nucleophiles, including nitrogen- and carbon-based donors, and demonstrated broad functional-group compatibility. Mechanistic analysis suggested that the unique geometry of the [3.3.1] scaffold and hydrogen bonding between the sulfoxide and nucleophile synergistically facilitate metal activation and turnover. As a proof of concept, the methodology enabled a concise four-step synthesis of the antifungal drug Naftifine. The modular architecture of this ligand framework also offers potential for future incorporation of oligopeptide motifs, bridging organometallic catalysis with biomolecular design.
The second chapter focuses on expanding the scope of native chemical ligation (NCL) through thiolactone chemistry. A β-thiolactone-based activation strategy was developed to form native amide bonds directly from unfunctionalized peptide C-termini in water, bypassing the need for pre-installed thioesters or external thiol additives. Using isonitrile-mediated intramolecular activation, this method enabled efficient peptide segment condensation and iterative elongation cycles under mild aqueous conditions. The approach was further extended to cysteine-free ligations via β-thiolated amino acids and N-thiol auxiliaries, and applied to side-chain cyclization of the protein kinase inhibitor peptide IP20 to yield a conformationally constrained variant. Mechanistic and kinetic studies elucidated key structural determinants governing thiolactone formation, including the position of cysteine residues and the influence of terminal amino acids.
Finally, in chapter 3, the iterative thiolactone-mediated ligation platform was demonstrated through the total synthesis and oxidative folding of short neurotoxin 1 (SNT1), a 61-residue three-finger toxin, entirely in aqueous phase. Building on this foundation, future efforts will focus on incorporating sulfur handles or thioauxiliary motifs onto small-molecule and peptide modifiers—such as glycans, lipids, and monoamine donors—to enable chemoselective installation of post-translational-modification-like moieties under mild aqueous conditions.
Collectively, this work introduces a unified framework that integrates organometallic ligand design and peptide chemistry, offering versatile tools for C–H activation, bioconjugation, and protein synthesis in water. The methodologies developed herein expand the synthetic accessibility of both small-molecule catalysts and cysteine-rich proteins, contributing to the convergence of synthetic organic chemistry and chemical biology.
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Wen, Yuming, "Sulfur Chemistry for Protein Synthesis and Modification: From Thiolactone to Bicyclic Sulfoxide Frameworks" (2025). Electronic Theses & Dissertations (2024 - present). 348.
https://scholarsarchive.library.albany.edu/etd/348