Date of Award

12-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Committee Chair/Advisor

Dr Byoungmoo Kim

Committee Member

Dr Daniel C. Whitehead

Committee Member

Dr Rhett C. Smith

Committee Member

Dr William Pennington

Abstract

Alcohols represent an important class of functional group in organic synthesis and medicinal chemistry, given that they are structurally diverse and prevalent in many natural products, biomolecules and renewable feedstocks. As such, they are highly attractive precursors for building-block synthesis, late-stage functionalization, and numerous synthetic transformations. However, existing strategies for the deoxygenative diversification of alcohols operate under constrained conditions, often leading to competing pathways (such as elimination), poor stereospecificity, low efficiencies, and limited substrate compatibility. To address these challenges, we have developed a conceptually novel use of sulfonyl fluorides as bifunctional reagents for the one-step deoxygenative diversification of complex alcohol libraries.

Our initial design features a cascade diversification of alcohols with silylated nucleophiles via a Sulfur(VI) Fluoride Exchange (SuFEx) reaction. This pioneering technique addresses the limitations of existing deoxy-functionalization strategies by providing a robust, operationally simple, and versatile method for the seamless diversification of natural products and biomolecules via their embedded alcohol handles to generate diversified analogs featuring highly desirable bond connections such as C−C, C−N, and C−X (where X = Cl or Br).

Mechanistic studies provided valuable insights that allowed us to expand the transformation beyond silylated nucleophiles, enabling the SuFEx-mediated direct alkylation of amines with alcohols. The robustness of the amine alkylation method was demonstrated through an expansive substrate scope, where alcohols derived from libraries of complex natural products and biomolecules were successfully coupled with amines that are commonly found in drug molecules and bioactive compounds. The simplicity and efficiency of the protocol addressed critical limitations of traditional amination methods, such as over-alkylation, poor stereospecificity, and reliance on toxic metal catalysts.

Overall, the SuFEx-enabled deoxygenative diversification methodologies described herein offer innovative protocols for the sustainable diversification of complex alcohols with high functional group tolerance and stereospecificity, thus opening new avenues for research and application in medicinal chemistry campaigns and beyond.

Author ORCID Identifier

https://orcid.org/0000-0002-4574-9598

Available for download on Wednesday, December 31, 2025

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