Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Miller, Scott

Abstract

This dissertation outlines our efforts in advancing small-molecule, peptide-based organocatalysts for applications in asymmetric catalysis. The catalytic systems developed span a wide range of reactivities, including transition-metal-catalyzed, Brønsted basic, Brønsted acidic, and Lewis basic transformations. Chapter 1 details the development of an enantioselective copper-catalyzed aromatic Finkelstein reaction, mediated by a guanidinylated peptide ligand for the remote desymmetrization of diarylmethanes (up to 95:5 er). Furthermore, by leveraging the reactivity differences of aryl iodides and aryl bromides in transition-metal catalysis, the resulting enriched aryl iodide products could be chemoselectively modified, allowing access to a diverse library of diarylmethane analogs from a common intermediate. Mechanistic insights were gained from both experimental and computational observations, revealing the significant influence that diarylmethane structure has on the reaction outcome—a discovery with potential implications for future campaigns on this medicinally relevant motif. Chapter 2 describes the development of a protocol for the enantioselective acylation of sulfondiimines, the diaza analog of sulfones, mediated by dimethylaminoalanine (Dmaa)-containing peptides. Through rigorous optimization of both the secondary structure of the peptide catalyst and the reaction parameters, enantioenriched acylated sulfondiimines were able to be accessed in excellent conversions and in high selectivities (up to 95% conversion and 97:3 er). Chapter 3 presents an investigation towards an enantioselective Brønsted-acid-catalyzed oxime formation, mediated by phosphothreonine (pThr)-containing peptide catalysts. The developed protocol furnished desymmetrized 1,3-diones in good yields and selectivities (up to 69% yield and 79:21 er), and these products are envisioned as suitable substrates for a stereospecific Beckmann rearrangement, allowing access to enantioenriched lactams. Chapter 4 outlines the development of an achiral, guanidine-mediated protocol for the catalytic deoxyfluorination of primary and secondary alcohols (up to 69 and 47% yield, respectively). Subsequent incorporation of the guanidine moiety into peptide frameworks would then allow for asymmetric deoxyfluorination investigations to commence. Overall, the work presented herein demonstrates the development and application of peptide-based catalysts across a diverse set of asymmetric transformations— showcasing distinct catalytic strategies to afford enriched medicinally relevant compounds.

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