Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Miller, Scott

Abstract

Chiral catalysts allow chemists to access enantioenriched materials without the use of proportionate amounts of chiral reagents, while lowering the energy barrier of the original reaction. One way to form bioactive, heteroatom-containing scaffolds asymmetrically is through the use of chiral organocatalysts. This dissertation covers the development of stereoselective reaction methodology to access bioactive scaffolds and mechanistic investigations into intriguing features therein. Chapter 1 describes the development of the asymmetric synthesis of axially chiral quinazolinones. In this project, complementary applications for two different scaffold classes of chiral phosphoric acid (CPA) catalysts are found. We observe that while a C2-symmetric CPA catalyst is most selective for the carbocyclic analog of the reaction, the heterocyclic analog is synthesized with highest selectivity using a phosphothreonine (pThr)-derived catalyst. We delve into mechanistic differences between these two systems and discuss a reactivity- and selectivity-boosting acid additive effect that is only observed in the heterocyclic analog of the reaction. Chapter 2 describes the development of the first catalytic asymmetric synthesis of axially chiral 1,2,4-triazoles. We discuss trends observed in the substrate tolerance of this reaction and demonstrate that recrystallization can allow access to enantiopure products. In parallel, we participated in a collaboration with the Anslyn group (UT Austin) to develop a high-throughput assay to determine the enantiomeric excess (ee) of our axially chiral triazole products via circular dichroism. Chapter 3 describes the development of a heterocyclic scaffold with two stereogenic axes using a common catalyst. We utilize a high-throughput experimentation (HTE) setup to investigate CPA catalysts from two different scaffold classes, as well as possible trends with or without an acid additive. Utilizing a common catalyst and reaction conditions, we demonstrate stereocontrol over two disparate chiral axes that are formed via different reaction mechanisms. Chapter 4 describes the development of a catalytic enantioselective desymmetrization of sulfonimidamides using a cinchona alkaloid-based catalyst. In this multi-group collaboration between the Miller, Toste (UC Berkeley), and Sigman (Univ. of Utah) groups and Genentech, Inc., the reaction was optimized and mechanistically investigated through data science-based modeling, density function theory (DFT) transition state analysis, reaction kinetics, and traditional mechanistic studies. We also demonstrate secondary functionalization of our enantioenriched products to form analogs of known drug candidates.

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