Date of Award

Spring 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Miller, Scott

Abstract

This dissertation describes our studies on the development of tetramethylguanidine (TMG)-based peptides as a new class of Brønsted basic catalysts and their application to challenging atroposelective reactions. The enhanced basicity of these peptides has enabled us to access novel reactivity to synthesize scaffolds of interest containing one or more stereogenic axes with high levels of catalyst control.Chapter 1 serves as an introduction to the concept of chirality, with a focus on its connection to the functional role of natural and synthetic molecules. An important subset of chirality is atropisomerism, which arises from restricted bond rotation most commonly between sp2–sp2 atoms. Atropisomerism is a critical consideration to drug development and we describe strategies prepare axially chiral biaryls. We also discuss the inspirations behind applying miniaturized peptides as catalysts in diverse asymmetric transformations. Chapter 2 outlines our motivations to pursue the novel class of TMG-based peptides, and our development of a modular synthetic route to build a library of these catalysts. We also highlight the properties of guanidines responsible for their reactivity, seminal work in the area of asymmetric guanidine catalysis, and challenges to address in the field. Chapter 3 discusses our development of an atroposelective ring-opening of biaryl lactones catalyzed by our new tetramethylguanidylalanine (Tmga) peptides. Optimization of this system revealed critical insights on the impact of solvent effects on pKa magnitudes and inhibition of reversible reaction pathways. We were able to design a Tmga peptide catalyst that could catalyze the ring-opening of buttressed lactones in up to 93:7 er. Chapter 4 details our studies on the catalyst-controlled synthesis of two-axis terphenyl atropisomers. The chemistry proceeds through a sequence of two distinct dynamic kinetic resolutions: first, an atroposelective ring opening of Bringmann-type lactones installs a first-axis while “turning on” the second step, stereoselective arene halogenation, which delivers the two-axis product. Notably, the TMG-based peptide enabled the first reported efficient atroposelective chlorination. In addition, a complementary bromination was established through chiral anion phase transfer catalysis by C2-symmetric phosphoric acids. These studies were done in collaboration with the Toste Group at UC Berkeley, and we established the fully catalyst-controlled stereodivergent synthesis of all possible chlorinated and brominated diastereomers with significant levels of enantioselectivity. Chapter 5 presents a novel atroposelective cyclization strategy to prepare axially chiral N-aryl maleimides and similar scaffolds. To date, a catalytic ring-closure to atropisomeric imides remains unreported, and previous approaches are limited to desymmetrizations. This reaction is catalyzed by Brønsted basic Tmga peptides, and we found that other catalyst types were not sufficiently reactive to deliver the product. In our studies, we observed a striking enantiodivergency that occurs by simple modulation of the substitution pattern on the D-proline residue. Accordingly, we present the full optimization of peptide catalysts, most recent results, and preliminary mechanistic insights on the reaction process. Ultimately, the studies presented herein unveil a new class of guanidinylated peptide catalysts which are significantly more basic than our group’s previously reported tertiary amine containing peptides. These TMG peptides can enable challenging reactivity with high levels of stereoselectivity and catalyst control, and we outline new strategies for the stereodivergent syntheses of multi-axis and imide-based atropisomer scaffolds.

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