Date of Award

Spring 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Miller, Scott

Abstract

Herein we report the 1) chirality-matched catalyst-enabled macrocyclization reactions and 2) site-selective arylation of tyrosine residues in short peptides, both via copper-catalyzed Ullmann coupling. Through the works presented herein, this dissertation explores key considerations in achieving site- and stereo-selective transformations by levereging non-covalent interactions. Chapter 1 provides an introduction to peptide-based catalysis and their utility in various desymmetrization reactions reported by the Miller group. We focus on desymmetrization of symmetrical diarylmethanes, and make a case that these rather simple scaffolds provide a powerful platform to interrogate distal, non-covalent interactions in asymmetric transformations. Examples employing transition-metal catalysis are surveyed in detail. This chapter provides a framework for how works described in Chapters 2, 3 and 4 were conceived from prior studies on enantioselective cross-coupling of diarylmethanes using copper/peptidyl complexes. Chapter 2 details an aspartic-acid directed, site-selective arylation of tyrosine residues in short di-tyrosine containing peptides via copper-catalyzed Ullmann coupling. We show that a canonical aspartic acid residue can be employed as a native directing motif to direct the site of O-arylation to a proximal over a distal tyrosine residue. High-throughput screening and intermolecular competition experiments of simple tetrapeptides were utilized for efficient reaction optimization. While good levels of site-selectivities are reported for a number of cases, we discuss both strengths and limitations of our approach. In Chapter 3, we describe a unique case of matched and mismatched effects between chiral ligands and substrates that proves decisive in macrocyclization reactions. We show that the chirality of the catalyst is essential for promoting favorable, matched transition-state relationships that favor macrocyclization of diarylmethanes with pre-existing stereogenic elements. Curiously, the chirality of the catalyst is essential for successful reactions, even though no new static stereogenic elements are created. Control experiments involving either achiral variants of the catalyst or the enantiomeric, “mismatched” form of the catalyst fail to deliver the macrocycles in significant quantity. Finally, Chapter 4 details our preliminary efforts to build on the lessons learned from Chapter 3 with a focus on diastereospecific macrocyclization of β-turn peptides. Syntheses of linear precursors bearing an aryl halide and a nucleophile are outlined. Facile cyclization via intramolecular coupling is observed without the aid of an exogenous ligand. Results from initial studies and future directions are discussed.

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