The Development and Study of Enantioselective Peptide-Catalyzed Halogenation and Oxidation Reactions

Date of Award

Fall 10-1-2021

Document Type


Degree Name

Doctor of Philosophy (PhD)



First Advisor

Miller, Scott


Inspired by nature’s nonpareil catalysts, enzymes, our lab designs small peptides to catalyze selective transformations. This dissertation describes the catalytic prowess of peptides bearing β-dimethylaminoalanine (Dmaa) or aspartic acid (Asp) to mediate halogenation and oxidation reactions, respectively. The development of novel reactions goes hand in hand with understanding mechanistic nuances of known transformations. Herein, we focus on this synergy as we develop tools to better understand structure-activity relations and implications of reported peptide-catalyzed reactions and apply these lessons to uncover novel reactivity. In particular, we explore the ramifications of subtle structural changes to the substrate and catalyst motifs as well as the importance of conformational dynamics and flexibility. Moreover, the peptide-catalyzed reactions studied herein utilize medicinally-relevant scaffolds as substrates and produce highly enantioenriched compounds bearing point, axial, or helical chirality, which adds to their value. Chapter 1 illuminates the importance and ubiquity of chirality. Though this property is relevant in many contexts, we focus on the significance of chirality in biological systems and the drug development process. Here, we make the case that asymmetric, catalytic methods must continue to be developed to synthesize enantioenriched materials. This sets the stage for our work exploring and creating asymmetric peptide-catalyzed transformations in the remainder of this dissertation. Chapters 2 and 3 focus on different approaches to study the mechanism of the atroposelective bromination of arylquinazolinones. Optimization of this reaction revealed that subtle changes to the primary and secondary structure of the Dmaa-containing peptide catalysts resulted in large effects on selectivity. Chapter 2 shares our collaboration with the Sigman Lab at the University of Utah in which we created a streamline method to compute stereoelectronic descriptors of the tetrapeptides. Using these parameters, we produced models containing features of the catalyst that most contribute to the enantioselectivity outcome of this reaction. Our strategy can be used to predict the performance of unexplored catalysts in this reaction, or to facilitate the development of entirely new transformations. The work in Chapter 3 was performed with the Baker Lab at the University of Washington. This mechanistic study of the atroposelective bromination of arylquinazolinones is centered on assessing the importance of catalyst secondary structure and flexibility. In this chapter, we describe the computational design, synthesis, and evaluation of cyclic peptides. Two of these peptides adopt the major conformations observed for the lead catalyst for this reaction. A third macrocyclic peptide was developed that is conformationally flexible and capable of sampling both conformers. This experimental and computational work highlights the importance of catalyst structure dynamics in this reaction and likely other peptide-mediated transformations. Furthermore, we are reminded that peptides act in a manner perhaps more similar to enzymes than traditional small-molecule catalysts. Chapter 4 provides a bridge, and a brief detour, between mechanistic interrogation and method development. Eager to apply our new insight and techniques, we began to optimize a novel atroposelective bromination reaction using medicinally-relevant imidazole-containing substrates. In pursuit of a more favorable substrate, we serendipitously synthesized one of the most twisted amides reported. This chapter provides a detailed characterization of the highly twisted N-acyl imidazoles synthesized. Moreover, we disclose studies regarding the reactivity of these compounds, such as the twist amide stability and their ability to serve as acyl transfer reagents. A complete story in the process of developing a novel peptide-catalyzed reaction is told in Chapter 5. Herein, we employ Asp-embedded peptides to mediate the asymmetric N-oxidation of loratadine (Claritin). The lead catalyst for this transformation must not only wrestle with issues of chemoselectivity, choosing to deliver an O-atom to the pyridine nitrogen rather than the neighboring olefin, but also produce the resulting helically chiral N-oxide in high enantioselectivity. We demonstrate the success of this reaction across a handful of substrates with our best cases providing >99:1 er and complete chemoselectivity for the N-oxide. The thread of flexibility and dynamics is woven into this chapter too, as we computationally and experimentally explore (i) how chirality arises in the product, (ii) the enantiomeric stability of these N-oxides, and (iii) the role of conformational dynamics in the antihistamine activity of loratadine and our analogues. Lastly, we provide preliminary findings regarding a related asymmetric pyridine N-oxidation reaction using Asp-containing peptides to produce atropisomers, which could serve as asymmetric catalysts themselves to mediate allylation reactions. Overall, the work in this dissertation aspires to inform and inspire the creation and understanding of new asymmetric reactions that rely on small peptides to solve big challenges in selectivity.

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