Peptide-Mediated Asymmetric Cross-Coupling and Related Studies [electronic resource].

9781088382561

Ann Arbor : ProQuest Dissertations & Theses, 2019.

1 online resource (474 p.)

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Herein we report the development of multifunctional guanidinylated peptide ligands and their application in asymmetric copper catalyzed cross-coupling. Initial studies described in Chapter 2 focus on the desymmetrization of a symmetric diarylmethine scaffold which contains enantiotopic aryl bromides that are three bonds removed from the prochiral center. High levels of enantioinduction and good yields were achieved using several malonate nucleophiles (up to 93:7 er and 76% yield). Mechanistic studies suggest the peptide acts as a bifunctional ligand, wherein the C-terminal carboxylate interacts with the substrate through a bridged Cs ion. Chapter 3 expands upon these studies and describes the first asymmetric intermolecular metal catalyzed C–O cross-coupling reaction. Among these phenols, a range of both electronic and steric perturbations were tolerated and provided the desired diaryl ether in good yield (up to 68% yield and 99:1 er). In addition, reasonable chemoselectivity was demonstrated for phenols with multiple nucleophilic functional groups.Chapter 4 discusses efforts towards achieving the site-selective arylation of tyrosine containing peptides by using aspartic acid as a directing group. As a proxy for peptides containing four tyrosine residues, optimization efforts were conducted as a series of competition studies performed using four tetrapeptides, which compete for a limited amount of aryl halide. These results were then successfully applied in peptides containing multiple tyrosine residues.

Dissertations & Theses @ Yale University.

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English

January 17, 2020

Thesis (Ph.D.)--Yale University, 2019.

Yale University. Chemistry.