Access Type

Dissertation/Thesis

Date of Award

January 2019

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

Jennifer L. Stockdill

Abstract

This thesis describes the exploration of accessing C-terminally modified and macrocyclic peptides through N-acyl urea (MeNbz) displacement. Prior to this work, the diaminobenzoyl linker was used to access thioesters for native chemical ligation. Only solution-phase displacement of the N-acyl urea with thiol nucleophiles was previously reported.

The N-Me-diaminobenzoyl (MeDbz) linker was initially used to access C-terminal glycine esters, amides, and acids from a single peptide substrate. This led to the total synthesis of Conopressin G and two analogs. The propensity of the C-terminal cysteine residue to undergo epimerization was investigated using this strategy. After optimization, C-terminal cysteine esters, amides, and acids were prepared with no detectible epimerization. This strategy was used toward the total synthesis of alpha-Conotoxin ImI. In addition, amino acids were used as nucleophiles to elongate the C terminus of the peptide, circumventing tedious solid-phase peptide syntheses. Lastly, an on-resin, self-cleaving macrocyclization strategy using an N-terminal cysteine was demonstrated to access conformationally constrained macrocyclic peptides.

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