Access Type
Open Access Dissertation
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.
Recommended Citation
Arbour, Christine, "Harnessing The Reactivity Of The N-Methyl Diaminobenzoyl Linker To Access C-Terminally Modified And Macrocyclic Peptides" (2019). Wayne State University Dissertations. 2141.
https://digitalcommons.wayne.edu/oa_dissertations/2141