Type of Document Dissertation Author Makley, Dawn Marie URN etd-11182012-215928 Title Umpolung amide synthesis: applications in enantioselective peptide synthesis Degree PhD Department Chemistry Advisory Committee
Advisor Name Title Dr. Jeffrey N. Johnston Committee Chair Dr. Carmello J. Rizzo Committee Member Dr. David W. Wright Committee Member Dr. Richard J. Armstrong Committee Member Keywords
- silyl imines
- n-halo amines
- natural product synthesis
- peptide synthesis
- amide synthesis
- methodology development
- umpolung amide synthesis
Date of Defense 2012-10-25 Availability unrestricted AbstractUMPOLUNG AMIDE SYNTHESIS: APPLICATIONS IN ENANTIOSELECTIVE PEPTIDE SYNTHESIS
DAWN M. MAKLEY
Dissertation under the direction of Professor Jeffrey N. Johnston
The development and application of the novel Umpolung Amide Synthesis (UmAS) reaction will be presented in this thesis. In this coupling reaction, á-bromo nitroalkanes are used as nucleophilic carbonyl surrogates, reacting with electrophilically activated amines to form the desired amide bond. Notably, the polarities of these two reactants are reversed (umpolung) from those seen in traditional amide coupling. In addition to being mechanistically interesting, the fact that the carbonyl surrogate is nucleophilic, as opposed to electrophilic, in nature mechanistically prevents epimerization at the á-carbon, an unsolved problem in traditional amide coupling.
The development of an efficient synthesis of chiral á-bromo nitroamines through the novel chiral proton-catalyzed enantioselective aza-Henry addition of bromonitromethane to N-silyl imines will also be presented. This methodology allows access to a wide range of N-protected non-natural amino acid surrogates, including highly epimerization-prone aryl glycine residues. By utilizing this reaction in combination with Umpolung Amide Synthesis (UmAS), arylglycine residues are synthesized and incorporated into peptides in a highly stereocontrolled manner. The utility of this methodology is demonstrated through efforts towards an enantioselective synthesis of the arylglycine-rich natural product peptide feglymycin.
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