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Title page for ETD etd-11182012-215928

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
  • silyl imines
  • n-halo amines
  • natural product synthesis
  • peptide synthesis
  • amide synthesis
  • umpolung
  • methodology development
  • chemistry
  • aza-Henry
  • umpolung amide synthesis
  • UmAS
Date of Defense 2012-10-25
Availability unrestricted


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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