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Title page for ETD etd-03302010-153810

Type of Document Dissertation
Author Shen, Bo
URN etd-03302010-153810
Title New Enantioselective Approaches to the Synthesis of Amino Acid Derivatives and Peptides Using Chiral Proton Catalysis
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Jeffrey N. Johnston Committee Chair
Brian O. Bachmann Committee Member
Charles M. Lukehart Committee Member
Gary A. Sulikowski Committee Member
  • Chiral Proton Catalysis
  • Enantioselective
  • Amino Acid
  • Peptide synthesis
  • aza-Henry reaction
Date of Defense 2009-11-24
Availability unrestricted
α,β-Diamino acids and β-amino acids are important constituents in countless natural products. These atypical amino acids often display interesting and useful biological properties and have also been used as useful building blocks for the synthesis of valuable pharmaceutical targets. This dissertation describes the application of chiral proton catalysis for the development of enantio- and diastereoselective aza-Henry reactions of nitroacetate pronucleophiles as a route towards α-nitro-β-amino acids. Direct reduction of the aza-Henry adducts afforded anti-α,β-diamino acid derivatives; alternatively, the post-addition epimerization/crystallization/reduction sequence generated syn-α,β-diamino acid derivatives. Following the aza-Henry reaction, denitration of the adducts provided β-amino acid derivatives with high ee, and this protocol was applied in the formal synthesis of (+)-chaenorhine. The amide functional group is one of Nature's key functional and structural elements, most notably within peptides. Amides are also key intermediates in the preparation of a diverse range of therapeutic small molecules. During the carbon-nitrogen bond forming step in most amide syntheses, the carbon and nitrogen bear electrophilic and nucleophilic character, respectively. The second half of the dissertation reveals the development of a novel method of amide bond formation deploying bromonitroalkanes and amines mediated by iodonium ion. Preliminary observations support a mechanistic construct in which reactant polarity is reversed (umpolung) during C-N bond formation relative to traditional approaches. This new approach leads to the development of an asymmetric aryl glycine amide synthesis without epimerization or extensive protection/deprotection schemes. And the first use of commercially available bromonitromethane in stereoselective peptide synthesis establishes a practical alternative to the longstanding reliance on the carboxylic acid feedstock.
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