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Title page for ETD etd-10262016-111459


Type of Document Dissertation
Author Schwieter, Kenneth Edward
URN etd-10262016-111459
Title Toward On-Demand Peptide Synthesis: Development and Application of Enantioselective Syntheses of Unnatural α-Amino Amides
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Jeffrey N. Johnston, Ph.D. Committee Chair
Gary A. Sulikowski, Ph.D. Committee Member
Nathan D. Schley, Ph.D. Committee Member
Robert H. Carnahan, Ph.D. Committee Member
Keywords
  • peptide synthesis
  • umpolung
  • amide synthesis
  • amino acids
  • aza-Henry
  • organocatalysis
Date of Defense 2016-10-13
Availability restricted
Abstract
Unnatural amino acid derived fragments are present in a multitude of pharmaceuticals and biologically relevant molecules including complex peptides. Current preparative methods focus almost entirely on the enantioselective synthesis of the α-amino acid and rely on traditional condensative amide bond formation for peptide synthesis. Herein we report the development and application of a two-step protocol for the synthesis of unnatural α-alkyl α-amino amides, featuring enantioselective aza-Henry additions that feed directly into Umpolung Amide Synthesis (UmAS). The first and second enantioselective additions of bromonitromethane to N-Boc alkyl imines are reported. In the first, a known cinchona alkaloid-derived phase-transfer catalyst was leveraged to provide β-amino-α-bromonitroalkanes in high enantiopurity. The second method employs a bifunctional bis(amidine) catalyst to obtain the same β-amino-α-bromonitroalkanes with increased scope (access to both enantiomers) and in improved yield. In a separate study, mechanistic insight led to the development of UmAS utilizing N-iodosuccinimide (NIS) as a substoichiometric promoter, providing access to α-amino amides as a single diastereomer using fully enantioselective and catalytic methods. This two-step peptide synthesis protocol was applied to the synthesis of a fluorinated analogue of the natural product feglymycin, a tridecapeptide featuring nine arylglycine residues. Additionally, a protocol for the one-pot oxidative amidation of primary nitroalkanes was developed.
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