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Title page for ETD etd-12052012-115555


Type of Document Dissertation
Author Dobish, Mark Christopher
URN etd-12052012-115555
Title Chiral bisamidine catalysis: enantioselective alkylations and halolactonizations with applications to small molecule therapeutics
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Jeffrey N. Johnston Committee Chair
Michael R. Waterman Committee Member
Ned A. Porter Committee Member
Timothy P. Hanusa Committee Member
Keywords
  • bisamidine catalysis
  • small molecule therapeutic
  • organocatalysis
  • chiral proton catalysis
  • Chagas disease
  • enantioselective iodolactonizations
Date of Defense 2012-12-04
Availability unrestricted
Abstract
Herein we demonstrate the development and application of chiral bis(amidines) as organocatalysts in novel enantioselective transformations. A chiral, Brønsted base-catalyzed asymmetric alkylation of nitroalkanes is described for the first time using bis(amidine) catalysis, delivering products with synthetically useful values of enantiomeric excess. Additionally, the first enantioselective synthesis of VNI, a potent CYP51 inhibitor, is divulged and highlighted by an enantioselective bromonitromethane aza-Henry addition to afford the desired intermediate with high enantioselectivity. Ultimately, gram quantities of VNI were synthesized to establish its efficacy in a murine model of chronic Chagas, a neglected tropical disease. Finally, the highly enantioselective iodolactonization of 1,1- and 1,2-disubstituted olefinic acids using chiral proton catalysis is reported, where steric and electronic modification of an achiral counterion offers a handle to control enantioselection.
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