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Title page for ETD etd-04042018-183234


Type of Document Dissertation
Author Knowe, Matthew Thomas
Author's Email Address matthew.t.knowe@vanderbilt.edu
URN etd-04042018-183234
Title Enantioselective desymmetrization of carboxylic acids by Brønsted base catalysis; preparation of arylglycine peptides; progress toward the synthesis of (+)-zwittermicin A
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Jeffrey Johnston Committee Chair
Gary Sulikowski Committee Member
Lars Plate Committee Member
Nathan Schley Committee Member
Keywords
  • Brønsted base catalysis
  • enantioselective
  • zwittermicin
  • arylglycine
  • amide synthesis
  • desymmetrization
  • crystal structure
  • iodolactonization
Date of Defense 2018-03-29
Availability unrestricted
Abstract
Carboxylic acids are employed throughout nature and synthetic chemistry as reactants as well as catalysts. However, carboxylic acids are underrepresented as nucleophiles in enantioselective organic reactions. This may be due in part to a limited understanding of catalyst-carboxylic acid interactions. For this reason, a Brønsted base catalyzed, enantioselective iodolactonization was developed through reaction and catalyst optimization. Two catalyst-substrate cocrystal structures were obtained, featuring a novel array of three hydrogen bonds. As a result, we hypothesized a Brønsted base catalyzed desymmetrization of a carboxylic acid, and this picture drove catalyst optimization to achieve high reactivity and enantioselectivity. The bicyclic lactone products are easily derivatized to provide access to carbocyclic nucleoside motifs. A novel activation mode of carboxylic acid nucleophiles by a Brønsted base has been discovered and characterized. Additionally, practical and reproducible method for the preparation of arylglycine containing peptides has been described, and optimization of several steps towards the total synthesis of (+)-zwittermicin A was achieved and has been reported.
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