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Title page for ETD etd-07192013-164751


Type of Document Dissertation
Author Schulte, Michael Lawrence
Author's Email Address mschulte326@gmail.com
URN etd-07192013-164751
Title Application of Organocatalysis to the Synthesis of Pharmaceutically Relevant Scaffolds: Chiral Aziridines and β-Fluoroamines; Total Synthesis of Stemaphylline; and Discovery of Selective PAR4 Antagonists.
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Craig W Lindsley Committee Chair
Gary A Sulikowski Committee Member
J. Scott Daniels Committee Member
Jeffrey N Johnston Committee Member
Keywords
  • organocatalysis
  • aziridines
  • fluoroamines
  • stemaphylline
  • stemaphylline N-oxide
  • protease activated receptor
Date of Defense 2013-05-14
Availability unrestricted
Abstract
Aziridines represent an important class of nitrogen-containing heterocycles with a wide range of synthetic utility. Despite their value, synthetic approaches are limited in terms of generality and diversity. On this basis, we developed a three step, one-pot protocol involving enantioselective α-chlorination of aldehydes, subsequent reductive amination with a primary amine, and SN2 displacement to afford chiral N-alkyl terminal aziridines in 40-65% yield and, in most cases, >90% ee. As an extension of this work, we employed organocatalysis in a short, high-yielding protocol for the highly diastereoselective (dr > 20:) and general synthesis of primary β-fluoroamines via α-fluorination of aldehydes, conversion into the N-sulfinyl aldimine, nucleophilic addition of various organometallic species, and amine liberation.

Stemona alkaloids represent a class of approximately 100 biogenetically intriguing and structurally unique natural products. Recently in 2009, stemaphylline and stemaphylline-N-oxide were isolated from the root extracts of Stemona aphylla by Pitchaya and co-workers. The total synthesis of stemaphylline and stemaphylline-N-oxide has been achieved along with the synthesis of the unnatural 9a-epi-stemaphylline and 9a-epi-stemaphylline-N-oxide. As a result of our synthetic efforts, a novel approach for the general asymmetric synthesis of azabicyclic ring systems has been developed.

Protease activated receptor-4 (PAR4) is one of the thrombin receptors on human platelets and is a potential target for the management of thrombotic disorders. We sought to develop potent, selective, and novel PAR4 antagonists to test the role of PAR4 in thrombosis and hemostasis. Development of an expedient three-step synthetic route to access a novel series of indole-based PAR4 antagonists provided novel compounds with moderate potencies. A small high-throughput screen based on these novel scaffolds revealed selective PAR4 antagonists for future antagonist development.

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