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Title page for ETD etd-07222011-142610


Type of Document Dissertation
Author Davis, Tyler Andrew
Author's Email Address tyler.andrew.davis@gmail.com
URN etd-07222011-142610
Title Electronic Modification and Development of a More Reactive Chiral Proton Catalyst for the Enantioselective Aza-Henry Reaction and its Application to the Synthesis of Therapeutics
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Professor Jeffrey N. Johnston Committee Chair
Professor Gary A. Sulikowski Committee Member
Professor Ned A. Porter Committee Member
Professor Piotr Kaszynski Committee Member
Keywords
  • Chiral Proton Catalysis
  • Aza-Henry Reaction
  • Enantioselective Synthesis of Nutlin-3
  • Chiral Bisamidine Catalyst
  • Asymmetric Catalysis
  • PBAM
Date of Defense 2011-07-13
Availability unrestricted
Abstract
BisAMidine chiral proton catalysts are a class of mixed Brønsted acid/Brønsted base reagents amenable to both electronic and steric modification. A counterintuitive approach in which the creation of more Brønsted basic versions of these Brønsted acid catalysts led to more reactive catalysts (PBAM) that delivered highly diastereo- and enantioselective aza-Henry reactions. Factors that influence the reactivity of these catalysts have been uncovered. The development of these new catalysts has permitted the considerable expansion of the nitroalkane scope, including secondary nitroalkanes.

Enantiomerically enriched compounds of medicinal importance are now easily accessible through this system. A potent GlyT1 inhibitor has been synthesized asymmetrically through an enantioselective aza-Henry reaction of a secondary nitroalkane and subsequent denitration. We also overcame the problems associated with the use of aryl nitromethane pronucleophiles in the aza-Henry reaction (low dr/ee), and have converted their addition products to the corresponding cis-imidazoline. This strategy has been successfully applied to the first enantioselective synthesis of (–)-Nutlin-3, a p53-MDM2 inhibitor currently in development by Hoffmann-La Roche.

The synthesis of a library of new BAM ligands has been described. Furthermore, a large scale Organic Syntheses procedure for the synthesis of PBAM has been developed.

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