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Title page for ETD etd-07222016-145717


Type of Document Dissertation
Author Sprague, Daniel James
Author's Email Address dsprague@mcw.edu
URN etd-07222016-145717
Title Chiral Proton Catalysis: New Applications in Enantioselective Hetero-Diels-Alder Reactions, Amino Acid Synthesis, and Tetrahydroisoquinoline Alkaloid Synthesis
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Jeffrey N. Johnston, Ph.D. Committee Chair
Janet E. Macdonald, Ph.D. Committee Member
Ned A. Porter, Ph.D. Committee Member
Timothy P. Hanusa, Ph.D. Committee Member
Keywords
  • aza-Henry
  • nitro Mannich
  • organocatalysis
  • amino acid
  • brevianamide
  • Diels-Alder
  • Biomimetic
Date of Defense 2016-07-14
Availability restricted
Abstract
The proton is the smallest Lewis acid and has been utilized in nature by enzymes for catalysis and stereocontrol of a variety of reactions long before chemistry was pursued as the discipline it is today. This precedent notwithstanding, there are very few examples of asymmetric catalysis which utilize a polar ionic hydrogen bond (essentially, a chiral proton complex). We have developed bifunctional Bis(AMidine) (BAM) catalysts that are efficient chiral proton catalysts for several mechanistically distinct transformations.

This dissertation explores a rationally designed extension of BAM catalysis to an aza-Henry reaction employing α-nitro esters as pronucleophiles. This allows for the enantio- and diastereoselective synthesis of α,β-diamino acid derivatives. A reagent-controlled diastereodivergence is observed from the selectivity typically observed in BAM catalysis and is further explored with preliminary computational analysis. This methodology was applied to the synthesis of a potent heterocyclic proteasome inhibitor. Additionally, a chiral proton chaperoned biomimetic hetero-Diels-Alder reaction was effected with moderate enantioselectivity, and preliminary results towards the synthesis of fluorinated tetrahydroisoquinoline alkaloids are reported.

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