Title page for ETD etd-10042007-161139


Type of Document Dissertation
Author Hsu, Danny Chung
Author's Email Address dhsu@vt.edu
URN etd-10042007-161139
Title Mechanistic Studies on Memory of Chirality Alkylations of 1,4-Benzodiazepin-2-ones & Structure-based Design of Insecticidal AChE Inhibitors for Malaria Mosquito, Anopheles gambiae
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Carlier, Paul R. Committee Chair
Deck, Paul A. Committee Member
Etzkorn, Felicia A. Committee Member
Kingston, David G. I. Committee Member
Tanko, James M. Committee Member
Taylor, Larry T. Committee Member
Keywords
  • Asymmetric Synthesis
  • Memory of Chirality
  • Anopheles gambiae
  • Sulfhydryl Reagents
  • Free Cysteine Targeting
  • Acetylcholinesterase
  • Kinetics
  • Freeze Frame Observation
  • Enolate Chemistry
  • 1 4-Benzodiazepin-2-one
  • Density Functional Theory
Date of Defense 2007-09-18
Availability unrestricted
Abstract
Memory of chirality (MOC) is an emerging strategy for asymmetric synthesis which relies upon the intermediacy of transiently non-racemic reactive species. In these reactions the configuration of the sole stereogenic center of the enantiopure starting material is "memorized" by a chiral non-racemic conformation in the intermediate; trapping then captures the stereochemical information, and generates a new stereogenic center with high fidelity. We experimentally and computationally studied the highly retentive deprotonation/alkylations of 1,4-benzodiazepin-2-ones (BZDs) that rely upon this strategy. We captured a transiently non-racemic BZD enolate intermediate in enantiopure form, then released the enolate and observed its subsequent reaction. This approach allowed the first ever step-wise observation of the stereochemical course of such a MOC process.

Approximately 2 million deaths are caused by malaria every year in the world. In total roughly 3.2 billion people are living under the risk of malaria transmission. Current use of anticholinesterase insecticides has been limited by their toxicity to human beings. A major African malaria insect vector, Anopheles gambiae (Ag), was targeted. Based on sequence alignment and homology models of AgAChE, a strategy of dual-site binding was adopted that targets Trp84 in the active site and Cys286 at the peripheral site. Selective AChE inhibitors have been designed and synthesized.

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