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Title page for ETD etd-12212012-101204


Type of Document Dissertation
Author Hempel, Jonathan Edward
URN etd-12212012-101204
Title Studies Toward the Total Synthesis of HMP-Y1 and Hibarimicinone
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Professor Gary A. Sulikowski Committee Chair
Professor Brian O. Bachmann Committee Member
Professor Craig W. Lindsley Committee Member
Professor Jeffrey N. Johnston Committee Member
Keywords
  • natural products
  • total synthesis
  • aromatic polyketides
  • Diels-Alder
Date of Defense 2012-12-13
Availability unrestricted
Abstract
The hibarimicin family of natural products was isolated in 1995 from the culture broth of the rare actinomycete Microbispora rosea subsp. hibaria TP-A0121. This complex polyketide type II family exhibits strong inhibition of src tyrosine kinase (IC50 = 580 nM to 2.32 µM), and hibarimicin B exhibited potent growth inhibition of the HL-60 leukemia cell line (IC50 = 58 nM) and in vitro cytotoxicity against B16-F10 and HCT-116 cells. Due to the inaccessibility of these biologically important compounds, we specifically sought out a synthetic route to access quantities of hibarimicin B and its biosynthetic precursors. Thus, chapter I details aromatic polyketides and related structural and synthetic considerations including the hibarimicins. Chapter II highlights application of the Diels-Alder reaction to total synthesis and previous synthetic efforts toward the hibarimicins. Chapter III discusses a two-directional strategy toward HMP-Y1 and hibarimicinone, and Chapters IV and V detail a biomimetic dimerization approach.
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