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Title page for ETD etd-12172010-164248


Type of Document Dissertation
Author Romaine, Ian Matthew
URN etd-12172010-164248
Title Progress Toward the Total Synthesis of HMP-Y1 and Hibarimicinone
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Gary A. Sulikowski Committee Chair
Brian O. Bachmann Committee Member
Michael P. Stone Committee Member
Piotr Kaszynski Committee Member
Keywords
  • Hibarimicin
  • HMP-Y1
  • Biaryl Coupling
Date of Defense 2010-12-10
Availability unrestricted
Abstract
In 1998, Hori and coworkers1 reported a small group of pseudodimeric aromatic polyketides, named hibarimicins, which are produced by Microbispora sp found in a soil sample. This group consisted of more than ten components. These natural products share a common aglycone (hibarimicinone) and differ exclusively with the oligosaccharides. Studies conducted by Uehra and coworkers2 revealed the hibarimicins to be specific tyrosine kinase inhibitors. Hibarimicin A-D have been evaluated for dose-dependent inhibition of cell proliferation and induction of cell differentiation of human myeloid leukemia (HL-60) cells (i.e. hibarimicin B IC50 = 0.1 mg/mL). In attempt to delineate the biosynthetic pathway, Kajura and coworkers3 produced a series of blocked mutants of which metabolite HMP-Y1 was identified.

Due to the structural complexity and interesting biological activities of hibarimicins, we currently are exploring the synthesis and assignment of absolute stereochemistry of hibarimicinone and HMP-Y1. Herein, we describe studies using a resolved biaryl ester in a two-directional bis-annulation to assign the absolute stereochemistry of HMP-Y6 (glycosylated HMP-Y1). A dynamic thermodynamic resolution has been shown to provide either atropo-enantiomer in a model system to allow a biomimetic oxidative coupling in route to HMP-Y1.

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