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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
  • Hibarimicin
  • HMP-Y1
  • Biaryl Coupling
Date of Defense 2010-12-10
Availability unrestricted
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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