Progress Toward the Total Synthesis of HMP-Y1 and Hibarimicinone

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.