Studies Toward the Total Synthesis of HMP-Y1 and Hibarimicinone

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.