Enantioselective Synthesis of Oasomycin A, Part I: Synthesis of the C1–C12 and C13–C28 Subunits

Abstract

Oasomycin A (I) is a member of the desertomycin family of macrolide natural products and was isolated in 1993 by Thiericke and co-workers during the screening of secondary metabolites of Streptoverticillium baldacii. The overall structure of oasomycin A was established through extensive NMR spectroscopic studies and by direct comparison to other members of the desertomycin family. In 2001, Kishi and coworkers issued a proposal for the relative and absolute stereochemistry of oasomycin A through the use of their “universal NMR database” (Scheme 1). To validate the structural assignment of oasomycin A, we decided to pursue the synthesis of the reported structure, I. Herein, and in the following Communications, we describe our efforts which culminated in the synthesis of oasomycin A (I) and confirm the stereochemical assignment by Kishi and co-workers. First, we describe the synthesis of the C1–C12 and C13–C28 subunits II and III, respectively, which will be united by using the Julia coupling reaction (Scheme 1). Our plan for the synthesis of the C13–C28 fragment III is outlined in Scheme 2. Aldehyde III could be derived from a chelate-controlled reduction of the a,b-unsaturated ketone IV, which in turn can be disconnected at the C21 C22 bond to afford fragments V and VI. We predict successful union of these two fragments because of the greater reactivity of the Weinreb amide VI, which is required to avoid self-condensation of V (M=Li, MgX). This prediction is based on the supposition that the inductive effect of the a-alkoxy substituent should elevate the amide reactivity of VI above that of its reaction partner V. Synthesis of subunit II commenced with the aldol addition of known b-ketoimide 1 to aldehyde 2, which afforded the desired anti,anti aldol adduct as an 84:16 mixture of Scheme 1. Retrosynthetic analysis of oasomycin A (I).