Enantioselective synthesis of oasomycin A, part III: fragment assembly and confirmation of structure.

Herein we address the total synthesis of the natural product oasomycin A by assembly of the C1–C12, C13–C28, and C29–C46 subunits, whose syntheses have been described in the preceding Communications. The synthesis plan (Scheme 1) incorporates a speculative late-stage macrolactonization of the linear seco acid precursor to form a 42-membered lactone that upon global deprotection would provide the natural product. Since oasomycin A is known to rearrange to the oasomycins D and E under basic conditions, an acid-mediated global deprotection was obligatory. It was our intention to assemble the requisite seco acid by using an aldol addition of the C1–C28 ketone I to the C29–C46 aldehyde II with a concomitant installation of the C29 stereocenter, followed by a stereoselective reduction of the C27 ketone. The assembly of ketone I through a Kocienski–Julia olefination of the C13–C28 aldehyde III with C1–C12 fragment IV was undertaken first (Scheme 2). Sulfone 1 was selectively deprotonated with KHMDS and treated with aldehyde 2 to afford the coupling product 3a as a 7:1 mixture of E/Z isomers (57% yield). In addition, a significant amount of a by-product was consistently formed in 15–25%