Enantioselective Synthesis of Oasomycin A, Part III: Fragment Assembly and Confirmation of Structure

Abstract

Dedicated to Professor Y. Kishi on the occasion of his 70th birthday.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.[1]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, [2] 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 [3] 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[3] to afford the coupling product 3 a 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 % yield in this and related olefinations. This by-product with the general structure 3 b (Scheme 2) may be rationalized by a Brook rearrangement of the Julia intermediate followed by alkoxide attack on the sulfur center. All efforts to suppress this side reaction were unsuccessful. [4] With both the C1-C28 and C29-C46 subunits in hand, we addressed the aldol coupling which would provide the oasomycin A skeleton. The logic behind the selection of an aldol addition to form the C28 À C29 bond was based on the fact that the diastereoselectivity of this reaction should be reinforced by resident chirality in both reaction partners: the C25 stereocenter on the enolate [Eq. (1)], [5] and the C31 stereocenter on the aldehyde fragment [Eq. (2)].[6] Although Scheme 1. Assembly of oasomycin A subunits.

Discovery of Novel Synthetic Methodologies and Reagents during Natural Product Synthesis in the Post-Palytoxin Era

“…In 2007, Evans et al − developed a synthetic strategy toward oasomycin A ( 219 ) to validate the structural assignment. Kishi and co-workers had previously proposed the absolute stereochemistry of oasomycin A ( 219 ), relying on their “universal NMR database.” A particularly challenging transformation toward the synthesis of oasomycin A ( 219 ) included installing the exocyclic five-membered lactone fragment on the “eastern-fragment” of the molecule while maintaining overall integrity of configuration .…”