Substrate-Controlled Formal Synthesis of (+)-Laurenyne by a Chemoselective Chelation-Controlled Alkylation Strategy

A substrate-controlled formal synthesis of (+)-laurenyne has been accomplished featuring a highly stereoselective chemoselective chelation-controlled amide enolate alkylation for synthesis of the α,α'-syn-bis-alkene without resorting to use of a chiral auxiliary.(+)-Laurenyne (1), a C 15 nonisoprenoid metabolite, was isolated from Laurencia obtusa collected in the Aegean Sea off the coast of Turkey by Thomson and co-workers in 1980. 1 The structure and absolute stereochemistry of the chlorinated α,α'-cis-oxocene marine natural product were proposed by the Thomsom group using X-ray crystallography. 1 The first total synthesis 2 of unnatural (-)-laurenyne by Overman and Thompson using an acetal-initiated cyclization confirmed the constitution and relative stereochemistry of laurenyne but reassigned the absolute stereochemisty as 2R,7R,8R. 2The recent asymmetric total synthesis of (+)-laurenyne by Boeckman and co-workers features a retro-Claisen rearrangement as a key step to construct the oxocene skeleton. 3Recently, Clark et al. reported a synthesis of the cyclic ether core of (+)-laurenyne by a ring-closing metathesis. 4Reported herein is a substrate-controlled synthesis of chloro tosylate 2 employing a highly stereoselective amide enolate alkylation based on a chemoselective chelation process as a key step.The chloro tosylate 2 represents the antipode of a late-stage intermediate in the total synthesis of (-)-laurenyne by Overman and Thompson.As shown in Scheme 1, we envisioned that chloro tosylate 2 could be elaborated from key α,α'-cis-disubstituted chloro oxocene 3, which in turn could be prepared from α,α'-syn-bis-alkene 4 by This paper is dedicated to Professor Dr.