Multimodule Assembly Strategy for Diverted Total Synthesis and Stereochemical Determination of Laingolide A and Laingolide

Abstract

Diverted total synthesis of diastereomers of laingolide A and laingolide has been accomplished and the stereochemistry of both (<i>E</i>)-enamide-containing 15-membered macrolides has been assigned. Laingolide A and laingolide have 3 and 4 stereogenic centers, respectively, and only their planar structures were reported. The former has 4 possible diastereomers while the latter has up to 8 diastereomers. A multimodule assembly (MMA) strategy was utilized to disconnect both target molecules into 5 small structural modules among which only one stereochemically varied module (stereo-module) needed to be prepared with other 4 modules available commercially. A sequence of ring-closing metathesis (RCM) and alkene isomerization was used for construction of the macrocyclic skeleton and installation of the (<i>E</i>)-enamide moiety. Four each diastereomers of laingolide A and laingolide have been synthesized, leading to assignment of (2<i>R</i>*,7<i>R</i>*,9<i>S</i>*) and (2<i>R</i>*,4<i>R</i>*,7<i>R</i>*,9<i>S</i>*) relative stereochemistry for laingolide A and laingolide, respectively. Moreover, according to the (2<i>S</i>,9<i>R</i>) absolute configuration of the congener, laingolide B, the (2<i>S</i>,7<i>S</i>,9<i>R</i>) and (2<i>S</i>,4<i>S</i>,7<i>S</i>,9<i>R</i>) absolute configurations are suggested for laingolide A and laingolide, respectively. The current synthetic efforts reveal, for the first time, that both laingolide A and laingolide possess the 7,9-<i>syn</i>-Me/<i>t</i>-Bu subunit.