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