Organic Chemistry

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



Diverted total synthesis of diastereomers of laingolide A and laingolide has been accomplished and the stereochemistry of both (E)-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 (E)-enamide moiety. Four each diastereomers of laingolide A and laingolide have been synthesized, leading to assignment of (2R*,7R*,9S*) and (2R*,4R*,7R*,9S*) relative stereochemistry for laingolide A and laingolide, respectively. Moreover, according to the (2S,9R) absolute configuration of the congener, laingolide B, the (2S,7S,9R) and (2S,4S,7S,9R) 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-syn-Me/t-Bu subunit.


Thumbnail image of Laingolide_&_A_dai_v1.pdf

Supplementary material

Thumbnail image of SI-laingolides_dai_v1.pdf
SI-laingolides dai v1