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

preprint
submitted on 31.03.2021, 20:11 and posted on 05.04.2021, 04:28 by Chengsen Cui, Yecai Lai, Wei-Min Dai
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.

Funding

General Research Fund grant (601211) from the Research Grant Council, The Hong Kong Special Administrative Region, P. R. China

History

Email Address of Submitting Author

chdai@ust.hk

Institution

The Hong Kong University of Science and Technology

Country

P. R. of China

ORCID For Submitting Author

0000-0001-5688-7606

Declaration of Conflict of Interest

No conflict of interest

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