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Organic Chemistry Highlights

Total Synthesis

Monday, January 1, 2024
Douglass F. Taber
University of Delaware

The Fan Synthesis of Trachinol

Trachinol (3), isolated fifty years ago from Sideritis canariensis Ait., a shrub of the Canary Islands, has an intriguing pentacyclic structure. Chun-An Fan of Lanzhou University devised an elegant preparation of 3, based on the iterative H-atom transfer cyclization of the diketone 1 to the cyclopropanol 2 (J. Am. Chem. Soc. 2023, 145, 311. DOI: 10.1021/jacs.2c09985).

The assembly of 1 began with the synthesis of the homoallylic bromide 11, following a modification of the literature procedures. Acylation of the commercial ketone with dimethyl carbonate delivered the the β-keto ester 6, that was cyclized to the the β-keto ester 7. Methylenation followed by ester hydrolysis generated the racemic acid 8, that was resolved via the salt with phenethylamine 9, leading to the enantiomerically-pure acid 10. Reduction followed by conversion of the alcohol to the bromide completed the preparation of 11.

Following the Nicolaou protocol, Diels-Alder cyclization of the alkynyl aldehyde 13 with the Rawal diene 12 led to the enantioenriched adduct 14, that was carried on to the crystalline enone 15. Gold-catalyzed cyclization of the derived silyl enol ether followed by Luche reduction delivered the bicyclic 16. Protection and deprotection gave the alcohol 17, that was oxidized, coupled with 11, and oxidized again, leading to 1.

The conversion of 1 to 2 probably proceeded in two stages. Intial H atom transfer and cyclization would give the trans,anti,trans diketone 18. A second H atom transfer would then close the cyclopropane ring.

The extra alcohol was removed by free radical reduction, leading to the ketone 19. Reduction of the ketone to the axial alcohol then completed the synthesis of trachinol 3.

D. F. Taber, Org. Chem. Highlights 2024, January 1.