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Organic Chemistry Highlights

Total Synthesis

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

The Ding Synthesis of Vulgarisin A

Vulgarisin A (3) was isolated from the Chinese medicinal herb Prunella vulgaris. A key transformation in the synthesis of 3 by Hanfeng Ding of Zhejiang University was the pinacol cyclization of the dialdehyde 1 to the diol 2 (Angew. Chem. Int. Ed. 2023, 62, e202303668. DOI: 10.1002/anie.202303668).

The assembly of 1 began with the known cyclization of 1,5-cyclooctadiene 4 to the racemic diol 5. Lipase-mediated acetylation removed the unwanted enantiomer, leaving 5 in > 99% ee. Swern oxidation followed by methylenation and IBX oxidation then completed the preparation of the enone 6.

The other cyclopropane of 1 was prepared by the enantioselective Nakada (Metal-Mediated Ring Construction: The Hoveyda Synthesis of (-)-Nakadomarin A 2013, December 9) intramolecular cyclopropanation of the α-diazo β-keto phosphonate 7, that the authors optimized on a decagram scale. One electron reduction opened the cyclopropane to give an intermediate that reacted with ethyl glyoxalate 9 to give the enone 10. Enol triflate formation followed by reduction and protection then led to the diene 11, that was added in a conjugate sense to the enone 6, leading to the ketone 12. Diazo transfer followed by Wolff rearrangement gave the cyclobutane ester, that via alkylation and deprotection was converted to the allylic alcohol 13. The derived stannyl ether was reduced, then transmetalated to give, after [2,3]-Wittig rearrangement and oxidation, the dialdehyde 1.

The pinacol cyclization of 1 to 2 is presumably proceeding by complexation of SmI2 to each of the carbonyls, followed by single electron transfer. The choice of reaction medium proved critical, with the complexing solvent tetraglyme giving the best results.

Selective Mukiayama hydration of the more electron-rich alkene of 2 followed by ozonolysis and reductive work-up led to the tetraol 15. Acylation with isobutyryl chloride 16 then completed the synthesis of vulgarisin A (3).

Although the authors used UV light to promote the Wolff rearrangement that led to 13, the use of visible light has recently been reported (Functional Group Interconversion: The Nagasawa/Iwabuchi Synthesis of Rumphellclovane E 2024, March 11).

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