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Organic Chemistry Highlights

Total Synthesis

Monday, January 3, 2022
Douglass F. Taber
University of Delaware

The Carreira Synthesis of Euphorikanin A

Euphorikanin A (3), isolated from the roots of the Chinese succulent herb Euphorbia kansui, showed the ability to reactivate latent HIV. En route to 3, Erick M. Carreira of ETH Zürich cyclized the keto ester 1 to the lactone 2 (J. Am. Chem. Soc. 2021, 143, 8261. DOI: 10.1021/jacs.1c04210).

The starting material for 1 was commercial (+)-3-carene (4). Following a modification of the Yamakawa protocol, ozonolysis delivered the acetal 5, that was converted to the corresponding silyl enol ether and cyclized to the cycloheptenone 6. Addition of lithium dimethyl cuprate followed by the aldehyde 7 and subsequent protection led to the ketone 8, that was alkylated with the 2-chlorodithiane 9 to give 10. Deprotection and oxidation followed by condensation with the Still-Gennari phosphonate completed the assembly of 1.

The cyclization of the keto ester 1 probably proceeds by intial complexation of SmI2 with each of the carbonyls, to give 11. Single electron transfer then leads to 2. It is noteworthy that reductive cyclization of the E isomer of 1 led to the other diastereomer of the product cyclopentane.

Oxidative hydrolysis of the dithiane 2 followed by condensation with the dibromophosphorane and deprotection led to the alcohol 12. Regioselective dehydration to the cyclopentene followed by reductive coupling with lithium dimethylcuprate and iodination gave the Z iodoalkene 13. Oxidation to the α-keto lactone 14 followed by reductive cyclization with t-butyl lithium completed the preparation of Euphorikanin A (3).

D. F. Taber, Org. Chem. Highlights 2022, January 3.