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Organic Chemistry Highlights

Total Synthesis

Monday, November 7, 2022
Douglass F. Taber
University of Delaware

The Jia Synthesis of Euphorikanin A

Euphorikanin A (3), isolated from the roots of the Chinese medicinal herb Euphorbia kansui, showed the ability to reactivate latent HIV. En route to 3, Yanxing Jia of Peking University cyclized the keto acid 1 to the β-lactone 2 (Angew. Chem. Int. Ed. 2022, 61, e202200576. DOI: 10.1002/anie.202200576).

The starting material for the synthesis was the inexpensive carene 4. In the first stage, the conversion of 4 to the iodide 5 was developed, leading to significantly improved production of the previously-known cycloheptenone 6. Conjugate addition of Me2CuLi proceeded across the exo face of the enone, to give a ketone that was kinetically deprotonated, then alkylated with the iodide 7, completing the assembly of 8. Aldol reaction with the aldehyde 9 followed by protection led to 10, that was deprotected and oxidized to the keto acid 1.

Following the Romo protocol, 1 was cyclized to the β-lactone 2. This cyclization probably proceeds via intramolecular aldol reaction of the mixed anhydride, leading to 11.

Reduction of 2 followed by desilylation led to the triol, the tertiary alcohol of which was prone to dehydration. Eventually conditions were found that allowed peracetylation, to give 12. Selective reduction followed by oxidation led to the dialdehyde, that was cyclized to the diol using the McMurry conditions. Dibal deprotected the tertiary acetate, and the mixture of triols was selectively oxidized, leading to 14 as a mixture of diastereomers. Corey-Kim oxidation to the diketone led to the hemiketal, that was protected and oxidized to give 15. Dehydration followed by allylic reduction and benzylic acid rearrangement then completed the synthesis of euphorikanin A (3).

It is instructive to compare the approach to euphorikanin A (3) outlined here to the route described by Carreira (The Carreira Synthesis of Euphorikanin A 2022, January 3).

D. F. Taber, Org. Chem. Highlights 2022, November 7.