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Organic Chemistry Highlights

Total Synthesis

Monday, April 2, 2018
Douglass F. Taber
University of Delaware

The Gong/Yang Synthesis of Pavidolide B

Pavidolide B (3), isolated from the marine soft coral Sinularia pavida, selectively inhibits the growth of human promyelocytic leukemia cell lines. Jian-Xian Gong of Peking University Shenzhen Graduate School and Zhen Yang of Peking University set (J. Am. Chem. Soc. 2017, 139, 13989. DOI: 10.1021/jacs.7b07388) the central five-membered ring of 3 by the cyclization of 1 to 2.

The convergent assembly of 1 began with commercial carvone (4). Oxidation converted it selectively to 5, that was selectively hydrogenated to 6.

The preparation of 10 commenced with the organocatalyst-mediated addition of bromomalonate 8 to sorbaldehyde (7) to give 9. After acetal formation, monosaponification led to the ester 10 as an inconsequential mixture of diastereomers. Mitsunobu coupling of 10 with 6 then proceeded with inversion to complete the assembly of 1.

The cyclization of 1 to 2 was effected by irradiation in the presence of an Ir catalyst, with thiophenol as a radical transfer agent. Addition of the thiyl radical to the alkene opened the strained cyclopropane, leading to a radical α to the two esters. Intramolecular addition of that radical to the enone gave a new radical 11, that added again in an intramolecular sense to the allylic sulfide to give a radical, that ejected the thiyl radical, to give 2.

Saponification of 2 followed by decarboxylation and acetal hydrolysis delivered the lactone 12. Ni-catalyzed addition of isoprene 13 to 12 gave an alcohol that was oxidized to the ketone 14. Ring-closing metathesis delivered the seven-membered ring, but as the undesired trans-fused diastereomer 15. The conditions for Rh-mediated migration of the double bond into conjugation also epimerized the bridgehead center, completing the synthesis of pavidolide B (3).

In addition to showcasing the efficiency of catalysis, both by transition metals and by a designed amine, this synthesis is noteworthy for the elegant combination of naturally-occurring building blocks. With the exception of the bromomalonate starting material, all of the carbons of 3 derived from carvone, sorbaldehyde and isoprene.

D. F. Taber, Org. Chem. Highlights 2018, April 2.