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Organic Chemistry Highlights

Total Synthesis

Monday, May 2, 2022
Douglass F. Taber
University of Delaware

The Dong Synthesis of Phainanoid A

Phainanoid A (3), isolated from the shrub Phyllanthus hainanensis Merr., found only on Hainan Island, showed both promising toxicity against cancer cell lines, and immunosuppressive activity. Guangbin Dong of the University of Chicago faced many challenges in assembling 3, including the cyclization of the ketone 1 to the cyclobutane 2 (J. Am. Chem. Soc. 2021, 143, 19311. DOI: 10.1021/jacs.1c11117).

The construction of the triflate 1 began with the triene alcohol 4. Claisen rearrangement with 5 followed by the addition of the ester enolate derived from 6 led to the β-keto ester 7. Oxidative cyclization led to the tricyclic ketone 8 with the expected high diastereocontrol. Remote hydroxylation of the derived ketone 9 led to 10, that was coupled with the iodoalkene 11. Protection followed by epoxidation and semi-pinacol rearrangement then established the correct diastereomer of the ketone 12. Deprotection of the diol followed by selective oxidation and protection gave the aldehyde 13. Coupling with the benzofuran 14 then led to 15.

Reduction of 15 led to 1, that was directly carried on to 2. The Pd-catalyzed cyclization proceeded with high diastereoselectivity, with the bulky aryl ketone on the more open face of the cyclobutane.

The last stage of the assembly of 3 was the Ni-mediated cyclization of 16. This apparently proceeded by initial enagement of the vinyl triflate with the exo alkylidene lactone. Subsequent Heck-type cyclization then established the cyclopropane.

Both the ketone 2 and the phosphonate used to carry it on to 16 were racemic, so 16 was a mixture of racemic diastereomers, the correct one of which was converted to racemic 3. If instead a single enantiomer of the phosphonate had been used, the yield of phainanoid A (3) would have been the same, but it would have been enantiomerically pure.

We note the passing of David A. Evans of Harvard University. In addition to their many contributions to organic synthesis, we all owe a debt of gratitude to the Evans group and Stewart Rubenstein for the development of ChemDraw.

D. F. Taber, Org. Chem. Highlights 2022, May 2.