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Organic Chemistry Highlights

Total Synthesis

Monday, December 5, 2022
Douglass F. Taber
University of Delaware

The Procter Synthesis of Phaeocaulisin A

Phaeocaulisin A (3), isolated from Curcuma phaeocaulis, a Chinese flowering plant in the ginger family, has been demonstrated to have promising anti-neoplastic activity. David J. Procter of the University of Manchester devised a synthetic route to 3 based on the SmI2-mediated reductive cyclization of the dienyl ketone 1 to the cyclopentanol 2 (J. Am. Chem. Soc. 2022, 144, 7457. DOI: 10.1021/jacs.2c02188).

The assembly of 1 began with the preparation of the silyl ether 5 by Negishi iodomethylation of the butynol 4 followed by protection. Coupling with 6 gave the enyne, that was dihydroxylated under the enantioselective Sharpless conditions, leading to the diol 7. Oxidation followed by the addition of vinyl magnesium bromide delivered the key diol 8 with high diastereocontrol. Desilylation led to the crystalline triol, that was oxidized to the lactone 9 with TEMPO and 1,3-diiodo-5,5-dimethylhydantoin. Hydration of the alkyne to the methyl ketone followed by Heck coupling with the iodide 10 completed the construction of the diene 1.

Reduction of 1 with SmI2 could proceed via initial complexation with any of the three carbonyls. Initially, the methyl ester was explored, but this gave little of the desired cyclization. Fortunately, the t-butyl ester was successful, suggesting that the bulky ester is blocking complexation of the SmI2 to that carbonyl.

The last rings of 3 were also to be assembled by SmI2 reduction. The bulky t-butyl ester would not participate, so 2 was converted to the methyl ester 12. Cyclization then proceeded smoothly to give the lactone, largely as diasteromer 13. The bottom face of the derived enolate was more open, so bromination with 1,3-dibromo-5,5-dimethylhydantoin proceeded to give the bromide 14. Ionization with stoichiometric silver then led to elimination to give, after deprotection, phaeocaulisin A (3).

The synthesis of phaeocaulisin A (3) outlined here is a tribute to the many years the Procter group has given to developing the chemistry of SmI2 as a reagent for organic synthesis.

D. F. Taber, Org. Chem. Highlights 2022, December 5.