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Organic Chemistry Highlights

Total Synthesis

Monday, February 6, 2023
Douglass F. Taber
University of Delaware

The Ding Synthesis of Crinipellin F

The crinipellins are the only tetraquinane natural products. The enone crinipellins have anticancer activity. Hanfeng Ding of Zhejiang University devised a general route to the crinipellins, illustrated by crinipellin F (3), based on the oxidative cyclization of the cyclopentenone 1 to the tricyclic enone 2 (J. Am. Chem. Soc. 2022, 144, 2495. DOI: 10.1021/jacs.1c13370).

The starting point for the synthesis was the aldehyde 4. Addition of the enolate derived from the vinylogous ester 5 followed by dehydration led to the enone 6. Enantioselective hydrogenation set the absolute configuration of 7. Addition of isopropenyl Grignard 8 followed by dehydration with BBr3 was accompanied by demethylation, leading to the phenol 9. Although 9 participated efficiently in the oxidative cyclization, the diastereoselectivity was improved significantly with the derived bromide 1.

Exposure of the phenol 1 to phenyliodine(III) bis-(trifluoroacetate) and NaHCO3 at 0C led smoothly to the tetracyclic bromide 2 and its easily separated diastereomer. The cyclization apparently proceeds by way of the intermediate carbocation 10. With DFT calculations, Hujun Xie of Zhejiang Gongshang University assisted in the development of the cyclization.

Addition of t-butyl hydroperoxide converted 2 to the solid epoxide 11, the structure of which was confirmed by x-ray analysis of a derivative. Hydrogenation over PtO2 reduced the ketone to the alcohol, and removed the bromide and one of the alkenes. Addition of CH3Li was followed by acidic workup to hydrolyze the enol ether. Dehydration then delivered the alkene 12. Radical reorganization of 12 proceeded via the anticipated Beckwith-Dowd rearrangement, leading to 14 by way of the alkoxy radical 13. Hydrogenation followed by oxidation, methylenation and reduction then completed the synthesis of crinipellin F (3).

Proceeding from these intermediates, the authors also prepared crinipellins A, B, C, D and E, in the process revising the structure of crinipellin D. It is striking that the accompanying experimental procedure describes the preparation of 1.9 grams of 14.

D. F. Taber, Org. Chem. Highlights 2023, February 6.