The Shenvi Synthesis of Cotylenol

Cotylenol (3) is the aglycon of cotylenin A, isolated from the fungus Phomopsis amygdali, a causative agent of peach rot. Both cotylenin A and 3 induce differentiation in murine leukemia cells. Ryan A. Shenvi of Scripps Research of La Jolla, CA envisioned assembling the central cyclooctene of 3 by the Claisen rearrangement of 1 followed by ene cyclization to 2 (J. Am. Chem. Soc. 2023, 145, 20634. DOI: 10.1021/jacs.3c07849).

The thioester 7 was prepared from limonene (4). Selective hydrogenation followed by oxidative cleavage gave the keto aldehyde. Aldol condensation and reduction then led to the allylic alcohol 5. This was converted to the thioether 6, that on exposure to dichlorocarbene was converted to an ylide. That in turn rearranged to an α,α-dichlorosulfide, that was hydrolyzed to the thioester 7.

The tertiary alcohol 10 was assembled by adding TMS acetylene 9 to the ketone 8, mediated by Et₂Zn and the Nugent camphor-derived amino alcohol. Addition of pinacol borane followed by ring-closing metathesis led to the cyclopentene 11, that was coupled with 7 to give the ketone 12. Luche reduction followed by addition of the secondary alcohol to methyl propiolate then completed the construction of 1.

On warming, the alkenyl ether 1 rearranged to the α-formyl ester 14. The aldehyde was then positioned to engage with the exo methylene and the allylic H, leading via ene reaction to the cyclooctene 2.

Oxidation of 2 to the ketone followed by decarboxylative aldol condensation with formaldehyde gave the alcohol 15. Dehydration led to the enone 16, that was α-hydroxylated with the oxaziridine 17, then reduced with diimide to 18. Reduction then completed the synthesis of cotylenol (3).