Monday, November 4, 2024
Douglass F. Taber
University of Delaware
The Liu/Qin Synthesis of Cyclopamine
Cyclopamine 3, a teratogenic alkaloid isolated from the California corn lily Veratrum californicum, has been shown to disrupt the hedgehog signalling pathway. Xiao-Yu Liu and Yong Qin of Sichuan University envisioned converting the readily-available steroid derivative 1 to 2, having the 6-6-5-6 ring system of 3 (Nature Commun. 2024, 15, 5332. DOI: 10.1038/s41467-024-49748-2).
The starting material for 1 was the inexpensive dehydroepiandrosterone (DHEA) 4. Following the Baran protocol, acetylation followed by Cu-mediated oxygenation led to the alcohol 5. Addition of ethynyl magnesium bromide 7 across the open face of the ketone followed by the addition of HCN then completed the preparation of 1.
Conversion of the secondary alcohol of 1 to the trifluoromethanesulfonate followed by ionization led to an initial carbocation, that via a 1,2-shift led to the carbocation 8. Trapping by the adjacent tertiary alcohol then gave the desired epoxide 2, the structure of which was confirmed by x-ray analysis.
Selective hydrogenation of the more open alkene of 2 proceeded with high diastereomeric control. Double dehydration then led to the diene 9. Reduction of the nitrile to the aldehyde also removed the acetate. Condensation with the sulfinamide 10 then gave the imine 11. Reductive coupling of 11 with the aldehyde 12 led to 13. Removal of the sulfinyl group followed by base treatment led to both spiro ether formation and lactamization, to give 14. Reduction then completed the synthesis of cyclopamine 3. It is a measure of the practicality of this approach that the final reduction was carried out on 1.6 grams of 14, leading to 1.4 grams of the natural product.
Athanassios Giannis of the Universität Leipzig also described a route from 4 to 3 (Angew. Chem. Int. Ed. 2009, 48, 7911. DOI: 10.1002/anie.200902520). For alternative approaches to 3, see 2024, March 4.
D. F. Taber, Org. Chem. Highlights 2024, March 4.
URL: https://www.organic-chemistry.org/Highlights/2024/04March.shtm