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Organic Chemistry Highlights

Total Synthesis

Monday, August 6, 2018
Douglass F. Taber
University of Delaware

The Dixon Synthesis of Himalensine A

Himalensine A (3) is a pentacyclic Daphniphyllum alkaloid isolated from the Himalayan evergreen Daphniphyllum himalense. Darren J. Dixon of the University of Oxford envisioned assembling 3 by the intramolecular Diels-Alder cyclization of 1 to 2 (J. Am. Chem. Soc. 2017, 139, 17755. DOI: 10.1021/jacs.7b10956).

The preparation of cycloheptenone 1 began with the ketone 4. Addition to 5 led to the enol 6. Krapcho decarboxylation followed by ketal formation led to 7. Saponification gave the free acid, that was coupled with 8 to give the imide 9. Deprotection completed the assembly of the ketone 10.

The absolute configuration of 3 would be set by the enantioselective prototropic shift of 10 to give the Diels-Alder precursor 1. After extensive investigation, a catalyst was found that delivered 2 in high ee.

The ketone 2 was rearranged and then reduced to give 11. Alkylation with 12 led to 13, that was selectively reduced and then dehydrated, giving 14. Conversion to the silyl enol ether set the stage for reductive addition of tributyltin hydride to the alkyne, leading to 15. The alkyne 13 was crystalline, and could readily be recrystallized to >99% ee.

The superfluous tin was removed by exposure to acid. The diastereoselectivity of the subsequent hydrogenation was optimized at low pressure using a mix of H2 and argon. Oxidation of 16 gave the ene dione 17. The derived enol triflate was coupled with 18, and the product acetal was deprotected. Catalytic Stetter cyclization followed by selective reduction of the amide to the amine completed the synthesis of himalensine A (3).

D. F. Taber, Org. Chem. Highlights 2018, August 6.