The Deslongchamps Synthesis of (+)-Cassaine

Although the Na+-K+-ATPase inhibitor (+)-cassaine 4 was isolated from the bark of Erythrophleum guineense in 1935, the structure was not established until 1959. Intriguing features of 4 include the unsaturated amide and the axial secondary methyl group, both pendant to the C ring. Pierre Deslongchamps, now at Université Laval, envisioned (Org. Lett. 2013, 15, 6270) that the relative stereochemistry of the second­ary methyl could be established kinetically by intramolecular Michael addition of the enolate formed by the addition of the anion of 2 to the enone 1 to give 3. The sulfoxide 2 was readily prepared by the addition (Tetrahedron Lett. 1990, 31, 3969) of the anion derived from methyl phenyl sulfoxide to methyl crotonate. The enone 1 was prepared from commercial dihydrocarvone 5. Robinson annula­tion with ethyl vinyl ketone 6 (Tetrahedron 2000, 56, 3409) led to 7, that was reduc­tively methylated, reduced further, and protected to give 8. Oxidative cleavage of the pendant isopropenyl group followed by Baeyer–Villiger oxidation, hydrolysis, and further oxidation gave the ketone 9, that was methoxycarbonylated, then oxidized further to 1. The addition of the anion derived from 2 to 1 presumably gave initially the axial adduct. Subsequent intramolecular Michael addition then proceeded selectively to one face of the residual enone to give, after elimination of the sulfoxide, the enone 3. The anionic cascade annulation that formed the C ring having been accomplished, the ester of 3 was removed by exposure to ethoxide to give 10, having the alkene con­jugated with the B-ring ketone. Selective reduction followed by protection gave 11. In the course of the hydrogenolytic deprotection of the A-ring alcohol, selective hydrogenation of the tetrasubstituted alkene was also observed. Increasing the H2 pressure and extending the reaction time gave complete conversion to the desired 12, the rela­tive configuration of which was established by X-ray crystallography. A series of protection, reduction, and oxidation steps led to the C-ring ketone, that was methoxycarbonylated to give 14. Reduction followed by dehydration gave the unsaturated ester, that was reduced to the saturated ester with Mg in methanol. Reduction followed by oxidation then delivered the aldehyde 15. After some investi­gation, it was found that the aldehyde could be converted to the desired enol triflate by exposure to KHMDS and the Comins reagent.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.