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Organic Chemistry Highlights

Total Synthesis

Monday, September 1, 2014
Douglass F. Taber
University of Delaware

The Deslongchamps Synthesis of (+)-Cassaine

Although the Na+-K+-ATPase inhibitor (+)-Cassaine (4) was isolated from the bark of Erythrophleum guinneese 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. DOI: 10.1021/ol4030937) 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.

The sulfoxide 2 was readily prepared by the addition (Tetrahedron Lett. 1990, 31, 3969. DOI: 10.1016/S0040-4039(00)94474-5) 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. DOI: 10.1016/S0040-4020(00)00240-4) 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. Deprotection and oxidation followed by Pd-mediated carbonylation in the presence of 2-dimethylaminoethanol and further deprotection then completed the synthesis of (+)-Cassaine (4).

It is instructive to compare this synthesis to the complementary preparation of (+)-Cassaine (4) previous reported (Intermolecular and Intramolecular Diels-Alder Reactions: Platencin (Banwell), Platensimycin (Matsuo), (+)-Cassaine (Deslongchamps), (-)-Halenaquinone (Trauner) 2009, August 24) by Professor Deslongchamps, that centered on a transannular intramolecular Diels-Alder cycloaddition. In that case, the axial secondary methyl was installed by conjugate addition to a preformed C ring.

D. F. Taber, Org. Chem. Highlights 2014, September 1.