Synthesis of the 14α- and 16α-epimers of bufotalin acetate and 16-deacetylcinobufagin

The syntheses of two new bufadienolides with ring-D oxygen substituents in abnormal configurations have been summarised. Sodium borohydride reduction of 3β-acetoxy-16-oxo-14β,15β-epoxy-5β-bufa-20,22-dienolide (3) provided a readily separable (1 : 1) mixture of 16α-deacetylcinobufagin (1a) and its previously known 16β-epimer. Also, 14-epi-bufotalin acetate (2a) was obtained by a sequence in which 14-dehydrobufotalin acetate (7) was epoxidised with m-perchlorobenzoic acid to give the diacetate (5a), selective alkaline hydrolysis of which gave the monoacetate (5b), which was then oxidised with chromium trioxide to give the ketone (8); reduction of (8) with chromium(II) acetate gave the alcohol (9), which was then reduced at the carbonyl to the diol (2b) with Urushibara nickel, and finally acetylated to afford the synthetic objective (2a).