Bufadienolides. 29. Synthetic Routes to Bufotalin

Two partial syntheses of bufotalin (1a) were developed as follows. The 16-ketone 3 was prepared from cinobufagin and the 14,15β-epoxide group was reduced with chromous acetate to yield β-hydroxy ketone 4 (61%) and α,β-unsaturated ketone 5 (27%). Selective reduction of β-ketone 4 with Urushibara nickel A afforded alcohol lb, which was acetylated to provide diacetate 1c. Treatment of diacetate lc with hydrochloric acid in methanol gave bufotalin (1a) accompanied by lesser amounts of other hydrolysis products (1b, 1d, and 6a). In an alternative approach, α,β-unsaturated ketone 5 was first reduced with Urushibara nickel A to allylic alcohol 6a. After acetylation (to 6b) the olefin was subjected to reaction with hypoiodous acid or hypobromous acid and the resulting halohydrin (7a or 7b) was treated with Urushibara nickel A. The product of hydrogenolysis was bufotalin 3β-acetate (1c).