Bufadienolides. 6. Synthesis of 17β-(6′α-Pyronyl)androstanes

Condensation of aldehyde 2a with the anion prepared from diethyl cyanomethylphosphonate provided the isomeric cis,trans- and cî's,as-dienes 3a and 4. The geometrical isomers gave Cotton-effect curves with opposite sign. Similarly, aldehyde 5 led to olefins 6a and 7. Ozonolysis of the isomeric dienes 6a and 7 gave, in each case, 17β-carboxylic acid methyl ester 8, thereby eliminating the possibility of epimerization at position 17. Aldehyde 2a, on condensation with the anion derived from diethyl carbethoxymethylphosphonate, gave a single product, cis,trans olefin 3b. The ester 3b was converted into isobufadienolide 10 by hydrolysis with perchloric acid in ether, saponification with 5% potassium hydroxide in methanol, and enol lactonization with ethyl acetate-acetic anhydride-perchloric acid. A related but more efficient synthesis of 2-pyrone 10 was realized using t-butyl ester 6b. An even more convenient new synthesis of 6-substituted 2-pyrones was achieved by condensation of the aldehyde (e.g., 2a) precursor with malonic acid. The scope of this new reaction was illustrated by preparing isobufadienolides 10, 12, and 16 and pyrone 14.