Digitalis-like compounds: Synthesis and biological evaluation of seco-D and D-homo derivatives

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The synthesis of seco-D and D-homo digitalis derivatives, from the carda-14,20(22)-dienolide 1, is described. Selective ozonolysis gave the seco-D 14-ketoaldehyde 2a. Modification of the two carbonyl groups and of the α, β-unsaturated lactone ring of the seco-D 14-ketoaldehyde 2a allowed preparation of derivatives with a broad range of binding affinity to the Na +, K +-ATPase receptor. Some of the seco-D derivatives ( 10, 11b, and 13b) showed a binding affinity similar to that of digitoxigenin, demonstrating that the D-ring is not essential for recognition by the digitalis receptor. In the class of D-homo derivatives the highest binding value, about 15 times lower than that of digitoxigenin, was that of the C >D cis compound 29b; the C D trans analog 28b showed a 7-fold decrease in binding affinity, indicating that the C D configuration plays an important role in D-homo derivatives as in the classical digitalis compounds.