Synthesis of the Antiproliferative Agent Hippuristanol and Its Analogues from Hydrocortisone via Hg(II)-Catalyzed Spiroketalization: Structure-Activity Relationship

An efficient synthesis of hippuristanol (1), a marine-derived highly potent antiproliferative steroidal natural product, and nine closely related analogues has been accomplished from the commercially available hydrocortisone utilizing Hg(II)-catalyzed spiroketalization of 3-alkyne-1,7-diol motif as a key strategy. This practical synthetic sequence furnished 1 in 11% overall yield from hydrocortisone in 15 linear steps. Modifications to the parent molecule 1 encompassed changing the functional groups on rings A and E. Each analogue was screened for their effects on inhibition of cap-dependent translation, and the assay results were used to establish structure-activity relationships. These results suggest that the stereochemistry and all substituents of spiroketal portion (rings E and F) and C3-alpha and C11-beta hydroxyl functional groups on rings A and C, respectively, are critical for the inhibitory activity of natural product 1.