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

Abstract

An efficient synthesis of hippuristanol (<b>1</b>), 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 <b>1</b> in 11% overall yield from hydrocortisone in 15 linear steps. Modifications to the parent molecule <b>1</b> 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-α and C11-β hydroxyl functional groups on rings A and C, respectively, are critical for the inhibitory activity of natural product <b>1</b>