Total Syntheses of Polyhydroxylated Steroids by an Unsaturation-Functionalization Strategy.

Highly oxygenated cardiotonic steroids, such as ouabain, possess a wide spectrum of biological functions and remain significant synthetic challenges. Herein, we have applied an unsaturation-functionalization strategy and developed a synthetic method in addressing the C19-hydroxylation issue for efficient synthesis of polyhydroxylated steroids. An effective asymmetric dearomative cyclization allowed the construction of the C19-hydroxy unsaturated steroidal skeleton in only four steps from the Hajos-Parrish ketone ketal 7. The synthetic sequence featured C3-OH-directed hydrogenation/epoxidation, m-CPBA-triggered epoxidation/S N 2' nucleophilic substitution, Birch reduction of an enone, and regioselective LiAlH 4 reduction to furnish the polyhydroxy functionalities on the steroid skeleton with high stereochemical control and efficiency. This approach ultimately enabled the total synthesis of 19-hydroxysarmentogenin and ouabagenin in 18 and 19 steps, respectively, overall. The synthesis of these polyhydroxylated steroids offers synthetic versatility and practicality in the search for new therapeutic agents.