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

Abstract

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 4 steps from the Hajos-Parrish ketone ketal 7. A synthetic sequence featured C3-OH directed hydrogenation/epoxidation, m-CPBA triggered epoxidation/S N 2' nucleophilic substitution, Birch reduction of enone, and regioselective LiAlH4 reduction furnished the polyhydroxy functionalities on the steroid skeleton in high stereochemical control and efficiency, which has ultimately enabled thetotal synthesis of 19-hydroxysarmentogenin and ouabagenin in 18 and 19 overall steps, respectively. The syntheses of these polyhydroxylated steroids has offered synthetic versatility and practicality in search for new therapeutic agents.