Synthesis of dydrogesterone by aromatization-dearomatization strategy

Abstract

Dydrogesterone as an agonist of the progesterone receptor is an important and selective synthetic progesterone used for the treatment of a variety of conditions associated with progesterone deficiency including menstrual cycle regulation, infertility, and prevention of miscarriage. Its manufacturing process employing photochemical reactions remains a significant challenge. Herein we report the first total synthesis of dydrogesterone via a key 10α-substitution-selective dearomative cyclizationfree of photochemical protocols starting from Hajos-Parrish ketone. A gram-scale synthesis is also accomplished from readily available 9-hydroxy-4-androstene-3,17-dione through a novel aromatization-dearomatization strategy of ring A in steroid chemistry. Key synthetic features include a facile chemical aromatization of 9-hydroxy-4-androstene-3,17-dione, efficient ligand-controlled asymmetric dearomative cyclization to install the 10α-Me group, and an effective hydroxyl-directed hydrogenation of sterically congested tetrasubstituted olefin to establish the 8β-H,9β-H stereochemistry.