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 menstr...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.展开更多
基金supported by the National Key R&D Program of China(Nos.2022YFA1503702 and 2021YFF0701001)NSFC(Nos.81971822,82183101,22071261 and 21725205)G.X.was grateful to the Youth Innovation Promotion Association,CAS.
文摘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.
