Three-Component Coupling Synthesis of Prostaglandins: The Aldol Route

Abstract

Abstract A one-pot, high yield construction of the whole prostaglandin (PG) skeleton is accomplishable by combination of the copper-mediated conjugate addition of an ω side-chain unit to a 4R-oxygenated 2-cyclopentenone derivative and aldol condensation of the in situ generated enolate with an α side-chain aldehyde. Subsequent removal of the 7-hydroxyl group from the adducts and deblocking of the protective groups give PGs of E series. PGE1 has been prepared in 56% overall yield through the five-step sequence. Selective transformation of the PGE to PGD structure can be realized simply by appropriate selection of the hydroxyl protective groups in the five-membered ring and ω side-chain units. The vicinal carba-condensation using methyl 6-formyl-5-hexynoate as the α side-chain aldehyde unit followed by deoxygenation from the aldol products gives the 5,6-didehydro-PGE2 derivatives which serve as key intermediates in the general synthesis of various natural PGs. An efficient method for resolution of 4-hydroxy-2-cyclopentenone is also described.