The Three-Component Coupling Synthesis of Prostaglandins

Article abstract of DOI:10.1021/ja00222a033

A convergent one-pot construction of the prostaglandin (PG) framework has been accomplished by the organocopper-mediated conjugate addition of the S configurated ω side-chain unit to a protected (R)-4-hydroxy-2-cyclopentenone followed by trapping of the enolate intermediate by α side-chain alkyl halides.Transmetalation with use of triphenyltin chloride at the enolate stage serves as key operation for the succesful three-component coupling synthesis.The use of methyl (Z)-7-iodo-5-heptenoate as the α side-chain component allows short synthesis of PGE₂ and PGD₂.Introduction of a triple bond at the C-5-C-6 positions with methyl 7-iodo-5-heptynoate as the α side-chain synthon has opened a general entry of PGs.The protected 5,6-didehydro-PGE₂ derivatives are convertible to a variety of PGs of 1 and 2 series by the controlled hydrogenation of the C-5-C-6 unsaturated bonds and α-selective (100percent) reduction of the C-9 keto function, if necessary.Lithium aluminum hydride reagents modified by (R)- and (S)-2,2'-dihydroxy-1,1'-binaphthyl exhibit a unique kinetic discrimination in reduction of PGE type compounds.A protected 5,6-didehydro-PGF_2α has been transformed stereoselectively to PGI₂ by using intramolecular alkoxypalladation/depalladation as the key step.