Synthesis of (5E)- and (5Z)-11-Deoxy-6,11α-epoxy-Δ5-prostaglandin F1α Sodium Salts: 6,11α-Enol Ether Isomers of Prostacyclin

Article abstract of DOI:10.1021/jo00146a019

The key intermediates, (5S,6R)- and (5R,6R)-11-deoxy-6,11α-epoxy-5-hydroxy cyclic ethers, 22a,b, were prepared from the reaction of a C-9 silyl PGF_2α derivative 12 with mercuric acetate (oxymercuration), followed by conversion of the mercurioacetate substituent to a hydroxy group.Attempts to construct the 6,11α oxygen bridge by reaction of 12 and other C-9 protected PGF_2α derivatives <9-tetrahydropyranyl (11), 9-acetyl (13)> with iodine, N-bromosuccinimide, and phenylselenenyl chloride were unsuccessful.Reaction of 11 and 12 with iodine resulted in removal of the C-9 blocking group and the isolation of 6,9-iodo cyclic ether products.Treatment of 13 with phenylselenenyl chloride gave the β-chlorophenylselenenyl addition adduct 18.Conversion of alcohols 22a,b to their mesylate derivatives, 25a,b, and subsequent reaction with potassium methoxide in dimethyl sulfoxide afforded the labile Δ⁵ enol ethers, 29a,b.The success of this elimination reaction was critically dependent on the base, the reaction solvent, and the workup conditions.The structural assignments of 29a,b were based on their spectral properties and hydrolysis to 6-keto-PGF_1α methyl ester.The stereoconfiguration at C-6 was assigned by conversion of the oxymercuration product obtained from 12 to the 5,6-dihydro-6,11α-cyclic ether 20.The C-5 stereoconfiguration of alcohols 22a,b was established by the mode of formation of enol ethers 29a,b.In contrast to PGI₂ methyl ester, 29a,b in aqueous acid showed a greater tendency to form the internal ketal 34 during hydrolysis to 6-keto-PGF_1α methyl ester.