AN EFFICIENT SYNTHESIS OF THE ANTISECRETORY PROSTAGLANDIN ENISOPROST

A 13-step synthesis of the antisecretory prostaglandin enisoprost was previously reported by Collins et al. 1 in 1983. The reported synthesis involved coupling of enone 6 with a cuprate reagent2 derived from a suitably substituted vinylstannane and cuprous pentyne to give enisoprost 10 in 60% yield after removal of protecting groups and chromatographic purification. Further development work on the synthesis of enisoprost has resulted in an improved method for preparing the key enone precursor 6 as outlined in Scheme I. Use of the trans-vinyl iodide 9 in place of the corresponding vinylstannane derivative and use of dilithiocyanocuprate3 coupling technology resulted in an 85% isolated yield of enisoprost 10 as outlined in Scheme II. Direct conversion of the terminal acetylene 8b into protected enisoprost via a one-pot process has also been accomplished as outlined in Scheme II. This latter modification greatly simplified the process and resulted in a 71% isolated yield of enisoprost 10.