Synthesis and gastrointestinal pharmacology of a 3E,5Z diene analog of misoprostol

Abstract

A stereospecific synthesis and the gastric antisecretory and diarrheal activity of a 3E,5Z diene analogue of misoprostol are described. The key intermediate in the synthesis was an alpha chain truncated acetylene that was obtained by a cuprate/enolate capture procedure on the corresponding cyclopentenone. Palladium-catalyzed coupling of the acetylene with methyl 4-iodo-3(E)-butenoate provided the conjugated enyne. Although selective hydrogenation of the enyne with Lindlar catalyst failed, the desired 3E,5Z diene was obtained with P-2 nickel as catalyst. The diene was about 3 times more potent than misoprostol in inhibiting gastric acid secretion in dogs and also in producing diarrhea in rats.