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The synthesis and gastric antisecretory activity in dogs of seven alpha chain diene derivatives of misoprostol are described. The key intermediates in the preparation of these compounds were C-9 tert-butyldimethylsilyl enol ethers that were obtained by in situ silylation of cuprate enolates derived from alpha chain unsaturated cyclopentenones. Selenylation chemistry on these intermediates provided the C2-C3 trans dienes that, where possible, were also deconjugated to produce the corresponding C3-C4 dienes. The most interesting structure in this series is the C5-C6 cis, C3-C4 cis/trans (1:1) diene that could not be readily separated chromatographically into its individual geometric isomers. The gastric antisecretory activity of the mixture of isomers was approximately 3 times greater than that of misoprostol by intragastric administration. The separation of undesired diarrheogenic effects from antisecretory activity was significantly improved relative to misoprostol.
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