19 Prostaglandin E_1および11α-Hydroxymethyl Prostaglandinの立体特異的合成

抄録

It is well known that the Prostaglandins have a various pharmacological activity, ex. an uterin muscle stimulant activity, an inhibition of gastric acid secretion, a bronchodilation activity. As a part of program to elarify the relationship between pharmacological activity and the structure, we undertook the total synthesis of 11α-hydroxymethyl Prostaglandins, in hope that those compounds will exhibit higher and or more selective biological activities than naturally occuring Prostaglandins. The trans-cis lactone (4a,4b) derived from readily prepared dimethoxy carbonyl cyclopentanone (1) has a structural advantage that C-2α will be stereospecifically alkylated by a various alkylating agent leading to PGE_1,PGE_2, 5-dehydro PGE_2 form, and the alkylated lactone (6a,6b) will be deearboxylated without any change of configuration to afford the common key intermediate (7a,7b) to PGE_1 or 11α-hydroxymethyl PGE_5. An optical resolution of (14) using d-ephedrine gave an optically active half ester (15), in which an absolute configuration was determined by two method. A) degradation of Brefeldin A. B) derivative from the enantiomer of Corey's synthetic intermediate. In addition to PGE_1 from (7a), (-)11-deoxy-11α-hydroxymethyl PGE_1, (±)11-deoxy-11α-hydroxymethyl PGE_2, (±)11-deoxy-11α-hydroxymethy1-5-dehydro PGE_2 were stereospecifically synthesized. (-)11-deoxy-11α-hydroxymethyl PGE_1 showed the same power as PGF_<2>α for uterine contraction in pregnant rat, and a diarrhoea as a side effect of natural PGE was not observed.