Synthesis of leukotriene B3 derivatives.

Leukotriene B4(LTB4), a metabolite of arachidonic acid, has been reported to have various pharmacological actions such as chemotaxis, chemokinesis, aggregation and degranulation of leukocytes in vitro.' Therefore, it is thought to be a primary mediator in inflammatory and allergic states, and inhibitors of its actions are expected to have therapeutic potential. We planned to synthesize several LTB4 derivatives for a study of the structure-activity relationships, focusing on the stereochemistry of the conjugated triene part.2) The influence of the C-14,15 double bond was removed by saturation, and the carboxyl group was changed into an N,N-dimethylcarbamoyl group, because LTB4 dimethylamide has a strong antagonistic activity.3) Though several synthetic studies on LTB4 itself4) have been reported since its discovery, we have devised a very useful method for constructing geometric isomers of LTB3 derivatives. It is characterized by the combination of two Wittig reactions. In this synthesis, the butyne derivative (5) was used as the middle olefinic part and the other two olefinic parts were introduced by means of Wittig reaction with two phosphonate derivatives, as illustrated in Chart 1. All-trans derivatives (la, lb) were synthesized by Wittig reaction of the enal (6) obtained from 5. trans-cis-trans derivatives (2a, 2b) were synthesized by hydrogenation of the corresponding acetylenic intermediates, which were prepared in a similar manner starting from the ynal (16). trans-trans-cis and cis-trans-trans derivatives (3a, 3b, 4a, 4b) were also synthesized by hydrogenation of the corresponding acetylenic intermediates, which were