Stereocontrolled synthesis of 4-substituted (±)-kainic acids

Racemic 4-substituted kainic acids 4a,b have been synthesized from ethyl (1SR, 2SR, 5RS, 6RS)-N-(benzyloxycarbonyl)-3-aza-6-hydroxy-6-methylbicyclo[3.3.0]octane-2-carboxylate (7) after its transformation in the pyroglutamate derivative 6. The key step in the synthesis has been the regioselective alkylation of 6 to obtain 11a,b, without compromising the stereogenic integrity of the potentially labile C-2 center. The elaboration of the C-3 and C-4 substituents of kainic acid over 11 was achieved after double bond isomerization of 11, oxidative double bond cleavage of 5, and chemoselective aldehyde reduction of 16 followed by Wittig olefination reaction of 17 and final alcohol oxidation and hydrolysis over 18 to the corresponding 4-methyl kainic acid 4a and 4-benzyl kainic acid 4b. The relatively small changes introduced in the structure of kainic acid 1 have been found to lead to a loss of affinity for kainate receptors.