合成路线1

Hydrolysis of diester (I) with KOH in water/EtOH at 55 C gives the dicarboxylic acid (II), which is subjected to cyclization by refluxing with propionic anhydride to provide anhydride (III). Cyclic anhydride (III) is opened with allyl alcohol (XI) in diethyl ether in the presence of (­)-quinine as asymmetric inducer to yield (­)-1,2-cis-4-methylenecyclopentane-1,2-dicarboxylic acid monoallyl ester (­)-(XII), which is then converted into the amide derivative (­)-(XIII) by activation of the carboxylic acid group with isobutyl chloroformate in ethyl acetate in the presence of N-ethylmorpholine at ­6 C, followed by reaction with aqueous ammonia. Removal of the allyl group of (­)-(XIII) with triphenylphosphine, tetrakis(triphenylphosphine)palladium and 2-ethylhexanoic acid sodium salt in ethyl acetate affords (­)-1,2-cis-2-(aminocarbonyl)-4-methylenecyclopentane-1-carboxylic acid sodium salt (­)-(XIV). Compound (­)-(XIV) is subjected to a Hofmann rearrangement with KOH and KOCl in water to provide a crude aqueous solution containing PLD-118, which is finally purified by protection of the free amine group with N-(9-fluorenylmethoxycarbonyloxy)succinimide by means of Na2CO3 in dioxane followed by Fmoc removal with piperidine in diethyl ether.