合成路线1

Basic hydrolysis of cis-4-methylenecyclopentane-1,2-dicarboxylic acid diethyl ester (I) with LiOH gives the free acid (II), which by refluxing with propionic anhydride yields the cyclic anhydride (III). Rearrangement using trimethylsilyl azide in dioxane at 80 C produces the oxazinedione (IV), which is hydrolyzed to (±)-cis-2-amino-4-methylenecyclopentane-1-carboxylic acid ethyl ester (V) by means of acetyl chloride in EtOH. Further hydrolysis of ester (V) with aqueous HCl provides the racemic amino acid (VI), which is coupled with N-(9-fluorenylmethoxycarbonyl)succinimide (VII) to afford the Fmoc-amino acid (VIII). Racemic (VIII) is resolved by treatment with (+)-(R)-1-phenylethylamine (IX) and crystallization of the resulting salt (X) in EtOH/methyl tert-butyl ether. Finally, acidification of salt (X) and extraction of the (1R,2S)-free acid, followed by removal of the Fmoc group with liquid ammonia, provides PLD-118 isolated as its hydrochloride salt.