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.

Cyclization of the tetracarboxylic acid (XV) gives 4-oxocyclopentane-1,2-dicarboxylic acid (XVI), which is esterified with ethanol and sulfuric acid to yield the diester (XVII). Reaction of diester (XVII) with methyl-(triphenyl)phosphonium bromide and t-BuOK in THF affords 4-methylenecyclopentane-1,2-dicarboxylic acid diethyl ester (XVIII), which is hydrolyzed with KOH in THF/water to provide the corresponding free acid (XIX). The anhydrization of (XIX) by means of propionic anhydride at 135 C gives anhydride (III), which is submitted to an enantioselective quinine-mediated alcoholysis with 3-phenyl-2-propen-1-ol (XX) to yield (1R,2S)-2-amino-4-methylenecyclopentane-1-carboxylic acid 3-phenyl-2-propenyl monoester (XXI). Degradation of the free carboxylic acid group of (XXI) by means of DPPA, TEA and alcohol (XX) in hot toluene affords carbamate (XXII), which is finally fully deprotected with Pd(OAc)2 and PPh3 in ethanol.

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 ? 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.

Cyclization of the tetracarboxylic acid (XV) gives 4-oxocyclopentane-1,2-dicarboxylic acid (XVI), which is esterified with ethanol and sulfuric acid to yield the diester (XVII). Reaction of diester (XVII) with methyl-(triphenyl)phosphonium bromide and t-BuOK in THF affords 4-methylenecyclopentane-1,2-dicarboxylic acid diethyl ester (XVIII), which is hydrolyzed with KOH in THF/water to provide the corresponding free acid (XIX). The anhydrization of (XIX) by means of propionic anhydride at 135 C gives anhydride (III), which is submitted to an enantioselective quinine-mediated alcoholysis with 3-phenyl-2-propen-1-ol (XX) to yield (1R,2S)-2-amino-4-methylenecyclopentane-1-carboxylic acid 3-phenyl-2-propenyl monoester (XXI). Degradation of the free carboxylic acid group of (XXI) by means of DPPA, TEA and alcohol (XX) in hot toluene affords carbamate (XXII), which is finally fully deprotected with Pd(OAc)2 and PPh3 in ethanol.

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.

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 ? 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.

Cyclization of the tetracarboxylic acid (XV) gives 4-oxocyclopentane-1,2-dicarboxylic acid (XVI), which is esterified with ethanol and sulfuric acid to yield the diester (XVII). Reaction of diester (XVII) with methyl-(triphenyl)phosphonium bromide and t-BuOK in THF affords 4-methylenecyclopentane-1,2-dicarboxylic acid diethyl ester (XVIII), which is hydrolyzed with KOH in THF/water to provide the corresponding free acid (XIX). The anhydrization of (XIX) by means of propionic anhydride at 135 C gives anhydride (III), which is submitted to an enantioselective quinine-mediated alcoholysis with 3-phenyl-2-propen-1-ol (XX) to yield (1R,2S)-2-amino-4-methylenecyclopentane-1-carboxylic acid 3-phenyl-2-propenyl monoester (XXI). Degradation of the free carboxylic acid group of (XXI) by means of DPPA, TEA and alcohol (XX) in hot toluene affords carbamate (XXII), which is finally fully deprotected with Pd(OAc)2 and PPh3 in ethanol.

Cyclization of the tetracarboxylic acid (XV) gives 4-oxocyclopentane-1,2-dicarboxylic acid (XVI), which is esterified with ethanol and sulfuric acid to yield the diester (XVII). Reaction of diester (XVII) with methyl-(triphenyl)phosphonium bromide and t-BuOK in THF affords 4-methylenecyclopentane-1,2-dicarboxylic acid diethyl ester (XVIII), which is hydrolyzed with KOH in THF/water to provide the corresponding free acid (XIX). The anhydrization of (XIX) by means of propionic anhydride at 135 C gives anhydride (III), which is submitted to an enantioselective quinine-mediated alcoholysis with 3-phenyl-2-propen-1-ol (XX) to yield (1R,2S)-2-amino-4-methylenecyclopentane-1-carboxylic acid 3-phenyl-2-propenyl monoester (XXI). Degradation of the free carboxylic acid group of (XXI) by means of DPPA, TEA and alcohol (XX) in hot toluene affords carbamate (XXII), which is finally fully deprotected with Pd(OAc)2 and PPh3 in ethanol.