PLD-118

Abstract

SynthesisPLD-18 can be obtained by three related ways: 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 Fmocamino 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 (1). Scheme 1.2) 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

Advanced procedure for the enzymatic ring opening of unsaturated alicyclic β-lactams

“…[1][2][3][4] Some cyclic b-amino acids themselves exhibit biological activity (e.g., cispentacin, with antibacterial activity; 5;6 or PLD-118, with antifungal activity, which is currently under clinical investigation). 7 Such compounds can be used as precursors of b-lactams; 8;9 as building blocks for the synthesis of modified peptides with increased activity and stability 10;11 or in drug research. [12][13][14] Cyclic b-lactams are also important as intermediates in the synthesis of b-amino acids, 15 short peptide segments, 16 taxoid antitumour agents, 17 alkaloids 18 and heterocycles of biological and medicinal importance.…”

Β-Amino ACIDS AND THEIR NATURAL BIOLOGICALLY ACTIVE DERIVATIVES. 5. DERIVATIVES OF UNUSUAL ALICYCLIC AND HETEROCYCLIC Β-Amimo ACIDS

“…For some 5and 6-membered β-amino acids a unique anti fungal activity has been observed, 7-membered β-amino acid derivatives have been investigated for neurological disorders (35). Alicyclic β-amino acids are one class of potent antifungals that have a dual mode of action: These compounds inhibit protein synthesis after concentrative uptake and interfere with self-regulatory mechanisms of amino acid metabolism (64). Alicyclic β-amino acids and their residues are amino acids with two chiral centers resulting in four possible configurations; two config-urational cis (R,S and S,R) and two configurational trans (R,R and S,S) forms.…”

“…Because of its potent specific activity observed against Candida spp. including azole-resistant strains in vitro and in vivo, in addition to its excellent pharmacokinetics, solubility and safety, PLD-118 was chosen for further development for systemic treatment of Candida infections(64).…”