Novel metal complex synthons for chiral 4-azaleucine, 2,3-diaminopropanoic acid and its elaboration

Abstract

Efficient syntheses of chiral Co(III) complexes with 2,3-diaminopropanoic acid (A2pr) have been developed. In these complexes, the amino acid zwitterion [A2pr(H+)O–] is bound didentate through the carboxylate and N2-amine groups while the N3-ammonio group [pKa = 7.19(2)] is unprotected. Syntheses of Λ(+)578- and Δ(–)578-[(en)2Co(S-A2pr(H+)O)]Cl3·H2O were effected stereoretentively from the similarly didentate aspartato complexes Λ- and Δ-[(en)2Co(S-Asp(OH)O)]Cl2 in reaction sequences transforming the unbound β-carboxyl group into an amine by Curtius rearrangement. The absolute configuration of the Λ(+)578-[(en)2Co(S-Asp(OH)O)](ClO4)2 complex was determined by X-ray crystallographic analysis and defined the absolute stereochemistry of diastereoisomers and derived products. Methylation of the N3-amine group of Λ(+)578-[(en)2Co(S-A2pr(H+)O)]Cl3·H2O gave the (S)-4-azaleucine complex Λ(+)578-[(en)2Co(S-A2pr(Me2H+)O)](C4F9SO3)3 from which enantiopure (+)-(S)-2-amino-3-(dimethylamino)propanoic acid dihydrochloride hemihydrate [=(+)-(S)-A2pr(Me2)·2HCl·0.5H2O] was obtained upon reductive removal of the protecting Co(III) centre. Racemic 4-azaleucine was easily produced by an alternative, but also metal-dependent method and the intermediate rac-(p)-[(tren)Co(A2pr(Me2H+)O)]Zn2Cl7·3H2O obtained in a simple solid-phase synthesis by selective reduction of achiral (p)-[(tren)Co(2-amino-3-(dimethylamino)acrylyl chloride)]3+ ion adsorbed on AG 50W-X2 cation exchange resin. The epimerization rate of the Λ-[(en)2Co(S-A2prO)]2+ complex ion was first-order in [HO–] [kE = 3.8 × 10–2 dm3 mol–1 s–1, I = 1.00 M (NaClO4), 25 °C] with the diastereoisomer ratio KC(=[Λ-R]/[Λ-S]) = 0.77(2) at equilibrium in 10 mM NaOH. However, no epimerization was observed after at least 3 hours in 6 M HCl at 45 °C.