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 [pK_a = 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^–] [k_E = 3.8 × 10^–2 dm³ mol^–1 s^–1, I = 1.00 M (NaClO₄), 25 °C] with the diastereoisomer ratio K_C(=[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.