Transesterification and amide cis–trans isomerization in Zn and Cd complexes of the chelating amino acid ligand Boc–Asp(Dpa)–OBzl

Abstract

The amino acid derivative Boc–Asp–OBzl (Boc = N-butyloxycarbonyl; Asp = aspartic acid; Bzl = benzyl) was functionalized by coupling its carboxylate side chain to dipicolylamine. This yielded the tridentate nitrogen donor ligand Boc–Asp(Dpa)–OBzl (1-OBzl). The compound 1-OBzlcontains three different carbonyl groups: a tertiary amide linkage between Asp and Dpa, a C-terminal benzyl ester function, and an N-terminal urethane protecting group. NMR spectra were used to compare the reactivity of these moieties. The Boc protecting group gives rise to two isomers, (E, 9%) and (Z, 91%). Coordination of Cd(NO₃)₂ and Zn(NO₃)₂ yielded the complexes 3 and 4. These compounds have significantly reduced barriers to rotation about the tertiary amide C–N bond compared with the free ligand (1-OBzl: 18.5 kcal mol^–1 in CDBr₃; 3: 12.9 kcal mol^–1 in (CD₃)₂CO; 4: 13.8 kcal mol^–1 in (CD₃)₂CO). Both complexes readily undergo transesterification in methanol or CD₃OD. Experimental pseudo-first order rate constants were determined in CD₃OD (3) and (CD₃)₂CO : CD₃OD (3 : 1; 4). It was found that the zinc complex 4 (k = (2.28 ± 0.02) × 10^–4 s^–1) is significantly more reactive than the cadmium complex 3 (k = (1.41 ± 0.03) × 10^–6 s^–1). In order to study their tertiary amide cis–trans isomerization, the cadmium complex [(1-OCH₃)Cd(NO₃)₂] (5) was synthesized, and the zinc complex [(1-OCD₃)Zn(NO₃)₂] (6) was generated in situ in (CD₃)₂CO : CD₃OD (3 : 1). The barriers to rotation were determined (5: 14.1 kcal mol^–1 in CD₃OD; 6: 13.4 kcal mol^–1 in (CD₃)₂CO : CD₃OD (3 : 1)). Our results show that the stronger Lewis-acid zinc(II) is significantly more active than cadmium(II) in the acceleration of the transesterification. This is in marked contrast to the tertiary amide bond rotation which is comparably fast with both metal ions.