Artificial metalloenzymes based on vancomycin for stereoselective catalysis in aqueous media

Background: Artificial metalloenzymes, stemming from the combination of transition metal catalysts embedded within a biological environment, have recently risen up as a promising approach to merge the reactivity of metal-based catalysis and the specificity of biocatalysis. Dalbapeptides, such as vancomycin, teicoplanin and ristocetin are variously substituted heptapeptides whose antibiotic activity depends on their binding to the D-Ala-D-Ala dimer of peptidoglycan precursors thus resulting in the inhibition of cell wall biosynthesis. In this system, indeed, the source of chirality is due to the presence not only of the aminoacidic chain, but also from the atropoisomerism of their structure. This interaction is stabilized by an array of hydrophobic interactions and five key hydrogen bonds and it is marked by such a low dissociation constant (KD = ~10-17 M). Objective: starting from this background, dalbapeptides can be employed as an innovative alternative to the classical biotin/(strept)avidin second sphere coordination system. Methods: In this context, aminoethylbenzensulfonamide ligands decorated with the D-Ala-D-Ala dimer at different positions of the phenyl ring were employed for the synthesis of the hybrid catalysts in association with an iridium centre. In the presence of vancomycin, a new class of artificial reductases was obtained and applied to the stereoselective synthesis of chiral cyclic in different aqueous media. Results: An encouraging 48% (S) e.e. was obtained in the asymmetric reduction of the salsolidine precursor in NaOAc 0.1 M buffer at pH 5 whereas in the case of the most demanding isoquinoline substrates, the meta-artificial metalloenzyme afforded the product in an outstanding 71% (S) e.e. when applied to quinaldine. Conclusion: The Van/ D-Ala-D-Ala dimer system resulted particularly sensitive to pH variations, thus indicating an interesting change in the conformational arrangement of Van. Indeed, the system shows remarkable potential for the synthesis of chiral sultam precursors under green reaction conditions.