One-pot synthesis of (S)-flavanones by a double-face promiscuous chemo-enzymatic cascade of lipases.

The one-pot stereoselective synthesis of (S)-flavanones from 2’-hydroxyacetophenone and substituted aromatic aldehydes was obtained by a double-face promiscuous chemo-enzymatic cascade of porcine pancreas and Mucor javanicus lipases.The reaction pathway comprises: A) cross-aldol condensation catalysed by porcine pancreas lipase to yield chalcone intermediates; B) unprecedented intramolecular oxa-Michael addition of chalcone intermediates to (S)-flavanones. Mucor javanicus lipase was the most effective enzyme in step B. Imidazole and 2-methylimidazole were studied as additive in order to improve the efficacy of the overall transformation. The sustainability of the chemo-enzymatic cascade was increased by immobilization of lipases on cross-linked hydroxy-methylated kraft lignin nanoparticles, by use of concanavalin A. Immobilization conferred considerable stability and reusability at the system for 4 runs. Noteworthy, the reaction mixture was significantly enriched in (S)-flavanones under both homogeneous and heterogeneous conditions. Computational studies encompassing docking and molecular dynamic analyses showed the role played by evolutionary conserved oxyanion holes and catalytic triad of Mucor javanicus lipase in the stereocontrol of the intra-molecular oxa-Michael addition.