Enhancing catalytic efficiency in asymmetric Henry reaction

AuszugChirotechnology is an important technique of modern chemical engineering that focuses on effective production of chiral chemicals, which market has been expanded continuously since the 1970s. The catalytic asymmetric Henry reaction is expected to find an application in chirotechnology. This reaction is economically attractive, because it produces valuable chiral compounds (ß-nitroalcohols) from cheap achiral bulk chemicals (carbonyls and nitroalkanes). However, despite high adding value potential the asymmetric Henry reaction has not been used on an industrial scale yet. The reason for that is the absence of suitable catalysts, which satisfy all process requirements: to be active, enantioselective, stable and cheap. Although there are plenty of highly enantioselective catalysts for the Henry reaction, virtually all of them have very low activity, which requires high catalyst loadings (up to 20 mol %) in order to get acceptable levels of product yield and enantiopurity. There are two different strategies to overcome this challenge: to search for a new more active catalyst, or to try to improve the existing ones by reaction and catalyst engineering. The present work focuses on the second approach applied to two distinct catalysts—the natural enzyme hydroxynitrile lyase from Hevea brasiliensis and the artificial “privileged” chiral ligand bisoxazoline. Condensation of benzaldehyde and nitromethane yielding 2-nitro-1-phenylethanol was selected as a model reaction system for both catalysts. In the first case study the enzyme was subjected to reaction engineering. The performed kinetic investigations revealed that the enzyme is more active in the retro-Henry reaction, where the (S)-ß-nitroalcohol is cleaved to benzaldehyde and nitromethane. Based on that finding, the effective racemic resolution of (rac)-2-nitro-1-phenylethanol was designed, in which the catalyst productivity could be increased 10-folds in comparison to synthesis of the ß-nitroalcohol. Moreover, the racemic resolution has made the enzyme enantioflexible: now the (S)-enantioselective biocatalyst can be used to produce either (R)- or (S)-enantiomers on demand. In the second case study bisoxazoline was subjected to the catalyst engineering, which goal was to make the catalyst rather recyclable than more active. To reach that goal, the ligand was immobilized on a hyperbranched polyglycerol via a specially designed easy-scalable synthetic route. The obtained “chemzyme”, which mimics enzymes in size, showed high enantioselectivity (up to 86 % ee) in the model reaction, and due to its high molecular weight could be easily recovered from the reaction mixture by ultrafiltration. The catalyst recovery by ultrafiltration allowed to carry out the continuous synthesis of (R)-2-nitro-1-phenylethanol in a membrane reactor operating for 20 days without significant loss of product enantiopurity.