Angew.Chem.Int.Ed.http://doi.org/f2tmj7(2014)

Chiral amines are found in numerous pharmaceuticals and bioactive natural products. As a result, methods for their asymmetric synthesis are in high demand. Reductive aminations to produce chiral primary amines — in which a prochiral ketone is combined with an amine donor — were identified by a recent round-table meeting of pharmaceutical producers as an aspirational target for green chemistry research. Several classes of enzyme have been shown capable of mediating such reactions and have been applied at both the discovery and manufacturing scale.

Now, Anthony Green and Nicholas Turner from the University of Manchester in collaboration with Elaine O'Reilly from Manchester Metropolitan University have reported the use of an amine donor that could dramatically enhance the efficiency of reductive aminations catalysed by ω-transaminases as well as facilitate the screening process used to identify active enzymes. The key to achieving useful conversions in these reactions is the displacement of an equilibrium that usually favours the starting materials, and several approaches to this have been developed. At the discovery laboratory level, the use of excess alanine as the amine donor, combined with a second enzyme to remove the pyruvate by-product, has been successful. On larger scales, the expense makes such an approach unfavourable and excess isopropylamine has been used as donor, with the by-product — in this case acetone — removed by evaporation. The researchers identified ortho-xylylenediamine as a particularly effective amine donor. Just one equivalent of it is required to obtain high conversions with a variety of ketone starting materials, and use of only 1.5 equivalents gave 73% conversion of the challenging substrate 1-indanone.

The by-product from this donor is removed from the equilibrium by cyclization followed by tautomerization to form isoindole. This then undergoes a spontaneous polymerization to produce a highly coloured product, which acts as a built-in detection system for conversion. Green, Turner and O'Reilly went on to show that this method of detection could facilitate the development of high-throughput screens for the identification of new enzymes.