David Rozzell

Formal Asymmetric Biocatalytic Reductive Amination

Asymmetric methods to prepare optically active a-chiral primary amines are highly demanded in asymmetric synthesis owing to the biological/pharmacological activity of many amines. Various techniques have been reported, such as asymmetric 1,2-addition to imines and asymmetric amination of a,a-disubstituted aldehydes, transformation of allylic alcohols into amines, (dynamic) kinetic resolution, and cyclic deracemization employing racemic amines as substrates. Asymmetric reductive amination of ketones has been investigated with transition-metal catalysts and organocatalysts, as well as via sulfinyl imine intermediates. Although tremendous progress in organo/metal catalysis has been achieved for the asymmetric reductive amination of ketones to access a-chiral amines, improved protocols are still required that are simple, green, and economically viable and that lead to high enantiomeric excesses. Biocatalytic reductive amination or transamination is well established for accessing a-amino acids from the corresponding a-keto carboxylic acids. However, the situation is different for primary amines that are not adjacent to a carbonic acid moiety. w-Transaminases have recently received attention for the preparation of such a-chiral unprotected amines. w-Transaminases are employed mainly in one way, namely for the kinetic resolution of racemic chiral amines; only a few reports deal with asymmetric synthesis by starting from a prochiral ketone, probably due to problems in shifting the equilibrium to the product side, as well as due to the moderate stereoselectivity of the employed w-transaminases. These asymmetric synthetic processes usually require at least stoichiometric amounts of an amine donor (for example, alanine). The latter leads to a side product (pyruvate), which has to be removed during the transformation by using, for instance, pyruvate decarboxylase or lactate dehydrogenase. Additionally, limitations due to inhibition by the product amine and by pyruvate have been reported. An ideal process would use ammonium as the amine donor, together with a cheap reducing agent (for example, formate, hydrogen, or glucose; see Scheme 1). Even