The use of enzymes in organic synthesis has become increasingly practical with the advent of directed evolution. This approach has allowed wild type proteins to be customized to accept foreign substrates and to function under reaction conditions not compatible with their wild type progenitors. With few exceptions, most enzyme classes employed to date for organic synthesis affect functional group manipulations or oxidation state changes. Examples include hydrolysis of esters, amides or nitriles; the reduction or transamination of ketones; and the oxidation of sulfides. There have been fewer examples, such as aldolases, where enzymes are used to give products with significant increases in molecular weight. In this report the development of reductive aminases through directed evolution will be presented. This class of enzymes allows for the combination of two simple components, a ketone and an amine of comparable molecular weight, to afford chiral amine products. As is normally the case with enzymatic catalysis, these transformations proceed with a high degree of stereo control. Libraries of reductive aminases have been built with enough diversity to access not only R and S enantiomers of the compounds of interest, but also to employ racemic ketones in dynamic kinetic resolution processes. This allows for selective access to all four possible isomeric products.

Development of reductive aminases: Useful tool for efficient chiral amine synthesis

2019 Fall National Meeting

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