Asymmetric Synthesis of Primary and Secondary β-Fluoro-arylamines using Reductive Aminases from Fungi

Gideon James Grogan, Mahima Sharma, Anibal Cuetos, Iván Lavandera, Vicente Gotor-Fernández, Daniel Gonzalez-Martinez, Marina Garcia-Ramos

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The synthesis of chiral amines is of central importance to pharmaceutical chemistry, and the inclusion of fluorine atoms in drug molecules can both increase potency and slow metabolism. Optically enriched β-fluoroamines can be obtained by the kinetic resolution of racemic amines using amine transaminases (ATAs), but yields are limited to 50%, and also secondary amines are not accessible. In order to overcome these limitations, we have applied NADPH-dependent reductive aminase enzymes (RedAms) from fungal species to the reductive amination of β-fluoroacetophenones with ammonia, methylamine and allylamine as donors, to yield β-fluoro primary or secondary amines with >90% conversion and between 85 and 99% ee. In addition, the effect of the progressive introduction of fluorine atoms to the β-position of the acetophenone substrate reveals the effect of mono-, di- and tri-fluorination on the proportion of amine and alcohol in product mixtures, shedding light on the promiscuous ability of imine reductase (IRED)-type dehydrogenases to reduce fluorinated acetophenones to alcohols.
Original languageEnglish
Early online date10 Feb 2020
Publication statusE-pub ahead of print - 10 Feb 2020

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