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 α‐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 α‐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.

中文翻译：

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使用真菌的还原性氨基酶不对称合成伯和仲β-氟代芳基胺

手性胺的合成对药物化学至关重要，药物分子中包含氟原子既可以提高药效又可以减缓新陈代谢。可以使用胺转氨酶（ATA）通过消旋外消旋胺的动力学拆分获得光学富集的β-氟胺，但收率限制为50％，而且仲胺也无法获得。为了克服这些局限性，我们将来自真菌物种的NADPH依赖性还原胺酶（RedAms）应用于以氨，甲胺和烯丙胺为供体的α-氟苯乙酮的还原胺化反应，以生成β-氟伯胺或仲胺，其中> 90％的转化率和85-99％ee。此外，将氟原子逐步引入苯乙酮底物的α位的影响揭示了单氟，二氟和三氟对产物混合物中胺和醇的比例的影响，使混杂溶液上的光减少亚胺还原酶（IRED）型脱氢酶将氟化苯乙酮还原为醇的能力。