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Asymmetric Synthesis of Primary and Secondary β‐Fluoro‐arylamines using Reductive Aminases from Fungi
Author(s) -
GonzálezMartínez Daniel,
Cuetos Aníbal,
Sharma Mahima,
GarcíaRamos Marina,
Lavandera Iván,
GotorFernández Vicente,
Grogan Gideon
Publication year - 2020
Publication title -
chemcatchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.497
H-Index - 106
eISSN - 1867-3899
pISSN - 1867-3880
DOI - 10.1002/cctc.201901999
Subject(s) - reductive amination , chemistry , methylamine , amine gas treating , kinetic resolution , yield (engineering) , allylamine , fluorine , primary (astronomy) , acetophenone , amination , imine , organic chemistry , reductase , substrate (aquarium) , combinatorial chemistry , enantioselective synthesis , enzyme , catalysis , materials science , polymer , physics , polyelectrolyte , oceanography , astronomy , geology , metallurgy
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.