82255-42-3Relevant articles and documents
Asymmetric Synthesis of Primary and Secondary β-Fluoro-arylamines using Reductive Aminases from Fungi
González-Martínez, Daniel,Cuetos, Aníbal,Sharma, Mahima,García-Ramos, Marina,Lavandera, Iván,Gotor-Fernández, Vicente,Grogan, Gideon
, p. 2421 - 2425 (2020/03/25)
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.
Efficient asymmetric synthesis of aryl difluoromethyl sulfoxides and their use to access enantiopure α-difluoromethyl alcohols
Batisse, Chloé,Céspedes Dávila, Maria F.,Castello, Marco,Messara, Amélia,Vivet, Bertrand,Marciniak, Gilbert,Panossian, Armen,Hanquet, Gilles,Leroux, Frédéric R.
, p. 3063 - 3079 (2019/05/07)
The -CHF2 moiety has shown a growing interest in pharmaceutical and agrochemical applications over the last few years. Its introduction is therefore a current research topic for organic chemists. Several groups have reported the synthesis of di
Molecular Basis for the High Activity and Enantioselectivity of the Carbonyl Reductase from Sporobolomyces salmonicolor toward α-Haloacetophenones
Chen, Xi,Zhang, Hongliu,Feng, Jinhui,Wu, Qiaqing,Zhu, Dunming
, p. 3525 - 3531 (2018/04/14)
In an effort to develop a practical method for the synthesis of optically pure 2,2,2-trifluoro-1-phenylethanol, we found that the carbonyl reductase (SSCR) from Sporobolomyces salmonicolor showed excellent activity and enantioselectivity toward the halogenated acetophenones. Especially, SSCR exhibited more than 1000 times higher activity toward α,α,α-trifluoroacetophenone than unsubstituted acetophenone, a strikingly different observation from the previously well-studied alcohol dehydrogenase (LBADH) from Lactobacillus brevis. Enzyme-substrate docking and site-directed mutagenesis studies revealed the molecular basis for the high enzyme activity and enantioselectivity of SSCR toward the α-halogenated acetophenones. The hydrogen bond of the Asn207 side chain with the substrate halogen atom and the XH/π interaction of the substrate phenyl group with the side chains of Ser222/Thr223 resulted in the formation of the highly reactive conformation of α-halogenated acetophenones in the active site of the enzyme. (S)-2,2,2-Trifluoro-1-phenylethanol was prepared in excellent isolated yield and enantiomeric excess from the reduction of α,α,α-trifluoroacetophenone with mutant T209A. These results suggest that tuning the interactions between the halogen atoms/phenyl group of the substrate and the amino acid residues of the enzyme would lead to valuable mutants for the practical synthesis of β-haloalcohols.
