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

doi:10.1002/cctc.201901999

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

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

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 language	English
Journal	ChemCatChem
Early online date	10 Feb 2020
DOIs	https://doi.org/10.1002/cctc.201901999
Publication status	E-pub ahead of print - 10 Feb 2020

Bibliographical note

© 2020 WILEY‐VCH Verlag GmbH & Co. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

Access to Document

10.1002/cctc.201901999

Accepted_Article
© 2020 WILEY‐VCH Verlag GmbH & Co. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.
Accepted author manuscript, 719 KB

Cite this

@article{64aeb42062d6433c80d86dca101355f7,

title = "Asymmetric Synthesis of Primary and Secondary β-Fluoro-arylamines using Reductive Aminases from Fungi",

abstract = "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.",

author = "Grogan, {Gideon James} and Mahima Sharma and Anibal Cuetos and Iv{\'a}n Lavandera and Vicente Gotor-Fern{\'a}ndez and Daniel Gonzalez-Martinez and Marina Garcia-Ramos",

note = "{\textcopyright} 2020 WILEY‐VCH Verlag GmbH & Co. This is an author-produced version of the published paper. Uploaded in accordance with the publisher{\textquoteright}s self-archiving policy. Further copying may not be permitted; contact the publisher for details.",

year = "2020",

month = feb,

day = "10",

doi = "10.1002/cctc.201901999",

language = "English",

journal = "ChemCatChem",

issn = "1867-3880",

publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - Asymmetric Synthesis of Primary and Secondary β-Fluoro-arylamines using Reductive Aminases from Fungi

AU - Grogan, Gideon James

AU - Sharma, Mahima

AU - Cuetos, Anibal

AU - Lavandera, Iván

AU - Gotor-Fernández, Vicente

AU - Gonzalez-Martinez, Daniel

AU - Garcia-Ramos, Marina

N1 - © 2020 WILEY‐VCH Verlag GmbH & Co. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

PY - 2020/2/10

Y1 - 2020/2/10

N2 - 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.

AB - 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.

U2 - 10.1002/cctc.201901999

DO - 10.1002/cctc.201901999

M3 - Article

SN - 1867-3880

JO - ChemCatChem

JF - ChemCatChem

ER -