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Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases

Chiral primary amines are important intermediates in the synthesis of pharmaceutical compounds. Fungal reductive aminases (RedAms) are NADPH-dependent dehydrogenases that catalyse reductive amination of a range of ketones with short-chain primary amines supplied in an equimolar ratio to give corresp...

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Autores principales: Mangas-Sanchez, Juan, Sharma, Mahima, Cosgrove, Sebastian C., Ramsden, Jeremy I., Marshall, James R., Thorpe, Thomas W., Palmer, Ryan B., Grogan, Gideon, Turner, Nicholas J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159254/
https://www.ncbi.nlm.nih.gov/pubmed/34122962
http://dx.doi.org/10.1039/d0sc02253e
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author Mangas-Sanchez, Juan
Sharma, Mahima
Cosgrove, Sebastian C.
Ramsden, Jeremy I.
Marshall, James R.
Thorpe, Thomas W.
Palmer, Ryan B.
Grogan, Gideon
Turner, Nicholas J.
author_facet Mangas-Sanchez, Juan
Sharma, Mahima
Cosgrove, Sebastian C.
Ramsden, Jeremy I.
Marshall, James R.
Thorpe, Thomas W.
Palmer, Ryan B.
Grogan, Gideon
Turner, Nicholas J.
author_sort Mangas-Sanchez, Juan
collection PubMed
description Chiral primary amines are important intermediates in the synthesis of pharmaceutical compounds. Fungal reductive aminases (RedAms) are NADPH-dependent dehydrogenases that catalyse reductive amination of a range of ketones with short-chain primary amines supplied in an equimolar ratio to give corresponding secondary amines. Herein we describe structural and biochemical characterisation as well as synthetic applications of two RedAms from Neosartorya spp. (NfRedAm and NfisRedAm) that display a distinctive activity amongst fungal RedAms, namely a superior ability to use ammonia as the amine partner. Using these enzymes, we demonstrate the synthesis of a broad range of primary amines, with conversions up to >97% and excellent enantiomeric excess. Temperature dependent studies showed that these homologues also possess greater thermal stability compared to other enzymes within this family. Their synthetic applicability is further demonstrated by the production of several primary and secondary amines with turnover numbers (TN) up to 14 000 as well as continous flow reactions, obtaining chiral amines such as (R)-2-aminohexane in space time yields up to 8.1 g L(−1) h(−1). The remarkable features of NfRedAm and NfisRedAm highlight their potential for wider synthetic application as well as expanding the biocatalytic toolbox available for chiral amine synthesis.
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spelling pubmed-81592542021-06-11 Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases Mangas-Sanchez, Juan Sharma, Mahima Cosgrove, Sebastian C. Ramsden, Jeremy I. Marshall, James R. Thorpe, Thomas W. Palmer, Ryan B. Grogan, Gideon Turner, Nicholas J. Chem Sci Chemistry Chiral primary amines are important intermediates in the synthesis of pharmaceutical compounds. Fungal reductive aminases (RedAms) are NADPH-dependent dehydrogenases that catalyse reductive amination of a range of ketones with short-chain primary amines supplied in an equimolar ratio to give corresponding secondary amines. Herein we describe structural and biochemical characterisation as well as synthetic applications of two RedAms from Neosartorya spp. (NfRedAm and NfisRedAm) that display a distinctive activity amongst fungal RedAms, namely a superior ability to use ammonia as the amine partner. Using these enzymes, we demonstrate the synthesis of a broad range of primary amines, with conversions up to >97% and excellent enantiomeric excess. Temperature dependent studies showed that these homologues also possess greater thermal stability compared to other enzymes within this family. Their synthetic applicability is further demonstrated by the production of several primary and secondary amines with turnover numbers (TN) up to 14 000 as well as continous flow reactions, obtaining chiral amines such as (R)-2-aminohexane in space time yields up to 8.1 g L(−1) h(−1). The remarkable features of NfRedAm and NfisRedAm highlight their potential for wider synthetic application as well as expanding the biocatalytic toolbox available for chiral amine synthesis. The Royal Society of Chemistry 2020-05-05 /pmc/articles/PMC8159254/ /pubmed/34122962 http://dx.doi.org/10.1039/d0sc02253e Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
Mangas-Sanchez, Juan
Sharma, Mahima
Cosgrove, Sebastian C.
Ramsden, Jeremy I.
Marshall, James R.
Thorpe, Thomas W.
Palmer, Ryan B.
Grogan, Gideon
Turner, Nicholas J.
Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases
title Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases
title_full Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases
title_fullStr Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases
title_full_unstemmed Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases
title_short Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases
title_sort asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159254/
https://www.ncbi.nlm.nih.gov/pubmed/34122962
http://dx.doi.org/10.1039/d0sc02253e
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