A Mechanism for Reductive Amination Catalyzed by Fungal Reductive Aminases

Sharma, Mahima; Mangas‐Sánchez, Juan; Aleku, Godwin A.; Montgomery, Sarah L.; Ramsden, Jeremy I.; Turner, Nicholas J.; Grogan, Gideon

doi:10.1021/acscatal.8b03491

Cited by 84 publications

(133 citation statements)

References 38 publications

(57 reference statements)

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“…A similar trend was observed for equivalent biotransformations catalyzed by NfRedAm from Neosartorya fumigatus (Figure 1). Additional results obtained for AtRedAm from Aspergillus terreus, [19] NfisRedAm from Neosartorya fischeri, and AspRedAm from Aspergillus oryzae [16] can be found in the Supporting Information (SI, Section VII, Figure S5, Table S2). It is important to note that in control reactions, which were performed in the absence of RedAm, but with both the cofactor and the cofactor recycling system, neither amination reactions, nor reduction of the ketones to alcohols, were observed.…”

Section: Biotransformations Of Fluorinated Acetophenones By Fungal Rementioning

confidence: 79%

“…Under these conditions, we assume that the RedAms are acting in an IRED mode, binding and reducing the imine formed in solution, as acetophenones are not good substrates for equimolar reductive amination reactions. [16,19] Details on gene cloning and protein purification can be found in the Supporting Information (SI, Sections III-IV). The synthesis of substrates and product standards is detailed in SI Section XI.…”

Section: Biotransformations Of Fluorinated Acetophenones By Fungal Rementioning

confidence: 99%

“…The stereoselectivity of the RedAm-catalyzed biotransformations is shown in Table 2 and in the SI (Table S3), and the analytical methods and results detailed in the Supporting Information (SI, Section X), with details on the assignment of absolute configuration (SI, Section XII). In most cases the enantioselectivity of the reactions was very high (up to 99 %), and although these enzymes have been described as (R)-selective, [16,19] products were of the (S)enantiomeric series, except amine 3 b, due to the change in Cahn-Ingold-Prelog (CIP) priority. The ee values for amines 1 b, 6 c and 6 d were especially high, with products obtained in enantiopure form for most examples (SI, Table S3).…”

Section: Biotransformations Of Fluorinated Acetophenones By Fungal Rementioning

confidence: 99%

“…A subgroup of IRED enzymes, reductive aminases (RedAms) [16][17][18] has also been shown to catalyze the formation of the iminium ion with certain ketone and amine partners, with the consequence that the coupling reaction is achieved with the supply of only an equimolar ratio of the substrates. [16,19] Interestingly, when presented with α,α,αtrifluoroacetophenone 5 a (Scheme 2), a promiscuous reduction of the ketone to the alcohol 5 e is performed by an IRED from Streptosporangium roseum (SrIRED), [20] a reaction which has thus far not been observed in any other IRED/RedAm-catalyzed transformation of any carbonyl substrate.…”

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

et al. 2020

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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. Chiral amines are significant functional groups that feature prominently in many pharmaceuticals. There are many asymmetric methods for their synthesis that use transition metal catalysis coupled to chiral ligands, [1,2] but considerations of selectivity, sustainability and green chemistry have dictated that biocatalytic methods have achieved prominence in recent years. [3][4][5] The synthesis of fluoroamines represents a special case of chiral amine synthesis, as the addition of the fluorine atom can improve the efficiency of bioactive molecules through increased potency or slower metabolism. [6,7] β-Fluoroamines are very interesting derivatives as they can be excellent pyridoxal 5'-phosphate (PLP)-dependent enzyme inhibitors. [8] They can be synthesized simply through the ring opening of N-tosyl aziridines with TBAF, [9] but their asymmetric synthesis is rare, and complicated if chirality at both the amine and fluorinebearing carbons is under consideration. In a recent example, Vara and Johnston used Brønsted base catalysts, such as (MeO) 2 PBAM · HNTf, for the enantioselective synthesis of Bocprotected β-amino-α-fluoro-nitroalkanes from α-fluoro arylnitromethane and aldimine precursors. [10] Other examples using organocatalytic catalysts have been provided by Lindsley and co-workers, [11,12] who performed the enantioselective fluorination of N-sulfinyl aldimines, followed by nucleophilic addition using a Grignard reagent, providing the final compounds in high dr (> 20 : 1).More recently, we showed that amine transaminases (ATAs) can be applied to the 100 mg scale asymmetric synthesis of βfluoroamines, with up to 99 % ee., through the kinetic resolution of racemic substrates. [13] A series of racemic β-fluoro arylethylamines including 1 b and 2 b (Scheme 1) was converted by both (S)-and (R)-selective ATAs to give the corresponding enantiopure β-fluoroamines, in addition to acetophenones 3 a and 4 a, co-products that arise through the enanti...

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Section: Biotransformations Of Fluorinated Acetophenones By Fungal Rementioning

confidence: 79%

Section: Biotransformations Of Fluorinated Acetophenones By Fungal Rementioning

confidence: 99%

Section: Biotransformations Of Fluorinated Acetophenones By Fungal Rementioning

confidence: 99%

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

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“…[2][3][4][5][6] Among these enzymes, imine reductases (IREDs), which catalyze the NAD(P)H-dependent reduction of prochiral imines to chiral amines, have assumed an important role within the biocatalytic toolbox for chiral amine synthesis, following their discovery by Mitsukura et al [7][8][9] A subgroup of IREDs, termed reductive aminases (RedAms), possesses additionally the distinctive ability to carry out reductive aminations in water, when presented with a range of carbonyl compounds and small amine donors in equimolar quantities. 10 We have recently demonstrated that these enzymes catalyze the condensation of cyclic and aliphatic ketones with short-chain amines as well as the subsequent reduction of the imine intermediate, 11 although the substrate scope has until now been mainly limited to the preparation of secondary and tertiary amines. The asymmetric synthesis of chiral primary amines, synthesized via reductive amination of ketones using inexpensive ammonia, continues to be a challenge in synthetic chemistry.…”

Section: Introductionmentioning

confidence: 99%