Efficient Biocatalytic Reductive Aminations by Extending the Imine Reductase Toolbox

Roiban, Gheorghe‐Doru; Kern, Marcelo; Zhi, Lin; Hyslop, Julia F.; Tey, Pei Lyn; Levine, Matthew S.; Jordan, Lydia S.; Brown, Kristin K.; Hadi, Timin; Ihnken, Leigh Anne F.; Brown, Murray J. B.

doi:10.1002/cctc.201701379

Cited by 85 publications

(94 citation statements)

References 33 publications

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“…[14,15] When presented with ketones, such as acetophenone, and a large excess of ammonia or other amine, these NADPH-dependent enzymes catalyze the asymmetric reduction of imines formed in solution, to give chiral amine products such as α-methylbenzylamine (3 b) in a theoretically quantitative yield and with high enantiomeric excess (Scheme 2). 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 [a] D.…”

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confidence: 99%

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

et al. 2020

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“…These included 44 new enzymes and 4 previously disclosed ones (Table S1 and Figure S1 in the Support-ing Information). [10][11] Genes encoding these IREDs were synthesized based on the codon bias of E. coli, cloned into pET28a or pET21a, and overexpressed in E. coli BL21 (DE3). The resulting cell-free extracts were used to examine their activity and enantioselectivity towards substrate 4 h, and the results are presented in Table 1.…”

Section: Resultsmentioning

confidence: 99%

Imine Reductase‐Catalyzed Enantioselective Reduction of Bulky α,β‐Unsaturated Imines en Route to a Pharmaceutically Important Morphinan Skeleton

Yao

Sheng

et al. 2018

Adv Synth Catal

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The morphinan skeleton is an important sub-structure in many medicines such as dextromethorphan, and can be constructed from 1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (1-benzyl-OHIQ) derivatives. 1-Benzyl-3,4,5,6,7,8-hexahydroisoquinolines (1-benzyl-HHIQs), the precursors of 1-benzyl-OHIQs, constitute a type of bulky a, b-unsaturated imines. Until now, the application of imine reductases (IREDs) to a, b-unsaturated imines has only rarely been reported. In this study, through evaluation of 48 IREDs, both enantiomers of 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (1-(4-methoxybenzyl)-OHIQ) were obtained in high yield and excellent optical purity. Among the enzymes, the most steric hindrance-tolerant IRED from Sandarearacinus amylolyticus (IR40) was able to convert various phenyl substituted 1-benzyl-HHIQ to the corresponding 1-benzyl-OHIQ derivatives with excellent enantiometric excess. These results provide an effective route to synthesize these important compounds via enantioselective reduction of bulky a, b-unsaturated imine precursors, which can be readily prepared from 2-(1-cyclohexenyl) ethylamine and corresponding aryl acetic acids.

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“…One of the more recent additions to the suite of biocatalysts available for chiral amine synthesis are imine reductases (IREDs), which catalyze the asymmetric reduction of prochiral imines by using the cofactor NADPH (Figure a) . It has also been shown that, as well as the reduction of preformed imines, certain enzymes of this class can also enable reductive amination between a carbonyl and amine substrate . Furthermore, we recently identified enzymes from a subgroup of the IRED enzyme family that catalyze imine formation as well as imine reduction.…”

Section: Figurementioning

confidence: 99%

“…Aniline ( d ), was also a substrate for several of the biocatalysts. Due to the lower nucleophilicity of arylamine systems compared to simple alkylamines, enzymes that are capable of utilizing d in reductive aminations with ketones are of particular interest, with some recent advances in this area made independently by Roiban et al . during the course of our investigations.…”

Section: Figurementioning

confidence: 99%

“…In summary, we identified a new set of bacterial enzymes capable of performing reductive amination reactions. Several enzymes were found that gave high conversions at low amine equivalents with primary and secondary amines, as well as some with aniline, which, until recently, had not been extensively demonstrated as a substrate for reductive aminations with RedAms or IREDs. Preparative‐scale biotransformations demonstrated the potential application of these enzymes, particularly for reactions with near‐stoichiometric quantities of ketone and amine.…”

Section: Figurementioning

confidence: 99%

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Identification of Novel Bacterial Members of the Imine Reductase Enzyme Family that Perform Reductive Amination

et al. 2018

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Reductive amination of carbonyl compounds constitutes one of the most efficient ways to rapidly construct chiral and achiral amine frameworks. Imine reductase (IRED) biocatalysts represent a versatile family of enzymes for amine synthesis through NADPH‐mediated imine reduction. The reductive aminases (RedAms) are a subfamily of IREDs that were recently shown to catalyze imine formation as well as imine reduction. Herein, a diverse library of novel enzymes were expressed and screened as cell‐free lysates for their ability to facilitate reductive amination to expand the known suite of biocatalysts for this transformation and to identify more enzymes with potential industrial applications. A range of ketones and amines were examined, and enzymes were identified that were capable of accepting benzylamine, pyrrolidine, ammonia, and aniline. Amine equivalents as low as 2.5 were employed to afford up to >99 % conversion, and for chiral products, up to >98 % ee could be achieved. Preparative‐scale reactions were conducted with low amine equivalents (1.5 or 2.0) of methylamine, allylamine, and pyrrolidine, achieving up to >99 % conversion and 76 % yield.

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Efficient Biocatalytic Reductive Aminations by Extending the Imine Reductase Toolbox

Cited by 85 publications

References 33 publications

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

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

Imine Reductase‐Catalyzed Enantioselective Reduction of Bulky α,β‐Unsaturated Imines en Route to a Pharmaceutically Important Morphinan Skeleton

Identification of Novel Bacterial Members of the Imine Reductase Enzyme Family that Perform Reductive Amination

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