Entwicklung einer Amindehydrogenase zur Synthese von chiralen Aminen

Abrahamson, Michael J.; Vazquez-Figueroa, Eduardo; Woodall, Nicholas B.; Moore, Jeffrey C.; Bommarius, Andreas S.

doi:10.1002/ange.201107813

Cited by 65 publications

(8 citation statements)

References 36 publications

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“…The activity of LeuDH was to provide the major inspiration for the engineering, by directed evolution of an “amine dehydrogenase” (AmDH) enzyme that would be capable of reductive amination of the ketone analogue of α‐ketoisocaproate 1 , methyl isobutyl ketone 3 (MIBK, Scheme ) …”

Section: Amino Acid Dehydrogenases and Their Evolution For The Reductmentioning

confidence: 99%

NAD(P)H‐Dependent Dehydrogenases for the Asymmetric Reductive Amination of Ketones: Structure, Mechanism, Evolution and Application

et al. 2017

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Asymmetric reductive aminations are some of the most important reactions in the preparation of active pharmaceuticals, as chiral amines feature in many of the world's most important drugs. Although many enzymes have been applied to the synthesis of chiral amines, the development of reductive amination reactions that use enzymes is attractive, as it would permit the one‐step transformation of readily available prochiral ketones into chiral amines of high optical purity. However, as most natural “reductive aminase” activities operate on keto acids, and many are able to use only ammonia as the amine donor, there is considerable scope for the engineering of natural enzymes for the reductive amination of ketones, and also for the preparation of secondary amines using alkylamines as donors. This review summarises research into the development of NAD(P)H‐dependent dehydrogenases for the reductive amination of ketones, including amino acid dehydrogenases (AADHs), natural amine dehydrogenases (AmDHs), opine dehydrogenases (OpDHs) and imine reductases (IREDs). In each case knowledge of the structure and mechanism of the enzyme class is addressed, with a further description of the engineering of those enzymes for the reductive amination of ketones towards primary and also secondary amine products.

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Section: Amino Acid Dehydrogenases and Their Evolution For The Reductmentioning

confidence: 99%

NAD(P)H‐Dependent Dehydrogenases for the Asymmetric Reductive Amination of Ketones: Structure, Mechanism, Evolution and Application

et al. 2017

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“…While natural AmDHs have not yet been identified, artificial amine dehydrogenases have been created via semi‐rational protein engineering of existing amino acid dehydrogenase scaffolds. In a first ground‐breaking study, L ‐leucine dehydrogenase from Bacillus stearothermophilus was chosen as starting point for directed evolution 89. Since a holo‐structure of this enzyme was not available, the X‐ray crystal structure of an analogous L ‐phenylalanine dehydrogenase was used for identifying potentially important positions in the amino acid sequence.…”

Section: Imine Reduction Using Defined Enzymesmentioning

confidence: 99%

Biocatalytic Imine Reduction and Reductive Amination of Ketones

2015

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Chiral aminesr epresent ap rominentf unctional group in pharmaceuticals and agrochemicals and are hence attractive targets for asymmetric synthesis.S ince the pharmaceutical industry has identified biocatalysis as av aluablet oolf or synthesising chiral molecules with high enantiomeric excess and under mild reactionc onditions,e nzymatic methods for chiral amine synthesisa re increasing in importance.A mong the strategies available in this context, the asymmetric reductiono fi mines by NAD(P)Hdependent enzymes andt he related reductive amination of ketones have long remained underrepresented. However, recent years have witnessed an impressive progress in the applicationo fn atural or engineered imine-reducing enzymes,s uch as imine reductases,o pine dehydrogenases,a mine dehydrogenases, and artificial metalloenzymes.T his review provides ac omprehensive overview of biocatalytic imine reductiona nd reductive amination of ketones,h ighlightingt he natural roles,s ubstrate scopes,s tructural features, and potential applicationf ields of the involvedenzymes.1I ntroduction 2I mine Reduction in Nature 2. 1I ntroductionChiral amines represent the core structure of am yriad of natural products as well as man-made compounds of public demand, such as pharmaceuticals and agrochemicals (Figure 1). Accordingt o recent estimates,c hiral amine moieties are present in about 40% of active pharmaceutical ingredients (APIs) and 20% of agrochemicals.[1] Moreover, optically pure amines,a mino acids,a nd amino alcohols are frequently employed in chemical synthesis as chiral auxiliariesorr esolving agents.Theirp aramount importance across several chemical disciplines andi ndustrial sectors has made chiral amines anda mino acids attractive targets for asymmetrics ynthesis.E stablished approachesf or their preparation are the stereoselective addition of nucleophiles to imines (including the famous Mannich and Strecker reactions), asymmetric C À Ha mination and hydroamination, and the asymmetric reductiono fe namines and imines,w hich may either be pre-formed or may occur as intermediates in an asymmetric reductive amination process.[2] Metallo-or organocatalytic methodsf or asymmetric imine and enamine reductiona re broadly applied, and intense research efforts are devoted to the improvement of the scope and stereoselectivity of these processes. [2,3] In cases where established asymmetric synthesism ethodsa re inapplicable or fail to provide the desired optical purity, diastereomeric salt crystallisation is still widely used for the classical resolution of racemic amines or for upgrading the enantiomeric excess of an optically enriched product.[2d]Biocatalytic transformationsa re increasingly being recognised as an attractive optionf or the asymmetric synthesiso fc hiral molecules.[4] Particularly in the

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“…[2] In recent years, the development and application of enzymes as biocatalysts for the asymmetric synthesis of chiral amines has received considerable attention. [3] Examples of enzyme classes that have been utilized for their synthesis include w-transaminases (w-TAs), [4] ammonia lyases, [5] imine reductases, [6] amine dehydrogenases, [7] and monoamine oxidases. [8] Increasingly sophisticated techniques for enzyme evolution [9] have led to the development of engineered biocatalysts, which have been optimized for application in industrial processes.…”

Section: In Memory Of Phyllis Oreillymentioning

confidence: 99%

Chiral Amine Synthesis Using ω‐Transaminases: An Amine Donor that Displaces Equilibria and Enables High‐Throughput Screening

2014

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The widespread application of ω-transaminases as biocatalysts for chiral amine synthesis has been hampered by fundamental challenges, including unfavorable equilibrium positions and product inhibition. Herein, an efficient process that allows reactions to proceed in high conversion in the absence of by-product removal using only one equivalent of a diamine donor (ortho-xylylenediamine) is reported. This operationally simple method is compatible with the most widely used (R)- and (S)-selective ω-TAs and is particularly suitable for the conversion of substrates with unfavorable equilibrium positions (e.g., 1-indanone). Significantly, spontaneous polymerization of the isoindole by-product generates colored derivatives, providing a high-throughput screening platform to identify desired ω-TA activity.

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Entwicklung einer Amindehydrogenase zur Synthese von chiralen Aminen

Cited by 65 publications

References 36 publications

NAD(P)H‐Dependent Dehydrogenases for the Asymmetric Reductive Amination of Ketones: Structure, Mechanism, Evolution and Application

NAD(P)H‐Dependent Dehydrogenases for the Asymmetric Reductive Amination of Ketones: Structure, Mechanism, Evolution and Application

Biocatalytic Imine Reduction and Reductive Amination of Ketones

Chiral Amine Synthesis Using ω‐Transaminases: An Amine Donor that Displaces Equilibria and Enables High‐Throughput Screening

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