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

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.

[1]  Nicholas J. Turner,et al.  Deracemization of α‐Methylbenzylamine Using an Enzyme Obtained by In Vitro Evolution , 2002 .

[2]  Paul N. Devine,et al.  Biocatalytic Asymmetric Synthesis of Chiral Amines from Ketones Applied to Sitagliptin Manufacture , 2010, Science.

[3]  Jack Liang,et al.  Efficient, chemoenzymatic process for manufacture of the Boceprevir bicyclic [3.1.0]proline intermediate based on amine oxidase-catalyzed desymmetrization. , 2012, Journal of the American Chemical Society.

[4]  John D. Hayler,et al.  Key green chemistry research areas—a perspective from pharmaceutical manufacturers , 2007 .

[5]  Nicholas J. Turner,et al.  Engineering an enantioselective amine oxidase for the synthesis of pharmaceutical building blocks and alkaloid natural products. , 2013, Journal of the American Chemical Society.

[6]  Byung Gee Kim,et al.  Asymmetric synthesis of chiral amines with ω‐transaminase , 1999 .

[7]  N. Turner,et al.  Directed Evolution of Galactose Oxidase: Generation of Enantioselective Secondary Alcohol Oxidases , 2008, Chembiochem : a European journal of chemical biology.

[8]  G. Guebitz,et al.  Formal asymmetric biocatalytic reductive amination. , 2008, Angewandte Chemie.

[9]  Wolfgang Kroutil,et al.  omega-Transaminases for the synthesis of non-racemic alpha-chiral primary amines. , 2010, Trends in biotechnology.

[10]  Jeffrey C. Moore,et al.  Entwicklung einer Amindehydrogenase zur Synthese von chiralen Aminen , 2012 .

[11]  Nicholas J. Turner,et al.  Biocatalytic Routes to Nonracemic Chiral Amines , 2010 .

[12]  Hyungdon Yun,et al.  High throughput screening methods for ω-transaminases , 2013, Biotechnology and Bioprocess Engineering.

[13]  D. Janssen,et al.  Priming ammonia lyases and aminomutases for industrial and therapeutic applications. , 2013, Current opinion in chemical biology.

[14]  Jeffrey C. Moore,et al.  Rapid screening and scale-up of transaminase catalysed reactions. , 2009, Organic & biomolecular chemistry.

[15]  G. Huisman,et al.  Engineering the third wave of biocatalysis , 2012, Nature.

[16]  Paul N Devine,et al.  Advances in the enzymatic reduction of ketones. , 2007, Accounts of chemical research.

[17]  Daniel Mink,et al.  Asymmetric Synthesis of (S)‐2‐Indolinecarboxylic Acid by Combining Biocatalysis and Homogeneous Catalysis , 2011 .

[18]  Henrik Land,et al.  An efficient single-enzymatic cascade for asymmetric synthesis of chiral amines catalyzed by ω-transaminase. , 2013, Chemical communications.

[19]  Andreas S Bommarius,et al.  Development of an amine dehydrogenase for synthesis of chiral amines. , 2012, Angewandte Chemie.

[20]  N. Turner,et al.  A chemo-enzymatic route to enantiomerically pure cyclic tertiary amines. , 2006, Journal of the American Chemical Society.

[21]  Nicholas J Turner,et al.  A Regio- and Stereoselective ω-Transaminase/Monoamine Oxidase Cascade for the Synthesis of Chiral 2,5-Disubstituted Pyrrolidines , 2014, Angewandte Chemie.

[22]  N. Turner,et al.  Monoamine Oxidase–ω‐Transaminase Cascade for the Deracemisation and Dealkylation of Amines , 2014 .

[23]  Jack Liang,et al.  Practical chiral alcohol manufacture using ketoreductases. , 2010, Current opinion in chemical biology.

[24]  Nicholas J Turner,et al.  Directed evolution drives the next generation of biocatalysts. , 2009, Nature chemical biology.

[25]  N. Turner,et al.  Asymmetric Reduction of Cyclic Imines Catalyzed by a Whole‐Cell Biocatalyst Containing an (S)‐Imine Reductase , 2013 .

[26]  David J Newman,et al.  Natural products as sources of new drugs over the 30 years from 1981 to 2010. , 2012, Journal of natural products.

[27]  Hyungdon Yun,et al.  ω-Transaminases for the Production of Optically Pure Amines and Unnatural Amino Acids , 2012 .

[28]  Matthew E Welsch,et al.  Privileged scaffolds for library design and drug discovery. , 2010, Current opinion in chemical biology.

[29]  N. Turner,et al.  Phenylalanine ammonia lyase catalyzed synthesis of amino acids by an MIO-cofactor independent pathway. , 2014, Angewandte Chemie.

[30]  A. Green,et al.  Monoamine Oxidase (MAO-N) Catalyzed Deracemization of Tetrahydro-β-carbolines: Substrate Dependent Switch in Enantioselectivity , 2013 .

[31]  Uwe T. Bornscheuer,et al.  Biocatalytic Routes to Optically Active Amines , 2009 .