Biocatalysis for pharmaceutical intermediates: the future is now.

Biocatalysis is continuing to gain momentum and is now becoming a key component in the toolbox of the process chemist, with a place alongside chemocatalysis and chromatographic separations. The pharmaceutical industry demands a speed of development that must be on a parallel with conventional chemistry and high optical purity for complex compounds with multiple chiral centres. This review describes how these demands are being addressed to make biocatalysis successful, particularly by the use of micro-scale technology for high-speed catalyst screening and process development alongside discipline integration of biology and engineering with chemistry. Developments in recombinant technology will further expand the repertoire of biocatalysis in the coming years to new chemistries and enable catalyst design to fit the process. Further development of biocatalysis for green chemistry and high productivity processes can also be expected.

[1]  M. Kataoka,et al.  Synthesis of optically active ethyl 4-chloro-3-hydroxybutanoate by microbial reduction , 1999, Applied Microbiology and Biotechnology.

[2]  J. Rozzell,et al.  Ketoreductases: stereoselective catalysts for the facile synthesis of chiral alcohols , 2005 .

[3]  John M Woodley,et al.  The use of microscale processing technologies for quantification of biocatalytic Baeyer-Villiger oxidation kinetics. , 2002, Biotechnology and bioengineering.

[4]  R. Sheldon,et al.  Characterisation of nitrilase and nitrile hydratase biocatalytic systems , 2004, Applied Microbiology and Biotechnology.

[5]  M. Hennig,et al.  Industrial Synthesis of the Key Precursor in the Synthesis of the Anti-Influenza Drug Oseltamivir Phosphate (Ro 64-0796/002, GS-4104-02): Ethyl (3R,4S,5S)-4,5-epoxy-3-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxylate , 1999 .

[6]  V. Alphand,et al.  Microbial Transformations, 56. Preparative Scale Asymmetric Baeyer–Villiger Oxidation using a Highly Productive “Two‐in‐One” Resin‐Based in situ SFPR Concept , 2004 .

[7]  R. Holt.  Microbial asymmetric reduction in the synthesis of a drug intermediate , 1996 .

[8]  Luuk A M van der Wielen,et al.  In situ product removal using a crystallization loop in asymmetric reduction of 4‐oxoisophorone by Saccharomyces cerevisiae , 2004, Biotechnology and bioengineering.

[9]  Wolfgang Kroutil,et al.  New enzymes for biotransformations. , 2005, Current opinion in chemical biology.

[10]  A. Bacher,et al.  Enoate Reductases of Clostridia , 2001, The Journal of Biological Chemistry.

[11]  C. Choi,et al.  Production of chiral epoxides: Epoxide hydrolase-catalyzed enantioselective hydrolysis , 2005 .

[12]  F. Arnold,et al.  Directed Evolution of a Cytochrome P450 Monooxygenase for Alkane Oxidation , 2001 .

[13]  Stu Borman.  IMPROVING EFFICIENCY: To eliminate R&D bottlenecks, drug companies are evaluating all phases of discovery and development and are using novel approaches to speed them up , 2006 .

[14]  A. Schmid,et al.  Stereospecific biocatalytic epoxidation: the first example of direct regeneration of a FAD-dependent monooxygenase for catalysis. , 2003, Journal of the American Chemical Society.

[15]  M. Mihovilovic,et al.  Baeyer-Villiger oxidations of representative heterocyclic ketones by whole cells of engineered Escherichia coli expressing cyclohexanone monooxygenase , 2001 .

[16]  John M. Woodley,et al.  Characterization of a recombinant Escherichia coli TOP10 [pQR239] whole-cell biocatalyst for stereoselective Baeyer–Villiger oxidations , 2003 .

[17]  Roger A. Sheldon,et al.  Biocatalysis in ionic liquids. , 2002, Chemical reviews.

[18]  Dunming Zhu,et al.  Evaluation of substituent effects on activity and enantioselectivity in the enzymatic reduction of aryl ketones , 2005 .

[19]  A. Banerjee,et al.  Screening for enantioselective nitrilases : Kinetic resolution of racemic mandelonitrile to (R)-(-)-mandelic acid by new bacterial isolates , 2004 .

[20]  M. North.  Synthesis and applications of non-racemic cyanohydrins , 2003 .

[21]  I. Alfonso,et al.  Enantioselective enzymatic desymmetrizations in organic synthesis. , 2005, Chemical reviews.

[22]  E. Grabowski,et al.  An enantioselective synthesis of the topically-active carbonic anhydrase inhibitor MK-0507: 5,6-dihydro-(S)-4-(ethylamino)-(S)-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride , 1993 .

[23]  G J Lye,et al.  Application of in situ product-removal techniques to biocatalytic processes. , 1999, Trends in biotechnology.

[24]  M. Chartrain,et al.  Implementation of a rapid microbial screening procedure for biotransformation activities. , 2000, Journal of bioscience and bioengineering.

[26]  Klaus Buchholz,et al.  Biocatalysts and Enzyme Technology , 2005 .

[27]  M. Burk,et al.  Creation of a productive, highly enantioselective nitrilase through gene site saturation mutagenesis (GSSM). , 2003, Journal of the American Chemical Society.

[28]  J. Mahy,et al.  Hemoabzymes: towards new biocatalysts for selective oxidations. , 2002, Journal of immunological methods.

[29]  Jeffrey C. Moore,et al.  Effective synthesis of (S)-3,5-bistrifluoromethylphenyl ethanol by asymmetric enzymatic reduction , 2006 .

[30]  Karlheinz Drauz,et al.  Enzyme Catalysis in Organic Synthesis , 1995 .

[31]  A. Kiener,et al.  Industrial biocatalysis today and tomorrow , 2001, Nature.

[32]  Jiang Pan,et al.  Enantioconvergent hydrolysis of styrene epoxides by newly discovered epoxide hydrolases in mung bean. , 2006, Organic letters.

[33]  Paul A Dalby,et al.  Optimising enzyme function by directed evolution. , 2003, Current opinion in structural biology.

[34]  John M. Woodley,et al.  Fluid mixing in shaken bioreactors: Implications for scale-up predictions from microlitre-scale microbial and mammalian cell cultures , 2006 .

[35]  H. Schoemaker,et al.  Dispelling the Myths--Biocatalysis in Industrial Synthesis , 2003, Science.

[36]  A. Maureen Rouchi,et al.  CHIRAL ROUNDUP: As pharmaceutical companies face bleak prospects, their suppliers diligently tend the fertile fields of chiral chemistry in varied ways , 2002 .

[37]  Kurt Faber,et al.  Biotransformations in Organic Chemistry , 1992 .

[38]  A. Schmid,et al.  Recombinant Chlorobenzene Dioxygenase from Pseudomonas sp. P51: A Biocatalyst for Regioselective Oxidation of Aromatic Nitriles , 2005 .

[39]  John M Woodley,et al.  Accelerated design of bioconversion processes using automated microscale processing techniques. , 2003, Trends in biotechnology.

[40]  John M. Woodley,et al.  Better Biocatalytic Processes Faster: New Tools for the Implementation of Biocatalysis in Organic Synthesis , 2002 .

[41]  M. Zmijewski,et al.  Large-scale stereoselective enzymatic ketone reduction with in situ product removal via polymeric adsorbent resins , 1997 .

[42]  Y. Asano,et al.  A new (R)-hydroxynitrile lyase from Prunus mume: asymmetric synthesis of cyanohydrins , 2005 .

[43]  Klaus Buchholz,et al.  Highlights in Biocatalysis – Historical Landmarks and Current Trends , 2005 .

[44]  J. Woodley,et al.  Choice of biocatalyst form for scalable processes. , 2006, Biochemical Society transactions.

[45]  M. Chartrain,et al.  Biocatalysis for pharmaceuticals--status and prospects for a key technology. , 2000, Metabolic engineering.

[46]  B. Junker,et al.  Microbial conversion of indene to indandiol: a key intermediate in the synthesis of CRIXIVAN. , 1999, Metabolic engineering.

[47]  U. Bornscheuer,et al.  Immobilization of enzymes in microtiter plate scale. , 2006, Biotechnology journal.

[48]  H. Gröger,et al.  From Enzymes to “Designer Bugs” in Reductive Amination: A New Process for the Synthesis of L‐tert‐Leucine Using a Whole Cell‐Catalyst , 2004 .

[49]  J. Vacca,et al.  The integration of medicinal chemistry, drug metabolism, and pharmaceutical research and development in drug discovery and development. The story of Crixivan, an HIV protease inhibitor. , 1998, Pharmaceutical biotechnology.

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

[51]  Urs von Stockar,et al.  In situ product removal (ISPR) in whole cell biotechnology during the last twenty years. , 2003, Advances in biochemical engineering/biotechnology.

[52]  Linqiu Cao,et al.  Immobilised enzymes: science or art? , 2005, Current opinion in chemical biology.

[53]  M. Kataoka,et al.  Synthesis of optically pure ethyl (S)-4-chloro-3-hydroxybutanoate by Escherichia coli transformant cells coexpressing the carbonyl reductase and glucose dehydrogenase genes , 2001, Applied Microbiology and Biotechnology.

[54]  M. Wubbolts,et al.  Diversity and Biocatalytic Potential of Epoxide Hydrolases Identified by Genome Analysis , 2006, Applied and Environmental Microbiology.

[55]  Andreas Schmid,et al.  The production of fine chemicals by biotransformations. , 2002, Current opinion in biotechnology.

[56]  B. Roth,et al.  The discovery and development of atorvastatin, a potent novel hypolipidemic agent. , 2002, Progress in medicinal chemistry.

[57]  U. Bornscheuer,et al.  Hydrolases in Organic Synthesis: Regio- and Stereoselective Biotransformations , 1999 .

[58]  T. Matsuda,et al.  Recent developments in asymmetric reduction of ketones with biocatalysts , 2003 .

[59]  Jing Li,et al.  Efficient synthesis of NK(1) receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation. , 2003, Journal of the American Chemical Society.

[60]  A. Banerjee,et al.  RETRACTED ARTICLE: The nitrile-degrading enzymes: current status and future prospects , 2002, Applied Microbiology and Biotechnology.

[61]  John M Woodley,et al.  Directed evolution of biocatalytic processes. , 2005, Biomolecular engineering.

[62]  Y. Ikenaka,et al.  Microbial synthesis of chiral amines by (R)-specific transamination with Arthrobacter sp. KNK168 , 2005, Applied Microbiology and Biotechnology.

[63]  Alexander Varvak,et al.  Development of an efficient, scalable, aldolase-catalyzed process for enantioselective synthesis of statin intermediates. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[64]  M. S. Smit.  Fungal epoxide hydrolases: new landmarks in sequence-activity space. , 2004, Trends in biotechnology.

[65]  J. Tao,et al.  Automated Enzyme Screening Methods for the Preparation of Enantiopure Pharmaceutical Intermediates , 2003 .

[66]  Detlev Belder,et al.  Enantioselective catalysis and analysis on a chip. , 2006, Angewandte Chemie.

[67]  J. Rozzell,et al.  Commercial scale biocatalysis: myths and realities. , 1999, Bioorganic & medicinal chemistry.

[68]  Roland Wohlgemuth,et al.  On the influence of oxygen and cell concentration in an SFPR whole cell biocatalytic Baeyer–Villiger oxidation process , 2006, Biotechnology and bioengineering.

[69]  Frances H. Arnold,et al.  Directed evolution: Creating biocatalysts for the future , 1996 .

[70]  Doreen R. Coppola.  CMO-grown innovation and technology: Helps pharma industry keep pace , 2004 .

[71]  U. Bornscheuer.  Trends and challenges in enzyme technology. , 2005, Advances in biochemical engineering/biotechnology.

[72]  J. W. Frost,et al.  Synthesis of aminoshikimic acid. , 2004, Organic letters.

[73]  John M Woodley,et al.  The search for the ideal biocatalyst , 2002, Nature Biotechnology.

[74]  K. Polizzi,et al.  Novel biocatalysts: Recent developments , 2006 .

[75]  J. Malone,et al.  Biocatalytic Asymmetric Dihydroxylation of Conjugated Mono- and Poly-alkenes to Yield Enantiopure Cyclic cis-Diols , 2005 .

[76]  Dirk Weuster-Botz,et al.  Efficient whole-cell biotransformation in a biphasic ionic liquid/water system. , 2004, Angewandte Chemie.

[77]  M. Truppo,et al.  Optimization and Scale-Up of a Lipase-Catalyzed Enzymatic Resolution of an Indole Ester Intermediate for a Prostaglandin D2 (DP) Receptor Antagonist Targeting Allergic Rhinitis , 2006 .

[78]  K. Drauz,et al.  Towards a Large‐Scale Asymmetric Reduction Process with Isolated Enzymes: Expression of an (S)‐Alcohol Dehydrogenase in E. coli and Studies on the Synthetic Potential of this Biocatalyst , 2003 .