Synthesis of chiral pharmaceutical intermediates by biocatalysis

Chiral intermediates were prepared by biocatalytic processes for the chemical synthesis of four pharmaceutical drug candidates. These include: (i) the microbial reduction of 3,5-dioxo-6-(benzyloxy) hexanoic ethyl ester to (3S,5R)-dihydroxy-6-(benzyloxy) hexanoic acid ethyl ester, an intermediate for a new anticholesterol drug; (ii) synthesis of (2R,3S)-(-)-N-benzoyl-3-phenyl isoserine ethyl ester, a taxol side-chain synthon; (iii) the microbial oxygenation of 2,2-dimethyl-2H-1-benzopyran-6-carbonitrile to the corresponding (3S,4S) epoxide and (3S,4R)-trans diol, intermediates for synthesis of potassium channel opener; (iv) the biotransformation of (exo,exo)-7-oxabicyclo [2.2.1] heptane-2,3-dimethanol to the corresponding chiral lactol and lactone, intermediates for thromboxane A2 antagonist.

[1]  U. Bornscheuer,et al.  Directed evolution of lipases and esterases. , 2004, Methods in enzymology.

[2]  V. Urlacher,et al.  Recent advances in oxygenase-catalyzed biotransformations. , 2006, Current opinion in chemical biology.

[3]  C. Augé,et al.  Synthesis with immobilized enzyme of the most important sialic acid. , 1984 .

[4]  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.

[5]  D. Ghisotti,et al.  RECOMBINANT BACTERIAL CELLS AS EFFICIENT BIOCATALYSTS FOR THE PRODUCTION OF NUCLEOSIDES , 2001, Nucleosides, nucleotides & nucleic acids.

[6]  Ramesh N. Patel,et al.  Microbial synthesis of (2R,3S)-(-)-N-benzoyl-3-phenyl isoserine ethyl ester-a taxol side-chain synthon , 1993 .

[7]  Radka Snajdrova,et al.  Resolution of fused bicyclic ketones by a recombinant biocatalyst expressing the Baeyer-Villiger monooxygenase gene Rv3049c from Mycobacterium tuberculosis H37Rv. , 2006, Bioorganic & medicinal chemistry letters.

[8]  E. Gelmann,et al.  The Acquired Immunodeficiency Syndrome: An Update , 1985 .

[9]  Ramesh N. Patel,et al.  Enantioselective microbial reduction of 2-oxo-2-(1′,2′,3′,4′-tetrahydro-1′,1′,4′,4′-tetramethyl-6′-naphthalenyl)acetic acid and its ethyl ester , 2002 .

[10]  Ramesh N. Patel,et al.  Stereoselective enzymatic hydrolysis of 2-cyclohexyl-and 2-phenyl-1,3-propanediol diacetate in biphasic systems , 1990, Applied Microbiology and Biotechnology.

[11]  Ramesh N. Patel,et al.  Deracemization of racemic 1,2-diol by biocatalytic stereoinversion , 1999 .

[12]  C. Cass,et al.  The role of nucleoside transporters in cancer chemotherapy with nucleoside drugs , 2007, Cancer and Metastasis Reviews.

[13]  Ramesh N. Patel,et al.  Synthesis of ethyl and t-butyl (3R,5S)-dihydroxy-6-benzyloxy hexanoates via diastereo- and enantioselective microbial reduction , 2006 .

[14]  M. Dawson,et al.  An efficient process for production of N-acetylneuraminic acid using N-acetylneuraminic acid aldolase. , 1997, Enzyme and microbial technology.

[15]  R. Müller,et al.  Myxobacteria: proficient producers of novel natural products with various biological activities--past and future biotechnological aspects with the focus on the genus Sorangium. , 2003, Journal of biotechnology.

[16]  S. Simon,et al.  Neuropeptides and capsaicin stimulate the release of inflammatory cytokines in a human bronchial epithelial cell line , 1999, Neuropeptides.

[17]  Ramesh N. Patel,et al.  Stereoselective microbial/enzymatic oxidation of (exo, exo)-7-oxabicyclo [2.2.1] heptane-2,3-dimethanol to the corresponding chiral lactol and lactone , 1992 .

[18]  R. Madsen,et al.  Enyne Metathesis Catalyzed by Ruthenium Carbene Complexes , 2003 .

[19]  H. Schwab,et al.  The synthesis of chiral cyanohydrins by oxynitrilases. , 2000, Trends in biotechnology.

[20]  K. Nicolaou,et al.  Chemical Biology of Epothilones. , 1998, Angewandte Chemie.

[21]  H. Bonkovsky,et al.  Comparative Effects of Different Doses of Ribavirin Plus Interferon-α2b for Therapy of Chronic Hepatitis C: Results of a Controlled, Randomized Trial , 2001, Digestive Diseases and Sciences.

[22]  N. Thornberry,et al.  Discovery of JANUVIA TM (Sitagliptin), a Selective Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type2 Diabetes. , 2007 .

[23]  W. Kroutil,et al.  Deracemization of compounds possessing a sec-alcohol or -amino group through a cyclic oxidation–reduction sequence: a kinetic treatment , 1998 .

[24]  J. McHutchison,et al.  Treatment of hepatitis C with interferon and ribavirin , 2000, Journal of gastroenterology and hepatology.

[25]  M. Fraaije,et al.  Enzymatic kinetic resolution of racemic ketones catalyzed by Baeyer-Villiger monooxygenases , 2007 .

[26]  M. Page,et al.  Chemoenzymatic dynamic kinetic resolution of secondary amines , 2007 .

[27]  J. Tao,et al.  An efficient enzymatic preparation of rhinovirus protease inhibitor intermediates , 2004 .

[28]  Sushil K. Srivastava,et al.  Process Research and Development for an Efficient Synthesis of the HIV Protease Inhibitor BMS-232632 , 2002 .

[29]  J. B. Jones,et al.  Enzymes in organic synthesis. 32. Stereospecific horse liver alcohol dehydrogenase-catalyzed oxidations of exo- and endo-oxabicyclic meso diols , 1984 .

[30]  A. Greene,et al.  An efficient, enantioselective synthesis of the taxol side chain , 1986 .

[31]  Sakayu Shimizu,et al.  Whole organism biocatalysis. , 2005, Current opinion in chemical biology.

[32]  M. Mihovilovic,et al.  Microbial Baeyer-Villiger oxidation of terpenones by recombinant whole-cell biocatalysts--formation of enantiocomplementary regioisomeric lactones. , 2007, Organic & biomolecular chemistry.

[33]  Michael Müller,et al.  Thiamin-diphosphate-dependent enzymes: new aspects of asymmetric C-C bond formation. , 2002, Chemistry.

[34]  Yvonne Genzel,et al.  Enhancing the enantioselectivity of an epoxide hydrolase by directed evolution. , 2004, Organic letters.

[35]  William R. Strohl,et al.  Biotechnology of antibiotics , 1997 .

[36]  V. Sabesan,et al.  Enzymatic Hydrolysis of a Prochiral 3‐Substituted Glutarate Ester, an Intermediate in the Synthesis of an NK1/NK2 Dual Antagonist , 2001 .

[37]  R. N. Brogden,et al.  Buspirone: An Updated Review of its Clinical Pharmacology and Therapeutic Applications , 1997 .

[38]  Ramesh N. Patel.  Biocatalysis: Synthesis of Chiral Intermediates for Pharmaceuticals , 2006 .

[39]  I. Blair,et al.  Metabolism of the antianxiety drug buspirone in human subjects. , 1989, Drug metabolism and disposition: the biological fate of chemicals.

[40]  K. Faber,et al.  Microbial epoxide hydrolases for preparative biotransformations. , 2001, Current opinion in biotechnology.

[41]  J. Stewart,et al.  Enantiodivergent, biocatalytic routes to both taxol side chain antipodes. , 2005, The Journal of organic chemistry.

[42]  Huimin Zhao,et al.  Recent advances in biocatalysis by directed enzyme evolution. , 2006, Combinatorial chemistry & high throughput screening.

[43]  David Weiner,et al.  An Enzyme Library Approach to Biocatalysis: Development of Nitrilases for Enantioselective Production of Carboxylic Acid Derivatives , 2002 .

[44]  R. Sykes,et al.  O-Sulfated .beta.-lactam hydroxamic acids (monosulfactams). Novel monocyclic .beta.-lactam antibiotics of synthetic origin , 1982 .

[45]  J. Imbach,et al.  Nucleoside Analogues as Chemotherapeutic Agents: A Review , 1992 .

[46]  K. Terao,et al.  Formation of carboxamides by direct condensation of carboxylic acids and amines in alcohols using a new alcohol- and water-soluble condensing agent: DMT-MM , 2001 .

[47]  Ramesh N. Patel,et al.  Preparation of a chiral synthon for an HBV inhibitor : enzymatic asymmetric hydrolysis of (1α,2β,3α)-2-(benzyloxymethyl)cyclopent-4-ene-1,3-diol diacetate and enzymatic asymmetric acetylation of (1α,2β,3α)-2-(benzyloxymethyl)cyclopent-4-ene-1,3-diol , 2006 .

[48]  G. Chuah,et al.  Dynamic kinetic resolution of secondary alcohols combining enzyme-catalyzed transesterification and zeolite-catalyzed racemization. , 2007, Chemistry.

[49]  Mahmoud Mahmoudian,et al.  Biocatalytic Production of Chiral Pharmaceutical Intermediates , 2000 .

[50]  V. Gotor,et al.  Candida antarctica lipase catalyzed resolution of ethyl (±)-3-aminobutyrate , 1997 .

[51]  R. Azerad,et al.  Dynamic resolution and stereoinversion of secondary alcohols by chemo-enzymatic processes. , 2000, Current opinion in biotechnology.

[52]  A. Matsuda,et al.  Nucleoside natural products and related analogs with potential therapeutic properties as antibacterial and antiviral agents , 2007 .

[53]  J. Vekemans,et al.  Efficient dynamic kinetic resolution of secondary alcohols with a novel tetrafluorosuccinato ruthenium complex , 2006 .

[54]  T. LaPorte,et al.  Fermentation and isolation of C10-deacetylase for the production of 10-deacetylbaccatin III from baccatin III. , 1995, Biotechnology and bioengineering.

[55]  C. Hansch,et al.  Comparative Quantitative Structure−Activity Relationship Studies on Anti-HIV Drugs , 1999 .

[56]  D. Drucker,et al.  Glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase IV inhibitors: new therapeutic agents for the treatment of type 2 diabetes , 2005 .

[57]  Keith E. J. Tyo,et al.  Expanding the metabolic engineering toolbox: more options to engineer cells. , 2007, Trends in biotechnology.

[58]  M. Mahmoudian.  Development of Bioprocesses for the Generation of Anti-Inflammatory, Anti-Viral and Anti-Leukaemic Agents , 2001 .

[59]  E. Rubin,et al.  Epothilones: mechanism of action and biologic activity. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[60]  S. Harusawa,et al.  A synthesis of taxusin , 1988 .

[61]  R. Parker,et al.  Synthesis, biological profile, and quantitative structure-activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. , 1990, Journal of medicinal chemistry.

[62]  I. Purvis,et al.  Enzymatic production of optically pure (2'R-cis)-2'-deoxy-3'-thiacytidine (3TC, lamivudine): a potent anti-HIV agent. , 1993, Enzyme and microbial technology.

[63]  K. Faber,et al.  Biocatalytic Deracemization Techniques: Dynamic Resolutions and Stereoinversions , 1997 .

[64]  P. Schiff,et al.  Promotion of microtubule assembly in vitro by taxol , 1979, Nature.

[65]  Ramesh N. Patel,et al.  Diastereoselective microbial reduction of (S)-[3-chloro-2-oxo-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester , 2003 .

[66]  G. Whitesides,et al.  Membrane-enclosed enzymic catalysis (MEEC): a useful, practical new method for the manipulation of enzymes in organic synthesis , 1987 .

[67]  Langer Sz,et al.  Alpha-adrenoreceptor subtypes in blood vessels: physiology and pharmacology. , 1984 .

[68]  C. Datz,et al.  Combination of interferon induction therapy and ribavirin in chronic hepatitis C , 2001, Hepatology.

[69]  V. Alphand,et al.  Optimizing Fermentation Conditions of Recombinant Escherichia coli Expressing Cyclopentanone Monooxygenase , 2006 .

[70]  Georg A. Sprenger,et al.  Microbial aldolases as C–C bonding enzymes—unknown treasures and new developments , 2006, Applied Microbiology and Biotechnology.

[71]  Manfred T. Reetz,et al.  Converting Phenylacetone Monooxygenase into Phenylcyclohexanone Monooxygenase by Rational Design: Towards Practical Baeyer-Villiger Monooxygenases , 2005 .

[72]  Marko D. Mihovilovic,et al.  Enzyme Mediated Baeyer-Villiger Oxidations , 2006 .

[73]  D. Robertson,et al.  Potassium channel modulators: scientific applications and therapeutic promise. , 1990, Journal of medicinal chemistry.

[74]  Chi-Huey Wong,et al.  Unprecedented Asymmetric Aldol Reactions with Three Aldehyde Substrates Catalyzed by 2-Deoxyribose-5-phosphate Aldolase , 1994 .

[75]  Yeuk-Chuen Liu,et al.  A practical chemoenzymic synthesis of the taxol C-13 side chain N-benzoyl-(2R,3S)-3-phenylisoserine , 1993 .

[76]  J. Tao,et al.  An efficient synthesis of a key intermediate for the preparation of the rhinovirus protease inhibitor AG7088 via asymmetric dianionic cyanomethylation of N-Boc-l-(+)-glutamic acid dimethyl ester , 2001 .

[77]  R. Csuk,et al.  Baker's yeast mediated transformations in organic chemistry , 1991 .

[78]  L. White.  HPLC in clinical microbiology laboratories. , 1981, The Journal of antimicrobial chemotherapy.

[79]  M. Ondetti,et al.  Inhibition of the renin-angiotensin system. A new approach to the therapy of hypertension. , 1981, Journal of medicinal chemistry.

[80]  M. Fraaije,et al.  Altering the substrate specificity and enantioselectivity of phenylacetone monooxygenase by structure-inspired enzyme redesign , 2007 .

[81]  B Rubin,et al.  Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. , 1977, Science.

[82]  Michael Müller,et al.  Regio and enantioselective reduction of t-butyl 6-chloro-3,5-dioxohexanoate with baker’s yeast , 2004 .

[83]  Ramesh N. Patel,et al.  Enzymatic synthesis of L-6-hydroxynorleucine. , 1999, Bioorganic & medicinal chemistry.

[84]  R. Furstoss,et al.  Biocatalytic Approaches for the Synthesis of Enantiopure Epoxides , 1999 .

[85]  U. Bornscheuer,et al.  Cloning, expression, and characterization of a Baeyer–Villiger monooxygenase from Pseudomonas fluorescens DSM 50106 in E. coli , 2007, Applied Microbiology and Biotechnology.

[86]  A. Kinney.  Metabolic engineering in plants for human health and nutrition. , 2006, Current opinion in biotechnology.

[87]  D. Kingston,et al.  The chemistry of taxol. , 1991, Pharmacology & therapeutics.

[88]  R. Coates,et al.  Synthesis and characterization of aza analog inhibitors of squalene and geranylgeranyl diphosphate synthases. , 1992 .

[89]  V. Alphand,et al.  Microbial transformations 59: first kilogram scale asymmetric microbial Baeyer-Villiger oxidation with optimized productivity using a resin-based in situ SFPR strategy. , 2005, Biotechnology and bioengineering.

[90]  Wei Zhang,et al.  Highly enantioselective epoxidation catalysts derived from 1,2-diaminocyclohexane , 1991 .

[91]  M. Yagasaki,et al.  Industrial biotransformations for the production of d-amino acids , 1998 .

[92]  M. R. Feng,et al.  Mediation of Highly Concentrative Uptake of Pregabalin by L-Type Amino Acid Transport in Chinese Hamster Ovary and Caco-2 Cells , 2005, Journal of Pharmacology and Experimental Therapeutics.

[93]  W. Fessner,et al.  Biocatalytic synthesis of hydroxylated natural products using aldolases and related enzymes. , 2001, Current opinion in biotechnology.

[94]  D. Matthews,et al.  Tripeptide aldehyde inhibitors of human rhinovirus 3C protease: design, synthesis, biological evaluation, and cocrystal structure solution of P1 glutamine isosteric replacements. , 1998, Journal of medicinal chemistry.

[95]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[96]  R. Jain,et al.  Enzymatic kinetic resolution of piperidine atropisomers: synthesis of a key intermediate of the farnesyl protein transferase inhibitor, SCH66336. , 2000, The Journal of organic chemistry.

[97]  C. T. Evans,et al.  Potential use of carbocyclic nucleosides for the treatment of AIDS: chemo-enzymatic syntheses of the enantiomers of carbovir , 1992 .

[98]  C. Allen,et al.  Aromatic dioxygenases: molecular biocatalysis and applications. , 2001, Current opinion in biotechnology.

[99]  Y. Kita,et al.  A dynamic kinetic resolution of allyl alcohols by the combined use of lipases and [VO(OSiPh3)3]. , 2006, Angewandte Chemie.

[100]  J. Bäckvall,et al.  Dynamic Kinetic Resolution of β-Azido Alcohols. An Efficient Route to Chiral Aziridines and β-Amino Alcohols , 2001 .

[101]  J. Tao,et al.  Cloning and optimization of a nitrilase for the synthesis of (3S)-3-cyano-5-methyl hexanoic acid , 2006 .

[102]  E. White,et al.  Comparison of the effect of Carbovir, AZT, and dideoxynucleoside triphosphates on the activity of human immunodeficiency virus reverse transcriptase and selected human polymerases. , 1989, Biochemical and biophysical research communications.

[103]  U. Kragl,et al.  N‐Acetylneuraminic Acid From a Rare Chemical from Natural Sources to a Multikilogram Enzymatic Synthesis for Industrial Application , 1995 .

[104]  R. Parker,et al.  Discovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. , 2005, Journal of medicinal chemistry.

[105]  M. Chartrain,et al.  Bioconversion of indene to cis (1S,2R) indandiol and trans (1R,2R) indandiol by Rhodococcus species , 1998 .

[106]  Ramesh N. Patel,et al.  Stereoselective acetylation of [1-(hydroxy)-4-(3-phenyl)butyl]phosphonic acid, diethyl ester , 1997 .

[107]  Ramesh N. Patel,et al.  Synthesis of l-β-hydroxyvaline from α-keto-β-hydroxyisovalerate using leucine dehydrogenase from Bacillus species , 1990 .

[108]  O. Ward,et al.  Optimisation of reaction conditions for production ofS-(−)-2-hydroxypropiophenone byAcinetobacter calcoaceticus , 1994, Journal of Industrial Microbiology.

[109]  G. Schulz,et al.  Chemie der pleuromutiline—IV: Synthese des 14-O-acetyl-8α-hydroxy-mutilins , 1983 .

[110]  Chi-Huey Wong,et al.  Recent advances in aldolase-catalyzed asymmetric synthesis , 2007 .

[111]  Ramesh N. Patel,et al.  Enzymatic synthesis of chiral intermediates for Omapatrilat, an antihypertensive drug. , 2001, Biomolecular engineering.

[112]  J. Stewart,et al.  Application of newly available bio-reducing agents to the synthesis of chiral hydroxy-β-lactams: model for aldose reductase selectivity , 2005 .

[113]  G. Wong,et al.  Pilot-Scale Lipase-Catalyzed Regioselective Acylation of Ribavirin in Anhydrous Media in the Synthesis of a Novel Prodrug Intermediate , 2003 .

[114]  E. Jacobsen,et al.  A Practical, Highly Enantioselective Synthesis of the Taxol Side Chain via Asymmetric Catalysis. , 1992 .

[115]  Michael Müller,et al.  Asymmetric benzoin reaction catalyzed by benzoylformate decarboxylase , 1999 .

[116]  C. Wandrey,et al.  Highly Regio- and Enantioselective Reduction of 3,5-Dioxocarboxylates. , 2000, Angewandte Chemie.

[117]  B Hauer,et al.  Continuous production of (R)-phenylacetylcarbinol in an enzyme-membrane reactor using a potent mutant of pyruvate decarboxylase from Zymomonas mobilis. , 2001, Biotechnology and bioengineering.

[118]  Ramesh N. Patel,et al.  Biocatalytic ammonolysis of (5S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)-5-ethyl ester: preparation of an intermediate to the dipeptidyl peptidase IV inhibitor Saxagliptin. , 2006, Bioorganic & medicinal chemistry letters.

[119]  J. Kessler,et al.  Activities of (-)-carbovir and 3'-azido-3'-deoxythymidine against human immunodeficiency virus in vitro , 1990, Antimicrobial Agents and Chemotherapy.

[120]  R. Hanson,et al.  Regioselective enzymatic aminoacylation of lobucavir to give an intermediate for lobucavir prodrug. , 2000, Bioorganic & medicinal chemistry.

[121]  G. Allan,et al.  Microbial deracemization of 1-aryl and 1-heteroaryl secondary alcohols. , 2001, The Journal of organic chemistry.

[122]  Ramesh N. Patel,et al.  Biocatalytic preparation of a chiral synthon for a vasopeptidase inhibitor: enzymatic conversion of N2-[N-Phenylmethoxy)carbonyl] L-homocysteinyl]- L-lysine (1- > 1′)-disulfide to [4S-(4I,7I,10aJ)] 1-octahydro-5-oxo-4-[phenylmethoxy)carbonyl]amino]-7H-pyrido-[2,1-b] [1,3]thiazepine-7-carboxylic acid , 2000 .

[123]  Martha Lovato Tse,et al.  Precursor-directed biosynthesis of epothilone in Escherichia coli. , 2004, Journal of the American Chemical Society.

[124]  Ramesh N. Patel.  Biocatalysis in the pharmaceutical and biotechnology industries , 2006 .

[125]  Daeho Kim,et al.  (S)-selective dynamic kinetic resolution of secondary alcohols by the combination of subtilisin and an aminocyclopentadienylruthenium complex as the catalysts. , 2003, Journal of the American Chemical Society.

[126]  David W. Smith,et al.  2,3-Benzodiazepin-1,4-diones as peptidomimetic inhibitors of γ-secretase , 2004 .

[127]  M. Seiden,et al.  BMS-247550 Bristol-Myers Squibb/GBF. , 2003, Current opinion in investigational drugs.

[128]  F. Arnold,et al.  Stereoselective hydroxylation of an achiral cyclopentanecarboxylic acid derivative using engineered P450s BM-3. , 2005, Chemical communications.

[129]  R. Hanson,et al.  Site-specific enzymatic hydrolysis of taxanes at C-10 and C-13. , 1994, The Journal of biological chemistry.

[130]  W. Fessner.  Enzyme‐catalyzed Aldol Additions , 2008 .

[131]  James G. Tarrant,et al.  The discovery of BMS-275183: an orally efficacious novel taxane. , 2003, Bioorganic & medicinal chemistry.

[132]  Hiroaki Yamamoto,et al.  Practical application of recombinant whole-cell biocatalysts for the manufacturing of pharmaceutical intermediates such as chiral alcohols , 2002 .

[133]  C. Wilcox,et al.  Serotonin 5-HT1a Receptor Agonists as Antidepressants , 1998 .

[134]  D. Hutchinson.  New approaches to the synthesis of antiviral nucleosides. , 1990, Trends in biotechnology.

[135]  Daniel Mink,et al.  Directed evolution of an industrial biocatalyst: 2-deoxy-D-ribose 5-phosphate aldolase. , 2006, Biotechnology journal.

[136]  L. L. Nielsen.  Incretin mimetics and DPP-IV inhibitors for the treatment of type 2 diabetes. , 2005, Drug discovery today.

[137]  C. Hewitt,et al.  Application of multi-parameter flow cytometry using fluorescent probes to study substrate toxicity in the indene bioconversion. , 2002, Biotechnology and bioengineering.

[138]  M. Kreiner,et al.  Microbial hydroxylation of 2-cycloalkylbenzoxazoles. Part III. Determination of product enantiomeric excess and cleavage of benzoxazoles , 1996 .

[139]  J. W. Frost,et al.  Prospects for Biocatalytic Synthesis of Aromatics in the 21st Century , 1994 .

[140]  U. Schwaneberg,et al.  Directed evolution of oxygenases: screening systems, success stories and challenges. , 2007, Combinatorial chemistry & high throughput screening.

[141]  C. Mcnamee,et al.  Stereoselective epoxidation of 2,2-dimethyl-2H-1-benzopyran-6-carbonitrile. , 1994, Bioorganic & medicinal chemistry.

[142]  Jaiwook Park,et al.  Dynamic kinetic resolution of primary amines with a recyclable Pd nanocatalyst for racemization. , 2007, Organic letters.

[143]  T. Kitahara,et al.  Preparation of chiral cyclohexanol derivative with high optical purity by yeast reduction , 1985 .

[144]  M. Mihovilovic,et al.  Monooxygenase‐Mediated Baeyer−Villiger Oxidations , 2002 .

[145]  Ramesh N. Patel,et al.  Enzymic hydrolysis of 7‐xylosyltaxanes by xylosidase from Moraxella sp. , 1997 .

[146]  A. Carnell.  Stereoinversions using microbial redox-reactions. , 1999, Advances in biochemical engineering/biotechnology.

[147]  V. Gotor,et al.  Biocatalytic selective modifications of conventional nucleosides, carbocyclic nucleosides, and C-nucleosides. , 2000, Chemical reviews.

[148]  C. Fairchild,et al.  Preclinical pharmacology of BMS-275183, an orally active taxane. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[149]  Christopher Williamson,et al.  Synthesis from (–)-aristeromycin and X-ray structure of (–)-carbovir , 1991 .

[150]  C. Wong,et al.  Chemo-enzymatic total synthesis of 3-epiaustraline, australine, and 7-epialexine. , 2000, The Journal of organic chemistry.

[151]  B. Gallwitz.  Glucagon- Like Peptide-1-Based Therapies for the Treatment of Type 2 Diabetes Mellitus , 2005, Treatments in endocrinology.

[152]  M. Deninno.  The Synthesis and Glycosidation of N-Acetylneuraminic Acid , 1991 .

[153]  M. Mahmoudian,et al.  Enzymic acylation of 506U78 (2‐amino‐9‐β‐D‐arabinofuranosyl‐6‐methoxy‐9H‐purine), a powerful new anti‐leukaemic agent , 1999, Biotechnology and applied biochemistry.

[154]  Ramesh N. Patel,et al.  Enantioselective microbial reduction of substituted acetophenones , 2004 .

[155]  W. Kroutil,et al.  Enzymatic Racemisation and its Application to Synthetic Biotransformations , 2003 .

[156]  Ramesh N. Patel,et al.  Preparation of an Amino Acid Intermediate for the Dipeptidyl Peptidase IV Inhibitor, Saxagliptin, using a Modified Phenylalanine Dehydrogenase , 2007 .

[157]  Richard L. Pederson,et al.  Enzyme-catalyzed aldol condensation for asymmetric synthesis of azasugars : synthesis, evaluation, and modeling of glycosidase inhibitors , 1991 .

[158]  G. Borisy,et al.  Characterization of microtubule assembly in porcine brain extracts by viscometry. , 1973, Biochemistry.

[159]  Ramesh N. Patel,et al.  Asymmetric acyloin condensation catalyzed by phenylpyruvate decarboxylase , 1999 .

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

[161]  Georg A. Sprenger,et al.  Synthetic potential of thiamin diphosphate-dependent enzymes , 1999 .

[162]  Michael L. Shuler,et al.  Taxol®: science and applications. , 1995 .

[163]  Y. Hashimoto,et al.  Retinobenzoic acids. 1. Structure-activity relationships of aromatic amides with retinoidal activity. , 1988, Journal of medicinal chemistry.

[164]  Harris,et al.  Synthesis of allysine ethylene acetal using phenylalanine dehydrogenase from Thermoactinomyces intermedius. , 2000, Enzyme and microbial technology.

[165]  S. Sauleda,et al.  Interferon and ribavirin combination therapy for chronic hepatitis C in human immunodeficiency virus–infected patients with congenital coagulation disorders , 2001, Hepatology.

[166]  Frances H Arnold,et al.  Synthetic gene circuits: design with directed evolution. , 2007, Annual review of biophysics and biomolecular structure.

[167]  A. Baldessari,et al.  One-pot biocatalyzed preparation of substituted amides as intermediates of pharmaceuticals , 2001 .

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

[169]  V. Gotor.  Lipases and (R)-oxynitrilases: useful tools in organic synthesis. , 2002, Journal of biotechnology.

[170]  M. Hirama,et al.  A chiral total synthesis of compactin , 1982 .

[171]  D K Robinson,et al.  Metabolic engineering and directed evolution for the production of pharmaceuticals. , 2000, Current opinion in biotechnology.

[172]  V. Alphand,et al.  Microbiological transformations. 22. Microbiologically mediated Baeyer-Villiger reactions: a unique route to several bicyclic .gamma.-lactones in high enantiomeric purity , 1992 .

[173]  N. Turner,et al.  A versatile chemo-enzymatic route to enantiomerically pure β-branched α-amino acids , 2004 .

[174]  O. Ward,et al.  Reductive biotransformations of organic compounds by cells or enzymes of yeast. , 1990, Enzyme and microbial technology.

[175]  R. Storer,et al.  The Resolution and Absolute Stereochemistry of the Enantiomers of cis-1-[2-(Hydroxymethyl)-1,3-oxathiolan-5-yl)cytosine (BCH189): Equipotent Anti-HIV Agents , 1993 .

[176]  S. Danishefsky,et al.  Novel stereospecific silyl group transfer reactions: practical routes to the prostaglandins , 1989 .

[177]  N. Vanthuyne,et al.  Dynamic kinetic resolution of amines involving biocatalysis and in situ free radical mediated racemization. , 2007, Organic letters.

[178]  Manfred T Reetz,et al.  Designing new Baeyer-Villiger monooxygenases using restricted CASTing. , 2006, The Journal of organic chemistry.

[179]  B. Martín‐Matute,et al.  Dynamic kinetic resolution catalyzed by enzymes and metals. , 2007, Current opinion in chemical biology.

[180]  J. Cameron,et al.  The separated enantiomers of 2'-deoxy-3'-thiacytidine (BCH 189) both inhibit human immunodeficiency virus replication in vitro , 1992, Antimicrobial Agents and Chemotherapy.

[181]  Eric Mathur,et al.  Exploring Nitrilase Sequence Space for Enantioselective Catalysis , 2004, Applied and Environmental Microbiology.

[182]  Chi‐Huey Wong,et al.  Enzymes in carbohydrate synthesis: N-acetylneuraminic acid aldolase catalyzed reactions and preparation of N-acetyl-2-deoxy-D-neuraminic acid derivatives , 1988 .

[183]  D. Robertson,et al.  Chapter 10. Potassium Channel Openers: New Biological Probes , 1989 .

[184]  V. Wendisch,et al.  Metabolic engineering of Escherichia coli and Corynebacterium glutamicum for biotechnological production of organic acids and amino acids. , 2006, Current opinion in microbiology.

[185]  Hydroxylation of Mutilin by Streptomyces griseus and Cunninghamella echinulata , 2002 .

[186]  J. B. Jones,et al.  Enzymes in organic synthesis. 34. Preparations of enantiomerically pure exo- and endo-bridged bicyclic [2.2.1] and [2.2.2] chiral lactones via stereospecific horse liver alcohol dehydrogenase catalyzed oxidations of meso diols , 1985 .

[187]  V. Alphand,et al.  Asymmetric Baeyer–Villiger Biooxidation of α‐Substituted Cyanocyclohexanones: Influence of the Substituent Length on Regio‐ and Enantioselectivity , 2007 .

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

[189]  Ramesh N. Patel,et al.  Chemical and Enzymatic Resolution of (R,S)-N-(tert-Butoxycarbonyl)-3-hydroxymethylpiperidine , 2001 .

[190]  S. Danishefsky,et al.  The Total Synthesis of Allosamidin. Expansions of the Methodology of Azaglycosylation Pursuant to the Total Synthesis of Allosamidin. A Surprising Enantiotopic Sense for a Lipase-Induced Deacetylation , 1996 .

[191]  B. Buckland,et al.  Directed evolution of toluene dioxygenase from Pseudomonas putida for improved selectivity toward cis-indandiol during indene bioconversion. , 2000, Metabolic engineering.

[192]  W. Suen,et al.  Improved activity and thermostability of Candida antarctica lipase B by DNA family shuffling. , 2004, Protein engineering, design & selection : PEDS.

[193]  J. Binet,et al.  Synthesis and antihypertensive activity of a series of 4-amino-6,7-dimethoxyquinazoline derivatives. , 1986, Journal of medicinal chemistry.

[194]  N. Trippodo,et al.  Dual metalloprotease inhibitors: mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase. , 1997, Journal of medicinal chemistry.

[195]  Uwe T Bornscheuer,et al.  Methods to increase enantioselectivity of lipases and esterases. , 2002, Current opinion in biotechnology.

[196]  M. Kula,et al.  Dehydrogenases for the synthesis of chiral compounds. , 1989, European journal of biochemistry.

[197]  T. Pabst,et al.  Large-Scale Synthesis of (R)-2-Amino-1-(2-furyl)ethanol via a Chemoenzymatic Approach , 2006 .

[198]  T. Hamilton,et al.  Synthesis and antihypertensive activity of 6,7-disubstituted trans-4-amino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ols. , 1983, Journal of medicinal chemistry.

[199]  J. Clardy,et al.  Antileukemic alkaloids from Taxus wallichiana Zucc , 1981 .

[200]  Albrecht Berkessel,et al.  Lipase/aluminum-catalyzed dynamic kinetic resolution of secondary alcohols. , 2006, Angewandte Chemie.

[201]  Nicholas J Turner,et al.  Enzyme catalysed deracemisation and dynamic kinetic resolution reactions. , 2004, Current opinion in chemical biology.

[202]  C. Hamilton,et al.  Recent developments in preparative enzymatic syntheses of carbohydrates. , 2006, Natural product reports.

[203]  M. Reetz,et al.  Lipase-Catalyzed Dynamic Kinetic Resolution of Chiral Amines: Use of Palladium as the Racemization Catalyst , 1996, CHIMIA.

[204]  D. Ghisotti,et al.  Immobilized Biocatalysts for the Production of Nucleosides and Nucleoside Analogues by Enzymatic Transglycosylation Reactions , 2004 .

[205]  M. Delcourt,et al.  Directed Evolution of Biocatalysts , 2006 .

[206]  B. Martín‐Matute,et al.  (S)-selective kinetic resolution and chemoenzymatic dynamic kinetic resolution of secondary alcohols. , 2006, Chemistry.

[207]  F. Effenberger,et al.  Enzym‐katalysierte Synthese von 1‐Desoxymannojirimycin, 1‐Desoxynojirimycin und 1,4‐Didesoxy‐1,4‐imino‐D‐arabinitol , 1988 .

[208]  J. Snyder,et al.  Biochemistry and physiology of microtubules. , 1976, Annual review of biochemistry.

[209]  L. Itri,et al.  Retinoids and Cancer , 1984 .

[210]  Ramesh N. Patel,et al.  Stereoselective reduction of β-keto esters by Geotrichum candidum , 1992 .

[211]  V. Urlacher,et al.  Microbial P450 enzymes in biotechnology , 2004, Applied Microbiology and Biotechnology.

[212]  Ramesh N. Patel,et al.  Stereospecific enzymatic hydrolysis of racemic epoxide: a process for making chiral epoxide , 1999 .

[213]  Marco W. Fraaije,et al.  Baeyer-Villiger monooxygenases, an emerging family of flavin-dependent biocatalysts , 2003 .

[214]  Daeho Kim,et al.  Dynamic kinetic resolution of secondary alcohols by enzyme–metal combinations in ionic liquid , 2004 .

[215]  David A. Stock,et al.  BMS-232632, a Highly Potent Human Immunodeficiency Virus Protease Inhibitor That Can Be Used in Combination with Other Available Antiretroviral Agents , 2000, Antimicrobial Agents and Chemotherapy.

[216]  E. Baloglu,et al.  A new semisynthesis of paclitaxel from baccatin III. , 1999, Journal of Natural Products.

[217]  A. Iribarren,et al.  Microbial Synthesis of Antiviral Nucleosides Using Escherichia coli BL21 as Biocatalyst , 2002 .

[218]  Chi‐Huey Wong,et al.  Enzyme-catalyzed organic synthesis: practical routes to aza sugars and their analogs for use as glycoprocessing inhibitors , 1993 .

[219]  J. Smith.  Synthetically Useful Reactions of Epoxides , 1984 .

[220]  J. Harting,et al.  3-Methyl-2H-1-benzopyran potassium channel activators. , 1991, Journal of medicinal chemistry.

[221]  D. M. Ryan,et al.  Rational design of potent sialidase-based inhibitors of influenza virus replication , 1993, Nature.

[222]  Jie Chen,et al.  N-[2-[2-(4-Phenylbutyl)benzofuran-4-yl]cyclopropylmethyl]acetamide: an orally bioavailable melatonin receptor agonist. , 2004, Bioorganic & medicinal chemistry letters.

[223]  Chiehying Y Chang,et al.  Discovery of a (1H-benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924) inhibitor of insulin-like growth factor I receptor kinase with in vivo antitumor activity. , 2005, Journal of medicinal chemistry.

[224]  Jaiwook Park,et al.  Dynamic Kinetic Resolutions and Asymmetric Transformations by Enzyme-Metal Combo Catalysis , 2005 .

[225]  P. Seubert,et al.  Potential treatment opportunities for Alzheimer’s disease through inhibition of secretases and Aβ immunization , 2001, Journal of Molecular Neuroscience.

[226]  J. Mestan,et al.  New aza-dipeptide analogues as potent and orally absorbed HIV-1 protease inhibitors: candidates for clinical development. , 1998, Journal of medicinal chemistry.

[227]  Ramesh N. Patel,et al.  Enantioselective microbial reduction of 3,5-dioxo-6-(benzyloxy) hexanoic acid, ethyl ester , 1993 .

[228]  M Jason MacDonald,et al.  A modern view of phenylalanine ammonia lyase. , 2007, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[229]  R. Schwartz,et al.  Stereoselective epoxidation of octadiene catalyzed by an enzyme system of Pseudomonas oleovorans. , 1974, Journal of the American Chemical Society.

[230]  A. Linden.  Epoxidation of α-olefins by heptane-grown Pseudomonas cells , 1963 .

[231]  F. Arnold,et al.  Protein engineering of oxygenases for biocatalysis. , 2002, Current opinion in chemical biology.

[232]  Chi‐Huey Wong,et al.  Enzymes in Organic Synthesis: Aldolase‐Mediated Synthesis of Iminocyclitols and Novel Heterocycles , 2007 .

[233]  Ramesh N. Patel,et al.  Synthesis and activity of a C-8 keto pleuromutilin derivative. , 2003, Bioorganic & Medicinal Chemistry Letters.

[234]  R. Kazlauskas.  Enhancing catalytic promiscuity for biocatalysis. , 2005, Current opinion in chemical biology.

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

[236]  S. Shimizu,et al.  Microbial and Enzymatic Processes for the Production of Biologically and Chemically Useful Compounds [New Synthetic Methods (69)] , 1988 .

[237]  B. M. Pinto,et al.  The anomeric effect in 2-arylseleno-1,3-dithianes , 1985 .

[238]  J. S. Wells,et al.  Monobactams—monocyclic β -lactam antibiotics produced by bacteria , 1981 .

[239]  K. Altmann.  The merger of natural product synthesis and medicinal chemistry: on the chemistry and chemical biology of epothilones. , 2004, Organic & biomolecular chemistry.

[240]  J. Stewart.  Dehydrogenases and transaminases in asymmetric synthesis. , 2001, Current opinion in chemical biology.

[241]  A. McPhail,et al.  Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. , 1971, Journal of the American Chemical Society.

[242]  Ramesh N. Patel,et al.  Enzymatic preparation of (3R)-cis-3-acetyloxy-4-(1,1-dimethylethyl)-2-azetidinone: a side-chain synthon for an orally active taxane , 2003 .

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

[244]  J. Woodley,et al.  Towards large-scale synthetic applications of Baeyer-Villiger monooxygenases. , 2003, Trends in biotechnology.

[245]  Ramesh N. Patel,et al.  Purification and Cloning of a Ketoreductase used for the Preparation of Chiral Alcohols , 2005 .

[246]  M. Dawson,et al.  A practical enzymatic procedure for the resolution of N-substituted 2-azabicyclo[2.2.1]hept-5-en-3-one , 1999 .

[247]  Ramesh N. Patel,et al.  Enantioselective microbial reduction of 6-oxo-8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione: Cloning and expression of reductases , 2006 .

[248]  Enantioselective microbial reduction of 6-oxo-8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione , 2005 .