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j375 Index a a-alkyl-b-keto esters – bioreduction 315 – dynamic kinetic resolution 315, 319 a-aminobutyric acid 199 acetoacetyl-CoA reductase 154 acetophenone 154, 164, 247, 251 2-acetylbenzonitriles 106 Acinetobacter sp., cyclohexanol dehydrogenase (ACDH) 154 active pharmaceutical ingredient (API) syntheses 71, 74, 75, 329, 363 acutiphycins 96 a-acylaminoacrylic acid 49 (S)-acyloins 62 Aeropyrum camini 215 AG7088 (rupintrivir) 358 b-3 agonist precursors, synthesis using enzymatic reductions 92 alanine dehydrogenase (AlaDH) 226, 301, 302 Alcaligenes eutropha 214 Alcaligenes faecalis 288 – enantioselective biooxidation reaction 288 alcohol dehydrogenase (ADH) 2, 4, 6, 7, 31, 86, 99, 210, 240, 242, 265, 288, 308, 329 – anti-Prelog 290 – cascade, for in situ regeneration of NADH 220 – catalyzed reduction of phenylacetaldoxime 42 – Clostridium acetobutylicum (CaADH) 320 – enantioselectivity 257 – Lactobacillus brevis (LB-ADH) 90, 248, 290, 319, 339 – Lactobacillus kefir ADH (ADH-LK) 294 – oxidation reaction 288 – Prelog 290 – Ralstonia sp. (RasADH) 321 – reduction reaction 288 – Rhodococcus ruber ADH (ADH-A) 290 – Sphingobium yanoikuyae (SyADH) 321 – stability 248 – stereochemistry 150 – strategies to synthesis biologically active compounds involving 99 – T. ethanolicus (TESADH) 322 – Thermoanaerobacter ADH (ADH-T) 294 alcohols as stoichiometric reductants 218–220, 223 aldehyde dehydrogenase (AldDH) 97 – cascade, for in situ regeneration of NADH 220 aldehyde oxidoreductases 43 aldimine 189 aldo-keto reductase (AKR) 172 aldol-catalyzed reaction 104 alkene reductases 245 a-alkoxycyclohexenones 62 a-alkyl-b-arylketones 61 sec-alkyl 2-methyl-3-oxobutyrate – reduction of 313 allylic alcohols 103, 227 – biocatalytic redox isomerization 227 amine dehydrogenase 35, 329 amino acid dehydrogenase 34, 227 – catalyzed processes – – AG7088 (rupintrivir) 358 – – applications 333 – – corticotropin-releasing factor-1 (CRF-1) receptor antagonist 357–358 – – inogatran 357 – – omapatrilat 356–357 – – saxagliptin 355–356 amino acid dehydrogenases (AADHs) 295–297 – L-amino acid dehydrogenase (L-AADH) 297 amino acid dehydrogenases (AaDHs) 86 D-amino acid oxidase (D-AAO) 356 Synthetic Methods for Biologically Active Molecules: Exploring the Potential of Bioreductions, First Edition. Edited by Elisabetta Brenna. Ó 2014 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2014 by Wiley-VCH Verlag GmbH & Co. KGaA. 376 j Index b2-amino acids 353 c-aminobutanoic acid (GABA) derivatives 353 – microbial reduction of 354 (S)-3-(1-aminoethyl)phenyl ethyl(methyl) carbamate 363 2-amino-1-phenylpropane-1,3-diol 197 aminotransferases 188 – asymmetric synthesis, and resolution mode 188 – future research need 203 – improving reaction yield 197–200 – modified 191 – process scale-up 200–203 – (R)-aminotransferases 188, 197 – (S)-aminotransferases 188, 197 – shifted enantioselectivity 192 – stereoselectivity 189–192 – substrate specificity 197 – variant Trp60Cys 191 – v-aminotransferases 197 – wild-type, stereoselectivity 190 AMMOENGTM 101, 248 amprenavir precursors, through ADHcatalyzed bioreductions 93 30 - and 40 -halogenated acetophenones 154 anti-Alzheimers disease drug (S)-rivastigmine 300, 301 anti-(4S,5R)-5-hydroxy-c-decalactone 313 antistereochemistry 30 AOT-based microemulsions 255 AOT/isooctane reverse micelles 255 API synthesis – amino acid dehydrogenase-catalyzed reactions, applications 333 – ene reductase-catalyzed reactions, applications 335 – ketoreductase-catalyzed reactions, applications 330 aqueous–hexane (1:1) biphasic system 244 aqueous systems, bioreduction in 240, 241 armentomycin 70 Artemisia annua 60 artemisinin 60 Arthrobacter citreus 195, 197 aryl ketones 154 2-aryl-1-nitro-1-propenes 66 3-aryl-2-oxopropanoic acids 6 Aspergillus nidulans glycerol dehydrogenase 172 atazanavir synthesis 343 atomoxetine 97 atorvastatin calcium 105 avermectins 96 b Bacillus megaterium 197 Bacillus pumilus 89 Bacillus stearothermophilus 299 Bacillus subtilis 7, 129 Baeyer–Villiger monooxygenase (BVMO) 226 Baeyer–Villiger oxidation 226 bakers yeast-mediated reduction 294 Beauveria bassiana 61 2-benzenesulfonylcycloalkanones 310 benzoyl coenzyme A reductases 14 (2S,3S)-N-benzoyl-3-phenylisoserine ethyl ester 346 benzylacetone 167, 169 benzylic amines [a-methylbenzylamine (a-MBA)] 35 5-benzylidenethiazolidine-2,4-dione 74 (S)-BHBM production system, with KER and glucose dehydrogenase (GDH) 173 BINAP-Rh complex 59 BINAP-Ru catalyst 139 biocatalysis 44, 263 – gas/solid phase 252–254 biocatalyst format 269–273 – isolated enzyme processes 272, 273 – – bioreductions 273 – – enzyme-coupled cofactor regeneration 272, 273 – – enzymes dehydrogenases 272 – – substrate-coupled cofactor regeneration 272, 273 – whole-cell processes 271, 272 – – cofactor regeneration 271 – – ketone reduction 271 – – metal-catalyzed hydrogenation 271 – – n-butyl acetate-buffer biphasic system 271 – – Ru-based asymmetric hydrogenation 272 – – substrate-coupled regeneration 271 biocatalysts 2, 286–289, 293, 296, 298, 299, 302 biocatalytic – approach to montelukast key intermediate 340 – deoxygenation reactions 12–14 – hydrogenation reaction 214 – reductive processes approaches 28 biocatalytic (whole-cell) acid reduction scheme 215 biocatalytic reduction processes – C¼C double bonds 8–10 – C¼O double bonds 3 – – aldehydes to alcohols 6–8 – – carboxylic acids to alcohols 8 Index – – carboxylic acids to aldehydes 8 – – ketones to alcohols 3–6 – imines to amines 10–12 – nitriles to amines 12 – and optimization of redox state changes 1 – reaction engineering for 16, 17 biocatalytic reduction reactions, environmental issues 211 biocatalyzed – reduction 286 – – whole cell 308 – reductive amination – – in situ generation 296, 297, 299, 302 – synthesis 289 biodiesel 243 biologically active compounds through C¼O bioreduction – bulky–bulky ketones 96, 97 – dihydroisocoumarins 99 – diketones 90, 91 – ethyl 5-hydroxyhept-6-enoate 89, 90 – a-halo ketones 91–93 – (hetero)cyclic ketones 94–96 – b-hydroxy nitriles 98 – a-keto esters 87–89 – b-keto esters 89 – lisofylline 98 – (S)-1-[3,5-Bis(trifluoromethyl)phenyl] ethanol 98 – tetrahydroisoquinolines 99 bioreduction 31 – process engineering 265–267 – – carbon-oxygen double bond reduction 265 – – cofactor regeneration 266 – – whole-cell biocatalyst (See whole-cell biocatalyst) – supported processes 361–363 – a,b-unsaturated carboxylic compounds 32 biotransformation 30, 294 biphasic aqueous–organic systems, bioreduction in 243–245 Birch reduction mechanism 15 bisabolene sesquiterpenes 57 (S)-1-(3,5-bistrifluoromethylphenyl)ethanol 98 boronic acid 102 BRENDA database 2 (S)-2-bromobutanoic acid 71 a-bromoesters 71 buspirone 345 2-butanone 254 butyl acetate–water biphasic system 244 3-butyn-2-one 247 c-butyrolactones 64 BY-catalyzed reduction – a-(chloromethyl)cinnamaldehyde 56 BY-catalyzed reduction of (Z)alkoxycinnamaldehydes 55 c Candida boidinii 217, 245 Candida magnoliae 139, 338 Candida parapsilosis 11, 29, 139, 246, 312 capromorelin 96 b-carbolines – pharmacological activities 359–360 – yeast-mediated imine-reduction 360 carbonyl reductase 29, 105, 244 – Sporobolomyces salmonicolor (SSCR) 178 carbonyl reductases (CRs) 2, 85 carboxylic acid reductases (CARs) 8 carboxylic acids 43, 73 carvone 63 (5R)-carvone – diastereoselective reduction 348 cascade system – ADH-catalyzed reactions 291, 292 – ADH/ER system 291 – biocatalyzed reductive amination 296–302 – bioreduction, prochiral unstaturated aldehydes 295 – deracemization of racemic amino acids – – DAAOs-catalyzed reactions 298 – enantiopure amino acids synthesis, AADH 296, 297 – enantiopure (S)- or (R)-alcohols 288, 289 – enantioselective reduction, prochiral unsaturated aldehydes 195 – ER–ADH cascade system 294–296 – ER-catalyzed reductions 291, 292 – parallel interconnected kinetic asymmetric transformations (PIKAT ) 289, 290 – redox neutral 296 – redox neutral (or self-sufficient) cascade 289 CASTing 129 catalytic hydrogenations 1 CDOCKER energy 151 chemoselectivity 32 chiral alcohol 6, 139, 140 – asymmetric bioreduction 341 – optical purity 181 – oxidoreductases/microorganisms, for preparation of 139 – production level 168 – from various ketones by E. coli biocatalysts 166 j377 378 j Index chiral azetidone 64 chiral chlofibrate 317 chiral Co (II) salen complex 139 chiral cyclic pentanones 62 chiral 1, 3-diols 104 chirality generating tools 361 chiral lactones 64 chiral metal catalysts 139 chlofibrate 317 chlofibrate [ethyl 2-(4-chlorophenoxy)-2methylpropanoate] 317 20 -chloroacetophenone 164, 166, 168, 243 2-chloroacetophenone (phenacyl chloride) 155 40 -chloroacetophenone 245, 250 a-chloroalkenoates 70 4-chlorobenzophenone 241 3-chloro-4-(4-chlorophenyl)-2-butanone 322 a-chloroesters 71 achloro ketones 220, 289, 290 2-chloro-1-(3,4-methylenedioxyphenyl) ethanone 167 chloromethyl 3,4-methylenedioxyphenyl ketone 164, 165 (R)-1-chloro-2-propanol 180 (S)-4-chlroro-3-hydroxybutyrate (CHBE) 172 Chromobacterium violaceum 190, 191, 192 cinnamaldehydes 61 cinnamyl alcohol 363 cinnamyl aldehyde 6 cinnamylamine 363, 364 cis-diastereomer (1R,2S)-2-(3,4dimethoxyphenethoxy) cyclohexanamine 191 citraconic anhydride 74 citral 60 Citrobacter braakii 13 citronellal 59 citronellal cyclases 16 Clostridium acetobutylicum (CaADH) 100 Clostridium kluyveri 73 Clostridium ljungdahlii 8 Clostridium ragsdalei 8 Clostridium sporogenes 67 Clostridium tyrobutyricum 73 codeinone 32 cofactor-dependent enzyme 286 cofactor regeneration systems, for dehydrogenases 27 corticotropin-releasing factor-1 (CRF-1) receptor 357 Corynebacterium aquaticum 63 coupled-enzyme approach 86 coupled oxidation, reduction reactions 287–292 Curvularia falcata 3 a-cyano-a,b-unsaturated esters 75 b-cyano-a,b-unsaturated esters 10, 75 cyclic b-keto esters 309 cyclohexa-1,5-diene-1-carboxyl CoA 15 cyclohexane 246, 254 cyclohexenone 66 D-cyclohexylalanine 357 cyclopentenone 62 (S)-cyclopropylglycine – cyclopropylglyoxylic acid, conversion 358 d D-amino acid oxidases (DAAOs) 297, 298 2-dehydrogenase 154 d-decanolide 68 a,b-dehydroamino acid derivatives 354 dehydrocholic acid (DHCA) 16 dehydrogenase-catalyzed oxidation 296–298 dehydrogenases 28, 29 density 248 deracemization 101, 288 – preparation of propargylic alcohols 101 – propargylic alcohols 101 – (R)-chlorohydrins 104 – secondary alcohols, biocatalytic cascade 288 (see Alcaligenes faecalis) – using Pichia glucozyma in water/organic solvent biphasic systems 256 deracemizations 87 designer solvents 248 detoxification 30 dextroamphetamine 154, 195, 200 diastereomers 293, 315, 320, 346 dicarbonyl reductases 6 2,30 -dichloroacetophenone 164, 166 2,40 -dichloroacetophenone 164, 165, 166 diethyl-2-alkyl-3-ketoglutarates 317 diethyl ether 250 a,a-difluoro hydroxylated compounds 93 (11S)-dihydroartemisinic aldehyde 60 4,9-dihydro-1H-carbazol-3 (2H)-one 340 dihydrocarvone 63 dihydrofolate reductase (DHFR) 329, 359 – (6S)-tetrahydrofolic acid 359 4,9-dihydro-1H-carbazol-3(2H)-one 340 dihydroisocoumarins 99 2,3-dihydroxy-isovalerate (DHIV) 177 1,3-dihydroxy-1-phenylpropan-2-one 197 diisopropyl ether 246 diketone – corresponding 1,3 diols through dynamic kinetic resolution 318 D-arabinitol Index – dynamic kinetic resolution 318 – through ADH-mediated processes 90 6,7-dimethoxy-1-methyl-3,4dihydroisoquinoline 11 2-(3,4-dimethoxyphenethoxy) cyclohexanone 191, 193 4,4-dimethoxytetrahydro-2H-pyran-3-one, asymmetric reduction 344 dimethyl(1-chloro-2-oxopropyl) phosphonate 100 dimethyl citraconate 74 dimethyl (S)-2-methylsuccinate 71 a,b-dimethyl nitrostyrenes 67 dispirotetraoxane 63 DKR methodology 101 D-Lactate dehydrogenase (D-Lactate DH) 358 DMSO reductase 12 DNA – sequencing 337 – shuffling 115 Docetaxel 100 dolastatin 97 L-DOPA 49 dynamic kinetic resolution (DKR) – approach 99, 100 – process 307 – – acyclic a-substituted b-keto esters 313–321 – – acyclic ketones 322, 323 – – of aldehyde 323 – – aldehydes 322, 323 – – 2-benzenesulfonylcyclopentanone and cyclohexanone 310 – – carboxamides, microbial reduction of 310 – – cyclic compounds 309–312 – – cycloalkanecarbonitriles 310 – – diketo ester 320 – – ketoreductases (KREDs) 311 – – 3-oxo-4-phenyl-b-lactam 311 – – of 2-phenylpropanal 322 – – 2-substituted-3-carbonyl butanoates 313–321 – – a-substituted carbonyl compounds 309 e (E)-2-ethoxy-3-(p-methoxyphenyl) prop-2-ene-1-al 10 electrochemical regeneration, of NAD(P)H 212 electroenzymatic reduction system 212, 213 electron-withdrawing groups (EWGs) 113 emerging reductive biocatalytic reactions 14–16 enantiomeric 3-hydroxy-2-methylpropionate, see Roche ester enantiomeric purity 296 enantiopure 2hydroxycyclopentanecarboxamides 310 enantiopure (S)-phenylglycine 226 enantioselective – biocatalytic reduction 29 – organic synthesis 139 enantioselectivity 31, 126, 132 ene reductase (ERs) 30, 50, 64, 66, 294, 353 – amino acid derivatives, asymmetric synthesis 353–355 – amphidinolides 348, 349 – butyrolactone – jasplakinolide 348, 349 – catalyzed reduction 10 – (þ)-dihydrocarvone 348 – ethyl (S)-2-ethoxy-3-(4-methoxyphenyl) propanoate (EEHP) 350 – (R)-flurbiprofen 349, 350 – human neurokinin-1 receptor antagonists 352 – levodione 347, 348 – methyl (z)-2-bromocrotonate – antidiabetic drug candidates 350, 351 – OYE1 – – reduction, mediated 294 – – Saccharomyces pastorianus 294 – OYE2 294, 295 – OYE3 294, 295 – Roche ester 351, 352 engineering database 179, 180 engineering of b-keto ester reductase (KER) 172–174 – and characterization of mutant enzymes 175–177 – for raising thermal stability and stereoselectivity 172 engineering of PAR – in 2-propanol/water medium – – characterization of Sar268 and HAR1 161–165 – – construction of HAR1 mutant 160, 161 – – construction of Sar268 mutant 157–159 engineering substrate- and stereospecificity of reductases 178, 179 E-nitroolefins 126 enoate 30 enoate reductase (ER) 31, 34, 50, 51, 227, 228 – catalytic mechanism 30, 229 – NAD(P)H independent regeneration approaches 230 enzymatic methods 86 j379 380 j Index enzyme – modification 200 – selectivity, solvent control of 255–257 epimerization 66 epoxide hydrolase 129 epoxides 139 error-prone polymerase chain reaction (epPCR) 115 Escherichia coli 3, 4, 12, 140, 311 – biocatalysts possessing 140 ethyl benzoylformate 180 ethyl 1-benzyl-3-oxo-piperidine-4-carboxylate – microbial reduction of 312 ethyl benzylpyruvate 164, 166 ethyl b-nitroacrylates 67 ethyl 4-chloroacetoacetate (CAE) 172 ethyl 4-chloro-3-hydroxybutanoate (CHBE) 244, 338 ethyl (S)-4-chloro-3-hydroxybutyrate 106 ethyl 4-chloro-3-oxobutanoate (COBE) 164, 166, 244, 337 ethyl (S)-2-ethoxy-3-(4-methoxyphenyl) propanoate (EEHP) – OYE-mediated gram-scale synthesis 350 ethyl (S)-2-ethoxy-3-(4-methoxyphenyl) propanoate – gram-scale enzymatic production 350 ethyl 5-hydroxyhept-6-enoate, synthesis employing isolated ADHs 90 (R)-ethyl mandelate 180 ethyl (E)-2-methyl-4-oxopent-2-enoate 348 ethyl 3-oxobutanoate 166 ethyl 3-oxobutanotate 164 ethyl pyruvate 164, 166 ezetimibe 96, 341 – promoted bioreduction reactions 216, 217 – regeneration system 217 formates, as reducing agents 215, 217, 218 fosfomycin 101 (–)-fosfomycin 101 furfural 6 g gas/solid continuous reactor 254 Geobacillus kaustophilus 12, 13, 41 Geobacter metallireducens 15 Geotrichum candidum 3, 251 Geotrichum sp. 313 Gibberella zeae reductase 172 gluconate 5-dehydrogenase 154 gluconic acid 224 Gluconobacter oxydans 6, 7 1,5-gluconolactone 223 glucose as stoichiometric reductant 223, 224 glucose dehydrogenase 6, 210, 223, 224, 244 glucose 1-dehydrogenase 154 glucose dehydrogenase (GDH) 86, 176, 223, 224, 240, 265, 271, 272, 321, 337 – mediated regeneration of NAD(P)H by means of glucose oxidation 223 – promoted reduction reactions 224 glucose-6-phosphate dehydrogenase (G6PDH) 271, 345 glutamate dehydrogenase (GluDH) 356 – L-6-hydroxynorleucine 356 glutaraldehyde (GA) 169 glycerol 242 good manufacturing practices (cGMPs) 200 green chemistry 85, 225 h f fenpropidine 54 ferredoxins 51 flavin mononucleotide (FMN) 30, 113 flavoprotein 49 a-fluorocinnamyl alcohol 55 (R)-3-(4-fluorophenyl)-2-hydroxypropionic acid 358 (1R,2R)-2-(4-fluorophenyl)-3oxocyclopentanecarboxylate 352 3-fluoropyruvate 190 fluoxetine 97 flurbiprofen, anti-inflammatory drug 349 FMN oxidation 30 formate dehydrogenase (FDH) 86, 210, 245, 271, 312 – catalyzed regeneration of NAD(P)H 215 a-halogenated cinnamic esters 354 halohydrin dehalogenase (HHDH) 105, 106, 338 halohydrins 92 a-haloketones 225 Hansenula sp. 346 Hase 210 Hase-driven NAD(P)H-dependent carbonyl reduction reactions 214 H2 as reducing agent 213–215 Heck reaction 103 Helional 58 2-heptanone 254 (hetero)cyclic alcohols 95 hexane 246 hexane–buffer system 251 hexanones 62 Index HIV-1 protease inhibitors 55 HLADH-catalyzed reduction 6 horse liver alcohol dehydrogenase (HLADH) 59, 226, 294, 295, 322 human neurokinin-1 (hNK-1) 65 hydride–Meisenheimer complex 34 hydrocodone 32 hydrogenases (Hases) 43, 214 hydrogenation 105, 256 Hydrogenovibrio marinus 215 hydromorphinone 32 hydrophobicity 248 hydrophobic solvents 243, 246 (S)-3-hydroxyadamantylglycine 356 6-hydroxybuspirone 345 6-hydroxybuspirone (6-hydroxy-8–8-azaspiro [4.5]decane-7,9-dione) 345 (2S,3S)-hydroxyester 64 (2R,3S,1R)-hydroxy ester 314 cis-(3R,4R)-Hydroxy ester 312 hydroxyesters 64 a-hydroxy esters, synthesis using alcohol dehydrogenases 88 b-hydroxy esters, synthesized by means of enzymatic bioreductions 89 hydroxy keto ester 313 2-hydroxy-methylacrylic acid methylester 10 3-hydroxy-3-methyl-glutaryl-CoA (HMGCoA) reductase inhibitors 337 L-6-hydroxynorleucine – enzymatic route 356 – 2-keto-6-hydroxyhexanoic acid 356 3a-hydroxysteroiddehydrogenase (HSDH) 255 i IlvC gene 177 imine complex 188 imine reductases 36–38 in situ product removal (ISPR) technologies 263, 267–269, 346 – biocatalytic processes 267 – capacity 269 – couple scheme, systematic evalutaion 277 – fermentation 267 – flow sheet options 270 – indutrial scale implementation 268 – ISPR with crystallization 274, 275 – – asymmetric reduction 4oxoisophorone 275 – – in situ product crystallization (ISPC) – – systematic evaluation, ISPR 275 – ISPR with resins 273, 274 – – Amberlite XAD-7HP 274 – – AmberliteÒ XAD-2 resin 273 – – fed-batch strategy 274 – – large-scale stereoselective enzymatic reduction 273 – – o-chloroacetophenone, bioreduction 274 – – in situ substrate supply 274 – ISPR with solvent extraction 274 – – two-phase system, ISPR 274 – membrane technology 269 – methods, and choice 268, 269, 276–278 – – cost-benefit analysis 278 – – ISPR benefits 277 – – ISPR technologies qualitative comparison, alcohol removal 278 – – qualitative comparison of ISPR technologies, alcohol removal 278 – – removal of alcohol methods comparison 278 – potential benefits 268 – process integration 278, 279 – – simulated moving bed (SMB) technology 289 – rate of removal 679 – removal of acetone 275 – – coupled-substrate, cofactor regeneration 275 – in situ coproduct removal (IScPR) 267, 268 in situ redox cofactor regeneration system 286, 288 – enzyme coupled 286 – formate/formate dehydrogenase (FDH) 296, 298 – glucose/glucose dehydrogenase (GDH) system 293 in situ SFPR technology 59 ionic liquids (ILs) 247–250 – combining with supercritical fluids 251, 252 – continuous biocatalytic synthesis of (R)-2-octanol in 252 – water-miscible 248 IPA–aqueous solution system 140 irreversible morphinone reductase reaction isonitramine 96 isopropanol 242, 247 isopropylamine 190, 198 isopulegol 59 isoxazoles 66 isoxazolines 66 iterative saturation mutagenesis (ISM) 116 k ker gene 177 KER mutants 175 ketamine 189 j381 382 j Index a-keto acid 34, 199 2-keto-3-(N-benzoylamino)-3-phenylpropionic acid ethyl ester – diastereoselective reduction 347 keto ester 65 – enzymatic reduction of 314 b-keto ester 164 – diastereoselective reductions 316 – dynamic kinetic resolution 321 – reduction 314 b-keto ester reductase (KER) 140, 149 a-keto esters 164 a-ketoglutarate – L-GluDH/NADH oxidase, coupled-enzyme system 361 2-keto-6-hydroxyhexanoic acid 356 ketoisophorone 63 – microbial reduction 347 ketol-acid reductoisomerase (KARI) 177 ketones 113 ketoreductase 2, 5, 7, 329 – atazanavir 343 – atorvastatin 338, 339 – chemokine receptor inhibitor 343, 344 – chiral precursor, stereoselective synthesis 344 – duloxetin 344 – ethyl 4-chloro-3-hydroxybutanoate (CHBE) 338 – ezetimibe 341, 342 – 6-hydroxybuspirone 345, 346 – LY 300164 346 – montelukast 339, 340 – paclitaxel 346, 347 – profens 342, 343 – ramatroban 340, 341 ketoreductases (KREDs) 85, 311 12-keto-ursodeoxycholic acid 16 kinetic – oxidative resolution 289, 290 – resolutions (KRs) 100, 307 Klebsiella oxytoca 215 Kluyveromyces marxianus 100, 317 Kluyveromyces thermotolerans 4 KRED kit 312 l lactate dehydrogenase (LDH) 299, 301, 361 Lactobacillus brevis 248, 319 Lactobacillus kefir 3, 7, 139 Lactobacillus kefir ADH (LKADH) 96 Lactobacillus kefiri 91 Lactobacillus leichmannii 13 lactones 64 LbADH-catalyzed reduction of aliphatic ketones 248 Leifsonia alcohol dehydrogenase (LSADH) 140 – amino acid sequence alignment 154 – enzymatic properties 153–155, 157 – physicochemical properties 153 – properties 149 – purified, substrate specificity of 164 – screening, from styrene-assimilating soil microorganisms 151, 152 – stereochemistry 150 – substrate and stereospecificity 145–147 leucine dehydrogenase (LeuDH) 357 Leuckart–Wallach reaction 35 (S)-leucovorin [(6S)-5-formyl-5,6,7, 8-tetrahydrofolate] – cancer chemotherapy 359 leukotriene B4 12-hydroxydehydrogenase 57 (6R)-levodione 347 levodione reductase (LVR) 63 light-driven system 265 lipases 308 lisofylline 98 lithium aluminum hydride 1 m mandelate dehydrogenase 227 mandelate racemase (MR) 226 marine microalgae 314 Meerwein–Ponndorf–Verley (MPV) reduction 85, 219, 220 melilotol 68 menthol 59 metagenomics 180, 181 metal-catalyzed hydrogenation 85 methoxyacetone 190, 191 40 -methoxyacetophenone 249 – biocatalytic anti-prelog stereoselective reduction 249 5-methoxy-2-aminotetralin 201 (R)-1-(40 -methoxyphenyl)-ethanol 179 methyl acrylate 68 2-methyl-3-aryl-propanols 10 4-methylbenzophenone 241 methyl benzoylformate 242 methylbenzylamine 199 methyl (S)-BHBM 172 methyl 4-bromo-3-hydroxybutanoate 174 methyl (S)-4-bromo-3-hydroxybutyrate (BHBM) 172 methyl 4-bromo-3-oxobutyrate (BAM) 172 methyl (S)-2-bromopropionate 351 Index methyl (Z)-2-chloro-3-(4-fluorophenyl) acrylate 355 methyl (S)-4-chloro-3-hydroxybutanoate (CHBE) 174 methyl cinnamate 68 methyl crotonate 68 3-methyl-2-cyclohexenone 130 a-methylcyclohexenone 50 3-methyl-3,4-dihydroisocoumarins 98 3,4-methylenedioxyphenylacetone – biocatalytic reduction 346 3,4-methylene-dioxyphenyl acetone 16 methylenic methylesters 69 methylesters 70 methyl 2-(3-fluoro-4-hydroxyphenyl) acrylate 349 methyl (R)-4-fluorophenylalanine hydrochloride 355 methyl 2-hydroxymethylacrylate 69 methyl isobutyl ketone 365 methyl methacrylate 68 2-methylpent-2-enal 129 methyl tert-butyl ether (MTBE) 96 3-methyl-1,2,3,4-tetrahydroisoquinolines 98 Metrosideros polymorpha 316 rac-mexiletine 362 mexiletine (R)/(S)-enantiomers 361 miconazole, synthesis using enzymatic reductions 92 micro- or nonaqueous systems, bioreduction in 245–247 Mitsunobu reaction 227 monophasic aqueous–organic systems, bioreduction in 241–243 morphine dehydrogenase 33 morphinone reductase 32 Mucor javanicus 3 Mucor rouxii 315 multienzymatic processes 285 – cascades – – bioreductive reactions 302–304 – one-pot processes 285, 286 (See one-pot processes) – representation 286 – synthesis 285 – – in vitro 285 – – in vivo 285 mutations 115 mutator strain 115 Mycobacterium marinum 8 n NADH 288 – NADH-dependent ene reductase (ER) 291 – NADH-dependent enzymes 35 – NADH-dependent phenylacetaldehyde reductase (PAR) 140 – – characterization 140 – – docking model construction 151 – – 3D structural models 148, 151 – – enzymatic properties 147, 149–151 – – kinetic parameters 162 – – location in styrene metabolic pathway 140–142 – – metabolic pathway of styrene by Rhodococcus sp. 141 – – physicochemical properties 142, 147 – – stereochemistry 150 – – substrate and stereospecificity 143, 144 – – substrate specificity – – for oxidative reaction 156 – – purified 164 – NADH regeneration system 217 NAD(P)H 288 – dependent b-keto ester reductase 173 – dependent 2-cyclohexen-1-one reductase (NCR) 32 – dependent dehydrogenases 361 – dependent ketoreductases (KRED) 292, 293, 317 – dependent oxidoreductases – – one-spot processes 287 – oxidation 30 – substrate-coupled regeneration of 219 NAD(P)þ-linked biocatalytic redox processes 225 Na2HPO3/phosphite dehydrogenase (PDH) recycling system 352 Nannochloropsis sp. 314 naproxen precursor 343 N-based enzymatic reductions 41, 42 1-N-Boc-3-pyrrolidinone 164, 167, 168 Nef pathway 42 N-gluconyl glutamic acid didecyl ester 255 Nicotiana tabacum 31 nicotinamide cofactor 209, 228 – chemical structure 209 – electrochemical regeneration 212 – electrochemistry 210 – regeneration methods 210 nicotinamide-dependent 2-cyclohexenone reductase 129 nicotin-amide-independent system 265 nicotinamide recycling system 344 nitrile reductases 38–41 – postulated mechanism 40 nitroalkenes 41, 65 j383 384 j Index 1-nitro-1-alkenes 30 nitrocyclohexene 66 nitroolefin reduction, catalyzed by PETN reductase 126 nitroolefins 65, 66, 113 – bioreduction of 65–67 N-nitramines 33 nonconventional media, bioreduction in 247 – combining ILs and SFs 251, 252 – gas-phase media 252–254 – ionic liquids 247–250 – reverse micelles 254, 255 – supercritical fluids 250, 251 c-2-nonenolide 68 nonflavin-dependent ene reductases 50 nonflavo ene reductases 51 nonselective reductions 1 nonsteroidal anti-inflammatory drugs (NSAIDs) 69 N-substituted-2-methylmaleimide 74 o 2-octanone 250 old yellow enzyme (OYE) 117, 265 – enhancement of selectivity 133 – evolving, in stereoselective reduction 117, 119 – – NCR for a,b-unsaturated ketones 129 – – OYE1 for 3-alkyl-2-cyclohexenone derivatives 119–122 – – PETN reductase for a,b-unsaturated carbonyl compounds and E-nitroolefins 123, 126 – – YqjM for a,b-unsaturated ketones 129–133 – mutants, excellent catalysts in reduction 133 – rational design 117 – structural overview 118 old yellow enzymes (OYEs) 10, 17, 30–34, 50, 51, 53, 58, 59, 61, 63, 67, 73, 114, 117, 119, 134, 295, 302, 315, 317, 318, 320, 322 oligomerizations 30 omapatrilat synthesis 356 one-pot chemo/biocatalyzed cascade reactions, in biphasic system 249 one-pot processes 285–287 – cascade reductions 292–296 (see cascade system) – consecutive reductions 292–296 – linear (or sequential) reactions 285, 286 – mixed-type reactions 286 – multienzymatic synthesis – – 12-ketoursodeoxycholic acid 289 – – optically pure b-hydroxy carboxylic acids 302 – orthogonal (or parallel) reactions 286 – stereoselective synthesis 292 (see also NAD(P)H) – – 2-alkyl-1,3-diols, KRED 292, 293 – – tert-butyl 3,5-dihydroxyhexanoate stereoisomers 293 – synthesis – – enantiopure bazidoalcohols and b-hydroxynitriles 303, 304 – – enantiopure b-hydroxytriazoles 303, 304 – two step synthesis, enantiopure 2,4-dimethylbutyrolactones 294 – in vitro chemoenzymatic synthesis 294 – vs. cascade processes 286 OPR1 (12-oxophytodienoate reductase 1) 58 optically active hydroxyl ester (CHBE) 244 organoboranes 1 oscillatoxins 96 oxazete formation 42 oxcarbazepine 95 – transformation 95 oxidized NADþ cofactor 302 oxidoreductases 3, 6, 10, 28, 29, 39, 85, 86, 102, 113, 183, 337 oximes 41 3-oxoacyl-[acylcarrier-protein] reductase – amino acid sequence alignment 154 2-oxocycloalkanecarbonitriles – enantio- and diastereoselective bioreduction of 310 b-oxoesters 309 2-oxotetralin 191 OYE-catalyzed reduction 30 OYE3-catalyzed reduction 10 OYE-catalyzed reduction reaction 30 – of alkene 114 OYE homologs PETN reductase 34 OYE-like ene reductases 51 OYE-like flavoproteins 71 OYE1 mutants 69 p par gene 142 Pd catalyst 250 Pd(II)-catalyzed Wacker-type oxidation 102 Penicillium citrinum 139, 140 – substrate specificity of recombinant KER 174 pentaerythritol tetranitrate (PETN) reductase 33 PETNR (pentaerythritol tetranitrate reductase) 60 PETN reductase mutants 126 Index pharmaceutical intermediate 4-phenylpyrrolidin-2- one 300, 301 phenylacetic acid (PAA) 142 phenylacetone, asymmetric reduction 247 2-phenylacrylonitrile 74 phenylalanine dehydrogenase (PheDH) 355 (S)-1-phenyl-1-butanol 257 1-phenyl-1-butanone 155 1-phenyl-3-butanone 155 1-phenylethanol 154 phenyl n-propyl ketone 257 1-phenyl-2-propyn-3-trimethylsilyl-1-on 16 phenyl trifluoromethyl ketone (PTK) 151 phosphite dehydrogenase 210, 218 phosphites, as stoichiometric reductants 218 Pichia glucozyma 255, 256 Pichia stipitis 61 piperidin-3-ols 95 piperonylacetone 167 piperonyl methyl ketone 164 Plasmodium falciparum 60 polar organic solvents 248 polyethyleneimine (PEI) 169 Prelogs rule 3, 4, 316 profens 342, 343 (S)-proline 359 2-propanol [isopropyl alcohol (IPA)] 140 propionoic acid class, see profens protection–deprotection steps 1 protein engineering 10, 31, 114, 218, 276 – B-FIT method, for improving thermostability/robustness 116 – combinatorial active-site saturation test (CAST) 116 – combinatorial space 115 – examples 276 – generation of high-quality (smart) libraries 115 – mutations 115, 116 – reductase enzymes 276 – screening effort 115 – in situ product removal 276 – synthetic chemistry 276 protein–inhibitor complexes 50 Proteus mirabilis 13 Pseudomonas aeruginosa 12 Pseudomonas fluorescens 288 Pseudomonas testosteroni 255 Pseudotriton ruber 321 pyridoxamine 5-phosphate (PMP) 188, 189 Pyrococcus furiosus 8, 43, 214, 255 pyrrolidin-3-ols 95 pyrrolo[2,1-c][1,4]benzodiazepines – biocatalytic azide reduction–cyclization sequence 359 pyrrolo[2,1-c][1,4]benzodiazepines (antitumor agents) 358, 359 pyrrolo[2,1-c][1,4]benzodiazepines (PDB) 359 q quick quality control (QQC) 115 3-quinuclidinone 164, 167, 168 r racemic ketone 311 racemization 67 Rac-2-hydroxycyclohexanone 312 Ralstonia eutropha 215 (R)-aminotetralin 191 (R)-2-aminotetralin 190 (R)-ramatroban, synthesis 340 random mutagenesis 115 Raney Ni-catalyzed hydrogenation 353 (R)-1-cyclopropylethylamine 197 (R)-4,4-dimethoxytetrahydro-2H-pyran3-ol 96 reaction engineering for biocatalytic reduction processes 16, 17 recombinant enoate reductase (ER) 105 redox economy 1 redox isomerizations 227 reductases 27 reductive amination 35 reductive denitration 33 reverse micelles 254, 255 – water-to-surfactant ratio 254 (R)-3-fluoroalanine 190, 195 Rhizopus arrhizus 309 rhodium complexes 217 Rhodobacter capsulatus 12 Rhodoccocus ruber 341 Rhodococcus erythropolis 141, 254 Rhodococcus opacus 142 Rhodococcus ruber 246 Rhodococcus sp. 320 Rhodotorula rubra 61 (S)-rivastigmine synthesis 363 (R)-1-methoxy2-propanamine 197 (R)-2-methylpyrrolidine 11 robalzotan 59 Roche ester 69, 351, 352 – stereocomplementary strategies 352 rotigotine 59 (R)-4-phenyl-2-butanamine 197 (R)-4-phenyl-2-butanol 168, 169 (R)-(–)-3-quinuclidinol production system 171 j385 386 j Index (1R,2R)-2-(3,4-dimethoxyphenethoxy) cyclohexanamine 190, 193 (R)-rhododendrol 103 (R)-sec-butylamine 197 (R)-tamsulosin 98 (R)-tetrahydrothiophene-3-ol 96 ruthenium complexes 217 s Saccharomyces cerevisiae 3, 49, 56, 320 – D-arabinose dehydrogenase 172 Saccharomyces montanus 310 (S)-(a)-methylbenzylamine 190 (S)-a-methylbenzylamine 197 (S)-2-aminotetralin 191 saturation mutagenesis 115 saxagliptin 355 (S)-2-bromo-2-cyclohexen-1-ol 16 (S)-2-butanamine 197 scale-up processes, requirement 263–265 – biocatalyst yield 264 – biocatalytic processes 263–265 – product concentration 264 – reaction yield 264 – space-time yield (STY) 264 scCO2–buffer biphasic system 251 Schiffs base 188 serotonin (5-hydroxytryptamine 5-HT) transporter 344 (S)-2-ethoxy-3-(p-methoxyphenyl)propion-1aldehyde 10 Sheldons E-factor 211 sibirine 96 sitagliptin 35, 36, 156 site-specific mutagenesis 114, 115 sitophilate 319 Sitophilus granarius 318 (S)-licarbazepine 95 (S)-7-methoxy-2-aminotetralin 198, 201 (S)-methoxyisopropylamine 190, 191, 198 – synthesis, from methoxyacetone 191 (S)-1-methoxy-2-propanamine 197 (S)-3,4-methylene-dioxyphenyl isopropanol 16 (S)-methyl p-tolyl sulfoxide 12 (S)-2-methylpyrrolidine 10 sodium bicarbonate 251 sodium borohydride 1 sodium dioctyl sulfosuccinate 255 solid-phase extraction (SPE) 252 solvent control, of enzyme selectivity 255–257 solvent systems, for biocatalytic reductions 239 (S)-phenylethylamine 190 (S)-1-phenylethylamine 189 (S)-1-phenyltrifluoroethanol (PTE) 151 Sphingomonas pausimobilis 2,5dichloro-2,5-cyclodiene-1,4-diol dehydrogenase (SDCDDH) 154 (S)-phthalides 106 spiro nitrile 74 Sporidiobolus salmonicolor – aldehyde reductase 172 Sporobolomyces salmonicolor 92, 139 squalene–hopene cyclase 16 stegobinone 319 stegobiol 319 stenusine 61 stereocontrol strategies, for bioreduction 52 stereoisomeric products, asymmetric reduction 308 stereoisomers 292, 293 – tert-butyl 3,5-dihydroxyhexanoate 293 stereoselective reduction 289, 290 Streptomyces coelicolor (ScCR) 244 Streptomyces fradiae 100 Streptomyces virginiae 35 Streptosporangium roseum 11 structure–function relationships 2 styAB gene 142 styCD gene 142 a-substituted b-keto esters – ruthenium-catalyzed hydrogenation 308 2-substituted-3-carbonyl butanoate 313 substrate-coupled biocatalytic reduction reactions 221, 222 substrate feeding product removal (SFPR) concept 350 Sulfolobus solfataricus 323 supercritical carbon dioxide (scCO2) 251, 252 supercritical fluids (SFs) 250 Suzuki cross-coupling 102 Suzuki–Miyaura coupling 349 syn-hydrogenation 31 – N. tabacum OYE-catalyzed, for enones 31 syn-(1R,2S) halohydrin 101 synthetic mNADs 228 t talaromycins 96 taxoid anticancer drugs 321 taxotere 100, 321 4-tert-butylcyclohexanone 96 Index tetrahydroisoquinolines 99 Thermoactinomyces intermedius 355 Thermoanaerobacter species 348 Thermoanaerobium brockii 3, 139 thermophilic microorganism 299 Thermoplasma acidophilum 6 thiazolidine-2,4-diones 74 three-enzyme system – biotransformation of morphine to hydromorphone 287, 288 – irreversible morphinone reductase reaction 288 toluene 244, 246 toluene–buffer biphasic system 244 total turnover number (TTN) 211, 212 a-transaminases – application 299, 300 – D-amino acids synthesis 300 – the herbicide L-phosphothricin synthesis 300 v-transaminase (v-TA)-catalyzed processes 35, 299–301, 361 – application 300, 301 – catalyzed transamination 302 – multienzymatic cascade 301 – optically pure amines synthesis 299 – redox-neutral cascade 301, 302 transamination reaction 188, 189 – mechanism 189 transition metal catalysis 113 transition metal complexes 217 trans-stereospecificity 8 2,2,2-trifluoroacetophenone 164, 165, 167 Trigonopsis variabilis 249 trinitrotoluene (TNT) 34 triphenylphosphane 102 Triton X-100 199, 255 tyrosine 113 u a,b-unsaturated aldehydes 30, 113 – chemical pathway of bioreduction 53 a,b-unsaturated carbonyl compounds, bioreduction 53 – aldehydes 54–60 – ketones 61–65 a,b-unsaturated carboxylic acids and derivatives, bioreduction 68 – anhydrides 73, 74 – carboxylic acids 73 – diesters 71–73 – imides 73, 74 – lactones 68–71 – monoesters 68–71 a,b-unsaturated nitriles, bioreduction 74–76 v viscosity 248, 252, 274 w Wacker–Tsuji oxidation 103 water-miscible ionic liquids 248 whole-cell biocatalysts – limited substrate 266 – possessing mutant PARs and LSADH, applications – – continuous production of chiral alcohol 166, 168–171 – – immobilized E. coli whole-cell catalysts mutants 165, 168, 170 – – for regenerating NADH with IPA 171, 172 – product transport into and out 266 – slide reaction 266 – toxic substrates, products 266, 267 Wittig reaction 32, 103 WT PETN reductase 126 – catalytic performance 127, 128 x xylitol 225 xylose 225 y yeast alcohol dehydrogenase (YADH) 255 Yersinia enterocolitica 12 YqjM mutants 131–133 – evaluation 131 – pathways leading maximum enantioselectivity 132 – from saturation mutagenesis 133 z zeaxanthin 63 zinc-containing ADHs 142 Zn2þ–cyclen complexes 105 Zn2þ ion cofactor 257 Zygosaccharomyces rouxii 16, 346 – glycerol dehydrogenase 172 Zymomonas mobilis 16, 129 j387