Α-Alkyl-Β-Keto Esters

j375

Index

a – Rhodococcus ruber ADH (ADH-A) 290 a-alkyl-b-keto esters – Sphingobium yanoikuyae (SyADH) 321 – bioreduction 315 – stability 248 – dynamic kinetic resolution 315, 319 – stereochemistry 150 a-aminobutyric acid 199 – strategies to synthesis biologically active acetoacetyl-CoA reductase 154 compounds involving 99 acetophenone 154, 164, 247, 251 – T. ethanolicus (TESADH) 322 2-acetylbenzonitriles 106 – Thermoanaerobacter ADH (ADH-T) 294 Acinetobacter sp., cyclohexanol dehydrogenase alcohols as stoichiometric reductants (ACDH) 154 218–220, 223 active pharmaceutical ingredient (API) aldehyde dehydrogenase (AldDH) 97 syntheses 71, 74, 75, 329, 363 – cascade, for in situ regeneration of acutiphycins 96 NADH 220 a-acylaminoacrylic acid 49 aldehyde oxidoreductases 43 (S)-acyloins 62 aldimine 189 Aeropyrum camini 215 aldo-keto reductase (AKR) 172 AG7088 (rupintrivir) 358 aldol-catalyzed reaction 104 b-3 agonist precursors, synthesis using alkene reductases 245 enzymatic reductions 92 a-alkoxycyclohexenones 62 alanine dehydrogenase (AlaDH) 226, 301, 302 a-alkyl-b-arylketones 61 Alcaligenes eutropha 214 sec-alkyl 2-methyl-3-oxobutyrate Alcaligenes faecalis 288 – reduction of 313 – enantioselective biooxidation reaction 288 allylic alcohols 103, 227 alcohol dehydrogenase (ADH) 2, 4, 6, 7, 31, 86, – biocatalytic redox isomerization 227 99, 210, 240, 242, 265, 288, 308, 329 amine dehydrogenase 35, 329 – anti-Prelog 290 amino acid dehydrogenase 34, 227 – cascade, for in situ regeneration of – catalyzed processes NADH 220 ––AG7088 (rupintrivir) 358 – catalyzed reduction of ––applications 333 phenylacetaldoxime 42 ––corticotropin-releasing factor-1 (CRF-1) – Clostridium acetobutylicum (CaADH) 320 receptor antagonist 357–358 – enantioselectivity 257 ––inogatran 357 – Lactobacillus brevis (LB-ADH) 90, 248, 290, ––omapatrilat 356–357 319, 339 ––saxagliptin 355–356 – Lactobacillus keﬁr ADH (ADH-LK) 294 amino acid dehydrogenases (AADHs) – oxidation reaction 288 295–297 – Prelog 290 – L-amino acid dehydrogenase (L-AADH) 297 – Ralstonia sp. (RasADH) 321 amino acid dehydrogenases (AaDHs) 86 – reduction reaction 288 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. 376j Index

2 b -amino acids 353 b c -aminobutanoic acid (GABA) derivatives 353 Bacillus megaterium 197 – microbial reduction of 354 Bacillus pumilus 89 (S)-3-(1-aminoethyl)phenyl ethyl(methyl) Bacillus stearothermophilus 299 carbamate 363 Bacillus subtilis 7, 129 2-amino-1-phenylpropane-1,3-diol 197 Baeyer–Villiger monooxygenase (BVMO) 226 aminotransferases 188 Baeyer–Villiger oxidation 226 – asymmetric synthesis, and resolution bakers yeast-mediated reduction 294 mode 188 Beauveria bassiana 61 – future research need 203 2-benzenesulfonylcycloalkanones 310 – – improving reaction yield 197 200 benzoyl coenzyme A reductases 14 – ﬁ modi ed 191 (2S,3S)-N-benzoyl-3-phenylisoserine ethyl – – process scale-up 200 203 ester 346 – (R)-aminotransferases 188, 197 benzylacetone 167, 169 – (S)-aminotransferases 188, 197 benzylic amines [a-methylbenzylamine – shifted enantioselectivity 192 (a-MBA)] 35 – – stereoselectivity 189 192 5-benzylidenethiazolidine-2,4-dione 74 – ﬁ substrate speci city 197 (S)-BHBM production system, with KER and – variant Trp60Cys 191 glucose dehydrogenase (GDH) 173 – v -aminotransferases 197 BINAP-Rh complex 59 – wild-type, stereoselectivity 190 BINAP-Ru catalyst 139 TM AMMOENG 101, 248 biocatalysis 44, 263 amprenavir precursors, through ADH- – gas/solid phase 252–254 catalyzed bioreductions 93 biocatalyst format 269–273 0 0 3 - and 4 -halogenated acetophenones 154 – isolated enzyme processes 272, 273 anti-Alzheimers disease drug –– bioreductions 273 (S)-rivastigmine 300, 301 –– enzyme-coupled cofactor anti-(4S,5R)-5-hydroxy-c-decalactone 313 regeneration 272, 273 antistereochemistry 30 –– enzymes dehydrogenases 272 AOT-based microemulsions 255 –– substrate-coupled cofactor AOT/isooctane reverse micelles 255 regeneration 272, 273 API synthesis – whole-cell processes 271, 272 – amino acid dehydrogenase-catalyzed –– cofactor regeneration 271 reactions, applications 333 –– ketone reduction 271 – ene reductase-catalyzed reactions, –– metal-catalyzed hydrogenation 271 applications 335 –– n-butyl acetate-buffer biphasic system 271 – ketoreductase-catalyzed reactions, –– Ru-based asymmetric hydrogenation 272 applications 330 –– substrate-coupled regeneration 271 – aqueous hexane (1:1) biphasic system 244 biocatalysts 2, 286–289, 293, 296, 298, aqueous systems, bioreduction in 240, 241 299, 302 armentomycin 70 biocatalytic Artemisia annua 60 – approach to montelukast key artemisinin 60 intermediate 340 Arthrobacter citreus 195, 197 – deoxygenation reactions 12–14 aryl ketones 154 – hydrogenation reaction 214 2-aryl-1-nitro-1-propenes 66 – reductive processes approaches 28 3-aryl-2-oxopropanoic acids 6 biocatalytic (whole-cell) acid reduction Aspergillus nidulans glycerol scheme 215 dehydrogenase 172 biocatalytic reduction processes atazanavir synthesis 343 – C¼C double bonds 8–10 atomoxetine 97 – C¼O double bonds 3 atorvastatin calcium 105 –– aldehydes to alcohols 6–8 avermectins 96 –– carboxylic acids to alcohols 8 Index j377

––carboxylic acids to aldehydes 8 c-butyrolactones 64 ––ketones to alcohols 3–6 BY-catalyzed reduction – imines to amines 10–12 – a-(chloromethyl)cinnamaldehyde 56 – nitriles to amines 12 BY-catalyzed reduction of (Z)- – and optimization of redox state changes 1 alkoxycinnamaldehydes 55 – reaction engineering for 16, 17 biocatalytic reduction reactions, environmental c issues 211 Candida boidinii 217, 245 biocatalyzed Candida magnoliae 139, 338 – reduction 286 Candida parapsilosis 11, 29, 139, 246, 312 ––whole cell 308 capromorelin 96 – reductive amination b-carbolines ––in situ generation 296, 297, 299, 302 – pharmacological activities 359–360 – synthesis 289 – yeast-mediated imine-reduction 360 biodiesel 243 carbonyl reductase 29, 105, 244 biologically active compounds through C¼O – Sporobolomyces salmonicolor (SSCR) 178 bioreduction carbonyl reductases (CRs) 2, 85 – bulky–bulky ketones 96, 97 carboxylic acid reductases (CARs) 8 – dihydroisocoumarins 99 carboxylic acids 43, 73 – diketones 90, 91 carvone 63 – ethyl 5-hydroxyhept-6-enoate 89, 90 (5R)-carvone – a-halo ketones 91–93 – diastereoselective reduction 348 – (hetero)cyclic ketones 94–96 cascade system – b-hydroxy nitriles 98 – ADH-catalyzed reactions 291, 292 – a-keto esters 87–89 – ADH/ER system 291 – b-keto esters 89 – biocatalyzed reductive amination 296–302 – lisofylline 98 – bioreduction, prochiral unstaturated – (S)-1-[3,5-Bis(trifluoromethyl)phenyl] aldehydes 295 ethanol 98 – deracemization of racemic amino acids – tetrahydroisoquinolines 99 ––DAAOs-catalyzed reactions 298 bioreduction 31 – enantiopure amino acids synthesis, – process engineering 265–267 AADH 296, 297 ––carbon-oxygen double bond reduction 265 – enantiopure (S)- or (R)-alcohols 288, 289 ––cofactor regeneration 266 – enantioselective reduction, prochiral ––whole-cell biocatalyst (See whole-cell unsaturated aldehydes 195 biocatalyst) – ER–ADH cascade system 294–296 – supported processes 361–363 – ER-catalyzed reductions 291, 292 – a,b-unsaturated carboxylic compounds 32 – parallel interconnected kinetic asymmetric biotransformation 30, 294 transformations (PIKAT ) 289, 290 biphasic aqueous–organic systems, – redox neutral 296 bioreduction in 243–245 – redox neutral (or self-sufficient) cascade 289 Birch reduction mechanism 15 CASTing 129 bisabolene sesquiterpenes 57 catalytic hydrogenations 1 (S)-1-(3,5-bistrifluoromethylphenyl)- CDOCKER energy 151 ethanol 98 chemoselectivity 32 boronic acid 102 chiral alcohol 6, 139, 140 BRENDA database 2 – asymmetric bioreduction 341 (S)-2-bromobutanoic acid 71 – optical purity 181 a-bromoesters 71 – oxidoreductases/microorganisms, for buspirone 345 preparation of 139 2-butanone 254 – production level 168 butyl acetate–water biphasic system 244 – from various ketones by E. coli 3-butyn-2-one 247 biocatalysts 166 378j Index

chiral azetidone 64 Curvularia falcata 3 chiral chlofibrate 317 a-cyano-a,b-unsaturated esters 75 chiral Co (II) salen complex 139 b-cyano-a,b-unsaturated esters 10, 75 chiral cyclic pentanones 62 cyclic b-keto esters 309 chiral 1, 3-diols 104 cyclohexa-1,5-diene-1-carboxyl CoA 15 chirality generating tools 361 cyclohexane 246, 254 chiral lactones 64 cyclohexenone 66 chiral metal catalysts 139 D-cyclohexylalanine 357 chlofibrate 317 cyclopentenone 62 chlofibrate [ethyl 2-(4-chlorophenoxy)-2- (S)-cyclopropylglycine methylpropanoate] 317 – cyclopropylglyoxylic acid, conversion 358 20-chloroacetophenone 164, 166, 168, 243 2-chloroacetophenone (phenacyl chloride) 155 d 0 4 -chloroacetophenone 245, 250 D-amino acid oxidases (DAAOs) 297, 298 a-chloroalkenoates 70 D-arabinitol 2-dehydrogenase 154 4-chlorobenzophenone 241 d-decanolide 68 3-chloro-4-(4-chlorophenyl)-2-butanone 322 a,b-dehydroamino acid derivatives 354 a-chloroesters 71 dehydrocholic acid (DHCA) 16 achloro ketones 220, 289, 290 dehydrogenase-catalyzed oxidation 296–298 2-chloro-1-(3,4-methylenedioxyphenyl) dehydrogenases 28, 29 ethanone 167 density 248 chloromethyl 3,4-methylenedioxyphenyl deracemization 101, 288 ketone 164, 165 – preparation of propargylic alcohols 101 (R)-1-chloro-2-propanol 180 – propargylic alcohols 101 (S)-4-chlroro-3-hydroxybutyrate (CHBE) 172 – (R)-chlorohydrins 104 Chromobacterium violaceum 190, 191, 192 – secondary alcohols, biocatalytic cascade 288 cinnamaldehydes 61 (see Alcaligenes faecalis) cinnamyl alcohol 363 – using Pichia glucozyma in water/organic cinnamyl aldehyde 6 solvent biphasic systems 256 cinnamylamine 363, 364 deracemizations 87 cis-diastereomer (1R,2S)-2-(3,4- designer solvents 248 dimethoxyphenethoxy) detoxification 30 cyclohexanamine 191 dextroamphetamine 154, 195, 200 citraconic anhydride 74 diastereomers 293, 315, 320, 346 citral 60 dicarbonyl reductases 6 Citrobacter braakii 13 2,30-dichloroacetophenone 164, 166 citronellal 59 2,40-dichloroacetophenone 164, 165, 166 citronellal cyclases 16 diethyl-2-alkyl-3-ketoglutarates 317 Clostridium acetobutylicum (CaADH) 100 diethyl ether 250 Clostridium kluyveri 73 a,a-difluoro hydroxylated compounds 93 Clostridium ljungdahlii 8 (11S)-dihydroartemisinic aldehyde 60 Clostridium ragsdalei 8 4,9-dihydro-1H-carbazol-3 (2H)-one 340 Clostridium sporogenes 67 dihydrocarvone 63 Clostridium tyrobutyricum 73 dihydrofolate reductase (DHFR) 329, 359 codeinone 32 – (6S)-tetrahydrofolic acid 359 cofactor-dependent enzyme 286 4,9-dihydro-1H-carbazol-3(2H)-one 340 cofactor regeneration systems, for dihydroisocoumarins 99 dehydrogenases 27 2,3-dihydroxy-isovalerate (DHIV) 177 corticotropin-releasing factor-1 (CRF-1) 1,3-dihydroxy-1-phenylpropan-2-one 197 receptor 357 diisopropyl ether 246 Corynebacterium aquaticum 63 diketone coupled-enzyme approach 86 – corresponding 1,3 diols through dynamic coupled oxidation, reduction reactions 287–292 kinetic resolution 318 Index j379

– dynamic kinetic resolution 318 enantiomeric 3-hydroxy-2-methylpropionate, – through ADH-mediated processes 90 see Roche ester 6,7-dimethoxy-1-methyl-3,4- enantiomeric purity 296 dihydroisoquinoline 11 enantiopure 2- 2-(3,4-dimethoxyphenethoxy) hydroxycyclopentanecarboxamides 310 cyclohexanone 191, 193 enantiopure (S)-phenylglycine 226 4,4-dimethoxytetrahydro-2H-pyran-3-one, enantioselective asymmetric reduction 344 – biocatalytic reduction 29 dimethyl(1-chloro-2-oxopropyl) – organic synthesis 139 phosphonate 100 enantioselectivity 31, 126, 132 dimethyl citraconate 74 ene reductase (ERs) 30, 50, 64, 66, 294, 353 dimethyl (S)-2-methylsuccinate 71 – amino acid derivatives, asymmetric a,b-dimethyl nitrostyrenes 67 synthesis 353–355 dispirotetraoxane 63 – amphidinolides 348, 349 DKR methodology 101 – butyrolactone – jasplakinolide 348, 349 D-Lactate dehydrogenase (D-Lactate DH) 358 – catalyzed reduction 10 DMSO reductase 12 – (þ)-dihydrocarvone 348 DNA – ethyl (S)-2-ethoxy-3-(4-methoxyphenyl) – sequencing 337 propanoate (EEHP) 350 – shuffling 115 – (R)-flurbiprofen 349, 350 Docetaxel 100 – human neurokinin-1 receptor dolastatin 97 antagonists 352 L-DOPA 49 – levodione 347, 348 dynamic kinetic resolution (DKR) – methyl (z)-2-bromocrotonate – antidiabetic – approach 99, 100 drug candidates 350, 351 – process 307 – OYE1 ––acyclic a-substituted b-keto esters ––reduction, mediated 294 313–321 ––Saccharomyces pastorianus 294 ––acyclic ketones 322, 323 – OYE2 294, 295 ––of aldehyde 323 – OYE3 294, 295 ––aldehydes 322, 323 – Roche ester 351, 352 ––2-benzenesulfonylcyclopentanone and engineering database 179, 180 cyclohexanone 310 engineering of b-keto ester reductase ––carboxamides, microbial reduction of 310 (KER) 172–174 ––cyclic compounds 309–312 – and characterization of mutant ––cycloalkanecarbonitriles 310 enzymes 175–177 ––diketo ester 320 – for raising thermal stability and ––ketoreductases (KREDs) 311 stereoselectivity 172 ––3-oxo-4-phenyl-b-lactam 311 engineering of PAR ––of 2-phenylpropanal 322 – in 2-propanol/water medium ––2-substituted-3-carbonyl butanoates ––characterization of Sar268 and HAR1 313–321 161–165 ––a-substituted carbonyl compounds 309 ––construction of HAR1 mutant 160, 161 ––construction of Sar268 mutant 157–159 e engineering substrate- and stereospecificity of (E)-2-ethoxy-3-(p-methoxyphenyl) reductases 178, 179 prop-2-ene-1-al 10 E-nitroolefins 126 electrochemical regeneration, of enoate 30 NAD(P)H 212 enoate reductase (ER) 31, 34, 50, 51, 227, 228 electroenzymatic reduction system 212, 213 – catalytic mechanism 30, 229 electron-withdrawing groups (EWGs) 113 – NAD(P)H independent regeneration emerging reductive biocatalytic approaches 230 reactions 14–16 enzymatic methods 86 380j Index

enzyme – promoted bioreduction reactions 216, 217 – modification 200 – regeneration system 217 – selectivity, solvent control of 255–257 formates, as reducing agents 215, 217, 218 epimerization 66 fosfomycin 101 epoxide hydrolase 129 (–)-fosfomycin 101 epoxides 139 furfural 6 error-prone polymerase chain reaction (epPCR) 115 g Escherichia coli 3, 4, 12, 140, 311 gas/solid continuous reactor 254 – biocatalysts possessing 140 Geobacillus kaustophilus 12, 13, 41 ethyl benzoylformate 180 Geobacter metallireducens 15 ethyl 1-benzyl-3-oxo-piperidine-4-carboxylate Geotrichum candidum 3, 251 – microbial reduction of 312 Geotrichum sp. 313 ethyl benzylpyruvate 164, 166 Gibberella zeae reductase 172 ethyl b-nitroacrylates 67 gluconate 5-dehydrogenase 154 ethyl 4-chloroacetoacetate (CAE) 172 gluconic acid 224 ethyl 4-chloro-3-hydroxybutanoate Gluconobacter oxydans 6, 7 (CHBE) 244, 338 1,5-gluconolactone 223 ethyl (S)-4-chloro-3-hydroxybutyrate 106 glucose as stoichiometric reductant 223, 224 ethyl 4-chloro-3-oxobutanoate (COBE) 164, glucose dehydrogenase 6, 210, 223, 224, 244 166, 244, 337 glucose 1-dehydrogenase 154 ethyl (S)-2-ethoxy-3-(4-methoxyphenyl) glucose dehydrogenase (GDH) 86, 176, 223, propanoate (EEHP) 224, 240, 265, 271, 272, 321, 337 – OYE-mediated gram-scale synthesis 350 – mediated regeneration of NAD(P)H by ethyl (S)-2-ethoxy-3-(4-methoxyphenyl) means of glucose oxidation 223 propanoate – promoted reduction reactions 224 – gram-scale enzymatic production 350 glucose-6-phosphate dehydrogenase ethyl 5-hydroxyhept-6-enoate, synthesis (G6PDH) 271, 345 employing isolated ADHs 90 glutamate dehydrogenase (GluDH) 356 (R)-ethyl mandelate 180 – L-6-hydroxynorleucine 356 ethyl (E)-2-methyl-4-oxopent-2-enoate 348 glutaraldehyde (GA) 169 ethyl 3-oxobutanoate 166 glycerol 242 ethyl 3-oxobutanotate 164 good manufacturing practices (cGMPs) 200 ethyl pyruvate 164, 166 green chemistry 85, 225 ezetimibe 96, 341 h f a-halogenated cinnamic esters 354 fenpropidine 54 halohydrin dehalogenase (HHDH) 105, ferredoxins 51 106, 338 flavin mononucleotide (FMN) 30, 113 halohydrins 92 flavoprotein 49 a-haloketones 225 a-fluorocinnamyl alcohol 55 Hansenula sp. 346 (R)-3-(4-fluorophenyl)-2-hydroxypropionic Hase 210 acid 358 Hase-driven NAD(P)H-dependent carbonyl (1R,2R)-2-(4-fluorophenyl)-3- reduction reactions 214 oxocyclopentanecarboxylate 352 H2 as reducing agent 213–215 3-fluoropyruvate 190 Heck reaction 103 fluoxetine 97 Helional 58 flurbiprofen, anti-inflammatory drug 349 2-heptanone 254 FMN oxidation 30 (hetero)cyclic alcohols 95 formate dehydrogenase (FDH) 86, 210, 245, hexane 246 271, 312 hexane–buffer system 251 – catalyzed regeneration of NAD(P)H 215 hexanones 62 Index j381

Ò HIV-1 protease inhibitors 55 ––Amberlite XAD-2 resin 273 HLADH-catalyzed reduction 6 ––fed-batch strategy 274 horse liver alcohol dehydrogenase ––large-scale stereoselective enzymatic (HLADH) 59, 226, 294, 295, 322 reduction 273 human neurokinin-1 (hNK-1) 65 ––o-chloroacetophenone, bioreduction 274 hydride–Meisenheimer complex 34 ––in situ substrate supply 274 hydrocodone 32 – ISPR with solvent extraction 274 hydrogenases (Hases) 43, 214 ––two-phase system, ISPR 274 hydrogenation 105, 256 – membrane technology 269 Hydrogenovibrio marinus 215 – methods, and choice 268, 269, 276–278 hydromorphinone 32 ––cost-benefit analysis 278 hydrophobicity 248 ––ISPR benefits 277 hydrophobic solvents 243, 246 ––ISPR technologies qualitative comparison, (S)-3-hydroxyadamantylglycine 356 alcohol removal 278 6-hydroxybuspirone 345 ––qualitative comparison of ISPR 6-hydroxybuspirone (6-hydroxy-8–8-azaspiro technologies, alcohol removal 278 [4.5]decane-7,9-dione) 345 ––removal of alcohol methods (2S,3S)-hydroxyester 64 comparison 278 (2R,3S,1R)-hydroxy ester 314 – potential benefits 268 cis-(3R,4R)-Hydroxy ester 312 – process integration 278, 279 hydroxyesters 64 ––simulated moving bed (SMB) technology 289 a-hydroxy esters, synthesis using alcohol – rate of removal 679 dehydrogenases 88 – removal of acetone 275 b-hydroxy esters, synthesized by means of ––coupled-substrate, cofactor enzymatic bioreductions 89 regeneration 275 hydroxy keto ester 313 – in situ coproduct removal (IScPR) 267, 268 2-hydroxy-methylacrylic acid methylester 10 in situ redox cofactor regeneration system 286, 3-hydroxy-3-methyl-glutaryl-CoA (HMGCoA) 288 reductase inhibitors 337 – enzyme coupled 286 L-6-hydroxynorleucine – formate/formate dehydrogenase – enzymatic route 356 (FDH) 296, 298 – 2-keto-6-hydroxyhexanoic acid 356 – glucose/glucose dehydrogenase (GDH) 3a-hydroxysteroiddehydrogenase(HSDH) 255 system 293 in situ SFPR technology 59 i ionic liquids (ILs) 247–250 IlvC gene 177 – combining with supercritical fluids 251, 252 imine complex 188 – continuous biocatalytic synthesis imine reductases 36–38 of (R)-2-octanol in 252 in situ product removal (ISPR) – water-miscible 248 technologies 263, 267–269, 346 IPA–aqueous solution system 140 – biocatalytic processes 267 irreversible morphinone reductase reaction – capacity 269 isonitramine 96 – couple scheme, systematic evalutaion 277 isopropanol 242, 247 – fermentation 267 isopropylamine 190, 198 – flow sheet options 270 isopulegol 59 – indutrial scale implementation 268 isoxazoles 66 – ISPR with crystallization 274, 275 isoxazolines 66 ––asymmetric reduction 4- iterative saturation mutagenesis (ISM) 116 oxoisophorone 275 ––in situ product crystallization (ISPC) k ––systematic evaluation, ISPR 275 ker gene 177 – ISPR with resins 273, 274 KER mutants 175 ––Amberlite XAD-7HP 274 ketamine 189 382j Index

a-keto acid 34, 199 lactones 64 2-keto-3-(N-benzoylamino)-3-phenylpropionic LbADH-catalyzed reduction of aliphatic acid ethyl ester ketones 248 – diastereoselective reduction 347 Leifsonia alcohol dehydrogenase (LSADH) 140 keto ester 65 – amino acid sequence alignment 154 – enzymatic reduction of 314 – enzymatic properties 153–155, 157 b-keto ester 164 – physicochemical properties 153 – diastereoselective reductions 316 – properties 149 – dynamic kinetic resolution 321 – purified, substrate specificity of 164 – reduction 314 – screening, from styrene-assimilating soil b-keto ester reductase (KER) 140, 149 microorganisms 151, 152 a-keto esters 164 – stereochemistry 150 a-ketoglutarate – substrate and stereospecificity 145–147 – L-GluDH/NADH oxidase, coupled-enzyme leucine dehydrogenase (LeuDH) 357 system 361 Leuckart–Wallach reaction 35 2-keto-6-hydroxyhexanoic acid 356 (S)-leucovorin [(6S)-5-formyl-5,6,7, ketoisophorone 63 8-tetrahydrofolate] – microbial reduction 347 – cancer chemotherapy 359 ketol-acid reductoisomerase (KARI) 177 leukotriene B4 12-hydroxydehydrogenase 57 ketones 113 (6R)-levodione 347 ketoreductase 2, 5, 7, 329 levodione reductase (LVR) 63 – atazanavir 343 light-driven system 265 – atorvastatin 338, 339 lipases 308 – chemokine receptor inhibitor 343, 344 lisofylline 98 – chiral precursor, stereoselective lithium aluminum hydride 1 synthesis 344 – duloxetin 344 m – ethyl 4-chloro-3-hydroxybutanoate mandelate dehydrogenase 227 (CHBE) 338 mandelate racemase (MR) 226 – ezetimibe 341, 342 marine microalgae 314 – 6-hydroxybuspirone 345, 346 Meerwein–Ponndorf–Verley (MPV) – LY 300164 346 reduction 85, 219, 220 – montelukast 339, 340 melilotol 68 – paclitaxel 346, 347 menthol 59 – profens 342, 343 metagenomics 180, 181 – ramatroban 340, 341 metal-catalyzed hydrogenation 85 ketoreductases (KREDs) 85, 311 methoxyacetone 190, 191 12-keto-ursodeoxycholic acid 16 40-methoxyacetophenone 249 kinetic – biocatalytic anti-prelog stereoselective – oxidative resolution 289, 290 reduction 249 – resolutions (KRs) 100, 307 5-methoxy-2-aminotetralin 201 Klebsiella oxytoca 215 (R)-1-(40-methoxyphenyl)-ethanol 179 Kluyveromyces marxianus 100, 317 methyl acrylate 68 Kluyveromyces thermotolerans 4 2-methyl-3-aryl-propanols 10 KRED kit 312 4-methylbenzophenone 241 methyl benzoylformate 242 l methylbenzylamine 199 lactate dehydrogenase (LDH) 299, 301, 361 methyl (S)-BHBM 172 Lactobacillus brevis 248, 319 methyl 4-bromo-3-hydroxybutanoate 174 Lactobacillus kefir 3, 7, 139 methyl (S)-4-bromo-3-hydroxybutyrate Lactobacillus kefir ADH (LKADH) 96 (BHBM) 172 Lactobacillus kefiri 91 methyl 4-bromo-3-oxobutyrate (BAM) 172 Lactobacillus leichmannii 13 methyl (S)-2-bromopropionate 351 Index j383 methyl (Z)-2-chloro-3-(4-fluorophenyl) – NADH-dependent enzymes 35 acrylate 355 – NADH-dependent phenylacetaldehyde methyl (S)-4-chloro-3-hydroxybutanoate reductase (PAR) 140 (CHBE) 174 ––characterization 140 methyl cinnamate 68 ––docking model construction 151 methyl crotonate 68 ––3D structural models 148, 151 3-methyl-2-cyclohexenone 130 ––enzymatic properties 147, 149–151 a-methylcyclohexenone 50 ––kinetic parameters 162 3-methyl-3,4-dihydroisocoumarins 98 ––location in styrene metabolic pathway 3,4-methylenedioxyphenylacetone 140–142 – biocatalytic reduction 346 ––metabolic pathway of styrene by 3,4-methylene-dioxyphenyl acetone 16 Rhodococcus sp. 141 methylenic methylesters 69 ––physicochemical properties 142, 147 methylesters 70 ––stereochemistry 150 methyl 2-(3-fluoro-4-hydroxyphenyl) acrylate 349 ––substrate and stereospecificity 143, 144 methyl (R)-4-fluorophenylalanine ––substrate specificity hydrochloride 355 –– for oxidative reaction 156 methyl 2-hydroxymethylacrylate 69 –– purified 164 methyl isobutyl ketone 365 – NADH regeneration system 217 methyl methacrylate 68 NAD(P)H 288 2-methylpent-2-enal 129 – dependent b-keto ester reductase 173 methyl tert-butyl ether (MTBE) 96 – dependent 2-cyclohexen-1-one reductase 3-methyl-1,2,3,4-tetrahydroisoquinolines 98 (NCR) 32 Metrosideros polymorpha 316 – dependent dehydrogenases 361 rac-mexiletine 362 – dependent ketoreductases (KRED) 292, mexiletine (R)/(S)-enantiomers 361 293, 317 miconazole, synthesis using enzymatic – dependent oxidoreductases reductions 92 ––one-spot processes 287 micro- or nonaqueous systems, bioreduction – oxidation 30 in 245–247 – substrate-coupled regeneration of 219 þ Mitsunobu reaction 227 NAD(P) -linked biocatalytic redox monophasic aqueous–organic systems, processes 225 – bioreduction in 241 243 Na2HPO3/phosphite dehydrogenase (PDH) morphine dehydrogenase 33 recycling system 352 morphinone reductase 32 Nannochloropsis sp. 314 Mucor javanicus 3 naproxen precursor 343 Mucor rouxii 315 N-based enzymatic reductions 41, 42 multienzymatic processes 285 1-N-Boc-3-pyrrolidinone 164, 167, 168 – cascades Nef pathway 42 ––bioreductive reactions 302–304 N-gluconyl glutamic acid didecyl ester 255 – one-pot processes 285, 286 (See one-pot Nicotiana tabacum 31 processes) nicotinamide cofactor 209, 228 – representation 286 – chemical structure 209 – synthesis 285 – electrochemical regeneration 212 ––in vitro 285 – electrochemistry 210 ––in vivo 285 – regeneration methods 210 mutations 115 nicotinamide-dependent 2-cyclohexenone mutator strain 115 reductase 129 Mycobacterium marinum 8 nicotin-amide-independent system 265 nicotinamide recycling system 344 n nitrile reductases 38–41 NADH 288 – postulated mechanism 40 – NADH-dependent ene reductase (ER) 291 nitroalkenes 41, 65 384j Index

1-nitro-1-alkenes 30 – orthogonal (or parallel) reactions 286 nitrocyclohexene 66 – stereoselective synthesis 292 (see also nitroolefin reduction, catalyzed by PETN NAD(P)H) reductase 126 –– 2-alkyl-1,3-diols, KRED 292, 293 nitroolefins 65, 66, 113 –– tert-butyl 3,5-dihydroxyhexanoate – bioreduction of 65–67 stereoisomers 293 N-nitramines 33 – synthesis nonconventional media, bioreduction in 247 –– enantiopure bazidoalcohols and – combining ILs and SFs 251, 252 b-hydroxynitriles 303, 304 – gas-phase media 252–254 –– enantiopure b-hydroxytriazoles 303, 304 – ionic liquids 247–250 – two step synthesis, enantiopure – reverse micelles 254, 255 2,4-dimethylbutyrolactones 294 – supercritical fluids 250, 251 – in vitro chemoenzymatic synthesis 294 c-2-nonenolide 68 – vs. cascade processes 286 nonflavin-dependent ene reductases 50 OPR1 (12-oxophytodienoate reductase 1) 58 nonflavo ene reductases 51 optically active hydroxyl ester (CHBE) 244 nonselective reductions 1 organoboranes 1 nonsteroidal anti-inflammatory drugs oscillatoxins 96 (NSAIDs) 69 oxazete formation 42 N-substituted-2-methylmaleimide 74 oxcarbazepine 95 – transformation 95 þ o oxidized NAD cofactor 302 2-octanone 250 oxidoreductases 3, 6, 10, 28, 29, 39, 85, 86, 102, old yellow enzyme (OYE) 117, 265 113, 183, 337 – enhancement of selectivity 133 oximes 41 – evolving, in stereoselective reduction 117, 3-oxoacyl-[acylcarrier-protein] reductase 119 – amino acid sequence alignment 154 –– NCR for a,b-unsaturated ketones 129 2-oxocycloalkanecarbonitriles –– OYE1 for 3-alkyl-2-cyclohexenone – enantio- and diastereoselective bioreduction derivatives 119–122 of 310 –– PETN reductase for a,b-unsaturated b-oxoesters 309 carbonyl compounds and 2-oxotetralin 191 E-nitroolefins 123, 126 OYE-catalyzed reduction 30 ––YqjM for a,b-unsaturated ketones 129–133 OYE3-catalyzed reduction 10 – mutants, excellent catalysts in reduction 133 OYE-catalyzed reduction reaction 30 – rational design 117 – of alkene 114 – structural overview 118 OYE homologs PETN reductase 34 old yellow enzymes (OYEs) 10, 17, 30–34, 50, OYE-like ene reductases 51 51, 53, 58, 59, 61, 63, 67, 73, 114, 117, 119, OYE-like flavoproteins 71 134, 295, 302, 315, 317, 318, 320, 322 OYE1 mutants 69 oligomerizations 30 omapatrilat synthesis 356 p one-pot chemo/biocatalyzed cascade reactions, par gene 142 in biphasic system 249 Pd catalyst 250 one-pot processes 285–287 Pd(II)-catalyzed Wacker-type oxidation 102 – cascade reductions 292–296 (see cascade Penicillium citrinum 139, 140 system) – substrate specificity of recombinant – consecutive reductions 292–296 KER 174 – linear (or sequential) reactions 285, 286 pentaerythritol tetranitrate (PETN) – mixed-type reactions 286 reductase 33 – multienzymatic synthesis PETNR (pentaerythritol tetranitrate –– 12-ketoursodeoxycholic acid 289 reductase) 60 ––optically pureb-hydroxycarboxylicacids 302 PETN reductase mutants 126 Index j385 pharmaceutical intermediate – biocatalytic azide reduction–cyclization 4-phenylpyrrolidin-2- one 300, 301 sequence 359 phenylacetic acid (PAA) 142 pyrrolo[2,1-c][1,4]benzodiazepines (antitumor phenylacetone, asymmetric reduction 247 agents) 358, 359 2-phenylacrylonitrile 74 pyrrolo[2,1-c][1,4]benzodiazepines (PDB) 359 phenylalanine dehydrogenase (PheDH) 355 (S)-1-phenyl-1-butanol 257 q 1-phenyl-1-butanone 155 quick quality control (QQC) 115 1-phenyl-3-butanone 155 3-quinuclidinone 164, 167, 168 1-phenylethanol 154 phenyl n-propyl ketone 257 r 1-phenyl-2-propyn-3-trimethylsilyl-1-on 16 racemic ketone 311 phenyl trifluoromethyl ketone (PTK) 151 racemization 67 phosphite dehydrogenase 210, 218 Rac-2-hydroxycyclohexanone 312 phosphites, as stoichiometric reductants 218 Ralstonia eutropha 215 Pichia glucozyma 255, 256 (R)-aminotetralin 191 Pichia stipitis 61 (R)-2-aminotetralin 190 piperidin-3-ols 95 (R)-ramatroban, synthesis 340 piperonylacetone 167 random mutagenesis 115 piperonyl methyl ketone 164 Raney Ni-catalyzed hydrogenation 353 Plasmodium falciparum 60 (R)-1-cyclopropylethylamine 197 polar organic solvents 248 (R)-4,4-dimethoxytetrahydro-2H-pyran- polyethyleneimine (PEI) 169 3-ol 96 Prelogs rule 3, 4, 316 reaction engineering for biocatalytic reduction profens 342, 343 processes 16, 17 (S)-proline 359 recombinant enoate reductase (ER) 105 2-propanol [isopropyl alcohol (IPA)] 140 redox economy 1 propionoic acid class, see profens redox isomerizations 227 protection–deprotection steps 1 reductases 27 protein engineering 10, 31, 114, 218, 276 reductive amination 35 – B-FIT method, for improving reductive denitration 33 thermostability/robustness 116 reverse micelles 254, 255 – combinatorial active-site saturation test – water-to-surfactant ratio 254 (CAST) 116 (R)-3-fluoroalanine 190, 195 – combinatorial space 115 Rhizopus arrhizus 309 – examples 276 rhodium complexes 217 – generation of high-quality (smart) Rhodobacter capsulatus 12 libraries 115 Rhodoccocus ruber 341 – mutations 115, 116 Rhodococcus erythropolis 141, 254 – reductase enzymes 276 Rhodococcus opacus 142 – screening effort 115 Rhodococcus ruber 246 – in situ product removal 276 Rhodococcus sp. 320 – synthetic chemistry 276 Rhodotorula rubra 61 protein–inhibitor complexes 50 (S)-rivastigmine synthesis 363 Proteus mirabilis 13 (R)-1-methoxy2-propanamine 197 Pseudomonas aeruginosa 12 (R)-2-methylpyrrolidine 11 Pseudomonas fluorescens 288 robalzotan 59 Pseudomonas testosteroni 255 Roche ester 69, 351, 352 Pseudotriton ruber 321 – stereocomplementary strategies 352 pyridoxamine 5-phosphate (PMP) 188, 189 rotigotine 59 Pyrococcus furiosus 8, 43, 214, 255 (R)-4-phenyl-2-butanamine 197 pyrrolidin-3-ols 95 (R)-4-phenyl-2-butanol 168, 169 pyrrolo[2,1-c][1,4]benzodiazepines (R)-(–)-3-quinuclidinol production system 171 386j Index

(1R,2R)-2-(3,4-dimethoxyphenethoxy) solvent systems, for biocatalytic cyclohexanamine 190, 193 reductions 239 (R)-rhododendrol 103 (S)-phenylethylamine 190 (R)-sec-butylamine 197 (S)-1-phenylethylamine 189 (R)-tamsulosin 98 (S)-1-phenyltrifluoroethanol (PTE) 151 (R)-tetrahydrothiophene-3-ol 96 Sphingomonas pausimobilis 2,5- ruthenium complexes 217 dichloro-2,5-cyclodiene-1,4-diol dehydrogenase (SDCDDH) 154 s (S)-phthalides 106 Saccharomyces cerevisiae 3, 49, 56, 320 spiro nitrile 74 – D-arabinose dehydrogenase 172 Sporidiobolus salmonicolor Saccharomyces montanus 310 – aldehyde reductase 172 (S)-(a)-methylbenzylamine 190 Sporobolomyces salmonicolor 92, 139 (S)-a-methylbenzylamine 197 squalene–hopene cyclase 16 (S)-2-aminotetralin 191 stegobinone 319 saturation mutagenesis 115 stegobiol 319 saxagliptin 355 stenusine 61 (S)-2-bromo-2-cyclohexen-1-ol 16 stereocontrol strategies, for bioreduction 52 (S)-2-butanamine 197 stereoisomeric products, asymmetric scale-up processes, requirement 263–265 reduction 308 – biocatalyst yield 264 stereoisomers 292, 293 – biocatalytic processes 263–265 – tert-butyl 3,5-dihydroxyhexanoate 293 – product concentration 264 stereoselective reduction 289, 290 – reaction yield 264 Streptomyces coelicolor (ScCR) 244 – space-time yield (STY) 264 Streptomyces fradiae 100 – scCO2 buffer biphasic system 251 Streptomyces virginiae 35 Schiffs base 188 Streptosporangium roseum 11 serotonin (5-hydroxytryptamine 5-HT) structure–function relationships 2 transporter 344 styAB gene 142 (S)-2-ethoxy-3-(p-methoxyphenyl)propion-1- styCD gene 142 aldehyde 10 a-substituted b-keto esters Sheldons E-factor 211 – ruthenium-catalyzed hydrogenation 308 sibirine 96 2-substituted-3-carbonyl butanoate 313 sitagliptin 35, 36, 156 substrate-coupled biocatalytic reduction site-specific mutagenesis 114, 115 reactions 221, 222 sitophilate 319 substrate feeding product removal (SFPR) Sitophilus granarius 318 concept 350 (S)-licarbazepine 95 Sulfolobus solfataricus 323 (S)-7-methoxy-2-aminotetralin 198, 201 supercritical carbon dioxide (scCO2) 251, (S)-methoxyisopropylamine 190, 252 191, 198 supercritical fluids (SFs) 250 – synthesis, from methoxyacetone 191 Suzuki cross-coupling 102 (S)-1-methoxy-2-propanamine 197 Suzuki–Miyaura coupling 349 (S)-3,4-methylene-dioxyphenyl syn-hydrogenation 31 isopropanol 16 – N. tabacum OYE-catalyzed, for enones 31 (S)-methyl p-tolyl sulfoxide 12 syn-(1R,2S) halohydrin 101 (S)-2-methylpyrrolidine 10 synthetic mNADs 228 sodium bicarbonate 251 sodium borohydride 1 t sodium dioctyl sulfosuccinate 255 talaromycins 96 solid-phase extraction (SPE) 252 taxoid anticancer drugs 321 solvent control, of enzyme selectivity taxotere 100, 321 255–257 4-tert-butylcyclohexanone 96 Index j387 tetrahydroisoquinolines 99 – carboxylic acids 73 Thermoactinomyces intermedius 355 – diesters 71–73 Thermoanaerobacter species 348 – imides 73, 74 Thermoanaerobium brockii 3, 139 – lactones 68–71 thermophilic microorganism 299 – monoesters 68–71 Thermoplasma acidophilum 6 a,b-unsaturated nitriles, bioreduction 74–76 thiazolidine-2,4-diones 74 three-enzyme system v – biotransformation of morphine to viscosity 248, 252, 274 hydromorphone 287, 288 – irreversible morphinone reductase w reaction 288 Wacker–Tsuji oxidation 103 toluene 244, 246 water-miscible ionic liquids 248 toluene–buffer biphasic system 244 whole-cell biocatalysts total turnover number (TTN) – limited substrate 266 211, 212 – possessing mutant PARs and LSADH, a-transaminases applications – application 299, 300 ––continuous production of chiral – D-amino acids synthesis 300 alcohol 166, 168–171 – the herbicide L-phosphothricin ––immobilized E. coli whole-cell catalysts synthesis 300 mutants 165, 168, 170 v-transaminase (v-TA)-catalyzed ––for regenerating NADH with IPA 171, 172 processes 35, 299–301, 361 – product transport into and out 266 – application 300, 301 – slide reaction 266 – catalyzed transamination 302 – toxic substrates, products 266, 267 – multienzymatic cascade 301 Wittig reaction 32, 103 – optically pure amines synthesis 299 WT PETN reductase 126 – redox-neutral cascade 301, 302 – catalytic performance 127, 128 transamination reaction 188, 189 – mechanism 189 x transition metal catalysis 113 xylitol 225 transition metal complexes 217 xylose 225 trans-stereospecificity 8 2,2,2-trifluoroacetophenone 164, 165, 167 y Trigonopsis variabilis 249 yeast alcohol dehydrogenase (YADH) 255 trinitrotoluene (TNT) 34 Yersinia enterocolitica 12 triphenylphosphane 102 YqjM mutants 131–133 Triton X-100 199, 255 – evaluation 131 tyrosine 113 – pathways leading maximum enantioselectivity 132 u – from saturation mutagenesis 133 a,b-unsaturated aldehydes 30, 113 – chemical pathway of bioreduction 53 z a,b-unsaturated carbonyl compounds, zeaxanthin 63 bioreduction 53 zinc-containing ADHs 142 þ – aldehydes 54–60 Zn2 –cyclen complexes 105 þ – ketones 61–65 Zn2 ion cofactor 257 a,b-unsaturated carboxylic acids and Zygosaccharomyces rouxii 16, 346 derivatives, bioreduction 68 – glycerol dehydrogenase 172 – anhydrides 73, 74 Zymomonas mobilis 16, 129