257

Index

a L-aminoacylase 246 absolute configuration 39, 75 amount of substance 12 –ofL-(+)-alanine 83 asymmetric atom 39 – by anomalous dispersion effect in X-ray asymmetric disequilibrating transformation crystallography 78 151 – by chemical correlation 79 asymmetric induction 143 – correlation strategies 80 – of second kind 151 – by direct methods 78 asymmetric synthesis 139 – extended sense of 77 asymmetric transformation –ofD-glyceraldehyde 39 – of second kind 151 –ofD-(+)-glyceraldehyde 77 asymmetric transformation of the second kind – by indirect methods 79 173 –ofD-(–)-lactic acid 81 atropisomer 44, 73 – methods of determination 78 atropisomerism 24, 71 – of natural glucose 78, 82 autocatalysis – by predictive calculation of chiroptical data – a special case of organocatalysis 234 79 autocatalytic effect –of(R,R)-(+)-tartaric acid 78, 82 – of a zinc complex 238 achiral bidentate reagent Avogadro constant 12 – purification of enantiomers with 149 axial chirality 39, 44 achiral stationary phase 95 achirality, achiral 24, 29 b aci form 113 Baeyer–Villiger oxidation acylase I 161 – enanatiotope selective 253 AD-mix-𝛼 229 – enzymatic 253 AD-mix-𝛽 229 – microbial 166 alcohol dehydrogenases – regio- and enanatiomer selective 253 – Prelog’s rule 252 baker’s yeast aldol reactions – regio-, enantiotope and diastereotope – catalyzed with chiral ionic liquid 238 selective reduction with 186 – catalytic, double enantiotope selective 238 bidentate achiral reagent 90 – completely syn diastereoselective 238 Bijvoet, J. M. 78 – stereoselctive 209 BINAL-H 212 allene 44 BINAP amide-imido acid tautomerism 112 – ruthenium complex of 214 amino acids biocatalysis 244 enantiopure, D-andL- 250 – advantages of 245 D-amino acid oxidase 100 – disadvantages of 245

Stereochemistry and Stereoselective Synthesis: An Introduction, First Edition. László Poppe and Mihály Nógrádi. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2016 by Wiley-VCH Verlag GmbH & Co. KGaA. Companion Website: www.wiley.com/go/poppe/stereochemistry 258 Index

biocatalytic processes – by degradation of multiple asymmetric units – preparative 246 81 biotransformations – without influencing the asymmetric unit – enantiotope selective 251 81 – with more than one type of selectivity 186 – involving stereospecific reactions 83 biphenyl 71 –stereoconstructive 82 – o-substituted 72 chemical structure 8, 10 bond angle 8 –linearformula 6 bond length 8 –representation 6 bonding matrix 10 covalent bond 3 borane chemoselectivity 127, 130 – chiral, as reducing agents 216 – in biocatalysis 131 boranyl enolate – for manipulation of protecting groups 131 – antipodal 209 chiral aid – chiral 209 – important features of 141 bromobenzene – in selective synthesis of enantiomers 140 – regio- diastereo- and enantiotope- selective chiral aluminum-hydride reagent 211 oxidation of 253 chiral auxiliary groups 145, 151, 205 – enantiodivergent synthetic strategy with c 146 Candida antarctica lipase B 248, 250 – non-recoverable 145, 146 capillary electrophoresis 95 – of opposite stereoselectivity 205 carbon–carbon double bond – recoverable 145 – reduction by 252 – significance of separation of the forming carboxylesterase 163, 179 diastereomers 147 Cartesian coordinate 8 –ofC2 symmetry 208 catalytic antibody chiral catalysis 213 – enantiotomer-selective retro-aldol reaction chiral catalyst by 249 –CBS.BH3complex 216 – enantiotope selective aldol reaction by – functions as a phase transfer catalyst 233 249 chiral chemical catalytic processes catalytic cycle – examples of 213 – of ketone reduction with chiral Ru-complex chiral cobalt complex 215 – with sodium tetrahydridoborate (NaBH4) – of reduction with chiral rhodium complex 218 214 chiral derivatizing agent 79, 89, 94, 95 catalytic diol formation chiral ionic liquid – stereoselective 228 – as organocatalyst 239 catalytic epoxidation chiral ligands 213 – enantiotope selective 219 chiral organocatalyst 233 catalytic hydrogenation –fromL-amino acids 233 – chiral (asymmetric) 213 chiral osmium–tetroxide complex catalyst catalytic systems 229 –ofC2 symmetry for Diels–Alder reaction chiral oxazoline 242 – enantiodivergent strategy from 206 center chiral pool 140, 203 – of asymmetry 39, 41, 43 chiral samarium catalyst 221 – of chirality 29, 41 chiral shift reagent 93 – of pseudoasymmetry 52, 53 chiral solvating agent 92 C==C double bond chiral solvent 92 – catalytic chiral reduction of 214 chiral stationary phase (CSP) 96 chemical bond 15 – amylose based 99 chemical correlation – cellulose based 99 – by configurational correlation 83 – Chirasil-Val 97 Index 259

– cyclodextrin based 98 – relative population of 69 – efficiency of separation on 96 conformer 67 – phases in both configurations 96 constitution 23 –Pirkletype 98 constitutional isomer 26 –proteinbased 99 crystallization induced asymmetric – reversed elution order 96 transformations (CIAT) 150 – shape recognizing polymer 99 – involving diastereotopic interactions 149 chirality transfer 145, 149, 203, 205 crystallization induced dynamic resolution – enantioselective catalytic 213 (CIDR) 172 chirality, chiral 24, 27 – with a chiral additive 173 – at microscopic level 29 – enantiomer selective variant 172 – axial 39, 44 cumulene, E/Z 44 – center of 29, 39 cyclodextrins 98 –central 43 cyclohexanone monooxygenase (CHMO) – material assemblies 29 253 –planar 46 cyclopropanation, stereoselective chromatography 94 – of allyl alcohol derivatives 240 – on diastereoselective stationary phase 94, 95 d chromophore 79 deracemization 151, 175 chymotrypsin (CTR) diastereomer 27 – hydrolysis by 186 diastereomer selectivity 128, 141 C.I.P. system – types of 141 – sequence rule 41 diastereoselective resolution 151 classic resolution 154 diastereoselective stationary phase 94 coenzymes 244, 245 diastereoselectivity 128 –NAD(P)+ and NAD(P)H 251 diastereotope selective methods 128, 142 – regeneration of 251 – with an achiral reagent 143 245 – controlled by an auxiliary group 204 concerted diastereotope selectivity – between diastereotopic faces 143 – of chiral molecules 208 – in biotransformations 153 configuration 23, 27, 28, 75 – between specific parts of a molecule configurational inversion 142 – of unwanted enantiomer 156 – for preparation of pure enantiomers 203 conformation 24, 27, 67 diastereotope selective reaction –anticlinal 70 – of amides formed with (S)-prolinol 205 – antiperiplanar 70 diastereotopic –ofbiphenyl 71 – faces 37, 54, 143 –ofn-butane 70 – groups 34, 142 – of chlorocyclohexane 14 diastereotopic faces – of cyclohexane 27 – selective biotransformation of 153 – of 1,2-dichloroethane 70 diastereotopic groups –eclipsed 67 – selective biotransformation of 153 –energyof 70 Diels-Alder reaction – of ethane 67 – stereoselective, catalytic 240 –gauche 70 diethyl-zinc 232 –open 67 differential scanning calorimetry (DSC) 102 –synclinal 70 dihedral angle 10 – synperiplanar 70 dioxygenase conformational change 67 – enantiotope selective and cis-specific conformational range 71 dihydroxylation by 253 conformational state double asymmetric induction 145, 208, 220 –achial 68 double bond – chial 68 – hindered rotation 43 260 Index

dynamic kinetic resolution 156 – determination with bidentate achiral reagent – of 5-benzylhydantoin 251 90 – with biocatalysis 168 – determination with chiral derivatizing agent – using chemical systems 167 89 – DKR 151, 166 – determination with chiral solvent 92 – catalyzed 250 – by kinetic methods based on enantiomer – enzyme catalyzed, industrial application selectivity 99 250 – methods for determination 87, 88 – involving acid-catalyzed racemization 169 enantiomeric excess 87 – involving base-catalyzed racemization 168 – in enantiotope selective reaction 176 – involving biocatalytic racemization 171 – in kinetic resolution 157 – involving metal-catalyzed racemization – of the remaining enantiomer in kinetic 170 resolution 158 – with racemization by ring opening 169 enantiomeric products – by kinetic methods using catalysts 201 e – by stoichiometric methods 201 electrostatic potential surface 13 enantiomeric purity 87 enamine form 111 enantiomeric recognition enantiodivergent reactions 185 –principleof 96 enantiodivergent strategy 146 enantiomeric relationship 69 – for stereoselective alkylation 206 enantiomers enantiodivergent transformations 176 – purification of, with the aid of an achiral enantiomer 27 bidentate reagent 149 – chemical behavior of 27 – selective synthesis of 139 – scalar physical properties of 27 enantioselectivity 128 – vectorial physical properties of 27 enantiotope selective methods 128, 175, 211 enantiomer selective 128 – in biocatalytic systems 179 enantiomer selective process – reduction of carbon-carbon double bond, – irreversible 156 microbial 181 – reversible 156 – of chemical systems 177 enantiomer selectivity 128, 155 – degree of 176 –(E) 156 – independent of conversion 176 – degree of 155, 156 – intransformationofenantiotopicfaces 175 – in irreversible process 155, 156 – in transformation of enantiotopic groups enantiomeric composition 175 – by chromatography on chiral stationary enantiotope selective oxidation phase (CSP) 96 – by a dioxygenase 253 – by chromatography on diastereoselective enantiotope selective transformations stationary phase 94 – consequences of opposing 182 – determination based on diastereotopicity enantiotopic 89 – faces 36, 54, 175 – determination based on isotope dilution – groups 31, 175 102 enantiotopic groups – determination by chromatographic methods – transformations by biocatalysis 179 94 energy barrier – determination by diastereomeric salt –rotational 68 formation 91 energy barrier of transformation 24 – determination by differential scanning enol form 110 calorimetry (DSC) 102 enolization 108 – determination by enzymatic methods 100 – determination by NMR with chiral shift – active center of 244 reagent 93 – classification of 244 – determination by potentiometric methods – contain tightly bound cofactors 245 102 – enantiomer selectivity of 246 Index 261

– in enantiotope selective synthesis 251 – intramolecular 15 – features of the catalytic activity of 244 161, 245 – operate without a coenzyme 245 – in non-aqueous media 163 – as protein-based catalysts 244 -catalyzed process – six main classes of 245 – alcoholysis 163 – work with a transiently bound external – amidolysis 163 coenzyme 245 – hydrolysis 163 Enzyme Commission 244 – leaving alcohol, role of 163 enzyme–substrate complex 244 – nucleophile for 163 epoxide hydrolase 180 – thiolysis 163 epoxides hydroxynitrile (HNL) 253 – selective ring opening of 225 ethane i – optical inactivity of 68 identity transformation 18 (-)-exo-(dimethylamino)isoborneol imine form 110 – as chiral organocatalyst 235 imine-enamine tautomerism 110 E/Z-system 43 immobilized enzymes 246 internal coordinate 8, 10 f irreversibility FAD, FADH2 245 – of enantiotope selective process 176 Fischer formula 39 – of hydrolytic biotransformation 162 Fischer projection 76 isolability 26, 31 Fischer’s projection 39 – criterion of 24 Fischer, Hermann Emil 76 isomer 10, 25, 30 Fischer–Rosanoff convention 39 – E/Z 39, 43 formate dehydrogenase (FDH) 252 – constitutional 26 free rotation 70 – diastereo 27 –enantio 27 g –meso 29 gas chromatography (GC) 95 –stereo 26 – chiral stationary phase for 97 245 isomeric relationship 30 h isomerism 24, 25, 27, 30 Heck reaction 229 isomerization 105 – catalytic cycle of 230 – enantiotope selectively catalyzed 231 j helicity 44 Jacobsen’s catalyst 224 hexahelicene 46 – chromium or cobalt containing 226 high performance liquid chromatography (HPLC) 95 k homotopic Kekulè formula 4, 5, 7 –faces 36 kinetic amplification 184 –groups 31 kinetic resolution 99, 155 Horeau, A 89 – of alcohols, enzyme catalyzed 248 Horeau effect 89 – by biocatalysts 160, 246 Horeau’s method 149, 150 – followed by configurational inversion 174 horse liver alcohol dehydrogenase (HLADH) – with chemical systems 158 179 – enzyme catalyzed 247 – kinetic resolution with 165 – of esters, enzyme catalyzed 247 hydantoin 250 – by opposite reactions using the same catalyst hydantoinase 251 163 hydantoin racemase 251 – of racemic terminal epoxide, with chiral hydrogen bond 15 salene complex 227 – intermolecular 15 – shortcoming of 155 262 Index

Kumada reaction mirror plane 19 – enantiotope selective 185 mismatched pair – in double asymmetric induction 145, 208 l molecular assembly L-tert-leucine 252 –propertiesof 68 lactate dehydrogenase 100 molecular symmetry 17 lanthanide catalyst M/P descriptors 44 – enantioselectivity of 242 Mukaiyama 238 Le Bel, Joseph Achille 76 multiple bond 5, 7 leucine-dehydrogenase (LDH) 252 Lewis structure 3, 4 n 245 NAD+, NADH 245 linear formula 6 narwedine 172 lipase 163, 169, 170 Neu5Ac aldolase 255 – from Chromobacterium viscosum 134 Newman projection 67 – in kinetic resolution 165 nicotinamide-dinucleotide (NAD+) cofactor 181, 245, 253 100 L-lysine nitro form 113 – by DKR 171 nitrogen inversion 115 non-linear correlation (NLE) m – between the enantiomeric excess of catalyst macroscopic concept 3, 12, 13, 21, 30, 67, and product 177 75 normal condition 14, 24 mandelic acid Noyori 177 –(R)-and(S)-, enantiotope selective nucleophile preparation of 254 – in hydrolyse-catalyzed process 163 matched pair nucleophilic addition onto a carbonyl group – in double asymmetric induction 145, 208 – catalytic, stereoselective 234 Meerwein–Ponndorf–Verley reaction – enantiotope selective 217 o meso-compounds 52, 179 octet rule 3, 4 meso-dicarboxylic ester optical activity – enantiotope selective hydrolysis of 185 –ofn-butane 70 meso-diols – of carbon compounds 76 – inversion of enantiotope selective process – of 1,2-dichloroethane 70 182 – of ethane 67 meso-diol ester optical purity 87 – enantiotope selective hydrolysis of 186 optical rotation 76, 87, 89 meso-epoxide – of glyceraldehyde enanatiomers 76 – enantiotope selective ring opening of – of the pure enantiomer 89 227 optical rotatory power 78 Michael additions organocatalyst 178 – a chiral biphenyl ammonium derivative as – chiral ionic liquid as 239 catalyst for 233 osazones 82 – of diethyl malonate, enantiotope selective oxidoreductases 245, 251 233 oxime, E/Z 43 – of diethyl zinc, enantiotope selective 233 oxo form 110 – double enantiotope selectivity in 234 oxo-enol tautomerism 108 – stereoselective, catalytic 232 oxynitrilase 253 microbial oxidation – R-selective, from bitter almonds (Prunus – enantiotope selective 180 amygdalus) 254 microbial reduction – S-selective, from cauotchouc tree (Hevea – enantiotope selective 181 brasiliensis) 254 microscopic concept 3, 12, 13, 21, 30, 75 (R)-oxynitrilase 181 Index 263 p – base-catalyzed, in DKR 168 parallel kinetic resolution – biocatalytic, in DKR 171 – with biocatalysis 166 – in DKR process 166 – with chemical systems 160 – metal-catalyzed, in DKR 170 Pasteur, Louis 75 – methods of, in DKR 168 phenylalanine 250 – by ring opening, in DKR 169 phosphines Ra/Sa-descriptors 45 – as chiral ligands 213 reagent controlled selectivity 211 point group 21 reduction of ketones polarized light – with CBS as chiral catalyst 219 –rotation 69 – with Ru-complex of BINAP 215 porcine liver carboxyl esterase 134 reduction of the C==C bond Prelog’s rule – of unsaturated esters, enantiotope selective – of alcohol dehydrogenases 252 218 pro-E/pro-Z 49 regioselectivity 127, 131 pro-R/pro-S 51 – in enolization 132–133 pro-cis/pro-trans 49 – in steroid synthesis 134 prochiral 50 Re/Si-descriptors 50, 54, 55 prochiral compounds 52, 179 relative configuration 79 prochiral dicarboxylic ester – generalization 80 – enantiotope selective hydrolysis of 185 – of two different molecules 80 prochiral diol ester – to correlate absolute configuration 80 – enantiotope selective hydrolysis of 186 – within the same molecular entity 79 prochiral diols resolution – lipase-catalyzed transformation of 182 – classic 140 prochiral ketone 181 – kinetic 140 prochirality 48, 50 – of a racemic mixture 140 product regioselectivity 132 rhodium product selectivity 127 – as central metal atom 213 property 3, 10, 21 rhodium complex – isolated molecules 14 – with a chiral bidentate bisphosphine ligand – macroscopic 67 214 – molecular assemblies 14 rifamycin 204 –vectorial 76 ring-chain tautomerism 114 proprochiral 50 Rp/Sp-descriptors 46 prostereogenic Rosanoff, Martin André 77 –center 49 R/S system 41, 77 – element 48, 50 ruthenium prostereoisomerism 48, 49 – as central metal atom 213 prosthetic group 245 protease 163, 168 s pseudoasymmetry 52 salen-manganese complex pseudoasymmetric center 91 – as chiral catalyst 225 Seebach 234 q selectivity 127 quasi enantiomers 101 – of an elementary step vs overall process – mass spectral analysis of 101 149 quinine alkaloids – types of 127 – in stereoselective dihydroxylation 228 serine hydrolase 161 – acyl–enzyme intermediate 161 r – catalytic triade of 161 racemase 172 – tetrahedral intermediate 161 racemization 156 shape recognizing polymer 99 – acid-catalyzed, in DKR 169 Sharpless 228 264 Index

Sharpless epoxidation 184 – stereoformula 7 – enantiotope selective 219 structure–property correlation 13, 14 – catalyst in 222 substrate controlled selectivity 203 silyl enolether substrate regioselectivity 132 – in catalyzed aldol reaction 238 substrate selectivity 127 Simmons–Smith reaction stereoheterotopic group 50 – catalytic, enantiotope selective 239 supercritical solvent 169 spirane isomer 44 Suzuki–Miyaura reaction 231 stereochemical standard 77 – catalytic cycle of the 231 stereochemistry – chirally catalyzed 232 – concepts 17, 21, 23 C2 symmetry – of different modes of approach 31 – of a bis-sulfonamide as a chiral ligand 240 – of different molecules 23, 25 – of chiral auxiliary groups 208 – of different parts of a molecule 23, 31 – of chiral catalysts 178 –ofsingleobject 23 – of chiral ligands 213 stereodescriptor 28, 37 – of the chiral ligand (S)-BINAP 216 – E/Z system 43 symmetry 17 – M/P-system 44 – alternating axis of 20 – pro-E/pro-Z 49 –C1 axis of 18 – pro-cis/pro-trans 49 –C2 axis of 19 – pro-R/pro-S 51 –C3 axis of 19 –Ra/Sa-system 45 –C5 axis of 18 –Rp/Sp-system 46 –C6 axis of 19 – R/S system 41, 53 –Cn axis of 18 – Re/Si 50, 55 –S1 axis of 20 – D/l system 39 –S2 axis of 20 stereoformula 7, 39, 41 –S4 axis of 20 stereogenic –S6 axis of 20 –center 38 –Sn axis of 20 – element 29, 41 –centerof 20 stereoheterotopic – element 17, 18 –faces 54 –groups 17 stereoisomer, stereoisomerism 26, 29 – main axis of 19 stereoselective 125, 137 –memberof 18 stereoselective dihydroxylation 228 – molecular 17 stereoselective synthesis –operation 18 – types of 203 –planof 19 stereospecificity 137 – rotation-reflexion axis 20 – dicouraged use of 139 symmetry element stereostructure 8 –offirstorder 18 – Fischer projection 40 –ofsecondorder 18 (E)-stilbene D/L system 39, 77, 81 – cis-dihydroxylation of 229 stoichiometric methods t – with the chiral starting material is TADDOL incorporated into the product 203 – chiral titanium complex of 234, 240 – for the preparation of a chiral end product tautomer 11, 105 203 – degenerate 109 structural formula 4 tautomeric equilibrium 105 structure 3, 21 tautomerism 105 –condensedformula 7 – of aliphatic nitro compounds 113 – Kekulè formula 7 – amide-imido acid 112 –Linearformula 7 – of carbonic acid derivatives 113 –representation 7 – classic 107 Index 265

– imine-enamine 110 transition state 140, 162, 212 – methods for studying of 115 – of lower energy 157 – nitrogen inversion 115 transition states 208 – oxo-enol 108 – diastereomeric relationship 143, 178, 211, – prototropy 107 213 – ring-chain 114 – thioamide-imido thioacid 112 u – thiourea-isothiourea 112 urea-isourea tautomerism 112 – types of 106 – urea-isourea 112 v – valence 106 valence 5 tert-butyl-hydroperoxide (TBHP) 219 valence tautomerism 106 tetrahedral arrangement 9 van’t Hoff, Jacobus Henricus 76 thioamide-imido thioacid tautomerism 112 vinyl acetate thiourea-isothiourea tautomerism 112 – as acylating agent 165, 182 time scale 67 vinyl esters – of motion 12 – as irreversible acylating agent 163 titanium tetraisopropoxide 219 topicity 31 w torsion angle 10 Walden inversion 83 transfer of chirality 148 Wohl degradation 81 245 Wohl, Alfred 81