Discrimination of Chiral Compounds Using NMR Spectroscopy Book

Preface     xxi
Acknowledgments     xxiii
Introduction     1
Chiral Derivatizing Agents     1
Chiral Solvating Agents     2
Overview of Chiral Reagents and Methodologies     4
Future Prospects     6
Aryl-Containing Carboxylic Adds     8
Introduction     8
[alpha]-Methoxy-[alpha]-trifluoromethylphenylacetic Acid (MTPA-Mosher's Reagent)     11
Analysis of Secondary Alcohols     13
Analysis of Secondary Diols and Polyols     19
Analysis of Primary Alcohols     25
Analysis of Tertiary Alcohols     26
Analysis of Secondary Amines     26
Analysis of Primary Amines     28
Use as a Chiral Solvating Agent     29
Use of MTPA Derivatives with Paramagnetic Lanthanide Chelates     30
Use of MTPA Derivatives with Diamagnetic Lanthanide Chelates     34
Preparation of MTPA Derivatives     35
Liquid Chromatography-NMR Spectroscopy of MTPA Derivatives     35
Database Methods with MTPA     35
[alpha]-Methoxyphenylacetic Acid (O-methyl Mandelic Acid-MPA)     38
Analysis of Secondary Alcohols     39
Analysis of Diols     42
Analysis of Primary Alcohols     43
Analysis of Amines     44
Analysis of Sulfoxides     45
Variable-temperature Method for Assigning Absolute Stereochemistry     46
Barium(II) Method for Assigning Absolute Stereochemistry     47
Use of MPA Derivatives with Lanthanide Chelates     48
Use as a Chiral Solvating Agent     49
Preparation of MPA Derivatives-The "Mix and Shake" Method     50
Mandelic Acid (2-Hydroxy-2-phenyl Acetic Acid) (MA)     51
O-Acetyl Mandelic Acid (2-Acetoxy-2-phenyl Acetic Acid) (O-AMA)     53
Tetrahydropyranyl-protected Mandelic Acid [(2R)-2-phenyl-2[(2S)-tetrahydro-2-pyranyloxyl Ethanoic Acid]     56
O-Nitromandelic Acid     56
2-Phenylpropionic Acid (2-PPA)     57
2-Methoxy-2-phenylpropionic Acid     58
3-Phenylbutanoic Acid (3-PBA)/2-Phenylbutanoic Acid (2-PBA)     58
[alpha]-Methyl-[alpha]-methoxy(pentafluorophenyl) (Acetic Acid)     60
[alpha]-Cyano-[alpha]-fluorophenylacetic Acid (CFPA)/[alpha]-Cyano-[alpha]-fluoronaphthylacetic Acid (CFNA)/[alpha]-Cyano-[alpha]-fluoro-p-tolylacetic Acid (CFTA)     60
N-Boc Phenylglycine (BPG)     62
1,5-Difluoro-2,4-dinitrobenzene and Derivatives     63
N-(5-Fluoro-2,4-dinitrophenyl)-1-phenylethylamide      64
1-Fluoro-2,4-dinitrophenyl-5-(S)-alanine Amide (Marfey's Reagent)     65
2-Fluoro-2-phenylacetic Acid/2-Fluoro-2-(1-naphthyl)propionic Acid/2-Fluoro-2-(2-naphthyl)propionic Acid     66
[alpha]-Methoxy-[alpha]-(1-naphthyl) Acetic Acid (1-NMA)/[alpha]-Methoxy-[alpha]-(2-naphthyl) Acetic Acid (2-NMA)     67
2-(1-Naphthyl)-2-phenylacetic Acid     70
2-Methoxy-2-(1-naphthyl) Propionic Acid (M[alpha]NP)     71
1-Methoxy-2,3-dihydro-1H-cyclopenta[a]naphthalene-1-carboxylic Acid     72
O-Aryl Lactic Acids     72
[alpha]-(2-Anthryl)-[alpha]-methoxyacetic Acid (2-AMA)/[alpha]-(9-Anthryl)-[alpha]-methoxyacetic Acid (9-AMA)     74
([alpha]-[1-(9-Anthryl)]-2,2,2-trifluoroethoxy)acetic Acid     78
2-Methoxy-2-(9-phenanthryl)propionic Acid     78
Summary     79
Analysis of Primary Alcohols     79
Analysis of Secondary Alcohols     79
Analysis of Tertiary Alcohols     80
Analysis of Primary Amines     80
Analysis of Secondary Amines     81
Other Carboxylic Acid-based Reagents     82
Camphanic Acid     82
Menthoxyacetic Acid (MAA)     86
2-(2,3-Anthracenedicarboximido)cyclohexane Carboxylic Acid      87
3[beta]-Acetoxy-[Delta]5-etiocholenic Acid     88
Naproxen     89
2-tert-Butyl-2-methyl-1,3-benzodioxole-4-carboxylic Acid     90
Endo-3-Benzamidonorbornane-2-carboxylic Acid     90
Coumarin-based Reagents     91
2,2-Diphenylcyclopropane Carboxylic Acid     91
Amide Derivatives of Kemp's Triacid     91
Amino Acids     92
N-Boc-phenylalanine     92
Isotopically Substituted Amino Acids     92
(R)-(-)-(2,3,5,7-Tetranitro-9-fluorenyloximino)propanoic Acid     93
2-Chloropropanoic Acid (2-C1-PA)     93
Chlorofluoroacetic Acid     94
Perfluoropropoxy Propionic Acid/Perfluoro Isopropropoxy Propionic Acid     94
2-Methylbutyric Acid     94
Lactic Acid and Derivatives     95
Trifluorolactic Acid     95
(S)-O-Acetyllactylchloride     95
Lasalocid     96
Axial Chiral Carboxylic Acids     96
(+)-1-[2-Carboxy-6-(trifluoromethyl)phenyl]pyrrole-2-carboxylic Acid     96
2[prime]-Methoxy-1,1[prime]-binaphthyl-2-carboxylic Acid (MBNC)     97
2[prime]-Methoxy-1,1[prime]-binaphthalene-8-carboxylic Acid     98
2[prime]-Octylcarbamoyl-1,1[prime]-binaphthyl-2-dicarboxylic Acid      100
2-(2[prime]-Methoxy-1[prime]-naphthyl)-3,5-dichlorobenzoic Acid (MNCB)     100
Hydroxyl-and Thiol-Containing Reagents     102
2,2,2-Trifluorophenylethanol (TFPE)     103
2,2,2-Trifluoro-1-(9-anthryl)ethanol (Pirkle's Alcohol (TFAE)     109
Analysis of Sulfoxides     109
Analysis of Lactones     110
Analysis of Lactams     111
Analysis of Oxaziridines     112
Analysis of Axial Chiral Compounds     112
Analysis of Compounds that are Chiral by Virtue of Slow Rotation     113
Analysis of Metal Complexes     115
Analysis of Cyclophosphazenes     116
Analysis of Phosphine Oxides     117
Analysis of Calixarenes     118
Analysis of Other Substrates     119
Use of Lanthanide Chelates with TFPE and TFAE     122
Use as a Chiral Derivatizing Agent     123
Other Anthryl-based Reagents     123
Analogs of TFAE     123
Ethyl-2-(9-anthryl)-2-hydroxyacetate     126
2-(2,3-Anthracenedicarboximido)-1-cyclohexanol     127
2,2,2-Trifluoro-1-(1-pyrenyl)ethanol     127
2-(Trifluoromethyl)benzhydrol     127
1-Phenylethanol      128
Methyl Mandelate (MM)     129
Octahydro-8,9,9-trimethyl-5,8-methano-2H-1-benzopuran-2-ol (Noe's Reagent)     130
Menthol     132
Borneol     135
(-)-10-Mercaptoisoborneol     135
(R)-(-)-Pantolactone     136
Trans-Bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxacyclopentane     136
2-Hydroxymethyl-4,6-dimethyl-2-phenyl-1,3-dioxane     137
2-Butanol     137
Assignment of Absolute Configuration Using Glycosidation Shifts     138
Analysis of Di-and Polysaccharides     141
[beta]-D- and [beta]-L-Fucofuranoside/Arabinofuranoside     142
Linear Dextrins     144
Axial Chiral (Atropoisomeric) Alcohols     144
2,2[prime]-Dihydroxy-1,1[prime]-binaphthalene (BINOL)     145
8,8[prime]-Dihydroxy-1,1[prime]-binaphthalene     147
Alkyl-Substituted Binaphthols     147
2[prime]-Hydroxy-1,1[prime]-binaphthyl-2-yl[(3,5-dinitrobenzoyl) amino](phenyl)acetate     148
1,6-Di(o-chlorophenyl)-1,6-diphenylhexa-2,4-diyne-1,6-diol     148
4,4[prime]6,6[prime]-Tetrachloro-2,2[prime]-bis(hydroxydiphenylmethyl) biphenyl     148
Diol and Dithiol Reagents     149
Butane-2,3-diol/Butane-2,3-thiol      149
2,2-Dimethyl-1,3-propanediol     150
1,1,2-Triphenyl-1,2-ethanediol     151
Ethylene Dithiol     151
[alpha],[alpha],[alpha prime],[alpha prime]-Tetraphenyl-1,3-dioxolane-4,5-dimethanols) (TADDOL)     151
Amine-based Reagents     153
Primary Amines     154
1-Phenylethylamine (PEA)/1-(1 -Naphthyl)ethylamine (NEA)/1-(9-Anthryl)ethylamine(AEA)     154
Fluorinated Aryl Amines     161
9-(1-Amino-2,2-dimethylpropyl)-9,10 dihydroanthracene     161
(1S,2S)-1-Phenyl-2-amino-3-methoxy-1-propanol     162
Phenylglycinol     163
1-(3-Aminopropyl)-(5R,8S,10R)terguride     163
5-Amino-4-aryl-2,2-dimethyl-1,3-dioxans     164
Amino Acids     164
Peptides     164
Phenylglycine methyl ester (PGME)/Phenylglycine dimethyl-amide     165
L-Cysteine     168
L-Proline     169
(1R,2R)-1-(1[prime],8[prime]-Naphthalimide)-2-aminocyclohexane Derivatives     169
1-(1-Naphthyl)-2,2-dimethylpropylamine     170
1-Methoxy-2-aminopropane     170
(+)-2-Amino-1-methoxymenth-8-ene     171
Secondary Amines     171
Ephedrine     171
2-Methyl Piperidine      173
(N-Methyl)-[alpha]-isosparteinium cation     174
N-Boc-1-(1-naphthyl)ethylamine     174
N-Methyl-D-(-)-glucamine     175
(S)-2-(Diphenylmethyl)pyrrolidine     175
Tertiary Amines     175
Quinine/Cinchonidine/Quinidine     175
2,8-Dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5] diazocine (Troger's Base)     180
Brucine     180
Strychnine     181
(R)- and (S)-Tetrahydroisoquinoline     181
Diamine Reagents     182
1,2-Diphenyl-1,2-diaminoethane     182
N,N[prime]-Substituted 1,2-diphenyl-1,2-diaminoethane     183
Databases Using Amine Chiral Solvating Agents     184
N,[alpha]-Dimethylbenzylamine (DMBA)     184
Bis-1,3-methylbenzylamine-2-methylpropane (BMBA-pMe)     187
(R-[alpha]-Methoxy-[alpha]-trifluoromethylphenylacetic Acid (MTPA)/BMBA-pMe     189
Miscellaneous Organic-based Chiral Derivatizing and Solvating Agents     190
Amides     191
N-(3,5-Dinitrobenzoyl)-1-phenylethylamine (DNB-PEA)     191
N-(3,5-Dinitrobenzoyl)-L-leucine (DNB-Leu)     193
N-(3,5-Dinitrobenzoyl)phenylglycine     195
N-(3,5-Dinitrobenzoyl)-4-amino-3-methyl-1,2,3,4-tetrahydrophenanthrene (Whelk-O-1)     195
N-1-(1-Naphthyl)ethyltrifluoroacetamide     196
1-(1-Naphthyl)ethyl Urea Derivatives of Amino Acids (NEU-AA)     197
Bis Allyl Amide Derivatives     198
N,N[prime]-Diallyl-L-tartardiamide bis(4-tert-butylbenzoate)     198
(S,S)-trans-Acenaphthene-1,2-dicarboxylic acid bis allylamide     198
(R)-Phenylglycinol-N-3,5-dinitrobenzoyl-O-triethoxysilylpropylcarbamate     198
N-Methyl Amide of (R)-N-Acetyl-4-methoxy Phenyl Glycine     199
N-(n-Butylamide) of (S)-2-Phenylcarbamoyloxypropionic Acid     199
2,2[prime]-Oxybis[N-(1-phenylethyl)acetamide]     200
Tetrapeptide Species     200
Tetraamidic Selector     200
Lactams     201
Dihydropyrimidone     202
Amino Acid Isocyanurate Derivatives     202
Aldehydes     203
15-Formyl-14-hydroxy-2,8-dithia[9](2,5) pyridinophane     203
2[prime]-Methoxy-1,1[prime]-binaphthalene-8-carbaldehyde     203
2-Hydroxy-2[prime]-nitrobenzoate-3-aldehyde-1,1[prime]-binaphthalene     204
2-Hydroxy-2[prime]-substituted-3-aldehyde-1,1[prime]-binaphthalene     205
Ketones     205
1-Menthone     205
(S)-(+)-2-Propylcyclohexanone      206
Isocyanates     206
1-Phenylethyl Isocyanate (PE-I)     206
1-(1-Naphthyl)ethy] Isocyanate (NE-I)     208
Phenylethy Isothiocyanate (PE-IS)/Naphthylethyl Isothiocyanate (NE-IS)     209
[alpha]-Methoxy-[alpha]-(trifluoromethyl)benzyl Isocyanate     210
2,3,4,6-Tetra-O-acetyl-[beta]-D-glucopyranosyl Isothiocyanate     210
(S)-2-Chloro-2-fluoroethanoyl Isocyanate     211
Miscellaneous Reagents     211
2,2-Dimethoxypropane     211
(-)-Chloromethylmenthyl Ether     212
2-Oxazolidones     213
5(R)-Methyl-1-(chloromethyl)-2-pyrrolidinone     214
5-Methyl-5-phenylpyrroline N-oxide     215
(S)-2[(R)-Fluoro(phenyl)methyl]oxirane     215
(S)-Triazine Selector     216
2-Deuterio-2,3-dihydro-2-methyl-6-nitrobenzothiophene-1 -oxide     216
3a-Benzhydryl-3,3a,4,5-tetrahydro-2H-cyclopenta[b]furan     217
Camphor-10-sulfonic Acid (CSA)     217
Menthyl Chloroformate     219
(N-Methylphenylsulfoximidoyl)methyl Lithium     220
Coumarin Dimer     221
Di-O-benzoyl Tartrate/Di-O-p-toluoyl Tartrate     221
Dibenzoyl-L-tartaric Acid Anhydride     222
DNA      223
5,8-Bis(aminomethyl)-1,12-dimethylbenzo[c] phenanthrene     223
2[prime]-Methoxy-1,1[prime]-binaphthalene-2-carbohydroxymoyl Chloride (MBCC)     223
Self-discrimination of Chiral Compounds     224
High-throughput Optical Purity Measurements     227
Reagents Incorporating Phosphorus, Selenium, Boron, and Silicon Atoms     229
Phosphorus-containing Reagents     230
Phosphorus(V) Reagents     230
Phosphinic Amides (Phos1)     230
Phosphinothioic Acids (Phos2)     231
Cis-2-Chloro-3,4-dimethyl-5-phenyl-1,3,2-oxazophospholidin-2-one (Phos3)     234
(2-Chloro-4(R),5(R)-dimethyl-2-oxo-1,3,2-dioxaphospholane (Phos4)     236
L-Menthylphenylchlorophosphine Oxide (Phos5)     236
2-Chloro-5,5-dimethyl-4-phenyl-1,3,2-dioxaphosphorinane-2-oxide (Phos6)     236
O,O-Di-(2-(S)-(N,N-diethyl-2-hydroxypropyl) phosphonate (Phos7)     237
2-Chloro-3-phenyl-1,3,2-diazaphosphabicyclo [3.3.0]octane-2-oxide (Phos8)     238
Methyl Phosphonic Dichloride (Phos9)/Methyl Phosphonothioic Dichloride (Phos10)     239
O,O-Diphenyldithioic Acid (Phos11)     239
1,1[prime]-Binaphthyl-2,2[prime]-diylphosphoric Acid (Phos12)     240
Phosphorus(III) Reagents     242
Diazaphospholidines (Phos13-Phos20)      242
1,3,2-Dioxaphospholanes (Phos21-Phos27)     246
Dimenthyl Chlorophosphite (Phos28)     248
Dichloromenthylphosphine (Phos29)     248
Phosphorus Trichloride (Phos30)     249
Hexaalkylphosphorus Triamides (Phos31)     249
[alpha]-1-Phenylethylamino Trisaminoamine (Phos32)     249
[5] HELOL Phosphite (Phos33)     249
Ionic Reagents-TRISPHAT, BINPHAT, and BINTROP     250
Configurational Analysis of Phosphates     260
Oxygen Isotope Methods     260
ROESY Studies     263
Summary     264
Selenium-containing Reagents     264
4-Methyl-5-phenyloxazolidine-2-selone     264
(R,R)-N,N[prime]-Dimethylcyclohexyl-1,2-diazaselenophospholine     266
2-Phenylselenopropionic Acid     267
1,2,3-Selenadiazoles     267
Boron-containing Reagents     268
2-(1-Methoxyethyl)phenylboronic Acid     268
Phenylboronic Acid     269
Boric Acid [B(OH)[subscript 3]]     270
Camphanylboronic Acid     270
4S,5R-4-Methyl-5-phenyl-1,3,2-oxazaborolidine (Ephedrine Borane)     271
(S)-(+)-N-Acetylphenylglycine Boronic Acid      271
1-Benzamido-1-(2-methylphenyl)methaneboronic Acid     271
2-Formylphenylboronic Acid     272
2,2[prime]-(1,2-Phenylene)bis(4R,5R)-4,5-diphenyl-1,3,2-dioxaborolane     272
(1-Chloroalkyl)boronates     273
Silyl-containing Reagents     274
Menthylphenylsilylacetic Acid     274
(Benzylmethylphenylsilyl)methylamine     274
Monochlorosilanes     275
Host Compounds as Chiral NMR Discriminating Agents     278
Cyclodextrins     279
Introduction     279
Native Cyclodextrins     280
Lanthanide Coupling to Native Cyclodextrins     286
Neutral Cyclodextrin Derivatives     287
Hexakis(2,3,6-tri-O-methyl)-[alpha]-cyclodextrin (TM-[alpha]-CD)/Heptakis(2,3,6-tri-O-methyl)-[beta]-cyclodextrin (TM-[beta]-CD) - (Permethyl CDs)     287
Heptakis(2,6-di-O-methyl)-[beta]-cyclodextrin (2,6-DM-[beta]-CD)     289
Benzylated and Benzoylated Cyclodextrins     290
Carbamoylated Cyclodextrins     290
Octakis(3-O-butanoyl-2,6-di-O-pentyl)-[gamma]-cyclodextrin (BP-CD)     291
Hydroxyethyl and Hydroxypropyl Cyclodextrins (HE-CD, HP-CD)     291
Heptakis(2,3-di-O-acetyl)-[beta]-C D(2,3-DA-[beta]-CD)     291
Mono(2-acetylamino-2-deoxy)-, Mono (3-acetylamino-3-deoxy)- and Mono (6-acetylamino-6-deoxy)-[beta]-cyclodextrin (AA-[beta]-CD)     292
Mono-3,6-anhydro-[beta]-cyclodextrin     292
Heptakis(3-O-acetyl-2,6-di-O-pentyl)-[beta]-cyclodextrin     292
Octakis(2,6-di-O-pentyl-3-O-trifluoroacetyl)-[gamma]-cyclodextrin     292
Cyanoethylated-[beta]-cyclodextrin     292
Per-O-octyl-[alpha]-cyclodextrin     293
Biphenyl-capped-[beta]-cyclodextrin     293
Heptakis(2,3,6-tri-O-acetyl)-[beta]-CD (TA-[beta]-CD)     293
Anionic Cyclodextrin Derivatives     293
Carboxymethylated Cyclodextrins (CM-CD)     293
Heptakis(6-carboxymethylthio-6-deoxy)-[beta]-cyclodextrin (6-CMT-[beta]-CD)     296
Sulfobutylether-[beta]-cyclodextrin (SBE-[beta]-CD)     296
Heptakis(2,3-di-O-acetyl-6-sulfo)-[beta]-CD (HDAS-[beta]-CD)     297
Sulfated Cyclodextrins (S-CD)     298
Cationic Cyclodextrin Derivatives     298
Amino-substituted Cyclodextrins     298
Bis(6-trimethylammonio)-[beta]-cyclodextrin (TMA-[beta]-CD)     299
Mono(6-xylylenediamine)-[beta]-cyclodextrin (X-[beta]-CD)     299
Summary     299
Crown Ethers     300
Introduction     300
(18-Crown-6)-2,3,11,12-tetracarboxylic Acid (18-C-6-TCA)     301
Amide Derivatives of (18-Crown-6)-2,3,11,12-tetracarboxylic Acid     303
(18-Crown-6)-2,3,11,12-derivatives     303
Crown Ethers Incorporating a 2,2[prime]-Dihydroxy-1,1[prime]-binaphthalene Unit     305
Glycoside-derived Crown Ethers     305
Crown Ether-like Compounds with Nitrogen-heterocyclic Units     306
Triazole-18-crown-6 Ether     308
Crown Ether-like Compounds with Phenol Units     308
Aza Crown Ethers     309
Calixarenes and Calixresorcarenes     311
Introduction     311
Calix[4]resorcarenes     312
Calixarenes     315
Summary     319
Receptor Compounds for Carboxylic Acids     320
Cyclic Peptides     323
Miscellaneous Receptor Compounds     324
Cyclic Tetraamidic Reagent     324
Cyclosophoraoses (Cyclic(1-2)-[beta]-D-glucans)     325
Glycophane Receptor     325
Cyclophane Receptors     326
Cryptophane Receptor     326
Receptor for Secondary Amines     327
Spirobisindane Receptor     327
Receptors for Diols     328
1,1[prime]-Binaphthalene-based Receptors      328
Enzymes     329
Calmodulin     329
Chymotrypsin     330
Chiral Discrimination with Metal-based Reagents     331
Introduction     331
Lanthanide Complexes     332
Introduction     332
Peak Broadening with Lanthanide Shift Reagents     335
Catalytic Properties of Lanthanide Ions     337
Application of Lanthanide tris [beta]-diketonates     338
Discrimination of Prochiral Nuclei     339
Analysis of Deuterium-Substituted Compounds     341
Analysis of Compounds Chiral by Virtue of Slow Rotation     342
Analysis of Compounds Chiral by Virtue of Geometrical Constraints     344
Miscellaneous Applications of Lanthanide tris [beta]-diketonates     346
Analysis of Chiral Metal Complexes     348
Assignment of Absolute Stereochemistry     351
Pr(III) Complex of Tetraphenylimidodiphosphinate-Pr(tpip)[subscript 3]     354
Binuclear Lanthanide-silver Reagents     355
Analysis of Organic Salts     358
Aqueous Lanthanide Shift Reagents     359
Complexes of Propylenediaminetetraacetate (pdta)     360
Complexes of N,N,N[prime],N[prime]-Tetrakis(pyridylmethyl) propylene Diamine (TPPN)      361
Complexes with Other Ligands     362
Complexes with Tetraazocyclodecane Macrocyclic Ligands     364
Transition Metal Complexes     365
Palladium Complexes     365
Bridged Dimers with Amine Ligands     365
Miscellaneous Palladium Complexes     372
Platinum Complexes     374
Complexes w