Combinatorial Chemistry: A Practical Approach (Methods and Principles in Medicinal Chemistry)

3527301860......Page 1
Combinatorial Chemistry: A Practical Approach......Page 5
Contents......Page 9
1 General Introduction......Page 23
2.1 An Introduction to Solution Chemistry......Page 27
2.2.2 MCC Reactions involving Isonitriles......Page 28
2.2.3 Aminimides by Multicomponent Condensation......Page 34
2.2.5 Hantzsch Pyridine Synthesis......Page 35
2.2.7 More Component Reaction Based on the Tsuge Reaction......Page 38
2.2.9 Mannich Reaction......Page 40
2.2.10 Grieco Three-Component Reaction......Page 42
References......Page 43
2.3.2.1 Aqueous work-up......Page 44
2.3.2.2 “Fluorous work-up’’......Page 48
2.3.2.3 Phase Separation Techniques......Page 50
2.3.3.1 Silica Gel and Alumina......Page 51
2.3.3.3 Ion Exchange......Page 52
2.3.4.1 Solution Scavengers......Page 57
2.3.5 Polymer-Assisted Solution-Phase Chemistry (PASP)......Page 59
2.3.5.1 Scavenger Resins......Page 61
2.3.5.2 Resin Capture......Page 62
2.3.6 Complex Purification Strategies......Page 63
2.3.7 Conclusion and Outlook......Page 66
References......Page 67
3.1.1 General......Page 69
3.1.2.2 Linkers for Amino Functions......Page 70
3.1.2.2.1 Linkers Based on Benzyloxycarbonyl (Z)......Page 71
3.1.2.2.2 Linker Based on Tert.-Butoxycarbonyl (Boc)......Page 75
3.1.2.2.4 Benzyl-Linked Approaches for Secondary Amines......Page 77
3.1.2.2.5 Linkers Based on Acetyldimedone......Page 80
3.1.2.2.6 Trityl Linker......Page 81
3.1.2.3.1 Linker Based on the Tetrahydropyranyl (THP) Group......Page 84
3.1.2.3.2 Silyl Linker for the Attachment of Alcohols......Page 87
3.1.2.3.3 Miscellaneous Linkers for Alcohols......Page 88
3.1.2.3.4 Serine-Based Linker for Phenols......Page 89
3.1.2.4 Acetal Linker for the Preparation of Aldehydes......Page 90
3.1.3.1 Application of Hofmann Elimination in the Linker Design......Page 92
3.1.3.2 Traceless Linkers Based on Silylfunctionalization......Page 94
3.1.3.3 Traceless Linkers Based on Olefin Metathesis......Page 97
3.1.3.4 Traceless Synthesis by Using Polymer-Bound Triphenyl Phosphine......Page 102
3.1.3.6 Traceless Linker Based on Arylhydrazide......Page 103
3.1.4.1 Introduction......Page 106
3.1.4.2 Linkers Based on o-Nitrobenzyl......Page 107
3.1.4.3 Photocleavalble Linker Based on Pivaloylglycol......Page 108
3.1.5 Safety Catch Linkers......Page 110
3.1.6 Traceless Concept Based on Cycloaddition-Cycloreversion......Page 115
References......Page 117
3.2.1 Principles......Page 121
3.2.2.1 Hydantoins......Page 122
3.2.2.2 Pyrazolones......Page 124
3.2.2.3 Oxazolidinones......Page 126
3.2.2.4 Diketopiperazines......Page 127
3.2.2.5 Dihydropyridines......Page 129
3.2.2.7 2,4(1H,3H )-Quinazolinediones......Page 130
3.2.2.9 1,4-Benzodiazepine-2, 5-diones......Page 132
3.2.2.10 Tetrahydro-R-Carboline Derivatives......Page 133
3.2.2.1 1 Lactones......Page 134
3.2.2.12 Tetrahydrofurans......Page 135
3.2.3.1 Tetramic Acids......Page 136
3.2.3.2 Wittig-Type Reactions......Page 137
3.2.3.3 Stille Reactions......Page 139
3.2.4.1 Furans......Page 140
3.2.4.2 Phenols......Page 141
3.2.5 Summary......Page 142
References......Page 143
3.3.2.1 Suzuki Coupling......Page 145
3.3.2.2 Stille Coupling......Page 148
3.3.2.3 The Heck Reaction......Page 149
3.3.2.4 The Sonogashira Coupling......Page 151
3.3.3 Remarks on Pd-Mediated Couplings on a Polymeric Support......Page 152
3.3.4.1 Materials and Methods......Page 153
3.3.4.2 Suzuki Couplings......Page 154
3.3.4.3 Stille Coupling......Page 156
3.3.4.4 Heck Reaction......Page 157
3.3.4.5 Sonogashira Coupling......Page 158
3.3.5.2 Pd-Mediated Couplings with Organozinc Reagents......Page 160
3.3.5.3 General remarks on preparations involving water-sensitive reagents......Page 161
3.3.5.4 Experimental: Grignard on Solid Phase......Page 162
3.3.6.1 Mechanism......Page 163
3.3.6.2 Experimental: Metathesis on Solid Phase......Page 165
3.3.7 Generation of Carbanions and their Equivalents on the Solid Support......Page 166
3.3.7.1 Experimental Approach......Page 169
3.3.7.3 Wittig and Related Reactions......Page 171
3.3.8 Radical Reactions to Achieve C-C Bonds......Page 173
3.3.9.1 Experimental Approach......Page 174
References......Page 175
3.4.1 Introduction......Page 179
3.4.2 Benzodiazepines......Page 180
3.4.3 Hydantoins and Thiohydantoins......Page 185
3.4.4 β-Lactams (Azetidin-2-ones)......Page 188
3.4.5 β-Sultams......Page 189
3.4.6 Imidazoles......Page 191
3.4.7 Pyrazoles and Isoxazoles......Page 193
3.4.8 Thiazolidinones......Page 195
3.4.9 Thiotriazoles......Page 197
3.4.10 Piperazinones......Page 200
3.4.11 Piperazine-diones (Diketopiperazines)......Page 203
3.4.11.1 Diketopiperazines via Backbone Amide Linker (BAL) [78]......Page 204
3.4.11.2 Piperazine-diones by acid cyclative cleavage. Method A, including reductive alkylation......Page 205
3.4.11.3 Piperazine-diones by acid cyclative cleavage. Method B, including SN2 displacement......Page 207
3.4.12 Diketomorpholines......Page 208
3.4.13 Triazines......Page 209
3.4.14 Pyrimidines......Page 211
3.4.15 Indoles......Page 213
3.4.16 Quinazolines......Page 216
3.4.17 Benzopiperazinones......Page 221
3.4.18 Tetrahydro-β-carbolines......Page 223
References......Page 227
4.1 Introduction......Page 231
4.2 Preparation and Use of Polymer-Supported Reagents......Page 232
Activators for Amide Couplings......Page 233
Wittig Reagents......Page 236
Polymer-Supported Triphenylphosphine and Pd-Complexes......Page 237
Polymer (PEG)-Supported Burgess Reagent......Page 238
Organotin Reagents......Page 239
4.2.1.2 PSR Prepared by Polymerization......Page 240
Supported Borane Amino Alcohol Complexes and Other Supported Lewis Acids......Page 241
Polymer-Supported Quinine Based Catalysts......Page 243
Polymer-Supported Schiff Base Zinc Complexes......Page 245
4.2.2.1 Oxidants......Page 246
4.2.2.3 Alkoxides Bound to a Polymer Support......Page 249
4.2.2.5 Halogenating Agents......Page 250
4.3 Support-Bound Sequestering and Scavenging Agents......Page 252
4.4 Combination of PSRs......Page 253
4.5 Summary and Conclusion......Page 257
References......Page 258
5.2 Positional Encoding......Page 261
5.4 Chemical Encoding......Page 262
5.6 Radiofrequency Encoding......Page 263
References......Page 264
6.1 Introduction......Page 265
6.2.1 General Remarks......Page 266
6.2.2 Manual Systems......Page 268
6.2.3 Semiautomated Systems......Page 278
6.2.4 Automated Systems......Page 281
6.2.5.1 Process Development......Page 290
6.3 Liquid-Liquid Extraction......Page 291
6.4 Equipment for High-Throughput Evaporation......Page 293
6.5 Automated Resin Dispensing......Page 295
6.6 Suppliers......Page 296
7.1.1 Optimizing Combinatorial Libraries......Page 299
7.1.2 A Computer-Assisted Design Strategy......Page 300
7.1.3.1 First Examples......Page 301
7.1.3.2 Diversity of Drug Molecules......Page 302
7.1.3.3 Diversity and Similarity......Page 303
7.2.1 An Overview......Page 305
7.2.3 Classification and Mapping......Page 306
7.3 Descriptors......Page 307
7.3.1 Simple filters......Page 309
7.3.2.2 Estimation of pK^ Values......Page 310
7.3.3.1 Rule of 5......Page 311
7.3.3.2 Artificial Neural Networks......Page 312
7.3.5 Substructure Descriptors......Page 313
7.3.7 Topological Indices......Page 315
7.3.7.2 Molecule Indices......Page 316
7.3.9 Descriptors from a Pharmacophore Model......Page 317
7.3.10 Stereochemistry......Page 319
7.3.1 1 Descriptors from the Three-Dimensional Structure......Page 320
7.3.13.1 Based on Atom Coordinates......Page 322
7.3.14 Virtual Screening......Page 323
7.4.1.1 Tanimoto Coefficient......Page 324
7.4.1.4 Mahalanobis Distance......Page 325
7.4.2 Dissimilarity-Based Selection......Page 326
7.4.3 Mapping-Based Selection......Page 327
7.4.3.2 Self-organizing Maps......Page 328
7.4.4 Cluster-Based Selection......Page 329
7.5 Strategies for Compound Selection......Page 330
7.5.2 Optimization Based on Diversity of Product Libraries......Page 331
7.5.2.1 Advantages of Product-Based Optimization......Page 332
7.5.4 Evolutionary Design Circle......Page 334
7.6 Comparison of Descriptors and Selection Methods......Page 335
7.6.1 Topological Descriptors......Page 337
7.6.2 Descriptors Based on Three-Dimensional Structure......Page 338
7.6.3 Clustering Methods......Page 339
7.7 Example Library of Thrombin Inhibitors......Page 340
7.7.1 Virtual Library Design......Page 342
7.7.2.1 Maximum Diversity Library......Page 343
7.7.3 Comparison of the Libraries......Page 344
7.7.4 Summary......Page 346
References......Page 347
8.1 Introduction......Page 351
Abbreviations......Page 352
8.2.1.1 Alkylation of amines......Page 355
8.2.1.2 Alkylation of amides......Page 356
8.2.2.1 Acylation of amines......Page 357
8.2.3 N-sulfonation and sulfination......Page 358
8.2.5.1 Alkylation of alcohols......Page 359
8.2.5.3 Other O-alkylations......Page 360
8.2.9 O-sulfonation......Page 361
8.2.12 S-acylation......Page 362
8.2.13 C-alkylation......Page 363
8.2.16.2 Bromination......Page 364
8.3.3 S-nucleophiles......Page 365
8.4.2.4 Alkylation reactions......Page 366
8.5.1.2 with ketones......Page 367
8.5.2.2 N-nucleophiles......Page 368
8.5.3.3 Additions to carbonyl groups......Page 369
8.7.2 Knoevenagel condensation......Page 370
8.8.1 Ugi reaction......Page 371
8.9.1 Wittig and related reactions......Page 372
8.9.2.2 Ring closing metathesis......Page 373
8.10.2.1 Reactions of nitrile oxides......Page 374
8.10.3.1 Diels-Alder reactions......Page 375
8.1 1.1.1 Suzuki reaction......Page 376
8.11.1.3 Heck reaction......Page 377
8.1 1.1.5 Other Palladium catalyzed reactions......Page 378
8.11.3 Other transition metal catalyzed reactions......Page 379
8.13.1.5 Ketone to alcohol......Page 380
8.13.1.18 Reduction of C=C and C=C-bonds......Page 381
8.13.2.2 Amine + aldehyde......Page 382
8.14.2 2° alcohol to ketone......Page 383
8.14.13 Other oxidation reactions......Page 384
8.15.3.1 Imine formation......Page 385
8.15.5 Oxime formation......Page 386
8.15.8 Carbamate formation......Page 387
8.15.9 Urea formation......Page 388
8.15.13 Acid chloride formation......Page 389
8.15.20 Other carbonyl derivatives......Page 390
8.16.3 6-membered carbocycles......Page 391
8.17.3.1.1 5-MH with 1 N......Page 393
8.17.3.1.2 5-MH with 1 O......Page 398
8.17.3.1.3  5-MH with 1 S......Page 399
8.17.3.2.1 5-MH with 2 N......Page 400
8.17.3.2.2 5-MH with 1 N and 1 O......Page 406
8.17.3.3 5-MH with more than 2 heteroatoms......Page 409
8.17.4.1.1 6-MH with 1 N......Page 410
8.17.4.1.2 6-MH with 1 O......Page 416
8.17.4.2.1  6-MH with 2 N......Page 417
8.17.4.2.2 Other 6-MH with 2 heteroatoms......Page 422
8.17.5.2.1 7-MH with 2 N......Page 423
8.18.1 (De)protection of alcohols......Page 426
8.18.4 Ester cleavage reactions......Page 427
8.18.6 Other cleavage reactions......Page 428
8.20.4 Curtius degradation......Page 429
8.21 Miscellaneous......Page 430
References......Page 431
Index......Page 445