Combinatorial Chemistry

Combinatorial Chemistry......Page 2
Contents......Page 12
1.1 Introduction......Page 36
1.2 Principles of Combinatorial Chemistry......Page 37
1.3.1.1 Split-Pool Synthesis Towards Combinatorial Libraries......Page 39
1.3.1.2 Parallel Synthesis Towards Combinatorial Libraries......Page 42
1.3.1.3 Reagent Mixture Synthesis Towards Combinatorial Libraries......Page 45
1.3.2.1 Solid-Phase Organic Synthesis......Page 47
1.3.2.2 Synthesis in Solution and Liquid-Phase Synthesis......Page 48
1.4.1.1 Analytical Characterization of Compound Mixtures......Page 49
1.4.2.1 Strategies for Libraries of Compound Mixtures......Page 50
1.4.2.2 Strategies for Libraries of Separate Single Compounds......Page 58
1.5.1 Synthesis Automation and Data Processing......Page 59
1.5.2 Automated Purification......Page 60
1.6 Library Design and Diversity Assessment......Page 61
1.6.1 Diversity Assessment for Selection of Building Blocks or Compounds......Page 62
1.7 Economic Aspects......Page 63
1.9 References......Page 65
2.1 Introduction......Page 70
2.2.1.2 Emerging Solid-Phase Reactions......Page 71
2.3 Conclusions......Page 72
2.4.1 Substitution Nucleophilic and Electrophilic Type of Reaction: Amide Bond Formation and Related Reactions......Page 73
2.4.1.2 (Thio)urea......Page 74
2.4.1.4 Urethane......Page 75
2.4.1.6 Imide......Page 76
2.4.2 Type of Reaction: Aromatic Substitution; Electrophilic Carbon-Carbon Bond Formation......Page 77
2.4.2.2. Stille......Page 78
2.4.2.3 Heck......Page 79
2.4.3 Type of Reaction: Aromatic Substitution; Nucleophilic (N-Arylation)......Page 80
2.4.4.1 Cyclative Cleavage......Page 81
2.4.4.2 Functional Group: None (traceless)......Page 82
2.4.4.4 Functional Group: Alkenes......Page 83
2.4.4.6 Functional Group: Primary Amine......Page 84
2.4.4.8 Functional Group: tert-Amine......Page 85
2.4.4.10 Functional Group: Hydroxamic Acid......Page 86
2.4.4.13 Functional Group: sec Amide/tert Amide/Sulfonamide......Page 87
2.4.5 Type of Reaction: Condensation......Page 88
2.4.6.2 [3+2] Cycloaddition......Page 89
2.4.8 Type of Reaction: Heterocycle Formation......Page 90
2.4.8.1 Nitrogen-Containing Heterocycles......Page 91
2.4.8.2 Multiple Nitrogen-Containing Heterocycles......Page 92
2.4.9 Type of Reaction: Michael Addition......Page 93
2.4.9.3 Amine Addition......Page 94
2.4.10 Type of Reaction: Miscellaneous......Page 95
2.4.11.1 Wittig......Page 96
2.4.12.1 Alcohol to Aldehyde/Ketone......Page 97
2.4.12.2 Sulfide to Sulfoxide/Sulfone......Page 98
2.4.12.5 Other......Page 99
2.4.13.2 Nitro to Aniline......Page 100
2.4.13.5 Reductive Alkylation/Amination......Page 101
2.4.14.1 C-Alkylation (Aldol, Anion)......Page 102
2.4.14.2 0-Alkylation (Mitsunobu, Anion)......Page 103
2.4.14.4 N-Alkylation (Sulfonamide, Amide)......Page 104
2.5 References......Page 105
3.1 Comparison with Solid-Phase Combinatorial Synthesis......Page 112
3.2 Synthesis of Mixtures......Page 114
3.3 Reactions Applied to Solution Phase Combinatorial Chemistry......Page 115
3.3.1 Acylation of Alcohols and Amines......Page 116
3.3.4 Alkylation and Addition Reactions......Page 121
3.3.5 Reductive Amination......Page 123
3.3.8 Pd-Catalyzed C-C Bond Formation......Page 124
3.3.10 Multicomponent Reactions......Page 128
3.3.12 Miscellaneous Reactions......Page 130
3.3.13 Reaction Sequences......Page 138
3.4.1 Solid-Phase-Bound Reagents......Page 141
3.4.2 Solid-Phase Extraction......Page 144
3.4.3 Liquid-Phase Extraction......Page 149
3.4.4 Fluorous Synthesis......Page 151
3.4.5 Synthesis on Soluble Polymers......Page 152
3.6 References......Page 154
4.1 Classical and Modern Chemistry of Isocyanides and MCRs......Page 160
4.2 Early Studies and Concepts of MCR Chemistry......Page 161
4.3 Conceptual Differences between Conceptual Chemical Reactions andMCRs......Page 162
4.4 The Different Types of MCRs......Page 163
4.5 The First Century of Isocyanide Chemistry......Page 165
4.6 Complementary Aspects of Natural Product Syntheses by Tandem-Domino Reactions and MCR Chemistry......Page 167
4.7 Modern Synthesis of the Isocyanides......Page 169
4.8 The Introduction of the New Isocyanide MCRs and their Libraries......Page 170
4.9 The Great Variability of the U-4CR......Page 172
4.10 The Usual and Unusual Peptide Chemistry......Page 176
4.11 Stereoselective U-4CRs and their Secondary Reactions......Page 179
4.12 The MCRs of Educts with Two or Three Functional Groups......Page 184
4.13 Unions of MCRs and Related Reactions......Page 188
4.14 The MCRs of More than Four Functional Groups......Page 189
4.15 New Unions of the U-4CR and Further Chemical Reaction......Page 191
4.16 Progress in Combinatorial MCR Chemistry......Page 195
4.17 Perspectives......Page 196
4.19 References......Page 197
5.1 Introduction......Page 202
5.2 Acid-Labile Anchors......Page 206
5.3 Anchors Cleaved by Nucleophiles......Page 222
5.4 Photolysis-Labile Anchor......Page 235
5.5 Allyl-Functionalized Anchors......Page 239
5.6 Safety-Catch Anchor......Page 242
5.7 Silicium-Anchor/Traceless-Anchor......Page 247
5.8.1 Multifunctional Anchors......Page 251
5.8.2 Anchors Cleaved by Reduction......Page 252
5.8.3 Hydrogenolysis-Labile Anchors......Page 253
5.8.5 Enzymatically Cleavable Anchors......Page 254
5.9 Acknowledgements......Page 255
5.10 References......Page 256
6.1 Introduction......Page 264
6.2 Squaric Acid as Template......Page 266
6.3.1 Baylis-Hillman Reaction on the Solid Phase......Page 268
6.3.2 The Use of 3-Hydroxy-2-Methylidene Propionic Acids as Templates......Page 269
6.3.2.1 Michael Addition of Amines......Page 270
6.3.2.2 Mitsunobu Reaction......Page 271
6.3.2.3 1,3-Dipolar Cycloaddition with Nitrile oxides......Page 272
6.3.2.4 Synthesis of 2-Methylidene-β-Alanines......Page 273
6.3.2.5 Synthesis of Pyrazolones......Page 275
6.3.2.6 Synthesis of 2-Diethoxy-Phosphorylmethyl Acrylic Acids......Page 277
6.3.3 Alkylation of 2-Arylsulfonylaminomethyl Acrylic Acids......Page 278
6.4.1 Synthesis of Polymer-Bound 5-(2-Bromoacetyl)pyrroles......Page 279
6.4.3 Synthesis of Thiazolpyrroles, Aminothiazolylpyrroles and Selenazolylpyrroles......Page 281
6.4.4 Synthesis of Imidazol[l,2-a]Pyri(mi)dylpyrroles......Page 282
6.4.6 Examples......Page 283
6.5 The Use of Enones as Templates......Page 284
6.5.2 Michael Addition of Aryl Thiolates......Page 285
6.5.3 Synthesis of Pyridines and Pyrido[2,3-d]pyrimidines......Page 286
6.5.5 Synthesis of Pyrrolidines......Page 287
6.5.6 Synthesis of Pyrimidines and Pyrimidones......Page 288
6.5.7 Synthesis of Pyrazoles......Page 289
6.7 References......Page 290
7.1 Introduction......Page 292
7.2.1 Submonomer Approach to Peptoid Synthesis......Page 293
7.2.2 Monomer Approach to Peptoid Synthesis......Page 294
7.2.3 Peptomers......Page 295
7.2.4 Peralkylated Peptides......Page 296
7.2.5 β-Peptoids......Page 297
7.3 Oligocarbamates......Page 298
7.4 Sulfonopeptides and Vinylogous-Sulfonamidopeptides......Page 299
7.5 Poly-N-Acylated Aniines......Page 301
7.6.1 Linear Ureas......Page 303
7.6.3 Oligocycloureas and Cyclothioureas......Page 305
7.7.1 Poly-N-Methyl-Pyrroles and Imidazoles......Page 306
7.7.2 Thiazole and Oxazole Ring-Containing Peptides......Page 307
7.7.5 Oligotetrahydrofurans......Page 308
7.7.6 Pyrrolinone-Containing Oligomers......Page 309
7.8.1 Vinylogous Polypeptides......Page 310
7.8.2 Retro-inverso Pseudopeptides......Page 311
7.8.3 Azatides and Azapeptides......Page 312
7.8.5 β-Polypeptides......Page 313
7.8.6 α.α-Tetrasubstituted Amino Acids-Containing Peptides......Page 314
7.8.7 Peptide Nucleic Acids......Page 315
7.9.1 Thioamide Pseudopeptides......Page 316
7.9.3 N-Hydroxyamide Bond-Containing Peptides......Page 317
7.9.4 Hydroxyethylamine Peptide Bond Isosteres......Page 318
7.9.5 Methylene Ether Isosteres......Page 319
7.9.6 Phosphono- and Phosphinopeptides......Page 320
7.11 Acknowledgements......Page 321
7.12 References......Page 322
8.2 Proteins Recognising Carbohydrates......Page 326
8.3 The Carbohydrate Ligands......Page 328
8.4 Supports for Solid-Phase Libraries......Page 331
8.5.2 Analysis by Mass Spectrometry......Page 333
8.5.3 Structural Analysis of Compounds Linked to Single Beads by MAS-NMR......Page 335
8.7 Parallel Synthesis of Oligosaccharide Arrays......Page 336
8.8 Synthesis of Oligosaccharide Libraries......Page 337
8.9 Glycopeptide Templates as Oligosaccharide Mimetics......Page 340
8.10 Parallel Synthesis of Glycopeptide Arrays......Page 342
8.11 Preparation and AnaIysis of Solid-Phase Clycopeptide Template Libraries......Page 345
8.12 Screening of a Solid-Phase Glycopeptide Library......Page 347
8.14 Acknowledgements......Page 348
8.15 References......Page 349
9.1 Introduction......Page 354
9.2 Aptamers for Small Molecules......Page 355
9.3 Functional Aptamers for Proteins and their Application in Biotechnology, Molecular Medicine, and Diagnostics......Page 359
9.4 Functional Aptamers In Vivo......Page 362
9.5 Conclusions......Page 365
9.7 References......Page 366
10.1 Introduction......Page 370
10.2 Supramolecular Recognition Sites......Page 371
10.3 Macrocyclic Peptides......Page 374
10.4 Combinatorial Receptor Libraries......Page 375
10.5.1 Quartz Microbalance Measurements in the Liquid Phase......Page 377
10.5.2 Reflectometric Interference Spectroscopy (RIfS) in the Liquid Phase......Page 381
10.7 References......Page 386
11.1.1 Generation and Presentation of Antigens......Page 390
11.1.3 Peptide Libraries for the Investigation of TAP......Page 391
11.1.4 MHC Class I and Class I1 Molecules......Page 392
11.1.4.1 Peptide Ligands of MHC Class I Molecules......Page 393
11.1.4.2 Peptide Ligands of MHC Class I1 Molecules......Page 394
11.2.5.1 Recognition of MHC Class I-Bound Peptides by TCR......Page 395
11.1.5.2 Recognition of MHC Class 11-Bound Peptides by TCR......Page 396
11.2.1 Synthesis of Peptides and Peptide Libraries......Page 397
11.2.4 Isolation of HLA Class I1 Molecules......Page 398
11.3.2 Activity Pattern Describing DRl/Peptide Interaction......Page 401
11.3.2.1 Tolerance to Amino Acid Variations in a HLA Class I1 Ligand......Page 405
11.3.2.3 Predictions of HLA Class 11-Ligands and T-cell Epitopes by the Algorithm 'Actipat'......Page 406
11.3.2.4 Peptide Libraries and the Antigen Recognition of CD4+ T Cells......Page 407
11.3.2.5 T-cell Response to Completely Randomized Peptide Libraries......Page 408
11.3.2.6 Complete Dissection of the Epitope for TCC 5G7......Page 409
11.3.2.8 Superagonists and Prediction of Epitopes......Page 410
11.6 References......Page 411
12.2 Cloning of Biosynthetic Gene Clusters......Page 416
12.3 New Drugs by Genetic Engineering......Page 417
12.3.1 New Drugs by Targeted Gene Disruption......Page 419
12.3.2 New Drugs by Expression of Single Genes......Page 420
12.3.3 New Drugs by Expression of Gene Clusters......Page 423
12.3.5 New Drugs by Recombinant Assembly of Enzymatic Subunits......Page 425
12.3.5.1 Polyketide Synthases......Page 426
12.3.5.2 Peptide Synthases......Page 434
12.3.5.3 Proteins Involved in Deoxysugar Biosynthesis......Page 437
12.4.1 Use of Genes Involved in the Biosynthesis of Oligosaccharide Antibiotics......Page 438
12.5 References......Page 439
13.1 Introduction......Page 444
13.2 Concepts and Issues for Combinatorial Library Design......Page 445
13.3 The Similarity Principle......Page 447
13.4.1 Two-Dimensional Fingerprints......Page 448
13.4.3 Other Descriptors......Page 449
13.4.4 Compound Selection Techniques......Page 450
13.5 Selected Examples of New Approaches to Molecular Similarity......Page 451
13.5.1 Affinity Fingerprints......Page 452
13.5.2 Feature Trees......Page 453
13.6.1 2D Versus 3D Descriptors for Global Diversity......Page 455
13.6.2 Random Versus Rational Design for Global Diversity......Page 457
13.6.3 3D Pharmacophore Definition Triplets Versus 2D Fingerprints......Page 459
13.6.4 Local Similarity - The Radius of Similarity......Page 461
13.7.1 Strategy......Page 463
13.7.2 Practical Issues......Page 464
13.7.3 Analysis of Diverse Libraries......Page 467
13.8 Conclusions......Page 468
13.10 References......Page 470
14.1.1 A Rationale for New Methods in Drug Discovery......Page 476
14.1.2 Chemistry, Biology and Technology......Page 477
14.1.4 Demands on HTS......Page 479
14.2.1 Design and Production of Chemical Diversity......Page 480
14.2.3 Procedures for the Synthesis of Combinatorial Compounds......Page 481
14.2.4 Solution-Phase Combinatorial Chemistry......Page 482
14.3.1 The Ideal Read-out Technology: Confocal Fluorescence......Page 483
14.3.2.2 Fluorescence Resonance Energy Transfer (FRET)......Page 485
14.3.3 EVOscreen™......Page 486
14.3.3.1 Liquid Handling......Page 487
14.3.3.2 ScannerIPicker......Page 488
14.3.4 Blurring the Lines Between Primary, Secondary and Tertiary Screening......Page 489
14.4.1 Association Kinetics of Gene Product Fragments Derived from E. coli β-Galactosidase......Page 490
14.4.1.1 Association Kinetics......Page 492
14.5 Summary......Page 494
14.7 References......Page 495
15.1 Introduction......Page 498
15.2.1 Motivation for and Problems of HTE Approaches in Catalysis......Page 499
15.2.2 Strategies for Library Design and Testing......Page 502
15.3 Approaches to Synthesis......Page 504
15.4 Approaches to Testing......Page 506
15.5 Conclusions......Page 511
15.7 References......Page 512
16.2.1 KBr Pellet Method......Page 514
16.2.2 ATR-Spectroscopy......Page 517
16.2.3.1 Single Bead Reaction Monitoring......Page 519
16.2.3.2 Examination of the Interaction between Resin-Bound Reactive Groups via IR-Microscopy......Page 523
16.2.3.3 FT-IR Mapping: A New Tool for Spatially Resolved Characterization of Polymer-Bound Combinatorial Compound Libraries with IR-Microscopy......Page 525
16.2.4.1 DRIFTS (Diffuse Reflectance Infrared Fourier Transform) Spectroscopy......Page 531
16.3 Conclusions......Page 532
16.4 References......Page 533
17.2.1 Decisional Pathway for Combinatorial Synthesis and Analysis......Page 534
17.2.2 Mass Spectrometric Techniques for Combinatorial Compound Analysis......Page 537
17.2.2.1 Ionization Techniques......Page 538
17.2.3 Analysis of Peptide- and Oligonucleotide-Libraries......Page 539
17.2.4.2 Coupling of Separation Techniques with Mass Spectrometry......Page 540
17.2.6.1 High-Throughput Analysis......Page 541
17.2.6.2 High-Throughput Sample Purification using MS-Detection......Page 542
17.3 Application of ES-MS in Combinatorial Chemistry Analysis......Page 543
17.3.1.2 Influence of Reagents on the MS-Analysis......Page 544
17.3.1.4 High-Throughput Analysis......Page 546
17.3.2.1 ES-MS-Analysis of a Pyrrol-Library......Page 549
17.3.2.2 MS-Analysis of an Isoxazoline-Library......Page 558
17.5.1 Electrospray-Mass-Spectrometry......Page 563
17.7 Appendix......Page 564
17.8 References......Page 566
18.2 Methods Used for On-Bead NMR Analysis......Page 568
18.3 Sample Preparations, Observations and Quantifications by HR MAS NMR......Page 570
18.4 Use of Protonated Solvent in HR MAS NMR......Page 574
18.5 Summary and Perspectives......Page 575
18.6 References......Page 577
19.1 Introduction......Page 578
19.2 Parallel Synthesis of Individual Compounds......Page 579
19.4.1 General Considerations......Page 580
19.4.2 Decentralized Automation Systems......Page 584
19.4.3 Central-Controlled, Function-Oriented Multicomponcnt Systems......Page 585
19.4.4 Central-Automated, Sample-Oriented Multicomponent Systems......Page 586
19.5 Collateral Technologies for High-Throughput Purification and Analysis......Page 591
19.6 Summary and Prospects......Page 592
19.8 References......Page 593
20.1 Introduction......Page 596
20.2.1.1 Supercconducting Magnet......Page 597
20.2.1.3 Analyzer Cell......Page 598
20.2.2.1 Cyclotron Motion......Page 599
20.2.2.2 Signal Generation......Page 600
20.3.1 Combinatorial Compound Collections......Page 602
20.3.1.1 Synthesis of Pyrrole Amide Collections......Page 603
20.3.1.2 Automated Direct Measurement......Page 604
20.3.1.3 MicroLC/ES-FT-ICR-MS-Coupling......Page 608
20.3.2.1 Synthesis of Pyrrolidine Libraries......Page 610
20.3.2.2 Result of Single Bead Analysis......Page 612
20.4 Materials and Methods......Page 613
20.5 References......Page 614
Colour Plates......Page 618
Index......Page 624