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  Contents  
 
  Volume 1  
 
Part I General Aspects 1
1 Combinatorial Chemistry in Perspective
K. C. Nicolaou, R. Hanko, and W. Hartwig 		3
1.1 Introduction 3
1.2 Brief History of Combinatorial Chemistry 4
1.3 Applications of Combinatorial Chemistry 6
1.4 Outline of the Book 7
  Acknowledgments 8
  References 8
2 Introduction to Combinatorial Chemistry
David L. Coffen and Joachim E. A. Luithle 		10
2.1 Combinatorial Chemistry in Drug Discovery -- a Perspective 10
2.2 Key Issues 11
2.3 Combinatorial Synthesis 15
2.3.1 Solid-phase Combinatorial Synthesis 16
2.3.1.1 Reagents and Conditions 16
2.3.1.2 Automation 17
2.3.1.3 Split and Combine 17
2.3.1.4 Cost 19
2.3.1.5 The Products from Solid-phase Chemistry 19
2.3.2 Solution-phase Combinatorial Synthesis 19
2.3.2.1 Reagents and Conditions 19
2.3.2.2 Scavenger Resins, Polymer-supported Reagents and Fluorous Tags 20
2.3.2.3 Equipment and Costs 22
2.4 Conclusion 22
  References 22
  Valuable Internet Links 23
3 Solid Phase and Soluble Polymers for Combinatorial Synthesis
Rainer Haag, André Hebel, and Jean-François Stumbé 		24
3.1 Introduction 24
3.2 Solid-phase Supports 25
3.2.1 Polystyrene-based Resins 25
3.2.1.1 General Aspects 25
3.2.1.2 Macroporous Resins 28
3.2.1.3 Microporous Resins 31
3.2.2 Polystyrene Hybrid Supports 35
3.2.2.1 PEGylated Resins 35
3.2.2.2 High-loading PS Hybrid Supports 36
3.2.3 Other Crosslinked Polymeric Supports 41
3.2.3.1 Crosslinked Acrylamides 41
3.2.3.2 Crosslinked PEGs 44
3.2.4 Inorganic Supports 46
3.3 Soluble Polymeric Supports 46
3.3.1 Separation Techniques for Soluble Polymeric Supports 47
3.3.2 Terminal Functionalized Linear Polymeric Supports 49
3.3.3 Polyfunctional Linear Polymeric Supports 49
3.3.4 Dendritic Polymeric Supports 51
3.3.5 Microgels 54
3.4 Conclusions 54
  References 54
4 Linkers for Solid-phase Synthesis
Stefan Bräse and Stefan Dahmen 		59
4.1 Introduction 59
4.2 General Linker Structures 60
4.2.1 Immobilization of Molecules 60
4.2.2 Spacers 61
4.2.3 Functionalized Linkers as Analytical Constructs 62
4.3 Linker Families 62
4.3.1 Benzyl-type Linkers Including Trityl and Benzhydryl Linkers 63
4.3.2 Allyl-based Linkers 68
4.3.3 Ketal/Acetal-based Linkers 70
4.3.4 Ester-, Amide-, and Carbamate-based Linkers 71
4.3.5 Silyl Linkers 73
4.3.6 Boronate Linkers 76
4.3.7 Sulfur, Stannane- and Selenium-based Linkers 77
4.3.7.1 Sulfur-based Linkers 77
4.3.7.2 Stannane-based Linkers 81
4.3.7.3 Selenium-based Linkers 81
4.3.8 Triazene-based Linkers 83
4.3.9 Orthogonality Between Linkers 88
4.4 Cleavage 88
4.4.1 Electrophilic and Nucleophilic Cleavage 88
4.4.2 Oxidative/Reductive Methods 90
4.4.3 Photocleavable Linkers 91
4.4.4 Metal-assisted Cleavage 93
4.4.4.1 Cleavage with Ensuing Allylic Substitution or Cross-coupling Reactions 94
4.4.4.2 Cleavage via Alkene Metathesis 97
4.4.5 Unusual Cleavage Methods 98
4.5 Linker and Cleavage Strategies 98
4.5.1 Safety-catch Linkers 99
4.5.2 Cyclative Cleavage (Cyclorelease Strategy) 103
4.5.3 Cleavage-cyclization Cases 105
4.5.4 Fragmentation Strategies 107
4.5.5 Traceless Linkers 110
4.5.6 Multifunctional Cleavage 117
4.5.7 Linkers for Asymmetric Synthesis 120
4.6 Linkers for Functional Groups 121
4.6.1 Linkers for Nitrogen Functionalities 122
4.6.1.1 Linkers for Amines 123
4.6.1.2 Linkers for Primary Amines 123
4.6.1.3 Linkers for Secondary Amines 125
4.6.1.4 Linkers for Tertiary Amines 125
4.6.1.5 Linkers for Hydrazines, Hydrazones and Hydroxylamines 128
4.6.1.6 Linkers for Diazonium Salts 128
4.6.1.7 Linkers for Azides 129
4.6.1.8 Linkers for Nitro Compounds 129
4.6.1.9 Linkers for Azo Compounds 129
4.6.1.10 Linkers for Nitriles 129
4.6.1.11 Linkers for N-Heterocycles 129
4.6.2 Linkers for Carbonyl Functionalities 133
4.6.2.1 Linkers for Carboxylic Acids 133
4.6.2.2 Linkers for Carboxylic Esters, Anhydrides and Lactones 134
4.6.2.3 Linkers for Thiocarboxylic Acids and Esters 135
4.6.2.4 Linkers for Carboxamides and Related Structures 136
4.6.2.5 Linkers for Hydrazides and Semicarbazones 142
4.6.2.6 Linkers for Cyclic Amides and Related Structures 143
4.6.3 Linkers for Ketones and Aldehydes 144
4.6.4 Linkers for Alcohols, Phenols, Ethers, and Ketals 144
4.6.4.1 Linkers for Alcohols 144
4.6.4.2 Linkers for Phenols 146
4.6.5 Linkers for Sulfur Compounds 146
4.6.5.1 Linkers for Thiols and Thioethers 146
4.6.5.2 Linkers for Sulfonamides 147
4.6.5.3 Linkers for Sulfonic Acids 147
4.6.5.4 Linkers for Sulfones and Sulfoxides 148
4.6.5.5 Linkers for Sulfoximines 148
4.6.6 Linkers for Hydrocarbons 148
4.6.6.1 Linkers for Alkanes 149
4.6.6.2 Linkers for Arenes and Heteroarenes 149
4.6.6.3 Linkers for Alkenes 149
4.6.6.4 Linkers for Alkynes 150
4.6.7 Linkers for Aryl and Alkyl Halides 150
4.6.8 Linkers for Heterocycles 151
4.6.9 Linkers for Reactive Intermediates 151
4.6.10 Linkers for Other Functional Groups 152
4.6.10.1 Linkers for Phosphonates 152
4.6.10.2 Linkers for Boronates 152
4.6.10.3 Linkers for Silanes and Silanols 152
4.7 Overview for Linkers for Functional Groups 152
4.8 Conclusion, Summary and Outlook 152
  References 153
5 Encoding Technologies
Thomas Krämer, Valery V. Antonenko, Reza Mortezaei, Nicolay V. Kulikov 		170
5.1 Introduction 170
5.2 Chemical-encoding Methods 171
5.2.1 Oligonucleotide Tags 171
5.2.2 Peptide Tags 173
5.2.3 Haloaromatic Binary Coding 173
5.2.4 Secondary Amine Binary Coding 175
5.2.5 Mass Encoding 178
5.3 Nonchemical Encoding Methods 180
5.3.1 Positional Encoding 180
5.3.1.1 Light-directed Synthesis 180
5.3.1.2 Microtiter Plate-based Positional Encoding 181
5.3.2 Nonpositional Encoding 183
5.3.2.1 Tea-bag Approach 183
5.3.2.2 Cellulose and Laminar Supports 183
5.3.2.3 Radiofrequency Tags 183
5.3.2.4 Laser Encoding 186
5.4 Conclusion 186
  References 187
6 Instrumentation for Combinatorial Chemistry
Marcus Bauser and Hubertus Stakemeier 		190
6.1 Automation in Combinatorial Synthesis 190
6.1.1 General Remarks 190
6.1.2 Fully Automated Systems for Solid- and Solution-phase Synthesis 190
6.1.2.1 Robot-arm-based Systems 190
6.1.2.2 Fully Automated Workstation Systems 201
6.1.2.3 Modular Systems 207
6.2 Purification of Combinatorial Libraries 209
6.2.1 Automated Liquid--Liquid Extraction 210
6.2.2 Solid-phase Extraction 211
6.2.3 Normal Phase Chromatography 212
6.2.3.1 CombiFlashTM from Isco 212
6.2.3.2 Quad3TM from Biotage 212
6.2.3.3 FlashMasterTM from Jones Chromatography 213
6.2.4 Reversed Phase Chromatography 213
6.2.4.1 Biotage 214
6.2.4.2 Gilson 214
6.2.4.3 Merck 215
6.2.4.4 Varian 215
6.2.4.5 Shimadzu 215
6.2.5 Preparative HPLC-MS 215
6.2.5.1 PE Sciex 215
6.2.5.2 Waters Micromass 216
6.2.5.3 Merck-Hitachi 216
6.2.5.4 Shimadzu 216
6.2.5.5 Gilson ThermoQuest 216
6.3 Analysis of Combinatorial Libraries 216
6.3.1 Purity of Combinatorial Libraries 217
6.3.2 Identity of Combinatorial Libraries 218
6.3.3 Quantification of Combinatorial Libraries 219
6.4 Automated Sample Processing 219
6.4.1 Sample Logistics 219
6.4.2 Evaporation 221
  References 222
Part II Synthetic Chemistry 225
7 Radical Reactions in Combinatorial Chemistry
A. Ganesan and Mukund P. Sibi 		227
7.1 Introduction 227
7.2 Intramolecular Radical Additions to sp2 and sp Carbon 228
7.3 Intermolecular Radical Additions 230
7.4 Functional Group Removal 237
7.5 Polymer-supported Reagents for Radical Chemistry 238
7.5.1 Polymer-supported Tinhydrides 239
7.5.2 Polymer-supported Allyl Stannane 242
7.5.3 Polymer-supported Reagents for Atom-transfer Reactions 242
7.5.4 Photochemical Generation of Radicals 243
7.6 Summary 244
  References 244
8 Nucleophilic Substitution in Combinatorial and Solid-phase Synthesis
Jan-Gerd Hansel and Stephan Jordan 		247
8.1 Introduction 247
8.2 Nucleophilic Substitution at Aliphatic Carbons 247
8.2.1 General Remarks 247
8.2.2 Halogen Nucleophiles 248
8.2.3 Oxygen Nucleophiles 249
8.2.4 Sulfur Nucleophiles 251
8.2.5 Nitrogen Nucleophiles 251
8.2.6 Ring-closing Reactions 254
8.3 Nucleophilic Substitution at Aromatic Carbons 254
8.3.1 General Remarks 254
8.3.2 Nitrogen Nucleophiles 255
8.3.3 Oxygen Nucleophiles 262
8.3.4 Sulfur Nucleophiles 264
8.3.5 Macrocyclization Reactions 265
  References 266
9 Electrophilic Substitution in Combinatorial and Solid-phase Synthesis
Jan-Gerd Hansel and Stephan Jordan 		270
9.1 Introduction 270
9.2 Electrophilic Substitution at Aliphatic Carbons 271
9.2.1 Halogen Electrophiles 271
9.2.2 Nitrogen Electrophiles 271
9.2.3 Carbon Electrophiles 272
9.3 Electrophilic Substitution at Aromatic Carbons 272
9.3.1 General Remarks 272
9.3.2 Halogen Electrophiles 273
9.3.3 Nitrogen Electrophiles 274
9.3.4 Carbon Electrophiles 275
  References 277
10 Elimination Chemistry in the Solution- and Solid-phase Synthesis of Combinatorial Libraries
Demosthenes Fokas and Carmen Baldino 		279
10.1 Introduction 279
10.2 -Eliminations in Combinatorial Chemistry 279
10.2.1 The Hofmann Elimination Solid-phase Synthesis of Tertiary Amines 280
10.2.1.1 Via a Regenerated Michael Acceptor (REM) Resin 280
10.2.1.2 Via a Safety-catch Resin 282
10.2.1.3 Via a Hydroxylamine Resin 283
10.2.1.4 Alternative Cleavage Techniques 284
10.2.2 -Elimination on Selenyl Resins 286
10.2.3 -Elimination on Sulfone Resins 288
10.2.4 -Elimination on Silyl Resins 289
10.2.5 -Elimination on Fluorenyl Resins 291
10.2.6 -Elimination on 2-(2-Nitrophenyl)ethyl Resins 291
10.2.7 Radical-based -Eliminations 292
10.2.7.1 -C,O Bond Scission 292
10.2.7.2 -C,Se Bond Scission-release of Olefins 293
10.3 Conjugate Eliminations 293
10.3.1 1,6-Conjugate Eliminations 293
10.3.2 1,4-Conjugate Eliminations 295
10.4 Addition--Elimination Reactions 296
10.4.1 Addition--Elimination on Vinylogous Systems 296
10.4.1.1 Entry to Aminomethyleneoxazolones 296
10.4.1.2 Entry to Benzopyrones 297
10.4.1.3 2,3-Dihydro-4-pyridone Libraries 298
10.4.2 Cycloreversions 299
10.4.2.1 Pyrrole Libraries 299
10.4.2.2 Imidazole Libraries 300
10.4.2.3 Traceless Solid-phase Synthesis of Furans 300
10.4.2.4 1,2-Diazines 301
10.5 Summary 302
  References 302
11 Addition to CC Multiple Bonds (Except for CC Bond Formation)
Adrian L. Smith 		305
11.1 Introduction 305
11.2 Addition to C=C Double Bonds 306
11.2.1 Epoxidation and Subsequent Epoxide Opening 306
11.2.2 Dihydroxylation 309
11.2.3 Oxidative Cleavage 311
11.2.4 Electrophilic Addition of A-X 313
11.2.5 Hydrogenation 315
11.2.6 Hydrometallation 316
11.2.7 1,4-Addition to , -Unsaturated Carbonyl Systems 317
11.3 Addition to CC Triple Bonds 318
  References 319
12 Addition to Carbon--Hetero Multiple Bonds
Philipp Grosche, Jörg Rademann, and Günther Jung 		322
12.1 Introduction 322
12.2 Additions to CN Double Bonds in sp2 Systems 322
12.2.1 Attack by Hydride (Reductive Alkylation) 323
12.2.2 Addition of Carbon Nucleophiles 324
12.2.2.1 Imino Aldol Reaction 324
12.2.2.2 Reaction with Boronic Acids 326
12.2.2.3 Addition of Allylsilanes (Imino-Sakurai Reaction) 327
12.2.2.4 Reaction with Grignard Reagents, Lithium Organyles, and Zinc Organyles 328
12.2.2.5 Addition of Copper Alkynes 329
12.2.2.6 Addition of Electron-rich Aromatic and Heteroaromatic Cycles 329
12.2.2.7 Radical Reactions 330
12.2.3 Addition of Nitrogen Nucleophiles 331
12.2.4 Addition of Phosphorus Nucleophiles 332
12.2.5 Reactions with Oxygen Nucleophiles 333
12.2.6 Addition of Sulfur Nucleophiles 333
12.3 Additions to CN Double Bonds in sp-Systems 334
12.3.1 Additions to Carbodiimides 335
12.3.2 Reaction of Isocyanates and Isothiocyanates 335
12.3.2.1 Addition of Carbon Nucleophiles 336
12.3.2.2 Addition of Nitrogen Nucleophiles 336
12.3.2.3 Addition of Oxygen Nucleophiles 337
12.3.3 Addition to CS Double Bonds in sp2 Systems 338
12.3.4 Reaction of CS Double Bonds in sp Systems 339
12.4 Additions to CN Triple Bonds (Cyanides, not Isocyanides) 339
12.4.1 Addition of Carbon Nucleophiles 339
12.4.2 Addition of Nitrogen Nucleophiles 340
12.4.3 Addition of Sulfur Nucleophiles 342
  References 342
13 Chemistry of the Carbonyl Group
Tobias Wunberg 		346
13.1 Introduction 346
13.2 Chemistry of the Carbonyl Group and Combinatorial Chemistry 346
13.3 Chemistry of Carboxylic Acids 347
13.3.1 C(O)-X Bond-forming Reactions: General Remarks 347
13.3.1.1 Amides and Ureas 347
13.3.1.2 Esters and Urethanes 353
13.3.2 Transformation of Carboxylic Acids into Other Functional Groups 355
13.3.2.1 Formation of Ketones 355
13.3.2.2 Formation of Amines: Curtius Degradation 356
13.3.2.3 Tebbe Olefination 356
13.3.2.4 Formation of Thioamides 357
13.4 Reactions of Aldehydes and Ketones 357
13.4.1 Reactions of Carbonyl Groups with CaH Acidic Compounds 357
13.4.1.1 Wittig and Horner--Emmons Olefinations 357
13.4.2 Reductive Amination 360
13.4.2.1 General Aspects 360
13.4.2.2 Formation of Imines 360
13.4.2.3 Reduction of Imines/Enamines 361
13.4.2.4 Applications 362
  References 365
14 Oxidation Except CC Double Bonds
Henning Steinhagen 		369
14.1 Introduction 369
14.2 Oxidation of Alcohols to Aldehydes and Ketones 369
14.2.1 Examples of the Oxidation of Polymer-bound Primary Alcohols to Aldehydes 371
14.2.2 Examples of the Oxidation of Polymer-bound Secondary Alcohols to Ketones 372
14.2.3 Examples of the Oxidation of Alcohols by Polymer-bound Reagents 373
14.3 Oxidation of Polymer-bound Aldehydes to Carboxylic Acids 375
14.4 Oxidation of Sulfur-containing Compounds 376
14.4.1 Examples of the Oxidation of Polymer-bound Sulfides to Sulfoxides and Sulfones 376
14.5 Oxidation of Selenium- and Phosphorus-containing Compounds 378
14.5.1 Examples of the Oxidation (Cleavage) of Selenides to Selenoxides on Solid Support 378
14.6 Oxidative Formation of Heterocycles on Solid Support 379
14.7 Oxidative Coupling and Cleavage Reactions on Solid Support 380
14.7.1 Examples of Oxidative Coupling Reactions on Solid Support 381
14.7.2 Examples of Oxidative Cleavage Reactions on Solid Support 382
  References 382
15 Reductions in Combinatorial Synthesis
Christopher P. Corrette and Conrad W. Hummel 		387
15.1 Introduction 387
15.2 Solid-phase Reductions 387
15.2.1 Aldehyde Reductions 387
15.2.2 Ketone Reductions 388
15.2.3 Ester Reductions 390
15.2.4 Mixed Anhydride Reductions 392
15.2.5 Thioester Reductions 393
15.2.6 Weinreb Amide Reductions 394
15.2.7 Sulfur Reductions 396
15.2.8 Selenium Reductions 397
15.2.9 Quinone Reductions 399
15.2.10 Amide Reductions 399
15.2.11 Carbamate Reductions 400
15.2.12 Reductive Amination 401
15.2.12.1 General Considerations 401
15.2.12.2 Imine Formation 402
15.2.12.3 Reducing Agents for Reductive Amination 403
15.2.12.4 Reductive Aminations as the Entry Point for Library Preparation 403
15.2.12.5 Recent Examples of Reductive Amination on Resin 405
15.2.13 Azide Reductions 406
15.2.13.1 General Considerations 406
15.2.13.2 Azide Reductions in Glycopeptide Preparations 406
15.2.13.3 Small Molecule Libraries Incorporating Azide Reduction 407
15.2.13.4 Recent Examples of Azide Reduction on Resin 408
15.2.14 Nitro Group Reductions 409
15.2.14.1 General Considerations 409
15.2.14.2 Tin-mediated Nitro Reductions 409
15.2.14.3 Nitro Reductions with Alternative Reagents 411
15.2.14.4 Recent Examples of Nitro Reduction on Resin 411
15.2.15 Imine Reductions (not Reductive Amination) 411
15.2.16 Nitrile Reduction 413
15.2.17 N-N and N-O Bond Reductions 413
15.2.18 Miscellaneous Reductions 414
15.3 Solution-phase Reductions 414
15.3.1 Supported Reagents 414
15.3.1.1 Asymmetric Reagents 414
15.3.1.2 Non-asymmetric Reagents 415
15.3.2 Supported Catalysts 422
15.3.2.1 Asymmetric Catalysis 422
15.3.2.2 Non-asymmetric Catalysis 428
15.3.3 Unsupported Reagents Using Catch-and-release Purification 430
15.3.3.1 Reductive Amination 430
15.3.3.2 Amide Reductions 430
15.3.4 Fluorous Chemistry 430
15.4 Conclusions 431
  References 431
16 Cycloadditions in Combinatorial and Solid-phase Synthesis
Markus Albers and Thorsten Meyer 		440
16.1 Introduction 440
16.2 [4 + 2] Cycloadditions 441
16.2.1 Diels--Alder Reaction with Resin-bound Dienes 441
16.2.2 Diels--Alder Reaction with Resin-bound Dienophiles 445
16.2.3 Intramolecular Diels--Alder Reaction on Solid Support 448
16.2.4 Hetero-Diels--Alder Reaction on Solid Support 450
16.2.5 Diels--Alder Reaction in Solution Phase 451
16.3 [3 + 2] Cycloadditions 453
16.3.1 Formation of Isoxazoles, Isoxazolines, and Isoxazolidines 453
16.3.2 Formation of Pyrrolidines 458
16.3.3 Formation of Furans 460
16.3.4 Formation of Imidazoles, Pyrroles, Pyrazoles, and Other Nitrogen-containing Heterocycles 461
16.4 [ 2 + 2 ] Cycloadditions 463
16.5 [6 + 3] Cycloadditions on Solid Support 464
16.6 Rearrangements 465
  References 467
17 Main Group Organometallics
Christopher Kallus 		470
17.1 Introduction 470
17.2 Reactions of Metalated Aromatics 471
17.3 1,2-Additions to C=X Groups 474
17.3.1 Reactions with Aldehydes 474
17.3.2 Reaction with Ketones 477
17.3.3 Reaction with Imines 479
17.3.4 Reaction with Enolates 481
17.4 Conjugate Addition to , -Unsaturated Carbonyls and Related Systems 482
17.5 Nucleophilic Substitutions 483
17.6 Reactions on Carboxylic Acid Derivatives and Related Systems 484
17.6.1 Reaction with Esters 484
17.6.2 Reactions with Weinreb Amides and Related Systems 485
17.7 Aminolysis of Esters 489
  References 490
18 Enolates and Related Species in Combinatorial and Solid-phase Synthesis
Jochen Krüger 		492
18.1 Introduction 492
18.2 Aldol Reactions 492
18.2.1 General Aspects 492
18.2.2 Li, Na, K, and Zn Enolates in Aldol Reactions 493
18.2.3 Boron Enolates in Aldol Reactions 495
18.2.4 The Mukaiyama Aldol Reaction 498
18.2.4.1 Solution-phase Protocols Using Polymer-bound Reagents 498
18.2.4.2 Solid-phase Protocols 502
18.3 1,4-Addition of Enolates to Michael Acceptors 503
18.4 Alkylation of Enolates 506
18.4.1 -Alkylation of Carbonyl Compounds 506
18.4.2 - and -Alkylation of 1,3-Dicarbonyl Compounds 507
18.4.3 Stereoselective Alkylations of Enolates 510
18.4.4 Alkylation of Protected Glycines 513
18.5 Claisen-type Condensations 515
18.6 Dieckmann Condensations 516
18.7 Knoevenagel Condensations 518
18.8 Addition of Enolates to Imines 520
18.8.1 Synthesis of -Amino Esters and Alcohols via Enolate Addition to Imines 520
18.8.2 Solid-phase Synthesis of -Lactams via Enolate Additions to Imines 522
18.9 Nitro-aldol Reactions 522
18.10 The Baylis--Hillman Reaction 524
18.11 Miscellaneous 525
  References 527
19 Solid-phase Palladium Catalysis for High-throughput Organic Synthesis
Yasuhiro Uozumi and Tamio Hayashi 		531
19.1 Introduction 531
19.2 Carbon--Carbon and Carbon--Nitrogen Bond-forming Reactions of Aryl and Alkenyl Halides 531
19.2.1 Cross-coupling Reactions 531
19.2.1.1 Reactions of Aryl and Alkenyl Halides with Organoboron Reagents 532
19.2.1.2 Reactions of Aryl and Alkenyl Halides with Organotin Reagents 543
19.2.1.3 Reactions of Aryl Halides with Terminal Alkynes 544
19.2.1.4 Solid-phase Palladium-catalyzed Cross-coupling Using Aryl and Benzylzinc Reagents 553
19.2.2 Palladium-catalyzed Arylation and Alkenylation of Olefins 555
19.2.3 Amination of Aryl Halides 561
19.2.4 Miscellaneous Reactions 565
19.2.4.1 Heteroannulation 565
19.2.4.2 Insertion Cross-coupling Sequence (Dialkylation of Tropene) 566
19.2.4.3 Coupling Reactions on Various Solid Supports 567
19.3 Solid-phase Reactions by Way of -Allylpalladium Intermediates 568
19.3.1 Cleavage of Allyl Ester Linkers 568
19.3.2 N-Allylation via -Allylpalladium Intermediates 571
19.3.3 Insertion---Allylic Substitution System 571
19.4 Palladium Catalysis with Solid-supported Complexes 573
19.4.1 Preparation of Solid-supported Palladium Complexes and Their Use in Palladium Catalysis 574
19.4.2 Solid-supported Chiral Palladium Catalysts 579
  References 581
20 Olefin Metathesis and Related Processes for CC Multiple Bond Formation
Florencio Zaragoza 		585
20.1 Introduction 585
20.2 Olefin Metathesis in Solution 588
20.2.1 Scope and Limitations of Olefin Metathesis in Solution 588
20.2.2 Examples of Library Preparation by Cross-metathesis in Solution 589
20.2.3 Examples of Library Preparation by Ring-closing Metathesis in Solution 592
20.2.4 Examples of Library Preparation by Ring-opening Metathesis Polymerization in Solution 595
20.3 Olefin Metathesis on Solid Phase 595
20.3.1 Cleavage from the Support by Olefin Metathesis 597
20.3.1.1 Scope and Limitations 597
20.3.1.2 Examples of Cleavage from the Support by Olefin Metathesis 599
20.3.2 Ring-closing Metathesis on Solid Phase 600
20.3.2.1 Scope and Limitations 600
20.3.2.2 Examples of Ring-closing Metathesis on Solid Phase 601
20.3.3 Cross- and Self-metathesis on Solid Phase 603
20.3.3.1 Scope and Limitations 603
20.3.3.2 Examples of Cross- and Self-metathesis on Solid Phase 603
20.4 Conclusion 606
  References 606
 
  Volume 2  
 
Part III Special Synthetic Topics 611
21 Solid-phase Synthesis of Natural Products and Natural Product-like Libraries
K. C. Nicolaou and Jeffrey A. Pfefferkorn 		613
21.1 Introduction 613
21.2 Solid-phase Derivatization of Natural Product Scaffolds -- Combinatorial Semisynthesis 614
21.2.1 Solid-phase Semisynthesis of Rauwolfa Alkaloids 615
21.2.2 Solid-phase Synthesis of Purine Derivatives 617
21.2.3 Solid-phase Semisynthesis of a Taxoid Library 618
21.2.4 Solid-phase Semisynthesis of Sarcodictyns A and B and Libraries Thereof 620
21.2.5 Solid-phase Semisynthesis of Vancomycin 623
21.3 Solid-phase Total Synthesis of Natural Products -- Combinatorial Total Synthesis 626
21.3.1 Solid-phase Synthesis of Prostaglandins and Libraries Thereof 626
21.3.2 Solid-phase Synthesis of Epothilone A and Libraries Thereof 628
21.3.3 Solid-phase Synthesis of (S)-Zearalenone 630
21.3.4 Solid-phase Synthesis of (DL)-Muscone and Libraries Thereof 632
21.3.5 Solid-phase Synthesis of the Vitamin D3 System 633
21.3.6 Solid-phase Synthesis of Carpanone-like Molecules 634
21.4 Combinatorial Solid-phase Synthesis of Natural Product-like Libraries 634
21.5 Conclusion 639
21.6 Addendum 639
  References 640
22 Solid-phase Synthesis of Heterocyclic Systems (Heterocycles Containing One Heteroatom)
Roland E. Dolle 		643
22.1 Introduction 643
22.2 Solid-phase Synthesis of Heterocycles Containing One Nitrogen Atom 643
22.2.1 Aziridines 643
22.2.2 -Lactams 649
22.2.3 Pyrrolidines and Derivatives 651
22.2.4 Tetramic Acids 653
22.2.5 Pyrroles 655
22.2.6 Piperidine and Derivatives 655
22.2.7 Dihydropyridines 659
22.2.8 Pyridines 661
22.2.9 Azepanes, Benzazepines, and Derivatives 662
22.2.10 Indoles 665
22.2.11 Tetrahydroquinolines 668
22.2.12 Quinolinones 671
22.2.13 Quinolines 672
22.2.14 Tetrahydroisoquinolines 674
22.3 Solid-phase Synthesis of Heterocycles Containing One Oxygen Atom 675
22.3.1 Tetrahydrofurans and -Butyrolactams 675
22.3.2 Furans 676
22.3.3 Benzofurans 677
22.3.4 Pyrans, Benzopyrans, and Derivatives 678
22.4 Solid-phase Synthesis of Thiophenes 678
22.5 Summary 679
  References 680
23 Multicomponent Reactions
Arounarith Tuch and Stefan Wallé 		685
23.1 Introduction 685
23.2 Mannich Reaction 685
23.3 Hantzsch Reaction 689
23.4 Baylis--Hillman Reaction 690
23.5 Grieco Three-component Reaction 691
23.6 Biginelli Reaction 692
23.7 Multicomponent Reactions with Isocyanides 693
23.7.1 History of Isocyanides 693
23.7.2 Isocyanide Chemistry 694
23.7.3 Isocyanides on Solid Phase 695
23.7.4 Passerini Reaction 696
23.7.5 The Ugi Reaction 697
23.7.6 The Ugi Reaction on Solid Phase 699
23.7.7 Other Multicomponent Reactions with Isocyanides 701
  References 703
24 Strategies for Creating the Diversity of Oligosaccharides
Pamela Sears and Chi-Huey Wong 		706
24.1 Introduction 706
24.2 Chemical Synthesis of Oligosaccharides 707
24.3 Enzymatic Synthesis of Oligosaccharides 711
24.4 Programmable One-pot Synthesis 717
24.5 Conclusions 720
  References 721
Part IV Molecular Design and Combinatorial Compound Libraries 723
25 Design Criteria
Josef Pernerstorfer 		725
25.1 Introduction 725
25.2 Properties of Combinatorial Libraries for Drug Development 725
25.3 Differentiation of Drug-like and Nondrug-like Compounds 728
25.4 Diversity in Combinatorial Chemistry for Drug Development 730
25.4.1 Introduction 730
25.4.2 Descriptors 731
25.4.3 Selection Algorithms 732
25.4.4 Diversity Assessment 734
25.5 Privileged Structures 735
25.5.1 Introduction 735
25.5.2 Further Examples of Privileged Structural Motifs 736
25.5.3 Substructure Analysis of Drugs 738
25.6 Conclusion 740
  References 740
26 Estimation of Physicochemical and ADME Parameters
Michael W. Härter, Jörg Keldenich, and Walter Schmitt 		743
26.1 Introduction 743
26.2 ADME/PK Considerations in Combinatorial Library Design 744
26.3 Estimation of ADME/PK from Physicochemical Parameters 745
26.3.1 Models for Permeation Through Membranes (Absorption) 746
26.3.2 Models for Distribution in the Body 749
26.3.3 Models for Clearance and Metabolism 752
26.4 Estimation of Physicochemical Parameters 753
26.4.1 Lipophilicity 754
26.4.2 Solubility Including pKa Effects 755
26.4.3 Plasma Protein Binding 758
  References 758
27 Virtual Compound Libraries and Molecular Modeling
Roger M. Brunne, Gerhard Hessler, and Ingo Muegge 		761
27.1 Introduction 761
27.2 Lead-finding Libraries 762
27.2.1 Diversity Assessment of Library Compounds 762
27.2.2 ``Drug-likeness'' of Library Compounds 763
27.3 Focused Libraries 765
27.3.1 Targeting Protein Families 766
27.3.2 Privileged Structures 767
27.3.3 Similarity 770
27.3.4 Docking 772
27.4 Methods for Library Optimization 774
27.4.1 Genetic Algorithm 775
27.4.2 Fitness Function 775
27.4.2.1 Potency 775
27.4.2.2 Diversity 776
27.4.2.3 Physicochemical Properties 776
27.5 Conclusion 778
  References 781
28 Erythropoietin Sensitizer -- A Case Study
Berthold Hinzen, Gabriele Bräunlich, Christoph Gerdes, Thomas Krämer, Klemens Lustig, Ulrich Nielsch, Michael Sperzel, Josef Pernerstorfer 		784
28.1 Introduction 784
28.2 Results 785
28.2.1 High-throughput Screening and Biological Evaluations 785
28.2.2 Concept for Chemical Optimization 787
28.2.3 4-Fluoro-3-nitroaniline as Central Core 787
28.2.4 Libraries Around Single Heterocycles 789
28.2.4.1 Hydantoins 789
28.2.4.2 Pyrazoles 790
28.2.5 The Candidate for Preclinical Development 801
28.3 Combinatorial Chemistry in Drug Discovery 802
  Acknowledgements 802
  References 803
29 Estimation of Stability and Shelf Life for Compounds, Libraries, and Repositories in Combination with Systematic Discovery of New Rearrangement Pathways
Ferenc Darvas, György Dormán, Tamás Karancsi, Tamás Nagy, and István Bágyi 		806
29.1 Introduction 806
29.1.1 Stability and Shelf Life Characterization: the Need 806
29.1.2 Stability Characterization: Empirical Studies 807
29.1.3 Stability and Shelf Life Estimation: Model-based Approaches 807
29.2 Methods and Tools for Combinatorial Stability Assessment 808
29.2.1 Modeling Intrinsic and Extrinsic Factors Influencing the Stability of Individual Compounds 808
29.2.2 Modeling: from Compounds to Libraries 809
29.2.3 Modeling: from Libraries to Repositories 809
29.2.4 Realization of Shelf Life Estimation for Individual Compounds and Combinatorial Libraries 810
29.2.5 Instrumentation 812
29.3 Validation Studies for Combinatorial Stability Assessment 812
29.3.1 General Experimental Conditions 812
29.3.2 Stability Study for an Indole Library 812
29.3.3 Combinatorial Stability Investigation for a Small Repository 815
29.4 Stability Investigations in Combinatorial Drug Discovery 816
29.4.1 Pilot Design Phase 816
29.4.2 Libraries 817
29.5 A Way Towards Systematic Discovery of New Rearrangement Pathways 818
29.6 Summary 823
29.7 Appendix I: Stability Testing of Drug Substances 823
29.7.1 Stress Stability Testing 823
29.7.2 Accelerated Stability Testing 824
29.7.3 Long-term Stability Testing 824
29.8 Appendix II: The Arrhenius Model 824
29.9 Appendix III: Model Realization -- the StabexTM System 825
  Acknowledgements 827
  References 827
Part V Novel Applications of Combinatorial Chemistry 829
30 Concepts of Combinatorial Chemistry in Process Development
Markus Eckert and Ulrich Notheis 		831
30.1 Introduction 831
30.1.1 General 831
30.1.2 Subject of this Chapter 831
30.1.3 Literature 832
30.2 Process Development 834
30.2.1 Overview and Definition 834
30.2.2 Combinatorial Chemistry in Process Development 835
30.2.3 Demands on Process Development 835
30.2.4 Process Development for Different Applications 837
30.3 Parallelization in Process Development 838
30.3.1 Number of Experiments Compared with Scale of Experiment 838
30.3.2 Requirements and Equipment for Parallelization in Different Development Phases 840
30.3.2.1 Route Scouting 840
30.3.2.2 Process Screening 841
30.3.2.3 Process Optimization 847
30.3.2.4 Process Characterization and Validation 849
30.3.3 Requirements for Analytical Instruments 850
30.4 Planning of Parallel Process Development 851
30.4.1 Screening Strategies 851
30.4.1.1 Experimental Design 852
30.4.2 Strategies for the Selection of the Equipment 853
30.4.2.1 Automation versus Manual Work? 853
30.4.2.2 What is the Right Distribution and Number of Pieces of Apparatus for Different Stages? 855
30.4.2.3 Buying Commercially Available Systems or Carrying out In-house Development? 856
30.5 Case Studies 857
30.6 Summary 861
  References 861
31 High-throughput Screening Applied to Process Development
Oliver Brümmer, Bernd Jandeleit, Tetsuo Uno, and W. Henry Weinberg 		864
31.1 Introduction 864
31.1.1 General 864
31.1.2 Automation and Experimental Design 865
31.1.3 High-throughput Process Development 866
31.2 Case Studies 867
31.2.1 High-throughput Combinatorial Process Discovery 867
31.2.2 Route Scouting, Screening, Optimization, and Validation 869
31.2.3 Miscellaneous 880
31.3 Summary and Outlook 882
  Acknowledgments 883
  References 883
32 Combinatorial Methods in Catalysis
Bill Archibald, Oliver Bru¨mmer, Martin Devenney, Sasha Gorer, Bernd Jandeleit, Tetsuo Uno, W. Henry Weinberg, and Thomas Weskamp 		885
32.1 Introduction 885
32.1.1 Combinatorial Catalysis 885
32.1.2 Combinatorial Organic and Organometallic Catalysis 887
32.2 Metal-binding Ligands, Polymeric Enzyme Mimetics, and Metal Complexes as Enzyme Mimetics 888
32.2.1 Combinatorial Approaches to Metal-binding Ligands 888
32.2.1.1 Combinatorial Functionalization of Metal-binding Core Structures 888
32.2.1.2 Combinatorial Synthesis of Metal-binding Ligands from Building Blocks with Metal-coordinating Functionalities 892
32.2.1.3 Miscellaneous 895
32.2.2 Combinatorial Libraries of Polymeric Catalysts as Enzyme Mimetics 899
32.2.3 Combinatorial Synthesis Enzyme Mimetics 903
32.2.3.1 Hydrolytically Active Metal Complexes 903
32.2.3.2 Evolutionary Solid-phase Synthesis of Oxygenase Mimics 904
32.2.3.3 Libraries of Organic Acylation Catalysts 905
32.3 Combinatorial Catalysis in Asymmetric Synthesis 906
32.3.1 Combinatorial Catalyst Libraries in Enantioselective Additions of Dialkyl Zinc Reagents 906
32.3.2 Ligands for the Lewis Acid-catalyzed Asymmetric Aza-Diels--Alder Reaction 908
32.3.3 Divergent Ligand Synthesis for Enantioselective Alkylations 909
32.3.4 Chiral Phosphine Ligands for Asymmetric Hydrogenation 912
32.3.5 Asymmetric Reactions Catalyzed by Schiff Base-type Ligands -- the Positional Scanning Approach 913
32.3.6 Identification of Novel Catalysts for the Asymmetric Epoxidations via the Positional Scanning Approach 916
32.4 Multidimensional Combinatorial Screening 917
32.4.1 Catalyst Discovery and Optimization Using Catalyst Arrays 919
32.4.2 Parallel Array Screening for Catalyst Optimization Using Discovery and Focused Ligand Libraries 925
32.5 One-pot, Multisubstrate Screening 927
32.6 Combinatorial Approaches to Olefin Polymerization Catalysts 930
32.7 Combinatorial Inorganic Catalysis 936
32.7.1 Combinatorial Libraries of Homogeneous Polyoxometalate-based Catalysts 936
32.7.2 Combinatorial Libraries and High-throughput Screening of Heterogeneous Polyoxometalate Catalysts 938
32.8 Combinatorial Heterogeneous Catalysis 939
32.8.1 Introduction 939
32.8.2 Case Studies 944
32.8.2.1 Oxidative Dehydrogenation of Ethane 944
32.8.2.2 Oxidative Dehydrogenation of Propane 945
32.8.2.3 Catalytic Oxidation of CO and the Reduction of NO 947
32.9 Combinatorial Electrocatalysis 947
32.9.1 Electrocatalysts for Fuel Cells 947
32.9.2 Combinatorial Electrosynthesis 951
32.10 Novel High-throughput Screening Tools 952
32.10.1 Infrared Screening Tools 953
32.10.1.1 Infrared Thermography 953
32.10.1.2 High-throughput Infrared Spectroscopy 956
32.10.2 Optical High-throughput Screening Techniques 957
32.10.2.1 Colorimetric Assays 958
32.10.2.2 Resonance-enhanced Multiphoton Ionization (REMPI) 963
32.10.2.3 Photothermal Deflection 965
32.10.2.4 Enantiomeric Excess by Circular Dichroism 966
32.10.3 High-throughput Screening Using Mass Spectrometry 966
32.10.3.1 Scanning Mass Spectrometry 966
32.10.3.2 ``Mass Tags'' as Chirality Probes 968
32.10.4 Electronic High-throughput Methods 969
32.10.4.1 Electrochemical Analysis with Electrode Arrays 969
32.10.4.2 Solid-state Temperature Sensors 970
32.10.4.3 Solid-state Gas Sensors 971
32.10.5 Array Reactors 973
32.10.5.1 Array Microreactors 973
32.10.5.2 Micromachined Array Reactors 976
32.10.5.3 Catalysis on a Chip 977
32.10.6 Capillary Array Electrophoresis 977
32.11 Summary and Outlook 978
  Acknowledgements 979
  References 979
33 Diversity-Based Identification of Efficient Homochiral Organometallic Catalysts for Enantioselective Synthesis
Amir H. Hoveyda 		991
33.1 Introduction 991
33.2 Factors Critical to the Success of Diversity-based Reaction Development 992
33.3 Peptidic Schiff Bases as Chiral Ligands 994
33.3.1 Ti-Catalyzed Enantioselective Addition of Cyanide to Meso Epoxides 995
33.3.2 Ti-Catalyzed Enantioselective Addition of Cyanide to Imines 1000
33.3.3 Zr-Catalyzed Enantioselective Addition of Dialkyl Zincs to Imines 1004
33.3.4 Cu-Catalyzed Enantioselective Addition of Dialkyl Zincs to Allylic Phosphates: Pyridyl Dipeptides as Chiral Ligands 1006
33.3.5 Cu-Catalyzed Enantioselective Conjugate Addition of Dialkyl Zincs to Unsaturated Ketones: Peptidic Phosphines as Chiral Ligands 1009
33.4 Conclusions and Outlook 1012
  Acknowledgments 1013
  Endnotes and References 1013
34 Combinatorial Aspects of Materials Science
Bill Archibald, Oliver Brümmer, Martin Devenney, Daniel M. Giaquinta, Bernd Jandeleit, W. Henry Weinberg, and Thomas Weskamp 		1017
  Abstract 1017
34.1 Introduction 1018
34.2 Combinatorial Solid-state Materials Science 1020
34.2.1 Materials Library Synthesis 1022
34.2.2 Vapor Deposition Techniques 1022
34.2.3 Alternative Library Synthesis Techniques 1026
34.3 High-throughput Screening 1030
34.3.1 Optical Screening 1030
34.3.2 X-Ray Characterization 1031
34.4 Applications 1032
34.4.1 Superconductivity 1032
34.4.2 Ferromagnetic Semiconductors 1033
34.4.3 Magnetoresistant Materials 1034
34.4.4 Dielectric and Ferroelectric Materials 1035
34.4.5 Luminescent Materials 1038
34.5 Case Studies 1041
34.5.1 Materials Discovery 1041
34.5.2 Device Optimization 1042
34.6 Organic Materials and Polymers 1045
34.6.1 Schiff Bases for Nonlinear Optical (NLO) Materials 1045
34.6.2 Artificial Receptors for Small Organic Molecules 1046
34.6.3 New Materials for the Separation of Enantiomers 1046
34.6.4 Molecular Imprinting 1050
34.6.5 Polymers with Novel Topologies and Functionalization 1050
34.7 Summary and Outlook 1056
  Acknowledgments 1057
  References 1057
35 Reprogramming Combinatorial Biology for Combinatorial Chemistry
Sean V. Taylor 		1063
35.1 Introduction 1063
35.2 Combinatorial Biosynthesis: Creation of Novel Small-molecule Natural Products 1064
35.2.1 Polyketide Combinatorial Biosynthesis 1066
35.2.1.1 Combinatorial Biosynthesis from Type II PKSs 1068
35.2.1.2 Combinatorial Biosynthesis from Type I Modular PKSs 1070
35.2.2 Combinatorial Biosynthesis of Nonribosomal Peptide Products 1074
35.2.3 Combinatorial Biosynthesis from Hybrid PKS/NRPS Systems 1075
35.2.4 Combinatorial Biosynthesis of Carbohydrates 1077
35.3 Other Combinatorial Aspects of Biology 1081
35.3.1 Combinatorial Libraries of Random DNA and RNA 1082
35.3.2 Peptide Combinatorial Libraries 1084
35.3.3 Protein Combinatorial Libraries 1085
35.4 Perspectives 1090
  Acknowledgments 1092
  References 1092
  Index 1099

 
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