Linker Strategies in Solid-Phase Organic Synthesis

Linker Strategies In Solid-Phase Organic Synthesis......Page 3
Contents......Page 7
Foreword......Page 17
Preface......Page 21
List of Contributors......Page 23
About the Editor......Page 25
Abbreviations......Page 27
I INTRODUCTION......Page 31
1.1 Introduction, background and pivotal discoveries......Page 33
1.2.1 Apparatus......Page 39
1.2.2 Typical solid supports......Page 40
1.2.4 Linker strategies......Page 42
1.2.5 Challenges......Page 47
1.2.6 Linker groups......Page 48
1.3 Concluding comments......Page 50
1.4 Personal perspective and testimony: solid-phase Mannich chemistry......Page 51
References......Page 52
II TRADITIONAL LINKER UNITS FOR SOLID-PHASE ORGANIC SYNTHESIS......Page 55
2.1 Introduction......Page 57
2.2 Resins for use with electrophilic linkers......Page 58
2.3 Electrophile cleavable linkers......Page 60
2.3.1 Acid labile linkers......Page 61
2.4 Conclusion......Page 100
References......Page 101
3.1 Introduction......Page 107
3.2 Linker units......Page 108
3.3 Nucleophilic labile linker units......Page 109
3.3.1 Cleavage by saponification or basic trans-esterification......Page 110
3.3.2 Cleavage by aminolysis......Page 116
3.3.3 Cleavage by hydrazinolysis......Page 131
3.3.4 Cleavage by Hydroxylamines......Page 135
3.3.5 Cleavage by other nucleophiles......Page 139
3.3.6 Linker cleavage by intramolecular nucleophilic reaction......Page 149
3.4 Conclusion......Page 159
References......Page 160
4.1 Introduction......Page 165
4.2 C–N bond formation......Page 167
4.2.1 Cyclopeptides and cyclodepsipeptides......Page 168
4.2.2 Heterocycles, five-membered ring formation......Page 169
4.2.3 Heterocycles, six- and seven-membered ring formation......Page 172
4.3 C–O bond formation......Page 175
4.4 C–C bond formation......Page 176
References......Page 178
5.2 Linkers based on the ortho-nitrobenzyloxy function......Page 181
5.3 Linkers based on the ortho-nitrobenzylamino function......Page 188
5.4 Linkers based on the α-substituted ortho-nitrobenzyl group......Page 191
5.5 Linkers based on the ortho-nitroveratryl group......Page 195
5.6 Linkers based on the phenacyl group......Page 203
5.7 Linkers based on the para-methoxyphenacyl group......Page 206
5.8 Linkers based on the benzoin group......Page 210
5.9 Linkers based on the pivaloyl group......Page 214
5.11 Other types of photolabile linker units......Page 217
5.12 Conclusion......Page 218
References......Page 221
6.1 Introduction......Page 225
6.2.1 Kenner-type safety-catch linker......Page 226
6.2.2 N-boc-activated safety-catch linker......Page 227
6.2.3 Sulfide/sulfone safety-catch linker......Page 228
6.3.1 Carbonyl activation by oxidative aromatization......Page 229
6.3.3 Benzyl/phenyl-hydrazide safety-catch linker......Page 230
6.4.1 Benzhydryl-based safety-catch linker......Page 232
6.4.2 Indole-based safety-catch linker......Page 233
6.4.3 Nitrobenzyl alcohol-based safety-catch linker......Page 234
6.5 Aromatic SNAr substitution......Page 235
6.6 Fragmentation by β-elimination......Page 237
6.7.1 Geysen safety-catch linker......Page 238
6.7.3 Lyttle safety-catch linker......Page 240
6.7.4 Multiple cleavable linkers......Page 241
6.8 Photochemical activation......Page 242
6.9.1 Activation by reductive aromatization......Page 243
6.9.2 Activation via intramolecular H-bonding......Page 244
6.9.3 Activation by formation of an alkyne-cobalt complex......Page 245
6.9.4 Activation by oxidation of arylsulfide for pummerer rearrangement......Page 246
6.9.5 Activation by oxidative N-benzyl deprotection......Page 247
6.9.6 Activation by thioether alkylation......Page 248
References......Page 249
7.1 Introduction......Page 251
7.2.1 Exo linker units......Page 252
7.2.2 Endo linker units......Page 255
References......Page 267
III MULTIFUNCTIONAL LINKER UNITS FOR DIVERSITY-ORIENTED SYNTHESIS......Page 269
8.1 Introduction......Page 271
8.2 Exploring chemical space......Page 273
8.4 Enriching chemical space using DOS......Page 274
8.5 The subjective nature of ‘Diversity’......Page 275
8.6.1 DOS based on privileged scaffolds......Page 276
8.7 Generating skeletal diversity......Page 278
8.7.1 Strategy 1: Pluripotent functional groups......Page 279
8.7.2 Strategy 2: Pluripotent (densely functionalised) molecules......Page 283
8.7.3 Strategy 3: Folding pathways......Page 286
8.8 DOS and solid-phase organic synthesis......Page 287
8.8.1 An overview of linkage cleavage strategies......Page 288
8.8.2 Diversity linkers: A summary of the approaches used......Page 289
References......Page 290
9.1 Introduction......Page 293
9.2 The T1 linker......Page 294
9.2.1 The dibenzyl-type T1 resins......Page 296
9.2.2 The piperazinyl-type T1 resins......Page 308
9.3.1 The T2 Linker......Page 312
9.3.2 The T2. linker for synthesis......Page 317
9.3.3 The T2. scavenger resin......Page 322
9.4 Miscellaneous triazene linkers......Page 323
References......Page 330
10.2 Hydrazone linker units......Page 333
10.3 Conclusion......Page 342
References......Page 344
11.1 Introduction......Page 347
11.2.1 Carbon–carbon tethered benzotriazoles......Page 348
11.2.2 Ether tethered benzotriazoles......Page 349
11.2.3 Amide tethered benzotriazoles......Page 350
11.3.1 Mannich-type reaction and cleavage......Page 352
11.3.3 Urea synthesis......Page 355
References......Page 359
12.1 Introduction......Page 361
12.2.1 Diversity cleavage through the Wittig reaction......Page 362
12.2.2 Diversity cleavage using the Horner–Wadsworth–Emmons reaction......Page 366
12.3 Diversity cleavage of enol phosphonates through palladium catalysed cross-coupling reactions......Page 368
12.4 Oxidative diversity cleavage of cyanophosphoranes......Page 369
References......Page 370
13.1 Introduction......Page 373
13.2.1 Introduction......Page 374
13.2.2 Reductive traceless cleavage......Page 375
13.2.3 Multifunctional cleavage via nucleophilic substitution reactions......Page 377
13.2.4 Multifunctional cleavage via elimination reactions......Page 380
13.3 Sulfonium Linker Units......Page 381
13.4.1 Introduction......Page 384
13.4.3 Multifunctional cleavage using the pummerer rearrangment......Page 385
13.5.1 Introduction......Page 388
13.5.2 Reductive traceless cleavage......Page 390
13.5.3 Multifunctional cleavage via elimination reactions......Page 392
13.5.4 Multifunctional cleavage via nucleophilic substitution reactions......Page 400
13.6.2 Alkanesulfonate ester linker units......Page 403
13.6.3 Perfluoralkanesulfonyl (PFS) linker units......Page 408
13.6.4 Tetrafluoroarylsulfonyl linker units......Page 411
13.7 Sulfamate linker units......Page 413
13.8 Thioester linker units......Page 415
References......Page 417
14.2 Selenium- and tellurium-based linker group reagents and their syntheses......Page 421
14.3.2 Nucleophilic attachment at selenium......Page 428
14.3.4 Attachment at other positions......Page 432
14.4.1 Oxidative cleavage......Page 433
14.4.2 Nucleophilic displacement cleavage......Page 440
14.4.3 Homolytic cleavage......Page 441
14.5 Conclusions......Page 445
References......Page 446
15.1 Introduction......Page 449
15.2.1 Oxygen-based linkers......Page 450
15.2.3 Selenium-based linkers......Page 451
15.2.4 Tellurium-based linkers......Page 460
15.3.1 Ether and amine linkers cleaved by oxidative electron transfer......Page 461
15.3.2 A homobenzylic ether linker cleaved by oxidative electron transfer......Page 469
15.3.3 A sulfur linker cleaved by oxidative electron transfer with CAN......Page 470
15.3.4 Safety-catch linkers cleaved by oxidative electron transfer......Page 473
15.4 Linkers cleaved by reductive electron-transfer......Page 477
15.4.1 N–O linkers cleaved using samarium(II) iodide......Page 478
15.4.3 Ether linkers cleaved using samarium(II) iodide......Page 480
15.4.4 Alkyl and aryl sulfide/sulfone linkers cleaved by reductive electron-transfer......Page 483
15.5.2 Radical carbon–carbon bond formation as a trigger for linker cleavage......Page 492
References......Page 495
16.1 Introduction......Page 497
16.2.1 The preparation of silyl resins......Page 498
16.2.2 Activation of Si–H and Si–Aryl resins for substrate attachment......Page 501
16.2.3 Silyl ether linkers......Page 505
16.2.4 Fragmentation-based silyl linkers......Page 509
16.2.5 Traceless/diversity silyl linkers......Page 517
16.3 Germanium-based linkers......Page 525
16.3.1 The preparation of germyl resins......Page 526
16.3.2 Activation of Ge–Methyl and Ge–Aryl resins for substrate attachment......Page 527
16.3.3 Traceless/diversity germyl linkers......Page 528
16.4 Conclusions......Page 530
References......Page 531
17.1 Introduction......Page 535
17.2.1 Introduction......Page 537
17.2.2 Organostannane linker units......Page 538
17.3.1 Introduction......Page 541
17.3.2 Diversity cleavage through suzuki–miyaura reactions......Page 542
17.3.3 Alternative cleavage strategies from organoboron linkers......Page 544
References......Page 546
18.2 Bismuth linker units......Page 549
References......Page 553
19.2 Chromium carbonyl linker units......Page 555
19.3 Cobalt carbonyl linker units......Page 563
19.4 Manganese carbonyl linker units......Page 565
References......Page 566
20.1 Introduction......Page 567
20.2 Cycloolefins via method I......Page 569
20.3 Terminal olefins via route II......Page 575
20.4 Terminal and internal olefins via route III......Page 577
References......Page 578
IV ALTERNATIVE LINKER STRATEGIES......Page 581
21.1.2 Different types of fluorous linkers......Page 583
21.2.1 Synthesis of heterocyclic compounds......Page 587
21.2.2 Synthesis of natural product analogs......Page 592
21.2.3 Fluorous mixture synthesis......Page 593
21.3.2 Synthesis of oligosaccharides......Page 596
21.3.4 Synthesis of oligonucleotides......Page 599
21.4 Other applications of fluorous linkers......Page 600
21.4.1 Isolation of proteomics samples......Page 601
21.4.2 Microarray screening......Page 602
21.4.3 Enzymatic synthesis......Page 603
References......Page 604
22.1 Introduction......Page 607
22.2.1 Thin film radiochemistry......Page 608
22.2.2 Germanium solid-phase surrogates......Page 610
22.3.1 Stannane linkers in radiochemistry......Page 611
22.3.2 Germanium linkers in radiochemistry......Page 612
22.3.3 Fluorous linkers in radiochemistry......Page 613
22.4 Conclusions and perspectives......Page 615
References......Page 616
V LINKER SELECTION TABLES......Page 619
23.1 Introduction......Page 621
23.2 Linkers for alcohols, phenols and diols......Page 622
23.3 Linkers for carboxylic acids, esters and related compounds......Page 628
23.4 Linkers for aldehydes, ketones and related carbonyl compounds......Page 636
23.5 Linkers for amides, ureas and related compounds......Page 641
23.6 Linkers for amines......Page 653
23.8 Linkers for sugars......Page 659
23.9 Linkers liberating alkyl groups......Page 661
23.10 Linkers for alkenes, alkynes and related compounds......Page 665
23.11 Linkers for aryl compounds......Page 674
Index......Page 687