Table Of ContentLinker Strategies In Solid-Phase
Organic Synthesis
Linker Strategies in Solid-Phase Organic Synthesis Edited by Peter Scott
© 2009 John Wiley & Sons, Ltd. ISBN: 978-0-470-51116-9
Linker Strategies In Solid-Phase
Organic Synthesis
Edited by
PETER J. H. SCOTT
University of Michigan, Ann Arbor, USA
A John Wiley and Sons, Ltd., Publication
Thiseditionfirstpublished2009
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LibraryofCongressCataloging-in-PublicationData
Scott,PeterJ.H.
Linkerstrategiesinsolid-phaseorganicsynthesis/PeterJ.HScott.
p.cm.
Includesbibliographicalreferencesandindex.
ISBN978-0-470-51116-9
1. Solid-phasesynthesis. I. Title.
QD262.S362009
547(cid:3).2−dc22
2009030808
AcataloguerecordforthisbookisavailablefromtheBritishLibrary.
ISBN:978-0-470-51116-9
Typesetin10/12ptTimesbyLaserwordsPrivateLimited,Chennai,India
PrintedandboundintheUnitedKingdombyAntonyRoweLtd,Chippenham,Wiltshire
Contents
Foreword xv
Preface xix
ListofContributors xxi
AbouttheEditor xxiii
Abbreviations xxv
I INTRODUCTION 1
1 General Overview 3
Scott L. Dax
1.1 Introduction, background and pivotal discoveries 3
1.2 Fundamentals of conducting solid-phase organic chemistry 9
1.2.1 Apparatus 9
1.2.2 Typical solid supports 10
1.2.3 Fluorous supports 12
1.2.4 Linker strategies 12
1.2.5 Challenges 17
1.2.6 Linker groups 18
1.3 Concluding comments 20
1.4 Personal perspective and testimony: solid-phase Mannich chemistry 21
References 22
II TRADITIONAL LINKER UNITS FOR SOLID-PHASE ORGANIC SYNTHESIS 25
2 Electrophile Cleavable Linker Units 27
Michio Kurosu
2.1 Introduction 27
2.2 Resins for use with electrophilic linkers 28
2.3 Electrophile cleavable linkers 30
2.3.1 Acid labile linkers 31
2.4 Conclusion 70
References 71
3 Nucleophile Cleavable Linker Units 77
Andrea Porcheddu and Giampaolo Giacomelli
3.1 Introduction 77
vi Contents
3.2 Linker units 78
3.3 Nucleophilic labile linker units 79
3.3.1 Cleavage by saponification or basic trans-esterification 80
3.3.2 Cleavage by aminolysis 86
3.3.3 Cleavage by hydrazinolysis 101
3.3.4 Cleavage by Hydroxylamines 105
3.3.5 Cleavage by other nucleophiles 109
3.3.6 Linker cleavage by intramolecular nucleophilic reaction 119
3.4 Conclusion 129
References 130
4 Cyclative Cleavage as a Solid-Phase Strategy 135
A. Ganesan
4.1 Introduction 135
4.2 C–N bond formation 137
4.2.1 Cyclopeptides and cyclodepsipeptides 138
4.2.2 Heterocycles, five-membered ring formation 139
4.2.3 Heterocycles, six- and seven-membered ring formation 142
4.3 C–O bond formation 145
4.4 C–C bond formation 146
4.5 Conclusion 148
References 148
5 Photolabile Linker Units 151
Christian Bochet and Se´bastien Mercier
5.1 Introduction 151
5.2 Linkers based on the ortho-nitrobenzyloxy function 151
5.3 Linkers based on the ortho-nitrobenzylamino function 158
5.4 Linkers based on the α-substituted ortho-nitrobenzyl group 161
5.5 Linkers based on the ortho-nitroveratryl group 165
5.6 Linkers based on the phenacyl group 173
5.7 Linkers based on the para-methoxyphenacyl group 176
5.8 Linkers based on the benzoin group 180
5.9 Linkers based on the pivaloyl group 184
5.10 Traceless linkers 187
5.11 Other types of photolabile linker units 187
5.12 Conclusion 188
References 191
6 Safety-Catch Linker Units 195
Sylvain Lebreton and Marcel Pa´tek
6.1 Introduction 195
6.2 Activation of a carbonyl group by the inductive effect (I–) of an adjacent substituent 196
6.2.1 Kenner-type safety-catch linker 196
6.2.2 N-boc-activated safety-catch linker 197
Contents vii
6.2.3 Sulfide/sulfone safety-catch linker 198
6.2.4 Dpr(phoc) safety-catch linker 199
6.3 Activation by the mesomeric effect (M-) of the –X–Y=Z moiety adjacent to a carbonyl
group 199
6.3.1 Carbonyl activation by oxidative aromatization 199
6.3.2 Carbonyl activation by indole ring formation 200
6.3.3 Benzyl/phenyl-hydrazide safety-catch linker 200
6.3.4 Dehydration activated safety-catch linker 202
6.4 Activation by the positive mesomeric effect (M+) of the –X–Y=Z moiety adjacent to a
N-acyl or O-alkyl group 202
6.4.1 Benzhydryl-based safety-catch linker 202
6.4.2 Indole-based safety-catch linker 203
6.4.3 Nitrobenzyl alcohol-based safety-catch linker 204
6.5 Aromatic S Ar substitution 205
N
6.6 Fragmentation by β-elimination 207
6.7 Safety-catch linker for release in aqueous buffers 208
6.7.1 Geysen safety-catch linker 208
6.7.2 Frank safety-catch linker 210
6.7.3 Lyttle safety-catch linker 210
6.7.4 Multiple cleavable linkers 211
6.8 Photochemical activation 212
6.9 Miscellaneous safety-catch linkers 213
6.9.1 Activation by reductive aromatization 213
6.9.2 Activation via intramolecular H-bonding 214
6.9.3 Activation by formation of an alkyne-cobalt complex 215
6.9.4 Activation by oxidation of arylsulfide for pummerer rearrangement 216
6.9.5 Activation by oxidative N-benzyl deprotection 217
6.9.6 Activation by thioether alkylation 218
6.10 Conclusion 219
References 219
7 Enzyme Cleavable Linker Units 221
Mallesham Bejugam and Sabine L. Flitsch
7.1 Introduction 221
7.2 Enzyme cleavable linker units 222
7.2.1 Exo linker units 222
7.2.2 Endo linker units 225
7.3 Conclusion 237
References 237
III MULTIFUNCTIONAL LINKER UNITS FOR DIVERSITY-ORIENTED SYNTHESIS 239
8 An Introduction to Diversity-Oriented Synthesis 241
Richard J. Spandl, Gemma L. Thomas, Monica Diaz-Gavilan, Kieron M. G. O’Connell
and David R. Spring
8.1 Introduction 241
viii Contents
8.2 Exploring chemical space 243
8.3 Sources of skeletally diverse small molecules 244
8.4 Enriching chemical space using DOS 244
8.5 The subjective nature of ‘Diversity’ 245
8.6 Differing strategies towards similar goals 246
8.6.1 DOS based on privileged scaffolds 246
8.6.2 DOS from simple starting materials 248
8.7 Generating skeletal diversity 248
8.7.1 Strategy 1: Pluripotent functional groups 249
8.7.2 Strategy 2: Pluripotent (densely functionalised) molecules 253
8.7.3 Strategy 3: Folding pathways 256
8.8 DOS and solid-phase organic synthesis 257
8.8.1 An overview of linkage cleavage strategies 258
8.8.2 Diversity linkers: A summary of the approaches used 259
8.9 Conclusion 260
References 260
9 T1 and T2 – Versatile Triazene Linker Groups 263
Kerstin Knepper and Robert E. Ziegert
9.1 Introduction 263
9.2 The T1 linker 264
9.2.1 The dibenzyl-type T1 resins 266
9.2.2 The piperazinyl-type T1 resins 278
9.3 The T2 linker units 282
9.3.1 The T2 Linker 282
∗
9.3.2 The T2 linker for synthesis 287
∗
9.3.3 The T2 scavenger resin 292
9.4 Miscellaneous triazene linkers 293
9.5 Conclusion 300
References 300
10 Hydrazone Linker Units 303
Ryszard Lazny
10.1 Introduction 303
10.2 Hydrazone linker units 303
10.3 Conclusion 312
References 314
11 Benzotriazole Linker Units 317
Daniel K. Whelligan
11.1 Introduction 317
11.2 Syntheses of polymer-supported benzotriazoles 318
11.2.1 Carbon–carbon tethered benzotriazoles 318
11.2.2 Ether tethered benzotriazoles 319
11.2.3 Amide tethered benzotriazoles 320
Contents ix
11.2.4 Ester tethered benzotriazoles 322
11.3 Polymer-supported benzotriazole linked reactions 322
11.3.1 Mannich-type reaction and cleavage 322
11.3.2 Enolate acylation 325
11.3.3 Urea synthesis 325
References 329
12 Diversity Cleavage Strategies from Phosphorus Linkers 331
Patrick G. Steel and Tom M. Woods
12.1 Introduction 331
12.2 Diversity cleavage through olefination reactions 332
12.2.1 Diversity cleavage through the Wittig reaction 332
12.2.2 Diversity cleavage using the Horner–Wadsworth–Emmons reaction 336
12.3 Diversity cleavage of enol phosphonates through palladium catalysed cross-coupling
reactions 338
12.4 Oxidative diversity cleavage of cyanophosphoranes 339
References 340
13 Sulfur Linker Units 343
Peter J. H. Scott
13.1 Introduction 343
13.2 Sulfide linker units 344
13.2.1 Introduction 344
13.2.2 Reductive traceless cleavage 345
13.2.3 Multifunctional cleavage via nucleophilic substitution reactions 347
13.2.4 Multifunctional cleavage via elimination reactions 350
13.3 Sulfonium Linker Units 351
13.4 Sulfoxide linker units 354
13.4.1 Introduction 354
13.4.2 Traceless cleavage 355
13.4.3 Multifunctional cleavage using the pummerer rearrangment 355
13.5 Sulfone linker units 358
13.5.1 Introduction 358
13.5.2 Reductive traceless cleavage 360
13.5.3 Multifunctional cleavage via elimination reactions 362
13.5.4 Multifunctional cleavage via nucleophilic substitution reactions 370
13.6 Sulfonate ester linker units 373
13.6.1 Introduction 373
13.6.2 Alkanesulfonate ester linker units 373
13.6.3 Perfluoralkanesulfonyl (PFS) linker units 378
13.6.4 Tetrafluoroarylsulfonyl linker units 381
13.7 Sulfamate linker units 383
13.8 Thioester linker units 385
13.9 Conclusions 387
References 387
x Contents
14 Selenium- and Tellurium-Based Linker Units 391
Tracy Yuen Sze Butand Patrick H. Toy
14.1 Introduction 391
14.2 Selenium- and tellurium-based linker group reagents and their syntheses 391
14.3 Selenium-based linker group attachment methods 398
14.3.1 Electrophilic attachment at selenium 398
14.3.2 Nucleophilic attachment at selenium 398
14.3.3 Radical attachment at selenium 402
14.3.4 Attachment at other positions 402
14.4 Selenium-based linker group cleavage methods 403
14.4.1 Oxidative cleavage 403
14.4.2 Nucleophilic displacement cleavage 410
14.4.3 Homolytic cleavage 411
14.4.4 Miscellaneous cleavage methods 415
14.5 Conclusions 415
References 416
15 Linker Units Cleaved by Radical Processes: Cleavage of Carbon-Sulfur, -Selenium,
-Tellurium, -Oxygen, -Nitrogen and -Carbon Linkers 419
Giuditta Guazzelli, Marc Miller and David J. Procter
15.1 Introduction 419
15.2 Linkers cleaved using tin hydride, alkyltin and silicon hydride reagents 420
15.2.1 Oxygen-based linkers 420
15.2.2 Sulfur-based linkers 421
15.2.3 Selenium-based linkers 421
15.2.4 Tellurium-based linkers 430
15.3 Linkers cleaved by oxidative electron-transfer 431
15.3.1 Ether and amine linkers cleaved by oxidative electron transfer 431
15.3.2 A homobenzylic ether linker cleaved by oxidative electron transfer 439
15.3.3 A sulfur linker cleaved by oxidative electron transfer with CAN 440
15.3.4 Safety-catch linkers cleaved by oxidative electron transfer 443
15.4 Linkers cleaved by reductive electron-transfer 447
15.4.1 N–O linkers cleaved using samarium(II) iodide 448
15.4.2 Sulfonamide linkers cleaved by reductive electron-transfer 450
15.4.3 Ether linkers cleaved using samarium(II) iodide 450
15.4.4 Alkyl and aryl sulfide/sulfone linkers cleaved by reductive electron-transfer 453
15.5 Radical processes that indirectly trigger linker cleavage 462
15.5.1 Nitro group reduction as a trigger for linker cleavage 462
15.5.2 Radical carbon–carbon bond formation as a trigger for linker cleavage 462
15.6 Conclusions 465
References 465
16 Silicon and Germanium Linker Units 467
Alan C. Spivey and Christopher M. Diaper
16.1 Introduction 467
16.2 Silicon-based linkers 468
Contents xi
16.2.1 The preparation of silyl resins 468
16.2.2 Activation of Si–H and Si–Aryl resins for substrate attachment 471
16.2.3 Silyl ether linkers 475
16.2.4 Fragmentation-based silyl linkers 479
16.2.5 Traceless/diversity silyl linkers 487
16.3 Germanium-based linkers 495
16.3.1 The preparation of germyl resins 496
16.3.2 Activation of Ge–Methyl and Ge–Aryl resins for substrate attachment 497
16.3.3 Traceless/diversity germyl linkers 498
16.4 Conclusions 500
References 501
17 Boron and Stannane Linker Units 505
Peter J. H. Scott
17.1 Introduction 505
17.2 Organostannane linker units 507
17.2.1 Introduction 507
17.2.2 Organostannane linker units 508
17.3 Organoboron linker units 511
17.3.1 Introduction 511
17.3.2 Diversity cleavage through suzuki–miyaura reactions 512
17.3.3 Alternative cleavage strategies from organoboron linkers 514
17.4 Conclusion 516
References 516
18 Bismuth Linker Units 519
Peter J. H. Scott
18.1 Introduction 519
18.2 Bismuth linker units 519
18.3 Conclusions 523
References 523
19 Transition Metal Carbonyl Linker Units 525
Susan E. Gibson and Amol A. Walke
19.1 Introduction 525
19.2 Chromium carbonyl linker units 525
19.3 Cobalt carbonyl linker units 533
19.4 Manganese carbonyl linker units 535
19.5 Conclusion 536
References 536
20 Linkers Releasing Olefins or Cycloolefins by Ring Closing Metathesis 537
Jan H. van Maarseveen
20.1 Introduction 537
