Solid–Phase Organic Synthesis: Concepts, Strategies, and Applications

Presents both the fundamental concepts and the most recentapplications in solid–phase organic synthesis

With its emphasis on basic concepts, Solid–Phase OrganicSynthesis guides readers through all the steps needed to designand perform successful solid–phase organic syntheses. The authorsfocus on the fundamentals of heterogeneous supports in thesynthesis of organic molecules, explaining the use of a solidmaterial to facilitate organic synthesis. This comprehensive textnot only presents the fundamentals, but also reviews the mostrecent research findings and applications, offering readerseverything needed to conduct their own state–of–the–art scienceexperiments.

Featuring chapters written by leading researchers in the field,Solid–Phase Organic Synthesis is divided into two parts:

Part One, Concepts and Strategies, discusses the linkergroups used to attach the synthesis substrate to the solid support,colorimetric tests to identify the presence of functional groups,combinatorial synthesis, and diversity–oriented synthesis. Readerswill discover how solid–phase synthesis is currently used tofacilitate the discovery of new molecular functionality. The finalchapter discusses how using a support can change or increasereaction selectivity.

Part Two, Applications, presents examples of thesolid–phase synthesis of various classes of organic molecules.Chapters explore general asymmetric synthesis on a support,strategies for heterocyclic synthesis, and synthesis of radioactiveorganic molecules, dyes, dendrimers, and oligosaccharides.

Each chapter ends with a set of conclusions that underscore thekey concepts and methods. References in each chapter enable readersto investigate any topic in greater depth.

With its presentation of basic concepts as well as recentfindings and applications, Solid–Phase Organic Synthesis isthe ideal starting point for students and researchers in organic,medicinal, and combinatorial chemistry who want to take fulladvantage of current solid–phase synthesis techniques.

Preface xv

Acknowledgments xvii

Contributors xix

Part I CONCEPTS AND STRATEGIES 1

1 LINKER STRATEGIES IN MODERN SOLID–PHASE ORGANIC SYNTHESIS3
Peter J. H. Scott

1.1 Introduction 3

1.2 Classical Linker Strategies 5

1.3 Multifunctional Linker Strategies 28

1.4 Conclusions 73

2 COLORIMETRIC TEST FOR SOLID–PHASE ORGANIC SYNTHESIS 83
Yan Teng and Patrick H. Toy

2.1 Introduction 83

2.2 Functional Group Tests 84

2.3 Conclusions 92

3 PRACTICAL ASPECTS OF COMBINATORIAL SOLID–PHASE SYNTHESIS95
Jan Hlavac, Miroslav Soural, and Viktor Krchnak

3.1 Introduction 95

3.2 Strategies in Combinatorial Solid–Phase Synthesis 101

3.3 Equipment and Instrumentation 112

3.4 Characterization and Purification 118

3.5 Conclusions 121

4 DIVERSITY–ORIENTED SYNTHESIS 131
Kieron M. G. O′Connell, Warren R. J. D Galloway, Brett M.Ibbeson, Albert Isidro–Llobet, Cornelius J. O Connor, andDavid R. Spring

4.1 Introduction 131

4.2 Small Molecules and Biology 131

4.3 Diversity–Oriented Synthesis, Target–Oriented Synthesis, andCombinatorial Chemistry 133

4.4 Molecular Diversity 134

4.5 Diversity–Oriented Synthesis on Solid Phase 137

4.6 Diversity–Oriented Synthesis Around Privileged Scaffolds146

4.7 Diversity Linker Units in Solid–Phase Organic Synthesis147

4.8 Conclusions 148

5 DIVERSITY–ORIENTED SYNTHESIS OF PRIVILEGED HETEROCYCLES USINGDIVERGENT STRATEGY 151
Seung Bum Park and Jonghoon Kim

5.1 Introduction 151

5.2 Divergent Synthesis of Natural Product–Like PolyheterocyclesUsing a Cyclic Iminium as a Single Key Intermediate 153

5.3 Conclusions 168

6 CHEMO– AND REGIOSELECTIVITY ENHANCEMENT IN SOLID–SUPPORTEDREACTIONS 171
Douglas D. Young and Alexander Deiters

6.1 Introduction 171

6.2 Transition Metal–Mediated Solid–Supported Reactions 172

6.3 Non–transition Metal–Mediated Solid–Supported Reactions186

6.4 Traceless Cleavage 192

6.5 Conclusions 201

Part II Applications 205

7 ASYMMETRIC SYNTHESIS ON SOLID SUPPORT 207
Baburaj Baskar and Kamal Kumar

7.1 Introduction 207

7.2 Asymmetric Chemical Transformations of Solid–SupportedSubstrates 208

7.3 Asymmetric Transformations Using Resin–Bound ChiralCatalysts and Auxiliaries 219

7.4 Conclusions 227

8 RECENT ADVANCES IN MICROWAVE–ASSISTED SOLID–PHASE SYNTHESIS OFHETEROCYCLES 231
Prasad Appukkuttan, Vaibhav, P. Mehta, and Erik Van derEycken

8.1 Introduction 231

8.2 Fused 1,3–oxazin–6–ones 232

8.3 Thiazolo[4,5–d]pyrimidine–5,7–diones 233

8.4 Pyrazoles 234

8.5 HSP70 Modulators 234

8.6 Benzimidazo[2,1–b]quinazolin–12(5H)–ones 236

8.7 Imidazoles 237

8.8 1,4–Naphthoquinones 238

8.9 Phthalocyanines 238

8.10 1,2,3,4–Tetrahydroquinolines 242

8.11 1,2,3–Triazoles 243

8.12 2,8–Diaminopurines 244

8.13 Imidazolidin–4–ones 245

8.14 Indoles 247

8.15 1,2,3,4–Tetrahydroquinolines Using a SmI2–Cleavable Linker248

8.16 Hydantoins 249

8.17 Imatinib 250

8.18 Isoindolines 252

8.19 2–(Benzylthio)imidazo[1,2a]–pyrimidin–5–ones 253

8.20 2–Aminobenzothiazoles 254

8.21 Pyrimidines, Pyrazoles, and Isoxazoles 255

8.22 Quinolin–2(1H)–ones and Coumarins 256

8.23 Benzofurans 257

8.24 i–Condensed Purines 258

8.25 2(1H)–Pyrazinones 259

8.26 Conclusions 260

References 261

9 SOLID–PHASE SYNTHESIS OF HETEROCYCLES FROM PEPTIDES AND AMINOACIDS 269
Zhi Li, Marc Giulianotti, Wenteng Chen, Richard A. Houghten, andYongping Yu

9.1 Introduction 269

9.2 Synthesis of Various Heterocycles 269

10 GENERATION OF DRUG–LIKE FIVE–MEMBERED HETEROCYCLIC LIBRARIESUSING CARBON DISULFIDE AND MERRIFIELD RESIN 319
Young–Dae Gong and Taeho Lee

10.1 Introduction 319

10.2 Solid–Phase Synthesis of Related Thiazole Compounds 320

10.3 Solid–Phase Synthesis of Benzoxazoles 333

10.4 Solid–Phase Synthesis of Related Pyrazole Compounds and1,3,4–Triazoles via a Dithiocarbazate Linker 334

10.5 Solid–Phase Synthesis of 1,3,4–Oxadiazoles and1,3,4–Thiadiazoles via Selective Cyclization 342

10.6 Solid–Phase Synthesis of 1,2,4–Thiadiazoles 347

10.7 Summary 350

11 RECENT ADVANCES IN SOLID–PHASE 1,3–DIPOLAR CYCLOADDITIONREACTIONS 355
Kirsi Harju and Jari Yli–Kauhaluoma

11.1 Introduction 355

11.2 Solid–Phase Synthesis of Pyrrolidines, Pyrrolines, andPyrroles 356

11.3 Synthesis of Pyrazolines and Pyrazoles 361

11.4 Solid–Phase Synthesis of Imidazoles, 1,2,4–Triazoles, and1,2,3–Triazoles 364

11.5 Solid–Phase Synthesis of Isoxazolidines, Isoxazolines, andIsoxazoles 369

11.6 Conclusions 378

12 SULFONES IN SOLID–PHASE HETEROCYCLE SYNTHESIS 383
Chai Hoon Soh and Yulin Lam

12.1 Introduction 383

12.2 Linkers 384

12.3 Conclusions 411

13 SOLID–PHASE ORGANIC RADIOSYNTHESIS 415
Raphael Hoareau and Peter J. H. Scott

13.1 Introduction 415

13.2 Solid–Phase Organic Radiosynthesis with Fluorine–18 416

13.3 Solid–Phase Organic Radiosynthesis with Carbon–11 421

13.4 Solid–Phase Organic Radiosynthesis with Other Radioisotopes422

13.5 Conclusions 424

14 SOLID–PHASE SYNTHESIS OF DYES AND THEIR APPLICATION ASSENSORS AND BIOIMAGING PROBES 427
Marc Vendrell, Hyung–Ho Ha, Sung Chan Lee, and Young–TaeChang

14.1 Introduction 427

14.2 On–Bead Sensors 428

14.3 Solid–Phase Approaches in Fluorescent Labeling 429

14.4 Solid–Phase Derivatization of Fluorescent Scaffolds 430

14.5 Diversity–Oriented Fluorescent Libraries 433

14.6 Conclusions 437

14.7 Acknowledgments 437

15 DENDRITIC MOLECULES ON SOLID SUPPORT: SOLID–PHASE SYNTHESISAND APPLICATIONS 441
Kerem Goren and Moshe Portnoy

15.1 Introduction 441

15.2 Synthesis 442

15.3 Applications of Dendronized Supports 464

15.4 Conclusions 480

16 OLIGOSACCHARIDE SYNTHESIS ON SOLID, SOLUBLE POLYMER, AND TAGSUPPORTS 489
Katsunori Tanaka and Koichi Fukase

16.1 Introduction 489

16.2 Solid–Phase Methods for Synthesis of Oligosaccharides490

16.3 Polymer–Supported and Tag–Assisted OligosaccharideSynthesis in Solution 516

16.4 Conclusions 526

16.5 Acknowledgments 527

References 527

Index 531

PATRICK H. TOY, PhD, is an Associate Professor in theDepartment of Chemistry at the University of Hong Kong, where hewas recognized as an Outstanding Young Researcher. Dr. Toy′s reviewof the Mitsunobu reaction is one of the most frequently downloadedarticles ever published in Chemistry–An Asian Journal.

YULIN LAM, PhD, is an Associate Professor in theDepartment of Chemistry at the National University of Singapore.Dr. Lam is a reviewer for several major journals and is anEditorial Advisory Board member of ACS Combinatorial Science.