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

Patrick H. Toy (Editor), Yulin Lam (Editor)
ISBN: 978-1-118-14163-2
560 pages
January 2012
Solid-Phase Organic Synthesis: Concepts, Strategies, and Applications (1118141636) cover image
Presents both the fundamental concepts and the most recent applications in solid-phase organic synthesis

With its emphasis on basic concepts, Solid-Phase Organic Synthesis guides readers through all the steps needed to design and perform successful solid-phase organic syntheses. The authors focus on the fundamentals of heterogeneous supports in the synthesis of organic molecules, explaining the use of a solid material to facilitate organic synthesis. This comprehensive text not only presents the fundamentals, but also reviews the most recent research findings and applications, offering readers everything needed to conduct their own state-of-the-art science experiments.

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 linker groups 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. Readers will discover how solid-phase synthesis is currently used to facilitate the discovery of new molecular functionality. The final chapter discusses how using a support can change or increase reaction selectivity.

  • Part Two, Applications, presents examples of the solid-phase synthesis of various classes of organic molecules. Chapters explore general asymmetric synthesis on a support, strategies for heterocyclic synthesis, and synthesis of radioactive organic molecules, dyes, dendrimers, and oligosaccharides.

Each chapter ends with a set of conclusions that underscore the key concepts and methods. References in each chapter enable readers to investigate any topic in greater depth.

With its presentation of basic concepts as well as recent findings and applications, Solid-Phase Organic Synthesis is the ideal starting point for students and researchers in organic, medicinal, and combinatorial chemistry who want to take full advantage of current solid-phase synthesis techniques.

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Preface xv

Acknowledgments xvii

Contributors xix

Part I CONCEPTS AND STRATEGIES 1

1 LINKER STRATEGIES IN MODERN SOLID-PHASE ORGANIC SYNTHESIS 3
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 SYNTHESIS 95
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, and David R. Spring

4.1 Introduction 131

4.2 Small Molecules and Biology 131

4.3 Diversity-Oriented Synthesis, Target-Oriented Synthesis, and Combinatorial Chemistry 133

4.4 Molecular Diversity 134

4.5 Diversity-Oriented Synthesis on Solid Phase 137

4.6 Diversity-Oriented Synthesis Around Privileged Scaffolds 146

4.7 Diversity Linker Units in Solid-Phase Organic Synthesis 147

4.8 Conclusions 148

5 DIVERSITY-ORIENTED SYNTHESIS OF PRIVILEGED HETEROCYCLES USING DIVERGENT STRATEGY 151
Seung Bum Park and Jonghoon Kim

5.1 Introduction 151

5.2 Divergent Synthesis of Natural Product-Like Polyheterocycles Using a Cyclic Iminium as a Single Key Intermediate 153

5.3 Conclusions 168

6 CHEMO- AND REGIOSELECTIVITY ENHANCEMENT IN SOLID-SUPPORTED REACTIONS 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 Reactions 186

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-Supported Substrates 208

7.3 Asymmetric Transformations Using Resin-Bound Chiral Catalysts and Auxiliaries 219

7.4 Conclusions 227

8 RECENT ADVANCES IN MICROWAVE-ASSISTED SOLID-PHASE SYNTHESIS OF HETEROCYCLES 231
Prasad Appukkuttan, Vaibhav, P. Mehta, and Erik Van der Eycken

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 Linker 248

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 AMINO ACIDS 269
Zhi Li, Marc Giulianotti, Wenteng Chen, Richard A. Houghten, and Yongping Yu

9.1 Introduction 269

9.2 Synthesis of Various Heterocycles 269

10 GENERATION OF DRUG-LIKE FIVE-MEMBERED HETEROCYCLIC LIBRARIES USING 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 and 1,3,4-Triazoles via a Dithiocarbazate Linker 334

10.5 Solid-Phase Synthesis of 1,3,4-Oxadiazoles and 1,3,4-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 CYCLOADDITION REACTIONS 355
Kirsi Harju and Jari Yli-Kauhaluoma

11.1 Introduction 355

11.2 Solid-Phase Synthesis of Pyrrolidines, Pyrrolines, and Pyrroles 356

11.3 Synthesis of Pyrazolines and Pyrazoles 361

11.4 Solid-Phase Synthesis of Imidazoles, 1,2,4-Triazoles, and 1,2,3-Triazoles 364

11.5 Solid-Phase Synthesis of Isoxazolidines, Isoxazolines, and Isoxazoles 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 Radioisotopes 422

13.5 Conclusions 424

14 SOLID-PHASE SYNTHESIS OF DYES AND THEIR APPLICATION AS SENSORS AND BIOIMAGING PROBES 427
Marc Vendrell, Hyung-Ho Ha, Sung Chan Lee, and Young-Tae Chang

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 SYNTHESIS AND 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 TAG SUPPORTS 489
Katsunori Tanaka and Koichi Fukase

16.1 Introduction 489

16.2 Solid-Phase Methods for Synthesis of Oligosaccharides 490

16.3 Polymer-Supported and Tag-Assisted Oligosaccharide Synthesis in Solution 516

16.4 Conclusions 526

16.5 Acknowledgments 527

References 527

Index 531

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PATRICK H. TOY, PhD, is an Associate Professor in the Department of Chemistry at the University of Hong Kong, where he was recognized as an Outstanding Young Researcher. Dr. Toy's review of the Mitsunobu reaction is one of the most frequently downloaded articles ever published in Chemistry-An Asian Journal.

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

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