Handbook of Metathesis, Volume 2 E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 981

Veröffentlichungsjahr: 2015

Beschreibung

The second edition of the "go-to" reference in this field is completely updated and features more than 80% new content, with emphasis on new developments in the field, especially in industrial applications. No other book
covers the topic in such a comprehensive manner and in such high quality.

Edited by the Nobel laureate R. H. Grubbs and D. J. O´Leary, Volume 2 of the 3-volume work focusses on applications in organic synthesis. With a list of contributors that reads like a "Who's-Who" of metathesis, this is an
indispensable one-stop reference for chemists in academia and industry.

View the set here - http://www.wiley.com/WileyCDA/WileyTitle/productCd-3527334246.html

Other available volumes:

Volume 1: Catalyst Development and Mechanism, Editors: R. H. Grubbs and A. G. Wenzel - http://www.wiley.com/WileyCDA/WileyTitle/productCd-3527339485.html

Volume 3: Polymer Synthesis, Editors: R. H. Grubbs and E. Khosravi - http://www.wiley.com/WileyCDA/WileyTitle/productCd-3527339507.html

Leseprobe

Table of Contents

Cover

Title Page

Copyright

Preface

List of Contributors

List of Abbreviations

Chapter 1: General Ring-Closing Metathesis

1.1 Introduction

1.2 Carbocycles (Introduction)

1.3 Synthesis of Bridged Bicycloalkenes

1.4 Synthesis of Heterocycles Containing Si, P, S, or B

1.5 Synthesis of O-Heterocycles

1.6 Synthesis of N-Heterocycles

1.7 Synthesis of Cyclic Conjugated Dienes

1.8 Alkyne Metathesis

1.9 Enyne Metathesis

1.10 Tandem Processes

1.11 Synthesis of Macrocycles

1.12 RCM and Isomerization via Ru-H

1.13 Relay RCM (RRCM)

1.14

Z

-Selective RCM

1.15 Enantioselective RCM

1.16 Conclusion

1.17 Acknowledgments

References

Chapter 2: Cross-Metathesis

2.1 Early Examples Using Well-Defined Molybdenum and Ruthenium Catalysts

2.2 The General Model for Selectivity in CM Reactions

2.3 Definition of Cross-Metathesis Reaction Categories and Chapter Organization

2.4 Hydrocarbons

2.5 Boron

2.6 Nitrogen

2.7 Oxygen

2.8 Halides

2.9 Phosphorus

2.10 Sulfur

2.11 Fragment Coupling Reactions

2.12 Conclusions

References

Chapter 3: Vignette: Extending the Application of Metathesis in Chemical Biology – The Development of Site-Selective Peptide and Protein Modifications

3.1 Introduction

3.2 Cross-Metathesis Methodology Studies in Aqueous Media

3.3 Strategies for Allyl Chalogenide Incorporation into Proteins

3.4 Olefin Metathesis on Proteins

3.5 Outlook

References

Chapter 4: Ruthenium-Catalyzed Tandem Metathesis/Non-Metathesis Processes

4.1 Introduction

4.2 Metathesis/Isomerization

4.3 Metathesis/Hydrogenation

4.4 Metathesis/Oxidation

4.5 Metathesis/Cyclization

4.6 Metathesis/Atom-Transfer Radical Addition

4.7 Metathesis/Rearrangement

4.8 Metathesis/Cyclopropanation

4.9 Metathesis/Miscellaneous

4.10 Conclusions

References

Chapter 5: Enyne Metathesis

5.1 Introduction

5.2 Enyne Metathesis

5.3 Strategic Application of Enyne Metathesis in Organic Synthesis

5.4 Perspective

References

Chapter 6: Alkyne Metathesis

6.1 Introduction

6.2 Background Information

6.3 Molybdenum Alkylidyne Catalysts with Silanolate Ligands

6.4 Other Catalytically Active Molybdenum Alkylidyne Complexes

6.5 Novel Tungsten Alkylidyne Catalysts

6.6 Basic Types of Applications

6.7 Selected Applications

6.8 Conclusions

References

Chapter 7: Catalyst-Controlled Stereoselective Olefin Metathesis

7.1 Introduction

7.2 Enantioselective Ring-Opening/Cross-Metathesis (EROCM)

7.3 Enantioselective Ring-Opening/Ring-Closing Metathesis (ERORCM)

7.4 Enantioselective Ring-Closing Metathesis (ERCM)

7.5

Z

-Selective Olefin Metathesis Reactions with Mo- and W-Based Complexes

7.6

Z

-Selective Olefin Metathesis Reactions with Ru Complexes

7.7

Z

-Selective Ring-Opening Metathesis Polymerization

7.8 Conclusions and Outlook

Acknowledgments

References

Chapter 8: Two Vignettes: RCM in Natural Product Total Synthesis

8.1 Vignette 1: Allylsilane RCM/Electrophilic Desilylation as a Means to Access Rings with Exocyclic Alkenes

8.2 Vignette 2: Synthesis of Antimetastatic Agents Using Ring-Closing Metathesis

References

Chapter 9: Metathesis of Silicon-Containing Olefins

9.1 Introduction

9.2 Homo and Cross-Metathesis versus Silylative Coupling of Vinylsilicon Compounds

9.3 Homometathesis of Allylsilanes and Their Cross-Metathesis with Olefins

9.4 Silylative Coupling versus Cross-Metathesis of Vinylsilanes in Sequential Synthesis of Functionalized Alkenes

9.5 Silylative Coupling Cyclization of Silicon-Containing Dienes

9.6 Ring-Closing Metathesis of Silicon-Containing Dienes

9.7 Acyclic Diene Metathesis (ADMET) versus Silylative Coupling (SC) Polycondensation of Silicon-Containing Dienes

9.8 Ring-Opening Metathesis Polymerization of Silyl-Substituted Cycloalkenes

References

Chapter 10: Ring-Closing Metathesis in the Large-Scale Synthesis of Pharmaceuticals

10.1 Introduction

10.2 Ciluprevir (BILN2061) and Analogs

10.3 Vaniprevir (MK-7009)

10.4 Simeprevir (TMC435)

10.5 SB-462795

10.6 Approaches to the Scale-Up of RCM Reactions

References

Chapter 11: Metathesis Strategies in Diversity-Oriented Synthesis

11.1 Introduction

11.2 Synthesis of Small- to Medium-Sized Rings via Metathesis Strategies

11.3 Synthesis of Macrocycles via Metathesis Strategies

11.4 Metathesis Cascade Strategies in Diversity-Oriented Synthesis

11.5 Synthesis of Small- to Medium-Sized Rings via Metathesis Cascade Strategies

11.6 Synthesis of Macrocycles via Metathesis Cascade Strategies

11.7 Metathesis Strategies in Solid-Phase Library Synthesis

11.8 Immobilized Scavengers and Catalysts

11.9 Conclusions

Acknowledgments

References

Chapter 12: Olefin Metathesis: Commercial Applications and Future Opportunities

12.1 Introduction

12.2 Ruthenium Olefin Metathesis Catalysts

12.3 Renewable Seed Oil Feedstocks

12.4 Production of Fatty acids and Amino Acids from Renewables

12.5 Olefin Metathesis and Natural Materials Chemistry

12.6 Pharmaceutical Applications

12.7 ROMP-Derived Oligomers for Facilitated Synthesis

12.8 Conclusion

References

Index

End User License Agreement

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Guide

Cover

Table of Contents

Preface

Begin Reading

List of Illustrations

Figure 1.1

Scheme 1.1

Scheme 1.2

Scheme 1.3

Scheme 1.4

Scheme 1.5

Scheme 1.6

Scheme 1.7

Scheme 1.8

Scheme 1.9

Scheme 1.10

Scheme 1.11

Scheme 1.12

Scheme 1.13

Scheme 1.14

Scheme 1.15

Scheme 1.16

Scheme 1.17

Scheme 1.18

Scheme 1.19

Scheme 1.20

Scheme 1.21

Scheme 1.22

Scheme 1.23

Scheme 1.24

Scheme 1.25

Scheme 1.26

Scheme 1.27

Scheme 1.28

Scheme 1.29

Scheme 1.30

Scheme 1.31

Scheme 1.32

Scheme 1.33

Scheme 1.34

Scheme 1.35

Scheme 1.36

Scheme 1.37

Scheme 1.38

Scheme 1.39

Scheme 1.40

Scheme 1.41

Scheme 1.42

Scheme 1.43

Scheme 1.44

Scheme 1.45

Scheme 1.46

Scheme 1.47

Scheme 1.48

Scheme 1.49

Scheme 1.50

Scheme 1.51

Scheme 1.52

Scheme 1.53

Scheme 1.54

Scheme 1.55

Scheme 1.56

Scheme 1.57

Scheme 1.58

Scheme 1.59

Scheme 1.60

Scheme 1.61

Scheme 1.62

Scheme 1.63

Scheme 1.64

Scheme 1.65

Scheme 1.66

Scheme 1.67

Scheme 1.68

Scheme 1.69

Scheme 1.70

Scheme 1.71

Scheme 1.72

Scheme 1.73

Scheme 1.74

Scheme 1.75

Scheme 1.76

Scheme 1.77

Scheme 1.78

Scheme 1.79

Scheme 1.80

Scheme 1.81

Scheme 1.82

Scheme 1.83

Scheme 1.84

Scheme 1.85

Scheme 1.86

Scheme 1.87

Scheme 1.88

Scheme 1.89

Scheme 1.90

Scheme 1.91

Scheme 1.92

Scheme 1.93

Scheme 1.94

Scheme 1.95

Scheme 1.96

Scheme 1.97

Scheme 1.98

Scheme 1.99

Scheme 1.100

Scheme 1.101

Scheme 1.102

Scheme 1.103

Scheme 1.104

Scheme 1.105

Scheme 1.106

Scheme 1.107

Scheme 1.108

Scheme 1.109

Scheme 1.110

Scheme 1.111

Scheme 1.112

Scheme 1.113

Scheme 1.114

Scheme 1.115

Scheme 1.116

Scheme 1.117

Scheme 1.118

Scheme 1.119

Scheme 1.120

Scheme 1.121

Scheme 1.122

Scheme 1.123

Scheme 1.124

Scheme 1.125

Scheme 1.126

Scheme 1.127

Scheme 1.128

Scheme 1.129

Scheme 1.130

Scheme 1.131

Scheme 1.132

Scheme 1.133

Scheme 1.134

Scheme 1.135

Scheme 1.136

Scheme 1.137

Scheme 1.138

Scheme 1.139

Scheme 1.140

Scheme 1.141

Scheme 1.142

Scheme 1.143

Scheme 1.144

Scheme 1.145

Scheme 1.146

Scheme 1.147

Scheme 1.148

Scheme 1.149

Scheme 1.150

Scheme 1.151

Scheme 1.152

Scheme 1.153

Scheme 1.154

Scheme 1.155

Scheme 1.156

Scheme 1.157

Scheme 1.158

Scheme 1.159

Scheme 1.160

Scheme 1.161

Scheme 1.162

Scheme 1.163

Scheme 1.164

Scheme 1.165

Scheme 1.166

Figure 2.1

Figure 2.2

Figure 2.3

Scheme 2.1

Scheme 2.2

Scheme 2.3

Scheme 2.4

Scheme 2.5

Scheme 2.6

Scheme 2.7

Scheme 2.8

Scheme 2.9

Scheme 2.10

Scheme 2.11

Scheme 2.12

Scheme 2.13

Scheme 2.14

Scheme 2.15

Scheme 2.16

Scheme 2.17

Scheme 2.18

Scheme 2.19

Scheme 2.20

Scheme 2.21

Scheme 2.22

Scheme 2.23

Scheme 2.24

Scheme 2.25

Scheme 2.26

Scheme 2.27

Scheme 2.28

Scheme 2.29

Scheme 2.30

Scheme 2.31

Scheme 2.32

Scheme 2.33

Scheme 2.34

Scheme 2.35

Scheme 2.36

Scheme 2.37

Scheme 2.38

Scheme 2.39

Scheme 2.40

Scheme 2.41

Scheme 2.42

Scheme 2.43

Scheme 2.44

Scheme 2.45

Scheme 2.46

Scheme 2.47

Scheme 2.48

Scheme 2.49

Scheme 2.50

Scheme 2.51

Scheme 2.52

Scheme 2.53

Scheme 2.54

Scheme 2.55

Scheme 2.56

Scheme 2.57

Scheme 2.58

Scheme 3.1

Scheme 3.2

Scheme 3.3

Scheme 3.4

Scheme 3.5

Scheme 3.6

Scheme 3.7

Scheme 3.8

Scheme 3.9

Scheme 3.10

Scheme 3.11

Scheme 3.12

Scheme 3.13

Figure 4.1

Scheme 4.1

Scheme 4.2

Scheme 4.3

Scheme 4.4

Scheme 4.5

Scheme 4.6

Scheme 4.7

Scheme 4.8

Scheme 4.9

Scheme 4.10

Scheme 4.11

Scheme 4.12

Scheme 4.13

Scheme 4.14

Scheme 4.15

Scheme 4.16

Scheme 4.17

Scheme 4.18

Scheme 4.19

Scheme 4.20

Scheme 4.21

Scheme 4.22

Scheme 4.23

Scheme 4.24

Scheme 4.25

Scheme 4.26

Scheme 4.27

Scheme 4.28

Scheme 4.29

Scheme 4.30

Scheme 4.31

Scheme 4.32

Scheme 4.33

Scheme 4.34

Scheme 4.35

Scheme 4.36

Scheme 4.37

Scheme 4.38

Scheme 4.39

Scheme 4.40

Scheme 4.41

Scheme 4.42

Scheme 4.43

Scheme 4.44

Scheme 4.45

Scheme 4.46

Scheme 4.47

Scheme 5.1

Scheme 5.2

Scheme 5.3

Scheme 5.4

Figure 5.1

Scheme 5.5

Scheme 5.6

Scheme 5.7

Scheme 5.8

Scheme 5.9

Scheme 5.10

Scheme 5.11

Scheme 5.12

Scheme 5.13

Scheme 5.14

Scheme 5.15

Scheme 5.16

Scheme 5.17

Scheme 5.18

Scheme 5.19

Scheme 5.20

Scheme 5.21

Scheme 5.22

Scheme 5.23

Scheme 5.24

Scheme 5.25

Scheme 5.26

Scheme 5.27

Scheme 5.28

Scheme 5.29

Scheme 5.30

Scheme 5.31

Scheme 5.32

Scheme 5.33

Scheme 5.34

Scheme 5.35

Scheme 5.36

Scheme 5.37

Scheme 5.38

Scheme 5.39

Scheme 5.40

Scheme 5.41

Scheme 5.42

Scheme 5.43

Scheme 5.44

Scheme 5.45

Scheme 5.46

Scheme 5.47

Scheme 5.48

Scheme 5.49

Scheme 5.50

Scheme 5.51

Scheme 5.52

Scheme 5.53

Scheme 5.54

Scheme 5.55

Scheme 5.56

Scheme 5.57

Scheme 5.58

Scheme 5.59

Scheme 5.60

Scheme 5.61

Scheme 5.62

Scheme 5.63

Scheme 5.64

Scheme 5.65

Scheme 5.66

Scheme 5.67

Scheme 5.68

Scheme 5.69

Scheme 5.70

Scheme 5.71

Scheme 5.72

Scheme 5.73

Scheme 5.74

Scheme 5.75

Scheme 5.76

Scheme 5.77

Scheme 5.78

Scheme 5.79

Scheme 5.80

Scheme 5.81

Scheme 5.82

Scheme 5.83

Scheme 5.84

Scheme 5.85

Scheme 5.86

Scheme 5.87

Scheme 5.88

Scheme 5.89

Scheme 5.90

Scheme 5.91

Scheme 5.92

Scheme 5.93

Scheme 5.94

Scheme 5.95

Scheme 5.96

Scheme 5.97

Scheme 5.98

Scheme 5.99

Scheme 5.100

Scheme 5.101

Scheme 5.102

Scheme 5.103

Scheme 5.104

Scheme 5.105

Scheme 5.106

Scheme 5.107

Scheme 5.108

Scheme 5.109

Scheme 5.110

Scheme 5.111

Scheme 5.112

Scheme 5.113

Scheme 5.114

Scheme 5.115

Scheme 6.1

Scheme 6.2

Figure 6.1

Scheme 6.3

Figure 6.2

Figure 6.3

Scheme 6.4

Scheme 6.5

Scheme 6.6

Scheme 6.7

Scheme 6.8

Figure 6.4

Scheme 6.9

Figure 6.5

Scheme 6.10

Figure 6.6

Scheme 6.11

Scheme 6.12

Scheme 6.13

Scheme 6.14

Scheme 6.15

Scheme 6.16

Scheme 6.17

Scheme 6.18

Scheme 6.19

Scheme 6.20

Scheme 6.21

Scheme 6.22

Scheme 6.23

Scheme 6.24

Scheme 6.25

Scheme 6.26

Scheme 6.27

Scheme 6.28

Scheme 6.29

Scheme 6.30

Scheme 6.31

Scheme 6.32

Scheme 6.33

Scheme 6.34

Scheme 6.35

Scheme 6.36

Scheme 6.37

Scheme 7.1

Scheme 7.2

Scheme 7.3

Scheme 7.4

Scheme 7.5

Scheme 7.6

Scheme 7.7

Scheme 7.8

Scheme 7.9

Scheme 7.10

Scheme 7.11

Scheme 7.12

Scheme 7.13

Scheme 7.14

Scheme 7.15

Scheme 7.16

Scheme 7.17

Scheme 7.18

Scheme 7.19

Scheme 7.20

Scheme 7.21

Scheme 7.22

Scheme 7.23

Scheme 7.24

Scheme 7.25

Scheme 7.26

Scheme 7.27

Scheme 7.28

Scheme 7.29

Scheme 7.30

Scheme 7.31

Scheme 7.32

Scheme 7.33

Scheme 7.34

Scheme 7.35

Scheme 7.36

Scheme 7.37

Figure 8.1

Scheme 8.1

Scheme 8.2

Figure 8.2

Figure 8.3

Figure 8.4

Scheme 8.3

Scheme 8.4

Scheme 8.5

Scheme 8.6

Scheme 8.7

Scheme 8.8

Scheme 8.9

Scheme 8.10

Scheme 8.11

Scheme 8.12

Scheme 8.13

Figure 9.1

Scheme 9.1

Scheme 9.2

Scheme 9.3

Figure 9.2

Scheme 9.4

Scheme 9.5

Scheme 9.6

Scheme 9.7

Scheme 9.8

Scheme 9.9

Scheme 9.10

Scheme 9.11

Figure 9.3

Scheme 9.12

Figure 9.4

Figure 9.5

Figure 9.6

Figure 9.7

Figure 9.8

Figure 10.1

Scheme 10.1

Scheme 10.2

Scheme 10.3

Scheme 10.4

Scheme 10.5

Scheme 10.6

Scheme 10.7

Figure 10.8

Scheme 10.9

Scheme 10.10

Scheme 10.11

Scheme 10.12

Scheme 10.13

Scheme 10.14

Scheme 10.15

Scheme 10.16

Scheme 10.17

Scheme 10.18

Scheme 10.19

Scheme 10.20

Scheme 10.21

Figure 11.1

Scheme 11.1

Scheme 11.2

Scheme 11.3

Scheme 11.4

Scheme 11.5

Scheme 11.6

Scheme 11.7

Scheme 11.8

Scheme 11.9

Scheme 11.10

Figure 11.2

Scheme 11.11

Scheme 11.12

Scheme 11.13

Scheme 11.14

Scheme 11.15

Scheme 11.16

Scheme 11.17

Scheme 11.18

Scheme 11.19

Scheme 11.20

Scheme 11.21

Scheme 11.22

Scheme 11.23

Scheme 11.24

Scheme 11.25

Scheme 11.26

Scheme 11.27

Scheme 11.28

Scheme 11.29

Scheme 11.30

Scheme 11.31

Scheme 11.32

Scheme 11.33

Scheme 11.34

Figure 11.3

Figure 11.4

Figure 12.1

Figure 12.2

Figure 12.3

Scheme 12.1

Scheme 12.2

Scheme 12.3

Scheme 12.4

Scheme 12.5

Scheme 12.6

Scheme 12.7

Scheme 12.8

Figure 12.4

Scheme 12.9

Scheme 12.10

Scheme 12.11

Scheme 12.12

Figure 12.5

Figure 12.6

Scheme 12.13

Scheme 12.14

Scheme 12.15

Scheme 12.16

Scheme 12.17

Scheme 12.18

Scheme 12.19

List of Tables

Table 2.1

Table 2.2

Table 2.3

Table 2.4

Table 2.5

Table 2.6

Table 2.7

Table 2.8

Table 2.9

Table 2.10

Table 2.11

Table 2.12

Table 2.13

Table 2.14

Table 2.15

Table 2.16

Table 2.17

Table 2.18

Table 2.19

Table 2.20

Table 2.21

Table 2.22

Table 2.23

Table 2.24

Table 2.25

Table 2.26

Table 2.27

Table 2.28

Table 2.29

Table 2.30

Table 2.31

Table 2.32

Table 2.33

Table 2.34

Table 2.35

Table 2.36

Table 2.37

Table 2.38

Table 2.39

Table 2.40

Table 2.41

Table 2.42

Table 2.43

Table 2.44

Table 2.45

Table 46

Table 48

Table 4.1

Table 4.2

Table 4.3

Table 4.4

Table 4.5

Table 4.6

Table 4.7

Table 4.8

Table 4.9

Table 4.10

Table 4.11

Table 4.12

Table 4.13

Table 4.14

Table 4.15

Table 4.16

Table 4.17

Table 4.18

Table 4.19

Table 4.20

Table 4.21

Table 4.22

Table 4.23

Table 4.24

Table 4.25

Table 4.26

Table 4.27

Table 4.28

Table 4.29

Table 4.30

Table 4.31

Table 4.32

Table 4.33

Table 4.34

Table 4.35

Table 4.36

Table 4.37

Table 4.38

Table 4.39

Table 4.40

Table 4.41

Table 4.42

Table 4.43

Table 4.44

Table 4.45

Table 4.46

Table 4.47

Table 4.48

Table 4.49

Table 4.50

Table 4.51

Table 4.52

Table 6.1

Table 6.2

Table 6.3

Table 6.4

Table 6.5

Table 7.1

Table 7.2

Table 7.3

Table 7.4

Table 8.1

Table 12.1

Table 12.2

Table 12.3

Table 12.4

Edited by Robert H. Grubbs and Daniel J. O'Leary

Handbook of Metathesis

Volume 2: Applications in Organic Synthesis

Second Edition

Editors

Prof. Robert H. Grubbs

California Inst. of Technology

Div. Chem. and Chemical Eng.

1200 E. California Blvd

Pasadena, CA 91125

United States

Prof. Daniel J. O'Leary

Pomona College

Dept. of Chemistry

645 North College Avenue

Claremont, CA 91711

United States

Handbook of Metathesis

Second Edition

Set ISBN (3 Volumes): 978-3-527-33424-7

oBook ISBN: 978-3-527-67410-7

Vol 1: Catalyst Development and Mechanism, Editors: R. H. Grubbs and A. G. Wenzel ISBN: 978-3-527-33948-8

Vol 3: Polymer Synthesis, Editors: R. H. Grubbs and E. Khosravi ISBN: 978-3-527-33950-1

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

Library of Congress Card No.: applied for

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A catalogue record for this book is available from the British Library.

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Print ISBN: 978-3-527-33949-5

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ePub ISBN: 978-3-527-69404-4

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Preface

In 2003, the first edition of the Handbook of Metathesis comprehensively covered the origins of the olefin metathesis reaction and the myriad of applications blossoming from the development of robust, homogeneous transition-metal catalysts. In the intervening 10 years, applications and advances in this field have continued to exponentially increase. To date, 3732 publications regarding olefin metathesis have been reported; of these, 2292 have been reported since 2003!1 By 2005, olefin metathesis had become so integral to the field of organic synthesis that the Nobel Prize in Chemistry was awarded to the field (Yves Chauvin, Robert H. Grubbs, and Richard R. Schrock) [1, 2].

In light of these many advancements, a second edition of the Handbook is quite timely. Early on in the planning, it was decided that rather than simply updating the 2003 edition, the second edition would instead emphasize important advancements (e.g., new ligands, diastereoselective metathesis, alkyne metathesis, industrial applications, self-healing polymers) that have occurred during the past decade. In addition, the past 10 years have seen important developments in our understanding of the metathesis mechanism utilizing both computational and mechanistic studies. A greater knowledge of catalyst decomposition, product purification, and the use of supported catalysts and nontraditional reaction media have further enhanced the utility of metathesis systems. A number of new applications are now becoming commercialized based on these new catalyst systems. For example, the first pharmaceutical that uses olefin metathesis in a key step is now commercially available, and a biorefinery that utilizes a homogeneous catalyst is now in production.

Similar to the first edition of this Handbook, contributions have been arranged into three volumes. Volume I (Anna Wenzel, coeditor) emphasizes recent catalyst developments and mechanism and is intended to provide a foundation for the applications discussed throughout the rest of the Handbook. Volume II (Dan O'Leary, coeditor) covers synthetic applications of the olefin metathesis reaction, and polymer chemistry is the topic of Volume III (Ezat Khosravi, coeditor). Chapter topics have been selected to provide comprehensive coverage of these areas of olefin metathesis. Contributors, many of whom are pioneers in the field, were chosen based on their firsthand experience with the topics discussed.

We wish to sincerely thank all the contributors for their diligence in writing and editing their chapters. Our goal was to comprehensively cover the complete breadth of the olefin metathesis reaction – this Handbook would not have been possible without all their time and effort! It was truly a pleasure and an honor to work with everyone!

Claremont, CA

Durham, UK

Pasadena, CA

Anna G. Wenzel, Daniel J. O'Leary

Ezat Khosravi, and

Robert H. Grubbs

November 20th, 2014

1

 Data obtained from keyword searches conducted within the ISI Web of Science (accessed 1/18/2014).

References

1. Nobel Prizes.org Development of the Metathesis Method in Organic Synthesis,

http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2005/advanced-chemistryprize2005.pdf

(accessed 18 January 2014).

2. Rouhi, M. (2005)

Chem. Eng. News

,

83

, 8.

List of Contributors

Rambabu Chegondi

University of Kansas

Department of Chemistry

1251 Wescoe Hall Drive

Lawrence, KS 66045

USA

Samuel J. Danishefsky

Columbia University

Department of Chemistry

Havemeyer Hall

MC 3106

3000 Broadway

New York, NY 10027

USA

Benjamin G. Davis

University of Oxford

Department of Chemistry

Mansfield Road

Oxford, OX1 3TA

UK

Vittorio Farina

Janssen Pharmaceutica NV

Turnhoutseweg 30

2340 Beerse

Belgium

Alois Fürstner

Max-Planck-Institut für Kohlenforschung

Kaiser-Wilhelm-Platz 1

45470 Mülheim/Ruhr

Germany

Paul R. Hanson

University of Kansas

Department of Chemistry

1251 Wescoe Hall Drive

Lawrence, KS 66045

USA

András Horváth

Janssen Pharmaceutica NV

Turnhoutseweg 30

2340 Beerse

Belgium

Amir H. Hoveyda

Boston College

Department of Chemistry

Merkert Chemistry Center

Chestnut Hill, MA 02467

USA

Adam Johns

Materia Inc

60 N. San Gabriel Blvd

Pasadena, CA 91107

USA

R. Kashif M. Khan

Boston College

Department of Chemistry

Merkert Chemistry Center

Chestnut Hill, MA 02467

USA

Daesung Lee

University of Illinois

Department of Chemistry

845 West Taylor Street

Chicago, IL 60607-7061

USA

Jingwei Li

University of Illinois

Department of Chemistry

845 West Taylor Street

Chicago, IL 60607-7061

USA

Yuya A. Lin

University of Oxford

Department of Chemistry

Mansfield Road

Oxford, OX1 3TA

UK

Soma Maitra

University of Kansas

Department of Chemistry

1251 Wescoe Hall Drive

Lawrence, KS 66045

USA

Steven J. Malcolmson

Boston College

Department of Chemistry

Merkert Chemistry Center

Chestnut Hill, MA 02467

USA

Lisa A. Marcaurelle

H3 Biomedicine Inc.

300 Technology Square

Cambridge, MA 02139

USA

Bogdan Marciniec

Adam Mickiewicz University in Poznań

Faculty of Chemistry

Umultowska 89b

61-614 Poznań

Poland

Jana L. Markley

University of Kansas

Department of Chemistry

1251 Wescoe Hall Drive

Lawrence, KS 66045

USA

Youn H. Nam

Boston College

Department of Chemistry

Merkert Chemistry Center

Chestnut Hill, MA 02467-3860

USA

Daniel J. O'Leary

Pomona College

Department of Chemistry

645 North College Avenue

Claremont, CA 91711

USA

Gregory W. O'Neil

Western Washington University

Department of Chemistry

516 High Street

Bellingham, WA 98225

USA

Piotr Pawluć

Adam Mickiewicz University in Poznań

Faculty of Chemistry

Umultowska 89b

61-614 Poznań

Poland

Richard Pederson

Materia Inc

60 N. San Gabriel Blvd

Pasadena, CA 91107

USA

Cezary Pietraszuk

Adam Mickiewicz University in Poznań

Faculty of Chemistry

Umultowska 89b

61-614 Poznań

Poland

Alan Rolfe

H3 Biomedicine Inc.

300 Technology Square

Cambridge, MA 02139

USA

Marc L. Snapper

Boston College

Department of Chemistry

Merkert Chemistry Center

Chestnut Hill, MA 02467-3860

USA

Diana Stoianova

Materia Inc

60 N. San Gabriel Blvd

Pasadena, CA 91107

USA

Sebastian Torker

Boston College

Department of Chemistry

Merkert Chemistry Center

Chestnut Hill

MA 02467, USA

Christopher D. Vanderwal

University of California

Department of Chemistry

1102 Natural Sciences II

Irvine, CA 92697-2025

USA

Maciej A. Walczak

Columbia University

Department of Chemistry

Havemeyer Hall

MC 3106

3000 Broadway

New York, NY 10027

USA

List of Abbreviations

3-CR

three-component reaction

4CC

four-component condensation

Ac

acetyl

ACM

alkyne cross metathesis

ADMAC

acyclic diene metathesis macrocyclization

ADMET

acyclic diene metathesis

ADIMET

acyclic diyne metathesis

Agl

allyl glycine

AIBN

azobisisobutyronitrile

Alloc

allyl carbamate

API

active pharmaceutical ingredient

ARCM

asymmetric ring-closing metathesis

ATRA

atom transfer radical addition

AVM

arylenevinylene macrocycles

B/C/P

build/couple/pair

BBN

borabicyclo[3.3.1]nonane

BHT

2,6-di-

tert

-butyl-4-methylphenol

BINAP

2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

BINOL

1,1′-bi(2-naphthol)

Bn

benzyl

Boc

tert

-butyoxycarbonyl

BODIPY

boron-dipyrromethene

BOM

benzyloxymethyl

BOP

benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate

BPS, TBDPS

tert

–butyldiphenylsilyl

BRSM, brsm

based on recovered starting material

Bs

brosyl,

p

-bromobenzenesulfonyl

BTIB

bis(trifluoroacetoxy)iodobenzene

Bz

benzoyl

CAN

ceric ammonium nitrate

CBS

Corey–Bakshi–Shibata

Cbz

benzyloxycarbonyl

CD

circular dichroism

CDI

1,1'-carbonyldiimidazole

CDT

cyclododecatriene

CLPCS

cyclolinear polycarbosilanes

CM

cross-metathesis

CME

carboxymethyl migrastatin ether

CNS

central nervous system

COD

1,5-cyclooctadiene

COGs

cost-of-goods

Cp*

pentamethylcyclopentadienyl

CPA

chiral phosphoric acid

CSA

camphorsulfonic acid

CSI

chlorosulfonyl isocyanate

Cy

cyclohexyl

DA

Diels-Alder

DABCO

1,4-diazabicyclo[2.2.2]octane

Das

diaminosuberic acid

dba

dibenzylideneacetone

dbcot

dibenzo[a,e]cyclooctatetraene

DBU

1,8-diazabicyclo[5.4.0]undec-7-ene

DCC

dicyclohexylcarbodiimide

DCE

1,2-dichloroethane

DCM

dichloromethane

DDA

dodecenoate

DDE

dimethyl dodecanedioate

DDQ

2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DEAD

diethyl azodicarboxylate

DFT

density functional theory

Dha

dehydroalanine

DIAD

diisopropyl acetylenedicarboxylate

DIBAL-H

diisobutylaluminium hydride

DIEA, DIPEA

N

,

N

-diisopropylethylamine; Hünig's base

DMAD

dimethyl acetylenedicarboxylate

DMAP

4-dimethylaminopyridine

DMB

2,4-dimethoxybenzyl

DMBM

3,4-dimethoxybenzyloxymethyl

DMDA

dimethyldiacetylene

DME

1,2-dimethoxyethane

DMF

dimethylformamide

DMP

Dess-Martin periodinane

DMPU

N

,

N′

-dimethylpropylene urea

DMSO

dimethylsulfoxide

DOS

diversity-oriented synthesis

DOSP

N

-(dodecylbenzenesulfonyl)prolinate)

dppp

1,3-bis(diphenylphosphino)propane

DSRCM

diastereoselective ring-closing metathesis

DTBP

2,6-di-

tert

-butylphenol

DTS

diverted total synthesis

EDA

ethyl diazoacetate

EDC, EDCI

1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

EDG

electron donor group

ELT

end-of-life tire

EM

effective molarity

ERCM

enantioselective ring-closing metathesis

EROCM

enantioselective ring-opening/cross-metathesis

ERORCM

enantioselective ring-opening/ring-closing metathesis

Ery

erythromycin

EWB

electron withdrawing group

FAME

fatty acid methyl esters

FGP

functional group pairing

Fmoc

fluorenylmethyloxycarbonyl

FRET

fluorescence resonance energy transfer

F-SPE

fluorous-solid-phase extraction

FTO

freedom to operate

GFP

green fluorescent protein

GHRH

growth-hormone-releasing hormone

GSK

GlaxoSmithKline

HBS

hydrogen-bond surrogate

HCV

hepatitis C virus

HDAC

histone deacetylase

HFIP

hexafluoroisopropanol

HH

head-to-head

HMPA

hexamethylphosphoramide

HMSBO

hydrogenated metathesized soybean oil

HNBR

hydrogenated nitrile butadiene rubber

HO-DEAD

hydrogenated oligomeric azodicarboxylate

HPK

hetero-Pauson–Khand

HPLC

high-performance liquid chromatography

HRMS

high-resolution mass spectrometry

HT

head-to-tail

HTS

high-throughput screening

HWE

Horner–Wadsworth–Emmons

IMDA

intramolecular Diels-Alder

IMes

1,3-dimesityl-imidazolidin-2-ylidene

iNOS

inducible nitric oxide synthase

IP

intellectual property

Ipc

isopinocampheyl

KHMDS

potassium bis(trimethylsilyl)amide

LACDAC

Lewis acid catalyzed diene-aldehyde cyclocondensation

LCMS

liquid chromatography mass-spectrometry

LDA

lithium diisopropylamide

LiHMDS

lithium bis(trimethylsilyl)amide

LUMO

lowest unoccupied molecular orbital

M&M

metathesis and metallotropy

MALDI-MS

matrix-assisted laser desorption/ionization mass spectrometry

MAP

monoaryloxide pyrrolide

mCPBA

m

-chloroperbenzoic acid

ME

migrastatin ether

MEM

2-methoxyethoxymethyl

Mes

mesityl

MIDA

N

-methyliminodiacetic acid

MM

molecular mechanics

MO

methyl oleate

MOM

methoxymethyl

MPEG

methoxy poly(ethylene glycol)

MPM, PMB

p

-methoxybenzyl

MS

molecular sieve

Ms

methanesulfonyl

MSH

O

-mesitylenesulfonylhydroxylamine

MT

metric tons

MVK

methyl vinyl ketone

MW, μW

microwave

n.a.

not available

N.R.

no reaction

nAChR

nicotinic acetylcholine receptor

NAP

2-napthylmethyl

NBR

nitrile-butadiene rubber

NBS

N

-bromosuccinimide

NCI

National Cancer Institute

NCS

N

-chlorosuccinimide

NHC

N

-heterocyclic carbene

NIS

N

-iodosuccinimide

NMO

N

-methylmorpholine-

N

-oxide

NMR

nuclear magnetic resonance

Ns, Nos

nosyl, or 2-nitrobenzenesulfonyl

NXS

N

-halosuccinimide (halo = Cl, Br, I)

OBAC

oligomeric bis-acid chloride

ODDE

octadecenedioate

OLEC

olefinic ester cyclization

OM

olefin metathesis

OMAm

oligomeric amine

o

-NBSH

o

-nitrobenzenesulfonylhydrazide

OTf

trifluoromethanesulfonate

OTPP

oligomeric triphenylphosphine

PAE

poly(arylene ethynylene)

PBB

p

-bromobenzyl

PC

phosphatidylcholine

PDI

polydispersity index

PDLA

poly(D-lactide)

PGE

prostaglandin E

phen

phenanthroline

PHOX

phosphinooxazoline

Phth

phthaloyl

Pin

pinacolato

pip

piperidine

Piv

pivaloyl

PKR

Pauson-Khand reaction

PKS

polyketide synthase

plasm

plasmalogen

PLLA

poly(L-lactide)

PMB, MPM

p

-methoxybenzyl

pmdba

di(

p

-methoxybenzylidene)acetone

PMP

p

-methoxyphenyl

POSS

polyhedral oligomeric silsesquioxanes

PPTS

pyridinium

p

-toluenesulfonate

PTSA,

p

-TSA

p

-toluenesulfonic acid

PyBOP

benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate

R&D

research and development

RBD

refined, bleached, and deodorized

RCAM

ring-closing alkyne metathesis

RCDM

ring-closing diyne metathesis

RCEM

ring-closing enyne metathesis

RCM

ring-closing metathesis

ROCM

ring-opening cross-metathesis

ROM

ring-opening metathesis

ROMP

ring-opening metathesis polymerization

RORCM

ring-opening ring-closing metathesis

RRCM

relay ring-closing metathesis

RRM

ring-rearrangement metathesis

RT

room temperature

s.m.

starting material

Sac

S-allyl cysteine

SAMP

(

S

)-1-amino-2-methoxymethylpyrrolidine

SBO

soybean oil

SC

silylative coupling

SCLC

small-cell lung carcinoma

SHD

simulated high dilution

Shh

Sonic Hedgehog

SIMes

1,3-dimesityl-4,5-dihydroimidazol-2-ylidene

SI-ROMP

surface-initiated ring-opening metathesis polymerization

SOMO

singly occupied molecular orbital

SPPS

solid-phase peptide synthesis

TADA

transannular Diels-Alder

TAM

terminal alkyne metathesis

TASF

tris(dimethylamino)sulfur trimethylsilyl difluoride

TBAF

tetrabutylammonium fluoride

TBDPS, BPS

tert

-butyldiphenylsilyl

TBS, TBDMS

tert

-butyldimethylsilyl

TBSOTf

tert

-butyldimethylsilyl trifluoromethanesulfonate

TCE

1,1,2-trichloroethane

TCPC

tetracarbomethoxy palladacyclopentadiene

TCQ

tetrachloroquinone

TEA

triethylamine

TEMPO

(2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl

Teoc

trimethylsilylethyl carbamate

TES

triethylsilyl

TFA

trifluoroacetic acid

TFA-N

trifluoroacetamide

TFE

2,2,2-trifluoroethanol

THF

tetrahydrofuran

THP

tetrahydropyranyl

TIPS

triisopropylsilyl

TLC

thin layer chromatograhpy

TMEDA

tetramethylethylenediamine

TMS

trimethylsilyl

TMSB

tetramethyldisilacyclobutane

TMSOTf

trimethylsilyl trifluoromethanesulfonate

TOF

turnover frequency

TON

turnover number

Tr

trityl

TRAM

terminal ring-closing alkyne metathesis

Troc

2,2,2-trichloroethoxycarbonyl

Ts, Tos

tosyl, or

p

-toluenesulfonyl

UDA

undecenoate

UDDE

undecenedioate

URSM, ursm

unreacted starting material

USDA

United States Department of Agriculture

UV

ultraviolet

VDR

vitamin D receptor

xs

excess

1General Ring-Closing Metathesis

Paul R. Hanson, Soma Maitra, Rambabu Chegondi and Jana L. Markley

1.1 Introduction

Olefin metathesis catalyzed by transition-metal–carbene complexes is among the most powerful and important carbon–carbon bond-forming reactions in modern synthetic organic chemistry [1]. Metathesis transformations, including cross-metathesis (CM), ring-closing metathesis (RCM), enyne metathesis, alkyne metathesis, and ring-opening metathesis polymerization (ROMP), have gained prominence due to the high activity, high thermal stability, and excellent functional group compatibility of well-defined transition-metal alkylidene catalysts which have become available over the last two decades (Figure 1.1).

Figure 1.1 List of catalysts.

In 1980, the Villemin [2] and Tsuji and Hashiguchi [3] research groups individually reported the first RCM of a diene with tungsten metal complexes (Scheme 1.1, Eq. 1–2). In 1990, Schrock discovered the molybdenum metathesis complex [Mo]-I [4]. In 1992, Grubbs and coworkers employed [Mo]-I in the first transition-metal–carbine-catalyzed RCM of a diene for the synthesis of a cyclic ether (Eq. 3; Scheme 1.1) [5]. In 1995, Grubbs and coworkers developed the more active, thermal, and air-stable, moisture-tolerant ruthenium–carbene complexes termed the Grubbs first-generation catalyst G-I [6] and the Grubbs second-generation catalyst G-II [7]. Additional metathesis catalysts such as the Hoveyda–Grubbs catalyst HG-II [8] followed, with many commercially available at present.

Scheme 1.1 Early RCM examples.

Since its inception, RCM has continued to be a widely utilized metathesis reaction in a variety of settings including materials, small-molecule, and natural-product synthesis [1]. As illustrated in Scheme 1.2, the primary RCM reactions are divided into three general types: (i) ring-closing diene metathesis (RCM); (ii) ring-closing enyne metathesis (RCEM); and (iii) ring-closing alkyne metathesis (RCAM). In 1971, Chauvin and coworkers proposed a mechanism of the general alkene metathesis which involves the initial formation of the metal carbene species III as a key propagating intermediate [9]. Subsequent intramolecular [] cycloaddition of III with a distal olefin forms the metallacyclobutane intermediate IV, while retro [] reaction affords the final cyclized product (Scheme 1.2). Casey and Burkhardt [10], Katz and McGinnis [11], and Grubbs [12] later confirmed this mechanism with experimental evidence. The intent of this chapter is to highlight recent advances since the publication of the first edition of this Handbook in 2003 [13]. Some concepts, such as RCEM and RCAM, are covered in greater depth in later chapters.

Scheme 1.2 General ring-closing metathesis reactions.

1.2 Carbocycles (Introduction)

The abundance of carbocyclic moieties in synthetic intermediates, as well as in many natural products, has led to numerous synthetic efforts employing RCM toward their formation [14a,b]. This section provides a highlight of the work accomplished in this field since 2003. The section is divided into three subcategories based on the ring size.

1.2.1 Small-Sized Carbocycles

In 2003, Trost and coworkers reported the synthesis of the cyclopentyl core 4 of the antibiotic antitumor agent viridenomycin (5) (Scheme 1.3) [15]. Starting with diketone 1, alkylation via dynamic kinetic resolution was performed to establish the quaternary center in 2, which underwent an RCM reaction to yield the densely functionalized cyclopentenone subunit 3. A series of transformations were used to complete an 11-step synthesis of the cyclopentyl core 4 of viridenomycin (5).

Scheme 1.3 Synthetic studies toward viridenomycin.

In 2006, Fustero and coworkers reported the synthesis of an array of fluorinated cyclic α-amino esters (Scheme 1.4) [16]. Diene 6 was subjected to RCM to afford fluorinated cyclic α-amino ester 7 in good yield. In 2012, Xie and coworkers demonstrated another application of RCM in synthesizing entecavir (10), “an oral carbocyclic analog of 2-deoxyguanosine having a selective activity against hepatitis B virus” [17]. The key transformation of the synthesis included RCM of the diene moiety8 to yield the five-membered carbocycle 9, which was further transformed to entecavir over five steps (Scheme 1.4).

Scheme 1.4 Syntheses of fluorinated amino acid derivatives and entecavir.

In 2006, Saicic and coworkers published the synthesis of (Z)-configured, medium-sized cycloalkenes using RCM (Scheme 1.5) [18]. The synthesis started with functionalized cyclohexene moiety 11, which underwent RCM to provide the bicyclic product 12. The bicyclic adduct was then subjected to reduction, mesylation, and Grob fragmentation to afford the macrocyclic product 13, which was converted to (±)-periplanone C (14) in two steps. The trans stereochemistry of the hydroxyl and ester groups in 12, as well as the presence of the isopropyl handle, was found to be crucial for the desired product formation.

Scheme 1.5 RCM approach to (±)-periplanone C.

In addition to these small-membered carbocycles, RCM has also been applied successfully in synthesizing carbasugars and nucleoside derivatives. In 2006, Ghosh and coworkers reported the enantioselective synthesis of biologically important carbasugars starting from a single enantiomer of glyceraldehyde (Scheme 1.6) [19]. Cyclization of dienol 15 afforded the RCM product 16 in good yield. In 2003, Nielsen and coworkers utilized RCM to synthesize the conformationally restricted nucleoside 19 [20]. Diene 17 was subjected to RCM to afford 18, which was subsequently converted to the tricyclic nucleoside 19.

Scheme 1.6 RCM syntheses of carbasugars and nucleoside derivatives.

In 2010, Maffei and coworkers utilized RCM to prepare five- and six-membered cycloalkenyl bisphosphonates (Scheme 1.7) [21]. The five-membered RCM substrate 21, prepared by dialkylation of tetraethyl methylene bisphosphonate (21) with allyl and methallyl bromide, was subjected to RCM reaction by using the G-I or G-II catalyst. However, the reaction outcome was strongly influenced by olefinic substitution, and no reaction was observed when both olefins were disubstituted. The RCM precursor 25 was obtained by conjugate addition of olefinic Grignard reagents to tetraethyl vinylidene bisphosphonate (23). Both five- and six-membered cases afforded relatively good yields. Overall, these examples demonstrated the utility of RCM to quickly access several biologically important geminal bisphosphonates.

Scheme 1.7 Syntheses of five- and six-membered cycloalkenyl bisphosphonates.

In 2011, Srikrishna and coworkers reported the enantiospecific synthesis of the challenging ABC ring system of the marine diterpene aberrarane (30) and related derivatives (Scheme 1.8) [22]. The reaction sequence started with the conversion of readily available (S)-campholenaldehyde (27) to bicyclic diene 28. Subsequent RCM afforded the ABC ring system 29 in good yield. In 2007, Singh and coworkers accomplished the stereoselective formal synthesis of hirsutic acid (34) with a similar tricyclic framework [23]. Salicyl alcohol (31) was subjected to several transformations to afford the diene 32, which underwent RCM to provide the hirsutic acid tricyclic core 33 in 70% yield.

Scheme 1.8 RCM approaches to aberrarane ABC ring system and hirsutic acid.

In 2011, Mehta and coworkers demonstrated the utility of RCM in forming carbocycles in the context of the total synthesis of 11-O-methyldebenzoyltashironin, a tetracyclic oxygenated natural product (Scheme 1.9) [24]. The highly substituted allyl benzene derivative 35 was subjected to oxidative dearomatization by treatment with bis(trifluoroacetoxy)iodobenzene (BTIB) in the presence of an olefin partner. The intermediate thus obtained was heated in toluene to afford a [] cycloadduct 36. The cycloadduct 37 then underwent RCM to furnish the tricyclic core structure 38, en route to 11-O-methyldebenzoyltashironin (38).

Scheme 1.9 RCM in the total synthesis of 11-O-methyldebenzoyltashironin.

In 2012, Crimmins and coworkers reported the synthesis of aldingenin B (42), a secondary metabolite with a complex molecular architecture (Scheme 1.10) [25]. The key transformations included an asymmetric aldol reaction, RCM, and directed dihydroxylation. Starting from 39, two contiguous stereocenters were installed in diene 40 over two steps, and subsequent RCM gave access to one of the six-membered rings in the tricyclic framework of 42. The substituted cyclohexene 41 was carried forward to complete the synthesis of aldingenin B.

Scheme 1.10 RCM approaches to aldingenin B and (+)-harringtonolide.

In 2012, Abdelkafi and coworkers achieved the first asymmetric synthesis of the oxygen-bridged CD ring system 46 contained within the norditerpene alkaloid (+)-harringtonolide (Scheme 1.10) [26]. The challenging ring structure was constructed via a stereoselective intramolecular Diels–Alder reaction, RCM, and a one-step cascade cyclization of an epoxy alcohol intermediate. For the RCM process, cycloadduct 43 was converted to substituted cyclohexene 44, which cyclized in the presence of G-II to provide 5,6-fused ring system 45. This 5,6-fused ring system was later subjected to a series of reactions to afford the caged structure 46 of (+)-harringtonolide.

Yoshida and coworkers reported a general approach to substituted aromatic compounds using RCM/dehydration and RCM/tautomerization reactions. Initially, they synthesized phenols 48 from 1,4,7-trien-3-ones 47 via the ketonic tautomer using G-I and G-II catalysts (Eq. 1; Scheme 1.11) [27, 27]a. Similarly, benzenes 50 and styrenes 52 were prepared by RCM/dehydration of 1,4,7-octatriene-3-ols 49 (Eq. 2; Scheme 1.11) [27]b and RCEM/elimination of 3-acetoxy-4,7-ocadien-1-ynes 51 (Eq. 3; Scheme 1.11), [27c] respectively. In a manner related to their aforementioned RCM/elimination sequence, the authors developed an RCM/oxidation/deprotection of nitrogen-containing dienes 53 to furnish 3-hydroxypyridines 54 in excellent yields (Eq. 4; Scheme 1.11) [27d]. Recently, Yoshida and coworkers also utilized a new and efficient tandem RCEM/RCM/dehydration approach to the synthesis of biaryl compounds 56 from tetraenynes 55 in the presence of the G-II catalyst (Eq. 5; Scheme 1.11) [27e].

Scheme 1.11 RCM/dehydration and RCM/tautomerization approaches to substituted aromatic compounds.

1.2.2 Medium-Sized Carbocycles

In 2012, Stoltz and coworkers reported an efficient synthesis of bi- and tricyclic systems bearing a quaternary carbon stereocenter via an enantioselective decarboxylative allylation and RCM (Scheme 1.12) [28]. Decarboxylation of the allyl ester 57 with (S)-t-Bu-PHOX and Pd2(pmdba)3 in toluene provided vinylogous ester 58 in 91% yield and 88% ee, which was further subjected to various Grignard reagents (with CeCl3 additive) to deliver the cycloheptenone derivatives 59a–f. RCM of these compounds in the presence of HG-II catalyst furnished bi- and tricyclic fused carbocycles 60a–f in excellent yields.

Scheme 1.12 Syntheses of cyclic systems bearing quaternary carbon stereocenters.

In their 2011 study of pleuromutilin, Sorensen and coworkers highlighted the importance of nonbonding steric interactions in RCM reactions, which can play a significant role in the formation of products 62 and 64 from dienes 61 and 63, respectively (Scheme 1.13) [29]. In this work, the authors found that the C14 hydroxyl stereochemistry governs the RCM event as a result of steric interactions with the proximal C16 methyl group in the metallacyclobutane transition state (cf. 66 and 68), where the C14-epimer (67) failed to undergo RCM. In addition, an RCM rate enhancement was also observed with the bulky C14 hydroxyl protecting groups in diene 61, which was proposed to arise as a consequence of a bias favoring conformer 65B over 65A in the metathesis cycle (Scheme 1.13).

Scheme 1.13 Synthetic studies toward pleuromutilin.

In 2011, Nakada et al. published the first enantioselective total synthesis of (+)-ophiobolin A (73) using RCM as one of the key steps (Scheme 1.14) [30]. The challenging eight-membered carbocyclic ring was constructed by RCM of diene 71, which in turn was synthesized by the coupling of 69 and 70. Further functional group manipulation provided the natural product 73.

Scheme 1.14 Total synthesis of (+)-ophiobolin A.

In 2011, Dixon and coworkers developed a scalable route to the highly functionalized core of daphniyunnine B (78) (Scheme 1.15) [31]. The cis-fused amide 76 was obtained in 52% yield via a stereo- and regiocontrolled intramolecular Michael addition and tandem enolate allylation through sequential addition of base and allyl chloride 75. Subsequent Claisen rearrangement of 76 in refluxing mesitylene provided the enolic RCM precursor in 53% yield. RCM using either HG-II or G-II furnished the unique seven-membered enol ether 77 in good yield.

Scheme 1.15 Route to daphniyunnine B core ring system.

Yang et al. successfully completed the stereoselective total synthesis of pseudolaric acid A (85) in 16 steps from commercially available starting materials (Scheme 1.16) [32]. They effectively utilized a SmI2-mediated intramolecular radical cyclization and RCM for the construction of the unusual trans-fused [5.7]-bicyclic core of 85. Diene 81 was synthesized in 82% yield from the allylation of the β-ketoester 79 with 3-bromo-2-methylpropene (80). Michael addition of diene 81 with acrolein in the presence of NaOMe, followed by Wittig olefination, provided the diester 82 in 78% yield. The SmI2-mediated alkene-ketyl radical annulation reaction of 82 in the presence of HMPA (10 equiv), followed by silylation, furnished the desired product 83 as major product (about 10 : 1 E/Z) in 78% yield. The construction of the bicycle 84 was achieved in 96% yield by RCM of 83 in the presence of G-II. A 10-step elaboration of bicycle 84 provided (±)-pseudolaric acid (85).

Scheme 1.16 Stereoselective total synthesis of pseudolaric acid A.

In 2010, Hall and coworkers developed an enantioselective route to (+)-chinensiolide B using diene metathesis to generate the central seven-membered ring (Scheme 1.17) [33]. The synthesis was initiated by the coupling of the fragment 88 with the subunit 87 (prepared from carvone (86) in six steps) in the presence of BF3·OEt2 to provide the trans-γ-lactone product 89 in 87% yield with 19 : 1 diastereoselectivity. Selective TBDPS deprotection and Grieco elimination gave the desired triene 90b in 60% yield along with undesired Michael by-product 90a in 20% yield. Triene 90b was subjected to G-II in CH2Cl2 to generate the seven-membered carbocycle 91 chemoselectively in 93% yield. Additional functional group manipulation of 91 afforded the natural product in four steps.

Scheme 1.17 Enantioselective route to (+)-chinensiolide B.

In 2009, Vanderwal and coworkers [34] reported an elegant allylsilane RCM and subsequent electrophilic desilylation for the synthesis of exo-methylidene containing six-, seven-, and eight-membered cycloalkane motifs present in many terpene natural products (Scheme 1.18). The route provided the synthesis of teucladiol (98) in just five steps from cyclopentenone (93). Conjugate addition of vinyl bromide 94 with enone 93 led to an intermediate enolate, which was trapped with aldehyde 95 to provide diene 96. Silylation followed by RCM delivered the seven-membered carbocycle 97 in excellent yield. Subsequent diastereoselective addition of methylcerium and electrophilic desilylation afforded synthetic (±)-teucladiol.

Scheme 1.18 Synthesis of (±)-teucladiol.

In 2010, the Vanderwal group reported the synthesis of a variety of analogs from RCM product 101, synthesized from diene 100 as outlined in Scheme 1.19. These included poitediol 102, dactylol 103, isodactylol 104, and the chlorinated analog 105, each made from 101 in one or two high-yielding steps [35]. The development of this chemistry is discussed in greater detail by Prof. Vanderwal in chapter 8.

Scheme 1.19 Synthesis of poitediol, dactylol, iso-dactylol, and chlorinated analog.

In 2006, Gais and coworkers reported the stereoselective synthesis of highly functionalized medium-sized carbocycles via RCM reaction from chiral sulfoximines (Scheme 1.20) [36]. When allylic sulfoximine 106 was treated with n-BuLi, ClTi(OiPr)3, and various aldehydes at −78 °C, it afforded the corresponding sulfoximine-substituted homoallylic alcohols 107a,b in 70–75% yield with ≥96% de. Silylation with TESCl gave sulfoximines 108a,b, and subsequent α-allylation provided E-sulfoximine-substituted trienes 109a,b as single isomers. RCM of these trienes with G-II furnished the Z-configured 9- and 10-membered carbocycles 110 and 111 with yields of 96 and 90%, respectively. Similar reactions of 108a,b with 4-pentenal provided silylated allylic alcohols 112a,b with 1 : 1 diastereoselectivity. These isomers were subjected to RCM to give carbocycles (R)-113, (S)-113, and (R)-114 in good yields. In the 11-membered RCM reaction, a minor amount of the E-isomer (R)-115 was detected.

Scheme 1.20 Functionalized carbocycles via RCM reaction from chiral sulfoximines.

In 2006, Chavan and coworkers reported the first enantiospecific total synthesis of (−)-parvifoline (122, Scheme 1.21) [37]. (R)-(+)-citronellal (116) served as the starting material, which was converted into enone 117 (1 : 1 dr) with a known procedure. Rubottom oxidation of enone 117 provided the α-hydroxy-enone 118 in 70% yield, followed by 1,2-addition with MeMgI, acetylation of the secondary alcohol, and 1,3-carbonyl transposition with PCC (pyridinium chlorochromate) to afford enone 119 in excellent yield. Enone 119 was treated with methallyl magnesium chloride under Barbier conditions, followed by Dess–Martin oxidation, to furnish tertiary alcohol 120. Mesylation of alcohol 120 and subsequent hydrolysis using KOH in MeOH gave the requisite phenol intermediate 121 in 79% yield. The key RCM of phenol 121 using G-II in toluene furnished (−)-parvifoline (122) in 90% yield.

Scheme 1.21 Enantiospecific total synthesis of (−)-parvifoline.

In 2004, Rychnovsky and coworkers reported chirality transfer in the transannular radical cyclization of cyclodecene 128 to produce bicyclo[5.3.0]decane 129 (Scheme 1.22) [38]. They synthesized the radical precursor 128 in 88% yield using a 10-membered RCM of diene 127. The synthesis of the RCM substrate began with a Mukaiyama–Keck aldol reaction of aldehyde 123 using silyl ether 124 to afford the β-hydroxy ester 125 in 89% yield and 89% ee. Silyl protection, followed by reduction and iodination, gave alkyl iodide 126 in excellent yield. Coupling of the iodide 126 with allyl dibenzylmalonate gave the requisite diene 127 in 96% yield.

Scheme 1.22 Ten-membered RCM construction of a radical precursor.

In 2004, Martin and coworkers synthesized a number of enantiomerically enriched fused carbocycles via a γ-lactone tether-mediated RCM (Scheme 1.23) [39]. Regioselective opening of epoxy alcohol 130 using thiophenyl acetic acid gave the ester 131, followed by a sequence consisting of oxidative cleavage, Wittig reaction, stereoselective intramolecular Michael addition, and ester hydrolysis to provide the γ-lactone 132. Diene 134 was synthesized from 132 via the intermediate133 using a chemo- and stereoselective contra-steric alkylation with a variety of alkenyl halides. RCM with G-II provided the bicyclic structures 135 in moderate to good yield depending on the ring size.

Scheme 1.23 Synthesis of carbocycles fused to γ-lactones.

In 2003, Madsen and coworkers used a seven-membered RCM for the efficient syntheses of enantiopure calystegine B2, B3, and B4 starting from glucose, galactose, and mannose, respectively (Scheme 1.24) [40]. The synthesis of calystegine B2 started from benzyl-protected iodoglycoside 136, which is available in three steps from d-glucose. A Zn-mediated fragmentation of 136, coupled with in situ benzyl imine formation and Barbier-type allylation, gave a product which was Cbz-protected to provide diene 137 with 5 : 1 diastereoselectivity. After separation of the major diastereomer by chromatography, the major isomer was subjected to RCM, followed by hydroboration–oxidation, and DMP (Dess–Martin-periodinane) oxidation to generate the ketones 138 and 139 in 81% overall yield and 1 : 3 regioselectivity, respectively. These regioisomers could be easily separated by chromatography, and hydrogenolysis of 139 generated calystegine B2 (141) in excellent yield. Hydrogenolysis of the minor ketone 138 provided the hemiketal 140. Using the same approach, calystegines B3 (143) and B4 (145) were synthesized from benzyl-protected methyl 6-iodo-galactopyranoside 142 and benzyl-protected methyl 6-iodo-mannopyranoside 144, respectively.

Scheme 1.24 Seven-membered RCM of carbohydrate derivatives for calystegine syntheses.

1.2.3 Spiro Carbocycles

RCM has also played an important role in the synthesis of spirocycles. In 2002, Suga and coworkers synthesized azaspiro compounds possessing a pyrrolidine skeleton using electroauxiliary-assisted sequential α-alkyl/allylation followed by RCM (Scheme 1.25) [41]. Disilylpyrrolidine 147 was prepared from monosilylpyrrolidine 146 using Beak's method (addition of sec-BuLi in Et2O with HMPA as an additive, followed by TMSCl addition). For a more efficient electrochemical oxidation, pyrrolidine 147 was converted into the methyl ester 148 via a deprotection/protection sequence. Oxidation of methyl carbamate 148 using the “cation pool” method at −78 °C generated a 2-silylpyrrolidinium ion which reacted with nucleophiles such as allyltrimethylsilane or homoallylmagnesium bromide to generate products 149 and 150, respectively. Further oxidation of these products gave the dialkylated RCM precursors, which afforded the corresponding spirocyclized products.

Scheme 1.25 Azaspirocycle RCM syntheses.

In 2004, Trost and coworkers described the synthesis of α-hydroxycarboxylic acid derivatives using 5-alkyl-2-phenyl-oxazol-4-one (157) as a nucleophile (Scheme 1.26) [42]. Starting with 157, 5,5-disubstituted-phenyloxazolone derivatives 158 were prepared via Mo-catalyzed asymmetric allylic alkylation (AAA). The reaction product thus obtained was subjected to RCM conditions (when R = allyl) to afford the spirocyclic RCM products 159 in excellent yield. Further hydrolysis of 159 afforded the cyclic hydroxy carboxamide 160.

Scheme 1.26 α-Hydroxycarboxylic acids from spirocyclic-RCM products.

In 2005, Kim et al. [43] reported a formal synthesis of (−)-perhydrohistrionicotoxin (168) starting from 6-oxopipecolic acid (161) (Scheme 1.27). A Claisen rearrangement and an RCM reaction were utilized as key steps for the construction of the azaspirocyclic skeleton. The synthesis began with the preparation of ester 163 by coupling the racemic acid 161 with allylic alcohol (S)-162 on a multi-gram scale. Ester-enolate Claisen rearrangement of 163 under Kazmaier conditions produced the desired isomer 164 in high yield (75%) and stereoselectivity (30 : 1). Ester 164 was reduced under Luche conditions, and subsequent oxidation and allylation generated homoallyl alcohol 165 in excellent yield. The spirocycle was formed by RCM with G-II to produce olefin 166 in 84% yield. Deoxygenation of 166 was readily accomplished with the Barton–McCombie procedure to provide the lactam 167 in 54% overall yield. Finally, oxone-mediated epoxidation (30 : 1 dr) and DIBAL-H reduction afforded (–)-perhydrohistrionicotoxin (168) in good yield.

Scheme 1.27 Formal synthesis of (−)-perhydrohistrionicotoxin