Linkers for Solidphase Synthesis

Stefan Brase and Stefan Dahmen

4.1 Introduction 59

4.2 General Linker Structures 60

4.2.1 Immobilization of Molecules 60

4.2.2 Spacers 61

4.2.3 Functionalized Linkers as Analytical Constructs 62

4.3 Linker Families 62

4.3.1 Benzyl-type Linkers Including Trityl and Benzhydryl Linkers 63

4.3.2 Allyl-based Linkers 68

4.3.3 Ketal/Acetal-based Linkers 70

4.3.4 Ester-, Amide-, and Carbamate-based Linkers 71

4.3.5 Silyl Linkers 73

4.3.6 Boronate Linkers 76

4.3.7 Sulfur, Stannane- and Selenium-based Linkers 77

4.3.7.1 Sulfur-based Linkers 77

4.3.7.2 Stannane-based Linkers 81

4.3.7.3 Selenium-based Linkers 81

4.3.8 Triazene-based Linkers 83

4.3.9 Orthogonality Between Linkers 88

4.4 Cleavage 88

4.4.1 Electrophilic and Nucleophilic Cleavage 88

4.4.2 Oxidative/Reductive Methods 90

4.4.3 Photocleavable Linkers 91

4.4.4 Metal-assisted Cleavage 93

4.4.4.1 Cleavage with Ensuing Allylic Substitution or Cross-coupling Reactions 94

4.4.4.2 Cleavage via Alkene Metathesis 97 4.4.5 Unusual Cleavage Methods 98

4.5 Linker and Cleavage Strategies 98

4.5.1 Safety-catch Linkers 99

4.5.2 Cyclative Cleavage (Cyclorelease Strategy) 103

4.5.3 Cleavage-cyclization Cases 105

4.5.4 Fragmentation Strategies 107

4.5.5 Traceless Linkers 110

4.5.6 Multifunctional Cleavage 117

4.5.7 Linkers for Asymmetric Synthesis 120

4.6 Linkers for Functional Groups 121

4.6.1 Linkers for Nitrogen Functionalities 122

4.6.1.1 Linkers for Amines 123

4.6.1.2 Linkers for Primary Amines 123

4.6.1.3 Linkers for Secondary Amines 125

4.6.1.4 Linkers for Tertiary Amines 125

4.6.1.5 Linkers for Hydrazines, Hydrazones and Hydroxylamines 128

4.6.1.6 Linkers for Diazonium Salts 128

4.6.1.7 Linkers for Azides 129

4.6.1.8 Linkers for Nitro Compounds 129

4.6.1.9 Linkers for Azo Compounds 129

4.6.1.10 Linkers for Nitriles 129

4.6.1.11 Linkers for N-Heterocycles 129

4.6.2 Linkers for Carbonyl Functionalities 133

4.6.2.1 Linkers for Carboxylic Acids 133

4.6.2.2 Linkers for Carboxylic Esters, Anhydrides and Lactones 134

4.6.2.3 Linkers for Thiocarboxylic Acids and Esters 135

4.6.2.4 Linkers for Carboxamides and Related Structures 136

4.6.2.5 Linkers for Hydrazides and Semicarbazones 142

4.6.2.6 Linkers for Cyclic Amides and Related Structures 143

4.6.3 Linkers for Ketones and Aldehydes 144

4.6.4 Linkers for Alcohols, Phenols, Ethers, and Ketals 144

4.6.4.1 Linkers for Alcohols 144

4.6.4.2 Linkers for Phenols 146

4.6.5 Linkers for Sulfur Compounds 146

4.6.5.1 Linkers for Thiols and Thioethers 146

4.6.5.2 Linkers for Sulfonamides 147

4.6.5.3 Linkers for Sulfonic Acids 147

4.6.5.4 Linkers for Sulfones and Sulfoxides 148

4.6.5.5 Linkers for Sulfoximines 148

4.6.6 Linkers for Hydrocarbons 148

4.6.6.1 Linkers for Alkanes 149

4.6.6.2 Linkers for Arenes and Heteroarenes 149

4.6.6.3 Linkers for Alkenes 149

4.6.6.4 Linkers for Alkynes 150

4.6.7 Linkers for Aryl and Alkyl Halides 150

4.6.8 Linkers for Heterocycles 151

4.6.9 Linkers for Reactive Intermediates 151

4.6.10 Linkers for Other Functional Groups 152

4.6.10.1 Linkers for Phosphonates 152

4.6.10.2 Linkers for Boronates 152

4.6.10.3 Linkers for Silanes and Silanols 152

4.7 Overview for Linkers for Functional Groups 152

4.8 Conclusion, Summary and Outlook 152 References 153

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