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A combinatorial approach towards pharmaceutically relevant cyclic peptides
Springer, J.
Publication date 2008
Link to publication
Citation for published version (APA):
Springer, J. (2008). A combinatorial approach towards pharmaceutically relevant cyclic peptides.
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Contents
Chapter 1 General Introduction
1.1 Cyclic peptides 2
1.2 Difficulties in peptide cyclizations 4
1.3 Combinatorial chemistry 8
1.4 Combinatorial synthesis of cyclic peptides 9
1.5 Outline of the thesis 13
1.6 References and notes 15
Chapter 2 Improved Auxiliary for the Synthesis of Medium-Sized Bis(lactams)
2.1 Introduction 24
2.2 Development and synthesis of the different auxiliaries 28 2.3 Evaluation of the TBS-substituted auxiliary 29 2.4 The isopropyl-substituted auxiliary proved to be optimal 30 2.5 Synthesis of eight-membered bis(lactams) 33 2.6 Towards a solid phase immobilized auxiliary 36
2.7 Conclusions 41
2.8 Acknowledgments 42
2.9 Experimental section 42
2.10 References and notes 56
Chapter 3 Backbone Amide Linker Strategy for the Synthesis of 1,4-Triazole Containing Cyclic Tetra- and Pentapeptides
3.1 Introduction 60
3.2 Copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition reaction 60 3.3 Synthesis of triazole-containing cyclic pseudopeptides 61 3.4 Combinatorial approach towards triazole-containing cyclic peptides 64 3.5 Synthesis of the backbone amide linker 66 3.6 Synthesis of the azido acids 66 3.7 Synthesis of the amino alkynes 67 3.8 Solution phase approach towards the triazole-containing
cyclic pseudopeptides 69
3.9 Solution phase copper-catalyzed cyclization of the linear peptides 71 3.10 Solid phase approach towards the triazole-containing
cyclic pseudopeptides 72
3.11 Solid supported copper-catalyzed cyclization of the linear peptides 73 3.12 Synthesis of a library of cyclic pseudotetrapeptides 74
Contents
3.13 Synthesis of a triazole analogue of the cyclic pentapeptide segetalin B 75 3.14 Conformational analysis of the cyclic peptide analogue 77
3.15 Conclusions 82
3.16 Acknowledgments 83
3.17 Experimental section 83
3.18 References and notes 100
Chapter 4 Synthesis of 1,5-Connected Triazole-Containing Cyclic Pseudotetrapeptides
4.1 Introduction 106
4.2 Towards the synthesis of cyclo-[Pro−ψ(triazole)−Gly−Pro−Tyr] 110 4.3 Synthesis of cyclo-[Tyr−Pro−Gly−ψ(triazole)−Gly] 111 4.4 Synthesis of cyclo-[Tyr−Pro−Val−ψ(triazole)−Gly] 113
4.5 Conclusions 116
4.6 Acknowledgments 116
4.7 Experimental section 116
4.8 References and note 124
Chapter 5 Combined Ugi-4CR and Azide-Alkyne Cycloaddition Reaction for the Fast Assembly of Small and Diverse Cyclic Peptides
5.1 Introduction 128
5.2 Small cyclic pseudopeptides, first generation isonitrile 131 5.3 Small cyclic pseudopeptides, second generation isonitrile 133 5.4 Towards small cyclic pseudopeptides, third generation isonitrile 135 5.5 Towards cyclic pseudo tetrapeptides 142 5.6 Triazole-containing analogue of chlamydocin 146
5.7 Conclusions 153
5.8 Acknowledgments 154
5.9 Experimental section 154
5.10 References and notes 181
Chapter 6 Retrospection and Outlook
6.1 Auxiliary mediated synthesis of medium-sized bis(lactams) 186 6.2 Backbone amide linker strategy for the synthesis of
1,4-triazole-containing cyclic peptides 186 6.3 Synthesis of 1,5-connected triazole-containing cyclic peptides 187
Contents
6.4 Combined Ugi-4CR and azide-alkyne cycloaddition reaction for
the synthesis of cyclic pseudopeptides 188
6.5 References and notes 189
Summary 191
Samenvatting 195
