Citation for published version (APA): Jäger, M. (2015). Selective oxidation of glycosides [Groningen]: University of Groningen

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1 University of Groningen Selective oxidation of glycosides Jäger, Manuel IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2015 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Jäger, M. (2015). Selective oxidation of glycosides [Groningen]: University of Groningen Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Selective oxidation of glycosides Manuel Jäger

3 Selective oxidation of glycosides Manuel Jäger Ph.D. Thesis University of Groningen, The Netherlands The research described in this thesis was carried out within the Stratingh Institute for Chemistry, University of Groningen, The Netherlands. In compliance with the requirements of the Graduate School of Science of the Faculty of Mathematics and Natural Science, University of Groningen, The Netherlands. This research has been performed within the framework of the CatchBio program. The authors gratefully acknowledge the support of the Smart Mix Program of the Netherlands Ministry of Economic Affairs and The Netherlands Ministry of Education, Culture and Science. Printed by Ipskamp Drukkers BV, Enschede, The Netherlands Coverdesign: Markus Oskamp and Manuel Jäger. Inspired by Deviantart, user uppercasem ( ISBN: (printed) (digital) Manuel Jäger

4 Selective oxidation of glycosides PhD thesis to obtain the degree of PhD at the University of Groningen on the authority of the Rector Magnificus Prof. E. Sterken and in accordance with the decision by the College of Deans This thesis will be defended in public on Friday 26 June 2015 at 9:00 By Manuel Jäger born on 26. October 1982 in Oelde, Germany

5 Supervisors Prof. A. J. Minnaard Prof. J. G. de Vries Assessment committee Prof. P. H. Seeberger Prof. B. L. Feringa Prof. W. R. Browne

6 Für Anja

7 Table of Contents Chapter 1 - Regioselective Modification of Carbohydrates 1 Introduction 2 Structure and nomenclature of glycosides 5 Selective protection of glycosides 6 Inherent reactivity of glycoside hydroxyl groups 7 Tin mediated protection of glycosides 9 Metal- and metalloid-mediated protection of glycosides other than tin 12 Biomimetic and stereoselective catalysis in glycoside protection 13 Enzyme-catalyzed protection of carbohydrates 15 Selective non-protective modification of carbohydrates 16 Halogen introduction 17 Deoxygenation and epimerization of glycosides 19 Selective oxidation of carbohydrates 20 Chemical oxidation of glycosides 20 Enzymatic oxidation of carbohydrates 22 Aim and Outline of this thesis 24 Aim 24 Outline 25 Literature 26 Chapter 2 - Catalytic Regioselective Oxidation of Glycosides 31 Introduction 32 Goal 33 Results and discussion 34 Substrate Scope 35 Possible Mechanism 38 Synthesis of methyl allopyranoside and aminoglucoside 40 Conclusion 40 Experimental Section 41 Literature 51 Chapter 3 - Catalytic Regioselective Oxidation of Partially Protected Glycosides 53 Introduction 54 Selective alcohol oxidation 54 Goal 56 Synthetic approach 58 Results and discussion 60 Substrate synthesis 60 Oxidation 61 Isolation and purification 62 On the regioselectivity of the oxidation 63 On the reaction rate of the oxidation 64 Chemical shifts in NMR as indication for electron density 65

8 Conclusion 70 Experimental Section 72 Acknowledgements 80 Literature 81 Chapter 4 - Selective Oxidation and Modification of Aminoglycoside Antibiotics 83 Introduction 84 Structure of aminoglycosides 84 Mode of action of aminoglycoside antibiotics 86 Bacterial resistance against aminoglycoside antibiotics 87 Aminoglycosides as RNA binders 90 Total synthesis of aminoglycosides 90 (Selective)-modification of aminoglycosides 91 Goal 95 Results and discussion 95 Global amine protection of aminoglycosides 96 Oxidation of the amine-protected aminoglycosides Keto-aminoglycosides as antibiotics 101 Selective modification to 3 -epi-aminoglycosides 101 Deprotection and final purification 103 Targeting two mechanisms of bacterial resistance against aminoglycoside antibiotics Conclusions and future perspectives 110 Experimental Section 112 Acknowledgements 129 Literature 130 Chapter 5 - Future Perspectives in the Selective Oxidation of Glycosides and Aminoglycoside Antibiotics 135 Introduction 136 Catalytic system 136 Deuteration as protection 138 Is this catalyst unique? 143 Substrates for the selective oxidation 146 Glucosides 146 Natural sweeteners 147 Aminoglycosides 149 Origin of the regioselectivity 149 Conclusion 151 Experimental Section 151 Literature 155 Samenvatting 156 Summary 161 Acknowledgements

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