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University of Groningen Stereoselective synthesis of glycerol-based lipids Fodran, Peter 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): Fodran, P. (2015). Stereoselective synthesis of glycerol-based lipids [S.l.]: [S.n.] 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): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 10-08-2017 Stereoselective Synthesis of Glycerol-based Lipids Peter Fodran 1 The work described in this thesis was carried out at the Stratingh Institute for Chemistry, University of Groningen, The Netherlands. This work was financially supported by the Zernike Institute for Advanced Materials. Printed by: Ipskamp Drukkers, Enschede Cover design: Peter Fodran Stereoselective Synthesis of Glycerol-based Lipids 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 13th March 2015 at 12:45 By Peter Fodran born on 12th June 1985 in Bratislava, Slovak Republic 3 Supervisor Prof. A. J. Minnaard Assessment committee Prof. M. H. Clausen Prof. F. J. Dekker Prof. J. G. Roelfes How come it is not possible? People are flying to the moon and you want to tell me that you cannot fix this (vacuum cleaner, stove, hairdryer…)? (Iveta Fodranová) 5 CONTENTS Chapter 1 An Introduction to Phospholipids Introduction Nomenclature Biosynthesis of fatty acids, sphingolipids, triacylglycerols, glycerophospholipids Biosynthesis of fatty acids Biosynthesis of sphingolipids Biosynthesis of triacylglycerols and glycerophospholipids Biosynthesis of non-archaeal ether based lipids Outline of this thesis References and footnotes Chapter 2 Synthesis of Methyl-branched Fatty Acids Introduction Tuberculostearic acid Results and discussion (R)-Tuberculostearic acid Caspofungin fatty acid Conclusions Experimental part References and footnotes Chapter 3 Catalytic Synthesis of Enantiopure Mixed Diacylglycerols Introduction Results and discussion Synthesis of enantiopure phospholipids Enantiopurity does not decrease during the ring opening Synthesis of the platelet-activating factor (PAF) Conclusions Experimental section References and footnotes Chapter 4 Enantiopure Triacylglycerols in Three Steps Introduction Reported syntheses of triacylglycerols Results and discussion Co[(R,R)-salen] catalyzed ring opening of glycidyl esters Towards the automated synthesis of triacylglycerols Conclusions Experimental part References and footnotes 1 2 4 and 6 6 8 10 15 16 18 21 22 25 27 27 28 32 32 42 45 46 49 49 51 52 53 53 61 63 64 64 68 68 70 75 75 93 7 Chapter 5 A Methyl Matters 95 Introduction 96 Results and discussion 101 Chemical synthesis of the phospholipids 101 Formation of the liposomes and proteoliposomes 102 Molecular dynamics study of the bilayers 104 Calcein efflux assay 106 Conclusions and outlook 110 Experimental part 111 References and footnotes 121 Chapter 6 Synthesis of a Cyclooctyne–based Lipidation Probe 123 Introduction 124 Design of a lipophilic lipidation probe 127 Results and discussion 128 Conclusions and outlook 131 Experimental part 132 References 140 Chapter 7 A Missing Link in Archaeal Lipid Biosynthesis; a Contribution from Organic Synthesis 143 Introduction 144 Biosynthesis of archaeal membrane lipids 145 Archaeal lipids as taxanomic markes 149 Results and discussion 149 Synthesis of 2,3-bis-O-(geranylgeranyl)-sn-glycero-1-phosphate 149 Identification of CDP-archaeol synthase 153 Catalytic alcoholysis of benzylglycidol as a key step in the synthesis of cycloarchaeol and -glucosyl-cyclo-archaeol 154 Conclusion 157 Experimental part 157 References and footnotes 167 Summary 171 Samenvatting 175 Acknowledgements 180