Method Development in the Regioselective Glycosylation of Unprotected Carbohydrates
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Downloaded from orbit.dtu.dk on: Oct 10, 2021 Method Development in the Regioselective Glycosylation of Unprotected Carbohydrates Niedbal, Dominika Alina Publication date: 2016 Document Version Publisher's PDF, also known as Version of record Link back to DTU Orbit Citation (APA): Niedbal, D. A. (2016). Method Development in the Regioselective Glycosylation of Unprotected Carbohydrates. DTU Chemistry. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal 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. Method Development in the Regioselective Glycosylation of Unprotected Carbohydrates Ph.D. Thesis Dominika Alina Niedbal August 2016 Department of Chemistry Technical University of Denmark Method Development in the Regioselective Glycosylation of Unprotected Carbohydrates Ph.D. Thesis by Dominika Alina Niedbal Acknowledgments First, I would like to thank Professor Robert Madsen for supervising me during three years I have spent on the project and his help with practical and theoretical aspects of organic chemistry. I would like to express my gratitude to the entire Madsen group and Department of Chemistry, both past and present members, for creating a good working atmosphere. Special thanks to Gyrithe Lanz for being a great lab mate. It was a pleasure to share lab with you, discuss chemistry, life, and listen to good music. I am very grateful to Tamara Lang and Andreas Ahlburg for proofreading this thesis. The Novo Nordisk Foundation is acknowledged for financing my Ph.D. project. Finally, I would like to thank my family and friends for their patience and support. Dominika Niedbal Kongens Lyngby, August 2016 i Abstract The present dissertation describes the research performed at the Technical University of Denmark in the period of February 2013 – January 2016 and involves a study on the tin- and boron-mediated glycosylation of unprotected carbohydrates. Project 1: Tin-mediated glycosylation of unprotected hexopyranosides The regioselective glycosylation at the 6 position in 2,3,4,6-unprotected hexopyranosides has been investigated with dibutyltin oxide as the directing agent. Perbenzylated hexopyranosyl bromides were employed as the donors and the glycosylations were promoted by tetrabutylammonium bromide. The couplings were completely selective and gave rise to a number of 1,6-linked disaccharides with 1,2- cis-linked orientation. Project 1 Tin-mediated glycosylation of unprotected hexopyranosides. Project 2: Boron-mediated glycosylation of unprotected carbohydrates Boron-mediated regioselective Koenigs-Knorr glycosylation has been studied with unprotected acceptors. By means of organoboron derivatives, cis-diols in acceptors can be either activated or masked via an ester formation. Project 2 Organoboron-mediated glycosylation of unprotected carbohydrates. ii Resumé Denne afhandling omhandler forskning, som er udført på Danmarks Tekniske Universitet i perioden februar 2013 – januar 2016 og beskriver undersøgelse af bor og tin medieret glykosylering af ubeskyttede kulhydrater. Projekt 1 Tin medieret glykosylering af ubeskyttede kulhydrater Regioselektive 6-O-glykosyleringer af ubeskyttede glycopyranosider med dibutyltin oxid er undersøgt. Denne glykosyleringsreaktion mellem tin aktiverede acceptorer og ”armed” bromid donorer, under anvendelse af tetrabutylammonium bromid som promotorsystem, gav de tilsvarende (1→6) disakkarider i gode udbytter. Projekt 1 Tin medieret glykosylering af ubeskyttede kulhydrater. Projekt 2 Bor medieret glykosylering af ubeskyttede kulhydrater Bor medieret regioselektiv Koenigs-Knorr glykosylering med ubeskyttede acceptorer er undersøgt. Organoborforbindelser kan enten aktivere eller blokere cis- dioler i acceptoren, og derfor hjælpe med regioselektiv og stereospecifik dannelse af den glykosidiske binding. Projekt 2 Bor medieret glykosylering af ubeskyttede kulhydrater. iii List of Abbreviations Å Angstrom Ac Acetyl acac Acetylacetonate AgOTf Silver triflate Bn Benzyl BTF Benzotrifluoride Bu n-Butyl Bz Benzoyl CSA Camphorsulfonic acid d Doublet (spectral) DAST Diethylaminosulfur trifluoride DCE 1,2-dichloroethane DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DEAD Diethyl azodicarboxylate DIPEA N,N-Diisopropylethylamine DMAP 4-Dimethylaminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO Dimethyl sulfoxide DMTST Dimethyl-(methylthio)-sulfonium triflate DTBPI 2,6-di-tert-butyl pyridinium iodide equiv Equivalent(s) iv Et Ethyl Et2O Diethyl ether Et3N Triethylamine Gal Galactoside Glc Glucoside h Hour(s) HMBC Heteronuclear multiple-bond correlation HRMS High resolution mass spectrometry HSQC Heteronuclear single-quantum correlation IDCP Iodonium dicollidine perchlorate IR Infrared spectroscopy J Coupling constant LG Leaving group m Meta m Multiplet (spectral) Me Methyl MS Molecular sieves NBS N-Bromosuccinimide NIS N-Iodosuccinimide NMR Nuclear magnetic resonance NPG Non-participating group o Ortho p Para Pent n-Pentenyl v PG Participating group Ph Phenyl Phth Phthalimido ppm Parts per million rt Room temperature RVC cathode Reticulated Vitreous Carbon cathode s Singlet (NMR) SET Single-electron Transfer t Triplet (NMR) TBAHS Tetrabutylammonium hydrogen sulfate TBDMSCl tert-Butyldimethylsilyl chloride TBTU 2-(1H-Benzotriazole-1-yl)-1,1,3,3- tetramethyluronium tetrafluoroborate Tf Trifluoromethanesulfonyl TfO- Trifluoromethanesulfonate THF Tetrahydrofuran TLC Thin layer chromatography TMS Trimethylsilyl TMSI Trimethylsilyl iodide TMU 1,1,3,3-tetramethylurea TMSOTf Trimethylsilyl trifluoromethanesulfonate Tol Tolyl UV Ultraviolet vi vii Publications Publication Included in the Appendix “Halide-mediated regioselective 6-O-glycosylation of unprotected hexopyranosides with perbenzylated glycosyl bromide donors” viii Table of Contents Acknowledgments ...................................................................................................... i Abstract ..................................................................................................................... ii Resumé ..................................................................................................................... iii List of Abbreviations ............................................................................................... iv Publications ............................................................................................................ viii 1 Aim of the project .............................................................................................. 1 2 Introduction ........................................................................................................ 3 2.1 Anomeric effect .......................................................................................... 6 2.2 Glycosyl donors .......................................................................................... 8 2.2.1 n-Pentenyl glycosides ......................................................................... 8 2.2.1.1 Armed-disarmed approach ........................................................... 9 2.2.2 Glycosyl imidates .............................................................................. 10 2.2.3 Thioglycosides .................................................................................. 12 2.2.4 Glycosyl halides ................................................................................ 16 2.2.4.1 Glycosyl fluorides ...................................................................... 16 2.2.4.2 Glycosyl bromides ..................................................................... 17 2.2.4.3 Glycosyl iodides ........................................................................ 20 2.3 1,2-cis O-glycosylations ........................................................................... 23 2.4 Glycosylation with unprotected or partially protected carbohydrates ...... 32 2.5 Metal-mediated alkylations, acylations and glycosylations ..................... 38 2.5.1 Tin-mediated glycosylations ............................................................. 45 2.5.2 Boron-mediated glycosylations......................................................... 53 3 Results and discussion ..................................................................................... 57 3.1 Halide-mediated glycosylation ................................................................. 57 3.1.1 Synthesis of glycosyl donors............................................................. 57 ix 3.1.2 Optimization of glycosylation ........................................................... 65 3.1.2.1 Solvent studies ........................................................................... 66 3.1.2.2 Studies of different tin species ................................................... 70 3.1.2.3 Promoter studies ........................................................................ 71 3.1.2.4 Further optimization and synthesis of various