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Structure, dynamics and reactivity of carbohydrates: NMR spectroscopic studies
Stockholm University, Faculty of Science, Department of Organic Chemistry.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The main focus of this thesis is on the ring conformations of carbohydrate molecules; how the conformational equilibria and the rates of the associated interconversions are affected by the molecular constitution and their surroundings.

The conformational equilibria of a group of amine linked pseudodisaccharides, designed as potential glycosidase inhibitors, comprising α-D-altrosides are described in Chapter 3. The OS2 conformation was largely populated, and the ring conformation was found to depend on the charge of the amine functionality.

The conformations of β-D-xylopyranoside derivatives with naphthyl-based aglycones, which are potential anti-cancer agents, are described in chapter 4. Solvent dependent flexibility was observed. Intramolecular hydrogen bonds were concluded to be involved in the stabilization of 1C4 conformers in non-hydrogen bonding solvents of low polarity.

Chapter 5 describes the first measurements of the conformational exchange rates of mannuronic acid ester derivatives between the 4C1 and 1C4 conformations, through DNMR measurements. The relative reactivity of glycosyl triflates as electrophiles in glycosylation reactions were investigated with NMR-based competition experiments.

In Chapter 6, investigations of ruthenium-catalyzed epimerizations of the allylic alcohols of glycal derivatives, and stereoselective synthesis of esters through a DYKAT protocol, are described. The kinetics of the epimerizations were elaborated through different NMR-spectroscopic methods.

Chapter 7 describes additions of NMR chemical shift data of mono- and oligosaccharides to database of the computer program CASPER, and applications thereof.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2013. , 67 p.
Keyword [en]
Carbohydrates, Conformation, NMR spectroscopy, Hydrogen bond
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-92408ISBN: 978-91-7447-730-6 (print)OAI: oai:DiVA.org:su-92408DiVA: diva2:641740
Public defence
2013-09-20, Magnélisalen, Kemiska Övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: Submitted. Paper 5: Manuscript.

Available from: 2013-08-29 Created: 2013-08-02 Last updated: 2016-04-11Bibliographically approved
List of papers
1. pK(a)-Determination and Conformational Studies by NMR Spectroscopy of D-Altrose-Containing and other Pseudodisaccharides as Glycosidase Inhibitor Candidates
Open this publication in new window or tab >>pK(a)-Determination and Conformational Studies by NMR Spectroscopy of D-Altrose-Containing and other Pseudodisaccharides as Glycosidase Inhibitor Candidates
2012 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 1, 74-84 p.Article in journal (Refereed) Published
Abstract [en]

The pK(a) values of six amine-linked pseudodisaccharides have been determined by using an NMR-based titration method. The pK(a) varies significantly depending on the linkage position and is inversely correlated with the number of electronegative groups in the beta-position to the amino group. Four of the pseudodisaccharides contain alpha-altroside moieties, the conformations of which were determined in the protonated and neutral states, again by using NMR techniques. In the neutral state, 2-amino-2-deoxyaltrosides and 3-amino-3-deoxyaltrosides were both found to occupy C-4(1) and S-O(2) conformations. On protonation, little change in the population distribution was seen for the 3-amino-3-deoxyaltrosides, but for the 2-amino-2-deoxyaltrosides, a shift in equilibrium position towards the skew conformer (more than 80% populated) takes place, and also a small amount of the other chair conformer (i.e., C-1(4), approximately 10% populated) was observed. 3-Amino-3-deoxyaltrosides have been shown to act as glycosidase inhibitors and insights into conformational equilibria as a function of protonation state should facilitate the design of better glycosidase inhibitors based on flexible monosaccharide amines.

Keyword
Carbohydrates, Conformation analysis, NMR spectroscopy, Protonation, Inhibitors, Enzymes
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-76752 (URN)10.1002/ejoc.201101385 (DOI)000299294000010 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Note
4Available from: 2012-05-18 Created: 2012-05-16 Last updated: 2017-12-07Bibliographically approved
2. Synthesis, conformation and biology of naphthoxylosides
Open this publication in new window or tab >>Synthesis, conformation and biology of naphthoxylosides
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2011 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 19, no 13, 4114-4126 p.Article in journal (Refereed) Published
Abstract [en]

Proteoglycans (PG) are polyanionic proteins consisting of a core protein substituted with carbohydrate chains, that is, glycosaminoglycans (GAG). The biosynthesis of GAG can be manipulated by simple xylosides carrying hydrophobic aglycons, which can enter the cell and initiate the biosynthesis. While the importance of the aglycon is well investigated, there is far less information on the effect of modifications in the xylose residue.

We have developed a new synthetic protocol, based on acetal protection and selective benzylation, for modification of the three hydroxyl groups in xylose. Thus we have synthesized twelve analogs of 2-naphthyl β-d-xylopyranoside (XylNap), where each hydroxyl group has been epimerized or replaced by methoxy, fluoro, or hydrogen.

To gain more information about the properties of xylose, conformational studies were made on some of the analogs. It was found that the 4C1 conformation is highly predominant, accompanied by a nonnegligible population of the 2S0 conformation. However, deoxygenation at C3 results in a large portion of the 1C4 conformation.

The GAG priming ability and proliferation activity of the twelve analogs, were investigated using a matched pair of human breast fibroblasts and human breast carcinoma cells. None of the analogs initiated the biosynthesis of GAG, but an inhibitory effect on endogenous PG production was observed for analogs fluorinated or deoxygenated at C4. From our data it seems reasonable that all three hydroxyl groups in XylNap are essential for the priming of GAG chains and for selective toxicity for tumor cells.

Keyword
Naphthoxylosides, synthesis, conformational analysis, antiproliferative activity, tumor cells, glycosaminoglycan
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-59713 (URN)10.1016/j.bmc.2011.05.007 (DOI)000291934700027 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2011-07-06 Created: 2011-07-06 Last updated: 2017-12-11Bibliographically approved
3. Exploration of conformational flexibility and hydrogen bonding of xylosides in different solvents, as a model system for enzyme active site interactions
Open this publication in new window or tab >>Exploration of conformational flexibility and hydrogen bonding of xylosides in different solvents, as a model system for enzyme active site interactions
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2013 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 11, no 33, 5465-5472 p.Article in journal (Refereed) Published
Abstract [en]

The predominantly populated conformation of carbohydrates in solution does not necessarily represent the biologically active species; rather, any conformer accessible without too large an energy penalty may be present in a biological pathway. Thus, the conformational preferences of a naphthyl xyloside, which initiates in vivo synthesis of antiproliferative glycosaminoglycans, have been studied by using NMR spectroscopy in a variety of solvents. Equilibria comprising the conformations 4C12SO and 1C4 were found, with a strong dependence on the hydrogen bonding ability of the solvent. Studies of fluorinated analogues revealed a direct hydrogen bond from the hydroxyl group at C2 to the fluorine atom at C4 by a 1hJF4,HO2 coupling. Hydrogen bond directionality was further established via comparisons of fluorinated levoglucosan molecules.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-92472 (URN)10.1039/C3OB40991K (DOI)000323141800010 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2013-08-07 Created: 2013-08-06 Last updated: 2017-12-06Bibliographically approved
4. Chair interconversion and reactivity of mannuronic acid esters
Open this publication in new window or tab >>Chair interconversion and reactivity of mannuronic acid esters
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2013 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 11, no 46, 8127-8134 p.Article in journal (Refereed) Published
Abstract [en]

Mannopyranosyluronic acids display a very unusual conformation behavior in that they often prefer to adopt a C-1(4) chair conformation. They are endowed with a strikingly high reactivity when used in a glycosylation reaction as a glycosyl donor. To investigate the unusual conformational behavior a series of mannuronic acid ester derivatives, comprising anomeric triflate species and O-methyl glycosides, was examined by dynamic NMR experiments, through lineshape analysis of H-1 and F-19 NMR spectra at various temperatures from -80 degrees C to 0 degrees C. Exchange rates between C-4(1) and C-1(4) chair conformations were found to depend on the electronic properties and the size of the C2 substituent (F, N-3 or OBn) and the aglycon, with higher exchange rates for the glycosyl triflates and smaller C2 substituents. Low temperature F-19 exchange spectroscopy experiments showed that the covalently bound anomeric triflates did not exchange with free triflate species present in the reaction mixture. To relate the conformational behavior of the intermediate triflates to their reactivity in a glycosylation reaction, their relative reactivity was determined via competition reactions monitored by H-1 NMR spectroscopy at low temperature. The 2-O-benzyl ether compound was found to be most reactive whereas the 2-fluoro compound - the most flexible of the studied compounds - was least reactive. Whereas the ring-flip of the mannuronic acids is important for the enhanced reactivity of the donors, the rate of the ring-flip has little influence on the relative reactivity.

National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-98249 (URN)10.1039/c3ob41747f (DOI)000327682400018 ()
Note

AuthorCount:5;

Available from: 2014-01-03 Created: 2014-01-03 Last updated: 2017-12-06Bibliographically approved
5. Epimerization of Glycal Derivatives by a Cyclopentadienylruthenium Catalyst: Application to Metalloenzymatic DYKAT
Open this publication in new window or tab >>Epimerization of Glycal Derivatives by a Cyclopentadienylruthenium Catalyst: Application to Metalloenzymatic DYKAT
2014 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, no 45, 14756-14762 p.Article in journal (Refereed) Published
Abstract [en]

Epimerization of a non-anomeric stereogenic center in carbohydrates is an important transformation in the synthesis of natural products. In this study an epimerization procedure of the allylic alcohols of glycals by cyclopentadienylruthenium catalyst 1 is presented. The epimerization of 4,6-O-benzylidene-D-glucal 4 in toluene is rapid, and an equlibrium with its D-allal epimer 5 is established within 5min at room temperature. Exchange rates for allal and glucal formation were determined by 1D H-1 EXSY NMR experiments to be 0.055s(-1) and 0.075s(-1), respectively. For 4-O-benzyl-L-rhamnal 8 the epimerization was less rapid and four days of epimerization was required to achieve equilibration of the epimers at room temperature. The epimerization methodology was subsequently combined with acylating enzymes in a dynamic kinetic asymmetric transformation (DYKAT), giving stereoselective acylation to the desired stereoisomers 12, 13, and 15. The net effect of this process is an inversion of a stereogenic center on the glycal, and yields ranging from 71% to 83% of the epimer were obtained.

Place, publisher, year, edition, pages
Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA, 2014
Keyword
carbohydrates, dynamic kinetic asymmetric transformation, enzyme catalysis, inversion, NMR spectroscopy
National Category
Chemical Sciences Organic Chemistry
Identifiers
urn:nbn:se:su:diva-110176 (URN)10.1002/chem.201403720 (DOI)000344358900029 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Note

AuthorCount:4;

Available from: 2015-02-09 Created: 2014-12-08 Last updated: 2017-12-04Bibliographically approved
6. Complete H-1 and C-13 NMR chemical shift assignments of mono- to tetrasaccharides as basis for NMR chemical shift predictions of oligosaccharides using the computer program CASPER
Open this publication in new window or tab >>Complete H-1 and C-13 NMR chemical shift assignments of mono- to tetrasaccharides as basis for NMR chemical shift predictions of oligosaccharides using the computer program CASPER
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2013 (English)In: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 380, 156-166 p.Article in journal (Refereed) Published
Abstract [en]

H-1 and C-13 NMR chemical shift data are used by the computer program CASPER to predict chemical shifts of oligo- and polysaccharides. Three types of data are used, namely, those from monosaccharides, disaccharides, and trisaccharides. To improve the accuracy of these predictions we have assigned the H-1 and C-13 NMR chemical shifts of eleven monosaccharides, eleven disaccharides, twenty trisaccharides, and one tetrasaccharide; in total 43 compounds. Five of the oligosaccharides gave two distinct sets of NMR resonances due to the alpha- and beta-anomeric forms resulting in 48 H-1 and C-13 NMR chemical shift data sets. In addition, the pyranose ring forms of Neu5Ac were assigned at two temperatures, due to chemical shift displacements as a function of temperature. The H-1 NMR chemical shifts were refined using total line-shape analysis with the PERCH NMR software. H-1 and C-13 NMR chemical shift predictions were subsequently carried out by the CASPER program (http://www.casper.organ.su.se/casper/) for three branched oligosaccharides having different functional groups at their reducing ends, namely, a mannose-containing pentasaccharide, and two fucose-containing heptasaccharides having N-acetyllactosamine residues in the backbone of their structures. Good to excellent agreement was observed between predicted and experimental H-1 and C-13 NMR chemical shifts showing the utility of the method for structural determination or confirmation of synthesized oligosaccharides.

Keyword
Oligosaccharide, Glycan, Chemical shift prediction, Automation
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-95416 (URN)10.1016/j.carres.2013.06.026 (DOI)000325167400024 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Note

AuthorCount:12;

Available from: 2013-10-31 Created: 2013-10-28 Last updated: 2017-09-07Bibliographically approved

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