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N-linked neodisaccharides: Synthesis facilitated by the enhanced reactivity of allylic electrophiles, and glycosidase inhibitory activity
(Docent Ian Cumpstey)
Stockholm University, Faculty of Science, Department of Organic Chemistry.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Neodisaccharides consisting of two monosaccharides linked by a bridging nitrogen atom have been synthesised. Converting one of the monosaccharide coupling components into an unsaturated derivative enhances its electrophilicity at the allylic position, facilitating coupling reactions. Mitsunobu coupling between nosylamides and 2,3-unsaturated 4-alcohols gave the 4-amino pseudodisaccharides with inversion of configuration as single regio- and diastereoisomers. A palladium catalysed coupling between an amine and a 2,3-unsaturated 4-trichloroacetimidate gave a 2-amino pseudodisaccharide as the major product along with other minor products. Derivatisation of the C=C double bond in pseudodisaccharides allowed the formation of Man(N4–6)Glc and Man(N4–6)Man neodisaccharides. The inhibitory activity of some N-linked neodisaccharides against the enzyme α-Glucosidase II is reported.

Keyword [en]
neodisaccharide, mitsunobu, N-linked, pseudodisaccharide, allylic alcohol, nosylamide, triflamide, Ferrier reaction, alkene functionalisation, alkene oxidation, asymmetric dihydroxylation, dihydroxylation, alfa-glucosidase, glucosidase II
National Category
Organic Chemistry Organic Chemistry
Research subject
Organic Chemistry
URN: urn:nbn:se:su:diva-44221OAI: diva2:360458
Available from: 2010-11-03 Created: 2010-11-03 Last updated: 2010-11-04Bibliographically approved
In thesis
1. Synthesis of O-linked Carbasugar Analogues of Galactofuranosides and N-linked Neodisaccharides
Open this publication in new window or tab >>Synthesis of O-linked Carbasugar Analogues of Galactofuranosides and N-linked Neodisaccharides
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis, carbohydrate mimicry is investigated through the syntheses of carbohydrate analogues and evaluation of their inhibitory effects on carbohydrate-processing enzymes.

Galactofuranosides are interesting structures because they are common motifs in pathogenic microorganisms but not found in mammals. M.tuberculosis, responsible for the disease tuberculosis, has a cell wall containing a repeating unit of alternating (1→5)- and (1→6)-linked β-D-galactofuranosyl residues. Synthetic inhibitors of the enzymes involved in the biosynthesis of the cell wall could find great therapeutic use.

The first part of this thesis describes the first synthesis of the hydrolytically stable carbasugar analogue of galactofuranose, 4a-carba-β-D-Galf, and the synthetic work of synthesising β-linked pseudodisaccharides containing carba-Galf, which were tested for glycosyltransferease inhibitory activity. The pseudodisaccharide carba-Galf-(β1→5)-carba-Galf was found to be a moderate inhibitor of the glycosyltransferase GlfT2 of M.tuberculosis. The thesis also describes how a general method towards biologically relevant α-linked carba-Galf ethers was developed.

The final part of this thesis is focussed on the formation of nitrogen-linked monosaccharides without the participation of the anomeric centre. Such a mode of coupling is called tail-to-tail neodisaccharide formation. The couplings of carbohydrate derivatives via the Mitsunobu reaction are successfully reported herein. The method describes the key introduction of an allylic alcohol in the electrophile and the subsequent functionalisation of the alkene to obtain the neodisaccharide. Two synthesised neodisaccharides presented in this thesis have been sent to be tested for glycosidase inhibitory activity.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2010. 80 p.
carbasugar, galactofuranose, mycobacterium, tuberculosis, ring-closing metathesis, GlfT2, galactan, epoxide-opening, pseudodisaccharide, etherification, regioselective, carbohydrate, carbocycles, glycomimetics, glucosidase, neodisaccharides, Mitsunobu
National Category
Organic Chemistry
Research subject
Organic Chemistry
urn:nbn:se:su:diva-43561 (URN)978-91-7447-168-7 (ISBN)
Public defence
2010-12-06, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript. Paper 5: Manuscript. Paper 6: Manuscript. Available from: 2010-11-14 Created: 2010-10-20 Last updated: 2010-11-17Bibliographically approved

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