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Synthesis of O-linked Carbasugar Analogues of Galactofuranosides and N-linked Neodisaccharides
Stockholm University, Faculty of Science, Department of Organic Chemistry. (Ian Cumpstey)
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.
Keyword [en]
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
Identifiers
URN: urn:nbn:se:su:diva-43561ISBN: 978-91-7447-168-7 (print)OAI: oai:DiVA.org:su-43561DiVA: diva2:360544
Public defence
2010-12-06, 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 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
List of papers
1. First synthesis of 4a-carba-beta-D-galactofuranose
Open this publication in new window or tab >>First synthesis of 4a-carba-beta-D-galactofuranose
2007 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 48, no 52, 9073-9076 p.Article in journal (Refereed) Published
Keyword
Carbasugars, Galactofuranose, Glycomimetics, Ring-closing metathesis
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-21160 (URN)10.1016/j.tetlet.2007.10.138 (DOI)000251846400001 ()
Available from: 2007-12-06 Created: 2007-12-06 Last updated: 2017-12-13Bibliographically approved
2. Synthesis of carbadisaccharide mimics of galactofuranosides
Open this publication in new window or tab >>Synthesis of carbadisaccharide mimics of galactofuranosides
2009 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 50, no 36, 5142-5144 p.Article in journal (Refereed) Published
Keyword
Carbasugars, Galactofuranose, Pseudodisaccharides, Ethers
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-29261 (URN)10.1016/j.tetlet.2009.06.115 (DOI)000268732400020 ()
Available from: 2009-08-19 Created: 2009-08-19 Last updated: 2017-12-13Bibliographically approved
3. Carbasugar analogues of galactofuranosides: β-O-linked derivatives
Open this publication in new window or tab >>Carbasugar analogues of galactofuranosides: β-O-linked derivatives
(English)Manuscript (preprint) (Other academic)
Abstract [en]

A selectively protected carbasugar analogue of β-galactofuranose was synthesised from glucose using ring-closing metathesis as the key step. The carbasugar was converted into an α-galacto configured 1,2-epoxide, which was an effective electrophile in Lewis acid catalysed coupling reactions with alcohols. The epoxide was opened with regioselective attack at C-1 to give β-galacto configured C-1 ethers. Using carbohydrates as nucleophiles, we synthesised a number of pseudodisaccharides.

Keyword
carbasugar, galactofuranose, galactofuranoside, tuberculosis, mycobacterium tuberculosis
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-44209 (URN)
Available from: 2010-11-03 Created: 2010-11-02 Last updated: 2010-11-04Bibliographically approved
4. Carbasugar Analogues of Galactofuranose: Pseudodisaccharide Mimics of Fragments of Mycobacterial Arabinogalactan
Open this publication in new window or tab >>Carbasugar Analogues of Galactofuranose: Pseudodisaccharide Mimics of Fragments of Mycobacterial Arabinogalactan
(English)Manuscript (preprint) (Other academic)
Abstract [en]

A partially protected carbasugar analogue of β-galactofuranose was converted into an α-galacto configured 1,2-epoxide, which was was opened by alcohols under Lewis acid catalysis with regioselective attack at C-1 to give β-galacto configured C-1 ethers. Using OH-5 and OH-6 carbagalactofuranose derivatives as nucleophiles, we synthesised pseudodisaccharide analogues of substructures of the arabinogalactan from M. tuberculosis. The dicarba analogue of the disaccharide Galf(β1→5)Galf was found to moderately inhibit the action of GlfT2 galactofuranosyl transferase from M. tuberculosis.

Keyword
mycobacterial, Glft2, carbasugar, galactofuranose, galactofuranoside, pseudodisaccharide
National Category
Organic Chemistry Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-44210 (URN)
Available from: 2010-11-03 Created: 2010-11-02 Last updated: 2010-11-04Bibliographically approved
5. Carbasugar analogues of galactofuranose: α-O-linked derivatives
Open this publication in new window or tab >>Carbasugar analogues of galactofuranose: α-O-linked derivatives
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Using an indirect method, we have synthesised α-linked carbasugar analogues of galactofuranosides for the first time. Opening of a β-talo configured carbasugar 1,2-epoxide by alcohol nucleophiles under Lewis acidic conditions proceeded with very good regioselectivity to give α-talo configured C-1-substituted ethers with OH-2 free. Inversion of configuration at OH-2 by an oxidation–reduction sequence gave the α-galacto configured carbahexofuranose C-1 ethers. A carbadisaccharide corresponding to the Galf(α1→3)Manp substructure from Apodus deciduus galactomannan was synthesised to exemplify the method.

Keyword
galactofuranose, galactofuranosides, alfa-linked, carbasugars, pseudodisaccharides, glycomimetics, etherification, regioselective
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-44211 (URN)
Available from: 2010-11-03 Created: 2010-11-02 Last updated: 2010-11-04Bibliographically approved
6. N-linked neodisaccharides: Synthesis facilitated by the enhanced reactivity of allylic electrophiles, and glycosidase inhibitory activity
Open this publication in new window or tab >>N-linked neodisaccharides: Synthesis facilitated by the enhanced reactivity of allylic electrophiles, and glycosidase inhibitory activity
Show others...
(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
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
Identifiers
urn:nbn:se:su:diva-44221 (URN)
Available from: 2010-11-03 Created: 2010-11-03 Last updated: 2010-11-04Bibliographically approved

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