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Synthesis of the tetrasaccharide glycoside moiety of Solaradixine and rapid NMR-based structure verification using the program CASPER
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
2016 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 72, no 7, 912-927 p.Article in journal (Refereed) Published
Abstract [en]

The major glycoalkaloid in the roots of Solanum laciniatum is Solaradixine having the branched tetrasaccharide beta-D-Glcp-(1 -> 2)-beta-D-Glcp-(1 -> 3)[alpha-L-Rhap-(1 -> 2)]-beta-D-Galp linked to O3 of the steroidal alkaloid Solasodine. We herein describe the synthesis of the methyl glycoside of the tetrasaccharide using a super-armed disaccharide as a donor molecule. A 2-(naphthyl)methyl protecting group was used in the synthesis of the donor since it was tolerant to a wide range of reaction conditions. The 6-O-benzylated-hexa-O-tert-butyldimethylsilyi-protected beta-D-Glcp-(1 -> 2)-beta-D-Glcp-SEt donor, which avoided 1,6-anydro formation, was successfully glycosylated at O3 of a galactoside acceptor molecule. However, subsequent glycosylation at O2 by a rhamnosyl donor was unsuccessful and instead a suitably protected alpha-L-Rhap(1 -> 2)-beta-D-Galp-OMe disaccharide was used as the acceptor molecule together with a super-armed beta-D-Glcp-(1 -> 2)-beta-D-Glcp-SEt donor in the glycosylation reaction, to give a tetrasaccharide in a yield of 55%, which after deprotection resulted in the target molecule, the structure of which was verified by the NMR chemical shift prediction program CASPER.

Place, publisher, year, edition, pages
2016. Vol. 72, no 7, 912-927 p.
Keyword [en]
Glycosylation, Oligosaccharide, Saponin, CASPER, Chemical shift prediction
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-127344DOI: 10.1016/j.tet.2015.12.042ISI: 000369461900004OAI: oai:DiVA.org:su-127344DiVA: diva2:911301
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2016-03-11 Created: 2016-03-02 Last updated: 2016-11-30Bibliographically approved
In thesis
1. Assembling and Unraveling Carbohydrates Structures: Conformational analysis of synthesized branched oligosaccharides
Open this publication in new window or tab >>Assembling and Unraveling Carbohydrates Structures: Conformational analysis of synthesized branched oligosaccharides
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Advances in the elaboration of vaccines and enzyme inhibitors rely on acquiring more knowledge about protein-carbohydrate binding events. Furthermore, the relationships between biological function and the three-dimensional properties of large glycans can be studied by focusing on the structural components they contained, namely, by scaling down the system under analysis. Chemical methods are useful assets as they allow the isolation and determination of epitopes; these small and recognizable fragments that lead to very specific interactions. In this thesis, biologically relevant saccharides were obtained using recently developed concepts in carbohydrate synthesis and NMR spectroscopy was used to unravel their conformational preferences.

In paper I, the convergent synthesis of the tetrasaccharide found in the natural product solaradixine is described. Reactivity enhanced disaccharide glycosyl donors were coupled to a disaccharide acceptor in a 2 + 2 fashion. The computer program CASPER was subsequently used to verify the synthesized structure.

The conformation arming concept employed in paper I was further investigated in paper II. An NMR-based methodology enabled the determination of the ring conformations of a set of donors. Subsequently, glycosylation reactions were performed and yields were correlated to donors ring shapes. Perturbations in the rings shape caused by bulky silyl ether protective groups were sufficient to boost the potency of several donors. As a matter of fact, complex branched oligosaccharides could be obtained in good to excellent yields.

In paper III, NMR spectroscopy observables were measured to elucidate the ring shape, the mutual orientation of the rings across the glycosidic bond and the positions of the side chains of 5 trisaccharides found in larger structures. With the aid of molecular dynamics simulations, their overall conformational propensities were revealed.

Finally, the software CASPER prediction skills were improved by adding, inter alia, NMR information of synthesized mono- and disaccharides to its database. Unassigned chemical shifts from polysaccharides served as input to challenge its ability to solve large carbohydrate structures.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2016. 85 p.
Keyword
Convergent carbohydrate synthesis, Super-armed donors, Glycosylation, Conformational analysis, NMR, Chemical shift prediction
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-133106 (URN)978-91-7649-473-8 (ISBN)
Public defence
2016-10-21, 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 2: Manuscript. Paper 4: Manuscript.

Available from: 2016-09-28 Created: 2016-08-31 Last updated: 2016-09-29Bibliographically approved

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