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Structure-Reactivity Relationships of Conformationally Armed Disaccharide Donors and Their Use in the Synthesis of a Hexasaccharide Related to the Capsular Polysaccharide from Streptococcus pneumoniae Type 37
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.ORCID-id: 0000-0001-8303-4481
2017 (Engelska)Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 82, nr 15, s. 8123-8140Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

To advance the field of glycobiology, efficient synthesis methods of oligosaccharides and glycoconjugates are a requisite. In glycosylation reactions using superarmed donors, both selectivity and reactivity issues must be considered, and we herein investigate these aspects for differently protected beta-linked 2-O-glycosylated glucosyl donors carrying bulky tert-butyldimethylsilyl groups to different extents. The acceptors in reactions being secondary alcohols presents a challenging situation with respect to steric crowding. Conformational pyranose ring equilibria of the superarmed disaccharide donors with axial-rich substituents contained skew and boat conformations, and three-state models were generally assumed. With NIS/TfOH as the promotor, 2,6-di-tert-butyl-4-methylpyridine as the base, and a dichloromethane/toluene solvent mixture, ethyl 1-thio-beta-d-glucosyl disaccharide donors having 6-O-benzyl group(s) besides tert-butyldimethylsilyl groups were efficiently coupled at -40 degrees C to the hydroxyl group at position 3 of glucopyranosyl acceptors to form beta-(1 -> 2),beta-(1 -> 3)-linked trisaccharides, isolated in excellent 95% yield. The more axial-rich donors in skew and boat conformations are thus preorganized closer to the assumed transition state in these glycosylation reactions. The developed methodology was subsequently applied in the synthesis of a multibranched hexasaccharide related to the capsular polysaccharide from Streptococcus pneumoniae type 37, which consists of a beta-(1 -> 3)-linked backbone and a beta-(1 -> 2)-linked side chain of D-glucosyl residues in disaccharide repeating units.

Ort, förlag, år, upplaga, sidor
2017. Vol. 82, nr 15, s. 8123-8140
Nationell ämneskategori
Organisk kemi
Forskningsämne
organisk kemi
Identifikatorer
URN: urn:nbn:se:su:diva-147106DOI: 10.1021/acs.joc.7b01264ISI: 000407307700041PubMedID: 28682619OAI: oai:DiVA.org:su-147106DiVA, id: diva2:1148487
Forskningsfinansiär
VetenskapsrådetKnut och Alice Wallenbergs Stiftelse
Anmärkning

Open Access 2019-09-01

Tillgänglig från: 2017-10-11 Skapad: 2017-10-11 Senast uppdaterad: 2019-09-09Bibliografiskt granskad
Ingår i avhandling
1. Assembling and Unraveling Carbohydrates Structures: Conformational analysis of synthesized branched oligosaccharides
Öppna denna publikation i ny flik eller fönster >>Assembling and Unraveling Carbohydrates Structures: Conformational analysis of synthesized branched oligosaccharides
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Stockholm: Department of Organic Chemistry, Stockholm University, 2016. s. 85
Nyckelord
Convergent carbohydrate synthesis, Super-armed donors, Glycosylation, Conformational analysis, NMR, Chemical shift prediction
Nationell ämneskategori
Organisk kemi
Forskningsämne
organisk kemi
Identifikatorer
urn:nbn:se:su:diva-133106 (URN)978-91-7649-473-8 (ISBN)
Disputation
2016-10-21, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (Engelska)
Opponent
Handledare
Anmärkning

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 4: Manuscript.

Tillgänglig från: 2016-09-28 Skapad: 2016-08-31 Senast uppdaterad: 2017-10-11Bibliografiskt granskad
2. The sweet side of molecular structure: NMR spectroscopic studies of glycans and their interactions with proteins
Öppna denna publikation i ny flik eller fönster >>The sweet side of molecular structure: NMR spectroscopic studies of glycans and their interactions with proteins
2015 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

In this thesis, within the topic of bioorganic chemistry, the molecular structure of carbohydrates has been studied. Carbohydrates, or glycans, are ubiquitous biomolecules exhibiting a wide range of biological roles. The specific functions of these molecules are largely determined by their interactions with proteins and molecular structure ultimately governs such specialized recognition events.

Glycan-binding proteins, such as lectins or enzymes, often interact with their sweet ligands in a transient fashion and nuclear magnetic resonance spectroscopy (NMR) is a viable technique to probe these complexes. In particular, ligand-based NMR techniques have been employed, typically in combination with other biophysical as well as biochemical and computational methods. The aim of this work has been to gain new insights about specific biological systems, to develop methods and to devise protocols for their studies.

The first two papers cover NMR-interaction studies of native ligands as well as inhibitor glycans with the enzyme hen egg-white lysozyme and the lectin botulinum neurotoxin type A. Screening experiments were performed to investigate ligand affinities and selectivities. Solution models in combination with X-ray crystal structures were compared in order to evaluate their agreement and the details of interactions.

A method for application in carbohydrate ligand NMR-screening was developed in paper three. The heteronucleus selenium was exploited as a reporter of selenoglycosides binding to lectins. 77Se NMR spectroscopy proved sensitive to binding events and the presented approach should be useful in large screenings of glycomimetic inhibitors.  In order to obtain sufficient amounts of glycans for bioorganic studies their production often relies on chemical synthesis. In the last paper, the structure of some conformationally highly activated glycosyl donors was thoroughly investigated and related to their reactivity in synthetic glycosylation reactions.  

Ort, förlag, år, upplaga, sidor
Stockholm: Department of Organic Chemistry, Stockholm University, 2015. s. 77
Nyckelord
bioorganic chemistry, glycans, ligand-based NMR, molecular simulations, protein-carbohydrate interactions, lectins, carbohydrate conformations, 77Se NMR, structure-reactivity relationships, super-armed donors
Nationell ämneskategori
Organisk kemi
Forskningsämne
organisk kemi
Identifikatorer
urn:nbn:se:su:diva-112350 (URN)978-91-7649-083-9 (ISBN)
Disputation
2015-02-20, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (Engelska)
Opponent
Handledare
Anmärkning

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.

 

Tillgänglig från: 2015-01-29 Skapad: 2015-01-12 Senast uppdaterad: 2017-10-11Bibliografiskt granskad

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