Document Type

Dissertation

Date of Degree

Summer 2015

Degree Name

PhD (Doctor of Philosophy)

Degree In

Chemistry

First Advisor

Hien M. Nguyen

Abstract

The stereoselective formation of 1,2-cis-2-amino glycosides remains a challenging obstacle for researchers seeking to study glycan function in nature. A variety of techniques to form α-linked C(2)-aminoglycosides are examined herein. The most prominent of these techniques is the nickel catalyzed stereoselective coupling of C(2)-N-benzylidine protected trichloroacetimidates to form 1,2-cis-2-amino sugars. This protocol demonstrates excellent α-selectivity and is applicable to a large structural variety of C(2)-aminoglycosyl donors and acceptors.

The application of the nickel catalyzed stereoselective coupling of C(2)-N-benzylidine protected trichloroacetimidates toward the synthesis of pseudosaccharides of glycosylphosphatidyl inositol (GPI) anchors and mycothiol (MSH) in good yield and with excellent α-selectivity was also examined. In stark contrast, employing conventional Lewis acids to activate trichloroacetimidate donors provided the desired pseudodisaccharides with poor α-selectivity. Additionally, the facile synthesis of both C(1)- and C(6)-hydroxyl myo-inositols bearing differentiated protecting groups from a common and easily attainable intermediate allows access to a wide variety of GPI anchor and MSH pseudosaccharides.

The highly α-selective and scalable synthesis of the Fmoc-protected GalNAc-threonine amino acid and TN antigen in large quantities is also described. The challenging 1,2-cis-2-amino glycosidic bond is addressed through a coupling of threonine residues with C(2)-N-ortho-(trifluoromethyl)benzylidenamino trihaloacetimidates mediated by Ni(4-F-PhCN)4(OTf)2. The desired 1,2-cis-2-amino glycoside was obtained in large quantities with α-only selectivity and subsequently transformed into the Fmoc-protected GalNAc-threonine and TN antigen.

With the establishment of 1,2-cis-selective synthesis of heparan disaccharides, we sought to develop multivalent inhibitors of heparanase. A model study of protein/glycan interactions, in which various macromolecular architectures were examined, was developed using Concanavalin A as the model protein. Preparations of the highly-ordered monoantennary, homofunctional diantennary, and heterofunctional diantennary glycopolymers of α-mannose and beta-glucose were achieved via ring opening metathesis polymerization. Isothermal titration calorimetry measurements of these synthetic glycopolymers with Concanavalin A, which has been reported to bind strongly to α-mannose unit, revealed that heterofunctional diantennary architectures bearing both α-mannose and non-binding beta-glucose residues, glucose units, enhanced binding affinity.

Public Abstract

The stereoselective formation of 1,2-cis-2-amino glycosides remains a challenging obstacle for researchers seeking to study glycan function in nature. A variety of techniques to form α-linked C(2)-aminoglycosides are examined herein. The most prominent of these techniques is the nickel catalyzed stereoselective coupling of C(2)- N-benzylidine protected trichloroacetimidates to form 1,2-cis-2-amino sugars. This protocol demonstrates excellent α-selectivity and is applicable to a large structural variety of C(2)-aminoglycosyl donors and acceptors.

The application of the nickel catalyzed stereoselective coupling of C(2)- N-benzylidine protected trichloroacetimidates toward the synthesis of pseudosaccharides of glycosylphosphatidyl inositol (GPI) anchors and mycothiol (MSH) in good yield and with excellent α-selectivity was also examined. In stark contrast, employing conventional Lewis acids to activate trichloroacetimidate donors provided the desired pseudodisaccharides with poor α-selectivity. Additionally, the facile synthesis of both C(1)- and C(6)-hydroxyl myo-inositols bearing differentiated protecting groups from a common and easily attainable intermediate allows access to a wide variety of GPI anchor and MSH pseudosaccharides.

The highly α-selective and scalable synthesis of the Fmoc-protected GalNAc-threonine amino acid and TN antigen in large quantities is also described. The challenging 1,2-cis-2-amino glycosidic bond is addressed through a coupling of threonine residues with C(2)- N-ortho-(trifluoromethyl)benzylidenamino trihaloacetimidates mediated by Ni(4-F-PhCN)4(OTf)2. The desired 1,2-cis-2-amino glycoside was obtained in large quantities with α-only selectivity and subsequently transformed into the Fmoc-protected GalNAc-threonine and TN antigen.

With the establishment of 1,2-cis-selective synthesis of heparan disaccharides, we sought to develop multivalent inhibitors of heparanase. A model study of protein/glycan interactions, in which various macromolecular architectures were examined, was developed using Concanavalin A as the model protein. Preparations of the highly-ordered monoantennary, homofunctional diantennary, and heterofunctional diantennary glycopolymers of α-mannose and β-glucose were achieved via ring opening metathesis polymerization. Isothermal titration calorimetry measurements of these synthetic glycopolymers with Concanavalin A, which has been reported to bind strongly to α-mannose unit, revealed that heterofunctional diantennary architectures bearing both α-mannose and non-binding β-glucose residues, glucose units, enhanced binding affinity.

Keywords

publicabstract

Pages

xxvi, 399 pages

Bibliography

Includes bibliographical references (pages 384-399).

Copyright

Copyright 2015 Matthew S. McConnell

Included in

Chemistry Commons

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