Document Type

Dissertation

Date of Degree

Summer 2015

Degree Name

PhD (Doctor of Philosophy)

Degree In

Chemistry

First Advisor

Hien M. Nguyen

First Committee Member

Daniel Quinn

Second Committee Member

Leonard MacGillivray

Third Committee Member

Scott Shaw

Fourth Committee Member

Horacio Olivo

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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