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Synthesis of a C-Glycoside Analogue of -D-Galactosyl Hydroxylysine and Incorporation in a Glycopeptide from Type II Collagen
Umeå University, Faculty of Science and Technology, Chemistry.
Umeå University, Faculty of Science and Technology, Chemistry.
Umeå University, Faculty of Science and Technology, Chemistry.
2006 (English)In: Journal of Organic Chemistry, Vol. 71, no 5, 1911-9 p.Article in journal (Refereed) Published
Abstract [en]

A stereoselective synthesis of the C-glycoside analogue of -D-galactosyl-(5R,2S)-hydroxylysine (1) has been achieved starting from tetra-O-benzyl-D-galactopyranosyl lactone. The synthesis involved establishment of three stereogenic centers in an unambiguous manner. A facially selective Grignard reaction followed by a silane reduction was used for the anomeric position of the C-galactose residue. An Evans allylation established the configuration of the -aminomethylene group of the hydroxylysine moiety, whereas an asymmetric hydrogenation utilizing Burk's catalyst was used for the -amino acid moiety itself. The synthesis was completed in 17 steps with an overall yield of 18%, resulting in the most complex and functionalized C-glycoside analogue of a naturally occurring glycosylated amino acid prepared to date. In addition, amino acid 1 was incorporated in a glycopeptide from type II collagen known to be crucial for the response of autoimmune T cells obtained in models of rheumatoid arthritis. A preliminary immunological study revealed that four out of five members in a panel of T cell hybridomas were able to recognize this C-linked glycopeptide when presented by Aq class II MHC molecules.

Place, publisher, year, edition, pages
2006. Vol. 71, no 5, 1911-9 p.
Identifiers
URN: urn:nbn:se:umu:diva-16100DOI: doi:10.1021/jo052256zOAI: oai:DiVA.org:umu-16100DiVA: diva2:155773
Available from: 2007-08-17 Created: 2007-08-17 Last updated: 2012-05-23Bibliographically approved
In thesis
1. Asymmetric Synthesis of C-Glycosylated Amino Acids: Incorporation in Collagen Glycopeptides and Evaluation in a Model for Rheumatoid Arthritis
Open this publication in new window or tab >>Asymmetric Synthesis of C-Glycosylated Amino Acids: Incorporation in Collagen Glycopeptides and Evaluation in a Model for Rheumatoid Arthritis
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes stereoselective syntheses of four amino acids, three of which are C-glycosidic analogues of glycosylated amino acids. The overall goal of the project was to probe the interactions between MHC molecules, glycopeptide antigens and T cell receptors, that are essential for development of collagen induced arthritis. Collagen induced arthritis is a frequently used mouse model for rheumatoid arthritis, an autoimmune disease that attacks joint cartilage and leads to a painful and eventually crippling condition.

The thesis is based on four studies. The first study describes the synthesis of hydroxylysine, an amino acid that is found in collagen and is an important constituent of the glycopeptide proposed as an antigen in collagen induced arthritis. During the synthesis of hydroxylysine some new insight into the mechanism of the reductive opening of p-methoxybenzylidene acetals was obtained.

The remaining three studies deals with the synthesis of C-glycosidic analogues of glycosylated amino acids, hydroxy norvaline, threonine and hydroxylysine.The synthesis of each amino acid required control of several stereogenic centra and utilizes a variety of approaches such as use of stereoselective reactions, chiral auxilaries, chiral templates and asymmetric catalysis.

The C-glycosidic analogues of galactosylated hydroxynorvaline and hydroxylysine were incorporated in glycopeptides from type II collagen and evaluated in T cell response assays. It was found that the T cells were stimulated by the C-glycopeptides, but that higher concentrations were required than for the native O-glycopeptide

Place, publisher, year, edition, pages
Umeå: Kemi, 2005. 93 p.
Keyword
Total synthesis, stereoselective synthesis, chiral glycine templates, Evan’s alkylation, asymmetric hydrogenation, alpha-amino acid synthesis, C-glycoside, rheumatoid arthritis, MHC, T cell
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-623 (URN)91-7305-975-7 (ISBN)
Public defence
2005-11-25, 13:00
Supervisors
Available from: 2005-11-03 Created: 2005-11-03 Last updated: 2012-05-23Bibliographically approved

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