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Asymmetric Synthesis of C-Glycosylated Amino Acids: Incorporation in Collagen Glycopeptides and Evaluation in a Model for Rheumatoid Arthritis
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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 [en]
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: urn:nbn:se:umu:diva-623ISBN: 91-7305-975-7 (print)OAI: oai:DiVA.org:umu-623DiVA: diva2:144020
Public defence
2005-11-25, 13:00
Supervisors
Available from: 2005-11-03 Created: 2005-11-03 Last updated: 2012-05-23Bibliographically approved
List of papers
1. A total synthesis of hydroxylysine in protected form and investigations of the reductive opening of p-methoxybenzylidene acetals
Open this publication in new window or tab >>A total synthesis of hydroxylysine in protected form and investigations of the reductive opening of p-methoxybenzylidene acetals
2004 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 69, no 25, 8694-8701 p.Article in journal (Refereed) Published
Abstract [en]

A synthesis of (2S,5R)-5-hydoxylysine, based on (R)-malic acid and Williams glycine template as chiral precursors, has been developed. This afforded hydroxylysine, suitably protected for direct use in peptide synthesis, in 32% yield over the 13-step sequence. Regioselective reductive opening of a p-methoxybenzylidene acetal and alkylation of the Williams glycine template were key steps in the synthetic sequence. Surprisingly, the regioselectivity in opening of the p-methoxybenzylidene acetal was reversed as compared to what was expected. It was found that this was due to chelation of the trialkylsilyl choride, used as an electrophile in the reductive opening, to an adjacent azide functionality. It was also discovered that an equivalent amount of trialkylsilyl hydride was formed in the reaction, a finding that led to additional mechanistic insight into reductive openings of p-methoxybenzylidene acetals with sodium cyanoborohydride as reducing agent.

Place, publisher, year, edition, pages
Easton, Pa.: American Chemical Society, 2004
Identifiers
urn:nbn:se:umu:diva-14341 (URN)10.1021/jo049136w (DOI)
Available from: 2007-05-29 Created: 2007-05-29 Last updated: 2011-04-15Bibliographically approved
2. Synthesis of a C-glycoside analogue of β-D-galactosyl hydroxynorvaline and its use in immunological studies
Open this publication in new window or tab >>Synthesis of a C-glycoside analogue of β-D-galactosyl hydroxynorvaline and its use in immunological studies
Show others...
2000 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 1, no 4, 272-280 p.Article in journal (Refereed) Published
Abstract [en]

A C-linked isostere of β-d-galactosylated hydroxynorvaline has been prepared in eight steps from per-O-benzylated galactopyranolactone. Addition of a homoallylic Grignard reagent to the lactone, reduction of the resulting hemiacetal with triethylsilane, and a Wittig reaction with Garner's aldehyde were key steps in this synthesis. The C-linked building block was then incorporated at position 264 into the fragment CII(256–270) from type II collagen by solid-phase synthesis using a combination of the tert-butoxycarbonyl (Boc) and 9-fluorenylmethoxycarbonyl (Fmoc) protective group strategies. Deprotection of the benzylated C-linked galactosyl moiety was achieved simultaneously with cleavage of the glycopeptide from the solid phase by using triethylsilyl trifluoromethanesulfonate in TFA. Helper T-cell hybridomas obtained in a mouse model for rheumatoid arthritis responded to the C-linked glycopeptide when presented by class II MHC molecules. However, 10- to 20-fold higher concentrations were required as compared to when O-linked β-d-galactosylated hydroxynorvaline or hydroxylysine (Hyl) were present at position 264 of CII(256–270). Thus, replacement of a single oxygen atom by a methylene group in the carbohydrate moiety of a glycopeptide antigen had a substantial influence on the T-cell response. This reveals that T cells are able to recognize the carbohydrate moiety of glycopeptide antigens with high specificity. Finally, the results suggest that structural modifications of β-d-Gal-Hyl264in CII(256–270) may give altered peptide ligands that can be used for induction of tolerance in autoimmune rheumatoid arthritis.

Place, publisher, year, edition, pages
John Wiley & Sons, 2000
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-4779 (URN)10.1002/1439-7633(20001117)1:4<272::AID-CBIC272>3.0.CO;2-W (DOI)
Available from: 2005-11-03 Created: 2005-11-03 Last updated: 2012-05-23Bibliographically approved
3. Synthesis of a C-glycoside analogue of β-D -galactosyl threonine
Open this publication in new window or tab >>Synthesis of a C-glycoside analogue of β-D -galactosyl threonine
2003 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 68, no 6, 2506-2509 p.Article in journal (Refereed) Published
Abstract [en]

C-linked analogue of β-d-galactosylthreonine has been prepared from 2,3,4,6-tetra-O-benzyl-d-galactopyranolactone (1) in 14 steps. Three stereogenic centers were created during the synthesis, with the anomeric center of the C-glycoside being generated first by addition of a Grignard reagent to 1 and subsequent reduction of the intermediate hemiacetal with triethylsilane. The two stereogenic centers in the threonine moiety were both established by alkylation of Evans' chiral N-acyloxazolidinone enolates.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2003
National Category
Inorganic Chemistry
Identifiers
urn:nbn:se:umu:diva-4780 (URN)10.1021/jo026758d (DOI)
Available from: 2005-11-03 Created: 2005-11-03 Last updated: 2012-05-23Bibliographically approved
4. Synthesis of a C-Glycoside Analogue of -D-Galactosyl Hydroxylysine and Incorporation in a Glycopeptide from Type II Collagen
Open this publication in new window or tab >>Synthesis of a C-Glycoside Analogue of -D-Galactosyl Hydroxylysine and Incorporation in a Glycopeptide from Type II Collagen
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.

Identifiers
urn:nbn:se:umu:diva-16100 (URN)doi:10.1021/jo052256z (DOI)
Available from: 2007-08-17 Created: 2007-08-17 Last updated: 2012-05-23Bibliographically approved

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