Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1998-11-17
2002-04-23
Woodward, Michael P (Department: 1631)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C549S356000, C549S429000, C549S563000
Reexamination Certificate
active
06376662
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method for synthesizing C-glycosides of ulosonic acids, as well as intermediates thereof and particular C-glycosides prepared by the method.
BACKGROUND ART
&agr;-O-glycosides of N-acetylneuraminic acid (Neu5Ac, 1, Scheme 1) are often found terminating the oligosaccharide component of cell-surface glycoproteins and glycolipids. Neu5Ac is involved in a number of important biological events: intercellular interactions such as adhesion, aggregation and agglutination; masking of antigenic oligosaccharides and suppressing undesired immune reactions (antirecognition phenomena); influencing the cell membrane permeability for permeability for ions, amino acids and proteins; and protection of glycoproteins against proteolysis
1
. Terminal Neu5Ac is an attachment site of pathogens to the cells and often catabolic and inflammatory processes are initiated on the removal of this carbohydrate group
2
. In general the “right” life time of a cell is a reflection of a delicate balance between the introduction and removal of terminal Neu5Ac or other sialic acids.
The glycosidic bond of Neu5Ac is cleaved in vivo by hydrolase type enzymes, called neuraminidases
3
. Therefore, designing nonhydrolyzable analogs of Neu5Ac-&agr;-O-glycosides is an attractive approach to control, at the molecular level, events of crucial importance to glycobiology and immunology. The replacement of the interglycosidic oxygen atom by a methylene group, for example, generates a class of hydrolytically and metabolically inert isosteres, the Neu5Ac C-glycosides. Despite several elegant methods for direct carbon-carbon (C—C) bond formation at the anomeric center in aldoses and ketoses
4
, no major advances have been reported in the synthesis of Neu5Ac C-glycosides
5
. The major problem confounding their synthesis is the requirement that the C—C bond being formed results in a quaternary C-atom.
DISCLOSURE OF THE INVENTION
Accordingly, an object of the present invention is to provide a method for synthesizing C-glycosides of ulosonic acids such as Neu5Ac, by which diastereocontrolled synthesis of &agr;-C-glycosides of ulosonic acids is attained. Another object of the present invention is to provide intermediates of the novel method, and to provide novel C-glycosides of particular ulosonic acids, which are synthesized by the novel method.
The present inventors intensively studied to discover that diastereocontrolled synthesis of &agr;-C-glycosides of ulosonic acids is attained by carrying out the reaction between ulosonic acid sulfone or phosphite with an aldehyde or ketone compound in the presence of a lanthanide metal halide such as SmI
2
, thereby completing the present invention.
That is, the present invention provides a method for synthesizing C-glycosides of ulosonic acids comprising the step of reacting an ulosonic acid sulfone or phosphite with an aldehyde or ketone compound in the presence of a lanthanide metal halide.
Preferably, the lanthanide metal halide of the invention is a halide of samarium (II).
The present invention also provides a method for synthesizing C-glycosides of carbohydrates containing a quaternary carbon comprising the step of reacting said carbohydrate with an aldehyde or ketone compound in the presence of a lanthanide metal halide.
The present invention still also provides a method for synthesizing C-glycosides of neuraminic acids or sialic acids comprising the step of reacting the protected neuraminic acid or sialic acid sulfone or phosphite with an aldehyde or ketone compound in the presence of a lanthanide metal halide.
The present invention still also provides a method for synthesizing C-glycosides of KDO comprising the step of reacting the protected KDO sulfone or phosphite with an aldehyde or ketone compound in the presence of a lanthanide metal halide.
The present invention still also provides a method for synthesizing C-glycosides of KDN comprising the step of reacting the protected KDN sulfone or phosphite with an aldehyde or ketone compound in the presence of a lanthanide metal halide.
The present invention still also provides a samarium III adduct of ulsonic acids. The present invention still further provides a samarium III adduct of ulsonic acids.
The present invention still further provides a samarium III adduct of carbohydrates containing a quaternary carbon. The present invention still further provides a samarium III adduct of neuraminic acids or sialic acids. The present invention still further provides a samarium III adduct of 3-deoxy-D-manno-octulosonic acid. The present invention still further provides a samarium III adduct of 2-keto-3-deoxy-D-glycero-d-galactonononanoic acid.
The present invention still further provides C-disaccharide having the structure, methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2,6-anhydro-3,5-dideoxy-2-C-{(S)-hydroxy-[3-(methyl-2,4,6-tri-O-benzyl-3-deoxy-&agr;-D-galactopyranosidyl)]-methyl}-D-erythro-L-manno-nonanate. The present invention still further provides C-glycoside having the structure, Methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2,6-anhydro-3,5-dideoxy-2-C-{hydroxy-4-(tert-butylcyclohexyl)]-D-erythro-L-manno-nonanate.
By the present invention, diastereocontrolled synthesis of &agr;-C-glycosides of ulosonic acids is first attained, and novel intermediates and C-glycosides of ulosonic acids were provided.
REFERENCES:
Luthman et al. Synthesis of C-glycosides of 3-deoxy-D-manno-2-octulosonic acid. Stereoselectivity in an enolate reaction. J. Org. Chem. 52 (17), 3777-3784. (Aug./1987).*
Nagy et al. The chemical-enzymatic synthesis of a carbon glycoside of N-acetyl neuraminic acid. Tetrahedron Lett. 32 (32), 3953-3956. (Aug./1991).*
Mazeas et al. A highly stereospecific synthesis of 1,2-trans-C-glycosides via glycosyl samarium (III) compounds. Angew. Chem. Int. Ed. Eng. 34(8), 909-912. (1995). No month.*
Hung et al. Samarium diiodide mediated coupling of glycosyl phosphates with carbon radical or anion acceptors-Synthesis of C-glycosides. Angew. Chem.Int. Ed. Eng. 35 (22), 2671-2674. (1996). No month.*
Jarreton et al. The stereospecific synthesis of methyl &agr;-C-mannobioside: a potential inhibitor of M. Tuberculosis binding to human macrophages. Chem. Commun. 14, 1661-1662. (Jul./1996).*
Vlahov et al. Diastereocontrolled synthesis of carbon glycosides of N-acetylneuraminic acid via glycosyl samarium (III) intermediates. J. Am. Chem. Soc. 119, 1480-1481. (Feb./1997).*
Zeng et al. Chemical Abstracts vol. 114, No. 10, abstract No. 93940. (Mar./1991). Abstract only.*
Zeng et al. Chemical Abstracts vol. 110, No. 16, abstract No. 146509. (Apr./1989). Abstract only.*
Brzyska, W. Chemical Abstracts vol. 86, No. 26, abstract No. 199131. (Jun./1977). Abstract only.
Linhardt Robert J.
Vlahov Iontcho R.
Moran Marjorie A.
University of Iowa Research Foundation
Woodward Michael P
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