# US 6,723,843 B2 · Oligosaccharide synthesis

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- Number: US 6,723,843 B2
- Document ID: US6723843B2
- Status: Granted
- Kind: B2
- Application number: 10/231,909
- Filed: 2002-08-30
- Published: 2003-02-06
- Granted: 2004-04-20
- Earliest claimed: 1996-08-26
- Assignees: Alchemia Pty Ltd
- Inventors: Istvan Toth; Gyula Dekany; Barry Kellam
- Web page: https://patentgrep.com/patent/US6723843B2

## CPC

- C07H 15/18: Acyclic radicals, substituted by carbocyclic rings
- C07C 59/90: containing singly bound oxygen-containing groups
- C07C 69/738: Esters of keto-carboxylic acids {or aldehydo-carboxylic acids}
- C07H 3/06: Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The invention provides a system for solid-phase synthesis of oligosaccharides, based on the discovery that a 2-substituted-1,3-dioxocycloalkyl linker group of general formula (I) can be used to couple saccharide groups of both the O-glycoside and N-glycoside type to a polymer support. The invention provides reagents, reagent kits and methods for solid-phase oligosaccharide synthesis.

## Claims

### Claim 1

A resin-linker-saccharide support for solid-phase synthesis of oligosaccharides, comprising:
(a) a resin;
(b) a linker covalently attached to said resin; and
(c) one or more saccharide groups covalently attached to said resin via said linker; wherein the support is a compound of formula I
in which
R1 is hydrogen or C1-4 alkyl;
R2 is hydrogen or C1-4 alkyl;
R′ is an amino sugar, a glycosylamine, or a glycosylamine of an oligosaccharide; a mono or oligosaccharide coupled through an alkyl-, substituted alkyl-, aryl-, substituted aryl-, cycloalkyl-, or substituted cycloalkyl-amino group; or a mono or oligosaccharide coupled through a carboxyalkyl-, substituted carboxyalkyl-, carboxyaryl-, substituted carboxyaryl-, carboxycycloalkyl-, or substituted carboxycycloalkyl-amino group; and
R″ is an alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, or substituted cycloalkyl spacer group that is directly coupled to the resin support or that is coupled to the resin via a functionality that is stable to conditions of oligosaccharide synthesis and cleavage.

### Claim 2 (depends on 1)

The support of claim 1, in which both R1 and R2 are methyl.

### Claim 3 (depends on 1)

The support of claim 1, in which R′ is an oligosaccharide-O—CH2—(C6H4)—NH, monosaccharide-O—CH2—(C6H4)—NH, amino-oligosaccharide-CO2CH2—(C6H4)NH, or amino-monosaccharide-CO2CH2—(C6H4)—NH group.

### Claim 4 (depends on 1)

The support of claim 1, in which the covalent linkage to said resin is provided by a —CONH—, —O—, —S—, —COO—, —CH═N—, —NHCONH—, —NHCSNH, or —NHNH— grouping.

### Claim 5 (depends on 1)

The support of claim 1, in which said linker is functionalized N-1-(4,4-Dimethyl-2,6-dioxocyclohexylidene)-ethyl, 6-Hydroxy-6-(4,4-dimethyl-2,6-dioxocyclohexyl-idene)hexanoic acid or functionalized 4-{N-[1-(4,4-dimethyl-2,6-dioxocyclo-hexylidene)-3-methylbutyl]-amino}benzyl alcohol.

### Claim 6 (depends on 1)

The support of claim 1, comprising said resin, said linker and a monosaccharide, an oligosaccharide, an aminosaccharide or an amino-oligosaccharide.

### Claim 7 (depends on 1)

A method of synthesis of the resin-linker support of claim 1, in which said comprises:
(a) obtaining a resin-linker support, wherein the support is a compound of formula II:
in which
(i) X is OH;
(ii) R1 is hydrogen or C1-4 alkyl;
(iii) R2 is hydrogen or C1-4 alkyl; and
(iv) R″ is an alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, or substituted cycloalkyl spacer group that is directly coupled to the resin support or that is coupled to the resin via a functionality that is stable to conditions of oligosaccharide synthesis and cleavage;
(b) swelling said resin-linker support in a suitable solvent; and
(c) treating the swollen resin with an amino sugar, a glycosylamine, or a glycosylamine of an oligosaccharide; a mono or oligosaccharide coupled through an alkyl-, substituted alkyl-, aryl-, substituted aryl-, cycloalkyl-, or substituted cycloalkyl-amino group; or a mono or oligosaccharide coupled through a carboxyalkyl-, substituted carboxyalkyl-, carboxyaryl-, substituted carboxyaryl-, carboxycycloalkyl-, or substituted carboxycycloalkyl-amino group.

### Claim 8 (depends on 7)

The method of claim 7, wherein the linker is 6-hydroxy-6-(4,4-dimethyl-2,6-dixocyclohexylidene)-hexanoic acid or an ester thereof.

### Claim 9

A linker-saccharide complex, having formula II
in which
R1 is hydrogen or C1-4 alkyl;
R2 is hydrogen or C1-4 alkyl; and
R′ is an amino sugar, a glycosylamine, or a glycosylamine of an oligosaccharide; a mono or oligosaccharide coupled through an alkyl-, substituted alkyl-, aryl-, substituted aryl-, cycloalkyl-, or substituted cycloalkyl-amino group; or a mono or oligosaccharide coupled through a carboxyalkyl-, substituted carboxyalkyl-, carboxyaryl-, substituted carboxyaryl-, carboxycycloalkyl-, or substituted carboxycycloalkyl-amino group; and
R″ is an alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, or substituted cycloalkyl spacer group that comprises a functionality capable of reacting with a functionalized resin.

### Claim 10 (depends on 9)

The linker-saccharide complex of claim 9, in which both R1 and R2 are methyl.

### Claim 11 (depends on 9)

The linker-saccharide complex of claim 9, in which the functionality on R″ is a carboxyl group.

### Claim 12 (depends on 9)

The linker-saccharide complex of claim 9, in which the linker is the compound 6-(4,4-dimethyl-2,6-dixocyclohexylidene)-hexanoic acid or an ester thereof and the saccharide is attached at position 6 of the linker.

### Claim 13 (depends on 12)

The linker-saccharide complex of claim 12, in which the linker is a benzyl, ethyl or t-butyl ester of the compound 6-(4,4-dimethyl-2,6-dixocyclohexylidene)-hexanoic acid and the saccharide is attached at position 6 of the linker.

### Claim 14 (depends on 9)

A linker-saccharide complex in which the linker is the linker compound of claim 9 and the saccharide is a monosaccharide, an oligosaccharide, an aminosaccharide or an amino-oligosaccharide.

### Claim 15 (depends on 14)

The linkerr-saccharide complex of claim 14, in which said linker compound comprises a methyl group at position R1 and a methyl group at position R2.

### Claim 16 (depends on 14)

The linker-saccharide complex of claim 14, in which the saccharide is an amino sugar, a glycosylamine, or a glycosylamine of an oligosaccharide; a mono or oligosaccharide coupled through an alkyl-, substituted alkyl-, aryl-, substituted aryl-, cycloalkyl-, or substituted cycloalkyl-amino group; or a mono or oligosaccharide coupled through a carboxyalkyl-, substituted carboxyalkyl-, carboxyaryl-, substituted carboxyaryl-, carboxycycloalkyl-, or substituted carboxycycloalkyl-amino group.

### Claim 17 (depends on 1)

A method of solid-phase synthesis of oligosaccharides, comprising sequentially linking mono- or oligosaccharide groups to the resin-linker-saccharide support of claim 1.

### Claim 18 (depends on 1)

A method of synthesis of the resin-linker-saccharide support of claim 1, in which said method comprises reaction of a linker-saccharide complex with a resin, wherein said linker-saccharide complex has formula II
in which
R1 is hydrogen or C1-4 alkyl;
R2 is hydrogen or C1-4 alkyl; and
R′ is an amino sugar, a glycosylamine, or a glycosylamine of an oligosaccharide; a mono or oligosaccharide coupled through an alkyl-, substituted alkyl-, aryl-, substituted aryl-, cycloalkyl-, or substituted cycloalkyl-amino group; or a mono or oligosaccharide coupled through a carboxyalkyl-, substituted carboxyalkyl-, carboxyaryl-, substituted carboxyaryl-, carboxycycloalkyl-, or substituted carboxycycloalkyl-amino group; and
R″ is an alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, or substituted cycloalkyl spacer group that comprises a functionality capable of reacting with a functionalized resin.