Chemical synthesis method of Plesiomonas shigelloides serotype O51 O-antigen oligosaccharide

Patent metadata

Field	Value
Publication number	US-10851130-B2
Application number	US-201816215349-A
Country	US
Kind code	B2
Filing date	Dec 10, 2018
Priority date	Jan 29, 2018
Publication date	Dec 1, 2020
Grant date	Dec 1, 2020

Abstract

The present disclosure discloses the chemical synthesis method of the Plesiomonas shigelloides serotype O51 O-antigen oligosaccharide, belonging to the field of chemistry. Source-abundant D-glucose, L-fucose, D-glucosamine and the like are used as raw materials to prepare three glycosylation building blocks, the synthetic route composed of 11 reaction modules is designed, and through the optimization of protecting group and the optimization of the time of introducing functional group, the preparation of the target oligosaccharide chain is successfully achieved. The oligosaccharide chain prepared in the present disclosure has the advantages of cheap and easy-to-get raw materials, and simple and easy-to-repeat preparation method. The present disclosure will have good application prospects in the aspects of development of new drugs and vaccines of Plesiomonas shigelloides, and the like.

First claim

What is claimed is:

1. A linked oligosaccharide chain fragment of the Plesiomonas shigelloides serotype O51 O-antigen polysaccharide, wherein the structure of the oligosaccharide chain fragment is expressed as the general Formula I:
V*—[U x+2 —U x+1 —U x ] n —V—O-L-NH 2   Formula I,

wherein:
X is 1, 2, or 3;
n is 1, 2, or 3;
—V— represents: the chemical bond, —U x+2 —, or —U x+2 —U x+1 —;
V*— represents: H—, H—U x —, or H—U x+1 —U x —;
L represents the linker; and
U x , U x+1 and U x+2 are as shown in Formula V:

2. The linked oligosaccharide chain fragment of the Plesiomonas shigelloides serotype O51 O-antigen polysaccharide according to claim 1 , wherein the structure of the oligosaccharide chain fragment is expressed as the general Formula II:
V*—[U x+2 —U x+1 —U x ] n —O-L-NH 2   Formula II,

wherein:
x, n, L, U x , U x+1 , U x+2 and V* are in accordance with the general Formula I; and
the general Formula II is further expressed as the general Formulae II-a, II-b, or II-c:

3. The linked oligosaccharide chain fragment of the Plesiomonas shigelloides serotype O51 O-antigen polysaccharide according to claim 1 , wherein the structure of the oligosaccharide chain fragment is expressed as the general Formula III:
V*—[U x+2 —U x+1 —U x ] n —U x+2 —O-L-NH 2   Formula III,

wherein:
x, n, L, U x , U x+1 , U x+2 and V* are in accordance with the general Formula I, and
the general Formula III is further expressed as the general Formulae III-a, III-b, or III-c:

4. The linked oligosaccharide chain fragment of the Plesiomonas shigelloides serotype O51 O-antigen polysaccharide according to claim 1 , wherein the structure of the oligosaccharide chain fragment is expressed as the general Formula IV:
V*—[U x+2 —U x+1 —U x ] n -U x+2 —U x+1 —O-L-NH 2   Formula IV,

wherein:
x, n, L, U x , U x+1 , U x+2 and V* are in accordance with the general Formula I, and
the general Formula IV is further specifically expressed as general Formulae IV-a, IV-b, and IV-c:

5. A method of preparing the linked oligosaccharide chain fragment of the Plesiomonas shigelloides serotype O51 O-antigen polysaccharide of Formula II-a according to claim 2 , which comprises:
providing a monosaccharide building block 1 as a starting material for synthesis of D-quinovosamine in an oligosaccharide chain,
wherein:
the monosaccharide building block 1 is expressed as Formula VI-1:

PG 1 is acetyl, levulinyl, benzoyl, chloroacetyl, dichloroacetyl, trichloroacetyl, pivaloyl, allyloxycarbonyl, 2-naphthylmethyl, p-methoxybenzyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or triethylsilyl;
PG 2 is benzyl; and
LG is ethylthio, p-tolylthio, phenylthio, bromine, fluorine, trichloroacetimidate, N-phenyl trifluoroacetimidate or dibutyl phosphate, and

performing chemical synthesis steps A through I in order:

wherein steps A through I are:
A: glycosylation of the monosaccharide building block 1,
B: reduction and acetylation of the azide group of the monosaccharide building block 1;
C: 3-position deprotection of the monosaccharide building block 1, followed by glycosylation of monosaccharide building block 1 with monosaccharide building block 2 to obtain a disaccharide 6, wherein:
the monosaccharide building block 2 is expressed as Formula VI-2:

PG 3 and PG 4 are acetyl, levulinyl, benzoyl, chloroacetyl, dichloroacetyl, trichloroacetyl, pivaloyl, allyloxycarbonyl, 2-naphthylmethyl, p-methoxybenzyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or triethylsilyl;
PG 9 and PG 10 are amino protecting groups, and can be benzyl (Bn) or benzyloxycarbonyl (Cbz), and
LG is ethylthio, p-tolylthio, phenylthio, bromine, fluorine, trichloroacetimidate, N-phenyl trifluoroacetimidate or dibutyl phosphate,

D: azido reduction and protection of disaccharide 6 by 2,2,2-trichloroethoxycarbonyl (Troc), followed by glycosylation of the disaccharide 6 with monosaccharide building block 3 to obtain a trisaccharide,
wherein:
the monosaccharide building block 3 is expressed as Formula VI-3:

PG 5 is trichloroacetyl, dichloroacetyl or chloroacetyl;
PG 6 is benzyl, 2-naphthylmethyl, p-methoxybenzyl or levulinyl;
PG 7 is benzyl; and wherein LG is ethylthio, p-tolylthio, phenylthio, bromine, fluorine, trichloroacetimidate, N-phenyl trifluoroacetimidate or dibutyl phosphate, and
LG is ethylthio, p-tolylthio, phenylthio, bromine, fluorine, trichloroacetimidate, N-phenyl trifluoroacetimidate or dibutyl phosphate;

E: fucosamine 3-/4-position-selective naphthylmethyl protection to obtain trisaccharide 8;
F: fucosamine 3-position acetylation of the trisaccharide 8;
G: azido reduction and butyrylation to provide trisaccharide 10;
H: removal of Troc and modification to acetamidine;
I: hydrogenation global deprotection;
J: glucuronic acid 4-position deprotection; and
K: azido reduction and modification to acetamidine.

6. A method of preparing the linked oligosaccharide of Formula II-c according to claim 2 , which comprises:
providing a monosaccharide building block 2 is used as starting material for synthesis of L-fucosamine in an oligosaccharide chain,
wherein:
the monosaccharide building block 2 is expressed as Formula VI-2:

PG 3 and PG 4 are acetyl, levulinyl, benzoyl, chloroacetyl, dichloroacetyl, trichloroacetyl, pivaloyl, allyloxycarbonyl, 2-naphthylmethyl, p-methoxybenzyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or triethylsilyl;
LG is ethylthio, p-tolylthio, phenylthio, bromine, fluorine, trichloroacetimidate, N-phenyl trifluoroacetimidate or dibutyl phosphate, and

performing chemical synthesis steps A, B, D, E, F, G, H, I, and J, in the following order:

wherein steps A, B, D, E, F, G, H, I, and J, are the following:
A: glycosylation of the monosaccharide building block 2;
D: azido reduction and protection by 2,2,2-trichloroethoxycarbonyl (Troc), E: fucosamine 3-/4-position-selective naphthylmethyl protection to obtain monosaccharide acceptor 19, followed by glycosylation of the monosaccharide acceptor 19 with monosaccharide building block 3 to obtain disaccharide 20,
wherein:
the monosaccharide building block 3 is expressed as Formula VI-3:

Assignees

• Univ Jiangnan
• Max Planck Inst Of Colloids And Interfaces

Inventors

• Yin Jian
• Hu Jing
• Seeberger Peter
• Qin Chunjun

Classifications

• C07H15/12 Primary

  attached to a nitrogen atom of the saccharide radical · CPC title

• A61K39/025

  Enterobacteriales, e.g. Enterobacter · CPC title

• A61K39/0208

  Specific bacteria not otherwise provided for · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title