Methods for glycosylation

Patent metadata

Field	Value
Publication number	US-12234255-B2
Application number	US-202017610996-A
Country	US
Kind code	B2
Filing date	May 14, 2020
Priority date	May 14, 2019
Publication date	Feb 25, 2025
Grant date	Feb 25, 2025

Abstract

Provided herein are methods of glycosylation in the formation of disaccharides, trisaccharides, and oligosaccharides using fluoroglycosides, silyl ether glycosides and a triaryl borane catalyst.

First claim

What is claimed:

1. A method comprising admixing at least one fluoroglycoside of formula (I) and a silyl ether glycoside, in the presence of a catalyst having a formula B (Ar 1 )(Ar 2 )(Ar 3 ) under conditions sufficient to form a glycoside product:

wherein
each of R 2 , R 3 , R 4 , and R 6 is independently H, C 1-6 alkyl, —N(R 1 ) 2 , —N 3 , CO 2 H, CO 2 C 1-6 alkyl, or —OR PG , or
two of R 2 , R 3 , R 4 , and R 6 , together with the atoms to which they are attached form a five to eight membered heterocycloalkyl having 1 to 3 ring heteroatoms selected from O, N, and S;
each of Ar 1 , Ar 2 , Ar 3 is independently a halophenyl;
each R 1 is independently H, C(O)C 1-6 alkyl, or an amino protecting group;
m is 0 or 1; and
each R PG is independently a hydroxyl protecting group or a saccharide.

2. The method of claim 1 , wherein at least one R 2 , R 3 , R 4 , and R 6 is —OR PG or C 1-6 alkyl.

3. The method of claim 2 , wherein at least one R PG is benzyl, acetyl, or methyl, and/or wherein at least one R PG comprises a saccharide, and/or wherein one R PG comprises a connection to a solid support or fluorinated alkyl chain.

4. The method of claim 1 , wherein at least one of R 2 , R 3 , R 4 , and R 6 is CO 2 H or CO 2 C 1-6 alkyl.

5. The method of claim 1 , wherein the silyl ether glycoside has a structure of Formula (II):

wherein each of R 1A , R 2A , R 3A , R 4A , and R 6A independently is H, an O-silyl ether, OR PG , CO 2 H, CO 2 C 1-6 alkyl, or C 1-6 alkyl,
each R PG is independently a hydroxyl protecting group or a saccharide; and
n is 0 or 1;
with the proviso that at least one of R 1A , R 2A , R 3A , R 4A , and R 6A comprises an O-silyl ether.

6. The method of claim 5 , wherein if more than one of R 1A , R 2A , R 3A , and R 4A comprises an O-silyl ether, then no two O-silyl ethers are identical, or wherein R 6A and one of R 1A , R 2A , R 3A , and R 4A comprise the same O-silyl ether, or two of R 1A , R 2A , R 3A , R 4A , and R 6A comprise an O-silyl ether.

7. The method of claim 5 , wherein one O-silyl ether comprises OTMS, OTBS, or OTIPS.

8. The method of claim 5 , wherein one O-silyl ether comprises a di-silyl ether having a structure of

wherein GLYC is a glycoside moiety.

9. The method of claim 8 , wherein GLYC has a structure selected from the group consisting of:

and each of R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 is independently H, —OR PG , C 1-6 alkyl, CO 2 H, CO 2 C 1-6 alkyl, Ar 4 , or —N(R 1 ) 2 , or
two of R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 , together with the atoms to which they are attached form a five to eight member heterocycloalkyl comprising 1 to 3 ring heteroatoms selected from O, N, and S, and each Ar 4 is independently selected from C 6 -C 22 aryl or a 5-12 membered heteroaryl comprising from 1 to 3 ring heteroatoms selected from O, N, and S.

10. The method of claim 9 , wherein at least one of R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 is —OR PG or C 1-6 alkyl, or Ar 4 .

11. The method of claim 10 , wherein at least one R PG is benzyl, acetyl, or methyl.

12. The method of claim 10 , wherein at least one Ar 4 is phenyl.

13. The method of claim 5 , wherein at least one of R 1A , R 2A , R 3A , R 4A , and R 6A is C 1-6 alkyl, CO 2 H or CO 2 C 1-6 alkyl.

14. The method of claim 1 , wherein at least one of Ar 1 , Ar 2 , and Ar 3 is a fluorophenyl or chlorophenyl.

15. The method of claim 1 , wherein the catalyst is

16. The method of claim 1 , wherein the catalyst is present in an amount of less than 10 mol %.

17. The method of claim 1 , wherein the glycoside product is formed stereoselectively and a single stereoisomer of the glycoside product is formed in 80% yield or more.

18. The method of claim 1 , wherein the fluoroglycoside and the silyl ether glycoside are present in a molar ratio of 0.9 to 1 to 1.1 to 1.

19. The method of claim 1 , wherein the glycoside product is selected from the group consisting of

20. The method of claim 1 , when the glycoside product comprises a second silyl ether, further comprising admixing a second fluoroglycoside with the glycoside product to form a second glycoside product between the second fluoroglycoside and the second silyl ether on the glycoside product.

21. The method of claim 20 , wherein the second glycoside product is a trisaccharide or a tetrasaccharide.

22. The method of claim 21 , wherein the second glycoside product
is

Assignees

• Univ Michigan Regents
• Univ Michigan

Inventors

• Montgomery John
• Sati Girish Chandra
• Martin Joshua Lane

Classifications

• C07H15/203

  Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems · CPC title

• C07H15/18

  Acyclic radicals, substituted by carbocyclic rings · CPC title

• C07H15/10

  containing unsaturated carbon-to-carbon bonds · CPC title

• C07F7/1804

  Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896) · CPC title

• C07H13/04

  having the esterifying carboxyl radicals attached to acyclic carbon atoms · CPC title