Solid-phase and solution-phase synthesis of glycosylphosphatidylinositol glycans

• US 20060089330A1
• Filed: 07/10/2003
• Published: 04/27/2006
• Est. Priority Date: 07/10/2002
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Seeberger, Peter H, Hewitt, Michael C
• Granted Patent: US 7,943,594 B2
• Time in Patent Office: Days
• US Class Current: 514/54
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: C07H 15/203 Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
• CPC Class Codes: C07H 15/207 Cyclohexane rings not substituted by nitrogen atoms, e.g. kasugamycins
• CPC Class Codes: C08B 37/006 Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof

Abstract

One aspect of the present invention relates to solution-phase approaches to GPI synthesis. Another aspect of the present invention relates to key building blocks, and syntheses thereof, useful for GPI assembly. Yet another aspect of the invention relates to an automated method for the synthesis of GPIs and fragments thereof.

Claims

1. A compound represented by formula I:

2. The compound of claim 1, wherein n is 1, 2, or 3.

3. The compound of claim 1, wherein n is 3.

4. The compound of claim 1, wherein R is H.

5. The compound of claim 1, wherein R¹ and R² taken together are P(O)OR⁵.

6. The compound of claim 1, wherein R³ is N₃.

7. The compound of claim 1, wherein R³ is —

NH₃X.

8. The compound of claim 1, wherein R⁴ represents independently for each occurrence H, —

CH₂Ph, or —

Si(alkyl)₃;

9. The compound of claim 1, wherein R⁴ represents independently for each occurrence H, —

CH₂Ph,-or P(O)OR⁵; and

R⁵ is an optionally substituted alkyl group.

10. The compound of claim 1, wherein said compound of formula I is selected from the group consisting of:

11. A compound represented by formula II:

12. The compound of claim 11, wherein n is 2 or 3.

13. The compound of claim 11, wherein n is 3.

14. The compound of claim 11, wherein m is 3.

15. The compound of claim 11, wherein R represents independently for each occurrence —

CH₂-aryl or —

Si(alkyl)₃.

16. The compound of claim 11, wherein R represents independently for each occurrence benzyl or —

Si(iPr)₃.

17. The compound of claim 11, wherein R¹ is trichloroacetimidate and R represents independently for each occurrence benzyl or —

Si(iPr)₃. and

18. The compound of claim 11, wherein said compound of formula II is selected from the group consisting of:

19. A method of preparing glycosylphosphatidylinositol glycans as depicted in Scheme 5:

20. The method of claim 19, wherein R is —

CH₂-aryl.

21. The method of claim 19, wherein R¹ and R² taken together are C(CH₃)₂.

22. The method of claim 19, wherein R³ is —

N₃.

23. The method of claim 19, wherein R⁶ is alkyl.

24. The method of claim 19, wherein R⁷ is —

C(O)-alkyl.

25. The method of claim 19, wherein R is benzyl, R¹ and R² taken together are C(CH₃)₂, and R³ is —

N₃.

26. The method of claim 19, wherein R is benzyl, R¹ and R² taken together are C(CH₃)₂, R³ is —

N₃, and R⁶ is ethyl.

27. A method of preparing glycosylphosphatidylinositol glycans, comprising the steps of:

binding a mannopyranoside to a solid support to provide a first substrate, reacting said first substrate with a mannopyranose trichloroacetimidate to give a disaccharide bound to said solid support, reacting said disaccharide with a mannopyranose trichloroacetimidate to give a triisaccharide bound to said solid support, reacting said trisaccharide with a mannopyranose trichloroacetimidate to give a tetrasaccharide bound to said solid support, and cleaving said tetrasaccharide from said solid support.

28. The method of claim 27, wherein said mannopyranoside is bound to said solid support through a glycosidic linkage.

29. The method of claim 27, wherein said tetrasaccharide is cleaved from said solid support using Grubbs'"'"' catalyst.

30. The method of claim 27, wherein said tetrasaccharide is represented by formula VI: