Synthetic lipid A derivative
View Patent ↗The invention provides functionalized monosaccharides and disaccharides suitable for use in synthesizing a lipid A derivative, as well as methods for synthesizing and using a synthetic lipid A derivative.
1. A compound having formula I:
wherein:
R 1 is an anomeric protecting group;
R 2 is azido;
R 3 is H or allyloxycarbonate (Alloc);
R 4 is a hydroxyl protecting group;
R 5 is —NHR 11 , wherein R 11 is fluorenylmethoxycarbamate (Fmoc) or 2,2,2-trichloroethoxycarbonyl (Troc);
R 6 is H, allyloxycarbonate (Alloc) or levulinate (Lev); provided that when R 6 is H, R 3 is allyloxycarbonate (Alloc); and
R 7 and R 8 are each independently H, a phosphate, a substituted phosphate, a hydroxyl protecting group, or together form a ring.
2. The compound of claim 1 wherein R 1 is tert-butyldimethylsilyl (TBS) or dimethylthexylsilyl (TDS).
3. The compound of claim 1 wherein R 7 and R 8 together form a ring comprising an acetal.
4. The compound of claim 1 , wherein one of R 3 and R 6 is H, and the other of R 3 and R 6 is Alloc.
5. The compound of claim 4 , comprising:
6. The compound of claim 4 , comprising:
7. The compound of claim 1 , wherein R 3 is Alloc and R 6 is Lev.
8. The compound of claim 7 , comprising:
9. A compound having formula I:
wherein:
R 1 is an anomeric protecting group;
R 2 is azido;
R 3 is H or allyloxycarbonate (Alloc);
R 4 is a hydroxyl protecting group;
R 5 is —NHR 11 , wherein R 11 is fluorenylmethoxycarbamate (Fmoc) or 2,2,2-trichloroethoxycarbonyl (Troc);
R 6 is acyl; and
R 7 and R 8 are each independently H, a phosphate, a substituted phosphate, a hydroxyl protecting group, or together form a ring.
10. The compound of claim 9 , comprising:
11. A method for making a lipid A derivative comprising:
selectively acylating the compound of claim 1 at at least one of positions C-2, C-3, C-2′ and C-3′ of the functionalized disaccharide to yield a lipid A derivative.
12. The method of claim 11 wherein selectively acylating the compound of claim 1 comprises selectively acylating the compound of claim 1 at two, three or four of positions C-2, C-3, C-2′ and C-3′.
13. The method of claim 11 further comprising phosphorylating the compound of claim 1 at either or both of the C-1 or C-4′ positions.
14. The method of claim 11 further comprising contacting the compound of claim 1 with a 3-deoxy-D-manno-oct-2-ulosonic acid (KDO) donor to yield a KDO glycoside at the C-6′ position.
15. The method of claim 11 wherein R 1 is tert-butyldimethylsilyl (TBS) or dimethylthexylsilyl (TDS).