Combinatorial library approach to iminocyclitols with biological activity
A method of synthesizing stereochemically defined iminocyclitol comprises replacing an intraring oxygen in a cyclic sugar by an intraring imine to form an iminocyclitol, wherein said iminocyclitol has a defined stereochemical configuration different from a stereochemical configuration of the cyclic sugar. The invention also provides combinatorial libraries of iminocyclitol compounds, allowing for diverse C1 and N-substitution. In addition, provided are methods of treating viral infections with iminocyclitols compounds.
1. A method of synthesizing a stereochemically defined iminocyclitol comprising
reacting a cyclic sugar containing an intraring oxygen with a reagent comprising NH 3 , wherein said reacting results in replacing the intraring oxygen in the cyclic sugar by an intraring nitrogen to form an iminocyclitol, wherein said iminocyclitol has a defined stereochemical configuration different from a stereochemical configuration of the cyclic sugar, wherein a ring size of said iminocyclitol is the same as a ring size of said cyclic sugar and wherein said nitrogen forms an imine group —N═ in said iminocyclitol, wherein the cyclic sugar is an aldopentose in a 4-deoxy 1,4 furanose form, an aldohexose in a 4-deoxy 1,4 furanose form or an aldohexose in a 2,5-dideoxy pyranose form and wherein the cyclic sugar is substituted at the C1 position by R 1 , wherein R 1 is an alkyl group comprising from 1 to 20 carbon atoms.
2. The method of claim 1 , further comprising reacting a protected lactone compound with a Grignard reagent R 1 MgX to form the cyclic sugar, wherein a stereochemical configuration of the protected lactone compound is the same as the stereochemical configuration of the cyclic sugar.
3. The method of claim 2 , further comprising protecting hydroxyl groups of an unprotected lactone compound to form the protected lactone compound, wherein a stereochemical configuration of the unprotected lactone compound is the same as the stereochemical configuration of the protected lactone compound.
4. The method of claim 3 , wherein the unprotected lactone compound is an aldopentose or an aldohexose in a 4-deoxy 1,4 furanose form and wherein said protecting hydroxyl groups comprises protecting a hydroxyl group on the C5 atom of the unprotected lactone compound with methanesulfonate, tosylate or triflate protective group.
5. The method of claim 3 , wherein the unprotected lactone compound is an aldohexose in a 4-deoxy 1,4 furanose form and wherein said protecting hydroxyl groups comprises protecting a hydroxyl group on the C6 atom of the unprotected lactone compound with a trityl or t-butyldimethylsiloxy group.
6. The method of claim 3 , wherein the unprotected lactone compound is an aldohexose in a 2,5-dideoxy pyranose form and wherein said protecting hydroxyl groups comprises protecting a hydroxyl group on the C6 atom of the unprotected lactone compound with a methanesulfonate protective group.
7. The method of claim 3 , wherein the unprotected lactone compound is an aldopentose or an aldohexose in a 4-deoxy 1,4 furanose and wherein said protecting hydroxyl groups comprises protecting a hydroxyl group on the C2 atom and a hydroxyl group on the C3 atom by an isopropylindene.
8. The method of claim 3 , wherein the unprotected lactone compound is an aldohexose in a 2,5-dideoxy pyranose form and wherein said protecting hydroxyl groups comprises protecting a hydroxyl group on the C3 atom and a hydroxyl group on the C4 atom by an isopropylindene.
9. The method of claim 3 , wherein the unprotected lactone compound is an aldopentose or an aldohexose in a 4-deoxy 1,4 furanose, wherein said protecting hydroxyl groups comprises protecting a hydroxyl group on the C2 atom and a hydroxyl group on the C3 atom by benzyl, t-butyldimethylsiloxy or triphenylmethyl groups.
10. The method of claim 3 , wherein the unprotected lactone compound is an aldohexose in a 2,5-dideoxy pyranose form and wherein said protecting hydroxyl groups comprises protecting a hydroxyl group on the C3 atom and a hydroxyl group on the C4 atom by benzyl, t-butyldimethylsiloxy or triphenylmethyl groups.
11. The method of claim 3 , further comprising hydrogenating the iminocyclitol to form a hydrogenated iminocyclitol, wherein a stereochemical configuration of the hydrogenated iminocyclitol is the same as the stereochemical configuration of the iminocyclitol.
12. The method of claim 11 , wherein hydrogenating the iminocyclitol is carried out in the presence of a catalyst.
13. The method of claim 12 , wherein the catalyst comprises Pd/C and acetic acid.
14. The method of claim 11 , further comprising alkylating the hydrogenated iminocyclitol to form a N-alkyl-C-alkyl iminocyclitol, wherein a stereochemical configuration of the N-alkyl-C-alkyl iminocyclitol is the same as the stereochemical configuration of the hydrogenated iminocyclitol.
15. The method of claim 14 , wherein said alkylating the hydrogenated iminocyclitol comprises (a) reacting the hydrogenated iminocyclitol with an aldehyde R 2 CHO and the N atom of the N-alkyl-C-alkyl iminocyclitol has a substituent group R 2 CH 2 , and wherein R 2 is hydrogen or an alkyl group comprising from 1 to 20 carbon atoms, and (b) deprotecting C2 and C3 hydroxyl groups of the N-alkyl-C-alkyl iminocyclitol.
16. The method of claim 15 , wherein the hydrogenating the iminocyclitol, the reacting the hydrogenated iminocyclitol with an aldehyde and the deprotecting C2 and C3 hydroxyl groups of the N-alkyl-C-alkyl iminocyclitol are carried out simultaneously.
17. The method of claim 2 , wherein the cyclic sugar is an aldopentose in a 4-deoxy-1,4-furanose form.
18. The method of claim 2 , wherein the cyclic sugar is an aldohexose in a 4-deoxy-1,4-furanose form.
19. The method of claim 2 , wherein the cyclic sugar is an aldohexose in a 2,5-dideoxy-pyranose form.
20. The method of claim 4 , wherein the unprotected lactone is an aldopentose in a 4-deoxy-1,4-furanose form.
21. The method of claim 4 , wherein the unprotected lactone is an aldohexose in a 4-deoxy-1,4-furanose form.
22. The method of claim 7 , wherein the unprotected lactone is an aldopentose in a 4-deoxy-1,4-furanose form.
23. The method of claim 7 , wherein the unprotected lactone is an aldohexose in a 4-deoxy-1,4-furanose form.
24. The method of claim 9 , wherein the unprotected lactone is an aldopentose in a 4-deoxy-1,4-furanose form.
25. The method of claim 9 , wherein the unprotected lactone is an aldohexose in a 4-deoxy-1,4-furanose form.
26. The method of claim 15 , wherein the N-alkyl-C-alkyl iminocyclitol has the following formula:
wherein R 1 is an alkyl group comprising 1 to 20 carbon atoms, R 2 is an alkyl group comprising 1 to 20 carbon atoms and R 6 is hydrogen.
27. The method of claim 15 , wherein the N-alkyl-C-alkyl iminocyclitol has the following formula:
wherein R 1 is an alkyl group comprising 1 to 20 carbon atoms, R 2 is an alkyl group comprising 1 to 20 carbon atoms and R 6 is hydrogen.
28. The method of claim 15 , wherein the N-alkyl-C-alkyl iminocyclitol has the following formula:
wherein R 1 is an alkyl group comprising 1 to 20 carbon atoms, R 2 is an alkyl group comprising 1 to 20 carbon atoms and R 6 is hydrogen.
29. A method of synthesizing a stereochemically defined iminocyclitol comprising:
(a) protecting hydroxyl groups of an unprotected lactone compound to form the protected lactone compound, wherein a stereochemical configuration of the unprotected lactone compound is the same as the stereochemical configuration of the protected lactone compound;
(b) reacting the protected lactone compound with a Grignard reagent R 1 MgX to form a cyclic sugar containing an intraring oxygen, wherein a stereochemical configuration of the protected lactone compound is the same as the stereochemical configuration of the cyclic sugar, wherein the cyclic sugar is an aldopentose in a 4-deoxy 1,4 furanose form, an aldohexose in a 4-deoxy 1,4 furanose form or an aldohexose in a 2,5-dideoxy pyranose form and wherein the cyclic sugar is substituted at the C1 position by R 1 , wherein R 1 is an alkyl group comprising from 1 to 20 carbon atoms;
(c) reacting the cyclic sugar with a reagent comprising NH 3 , wherein said reacting results in replacing the intraring oxygen in the cyclic sugar by an intraring nitrogen to form an iminocyclitol, wherein said iminocyclitol has a defined stereochemical configuration different from a stereochemical configuration of the cyclic sugar, wherein a ring size of said iminocyclitol is the same as a ring size of said cyclic sugar and wherein said nitrogen forms an imine group —N═ in said iminocyclitol; and
(d) hydrogenating the iminocyclitol to form a hydrogenated iminocyclitol, wherein a stereochemical configuration of the hydrogenated iminocyclitol is the same as the stereochemical configuration of the iminocyclitol.
30. The method of claim 29 , wherein the unprotected lactone is an aldopentose in a 4-deoxy-1,4-furanose form.
31. The method of claim 29 , wherein the unprotected lactone is an aldohexose in a 4-deoxy-1,4-furanose form.
32. The method of claim 29 , wherein the unprotected lactone is an aldohexose in a 2,5-dideoxy-pyranose form.
33. The method of claim 29 , further comprising alkylating the hydrogenated iminocyclitol to form a N-alkyl-C-alkyl iminocyclitol, wherein a stereochemical configuration of the N-alkyl-C-alkyl iminocyclitol is the same as the stereochemical configuration of the hydrogenated iminocyclitol.
34. The method of claim 33 , wherein the N-alkyl-C-alkyl iminocyclitol has the following formula:
wherein R 1 is an alkyl group comprising 1 to 20 carbon atoms, R 2 is an alkyl group comprising 1 to 20 carbon atoms and R 6 is hydrogen.
35. The method of claim 33 , wherein the N-alkyl-C-alkyl iminocyclitol has the following formula:
wherein R 1 is an alkyl group comprising 1 to 20 carbon atoms, R 2 is an alkyl group comprising 1 to 20 carbon atoms and R 6 is hydrogen.
36. The method of claim 33 , wherein the N-alkyl-C-alkyl iminocyclitol has the following formula:
wherein R 1 is an alkyl group comprising 1 to 20 atoms, R 2 is an alkyl group comprising 1 to 20 carbon atoms and R 6 is hydrogen.