反应详情

To a stirred solution of 1-(N,N-dimethylsulfamoyl)-1H-imidazole (875 mg, 5 mmol) in THF (15 ml) was dropwise added n-butyllithium (1.6 M in hexane, 3.1 ml, 5 mmol) at −78° C. during 30 min. Then a solution of ZnCl2 (1M in THF, 10 ml, 10 mmol) was dropwise added at −78° C. and the mixture was warmed to RT during 45 min. Resulting orange solution was transferred to an argon purged mixture of 2′,3′,5′-tri-O-TBS-7-iodotubericidine {compound 4 from Example 17, Step 1} (735 mg, 1 mmol) and Pd(PPh3)4 (116 mg, 0.1 mmol) and the mixture was stirred at 90° C. for 24 h. The mixture was diluted with AcOEt (50 ml) and washed with aq EDTA (sat., 25 ml). Aqueous layer was re-extracted with AcOEt (10 ml). Collected organic extracts were dried over MgSO4, evaporated and the residue was chromatographed on silica (hexanes/AcOEt, 5:1 →1:1; then AcOEt) affording product in a mixture with unseparable starting protected imidazole. This mixture was directly deprotected by stirring in aq HCl (1M, 2 ml) and MeOH (2 ml) at 100° C. for 24 h. Volatiles were removed in vacuo and the rest was co-evaporated with water (5×). The residue was treated with MeOH and undissolved solid (imidazole) was filtered off and washed with MeOH. Filtrate was evaporated and reverse phase chromatography (0-4100% MeOH in water) afforded crude product, which was yet re-purified by column chromatography on silica (8% MeOH in CHCl3) providing title compound 2s as yellowish foam (42 mg, 13%). Compound was recrystallized from MeOH/water. Mp 153-156° C. [α]D −72.1 (c 0.19, DMSO). 1H NMR (499.8 MHz, DMSO-d6): 3.56 (ddd, 1H, Jgem=11.9, J5′b,OH=6.5, =4.6, H-5′b); 3.64 (dd, 1H, Jgem=11.9, J5′a,OH=5.0, J5′a,4′=4.1, H-5′a); 3.92 (ddd, 1H, J4′,5′=4.6, 4.1, J4′,3′=3.4, H-4); 4.10 (ddd, 1H, J3′,OH=5.2, J3′,2′=5.0, J3′,4′=3.4, H-3′); 4.36 (ddd, 1H, J2′,OH 6.3, J2′,1′6.0, J2′,3′=5.0, H-2′); 5.16 (dd, 1H, JOH,5′=6.5, 5.0, OH-5′); 5.17 (d, 1H, JOH,3′=5.2, OH-3′); 5.39 (d, 1H, JOH,2′=6.3, OH-5′); 6.05 (d, 1H, J1′,2′=6.0, H-1′); 7.00 (t, 1H, J4,5=J4,NH=1.4, H-4-imidazole); 7.22 (dd, 1H, J5,NH=2.0, J5,4=1.4, H-5-imidazole); 7.24 (bs, 1H, NHaHb); 7.86 (s, 1H, H-6); 8.06 (s, 1H, H-2); 10.23 (bs, 1H, NHaHb); 12.42 (bs, 1H, NH-imidazole). 13C NMR (125.7 MHz, DMSO-d6): δ2.25 (CH2-5′); 70.90 (CH-3′); 73.99 (CH-2′); 85.27 (CH-4′); 87.33 (CH-1′); 100.12 (C-4a); 107.87 (C-5); 116.81 (CH-5-imidazole); 119.44 (CH-6); 127.22 (CH-4-imidazole); 142.49 (C-2-imidazole); 150.82 (C-7a); 152.91 (CH-2); 158.58 (C-4). MS (ESI) m/z 333 (M+H), 355 (M+Na). HRMS (ESI) for C14H17N6O4 [M+H] calcd: 333.1306. found: 333.1306. Anal. Calcd for C14H16N6O4.1.85H2O.0.55CH3OH: C, 45.60; 1-1, 5.76; N, 21.93. Found: C, 45.67; H, 5.66; N, 21.86.

1. customat −78° C.
2. customduring 30 min
3. customResulting orange solution
4. custompurged
5. washwashed with aq EDTA (sat., 25 ml)
6. extractionAqueous layer was re-extracted with AcOEt (10 ml)
7. dry with materialCollected organic extracts were dried over MgSO4
8. customevaporated
9. customthe residue was chromatographed on silica (hexanes/AcOEt, 5:1 →1:1
10. customthen AcOEt) affording product in a mixture
11. customVolatiles were removed in vacuo
12. additionThe residue was treated with MeOH and undissolved solid (imidazole)
13. filtrationwas filtered off
14. washwashed with MeOH
15. customFiltrate was evaporated
16. customafforded crude product, which
17. customwas yet re-purified by column chromatography on silica (8% MeOH in CHCl3)