Ring-Expanded Nucleoside and Nucleotide Analogues
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19 4159
13.04 (CHSi), 13.43 (CHSi), 16.86 (CCH3), 16.97 (CCH3), 16.97
(CCH3), 17.09 (CCH3), 17.31 (CCH3), 17.31 (CCH3), 17.39
(CCH3), 17.49 (CCH3), 41.70 (C-2′), 52.34 (OCH3), 52.50
(OCH3), 60.48 (C-5′), 67.52 (C-3′), 85.25 (C-4′), 86.02 (C-1′),
136.41 (C-4 or 5), 137.12 (C-2), 138.41 (C-5 or 4), 160.37 (Cd
O), 163.04 (CdO). Anal. (C24H42N2O8Si2) C, H, N.
(CDCl3) δ 21.58 (2PhCH3), 40.93 (C-2′), 52.23 (OCH3), 52.48
(OCH3), 63.99 (C-5′), 74.59 (C-3′), 85.52 (C-4′), 89.18 (C-1′),
129.28 (2 m-Ph), 129.33 (2 m-Ph), 129.59 (2 o-Ph), 129.68 (2
o-Ph), 136.47 (C-4 or 5), 137.11 (C-2), 138.58 (C-5 or 4), 144.16
(Ph-C1), 144.47 (Ph-C1), 160.48 (CdO), 162.87 (CdO), 165.76
(PhCdO), 166.02 (PhCdO). Anal. (C28H28N2O9 ‚0.3CF3SO3H)
C, H, N.
Met h yl 1-(2′-Deoxy-â-D-er yt h r op en t ofu r a n osyl)-4,5-
im id a zoled ica r boxyla te (8). A solution of 1 M tetra-n-
butylammonium fluoride in THF (2 mL, 2 mmol) was added
to an ice-cold solution of 7 (543 mg, 1 mmol) in 10 mL of dry
THF. The reaction was stopped after 45 min stirring at 0 °C.
The solvent was evaporated in vacuo, and the pure product
was obtained in 75% yield as a foam by silica gel column
chromatography (chloroform/methanol, 10:1. Rf 0.20, chloroform/
6-Am in o-1-(2′-d eoxy-r-D-er yt h r op en t ofu r a n osyl)-4,5-
d ih yd r o-8H-im id a zo[4,5-e][1,3]d ia zep in e-4,8-d ion e (15).
Guanidine hydrochloride (0.23 g, 2.4 mmol) was added to a
solution of methyl 1-(2′-deoxy-3′,5′-di-O-p-toluoyl-R-D-erythro-
pentofuranosyl)-4,5-imidazoledicarboxylate (13) (0.32 g, 0.6
mmol) in 30 mL of absolute methanol, containing 1 mL of 25%
(w/v) sodium methoxide solution. The mixture was stirred at
room temperature for 48 h. The reaction mixture was evapo-
rated in vacuo to a small volume and then was isolated by
preparative TLC on silica gel to give pure 15 as a white solid
(150 mg, 85%), mp >250 °C, Rf 0.41 [chloroform:methanol:30%
ammonium hydroxide (2:2:1)]; 1H NMR (DMSO-d6) δ 10.64
(brs, 1H, NH, exchangeable with D2O), 8.13 (s, 1H, imidazole),
7.08 (brs, 1H, NH, exchangeable with D2O), 6.67 (d, 1H, J )
6.0 Hz, 1′-H), 6.50 (brs, 1H, NH, exchangeable with D2O), 5.09
(brs, 1H, OH, exchangeable with D2O), 4.86 (brs, 1H, OH,
exchangeable with D2O), 4.26 (t, 1H, J ) 4.5 Hz, 4′-H), 4.19
(d, 1H, J ) 6.0 Hz, 3′-H), 3.41 (d, 2H, J ) 4.5 Hz, 5′-H), 2.63
(dt, 1H, J ) 14.4 and 6.0 Hz, 2′â-H), 2.00 (d, 1H, J ) 14.4 Hz,
2′R-H); 13C NMR (DMSO-d6) δ 43.25 (C-2′), 62.13 (C-5′), 71.25
(C-3′), 89.06 (C-4′), 90.38 (C-1′), 140.41 (C-2, 3a, 4, 8, 8a),
153.30 (C-6); HRMS (FAB) calcd for C11H14N5O5 (MH+) m/z
296.0995, found, 296.0992. Anal. (C11H13N5O5) C, H, N.
1
methanol (10:1); H NMR (CDCl3) δ 8.51 (s, 1H, imidazole),
6.38 (dd, 1H, J ) 6.2 and 3.4 Hz, 1′-H), 4.82 (brs, 1H, OH,
exchangeable with D2O), 4.54 (dd 1H, J ) 12.8 and 6.6 Hz,
3′-H), 4.15 (brs, 1H, OH, exchangeable with D2O), 3.98 (m, 3H,
4′,5′-H), 3.91 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 2.56 (ddd, 1H,
J ) 13.6, 12.8 and 6.2 Hz, 2′-H), 2.35 (ddd, 1H, J ) 13.6, 6.6
and 3.4 Hz, 2′-H); 13C NMR (CDCl3, 75.48 MHz) δ 42.49 (C-
2′), 52.42 (OCH3), 52.73 (OCH3), 60.62 (C-5′), 68.91 (C- 3′),
87.03 (C-4′), 87.21 (C-1′), 136.50 (C-4 or 5), 136.86 (C-5 or 4),
137.68 (C-2), 160.40 (CdO), 163.05 (CdO). Anal. (C12H16N2O7)
C, H, N.
6-Am in o-1-(2′-d eoxy-â-D-er yt h r op en t ofu r a n osyl)-4,5-
d ih yd r o-8H-im id a zo[4,5-e][1,3]d ia zep in e-4,8-d ion e (9). To
a solution of 8 (150 mg, 0.5 mmol) and guanidine hydrochloride
(240 mg, 2.5 mmol) in 30 mL of absolute methanol was added
1 mL of 25% (w/v) sodium methoxide solution in methanol.
The reaction mixture was stirred for 24 h at room temperature,
and then 1 g of silica gel was added. The resulting mixture
was evaporated to dryness and applied to a silica gel column.
The column was successively eluted with chloroform/methanol
(10:1) and methanol. The proper fraction was collected and
evaporated to afford 9 as a colorless solid, yield 110 mg (74.5%),
mp >250 °C. 1H NMR (DMSO-d6) δ 10.65 (brs, 1H, NH,
exchangeable with D2O), 8.47 (s,1H, imidazole), 7.62 (brs, 1H,
NH, exchangeable with D2O), 6.65 (t, 1H, J ) 5.7 Hz, 1′-H),
6.54 (brs, 1H, NH, exchangeable with D2O), 5.27 (d, 1H, J )
4.5 Hz, 3′-OH, exchangeable with D2O), 5.09 (t, 1H, J ) 4.8
Hz, 5′-OH, exchangeable with D2O), 4.24 (m, 1H, 4′-H), 3.84
(m, 1H, 3′-H), 3.60 (m, 2H, 5′-H), 2.18 (dt, 1H, J ) 13.5 and
5.7 Hz, 2′-H), 2.02 (d, 1H, J ) 13.5 Hz, 2′-H). HRMS (FAB)
calcd for C11H14N5O5 (MH+) m/z 296.0995, found, 296.0994.
Anal. (C11H13N5O5‚0.25H2O) C, H, N.
Meth yl 1-(2′-Deoxy-3′,5′-di-O-p-tolu oyl-r-D-er yth r open to-
fu r a n osyl)-4,5-im id a zoled ica r boxyla te (13). A solution of
methyl 4,5-imidazoledicarboxylate35,36 (1.84 g, 10 mmol) and
methyl 2-deoxy-3,5-di-O-p-toluoyl-â-D-erythropentofuranoside
(11)57 (3.84 g, 10 mmol) in dry acetonitrile (50 mL) was placed
into a flame-dried 100 mL round-bottom flask. The solution
was stirred in an ice bath for 10 min. Then, 1,1,1,3,3,3-
hexamethyldisilazane (HMDS) (7 mL, 33 mmol), chlorotri-
methylsilane (TMSCl) (4.5 mL, 36 mmol), and trifluoromethane-
sulfonic acid (TFMSA) (3 mL, 36 mmol) were consecutively
added to the above solution. The resulting solution was stirred
in an ice bath for 1 h. The reaction is complete by TLC analysis
[silica gel plates, chloroform:methanol (30:1)]. The reaction
mixture was evaporated to dryness in vacuo. The resulting
residue was dissolved in chloroform and washed successively
with saturated aqueous sodium bicarbonate and water. After
being dried over anhydrous MgSO4 and filtered, the chloroform
solution was evaporated to dryness in vacuo. The residue was
purified by column chromatography, eluting with chloroform
to give pure 13 as a colorless oily product (4.6 g, 86%), Rf 0.83
[chloroform-methanol (10:1)]. 1H NMR (CDCl3) δ 7.97 (s, 1H,
imidazole), 7.95 (d, 2H, J ) 8.1 Hz, o-Ph), 7.62 (d, 2H, J ) 8.1
Hz, o-Ph), 7.28 (d, 2H, J ) 8.1 Hz, m-Ph), 7.20 (d, 2H, J ) 8.1
Hz, m-Ph), 6.65 (d, 1H, J ) 6.6 Hz, 1′-H), 5.65 (d, 1H, J ) 6.6
Hz, 3′-H), 4.92 (t, 1H, J ) 3.6 Hz, 4′-H), 4.58 (d, 2H, J ) 3.6
Hz, 5′_H), 3.94 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.07 (dt,
1H, J ) 15.6 and 6.6 Hz, 2′â-H), 2.57 (d, 1H, J ) 15.6 Hz,
2′R-H), 2.44 (s, 3H, PhCH3), 2.39 (s, 3H, PhCH3); 13C NMR
Meth yl 1-[(2′-O-Meth yl-3′,5′-O-(1,1,3,3,-tetr a isop r op yl-
d isiloxa n e-1,3-d iyl))-â-D-r ibofu r a n osyl]-4,5-im id a zoled i-
ca r boxyla te (16). A mixture of methyl 1-[(3′,5′-O-(1,1,3,3,-
tetraisopropyldisiloxane-1,3-diyl))-â-D-ribofuranosyl]-4,5-
imidazoledicarboxylate (5) (560 mg, 1 mmol), Ag2O (1.85 g, 8
mmol), and MeI (10 mL) was refluxed for 5 h. The mixture
was diluted with Et2O and was filtered over Celite. The filtrate
was concentrated in vacuo, and the residue was purified by
silica gel column chromatography, eluting with chloroform, to
give 16 as a colorless oily product in quantitative yield, Rf 0.35
(hexane/ethyl acetate, 3:1); 1H NMR (CDCl3) 8.20 (s, 1H,
imidazole), 6.02 (s, 1H, 1′-H), 4.42 (dd, 1H, J ) 4.2 and 9.6
Hz, 3′-H), 4.28 (d, 1H, J gem ) 13.8 Hz, 5′-H), 4.16 (dd, 1H, J )
9.6 and 2.4 Hz, 4′-H), 4.00 (dd, 1H, J gem ) 13.8 Hz, J 5′,4′ ) 2.4
Hz, 5′-H), 3.94 (s, 3H, COOCH3), 3.93 (s, 3H, COOCH3), 3.78
(d, 1H, J ) 4.2 Hz, 2′-H), 3.69 (s, 3H, OCH3), 1.05 (m, 28H,
isopropyl groups); 13C NMR (CDCl3, 75.48 MHz) 12.53 (CHSi),
12.90 (CHSi), 12.96 (CHSi), 13.46 (CHSi), 16.87 (CCH3), 17.01
(CCH3), 17.01 (CCH3), 17.15 (CCH3), 17.30 (CCH3), 17.30
(CCH3), 17.38 (CCH3), 17.49 (CCH3), 52.45 (COOCH3), 52.62
(COOCH3), 59.46 (OCH3), 59.96 (C-5′), 68.66 (C-3′), 81.59 (C-
4′), 84.99 (C-2′), 90.76 (C-1′), 122.84 (C-4 or 5), 137.55 (C-2),
138.57 (C-5 or 4), 160.23 (CdO), 163.06 (CdO). Anal.
(C25H44N2O9Si2) C, H, N.
Met h yl 1-(2′-O-Met h yl-â-D-r ib ofu r a n osyl)-4,5-im id a -
zoled ica r b oxyla t e (17). A 1 M solution of tetra-n-butyl-
ammonium fluoride in THF (2 mL, 2 mmol) was added to an
ice-cold solution of methyl 1-[(2′-O-methyl-3′,5′-O-(1,1,3,3-tetra-
isopropyldisiloxane-1,3-diyl))-â-D-ribofuranosyl]-4,5-imidazoledi-
carboxylate (16) (573 mg, 1 mmol) in 10 mL of dry THF. The
reaction mixture was stirred for 45 min at 0 °C. The solvent
was evaporated in vacuo, and the pure product 17 was
obtained as a foam after silica gel column chromatography,
eluting with a mixture of chloroform-methanol (20:1), 85%
yield, Rf 0.29 (chloroform/methanol, 10:1); 1H NMR (CDCl3)
8.67 (s, 1H, imidazole), 6.17 (d, 1H, J ) 2.1 Hz, 1′-H), 5.03
(brs, 1H, 3′-OH, exchangeable with D2O), 4.47 (t, 1H, 5′-OH,
exchangeable with D2O), 4.12 (m, 2H, 2′,3′-H), 3.93 (s, 3H,
COOCH3), 3.91 (s, 3H, COOCH3), 3.91 (m, 2H, 4′,5′-H), 3.60
(s, 3H, OCH3), 3.32 (m, 1H, 5′-H); 13C NMR (CDCl3, 75.48 MHz)
52.31 (COOCH3), 52.74 (COOCH3), 59.10 (OCH3), 60.03 (C-
5′), 68.15 (C-3′), 84.85 (C-4′), 85.58 (C-2′), 88.83 (C-1′), 123.96
(C-4 or 5), 136.43 (C-5 or 4), 138.37 (C-2), 160.52 (CdO), 162.26
(CdO). Anal. (C13H18N2O8) C, H, N.