864 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5
Shi et al.
prepared from 2b/3b (67% yield): white foam; 1H NMR
(CDCl3) δ 9.32 (bs, 1H, NH), 7.73, 7.16 (2d, J ) 6.0 & 5.2 Hz,
1H, H-6), 7.68-7.64 (m, 4H, arom.), 7.48-7.38 (m, 6H, arom.),
7.04-6.99 (m, 1H, H-1′), 6.40, 6.26 (ddt, J ) 6.0, 6.0 & 1.6 Hz,
1H, H-3′), 5.92, 5.88 (2d, J ) 6.0 Hz, 1H, H-2′), 5.16-5.11,
4.92-4.88 (m, 1H, H-4′), 3.97, 3.83, 3.77 (3 dd, J ) 2.4, 12.0 &
4.0 Hz, 2H, H-5′), 1.08, 1.06 (2s, 9H, t-Bu).
â-D-5-Br om o-5′-O-(ter t-bu tyld ip h en ylsilyl)-2′,3′-d id eh y-
d r o-2′,3′-d id eoxycytid in e (4c). In an analogous manner to
the preparation of 4a , the title compound 4c was prepared
from 2c (92% yield): light-yellow oil; 1H NMR (CDCl3) δ 7.86
(s, 1H, H-6), 7.67-7.64 (m, 4H, arom.), 7.47-7.37 (m, 6H,
arom.), 6.92-6.91 (m, 1H, H-1′), 6.16 (d, J ) 6.0 Hz, 1H, H-3′),
6.04 (d, J ) 6.0 Hz, 1H, H-2′), 5.79 (bs, 1H, NH), 4.95 (bs, 1H,
H-4′), 3.97 (dd, J ) 12 & 3.2 Hz, 1H, H-5′a), 3.83 (dd, J ) 12
& 3.2 Hz, 1H, H-5′b), 1.07 (s, 9H, t-Bu).
stirred at room temperature for 2 h. The reaction mixture was
neutralized by addition of dilute AcOH and then concentrated
under reduced pressure. The orange-colored residue was
extracted by hot acetone, and the extraction was filtered and
concentrated. The residue was crystallized from CH2Cl2/
MeOH/hexane providing 6b (108 mg, 34%) as colorless crystals.
The physical and spectroscopic characteristics of the compound
prepared by this method were identical to that of the com-
pound described above.
â-D-5-Br om o-2′,3′-d id eh yd r o-2′,3′-d id eoxycytid in e (6c).
In an analogous manner to the preparation of 6a , the title
compound 6c was prepared from 4c (84% yield): white solid;
mp > 200 °C; 1H NMR (DMSO-d6) δ 8.22 (s, 1H, H-6), 7.90
(bs, 1H. NH), 7.04 (bs, 1H, NH), 6.84-6.82 (m, 1H, H-1′), 6.33
(dt, J ) 6.0 & 2.0 Hz, 1H, H-3′), 5.90 (d, J ) 5.2 Hz, 1H, H-2′),
5.11 (t, J ) 5.2 Hz, 1H, OH), 4.80 (bs, 1H, H-4′), 3.61-3.59
(m, 2H, H-5′); MS (ESI) m/e 288 (MH+). Anal. (C9H10
-
â-D-5′-O-(ter t-Bu tyld ip h en ylsilyl)-2′,3′-d id eh yd r o-2′,3′-
d id eoxy-5-iod ocytid in e (4d ). In an analogous manner to the
preparation of 4a , the title compound 4d was prepared from
BrN3O3‚0.5CH3OH) H, N; C: calcd, 37.52; found, 37.96. HRMS
(FAB) calcd for (C9H11BrN3O3): 287.9984, found, 287.9988.
â-D-2′,3′-Did eh yd r o-2′,3′-d id eoxy-5-iod ocytid in e (6d ). In
an analogous manner to the preparation of 6a , the title
compound 6d was prepared from 4d (86% yield): white solid;
mp > 200 °C; 1H NMR (DMSO-d6) δ 8.23 (s, 1H, H-6), 7.85
(bs, 1H. NH), 6.82 (d, J ) 2.0 Hz, 1H, H-1′), 6.65 (bs, 1H, NH),
6.33 (d, J ) 6.0 Hz, 1H, H-3′), 5.90 (d, J ) 4.2 Hz, 1H, H-2′),
5.09 (t, J ) 4.0 Hz, 1H, OH), 4.79 (bs, 1H, H-4′), 3.59-3.58
(m, 2H, H-5′); MS (ESI) m/e 336 (MH+). Anal. (C9H10IN3O3)
C, H, N.
1
2d (73% yield): yellow solid; mp > 200 °C; H NMR (CDCl3)
δ 7.88 (s, 1H, H-6), 7.67-7.64 (m, 4H, arom.), 7.47-7.37 (m,
6H, arom.), 6.90-6.89 (m, 1H, H-1′), 6.19 (d, J ) 6.0 Hz, 1H,
H-3′), 6.05 (d, J ) 6.0 Hz, 1H, H-2′), 5.80 (bs, 1H, NH), 4.96
(bs, 1H, H-4′), 3.95 (dd, J ) 12 & 3.6 Hz, 1H, H-5′a), 3.84 (dd,
J ) 12 & 3.6 Hz, 1H, H-5′b), 1.08 (s, 9H, t-Bu).
r-D-5′-O-(ter t-Bu tyld ip h en ylsilyl)-2′,3′-d id eh yd r o-2′,3′-
d id eoxy-5-flu or ocytid in e (5a ). In an analogous manner to
the preparation of 4a , the title compound 5a was prepared
from 3a (95% yield): white foam; mp 80-81 °C; 1H NMR
(CDCl3) δ 7.68-7.66 (m, 4H, arom.), 7.46-7.38 (m, 6H, arom.),
7.21 (d, J ) 6.0 Hz, 1H, H-6), 7.02-7.01 (m, 1H, H-1′), 6.28
(dt, J ) 6.0 & 1.6 Hz, 1H, H-3′), 6.01 (d, J ) 4.2 Hz, 1H, H-2′),
5.65 (bs, 1H, NH), 5.15-5.10 (m, 1H, H-4′), 3.80-3.75 (m, 2H,
H-5′), 1.06 (s, 9H, t-Bu); 13C NMR (CDCl3) δ 157.8, 157.7, 153.9,
137.8, 135.5, 135.4, 133.4, 133.1, 133.0, 129.8, 127.7, 127.4,
124.9, 124.5, 92.1, 87.6, 65.6, 26.7, 19.2.
â-D-2′,3′-Did eh yd r o-2′,3′-d id eoxy-5-flu or ocytid in e (6a ).
To a solution of 4a (9.7 g, 20.86 mmol) in THF (200 mL) was
added a solution of tetrabutylammonium fluoride (1 M solution
in THF, 20.86 mL, 20.86 mmol). The reaction mixture was
stirred at room temperature for 1.5 h, and then the solvent
was removed under reduced pressure. The residue, after
purification by chromatography over silica gel eluted with
CH2Cl2-MeOH (9:1), afforded 6a (4.392 g, 93%) as a white
solid: mp 175-176 °C; 1H NMR (DMSO-d6) δ 8.04 (d, J ) 7.6
Hz, 1H, H-6), 7.77 (bs, 1H, NH), 7.55 (bs, 1H, NH), 6.82 (bs,
1H, H-1′), 6.32 (d, J ) 7.6 Hz, 1H, H-3′), 5.88 (d, J ) 6.0 Hz,
1H, H-2′), 5.11 (t, J ) 6.0 Hz, 1H, OH), 4.78 (bs, 1H, H-4′),
3.62-3.61 (m, 2H, H-5′); 13C NMR (DMSO-d6) δ 157.7, 157.5,
153.7, 137.2, 134.8, 134.4, 126.7, 126.1, 125.8, 90.1, 87.3, 62.1;
MS (ESI) m/e 228 (MH+). Anal. (C9H10FN3O3) C, H, N.
r-D-2′,3′-Did eh yd r o-2′,3′-d id eoxy-5-flu or ocytid in e (7a ).
In an analogous manner to the preparation of 6a , the title
compound 7a was prepared from 5a (91% yield): white solid;
1
mp 128-130 °C; H NMR (DMSO-d6) δ 7.80, 7.54 (2 bs, 2H,
NH2), 7.48 (d, J ) 6.8 Hz, 1H, H-6), 6.84-6.83 (m, 1H, H-1′),
6.34 (dt, J ) 6.0 & 2.0 Hz, 1H, H-3′), 5.88 (d, J ) 6.0 Hz, 1H,
H-2′), 5.07-5.04 (m, 1H, H-4′), 4.83 (t, J ) 5.2 Hz, OH), 3.46-
3.39 (m, 2H, H-5′); 13C NMR (DMSO-d6) δ 157.6, 157.5, 153.5,
137.5, 135.1, 134.6, 126.2, 125.3, 124.9, 90.8, 87.6, 63.3; MS
(FAB) m/e 228 (MH+). Anal. (C9H10FN3O3) C, H, N.
â-L-5′-O-(ter t-Bu tyld iph en ylsilyl)-2′,3′-d id eoxy-5-flu or o-
2′-(p h en ylselen en yl)u r id in e (9). In an analogous manner
to the preparation of 2a , the title compound 9 was prepared
from 5-fluorouracil and the acetate 810 (66% yield): white foam;
1
mp 69-70 °C; H NMR (CDCl3) δ 8.12 (bs, NH), 7.74 (d, J )
6.0 Hz, 1H, H-6), 7.66-7.58 (m, 6H, arom.), 7.49-7.26 (m, 9H,
arom.), 6.13-6.11 (m, 1H, H-1′), 4.25-4.23 (m, 1H, H-4′), 4.05-
4.03 (m, 1H, H-2′), 3.75-3.71, 3.67-3.63 (m, 2H, H-5′), 2.49-
2.45, 2.15-2.07 (2m, 2H, H-3′), 1.11 (s, 9H, t-Bu).
â-L-5′-O-(ter t-Bu tyld ip h en ylsilyl)-2′,3′-d id eh yd r o-2′,3′-
d id eoxy-5-flu or ou r id in e (10). In an analogous manner to
the preparation of 4a , the title compound 10 was prepared
from 9 (91% yield): white foam; mp 64-66 °C; 1H NMR (CDCl3)
δ 8.46 (bs, 1H, NH), 7.72 (d, J ) 6.0 Hz, 1H, H-6), 7.66-7.63
(m, 4H, arom.), 7.46-7.38 (m, 6H, arom.), 6.98-6.95 (m, 1H,
H-1′), 6.27-6.26 (m, 1H, H-3′), 5.88-5.86 (m, 1H, H-2′), 4.89
(bs, 1H, H-4′), 3.97 (dd, J ) 3.6 & 12.0 Hz, 1H, H-5′a), 3.83
(dd, J ) 3.6 & 12.0 Hz, 1H, H-5b), 1.08 (s, 9H, t-Bu).
â-L-2′,3′-Did eh yd r o-2′,3′-d id eoxy-5-flu or ou r id in e (11).
In an analogous manner to the preparation of 6a , the title
compound 11 was prepared from 10 (83% yield): white solid;
mp 130-131 °C; 1H NMR (DMSO-d6) δ 11.86 (bs, 1H, NH),
8.18 (d, J ) 7.2 Hz, 1H, H-6), 6.80 (bs, 1H, H-1′), 6.39 (d, J )
5.6 Hz, 1H, H-3′), 5.91 (d, J ) 5.6 Hz, 1H, H-2′), 5.16 (t, J )
6.0 Hz, 1H, OH), 4.81 (bs, 1H, H-4′), 3.65-3.64 (m, 2H, H-5′);
13C NMR (DMSO-d6) δ 157.3, 157.0, 149.4, 140.8, 138.5, 135.3,
125.8, 125.5, 125.2, 89.4, 87.5, 61.8; MS (FAB) m/e 229 (MH+).
Anal. (C9H9FN2O4) C, H, N.
â-D-2′-Deoxy-3′,5′-d i-O-m esyl-5-flu or ou r id in e (13). To a
solution of â-D-2′-deoxy-5-fluorouridine (12; 1.23 g, 5 mmol)
in dry pyridine (10 mL) at -10 °C was added methanesulfonyl
chloride (1.317 g, 11.5 mmol, 0.9 mL) dropwise. The reaction
mixture was stored in a refrigerator overnight. After addition
of water (0.5 mL), the mixture was poured into a 500 mL of
ice-water and stirred for 1 h. The precipitates were filtered
and chromatographed on silica gel eluting with CH2Cl2/MeOH
â-D-2′,3′-Did eh yd r o-2′,3′-d id eoxy-5-flu or ou r id in e (6b)
an d r-D-2′,3′-Dideh ydr o-2′,3′-dideoxy-5-flu or ou r idin e (7b).
In an analogous manner to the preparation of 6a , the title
compounds 6b and 7b were prepared from 4b/5b and purified
by preparative TLC (eluting with CHCl3/MeOH, 12:1). 6b (41%
yield): white solid; Rf 0.36 (CHCl3/MeOH, 90:10); mp 129-
1
130 °C; H NMR (DMSO-d6) δ 8.04 (d, J ) 7.2 Hz, 1H, H-6),
6.81 (bs, 1H, H-1′), 6.36 (d, J ) 6.4 Hz, 1H, H-3′), 5.88 (d, J )
4.8 Hz, 1H, H-2′), 4.77 (bs, 1H, H-4′), 3.62-3.58 (m, 2H, H-5′);
13C NMR (DMSO-d6) δ 158.9, 158.7, 150.7, 141.2, 138.9, 135.0,
126.1, 124.8, 124.5, 89.5, 87.4, 62.0; MS (FAB) m/e 229 (MH+).
Anal. (C9H9FN2O4) C, H, N. 7b (25%): white sticky solid; Rf
1
0.32 (CHCl3/MeOH, 90:10); H NMR (DMSO-d6) δ 7.44 (d, J
) 7.2 Hz, 1H, H-6), 6.84 (d, J ) 4.8 Hz, 1H, H-1′), 6.38 (d, J
) 6.0 Hz, 1H, H-3′), 5.88 (d, J ) 6.0 Hz, 1H, H-2′), 5.05 (bs,
1H, H-4′), 3.48-3.40 (m, 2H, H-5′); 13C NMR (DMSO-d6) δ
159.1, 158.9, 150.7, 141.8, 139.4, 135.2, 125.5, 123.9, 123.6,
90.2, 87.7, 63.2; MS (FAB) m/e 229 (MH+). Anal. (C9H9FN2O4)
C, H, N.
â-D-2′,3′-Didehydro-2′,3′-dideoxy-5-fluorouridine (6b) was
also prepared from 1-(2-deoxy-3,5-epoxy-â-D-threo-pentofuran-
osyl)-5-fluorouracil (14). A mixture of t-BuOK (332 mg, 2.9
mmol) and 14 (319 mg, 1.4 mmol) in dry DMSO (15 mL) was