May 1998
SYNTHESIS
761
Table. Physical and Spectral Data of cis- and trans-2-Hydroxymethyl-4-(cytosin-1¢-yl)-1,3-oxathiolane and -1,3-dithiolane Derivatives
Product Yield mpb (°C)
(%)a
Molecular
formula
UV lmax (nm)c 1H-NMR (DMSO-d6)
d, J (Hz)
m/zd
(M+)
187a
197a
20
98
94
75
> 210 (dec) C8H10FN3O3S 284
3.78 (m, 2H), 3.91 (dd, 1H, J = 4.6, 10.6), 4.44 (d, 1H, J = 10.5),
5.18 (t, 1H, J = 5.5), 5.44 (t, 1H, D2O exchangeable), 6.28 (d, 1H,
J = 2.6), 7.56 (b, 1H, D2O exchangeable), 7.79 (lH, b, 1H, D2O
exchangeable)
247
> 200
108
C8H10FN3O3S 284
C8H11N3O2S2 275
C8H11N3O2S2 275
3.35 (m, 1H), 3.59 (m, 1H), 4.13 (dd, 1H, J = 4.7, 10.7), 4.25
(dd, 1H, J = 1.5, 10.7), 5.23 (t, 1H, D2O exchangeable), 5.63
(dd, 1H, J = 4.5, 7.3), 6.24 (dd, 1H, J = 1.7, 3.0), 7.57 (b, 1H,
D2O exchangeable), 7.81 (1H, d, 1H, J = 6.9)
247
246
3.33 (m, 1H), 3.49 (m, 1H), 3.76 (t, 2H), 4.63 (t, 1H), 5.52
(t, 1H, D2O exchangeable), 5.75 (d, 1H, J = 7.48), 6.49
(t, 1H, J = 4.33), 7.22 (d, 2H, D2O exchangeable), 8.06 (d, 1H,
J = 7.42)
21
22
77
93
202
3.48 (m, 1H), 3.52 (m, 2H), 4.76 (t, 1H), 5.39 (t, 1H, D2O
exchangeable), 5.72 (d, 1H, J = 7.57), 6.49 (t, 1H, J = 4.33),
7.30 (b, 2H, D2O exchangeable), 7.93 (d, 1H, J = 7.57)
246
244
102–104
C9H13N3O3S
C9H13N3O3S
276
276
1.66 (s, 3H), 3.23 (dd, 1H, J = 12, 7), 3.26 (dd, 1H, J = 12, 5),
4.26 (dd, 1H, J = 11, 4), 4.30 (d, 1H, J = 11), 5.23 (t, 1H, J = 6),
5.80 (d, 1H, J = 8), 6.23 (d, 1H, J = 4), 7.21 (bs, 2H, D2O
exchangeable), 7.69 (d, 1H, J = 8)
23
86
110–112
1.50 (s, 3H), 3.61 (ds, 2H, J = 6), 4.30 (dd, 1H, J = 11, 4), 4.35
(d, 1H, J = 11), 5.41 (t, 1H, D2O exchangeable), 6.27 (d, 1H,
J = 4), 7.16 (bs, 2H, D2O exchangeable), 7.93 (d, 1H, J = 8)
244
a Yield of isolated pure product of the last step (deprotection with ammonia).
b Uncorrected.
c log e = 4.01
d HRMS (FAB): 18 (C8H11FN3O3S) calcd 247.0428, found 247.0452; 19 (C8H11FN3O3S) calcd 247.0428, found 247.0415; 20 (C8H12N3O2S2)
calcd 246.0371, found 246.0383; 21 (C8H12N3O2S2) calcd 246.0371, found 246.0359; 22 (C9H14N3O3S) calcd 244.0756, found 244.0767; 23
(C9H14N3O3S) calcd 244.0756, found 244.0737.
1H NMR (CDCl3): d = 1.87 + 1.74 (s’s, 3H, CH3, 4.30 (m, 2H, CH2-O),
2 h. The HMDS was removed under reduced pressure and the silylat-
ed base was dried under high vacuum. To a solution of this base in
CH2Cl2 (50 mL), 4-benzoyloxy-2-benzoyloxymethyl-1,3-oxathi-
olane (13) (1.25 g, 3.6 mmol) in CH2Cl2 (30 mL) followed by TMSI
(0.75 mL, 4.5 mmol) were added. The resulting mixture was stirred
for 24 h at 25°C. The reaction was poured into sat. NaHCO3, the
aqueous phase was extracted with CH2Cl2 (100 mL). The combined
organic extracts were dried and concentrated to give a residue. This
was purified by flash chromatography (silica gel, 25% EtOAc/hex-
anes) to give pure benzoate cis isomer (0.682 g, 55%) and the trans
isomer (0.27 g, 22 %) as white solids mp 235–236°C (dec.).
1H NMR (CDCl3): d = 3.98 (dd, 1H, CH-O, J = 4.7, 11 Hz); 4.61 (d,
1H, CH-O, J = 11 Hz); 4.73 (m, 2H, CH2-OBz); 5.51 (t, 1H, CH-S, J
= 3.8 Hz); 6.28 (d, 1H, CH-N, J = 3 Hz); 7.52 (m, 2Harom); 7.58 (b,
1H, NH2); 7.68 (m, 1Harom); 7.80 (d, 2H, cytosine and 1H, NH2); 7.94
(m, 2Harom).
4.65 (m, 2H, CH2-OBz), 6.54+6.48 (d’s, 1H, CH-S, J = 3Hz), 7.48
(m, 6Harom), 8.08 (m, 4Harom).
cis- and trans-4-Benzoyloxy-2-benzoyloxymethyl-1,3-oxathiolane (3):
obtained by the Typical Procedure as a colorless oil.
1H NMR (CDCl3): d = 4.25–4.32 (m, 2H, CH2-O), 4.48-4.63 (m, 2H,
CH2-OBz), 5.79 (dd, 1H,CH-OBz, J = 3.5, 3.6 Hz), 6.51 (t, 1H, CH-
S, J = 2.6 Hz), 7.41–7.46 (m, 4Harom), 7.53–7.59 (m, 2Harom), 8.01–
8.07 (m, 4Harom).
13C NMR (CDCl3): d = 23.93, 25.43, 39.89, 65.33, 75.04, 82.53,
84.40,129.04, 130.35, 133.78, 134.12, 166.46, 166.56.
HRMS (FAB): M+ calcd for C18H17O5S 345.0796, found 345.0779.
cis- and trans-4-Benzoyloxy-2-benzoyloxymethyl-1,3-dithiolane (13):
obtained by the Typical Procedure as a pale yellow oil.
1H NMR (CDCl3): d = trans: 3.52–3.55 (m, 2H, CH2-S), 4.51–4.54
(m, 2H, CH2-OBz), 4.87–4.89 (m, 1H, CH-OBz), 6.92 (t, 1H, CH-S,
J = 3.2 Hz), 7.41–7.51 (m, 4Harom), 7.60–7.68 (m, 2Harom), 8.04–8.16
(m, 4H). cis: 3.51–3.56 (m, 2H, CH2-S), 4.36–4.48 (m, 2H, CH2-OBz),
4.87–4.89 (m, 1H, CH-OBz), 6.82 (dd, 1H, CH-S, J = 1.5, 1.6 Hz),
7.41–7.51 (m, 4Harom), 7.60–7.68 (1H, m, 2Harom), 8.04–8.16 (m,
4Harom).
The cis nucleoside was dissolved in a saturated solution ofmethanolic
ammonia (100 mL) and the mixture was stirred overnight. This af-
forded pure cis hydroxymethyl derivative 18 (0.43 g, 98%) as a white
solid material (for data see Table).
The authors wish to thank Drs. T. Mansour and C. Penney for their
advice and revision of the manuscript. The excellent technical assis-
tance of Ms. M. DiMarco for HPLC separation and the excellent sec-
retarial assistance of Ms. L. Marcil are also acknowledged.
13C NMR (CDCl3): d = 42.70, 51.27, 67.89, 86.92, 129.45, 130.54,
133.80, 134.09, 172.96.
HRMS (FAB): M -1 calcd for C18H15O4S2 359.0411, found 359.0409.
cis- and trans-4-(5¢-Fluorocytosin-1¢-yl)-2-hydroxymethyl-1,3-oxa-
thiolane 18: Typical Procedure:
5-Fluorocytosine (0.700 g, 5.4 mmol) was refluxed with HMDS (150
mL) and a catalytic amount of (NH4)2SO4 (0.030 g). After the solid
was dissolved (about 3 h), refluxing was continued for an additional
(1) Mitsuya, H.; Weinhold, J. K.; Furman, P. A.; St-Clair, M. H.;
Nusinoff-Lehrman, S.; Gallo, R. C.; Bolognesi, D.; Barry, D.
W.; Broder, S. Proc. Natl. Acad. Sci. USA. 1985, 82, 7096.