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S.-K. Chung et al. / Bioorg. Med. Chem. 8 (2000) 2475±2486
1
(®lm) n 2247, 1610 cm 1; H NMR (CDCl3) d 2.01 (m,
2H), 2.26 (d, J=6.4 Hz, 2H), 2.90 (m, 1H), 3.57 (t, J=8.6
Hz, 1H), 4.08 (m, 1H), 4.33 (d, J=14.3 Hz, 1H), 4.56 (d,
J=14.2 Hz, 1H), 6.87 (m, 2H), 7.48 (m, 1H), 7.86 (s, 1H),
8.08 (s, 1H); MS (EI) m/z 305 (M++1); HRMS (EI) calcd
for C15H15ON4F2 305.1214 (M++1), found 305.1226.
dried over anhydrous magnesium sulfate, and con-
centrated in vacuo. The residue was puri®ed by column
chromatography (EtOAc:hexane, 2:1, v/v) to give 21a
(0.26 g, 52.1%) as a solid: mp 62.4±63.6 ꢀC; [a]d22 56.4ꢀ
(c=0.5, CHCl3); IR (®lm) n 2729, 1722 cm 1; 1H NMR
(CDCl3) d 2.47 (m, 4H), 4.21 (m, 1H), 2.47 (m 1H), 4.47
(d, J=14.3 Hz, 1H), 4.63 (d, J=14.3 Hz, 1H), 6.84 (m,
2H), 7.36 (m, 1H), 7.84 (s, 1H), 8.12 (s, 1H), 9.67 (s,
1H); MS (EI) m/z 308 (M++1).
(2R-cis)- and (2R-trans)-4-Cyanomethyl-2-(2,4-di¯uoro-
phenyl)-2-[(1H-pyrrol-1-yl)methyl]tetrahydrofuran (19).
By the same method as described for 18a, 15 (2.66 g,
5.96 mmol) was converted to 19 (1.74 g, 97.2%) as a
solid, which was recrystallized from EtOAc±hexane: IR
(®lm) n 3103, 2943, 2867, 2248, 1617, 1598, 1497, 1422,
(2R-trans)-2-(2,4-Di¯uorophenyl)-4-formylmethyl-2-[(1H-
1,2,4 - triazol - 1 - yl)methyl]tetrahydrofuran (21b). By the
same method as described for 21a, 18b (1.0 g, 3.29
mmol) was converted to 21b (0.41 g, 40.4%) as an oil:
[a]2d2 30.4ꢀ (c=0.5, CHCl3); IR (®lm) n 2729, 1722
1289, 1269, 1137 cm 1; H NMR (CDCl3) d 1.78±1.98
1
(m, 2.6H), 2.20 (d, J=6.6 Hz, 1.2H), 2.39±2.51 (m, 0.6H),
2.66 (ddd, J=12.8, 7.2, 3.3 Hz, 0.6H), 3.50 (t, J=8.4 Hz,
0.6H), 3.65 (dd, J=9.8, 4.8 Hz, 0.4H), 3.91±4.20 (m,
3H), 6.09±6.12 (m, 2H), 6.65±6.69 (m, 2H), 6.81±6.90
(m, 2H), 7.44±7.59 (m, 1H); MS (EI) m/z 302 (M+);
HRMS (EI) calcd for C17H16ON2F2 302.1231 (M+),
found 302.1239.
1
cm 1; H NMR (CDCl3) d 1.83 (m, 1H), 2.16 (m, 1H),
2.40 (m, 2H), 3.39 (t, J=8.8 Hz, 1H), 4.20 (dd, J=8.4,
6.9 Hz, 1H), 4.36 (d, J=14.2 Hz, 1H), 4.54 (d, J=14.2
Hz, 1H), 6.84 (m, 2H), 7.43 (m, 1H), 7.84 (s, 1H), 8.09
(s, 1H), 9.64 (br, 1H); MS (EI) m/z 308 (M++1).
(2R-cis)- and (2R-trans)-2-(2,4-Di¯uorophenyl)-4-formyl-
methyl-2-[(1H-pyrrol-1-yl)methyl]tetrahydrofuran (22).
By the same method as described for 21a, 19 (1.5 g,
4.96 mmol) was converted to 22 (1.04 g, 68.7%) as an oil:
IR (®lm) n 2942, 2724, 1724, 1616, 1598, 1497, 1422, 1269,
1136, 963 cm 1; 1H NMR (CDCl3) d 1.66±1.78 (m, 1.2H),
1.98±2.10 (m, 0.6H), 2.26±2.36 (m, 1.6H), 2.38±2.50 (m,
1H), 2.67 (ddd, J=13.2, 8.0, 3.6 Hz, 0.6H), 3.34 (t, J=8.7
Hz, 0.6H), 3.42 (dd, J=8.3, 7.2 Hz, 0.4H), 4.0±4.20 (m,
3H), 6.07±6.09 (m, 2H), 6.62±6.66 (m, 3H), 6.79±6.86
(m, 2H), 7.43±7.54 (m, 1H), 9.61 (app t, J=1.2 Hz, 1H);
MS (EI) m/z 305 (M+); HRMS (EI) calcd for
C17H17O2NF2 305.1227 (M+), found 305.1225.
(2R-cis)-2-Benzyloxymethyl-4-cyanomethyl-2-(2,4-di¯uor-
ophenyl)tetrahydrofuran (20a). By the same method as
described for 18a, 16a (1.44 g, 3.04 mmol) was con-
verted to 20a (0.9 g, 88.8%) as an oil after puri®cation
by column chromatography (EtOAc±hexane gradient):
[a]1d8 2.80ꢀ (c=1.21, CHCl3); IR (®lm) n 3065, 2939,
2865, 2247, 1615, 1599, 1497, 1422, 1270, 1104, 1040
1
cm 1; H NMR (CDCl3) d 2.30±2.45 (m, 2H), 2.50±2.60
(m, 3H), 3.55 (dd, J=10.5, 1.8 Hz, 1H), 3.68 (dd, J=10.5,
1.8 Hz, 1H), 3.82 (dd, J=8.7, 4.2 Hz, 1H), 3.93±3.98 (m,
1H), 4.57 (s, 2H), 6.73±6.81 (m, 1H), 6.83±6.90 (m, 1H),
7.24±7.37 (m, 5H), 7.52±7.60 (m, 1H); MS (FAB) m/z
344 (M++1); HRMS (FAB) calcd for C20H20O2NF2
344.1462 (M++1), found 344.1458.
(2R-cis)-2-Benzyloxymethyl-2-(2,4-di¯uorophenyl)-4-(for-
mylmethyl)tetrahydrofuran (23a). By the same method
as described for 21a, 20a (0.86g, 2.51 mmol) was con-
verted to 23a (0.56 g, 64.1%) as an oil: [a]1d8 2.54ꢀ
(c=1.36, CHCl3); IR (®lm) n 2941, 2862, 2723, 1723,
(2R-trans)-2-Benzyloxymethyl-4-cyanomethyl-2-(2,4-di-
¯uorophenyl)tetrahydrofuran (20b). By the same method
as described for 18a, 16b (2.14 g, 4.51 mmol) was con-
verted to 20b (1.43 g, 95.1%) as an oil after puri®cation
by column chromatography (EtOAc±hexane gradient):
[a]2d0 19.03ꢀ (c=1.19, CHCl3); IR (®lm) n 3064, 2944,
2863, 2247, 1615, 1600, 1499, 1423, 1269, 1106 cm 1; 1H
NMR (CDCl3) d 1.86±1.95 (m, 1H), 2.30 (d, J=6.9 Hz,
2H), 2.76±2.87 (m, 2H), 3.49 (dd, J=10.5, 1.5 Hz, 1H),
3.62 (dd, J=8.4, 6.9 Hz, 1H), 3.65 (dd, J=10.2, 1.5 Hz,
1H), 4.24±4.29 (m, 1H), 4.54 (s, 2H), 6.73±6.80 (m, 1H),
6.84±6.90 (m, 1H), 7.22±7.35 (m, 5H), 7.59±7.67 (m,
1H); MS (FAB) m/z 344 (M++1); HRMS (FAB) calcd
for C20H20O2NF2 344.1462 (M++1), found 344.1461.
1
1614, 1600, 1497, 1420, 1269, 1106, 1031, 965 cm 1; H
NMR (CDCl3) d 2.04 (dd, J=12.8, 8.4 Hz, 1H), 2.42
(ddd, J=12.6, 6.9, 2.4 Hz, 1H), 2.50±2.74 (m, 3H),
3.60±3.72 (m, 3H), 4.16 (dd, J=8.4, 6.6 Hz, 1H), 4.55 (s,
2H), 6.71±6.79 (m, 1H), 6.84±6.90 (m, 1H), 7.21±7.34
(m, 5H), 7.55±7.64 (m, 1H), 9.71 (s, 1H); MS (FAB) m/z
347 (M++1); HRMS (FAB) calcd for C20H21O3F2
347.1459 (M++1), found 347.1457.
(2R-trans)-2-Benzyloxymethyl-2-(2,4-di¯uorophenyl)-4-
(formylmethyl)tetrahydrofuran (23b). By the same
method as described for 21a, 20b (1.23 g, 3.57 mmol) was
converted to 23b (0.92 g, 74.2%) as an oil: [a]1d9 13.81ꢀ
(c=0.91, CHCl3); IR (®lm) n 2944, 2860, 2724, 1723,
1615, 1600, 1497, 1421, 1269, 1104, 965 cm 1; 1H NMR
(CDCl3) d 1.74 (ddd, J=12.9, 8.4, 2.4 Hz, 1H), 2.36±2.52
(m, 2H), 2.70±2.80 (m, 1H), 2.84±2.97 (m, 1H), 3.44 (t,
J=8.4 Hz, 1H), 3.53 (dd, J=10.5, 1.5 Hz, 1H), 3.65 (dd,
J=10.2, 1.5 Hz, 1H), 4.31 (dd, J=8.1, 6.9 Hz, 1H), 4.54
(s, 2H), 6.71±6.79 (m, 1H), 6.83±6.90 (m, 1H), 7.20±7.33
(m, 5H), 7.60±7.68 (m, 1H), 9.71 (t, J=1.5 Hz, 1H); MS
(FAB) m/z 347 (M++1); HRMS (FAB) calcd for
C20H21O3F2 347.1459 (M++1), found 347.1458.
(2R-cis)-2-(2,4-Di¯uorophenyl)-4-formylmethyl-2-[(1H-
1,2,4-triazol-1-yl)methyl]tetrahydrofuran (21a). To
a
solution of 18a (0.49 g, 1.6 mmol) in toluene (13 mL) at
78 ꢀC was added dropwise diisobutylaluminum
hydride (1 M/toluene, 2 mL) over a period of 30 min.
After stirring at the same temperature for 30 min, the
mixture was allowed to warm up to room temperature,
and then was stirred for 4 h. The mixture was cooled to
10 ꢀC, and a saturated aqueous solution of NH4Cl was
added to the mixture, which was extracted with EtOAc
(50 mL). The extract was washed with brine (15 mL),