2454 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 12
Chen et al.
8.9), 6.39 (s, 1H), 7.44 (m, 6H), 7.54 (s, 1H), 7.55 (s, 1H), 7.70
(m, 4H). 13C NMR (CDCl3): δ 19.3, 27.0, 38.4, 64.0, 72.3, 84.4,
85.2, 101.7, 113.0, 120.9, 125.2, 126.0, 126.7, 127.4, 127.9,
130.0, 132.77, 132.83, 133.0, 135.6. HRMS for C29H30Cl3NO3-
Si: [M + NH4]+ Calcd, 591.1404; Found, 591.1389.
added, and the stirring was continued for 15 min. The mixture
was treated with 100 mL of water and extracted with EtOAc
(2 × 150 mL). The combined extracts were washed with brine
(100 mL), dried over Na2SO4, and concentrated to dryness. The
residue was purified by flash column chromatography (60%
EtOAc/Hex, 3 × 10 cm) to give 845 mg (61%) of 18 as a white
2-Ben zylth io-1-(2-d eoxy-5-O-ter t-bu tyld ip h en ylsilyl-3-
O-m e syl-â-D -er yt h r o-p e n t ofu r a n osyl)-5,6-d ich lor oin -
d ole (14). To a solution of compound 12 (2.46 g, 3.71 mmol)
in 60 mL of CH2Cl2 and 14 mL of pyridine at 0 °C was added
MsCl (1.4 mL, 18 mmol). The mixture was stirred at room
temperature for 4.5 h. After the addition of MeOH (12.4 mL)
and further stirring for 20 min, the mixture was concentrated
to dryness and coevaporated with toluene (2 × 15 mL). The
residue was dissolved in 200 mL of CH2Cl2. The CH2Cl2
solution was washed with brine (50 mL), dried over Na2SO4,
and concentrated to dryness. The residue was purified by flash
column chromatography (20% EtOAc/Hex, 4 × 10 cm) to give
2.52 g (92%) of 14 as a colorless foam: Rf (40% EtOAc/Hex) )
1
solid: mp 139-140 °C; Rf (60% EtOAc/Hex) ) 0.30. H NMR
(DMSO-d6): δ 3.71 (m, 2H), 3.94 (m, 1H), 4.16 (m, 3H), 4.48
(m, 1H), 5.22 (d, 1H, J ) 4.2, D2O exchangeable), 5.30 (t, 1H,
J
) 4.5, D2O exchangeable), 5.38 (d, 1H, J ) 6.6, D2O
exchangeable), 6.15 (d, 1H, J ) 7.8), 6.46 (s, 1H), 7.25 (m, 5H),
7.73 (s, 1H), 8.38 (s, 1H). 13C NMR (DMSO-d6): δ 61.2, 69.7,
71.0, 85.3, 88.7, 109.1, 114.9, 120.8, 122.9, 124.6, 127.2, 127.7,
128.3, 129.0, 133.9, 134.6, 137.0. HRMS for C20H19Cl2NO4S:
Calcd, 439.0412; Found, 439.0408. Anal. (C20H19Cl2NO4S) C,
H, N.
2,5,6-Tr ich lor o-(1-â-D-r ibofu r an osyl)in dole (19). Meth od
I. The procedure is the same as that described for 18, except
that 17 (0.65 g, 2.0 mmol) was used instead of 16. A 84% yield
(0.59 g, 1.7 mmol) of 19 was obtained as a white solid: mp
135 °C (dec); Rf (60% EtOAc/Hex) ) 0.30. 1H NMR (DMSO-
d6): δ 3.70 (m, 2H), 3.94 (m, 1H), 4.13 (m, 1H), 4.43 (m, 1H),
5.23 (d, 1H, J ) 4.5, D2O exchangeable), 5.32 (m, 2H, D2O
exchangeable), 5.88 (d, 1H, J ) 7.7), 6.68 (s, 1H), 7.80 (s, 1H),
8.42 (s, 1H). 13C NMR (DMSO-d6): δ 61.2, 69.6, 71.2, 85.7, 88.5,
1
0.40. H NMR (CDCl3): δ 1.12 (s, 9H), 1.99 (m, 1H), 2.70 (m,
1H), 2.99 (s, 3H), 3.92 (s, 2H), 3.97 (m, 2H), 4.14 (m, 1H), 5.39
(m, 1H), 6.42 (dd, 1H, J ) 9.7, 5.6), 6.51 (s, 1H), 7.10-7.56
(m, 11H), 7.54 (s, 1H), 7.57 (s, 1H), 7.70 (m, 4H). 13C NMR
(CDCl3): δ 19.3, 27.1, 36.0, 38.4, 42.3, 62.8, 79.1, 82.9, 84.7,
111.0, 113.3, 121.4, 124.9, 126.8, 127.6, 127.89, 127.91, 128.0,
128.1, 128.71, 128.74, 130.00, 130.04, 132.4, 132.6, 133.0,
134.6, 135.6, 135.7, 137.0. HRMS for C37H39Cl2NO5S2Si: Calcd,
739.1416; Found, 739.1425.
101.3, 114.8, 120.8, 123.6, 124.5, 127.3, 132.9. Anal. (C13H12
Cl3NO4) C, H, N.
-
1-(2-Deoxy-5-O-ter t-bu tyld ip h en ylsilyl-3-O-m esyl-â-D-
er yth r o-p en tofu r a n osyl)-2,5,6-tr ich lor oin d ole (15). The
procedure is the same as that described for 14, except that 13
(3.3 g, 5.7 mmol) was used instead of 12. A 91% yield (3.4 g,
5.2 mmol) of 15 was obtained as a colorless foam: Rf (25%
EtOAc/Hex) ) 0.30. 1H NMR (CDCl3): δ 1.12 (s, 9H), 2.50 (m,
1H), 2.80 (m, 1H), 3.01 (s, 3H), 4.00 (m, 2H), 4.25 (m, 1H),
5.46 (m, 1H), 6.34 (dd, 1H, J ) 9.7, 5.4), 6.43 (d, 1H, J ) 0.7),
7.44 (m, 6H), 7.57 (s, 1H), 7.60 (s, 1H), 7.70 (m, 4H). 13C NMR
(CDCl3): δ 19.3, 27.0, 36.7, 38.4, 62.7, 78.9, 83.4, 84.7, 102.1,
113.1, 121.0, 125.5, 126.4, 126.5, 127.4, 127.7, 127.89, 127.93,
130.0, 130.1, 132.3, 132.5, 133.0, 134.8, 135.6, 135.7. HRMS
for C30H32Cl3NO5SSi: [M + NH4]+ Calcd, 669.1180; Found,
669.1165.
2-Ben zylt h io-5,6-d ich lor o-1-(2,3-d id eoxy-â-D-glycer o-
p en t-2-en ofu r a n osyl)in d ole (16). To a solution of compound
14 (1.00 g, 1.35 mmol) in 14 mL of DMSO was added t-BuOK
(0.59 g, 5.25 mmol). The mixture was stirred at room temper-
ature for 10 min, then treated with 100 mL of cold water, and
extracted with EtOAc (2 × 100 mL). The combined extracts
were washed with water (150 mL) and brine (150 mL), dried
over Na2SO4, and concentrated to dryness. The residue was
purified by flash column chromatography (CHCl3, 2 × 10 cm)
to give 370 mg (67%) of 16 as a pale-yellow foam: Rf (50%
EtOAc/Hex) ) 0.30. 1H NMR (DMSO-d6): δ 3.61 (m, 2H), 4.18
(s, 2H), 4.80 (m, 1H), 4.99 (t, 1H, J ) 4.8, D2O exchangeable),
6.01 (m, 1H), 6.51 (m, 1H), 6.64 (s, 1H), 7.02 (m, 1H), 7.25 (m,
5H), 7.75 (s, 1H), 8.04 (s, 1H). 13C NMR (DMSO-d6): δ 42.0,
64.1, 86.2, 90.5, 111.1, 113.8, 121.2, 124.8, 126.4, 127.5, 128.3,
128.5, 128.8, 133.0, 133.9, 135.8, 137.1. HRMS for C20H17Cl2-
NO2S: Calcd, 405.0357; Found, 405.0338.
1-(2,3-Did eoxy-â-D-glycer o-p en t-2-en ofu r a n osyl)-2,5,6-
tr ich lor oin d ole (17). The procedure is the same as that
described for 16, except that 15 (1.8 g, 2.7 mmol) was used
instead of 14. A 76% yield (0.66 g, 2.1 mmol) of 17 was obtained
as a pale-yellow oil: Rf (2% MeOH/CHCl3) ) 0.25. 1H NMR
(CDCl3): δ 3.87 (m, 2H), 4.96 (m, 1H), 6.24 (m, 1H), 6.44 (m,
2H), 7.01 (m, 1H), 7.56 (s, 1H), 7.88 (s, 1H). 13C NMR
(CDCl3): δ 64.0, 86.7, 90.3, 101.9, 113.7, 120.8, 125.4, 125.9,
127.4, 127.8, 128.0, 133.8, 134.0. HRMS for C13H10Cl3NO2:
Calcd, 316.9777; Found, 316.9771.
2-Be n zylt h io-1-(â-D -r ib ofu r a n osyl)-5,6-d ich lor oin -
d ole (18). Compound 16 (1.27 g, 3.13 mmol) and N-methyl-
morpholine oxide (1.00 g, 8.51 mmol) were dissolved in 30 mL
of acetone-water (8:1), and OsO4 (3 mL, 0.30 mmol, 2.5 wt %
in 2-methyl-2-propanol) was added. The mixture was stirred
at room temperature for 20 h, 10% Na2S2O4 (10 mL) was then
Meth od II. Compound 19 may also be prepared from
compound 23. The procedure is the same as that described
for 25, except that 23 (5 mg, 0.013 mmol) was used instead of
24. A 54% yield (2.4 mg, 0.007 mmol) of 19 was obtained as a
white solid: mp 135 °C (dec).
1-(5-O-ter t-Bu tyld im eth ylsilyl-2,3-O-isop r op ylid en e-â-
D-r ibofu r a n osyl)-2,5,6-tr ich lor oin d ole (20). The procedure
is the same as that described for 21, except that 6 (1.6 g, 7.3
mmol) was used instead of 7. A 73% yield (2.7 g, 5.3 mmol) of
20 was obtained as a white foam: Rf (10% EtOAc/Hex) ) 0.70.
1H NMR (CDCl3): δ 0.16 (2s, 6H), 0.96 (s, 9H), 1.38 (s, 3H),
1.65 (s, 3H), 3.98 (m, 2H), 4.11 (m, 1H), 5.00 (m, 2H), 6.07 (d,
1H, J ) 4.1), 6.45 (s, 1H), 7.60 (s, 1H), 7.61 (s, 1H). 13C NMR
(CDCl3): δ 19.0, 25.8, 26.4, 27.7, 62.8, 79.4, 82.5, 84.1, 90.0,
102.2, 113.1, 116.0, 121.3, 125.8, 126.7, 127.1, 127.7, 133.5.
HRMS for C22H30Cl3NO4Si: Calcd, 505.1010; Found, 505.1009.
2-Br om o-1-(5-O-ter t-b u t yld im et h ylsilyl-2,3-O-isop r o-
p ylid en e-â-D-r ibofu r a n osyl)-5,6-d ich lor oin d ole (21). Com-
pound 7 (625 mg, 2.36 mmol) was dissolved in toluene (25 mL),
and NaH (118 mg, 2.95 mmol, 60% in mineral oil) was then
added at room temperature. The resulting brown suspension
was stirred at room temperature for 1 h, and the preprepared
5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-D-ribofurano-
syl R-chloride (4.9 mmol, in 16 mL of THF, not purified)19 was
then added at room temperature to give a brown solution. This
brown solution was stirred at 70 °C for 16 h. The reaction
mixture was cooled to room temperature and quenched with
10 mL of H2O dropwise. The resulting mixture was concen-
trated first to remove most of the organic solvents and then
extracted with EtOAc (3 × 20 mL). The combined EtOAc
extracts were washed with 30 mL of brine and dried over
MgSO4. The organic layer was concentrated to dryness. The
residue was purified by flash column chromatography (5%
EtOAc/Hex, 3 × 10 cm) to give 133 mg (21%) of compound 7
and 950 mg (92%, based on recovered starting material 7) of
compound 21 as a white solid: mp 88-89 °C; Rf (10% EtOAc/
1
Hex) ) 0.70. H NMR (CDCl3): δ 0.16 (2s, 6H), 0.96 (s, 9H),
1.36 (s, 3H), 1.65 (s, 3H), 3.96 (m, 2H), 4.12 (m, 1H), 4.98 (m,
2H), 6.08 (d, 1H, J ) 4.4), 6.55 (s, 1H), 7.59 (s, 1H), 7.62 (s,
1H). 13C NMR (CDCl3): δ 18.3, 25.2, 25.8, 27.0, 62.2, 78.8, 81.7,
83.3, 90.8, 105.7, 112.5, 113.8, 115.4, 120.5, 125.1, 125.9, 128.2,
133.5. Anal. (C22H30BrCl2NO4Si) C, H, N.
5,6-Dich lor o-1-(â-D-r ibofu r an osyl)in dol-2-on e (22). Com-
pound 20 (130 mg, 0.33 mmol) was dissolved in 2 mL of TFA-
water (9:1). The resulting solution was stirred at room
temperature for 30 min, and then concentrated to dryness to
give a colorless oil. This oil was purified by flash column