E. Roulland et al. / Bioorg. Med. Chem. 10 (2002) 3463–3471
3469
sodium hydrogenosulfite solution until discolouration
of the medium. The organic phase was separated, dried
over anhydrous magnesium sulfate, filtered and the sol-
vent was removed under reduced pressure. Purification
by flash chromatography on a silica gel column (cyclo-
hexane/ethyl acetate: 4/1) afforded the oxirane 19 as a
3.80–4.10 (m, 4H), 4.60 (d, 1H, J=5 Hz, H-1), 5.93 (d,
1H, J=1Hz, O–CH –O), 5.95 (d, 1H, J=1Hz, O–
2
CH2–O), 6.34 (s, 2H, H-20, H-60), 6.58 (s, 1H, H-8), 6.82
(s, 1H, H-5); MS (DCI/NH3): m/z 546 [M + NH4]+,
(DCI/CH4) m/z 529 [M + H]+; DCI-HRMS m/z calcd
for C28H37O8Si: 529.2258. Found: 529.2224.
20
colourless solid (79.1mg, 87%): mp 108 ꢀC. ½aꢁD À126
(c 1, CHCl3); IR (CHCl3, cmÀ1): 2931, 2857, 1775; H
40-Demethyl-4-deoxy-4-hydroxymethyl-epipodo- and podo-
phyllotoxin (22 and 23). A solution of alcohols 21
(752.2 mg, 1.42 mmol) in 60 mL of 95% ethanol was
refluxed for 17 h in the presence of PPTS (179 mg, 1/2
equiv). After addition of 10 mL of water and 20 mL of
dichloromethane, the organic phase was separated,
dried over anhydrous magnesium sulfate and filtered.
The solvent was removed under reduced pressure and
the residue purified by chromatography on a silica gel
column (cyclohexane/ethyl acetate: 1/2, the weight of
silica was 100 times equal to that of the crude material).
This led successively to 22 and 23 which were both
obtained as colourless solids (53.1mg, 87% overall
1
NMR (300 MHz, CDCl3) d 0.11 (s, 6H, Me2Si), 1.01 (s,
9H, Si-tBu), 2.90 (dd, 1H, J =14.0 Hz, 5.0 Hz, H-2),
3.10 (m, 1H, H-3), 3.10 (d, 1H, J =11.0 Hz, H-12a),
3.30 (d, 1H, J =11.0 Hz, H-12b), 3.55 (s, 6H, OMe-30
and -50), 3.94–4.07 (m, 2H, H-11a, H-11b), 4.41 (d, 1H,
J =5.0 Hz, H-1), 5.56 (d, 1H, J=1, OCH2O), 5.60 (d,
1H, J=1, OCH2O), 6.38 (s, 1H, H-8), 6.42 (s, 2H, H-
20, H-60), 6.55 (s, 1H, H-5); MS (DCI/NH3): m/z 544
(M+NH4)+. Anal. calcd for C28H34O8Si: C, 63.86; H,
6.51. Found: C, 63.51; H, 6.42.
40-Demethyl-4-deoxy-4-spiroepoxy-podophyllotoxin (20).
The oxirane derivative 19 (31mg, 59 mmol) was trea-
ted as previously described for obtaining 18 from 17.
Flash chromatography (cyclohexane/ethyl acetate: 2/1)
of the crude product afforded compound 20 as an
20
yield). 22: mp 130–135 ꢀC; ½aꢁD À125.5 (c 1, CHCl3); IR
(CHCl3, cmÀ1): 3619, 3539, 2923, 1773; 1H NMR
(300 MHz, CDCl3) d 2.13 (dd, 1H, J =6.0 Hz, 11.0 Hz,
H-4), 2.50 (m, 1H, H-3), 2.53 (dd, 1H, J =13.7 Hz, 4.6
Hz, H-2), 3.25 (t, 2H, H-12a, H-12b), 3.52 (s, 6H, OMe-
30 and -50), 3.95 (dd, 1H, J =8.5 Hz, 7.0 Hz, H-11a),
4.09 (dd, 1H, J =8.5 Hz, 9.1 Hz, H-11b), 4.52 (d, 1H, J
=4.6 Hz, H-1), 5.35 (d, 1H, OCH2O), 5.39 (d, 1H,
OCH2O), 6.55 and 6.56 (s, 2H, H-5, H-8), 6.62 (s, 1H,
H-20, H-60); MS (DCI/NH3): m/z 432 [M + NH4]+.
Anal. calcd for C22H22O6: C, 63.76; H, 5.35. Found: C,
20
amorphous solid (15.4 mg, 63%): ½aꢁD À145 (c 1,
CHCl3);. IR (CHCl3, cmÀ1): 3539, 2928, 1777; 1H NMR
(300 MHz, CDCl3) d 2.91(dd, 1H, J =5.0 Hz, 14.1 Hz,
H-2), 3.1 (m, 1H, H-3), 3.09 (d, 1H, J =11.0 Hz, H-
12a), 3.31 (d, 1H, J=11.0 Hz, H-12b), 3.59 (s, 6H,
OMe-30 and -50), 3.95–4.09 (m, 2H, H-11a, H-11b), 4.40
(d, 1H, J =5.0 Hz, H-1), 5.28 (s, 1H, OH), 5.59 (d,
1H, J=1.5 Hz, OCH2O), 5.64 (d, 1H, J=1.5 Hz,
OCH2O), 6.38 (s, 1H, H-8), 6.41 (s, 2H, H-20, H-60);
6.54 (s, 1H, H-5); MS (DCI/NH3): m/z 430 [M +
NH4]+. Anal. calcd for C22H20O8: C, 64.07; H, 4.89.
Found: C, 64.25; H, 5.02.
20
63.90; H, 5.51. 23: mp 130–135 ꢀC; ½aꢁD À77.8 (c 1,
1
CHCl3); IR (CHCl3, cmÀ1): 3539, 2928, 1775; H NMR
(300 MHz, CDCl3) d 2.13 (dd, 1H, J =4.5 Hz, J=14.0
Hz, H-2), 2.36 (m, 1H, H-4), 2.53 (m, 1H, H-3), 3.28
(m, 2H, H-12a, H-12b), 3.41 (dd, 1H, J =8.5 Hz,
J=10.4 Hz, H-11a), 3.52 (s, 6H, OMe-30 and -50), 4.16
(t, 1H, J=8.2 Hz, J=7.5 Hz, H-11b), 5.35 (d, 1H,
OCH2O), 5.38 (d, 1H, OCH2O), 5.41(s, 1H, OH), 6.58
(s, 1H, H-8), 6.70 (s, 1H, H-5), 6.72 (s, 2H, H-20, H-60);
MS (DCI/NH3): m/z 432 [M + NH4]+. Anal. calcd
for C22H22O6: C, 64.07; H, 4.89. Found: C, 63.93; H,
5.05.
40 -tert-Butyldimethylsilanyloxy-40 -demethyl-4-deoxy-4-
hydroxymethyl-podophyllotoxin (21). After the deriva-
tive 17 (232.6 mg, 455 mmol) was dissolved in 10 mL of
anhydrous THF under argon atmosphere, BH3/Me2S
(2 M THF solution, 455 mL) was added. After stirring
for 2 h, the borane formed was hydrolyzed by addition
of 10 mL of pH 7 phosphate buffer, 20 mL of methanol
and 10 mL of a 30% H2O2 solution in water. The mix-
ture was stirred for 1.5 h, and next 100 mL of water and
100 mL of dichloromethane were added. The organic
phase was separated, dried over anhydrous magnesium
sulfate, filtered and the solvent was removed under
reduced pressure. Purification by flash chromatography
(cyclohexane/ethyl acetate: 2/1) afforded a mixture (3/2)
of the inseparable alcohols 21 as a colourless solid
(197.7 mg, 82%): IR (CHCl3, cmÀ1): 3619, 2931, 2896,
40 -Benzyloxycarbonyl-40 -demethyl-4-deoxy-4-hydroxy-
methyl-podophyllotoxin (25). To a solution of the diol
23 (101 mg, 244 mmol) in anhydrous dichloromethane (7
mL) kept under an argon atmosphere and cooled to
0 ꢀC, 70 mL of triethylamine (2 equiv) and 50 mL of
benzylchloroformate (1.4 equiv) were added. After stir-
ring for 45 min at 0 ꢀC, 20 mL of water were added and
the organic phase was separated, dried over anhydrous
magnesium sulfate, filtered and the solvent was removed
under reduced pressure. Purification by flash chromato-
graphy (cyclohexane/ethyl acetate: 1/1) afforded the
1
2858, 1774; H NMR (300 MHz, CDCl3). For the iso-
mer 21ꢀ: d 0.10 (s, 6H, Me2Si), 0.98 (s, 9H, Si-t.Bu),
2.80–3.00 (m, 1H, H-3), 3.15–3.22 (m, 2H, J =5.0 Hz,
9.1Hz, H-2, H-4), 3.67 (s, 6H, OMe-3 0 and -50), 3.94 (m,
2H, CH2OH), 4.37–4.43 (m, 2H, H-11a, H-11b), 4.54 (d,
alcohol 25 as a colourless solid (126 mg, 94%): mp 115–
20
120 ꢀC. ½aꢁD À104 (c 1 , CHCl); IR (CHCl3, cmÀ1):
3
1
3539, 2828, 1775, 1672; H NMR (300 MHz, CDCl3) d
1H, J =5.0 Hz, H-1), 5.93 (d, 1H, J=1Hz, OCH O),
1.75 (t, 1H, J =4.3 Hz, OH), 2.80 (m, 1H, H-3), 2.86
(dd, 1H, J =4.3 Hz, 13.9 Hz, H-2), 3.11 (m, 1H, H-4),
3.76 (s, 6H, OMe-30 and -50), 3.89 (m, 1H, H-12a), 4.03
(t, 1H, J =9.9 Hz, 8.9 Hz, H-11a), 4.14 (m, 1H, H-12b),
4.65 (m, 1H, J =6.73 Hz, H-11b), 4.67 (d, 1H, J =4.7
2
5.96 (d, 1H, J=1Hz, OCH 2O), 6.25 (s, 2H, H-20, H-60),
6.52 (s, 1H, H-8), 6.76 (s, 1H, H-5). For the isomer 21ꢁ:
d 0.10 (s, 6H, Me2Si), 0.98 (s, 9H, Si-tBu), 2.80–3.00 (m,
1H, H-3), 2.70 (dd, 1H,), 3.67 (s, 6H, OMe-30, OMe-50),