Baldelli et al.
dilution with brine (10.0 mL), the mixture was extracted with
EtOAc (2 × 10 mL). The organic layer was dried and
evaporated. Workup of the residue as described above gave
12b (0.52 g, 0.73 mmol, 85%): mp 189-190 °C (EtOAc/
hexane); [R]20D ) +20.0 (c ) 1.0, CHCl3); IR (Nujol) νmax 3395,
2921, 2853, 1749, 1726, 1690, 1463, 1375, 1273, 1242; 1H NMR
(400 MHz, CDCl3) δ 8.08 (d, 2H), 7.46-7.66 (m, 3H), 6.53 (s,
1H), 5.89 (d, 1H, J ) 7.0 Hz), 4.93 (d, 1H, J ) 7.3 Hz), 4.49
(dd, 1H, J 1 ) 10.7, J 2 ) 6.6 Hz), 4.31 (s, 2H), 4.14 (d, 1H, J )
1.8 Hz), 3.87 (d, 1H, J ) 6.9 Hz), 3.73 (d, 1H, J ) 1.8 Hz),
3.64 (s, 1H), 2.46-2.61 (m, 1H), 2.26 (s, 3H), 2.24 (s, 3H), 2.14
(s, 3H), 1.83-2.05 (m, 1H), 1.75 (s, 3H), 1.28 (s, 3H), 1.24 (s,
3H), 0.91-0.99 (t, 9H, J ) 8.7 Hz), 0.58-0.66 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ 201.8, 200.1, 170.4, 169.3, 166.0,
153.5, 137.4, 133.9, 130.3, 129.8, 129.0, 84.3, 81.4, 76.4, 75.4,
74.4, 73.1, 72.9, 72.5, 59.4, 45.4, 43.5, 37.4, 33.2, 22.9, 22.0,
21.1, 14.0, 10.2, 7.1, 5.6; MS m/z 714.59 (M+ calcd for C37H50O12-
Si 714.87). Anal. Calcd for C37H50O12Si: C, 62.16; H, 7.05.
Found: C, 62.19; H, 6.98.
13-Oxo-7-BOC-14-â-h yd r oxyba cca tin III 1,14-Ca r bon -
a te (13a ). Compound 12a was prepared according to the
synthetic procedure reported before from 2a (2.0 g, 2.9 mmol)
and 9 (1.65 g, 5.40 mmol). After removal of the solvent, the
crude reaction mixture was dissolved in toluene (25.0 mL), and
carbonyldiimidazole (2.0 g, 12.0 mmol) was added at 20 °C.
The solution was stirred under argon for 50 min at 75 °C. After
the solution was cooled at 20 °C, HCl (15.0 mL, 0.2 N) and
AcOEt (15.0 mL) were added. The organic phase was sepa-
rated, washed with water, and dried, and the solvent was
evaporated. Chromatography of the residue (SiO2, n-pentane/
CH2Cl2/Et2O, 14:3.5:2.5) gave 13-oxo-7-BOC-14-â-OH-1,14-
carbonate baccatin III 13a (1.77 g, 2.43 mmol, 84%).
ment for chromatography purification in many steps.
These results provide an efficient industrial synthesis of
this class of taxoids.
Exp er im en ta l Section
13-Oxo-10-deacetylbaccatin III (13-Oxo-DAB) (5). Ozone
was passed through a solution of compound 3 (2.0 g, 3.67
mmol) in CH2Cl2/MeOH (200 mL, 5:1) at -78 °C for 35 min.
The reaction mixture was left at -78 °C for 1 h. The excess of
O3 was destroyed by addition of an excess of Me2S and
pyridine. The temperature was raised to 20 °C and the solvent
evaporated. The residue was treated twice with CCl4 to yield
2.0 g of solid which was chromatographed (SiO2, n-pentane/
Et2O/EtOAc, 2:1:1) to give 13-oxo-DAB 5 (1.83 g, 3.37 mmol,
92%).
13-Oxoba cca tin III (6). Yb(OTf)3 (0.21 g, 0.30 mmol) and
Ac2O (0.79 mL, 8.36 mmol) were added to a stirred solution of
5 (2.2 g, 4.06 mmol) in THF (20.0 mL) at 25 °C. EtOAc was
added after 4 h, the solution washed with saturated NH4Cl
and dried, and the solvent was evaporated. Chromatography
(SiO2, n-hexane/EtOAc, 1.5:1) gave compound 6 (2.16 g, 3.69
mmol, 91%).
13-Oxo-7-BOC-ba cca tin III (2a ). 13-Oxobaccatin III 6
(1.10 g, 1.9 mmol) in CH2Cl2 (0.5 mL) was added to CCl4 (14.0
mL) at 20 °C. 1-Methylimidazole (23 µL, 0.28 mmol) and
(BOC)2O (1.03 g, 4.7 mmol) were added under stirring.
1-Methylimidazole (16.0 µL, 0.20 mmol) was added after 8 h.
The solution was left at 20 °C for 24 h. The solvent was
evaporated, and the residue was dissolved in a mixture of
acetone/H2O (10.0 mL, 1:1) and left at 20 °C for 16 h. The
precipitate was filtrated to yield 2a (1.12 g, 1.63 mmol, 86%).
The residue was chromatographed to yield an additional
13-Oxo-7-TES-14-â-h yd r oxyba cca tin III 1,14-Ca r bon -
a te (13b). (a) A solution of phosgene (20%) (4.3 mL, 8.6 mmol,
20% in toluene) and pyridine (1.4 mL, 17.2 mmol) was added
to CH2Cl2 (15.0 mL) at 0 °C. A solution of 12b (0.47 g, 0.76
mmol) in CH2Cl2 (5.0 mL) was added. The reaction was
quenched after 20 min with methanol (1.0 mL) and diluted
with CH2Cl2 (10.0 mL). The mixture was washed with aqueous
NaHCO3 (15.0 mL), dried, and evaporated. Chromatography
(SiO2, EtOAc/cyclohexane, 15:85) gave 13b (0.48 g, 0.65 mmol,
85%). (b) Compound 12b (crude reaction mixture prepared as
reported above) was dissolved in CH2Cl2 (7.0 mL) and added
dropwise to a stirred solution of phosgene (4.26 mL, 20% in
toluene, 8.6 mmol) and pyridine (1.36 mL, 17.2 mmol) in
CH2Cl2 (15 mL) at 0 °C. After 20 min, the reaction was
quenched, washed, evaporated, and purified as described in
method a to give 13b (using oxidant 11: 75%; using oxidant
amount of 2a (0.12 g, 9%): mp ) 192-193 °C; [R]20 ) -35.6
D
(c ) 1.05, CHCl3); IR (CDCl3) νmax 3483, 1731, 1676, 1371, 1274;
1H NMR (400 MHz, CDCl3) δ 8.30 (d, 2H), 7.61-7.64 (m 1H),
7.44-7.50 (m, 2H), 6.57 (s, 1H), 5.67 (d, 1H, J ) 6.8 Hz), 5.39
(m, 1H, J 1 ) 10.4 Hz, J 2 ) 7.2 Hz), 4.94 (d, 1H, J 1 ) 9.5 Hz,
J 2 ) 2.0 Hz), 4.32 (d, 1H, J ) 9.0 Hz), 4.09 (d, 1H, J ) 9.0
Hz), 4.02 (d, 1H, J ) 6.8 Hz), 2.94 (d, 1H, J ) 19.6 Hz), 2.66
(d, 1H, J ) 19.6 Hz), 2.64 (m, 1H, J 1 ) 7.2 Hz, J 2 ) 14.8 Hz,
J 3 ) 9.5 Hz), 2.20 (s, 3H), 2.19 (s, 3H), 2.17 (s, 3H), 1.92 (b,
1H), 1.91 (m, 1H, J 1 ) 10.4 Hz, J 2 ) 14.8 Hz, J 3 ) 2.0 Hz),
1.76 (s, 3H), 1.47 (s, 9H), 1.22 (s, 3H), 1.20 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 200.5, 198.4, 170.3, 168.3, 167.0, 152.5,
152.4, 141.0, 134.3, 130.3, 129.0, 128.9, 84.0, 83.4, 80.5, 78.7,
77.4, 76.5, 76.3, 74.7, 72.8, 57.3, 46.7, 42.7, 33.6, 33.1, 27.9,
21.9, 21.0, 18.4, 14.0, 10.7; MS m/z 684.49 (M+ calcd for
C36H44O13 684.73). Anal. Calcd for C 36H44O13: C, 63.15; H, 6.48.
Found: C, 63.39; H, 6.60.
7: 80%): mp 190-191 °C; [R]20 ) +17.0 (c ) 1.0, CHCl3); IR
D
(Nujol) νmax 2953, 1828, 1754, 1731, 1459, 1376, 1240, 1224;
1H NMR (400 MHz, CDCl3) δ 8.01 (dd, 2H, J ) 7.0 Hz), 7.62-
7.70 (m, 1H), 7.51 (t, 2H), 6.54 (s, 1H), 6.15 (d, 1H, J ) 7.0
Hz), 4.93 (d, 1H, J ) 7.3 Hz), 4.81 (s, 1H), 4.49 (dd, 1H, J 1
)11.0, J 2 ) 7.0 Hz), 4.30 (m, 2H), 3.83 (d, 1H, J ) 7.0 Hz),
2.48-2.63 (m, 1H), 2.26 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H), 1.86-
2.13 (m, 1H), 1.75 (s, 3H), 1.39 (s, 3H), 1.21 (s, 3H), 0.91-0.99
(t, 9H, J ) 8.7 Hz), 0.58-0.66 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 199.0, 190.9, 170.3, 168.7, 164.5, 151.3, 151.2, 139.4,
134.5, 129.9, 129.1, 127.7, 86.4, 83.9, 80.6, 75.9, 74.7, 72.0, 68.3,
59.3, 45.5, 41.7, 37.0, 32.7, 21.8, 20.7, 19.5, 14.0, 9.9, 6.7, 5.3;
MS m/z 740.69 (M+ calcd for C38H48O13Si 740.86). Anal. Calcd
for C38H48O13Si: C, 61.60; H, 6.53. Found: C, 61.81; H, 6.65.
13-Oxo-7-BOC-14â-h yd r oxyba cca tin III (12a ). 13-Oxo-
7-BOC-baccatin III 2a (0.65 g, 0.95 mmol), dissolved in THF/
DMPU (11.0 mL, 8:3), was added under stirring to a THF (10
mL) solution of tBuOK (0.43 g, 3.79 mmol) at -65 °C. After 15
min, oxaziridine 9 (0.804 g, 2.63 mmol), dissolved in THF/
DMPU (10.0 mL, 9:1), was added, and the temperature was
t
raised to -55 °C h. An additional amount of BuOK (0.10 g,
0.89 mmol) was added. After 30 min, acetic acid (0.2 mL) and
aqueous NH4Cl (10%, 25.0 mL) were sequentially added. The
organic layer was extracted with water, dried, and evaporated.
The residue was chromatographed, giving 12a with minor
impurities. The mixture was treated with Et2O and filtered.
After the solvent was evaporated, the residue was chromato-
graphed to yield 12a (0.60 g, 0.84 mmol, 88%).
7-BOC-14-â-h yd r oxyba cca tin III 1,14-Ca r bon a tes (1a )
a n d (14a ). (a) Compound 13a (0.71 g, 0.98 mmol) in THF (3.0
mL) was added at -55 °C to a MeOH solution (11.0 mL) of
-
13-Oxo-7-TES-14â-h yd r oxyba cca tin III (12b). A solution
nBu4N+BH4 (1.29 g, 9.0 mmol). The reaction was quenched
t
of BuOK (2.2 mL of 1.0 M in THF) was added, at -65 °C, to
after 6 h with solid citric acid (0.6 g) and then with saturated
aqueous citric acid (10.0 mL). The reaction was extracted with
AcOEt and dried, and the solvent was evaporated. The crude
material was chromatographed (SiO2, n-hexane/ethyl acetate,
1.4:1.0) to yield 1a (0.49 g, 0.67 mmol, 68.0%) and 14a (0.13
g, 0.18 mmol, 19.0%).
a solution of 13-oxo-7-TES-baccatin III 2b (0.60 g, 0.86 mmol)
in THF/DMPU (11.0 mL, 8:3). Then a solution of oxaziridine
11 (0.30 g, 1.29 mmol) in THF (2.0 mL) was added. The
reaction mixture was quenched at -60 °C with acetic acid (0.2
mL, 40% in THF) and warmed to room temperature. After
9778 J . Org. Chem., Vol. 68, No. 25, 2003