Bicyclic Systems Related to Taxol
J . Org. Chem., Vol. 63, No. 1, 1998 141
mg, 0.41 mmol). The resulting solution was stirred overnight,
diluted with ethyl acetate, washed with saturated NaHCO3
solution and water, dried, and concentrated. Chromatography
of the residue on silica gel (elution with 20% ethyl acetate in
hexanes) gave 7b (38 mg, 53% overall) as a colorless oil: IR
(film, cm-1) 1713, 1611, 1513, 1291, 1248, 1091; 1H NMR (300
MHz, CDCl3) δ 8.05 (dd, J ) 7.2, 1.3 Hz, 2 H), 7.59 (t, J ) 7.3
Hz, 1 H), 7.46 (t, J ) 7.8 Hz, 2 H), 7.28 (d, J ) 8.3 Hz, 2 H),
6.88 (d, J ) 8.6 Hz, 2 H), 5.19 (d, J ) 5.9 Hz, 1 H), 4.75-4.64
(m, 3 H), 4.59 (d, J ) 4.4 Hz, 2 H), 4.52 (d, J ) 7.3 Hz, 1 H),
4.08 (d, J ) 9.8 Hz, 1 H), 3.88 (s, 1 H), 3.81 (s, 3 H), 3.78-3.62
(m, 2 H), 3.55-3.44 (m, 3 H), 3.36 (s, 3 H), 3.17-3.12 (m, 1
H), 2.86-2.85 (m, 1 H), 2.56-2.49 (m, 2 H), 2.45-2.34 (m, 1
H), 1.95-1.85 (m, 1 H), 1.81 (dd, J ) 16.5, 6.5 Hz, 1 H), 1.28
(s, 3 H), 1.26 (s, 3 H), 1.21 (s, 3 H), 1.03 (s, 3 H), 0.99-0.85
(m, 3 H), 0.00 (s, 9 H); 13C NMR (75 MHz, CDCl3) ppm 207.4,
166.3, 159.1, 133.3, 130.6, 129.8, 129.3, 129.2, 129.1, 128.4,
113.6, 96.7, 95.6, 92.9, 86.3, 81.7, 73.4, 71.7, 70.8, 67.6, 65.4,
59.0, 55.2, 52.8, 50.3, 37.4, 36.7, 34.3, 30.4, 27.1, 23.8, 23.3,
21.6, 18.1, -1.5; FAB MS m/z (M+) calcd 728.40, obsd 728.50;
(7.7 mg, 72%) as a colorless oil: IR (film, cm-1) 3450, 1717,
1281, 1011; 1H NMR (300 MHz, CDCl3) δ 8.09-8.06 (m, 2 H),
7.62-7.52 (m, 1 H), 7.49-7.44 (m, 2 H), 5.45-5.43 (m, 1 H),
4.75 (d, J ) 7.2 Hz, 1 H), 4.66 (d, J ) 7.2 Hz, 1 H), 4.49 (dd,
J ) 8.1, 1.8 Hz, 1 H), 3.97 (s, 1 H), 3.80-3.71 (m, 1 H), 3.69-
3.64 (m, 1 H), 3.59-3.52 (m, 3 H), 3.39 (s, 3 H), 2.27-2.21 (m,
1 H), 1.98-1.60 (m, 4 H), 1.40 (s, 3 H), 1.31 (s, 3 H), 1.26-
1.08 (m, 3 H), 1.04 (s, 3 H), 0.99 (s, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 165.0, 133.4, 129.8, 128.5, 101.5, 96.7, 86.4, 81.7,
80.0, 71.7, 67.4, 59.0, 46.1, 43.6, 40.1, 39.1, 32.3, 30.3, 28.3,
23.6, 22.5, 20.4, 19.4; MS m/z (M+) calcd 462.2617, obsd
462.2625; [R]22 -40.0 (c 0.01, CHCl3).
D
(1S,2S,3R,4S)-2-Isop r op en yl-3-(m eth oxym eth oxy)-7,7-
d im eth yl-1-vin ylbicyclo[2.2.1]h ep ta n -2-ol (2b). A solution
of tert-butyllthium in pentane (20 mL of 1.7 M, 34 mmol) was
added to 2-bromopropene (2.07 g, 17.1 mmol) dissolved in cold
(-78 °C), dry THF (25 mL) under N2. After 20 min at that
temperature, a solution of 1b3d (2.74 g, 12.2 mmol) in dry THF
(10 mL) was introduced and the reaction mixture was stirred
at -78 °C for 30 min, allowed to warm slowly to rt, quenched
with water, and extracted with ether. The combined extracts
were washed with water, dried, and concentrated in advance
of chromatographic purification on silica gel (elution with 5%
ethyl acetate in hexanes). There was obtained 2.7 g (84%) of
2b as a colorless oil: IR (film, cm-1) 3528, 1635, 1458, 1388,
1370, 1280; 1H NMR (300 MHz, CDCl3) δ 6.36-6.26 (m, 1 H),
5.15-5.10 (m, 1 H), 4.98-4.90 (m, 1 H), 4.87 (s, 1 H), 4.76 (s,
1 H), 4.71-4.62 (m, 2 H), 4.09 (s, 3 H), 3.33 (d, J ) 1.8 Hz, 3
H), 3.20 (d, J ) 1.8 Hz, 1 H), 1.89 (d, J ) 3.4 Hz, 1 H), 1.75 (s,
3 H), 1.69 (d, J ) 8.7 Hz, 2 H), 1.19 (s, 3 H), 1.17-0.98 (m, 2
H), 0.69 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 149.6, 137.3,
114.4, 109.5, 96.4, 84.8, 83.6, 57.7, 55.4, 51.4, 49.7, 24.2, 23.9,
22.3, 21.9, 21.2; MS m/z (M+) calcd 266.1882, obsd 266.1877;
[R]22 -8.5 (c 0.25, CHCl3).
D
(1S,3R,6S,7R,8S)-3-Hyd r oxy-7-[(p-m eth oxyben zyl)oxy]-
1-[[(p -m et h oxyb en zyl)oxy]m et h oxy]-6-[(2-m et h oxyet h -
oxy)m eth oxy]-5,5,11,11-tetr am eth ylbicyclo[6.2.1]u n decan -
2-on e Ben zoa te (9). Freshly prepared [(p-methoxybenzyl)-
oxy]methyl chloride (0.2 mL, 1.0 mmol) was added to a solution
of 6a (33 mg, 0.069 mmol) in CH2Cl2 (0.5 mL) containing tetra-
n-butylammonium iodide (270 mg, 1.88 mmol) and diisopro-
pylethylamine (0.3 mL, 3.0 mmol). The reaction mixture was
stirred at rt for 24 h, quenched with water, and extracted with
ethyl acetate. The combined organic layers were washed with
water, dried, and concentrated. Purification of the residue by
chromatography on silica gel (elution with 40% ethyl acetate
in hexanes) gave the protected R-hydroxy ketone (28 mg, 65%),
which was used directly.
[R]22 -12.8 (c 1.5, CHCl3).
D
(1S,2R,7E)-2-(Met h oxym et h oxy)-4,4,11,11-t et r a m et h -
ylbicyclo[6.2.1]u n d ec-7-en -3-on e (3b). A solution of potas-
sium hexamethyldisilazide in THF (36.8 mL of 0.5 M, 18.4
mmol) was added to a solution of 2b (2.45 g, 9.21 mmol) and
18-crown-6 (3.5 g, 13.2 mmol) in dry THF (100 mL) at -78 °C
under N2. The reaction mixture was stirred at -78 °C for 15
min, warmed to 9 °C for 15 min, returned to -78 °C, and
treated with methyl iodide (3 mL, 48 mmol). After an
additional hour at this temperature, water was introduced and
the product was extracted into ether after arrival at rt. The
combined ethereal solutions were washed with water, dried,
and concentrated to leave a residue, chromatography of which
on silica gel (elution with 10% ethyl acetate in hexanes)
Oxygen was bubbled through a solution of this material (90
mg, 0.143 mmol) and 18-crown-6 (200 mg, 0.529 mmol) in dry
THF (10 mL) for 2 min at -78 °C. Potassium hexamethyl-
disilazide (0.5 mL of 0.5 M in toluene, 0.25 mmol) was
introduced with continued bubbling of oxygen at this temper-
ature for 20 min, followed by triphenylphosphine (240 mg, 0.92
mmol). The reaction mixture was stirred at -78 °C for 20 min,
quenched with water, warmed to rt, and extracted with ethyl
acetate. The combined organic phases were dried and con-
centrated to leave a residue that was dissolved in CH2Cl2 (5
mL), treated with DMAP (100 mg, 0.819 mmol) and benzoic
anhydride (200 mg, 0.885 mmol), stirred at rt for 4 h, quenched
with water, and extracted with ethyl acetate. The extracts
were washed with water, dried, and concentrated. Purification
of the residue by chromatography on silica gel (elution with
30% ethyl acetate in hexanes) gave 9 as a colorless oil (89 mg,
85% overall): IR (film, cm-1) 1712, 1612, 1513, 1248, 1032;
1H NMR (300 MHz, CDCl3) δ 8.06-8.01 (m, 2 H), 7.59-7.54
(m, 1 H), 7.48-7.40 (m, 2 H), 7.38-7.19 (m, 4 H), 6.89-6.82
(m, 4 H), 5.18 (d, J ) 5.6 Hz, 1 H), 4.79-4.64 (m, 5 H), 4.61
(d, J ) 5.2 Hz, 3 H), 4.47 (d, J ) 11.4 Hz, 1 H), 4.09 (d, J )
9.8 Hz, 1 H), 3.89 (s, 1 H), 3.81 (s, 3 H), 3.79 (s, 3 H), 3.70-
3.66 (m, 2 H), 3.50-3.44 (m, 1 H), 3.36 (s, 3 H), 3.25-3.12 (m,
1 H), 2.91-2.83 (m, 1 H), 2.65-2.27 (m, 3 H), 1.96-1.50 (m, 2
H), 1.30 (s, 6 H), 1.21 (s, 3 H), 1.02 (s, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 207.3, 166.3, 159.1, 133.3, 130.6, 130.3, 129.8,
129.4, 129.3, 129.1, 128.3, 113.7, 113.6, 96.9, 95.6, 92.7, 86.3,
81.7, 73.4, 71.7 70.8, 69.6, 67.6, 59.0, 55.2, 52.8, 50.3, 37.4,
36.7, 34.4, 30.5, 27.1, 23.7, 23.3, 21.6; MS molecular ion too
fleeting for accurate measurement; [R]22D -42.7 (c 0.06, CHCl3).
(1R,2S,5S,6R,7S,10R)-7-[(p-Meth oxyeth oxy)m eth oxy]-
8,8,12,12-tetr a m eth yl-11-oxa tr icyclo[4.4.1.12,5]d od eca n e-
1,2,10-tr iol Ben zoa te (10). DDQ (25 mg, 0.110 mmol) was
added to a mixture of 9 (17 mg, 0.023 mmol) in CH2Cl2 (4 mL)
and water (0.2 mL). The resulting suspension was stirred at
rt for 5 h, quenched with saturated sodium bisulfite solution,
and extracted with ether. The combined organic layers were
washed with saturated sodium bicarbonate solution and water,
dried, and concentrated. Chromatography of the residue on
silica gel (elution with 40% ethyl acetate in hexanes) gave 10
provided 2.36 g (96%) of 3b as a colorless oil: IR (film, cm-1
)
1
1688, 1472, 1461, 1390, 1144; H NMR (300 MHz, CDCl3) δ
4.82-4.78 (m, 1 H), 4.52 (d, J ) 7.0 Hz, 1 H), 4.29 (d, J ) 7.0
Hz, 1 H), 4.13 (d, J ) 1.0 Hz, 1 H), 3.28 (s, 3 H), 2.54-2.50
(m, 1 H), 2.37-2.24 (m, 3 H), 2.17-2.14 (m, 2 H), 2.06-2.01
(m, 1 H), 1.74-1.65 (m, 1 H), 1.44-1.39 (m, 1 H), 1.28 (s, 3
H), 1.19 (s, 3 H), 1.06 (s, 3 H), 0.98 (s, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 216.2, 144.2, 124.2, 94.7, 84.3, 55.8, 55.4, 46.3,
45.9, 44.5, 31.6, 26.4, 26.2, 25.2, 23.4, 20.7, 18.6; MS m/z (M+)
calcd 280.2038, obsd 280.2051; [R]22 -112.3 (c 1.1, CHCl3).
D
(1S ,2R ,3S ,7E )-2-(Me t h oxym e t h oxy)-4,4,11,11-t e t r a -
m eth ylbicyclo[6.2.1]u n d ec-7-en -3-ol (4c). Lithium alumi-
num hydride (645 mg, 17.0 mmol) was added to a solution of
3b (2.26 g, 8.07 mmol) in ether (130 mL) at 0 °C under N2.
The resulting suspension was stirred in the cold for 1 h,
quenched with water (3 mL), dried, and concentrated to give
4c as a colorless oil (2.10 g, 93%): IR (film, cm-1) 3496, 1462,
1386, 1280; 1H NMR (300 MHz, CDCl3) δ 5.31-5.26 (m, 1 H),
4.70 (d, J ) 6.9 Hz, 1 H), 4.59 (d, J ) 6.9 Hz, 1 H), 3.81-3.78
(m, 1 H), 3.38 (s, 3 H), 3.36-3.31 (m, 1 H), 2.74 (d, J ) 2.8 Hz,
1 H), 2.58-2.50 (m, 1 H), 2.36-2.27 (m, 1 H), 2.13-1.91 (m, 5
H), 1.38 (s, 3 H), 1.36-1.13 (m, 2 H), 1.09 (s, 3 H), 1.06 (s, 3
H), 0.91 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 142.8, 119.1,
96.2, 88.0, 84.7, 55.8, 54.7, 43.9, 38.2, 38.1, 37.6, 26.5, 25.7,
23.4, 23.1, 21.5; MS m/z (M+) calcd 282.2194, obsd 282.2193;
[R]22 -61.5 (c 0.3, CHCl3).
D
(1E ,6S ,7R ,8S )-6-[(Be n zyloxy)m e t h oxy]-7-(m e t h oxy-
m e t h oxy)-5,5,11,11-t e t r a m e t h ylb icyclo[6.2.1]u n d e c-1-