B. Zhou et al. / Tetrahedron 66 (2010) 5396e5401
5399
4.1.1. Methyl abietadien-18-oate (6). To a stirred solution of abietic
acid 3 (100 g, 0.331 mol), acetone (500 mL) and K2CO3 (50.2 g,
0.364 mol) was added Me2SO4 (31.36 mL, 0.331 mol) and the
resulting solution was stirred overnight at room temperature. After
removing the solvent the mixture was diluted with CH2Cl2, washed
product, which was chromatographed on silica gel (HeE, 50:1) to
20
give pure 10 (85.2 g, 91%) as a colourless solid, mp 84e86 ꢁC; [
a]
D
þ44 (c 0.19, CHCl3); 1H NMR (CDCl3, 300 MHz)
d
7.10 (d, J¼8.1 Hz,
1H), 7.02 (d, J¼8.1 Hz, 1H), 3.70 (s, 3H), 3.67 (s, 3H), 3.28 (sept,
J¼6.8 Hz, 1H), 2.96 (dd, J¼6.4, 17.6 Hz, 1H), 2.78 (m, 1H), 2.27 (d,
J¼12.4 Hz, 1H), 2.21 (dd, J¼10.7, 1.7 Hz, 1H), 1.82e1.62 (m, 5H),
1.56e1.43 (m, 2H), 1.28 (s, 3H), 1.22 (d, J¼3.7 Hz, 6H), 1.20 (s, 3H);
with brine, dried over MgSO4, filtered and concentrated to give 6
23
(104.6 g, 100%) as a colourless oil. [
NMR (CDCl3, 300 MHz)
a]
ꢀ65.3 (c 0.49, CHCl3); 1H
D
d
5.77 (s, 1H), 5.41 (m, 1H), 3.63 (s, 3H), 2.22
13C NMR (CDCl3, 100 MHz)
d 179.1, 154.8, 148.5, 138.0, 128.4, 123.7,
(m, 1H), 1.25 (s, 3H), 1.01 (d, J¼6.9 Hz, 3H), 1.00 (d, J¼6.9 Hz, 3H),
120.2, 60.4, 51.8, 47.5, 44.6, 38.1, 37.1, 36.5, 26.0, 25.1, 24.5, 23.9,
0.82 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d
179.0, 145.3, 135.5, 122.4,
23.8, 21.2, 18.5, 16.4; EIMS (70 eV, m/z): 344 (Mþ), 269 (100%).
120.6, 51.8, 50.9, 46.6, 45.1, 38.3, 37.1, 34.9, 34.5, 27.5, 25.7, 22.5,
21.4, 20.8, 18.1, 17.0, 14.0; EIMS (70 eV, m/z): 316 (Mþ, 100%).
4.1.5. 14-Methoxyabieta-8,11,13-trien-18-oic acid (5). KOH (48.8 g,
0.87 mol) and 10 (100 g, 0.29 mol) in ethylene glycol (500 mL) and
water (50 mL) were heated at 120 ꢁC for 10 h. The mixture was
poured into water, acidified and the precipitate was filtrated to give
4.1.2. Methyl 13b,14b-dihydroxyabieta-7-en-18-oate (7). To a solu-
tion of methyl abietadien-19-oate 6 (100 g, 0.316 mol) in acetone
(1000 mL) and deionized water (200 mL) were added N-methyl-
morpholine-N-oxide (60 wt % in water, 74.2 g, 0.380 mol), pyridine
(30.7 g, 0.316 mol) and potassium osmate dihydrate (0.23 g,
0.0006 mol). The mixture was stirred at reflux for 7 days. NaHSO3
(40 g) was added and the solvent was evaporated, then AcOEt
(600 mL) was added and the mixture was washed with 5% HCl
(100 mL), water (100 mL) and brine. The organic phase was dried
over Na2SO4 and concentrated to give a crude product, which was
the pure acid 5 (95.7 g, 100%), mp 162e164 ꢁC; [
CHCl3); 1H NMR (CDCl3, 300 MHz)
a
]
24 þ57.6 (c 0.59,
D
d
7.10 (d, J¼8.1 Hz, 1H), 7.02 (d,
J¼8.1 Hz, 1H), 3.74 (s, 3H), 3.30 (sept, J¼5.7 Hz, 1H), 3.00 (dd, J¼6.0,
5.4 Hz, 1H), 2.82 (m, 1H), 2.35e2.20 (m, 2H), 1.80e1.60 (m, 5H),
1.56e1.43 (m, 2H), 1.31 (s, 3H), 1.24 (d, J¼5.7 Hz, 6H), 1.24 (s, 3H);
13C NMR (CDCl3, 100 MHz)
d 185.3, 154.7, 148.4, 138.1, 128.5, 123.7,
120.3, 60.4, 47.4, 44.3, 38.0, 37.0, 36.7, 26.0, 25.1, 24.5, 24.0, 23.9,
21.3, 18.6, 16.2; EIMS (70 eV, m/z): 330 (Mþ), 315 (100%), 269 (92%),
227 (72%).
chromatographed on silica gel (HeE, 7:1) to give pure 7 (94.1 g,
25
85%) as a colourless solid, mp 105e107 ꢁC; [
a
]
ꢀ0.57 (c 0.7,
D
CHCl3); 1H NMR (CDCl3, 300 MHz)
d
5.87 (m, 1H), 3.94 (s, 1H), 3.62
4.1.6. 14-Methoxy-19-norabieta-4(18),8,11,13-tetraene (11). Oxalyl
chloride (28 mL, 0.319 mol) was added slowly to a stirred solution
of the acid 5 (100 g, 0.29 mol) and dimethylformamide (0.5 mL) in
dry THF (500 mL) and the mixture was stirred at room temperature
overnight. Solvent was removed under reduced pressure. The crude
acid chloride was dissolved in toluene (300 mL) and added to
a stirred suspension of the sodium salt of N-hydroxypyridine-2-
thione (51.4 g, 0.348 mol) and 4-dimethylaminopyridine (3.54 g,
0.029 mol) in toluene (500 mL) at reflux under nitrogen. The mix-
ture was heated under reflux for 3 h, the cooled suspension was
filtered through Celite and the solvent was removed under reduced
pressure. The crude pyridyl sulfides was dissolved in dichloro-
methane (800 mL) and a solution of m-chloroperbenzoic acid
(49.8 g, 0.29 mol) in dichloromethane (600 mL) was added drop-
wise at ꢀ78 ꢁC. The solution was stirred for 2 h, warmed to room
temperature and then added to benzene (800 ml) under reflux. The
solution was heated under reflux for 1e2 h, cooled to room tem-
perature, and the solvent removed under reduced pressure. The
residue was then chromatographed on silica, with ethyl acetate/
hexanes mixtures as eluent, to give the C4-(18)-alkenes 11 (69.2 g,
(s, 3H), 2.14 (sept, J¼6.9 Hz, 1H), 1.99 (m, 1H), 1.88 (dd, J¼12, 3.6 Hz,
1H), 1.86 (d, J¼11.7 Hz, 1H), 1.76 (m, 1H), 1.73 (m, 1H), 1.70 (m, 2H),
1.65 (m, 1H), 1.53 (m, 2H), 1.40 (d, J¼3.48 Hz, 1H), 1.37 (d, J¼3.16 Hz,
1H), 1.31 (dd, J¼13.2, 2.8 Hz, 1H), 1.25 (s, 3H), 1.11 (m, 1H), 0.93 (d,
J¼6.7 Hz, 3H), 0.90 (d, J¼7 Hz, 3H), 0.85 (s, 3H); 13C NMR (CDCl3,
100 MHz) d 179.2, 137.9, 120.0, 76.3, 73.3, 52.0, 51.3, 46.5, 44.7, 39.1,
36.9, 35.3, 33.1, 26.4, 25.0, 19.3, 18.0, 17.9, 17.5, 16.4, 15.6; HRMS-EI:
m/z calcd for C21H34O4 [M]þ: 350.24516; found: 350.24535.
4.1.3. Methyl 13b-hydroxy-14-oxoabieta-7-en-18-oate (8). To a so-
lution of 7 (100 g, 0.286 mol) in DMSO (142 mL, 2 mol) and
dichloromethane (200 mL) was added at 0 ꢁC triethylamine
(165 mL, 1.14 mol), followed by portionwise addition of sulfur tri-
oxideepyridine complex (136.4 g, 0.858 mol). The mixture was
stirred in the ice bath for 5 h at which time TLC analysis showed no
starting material. The reaction mixture was diluted with ethyl ac-
etate (1 L) and washed with 0.5 N HCl, water (300 mL) and brine.
The organic phase was dried over Na2SO4 and concentrated to yield
8 (94.6 g, 95%) as a colourless oil; [
a
]
24 þ55.8 (c 0.9, CHCl3); 1H NMR
D
(CDCl3, 300 MHz)
d
6.98 (s, 1H), 3.63 (s, 3H), 2.29 (m, 1H), 2.05 (m,
84%) as a white solid, mp 72e74 ꢁC; [
NMR (CDCl3, 300 MHz)
a
]
24 þ218 (c 0.28, CHCl3); 1H
D
1H), 2.01 (m, 2H), 1.88 (m, 1H), 1.80 (m, 1H), 1.85 (m, 1H), 1.79 (m,
1H), 1.68 (m, 1H), 1.65 (m, 2H), 1.57 (m, 2H), 1.29 (dd, J¼11.6, 5.1 Hz,
1H), 1.23 (s, 3H), 1.13 (m, 1H), 0.88 (d, J¼6.7 Hz, 3H), 0.77 (d,
d
7.07 (s, 2H), 4.86 (d, J¼1.5 Hz, 1H), 4.62 (d,
J¼1.5 Hz, 1H), 3.74 (s, 3H), 3.32 (sept, J¼3.0 Hz, 1H), 3.10 (dd, J¼7.2,
7.8 Hz, 1H), 2.73 (m, 1H), 2.40 (d, J¼10.5 Hz, 1H), 2.24 (m, 2H), 2.06
(m, 1H), 1.88 (m, 1H), 1.80e1.65 (m, 3H), 1.58 (m, 1H), 1.25 (d,
J¼2.7 Hz, 3H), 1.23 (d, J¼3.0 Hz, 3H), 1.01 (s, 3H); 13C NMR (CDCl3,
J¼6.7 Hz, 3H), 0.74 (s, 3H); 13C NMR (CDCl3,100 MHz)
d 204.2,178.5,
137.9, 135.2, 77.6, 52.0, 50.9, 46.1, 44.1, 37.6, 37.0, 35.5, 34.8, 31.4,
26.4, 18.9, 17.8, 16.6, 16.5, 16.1, 13.5; HRMS (FAB) m/z calcd for
C21H32O4Na, 371.2198; found, 371.2192.
100 MHz) d 154.8, 150.5, 146.3, 138.1, 128.6, 123.6, 121.4, 106.4, 60.4,
47.5, 39.3, 38.4, 36.2, 26.1, 24.1, 23.9, 23.9, 23.7, 22.7, 20.8; EIMS
(70 eV, m/z): 284 (Mþ), 269 (56%), 227 (100%).
4.1.4. Methyl 14-methoxyabieta-8,11,13-trien-18-oate (10). Ketone 8
(100 g, 0.287 mol) and p-toluenesulfonic acid (19 g, 0.1 mol) in
toluene (500 mL) were heated at reflux for 8 h. After removing the
solvent the mixture was diluted with CH2Cl2, washed with brine,
dried over MgSO4 and the solvent evaporated to give a crude
product phenol. K2CO3 (48 g, 0.35 mmol) and Me2SO4 (163 mL,
1.72 mol) were added to a solution of the crude phenol in acetone
(1000 mL), and the reaction mixture was kept stirring at reflux
overnight. Ammonium hydroxide (100 mL) was added and the
solvent was evaporated, then AcOEt (600 mL) was added and the
mixture was washed with water (100 mL) and brine. The organic
phase was dried over Na2SO4 and concentrated to give a crude
4.1.7. 14-Methoxy-18,19-bisnorabieta-8,11,13-trien-4-one (12). A flask
containing a solution of alkene 11 (100 g, 0.352 mol) in methanol
(700 mL) and dichloromethane (700 mL) was placed in a dry ice-
acetone bath at ꢀ78 ꢁC for 20 min before starting ozonolysis. Ozone
was generated by passing an oxygen stream through an electrical
discharge-type ozone generator. The ozonolysis of 11 at ꢀ78 ꢁC for
6 h was followed by the addition of dimethyl sulfide (62 mL, 0.7 mol)
at ꢀ78 ꢁC and the resulting solution was stirred overnight at room
temperature. After removing the solvent the mixture was diluted
with CH2Cl2, washed with brine, dried over MgSO4 and the solvent
evaporated to a crude product, which was dissolved in cyclohexane