´
M.A. Gonzalez et al. / European Journal of Medicinal Chemistry 45 (2010) 811–816
814
were recorded on a 300 MHz spectrometer with tetramethylsilane
as an internal standard. All spectra were recorded in CDCl3 as
solvent unless otherwise described. Complete assignments of 13C
NMR multiplicities were made on the basis of DEPT experiments.
J values are given in Hz. Mass spectra (MS) were run by electron
impact (EI) at 70 eV. Reactions were monitored by thin-layer
chromatography (TLC) using Merck silica gel 60 F-254 in 0.25 mm-
thick plates. Compounds on TLC plates were detected under UV
light at 254 nm and visualized by immersion in a 10% sulfuric acid
solution and heating on a hotplate. Purifications were performed by
flash chromatography on Merck silica gel (230–400 mesh). All non-
aqueous reactions were carried out in an argon atmosphere in
oven-dried glassware. Commercial reagent grade solvents and
chemicals were used as received unless otherwise noted. Combined
organic extracts were washed with brine, dried over anhydrous
sodium sulphate, filtered and concentrated under reduced pres-
sure. Methyl abietate (2) was prepared from commercial abietic
acid (Aldrich) as reported by us [12]. All compounds prepared in
this work exhibit spectroscopic data in agreement with the
proposed structures.
J ¼ 10.8), 3.21 (1H, d, J ¼ 10.8), 2.85 (1H, m), 1.21 (6H, d, J ¼ 6.9), 1.21
(3H, s), 0.87 (3H, s); 13C NMR (75 MHz) dC 147.2 (s), 145.4 (s), 134.7
(s), 126.7 (d), 124.1 (d), 123.7 (d), 72.1 (t), 43.8 (d), 38.3 (t), 37.8 (s),
37.2 (s), 35.0 (t), 33.4 (d), 30.0 (t), 25.2 (q), 24.0 (q), 24.0 (q), 18.8 (t),
18.6 (t), 17.3 (q); HRMS (EI) m/z 286.2265 [M]þ, calcd for C20H30O:
286.2297.
4.1.4. 8,11,13-Abietatrien-18-yl acetate
(dehydroabietinol acetate, 6)
A solution of the alcohol 5 (300 mg, 1 mmol) and dimethyla-
minopyridine (12 mg, 0.1 mmol) in triethylamine (8 mL) at 0 ꢁC was
treated with acetyl chloride (355 mL, 5 mmol) dropwise. The
resulting mixture was stirred for 16 h. Then, it was diluted with
diethyl ether and washed with water and brine. The aqueous phase
was extracted twice with diethyl ether and the combined organic
extracts were dried and concentrated. The residue was purified by
chromatography eluting with hexane-ethyl acetate (7:3) to give
20
258 mg (75%) of acetate 6 as a slightly yellow oil: [
a]
D þ 8.5
(c 0.5); 1H NMR (300 MHz)
d
7.18 (1H, d, J ¼ 8.1), 6.99 (1H, dd, J ¼ 8.1,
1.5), 6.90 (1H, br s), 3.98 (1H, d, J ¼ 10.8), 3.69 (1H, d, J ¼ 10.8), 2.85
(1H, m), 2.02 (3H, s), 1.22 (6H, d, J ¼ 6.6), 1.21 (3H, s), 0.94 (3H, s);
13C NMR (75 MHz) dC 171.3 (s),147.1 (s),145.6 (s),134.7 (s),126.8 (d),
124.2 (d), 123.9 (d), 72.4 (t), 44.0 (d), 38.2 (t), 37.4 (s), 36.7 (s), 35.5
(t), 33.4 (d), 30.2 (t), 25.3 (q), 24.0 (q), 24.0 (q), 21.0 (q), 18.9 (t), 18.5
(t), 17.5 (q); HRMS (EI) m/z 328.2422 [M]þ, calcd for C22H32O2:
328.2402.
4.1.1. Methyl 8,11,13-abietatrien-18-oate
(methyl dehydroabietate, 3)
To neat methyl abietate (2) (4.0 g, 12 mmol) 5% Pd/C (200 mg)
was added and then heated to 240–250 ꢁC for 2 h. Then, the
mixture was cooled to rt and diluted with hexane-ethyl acetate 8:2
and purified by flash chromatography, using hexane-ethyl acetate
(8:2) as eluent, to give methyl dehydroabietate 3 (3.3 g, 85%) as an
4.1.5. 8,11,13-Abietatrien-18-yl benzoate (dehydroabietinol
benzoate, 7)
A solution of the alcohol 5 (300 mg, 1 mmol) and dimethyla-
minopyridine (12 mg, 0.1 mmol) in triethylamine (8 mL) at 0 ꢁC was
20
orange oil: [
a
]
D þ 52.0 (c 1.0); 1H NMR (300 MHz)
d 7.16 (1H, d,
J ¼ 8.1), 6.99 (1H, dd, J ¼ 8.1, 1.5), 6.88 (1H, br s), 3.65 (3H, s), 1.27
(3H, s),1.23 (3H, s),1.21 (6H, s); 13C NMR (75 MHz) dC 179.1 (s),146.9
(s), 145.7 (s), 134.7 (s), 126.8 (d), 124.1 (d), 123.9 (d), 51.9 (d), 47.6 (s),
44.8 (d), 37.9 (t), 36.9 (s), 36.6 (t), 33.4 (d), 29.9 (t), 25.1 (q), 24.0 (q),
24.0 (q), 21.7 (t), 18.6 (t), 16.5 (q); HRMS (EI) m/z 314.2231 [M]þ,
calcd for C21H30O2: 314.2246.
treated with benzoyl chloride (580 mL, 5 mmol) dropwise. The
resulting mixture was stirred for 16 h. Then, it was diluted with
diethyl ether and washed with water and brine. The aqueous phase
was extracted twice with diethyl ether and the combined organic
extracts were dried and concentrated. The residue was purified by
chromatography eluting with hexane-ethyl acetate (7:3) to give
286 mg (70%) of benzoate 7 as a slightly yellow oil: 1H NMR
4.1.2. 8,11,13-Abietatrien-18-oic acid (dehydroabietic acid, 4)
A mixture of ester 3 (200 mg, 0.63 mmol), KOH (85%, 1.0 g,
15 mmol), H2O (2 mL) and methanol (12 mL) was refluxed for 16 h.
Then, additional KOH (85%, 400 mg, 7 mmol) was added and reflux
continued for 5 h more. After this time, the reaction mixture was
then cooled, poured into aqueous HCl (1.5 M, 20 mL) and extracted
three times with ethyl acetate. The organic extract was dried over
MgSO4 and concentrated under reduced pressure to give the crude
acid which was purified by chromatography eluting with hexane-
(300 MHz)
d 8.01 (2H, m), 7.53 (1H, m), 7.41 (2H, m), 7.20 (1H, d,
J ¼ 8.1), 7.00 (1H, dd, J ¼ 8.1,1.5), 6.88 (1H, br s), 4.21 (1H, d, J ¼ 10.8),
3.98 (1H, d, J ¼ 10.8), 2.85 (1H, m), 1.25 (3H, s), 1.22 (6H, d, J ¼ 6.9),
1.04 (3H, s); 13C NMR (75 MHz) dC 166.6 (s),146.9 (s), 145.5 (s), 134.7
(s), 132.8 (d), 130.3 (s), 129.5 ꢄ 2 (d), 128.4 ꢄ 2 (d), 126.9 (d), 124.3
(d), 123.9 (d), 73.0 (t), 44.9 (d), 38.3 (t), 37.6 (s), 37.1 (s), 35.8 (t), 33.4
(d), 30.1 (t), 25.5 (q), 23.9 (q), 23.9 (q), 19.1 (t), 18.6 (t), 17.6 (q);
HRMS (EI) m/z 390.2537 [M]þ, calcd for C27H34O2: 390.2559.
ethyl acetate (3:7) to give acid 5 (142 mg, 75%) as a foam:
20
[
a]
D þ 59.7 (c 0.5); 1H NMR (300 MHz)
d
7.16 (1H, d, J ¼ 8.4), 6.99
(1H, dd, J ¼ 8.1, 1.5), 6.88 (1H, br s), 2.85 (1H, m), 1.28 (3H, s), 1.21
(6H, d, J ¼ 6.9); 13C NMR (75 MHz) dC 184.5 (s), 146.7 (s), 145.7 (s),
134.7 (s), 126.9 (d), 124.1 (d), 123.8 (d), 44.6 (d), 37.9 (t), 36.8 (s),
36.7 (t), 33.4 (d), 30.0 (t), 25.1 (q), 24.0 (q), 24.0 (q), 21.7 (t), 18.5 (t),
16.2 (q); HRMS (EI) m/z 300.2068 [M]þ, calcd for C20H28O2:
300.2089.
4.1.6. 8,11,13-Abietatrien-18-yl nicotinate (dehydroabietinol
nicotinate, 8)
A suspension of nicotinic acid (2.46 g, 20 mmol) in thionyl
chloride (10 mL) was refluxed for 2 h, then it was cooled and
concentrated under vacuum. Then, 500 mg of the resulting solid
was added to a solution of the alcohol 5 (300 mg, 1 mmol) and
dimethylaminopyridine (12 mg, 0.1 mmol) in triethylamine (8 mL)
at 0 ꢁC. The resulting mixture was stirred for 48 h. Then, it was
diluted ethyl acetate and washed with water and brine. The
aqueous phase was extracted twice with ethyl acetate and
the combined organic extracts were dried and concentrated.
The residue was purified by chromatography eluting with hexane-
ethyl acetate (7:3) to give 328 mg (80%) of nicotinate 8 as a slightly
4.1.3. 8,11,13-Abietatrien-18-ol (dehydroabietinol, 5)
To a solution of ester 3 (1.78 g, 5.7 mmol) in tetrahydrofuran
(25 mL), LiAlH4 (1.20 g, 31.5 mmol) was added in portions and the
resulting mixture was refluxed for 16 h. Then, it was cooled to 0 ꢁC
and 1.2 mL of H2O, 1.2 mL of 15% NaOH and 3.6 mL of H2O were
added sequentially and carefully. The resulting white solid was
filtered off and washed with ethyl acetate. The extract was
concentrated and purified by chromatography eluting with hexane-
yellow solid: 1H NMR (300 MHz)
d
9.21 (1H, br d, J ¼ 2.1), 8.75 (1H,
dd, J ¼ 4.8, 1.5), 8.26 (1H, ddd, J ¼ 7.8, 2.1, 2.1), 7.36 (1H, dd, J ¼ 8.1,
5.1), 7.19 (1H, d, J ¼ 8.1), 7.00 (1H, dd, J ¼ 8.1,1.8), 6.88 (1H, br s), 4.25
(1H, d, J ¼ 10.8), 4.01 (1H, d, J ¼ 10.8), 2.85 (1H, m), 1.25 (3H, s), 1.22
(6H, d, J ¼ 6.9), 1.04 (3H, s); 13C NMR (75 MHz) dC 165.1 (s), 153.3 (d),
ethyl acetate (6:4) to give 1.46 g (90%) of pure alcohol 5 as a slightly
20
yellow oil: [
a
]
D þ 43.5 (c 0.6); 1H NMR (300 MHz)
d 7.17 (1H, d,
J ¼ 8.1), 6.98 (1H, dd, J ¼ 8.1, 1.5), 6.88 (1H, br s), 3.45 (1H, d,