Total synthesis of (±)-abieta-8, 11, 13-trien-7ss-ol

Article abstract of DOI:10.1002/jccs.200300066

The first total synthesis of (±)-abieta-8,11,13-trien-7ss-ol (1) was accomplished, in which α-cyclocitral was used as the A ring synthon, and triphenylphosphonium chloride (9), which was obtained from mbromobenzyl alcohol (4) via five steps, as the C ring

Full text of DOI:10.1002/jccs.200300066

Journal of the Chinese Chemical Society, 2003, 50, 429-432
429
Total Synthesis of (±)-Abieta-8,11,13-trien-7b-ol
Cheng-Lu Zhang (
Xuan-Jia Peng (
), Ping-Yan Bie (
) and Xin-Fu Pan* (
),
)
Department of Chemistry, National Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, P. R. China
The first total synthesis of (±)-abieta-8,11,13-trien-7b-ol (1) was accomplished, in which a-cyclocitral
was used as the A ring synthon, and triphenylphosphonium chloride (9), which was obtained from m-
bromobenzyl alcohol (4) via five steps, as the C ring synthon. The reduction of another natural organic com-
pound (±)-abieta-8,11,13-trien-7-one (2) with LiAlH4 gave exclusively the title compound 1.
Keywords: Total synthesis; Tricyclic diterpene; (±)-abieta-8,11,13-trien-7b-ol.
INTRODUCTION
steps.
To the solution of m-bromobenzyl alcohol 4 in THF, the
Diterpenes with the abietane skeleton exist in many
plants.1-6 Most of them exhibit significant bioactivities.7-10
(±)-Abieta-8,11,13-trien-7b-ol (1) was isolated from the
leaves of J. chinensis kaizuka by Fang J. M. et al. in Taiwan.11
To our knowledge no total synthetic work has been reported
on it. In order to study the further relationship between the
structure and bioactivities, we developed a simple route to
synthesize (±)-abieta-8,11,13-trien-7b-ol 1 based on our pre-
vious work.12-14
powdered NaH was added and the mixture was stirred for 30
min at room temperature, then MOMCl in THF was added.
After 20 min compound 5 was obtained in 80% yield. Com-
pound 5 in THF was first converted to Grignard reagent, and
then anhydrous acetone was added dropwise. After stirring
for 15 min, compound 6 was afforded in 92% yield. Dehydra-
tion and deprotection of 6 afforded compound 7 in 71% yield.
Compound 7 was reacted with SOCl2 to give compound 8 in
82% yield. Compound 8 and PPh3 were refluxed in benzene
to give compound 9 in 73% yield.
Our synthetic strategy is AC®ABC. We utilized a-cy-
clocitral (10) as the A ring synthon and the compound 9 as the
C ring synthon. The synthetic route is shown as Scheme II.
The condensation of 10 with 9 in the presence of n-
BuLi/THF under an atmosphere of nitrogen afforded 11 in
RESULTS AND DISCUSSION
As shown in Scheme I, triphenyl phosphonium chloride
(9) was obtained from m-bromoenzyl alcohol (4) via five
Scheme I
Scheme II
OH
Br
5
Br
4
c
a
b
a
b
+
CHO
CH OMOM
2
CH OMOM
2
CH OH
2
ClPh PH C
3
2
6
10
9
11
12
13
11
C
e
1
d
e
d
9
c
B
A
7
3
CH PPh Cl
2
3
5
OH
O
CH Cl
2
CH OH
2
7
8
9
3
2
1
(a) NaH, THF, MOMCl, r. t. , 80%; (b) Mg, THF, CH3COCH3, r. t., 92%; (c)
3N HCl, THF, r. t., 71%; (d) SOCl2, benzene, pyridine, reflux, 1 h, 82%; (e)
PPh3, benzene, reflux, 73%.
(a) n-BuLi, THF, r. t. , 73%; (b) 10% Pd/C, EtOH, r. t., 98%; (c) BF3·Et2O, CH2Cl2, r.
t., 89%; (d) CrO3, HOAc, r. t., 93%; (e) LiAlH4, THF, 0 °C, 2 h, 96%.
* Corresponding author. E-mail: panxf@lzu.edu.cn

430 J. Chin. Chem. Soc., Vol. 50, No. 3A, 2003
Zhang et al.
73% yield, which was then submitted to partial catalytic hy-
drogenation over Pd/C at room temperature to afford the cor-
responding phenethyl derivative (12) in 98% yield. Com-
pound 12 was treated with BF3·Et2O and afforded intramolec-
ular cyclization product 3 in trans form in 89% yield. The
trans-configuration of the A/B ring junction in 3 was sup-
ported by its 1H NMR spectrum, which showed a signal due
to the C4a methyl group at about 1.0 ppm.15 Compound 3 was
oxidized with CrO3/HOAc to yield the natural compound 2 in
93% yield. Reduction of 2 with LiAlH4 (THF, 0°C, 2 h) af-
forded exclusively the target molecule 1 as a consequence of
hydride attack from the less hindered a-face. The structure of
1 was thus confirmed as abieta-8,11,13-trien-7b-ol. The axial
7-H of 1 exhibited a double doublet signal (J = 10, 7.2 Hz)
while the equatorial 7-H showed a triplet (J = 3 Hz) according
to the literature.11
mosphere of nitrogen to yield Grignard reagent. Then anhy-
drous acetone (0.64 mL) in dry THF (2 mL) was added drop-
wise. After stirring for 15 min at room temperature, the mix-
ture was diluted with ether and then with aqueous ammonium
chloride and extracted with ether. The extract was washed
with brine and dried over Na2SO4. The dried extract was
evaporated in vacuo to obtain a crude product which was sub-
sequently purified by column chromatography on silica gel,
using hexane/AcOEt (5:1, v/v) as eluent, to afford colorless
oil 6 (462 mg, 92%). 1H NMR, d 1.51 (s, 2 × 3H), 3.34 (s, 3H),
4.55 (s, 2H), 4.66 (s, 2H), 7.20 (t, 1H, J = 7.8, 7.4 Hz), 7.30 (d,
1H, J = 7.4 Hz), 7.44 (d, 1H, J = 7.8 Hz), 7.54 (s, 1H); MS
(EI), m/z 210 (M+), 195, 165, 133, 91, 59, 43.
3-Isopropenylbenzyl alcohol (7)
A solution of 3N HCl (32 mL) in THF (32 mL) was
added to compound 6 (1.944 g, 9.2 mmol). The mixture was
refluxed for 2 h. After cooling, the mixture was quenched
with 10% NaOH and extracted with ether. The extract was
washed with brine and dried over Na2SO4. The extract was
evaporated in vacuo to give a crude product which was subse-
quently purified by column chromatography on silica gel, us-
ing hexane/AcOEt (10:1, v/v) as eluent, to afford colorless oil
7 (1.362 g, 71%). 1H NMR, d 2.17 (s, 3H), 4.69 (s, 2H), 5.11
(s, 1H), 5.39 (s, 1H), 7.21 (t, 1H, J = 7.8, 7.4 Hz), 7.30 (d, 1H,
J = 7.4 Hz), 7.43 (d, 1H, J = 7.8 Hz), 7.52 (s, 1H); MS (EI),
m/z 148 (M+), 140, 133, 108, 91, 79, 51.
EXPERIMENTAL
IR spectra (KBr) were recorded on a Nicolet 170
SXFT-IR spectrometer. 1H NMR spectra and 13C NMR were
recorded in CDCl3 solution on a Bruker AM-200 spectrome-
ter using TMS as internal standard. Mass spectra were re-
corded on a ZAB-HS spectrometer. Elemental analyses were
performed on a Carlo-Erba 1106 instrument. Column chro-
matographs were generally performed on silica gel (200-300
mesh) under positive nitrogen pressure.
3-Isopropenylbenzyl chloride (8)
Methoxymethyl (3-bromobenzyl) ether (5)
Compound 7 (205 mg, 1.4 mmol) in benzene (2.2 mL)
and one drop of pyridine were added to a solution of SOCl2
(0.12 mL) and benzene (0.5 mL). The mixture was refluxed
for 1 h and then poured into ice-water and extracted with
ether. The ether extract was washed successively with NaHCO3
and brine, dried over Na2SO4 and evaporated. The crude
product was purified by column chromatography on silica
gel, using hexane/AcOEt (30:1, v/v) as eluent, to afford col-
orless oil 8 (232 mg, 82%). 1H NMR, d 2.16 (s, 3H), 4.53 (s,
2H), 5.03 (s, 1H), 5.31 (s, 1H), 7.22 (t, 1H, J = 7.8, 7.4 Hz),
7.31 (d, 1H, J = 7.4 Hz), 7.44 (d, 1H, J = 7.8 Hz), 7.55 (s, 1H);
MS (EI), m/z 166 (M+), 131, 115, 91, 51.
NaH (0.288 g, 0.012 mol) was added to a solution of 4
(1.86 g, 0.01 mol) in THF (50 mL) at room temperature. The
mixture was stirred for 30 min at room temperature and then
MOMCl (0.96 g, 0.02 mol) was added dropwise. After stir-
ring for 15 min, the mixture was diluted with water and acidi-
fied with diluted hydrochloric acid and extracted with ether.
The extract was washed with brine, dried over Na2SO4, and
then evaporated. The crude product was purified by column
chromatography on silica gel, using hexane/AcOEt (30:1,
v/v) as eluent, to afford compound 5 as colorless oil (1.848 g,
1
80%). H NMR, d 3.04 (s, 3H), 4.16 (s, 2H), 4.22 (s, 2H),
6.73-7.00 (m, 4H), 7.10 (s, 1H); MS (EI), m/z 230 (M+), 200,
186, 119, 91, 45.
3-[3-Isopropenylstyryl]-2,4,4-trimethyl-1-cyclohexene (11)
A solution of n-BuLi in ether (2.5 mL, 2.6 mol/L) was
added to a suspension of 9 (2.717 g, 6.5 mmol) in THF (13
mL) under a stream of nitrogen at room temperature. The
mixture was stirred for 1 h and a solution of 10 (979 mg, 6.5
mmol) in THF (4 mL) was added. After stirring for 4 h at
room temperature, the mixture was acidified with dilute hy-
3-(2-Hydroxyisopropyl)methoxymethyl ether (6)
In a 50 mL three neck flask, Mg (52.8 mg, 2.2 mmol), a
small amount of dry THF and a catalytic amount I2 were
placed. Compound 5 (471 mg, 2.2 mmol) in dry THF (2 mL)
was then added dropwise into the above mixture under an at-

Total Synthesis of (±)-Abieta-8,11,13-trien-7b-ol
J. Chin. Chem. Soc., Vol. 50, No. 3A, 2003 431
drochloric acid, extracted with ether, and the extract was
washed with brine, and dried over Na2SO4 and then evapo-
rated. The residue was triturated with hexane, and the precip-
itate was filtered off. The filtrate was evaporated and the resi-
due was purified by column chromatography on silica gel, us-
ing hexane as eluent, to afford colorless oil 11 (1.234 mg,
73%). 1H NMR, d 0.88 (s, 3H), 0.94 (s, 3H), 1.18-2.16 (m,
4H), 1.64 (s, 3H), 2.16 (s, 3H), 2.27 (d, 1H, J = 9.4 Hz), 5.08
(s, 1H), 5.36 (s, 1H), 5.46 (s, 1H), 6.06 (t, 1H, J = 9.4, 15.6
Hz), 6.37 (d, 1H, J = 15.6 Hz), 7.18-7.39 (m, 4H); MS (EI),
m/z 266 (M+), 226, 210, 195, 170, 155, 131, 115, 107, 91, 41.
(20:1, v/v) as eluent afforded the pure product 2 as colorless
oil (264 mg, 93%). IR (KBr), n/cm-1: 1681 (C=O); 1H NMR, d
0.93 (s, 3H), 1.00 (s, 3H), 1.23 (d, 2 ´ 3H, J = 7.0 Hz), 1.25 (s,
3H), 1.52-2.72 (m, 9H), 2.87 (sept, 1H, J = 7.0 Hz), 7.26 (d,
1H, J = 8.0 Hz), 7.37 (d, 1H, J = 8.0 Hz), 7.87 (s, 1H); MS
(EI), m/z 284 (M+), 269, 227, 199, 157, 141, 115, 91, 69, 41.
Anal. Calcd for C20H28O: C, 84.51; H, 9.51. Found: C, 84.45;
H, 9.42.
(±)-Abieta-8,11,13-trien-7b-ol (1)
A mixture of 2 (142 mg, 0.5 mmol) and LiAlH4 (34 mg)
in dry THF (2 mL) was stirred at 0 °C under an atmosphere of
nitrogen for 2 h. The reaction was quenched with saturated
NH4Cl, extracted with ether, and the organic layer was
washed with brine and dried with Na2SO4. After evaporating
the solvent, column chromatography purification using hex-
ane/AcOEt (2:1, v/v) as eluent afforded the colorless oil 1
3-(3-Isopropylphenethyl)-2,4,4-trimethyl-1-cyclohexene (12)
A solution of 11 (1 g, 3.8 mmol) and 10% Pd/C (182
mg) in ethanol (50 mL) was stirred at room temperature in an
atmosphere of hydrogen. The reaction was monitored by
TLC when the reaction was completed. After two equivalents
of hydrogen had been absorbed, the mixture was filtered. The
filtrate was evaporated and the residue was purified by col-
umn chromatography on silica gel, using hexane as eluent, to
1
(137 mg, 96%). IR (KBr), n/cm-1: 3398 (OH); H NMR, d
0.93 (s, H-19), 0.95 (s, H-18), 1.22 (d, J = 6.9 Hz, H-16,
H-17), 1.25 (s, H-20), 2.86 (sept, J = 6.9 Hz, H-15), 4.79 (dd,
J = 10, 7.2 Hz, H-7), 7.07 (dd, J = 8.0, 1.8 Hz, H-12), 7.15 (d,
J = 8.0 Hz, H-11), 7.38 (br s, H-14); 13C NMR, d 19.1 (C-2),
21.5 (C-19), 23.9 (C-16), 24.1 (C-17), 25.3 (C-20), 30.3
(C-6), 33.1 (C-4), 33.1 (C-18), 33.6 (C-15), 38.2 (C-10), 38.7
(C-1), 41.3 (C-3), 49.2 (C-5), 71.3 (C-7), 124.3 (C-12), 125.0
(d, C-11), 125.7 (C-14), 137.7 (C-8), 146.2 (C-13), 147.3
(C-9); MS (EI), m/z 286 (M+), 271, 227, 211, 183, 162, 141,
129, 115, 91, 69, 55, 41; Anal. Calcd for C20H30O: C, 83.92;
H, 10.49. Found: C, 83.89; H, 10.20. The above data were
consistent with the literature.11
1
give colorless oil 12 (0.995 mg, 98%). H NMR, d 0.88 (s,
3H), 0.98 (s, 3H), 1.23 (d, 2 ´ 3H, J = 7.0 Hz), 1.38-2.68 (m,
9H), 1.68 (s, 3H), 2.88 (sept, 1H, J = 7.0 Hz), 5.31 (s, 1H),
6.98-7.22 (m, 4H); MS (EI), m/z 270 (M+), 255, 214, 199,
185, 171, 146, 133, 91, 41.
(±)-Abietane (3)
BF3·Et2O (0.1 mL) was added to a solution of 12 (50
mg, 1.8 mmol) in CH2Cl2 (3 mL) at room temperature. The
mixture was stirred for 15 min and allowed to stand over-
night, then ether (10 mL) was added. The mixture was neu-
tralized with saturated NaHCO3, extracted with ether, and the
organic layer was washed with brine and dried over Na2SO4.
After evaporating the solvent, column chromatography puri-
fication using hexane as eluent afforded the pure product 3 as
colorless oil (48.06 mg, 89%). 1H NMR, d 0.93 (s, 3H), 0.94
(s, 3H), 1.20 (d, 2 ´ 3H, J = 7.0 Hz), 1.23 (s, 3H), 1.40-2.42
(m, 11H), 2.88 (sept, 1H, J = 7.0 Hz), 6.89 (d, 1H, J = 8.2 Hz),
7.03 (d, 1H, J = 8.2 Hz), 7.17 (s, 1H); MS (EI), m/z 270 (M+),
255, 213, 199, 159, 131, 117, 91, 69, 41.
ACKNOWLEDGMENT
We are grateful to the national Nature Science Funda-
tion of China (29372050).
Received June 19, 2002.
(±)-Abieta-8,11,13-trien-7-one (2)
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brine and dried over Na2SO4. After evaporating the solvent,
column chromatography purification using hexane/AcOEt
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