Total asymmetric synthesis of (7S,9R)-(+)-bisacumol

Article abstract of DOI:10.1016/S0957-4166(02)00759-0

A facile stereoselective synthetic route to (7S,9R)-(+)-bisacumol 1 has been achieved. This novel approach derives its asymmetry by employing asymmetric dihydroxylation and CBS reduction processes. The resulting sesquiterpene 1 was produced with highly enantio- and diastereoselectivity.

Full text of DOI:10.1016/S0957-4166(02)00759-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 75–78
Total asymmetric synthesis of (7S,9R)-(+)-bisacumol
Anpai Li,a Guoren Yue,a Yang Li,a Xinfu Pana,* and Teng-Kuei Yangb
aDepartment of Chemistry, National Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
bDepartment of Chemistry, National Chung-Hsing University, Taichung, Taiwan
Received 17 September 2002; accepted 31 October 2002
Abstract—A facile stereoselective synthetic route to (7S,9R)-(+)-bisacumol 1 has been achieved. This novel approach derives its
asymmetry by employing asymmetric dihydroxylation and CBS reduction processes. The resulting sesquiterpene 1 was produced
with highly enantio- and diastereoselectivity. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Inspired by the synthesis of trans-2-phenylcyclohex-
anol,6 we aimed to prepare the chiral 2-phenyl alcohol
(+)-Bisacumol 1 (Fig. 1), a member of the aromatic
5 using the Sharpless AD reaction7 and from this
bisabolane sesquiterpene family, was isolated from the
versatile chiral synthon, (S)-(+)-ar-turmerone 2, which
rhizome of Curcuma Xanthorrhiza and its absolute
in turn could be subjected to CBS reduction8 to furnish
configuration was determined to be 7S,9R.1 As a result
the title chiral allylic alcohol 1. Our synthetic strategy is
of the wide distribution of this class of natural products
shown in full in Scheme 1.
and their high biological activities,2 many methods have
been developed to synthesize the compounds in racemic
form,3 however, only a few stereoselective syntheses
2. Results and discussion
were reported due to the difficulty of introducing a
stereogenic center in the benzylic position.4 To the best
Treatment of the styrene derivative 3 with AD-mix-a at
0°C afforded the (S)-(+)-diol 4 in 96% yield. Stereose-
of our knowledge, no total asymmetric synthesis of the
title compound has been reported. Herein, we describe
a short, efficient asymmetric synthesis of (7S,9R)-(+)-
bisacumol 1 along with its epimer (7S,9S)-(+)-bisacu-
mol, epi-1, and (+)-ar-turmerone 2, which was isolated
from the essential oil from the rhizome of turmeric
curcuma Curcuma Longa Linn.5 and is known to have
9S configuration.
lective reduction of the benzylic alcohol 4 with Raney
nickel in refluxing ethanol furnished the 2-phenyl-
propanol 5 (>93% e.e.) in 89% yield, in which retention
of the configuration was observed.9 The corresponding
alcohol was treated with PPh3 (1.2 equiv.) and CBr4
(1.1 equiv.) in CH2Cl2 at room temperature to afford
the bromide 6 in 99% yield. Due to the low reactivity of
Figure 1.
* Corresponding author. E-mail: panxf@lzu.edu.cn
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00759-0

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A. Li et al. / Tetrahedron: Asymmetry 14 (2003) 75–78
bromide 6, its reaction with magnesium powder to form
the alkylmagnesium bromide is sluggish. Thus, CH3I
(1.2 equiv.) was used, and by metal-halogen exchange in
refluxing ether, the desired Grignard reagent derived
from 6 can be obtained. After the addition of 3-methyl
crotonaldehyde 7 at −20°C, a pair of diastereoisomers 1
and epi-1 (ꢀ1:1 ratio) were obtained in 68% overall
yield and which were separable using column chro-
matography. Oxidation of the diastereoisomers with
MnO2 in CCl4 at 60°C afforded (+)-ar-turmerone 2 in
94% yield, the CBS reduction8 of compound 2 was
carried out with oxazaboralidine 8 (0.1 mol/mol of
ketone) and catecholborane (2 equiv.) at −78°C in
toluene for 15 h to provide the title compound (7S,9R)-
(+)-bisacumol 1 in 89% yield (d.e. >91%). The corre-
trometers. The chemical shifts are reported in ppm
relative to TMS or CDCl3. Optical rotations were
determined on a JASCO J-20C polarimeter with 0.2 dm
tube. Mass spectra were recorded on a ZAB-HS mass
spectrometer (EI). Microanalyses were performed on a
MOD-1106 elemental analyser. Chiral analysis was per-
formed on Varian Dynamax SD-300 using chiralcel
column CDMPC (150×4.6 mm D) with hexane/isopro-
pyl alcohol as eluant. Column chromatographs were
generally performed on silica gel (200–300 mesh) eluting
with petroleum ether:ethyl acetate.
3.2. (S)-(+)-diol, 4
A 250 mL round-bottom flask, equipped with a mag-
netic stirrer, was charged with tert-butyl alcohol (75
mL), water (75 mL), and AD-mix-a (21 g). Stirring at rt
produced two clear phases, the lower aqueous phase
being bright yellow. The mixture was cooled to 0°C
whereupon some of the dissolved salts precipitated.
4-(1-Methenyl ethyl) toluene 3 (2 g, 15 mmol) was added
at once, and the heterogeneous slurry was stirred vigor-
ously at 0°C for 18 h. While the mixture was stirred at
0°C, solid sodium sulfite (22.5 g) was added and the
mixture was allowed to warm to rt and stirred for 30
min, ethyl acetate 80 mL was added to the reaction
mixture, and after separation of the layer, the aqueous
phase was further extracted with ethyl acetate (3×50
mL). The combined organic extracts were dried over
anhydrous magnesium sulfate and concentrated to give
the diol. This crude product was purified by column
chromatography to afford the diol 4 (2.4 g, 96%) ([h]D20
1
sponding H and 13C NMR spectrum of this pair of
diastereoisomers have evident differences. Compared
with the spectroscopic data for the natural product (7S,
9R)-(+)-bisacumol, the absolute configuration of com-
pound 1 and epi-1 can be confirmed as (7S,9R) and
(7S,9S), respectively. The other spectroscopic data also
agreed with that of the natural product.1
In summary, we have successfully synthesized the natu-
ral (7S,9R)-(+)-bisacumol 1 in 48% overall yield from
the readily available 4-(1-methenylethyl)toluene, the
synthesis only required six separate chemical operations
and was highly enantio- and diastereoselective. Sharp-
less AD reaction and Raney nickel reduction induced
the stereogenicity in the formation of the benzylic cen-
ter, and CBS reduction furnished the chiral allylic
alcohol. Our strategy thus provides a general and
efficient access to aromatic enantiomerially enriched
bisabolane sesquiterpenoids, and is expected to find
more applications in the synthesis of other related
natural products, for example, heliannuol A-E.10
1
+15.1 (c 7.2, CHCl3, e.e.>95%). H NMR l 1.479 (s,
3H), 2.361 (S, 3H), 3.525 (d, 1H, J=11.4 Hz), 3.671 (d,
1H, J=11.4 Hz), 7.163 (d, 2H, J=8.2 Hz), 7.309 (d, 2H,
J=8.2 Hz). MS (EI): m/z 166, 151, 149 and 135.
3.3. (R)-(+)-2-(4-Methylphenyl)propanol, 5
3. Experimental
3.1. General
To a stirred solution of diol 4 (2.3 g, 13.8 mmol) in
ethanol (50 mL) was added freshly prepared Raney
nickel (14 g). The mixture was heated under reflux for
3 h, then the catalyst was filtered off and washed with
ethanol, the organic solution was evaporated and the
1
The H and 13C NMR data were recorded in CDCl3
solution with Bruker AM-200 or AM-400 MHz spec-
Scheme 1. Reagents and conditions: (i) AD-mix-a, t-BuOH/H2O, 0°C, 18 h; (ii) Raney Ni, EtOH, reflux, 3 h; (iii) PPh3, CBr4,
CH2Cl2, rt, 4 h; (iv) a. Mg powder, CH3I, Et2O, reflux, 3 h, b. 3-methyl crotonaldehyde, Et2O, −20°C; (v) MnO2, CCl4, 60°C, 30
min; (vi) oxazaboralidine 8 (0.1 mol/mol of ketone) and catecholborane (2 equiv.), toluene, −78°C, 15 h.

A. Li et al. / Tetrahedron: Asymmetry 14 (2003) 75–78
77
crude product was purified by column chromatography
3.6. (S)-(+)-ar-Turmerone, 2
to afford the alcohol 5 (1.85 g, 89%), [h]2D0 +14.6,
(c=5.0, CHCl3, e.e.>93%, lit.11 [h]D +14.01 (c 1.26,
To a solution of alcohol 1 and epi-1 (1.1 g, 5 mmol) in
carbon tetrachloride (20 mL) was added manganese
dioxide (4.4 g), the mixture was stirred at 60°C for 30
min and the oxidant was filtered off, the filtrate was
evaporated and the crude product was purified by
column chromatography to afford the ketone 2 (1.0 g,
94%), [h]2D0 +82.7 (c 6.8, CHCl3, lit.12 [h]D +81.56
1
CHCl3). H NMR l 1.208 (d, 3H, J=7.0 Hz), 2.303 (s,
3H), 2.790–2.894 (m, 1H), 3.565 (d, 2H, J=7.2 Hz),
7.096 (s, 4H). MS (EI): m/z 150, 119 and 91.
3.4. (R)-(+)-1-Bromo-2-(4-methylphenyl)propane, 6
1
To a solution of alcohol 5 (1.8 g, 12 mmol) together
with triphenyl phosphine (3.8 g, 14.5 mmol) in methyl-
ene dichloride 40 mL was added in portion carbon
tetrabromide (4.1 g, 12.4 mmol). After addition, the
solution was stirred at rt for 4 h, then petroleum ether
40 mL was added. The reaction mixture was filtered by
suction, and washed with petroleum ether: ethyl acetate
(10:1), the organic solution was evaporated and the
crude product was purified by column chromatography
to give the bromide 6 (2.52 g, 99%), [h]2D0 +24.2 (c 9.0,
(CHCl3). H NMR l 1.227 (d, 3H, J=7.0 Hz), 1.851
and 1.990 (s, each 3H), 2.306 (s, 3H), 2.540–2.776 (m,
2H), 3.244–3.351 (m, 1H), 6.026 (s, 1H), 7.104 (s, 4H).
13C NMR l 20.59, 20.87, 21.91, 27.49, 35.23, 52.62,
124.06, 126.59, 129.03, 135.42, 143.63, 154.84, 199.68.
MS (EI): m/z 216, 201, 132, 119, 83.
3.7. (7S,9R)-(+)-Bisacumol, 1
Under an atmosphere of Ar, to a solution of ketone 2
(430 mg, 2 mmol) and catalyst 8 (0.2 mmol) in toluene
(10 mL) was added dropwise catecholborane (1 M, 4
mL) at −78°C, the mixture was stirred at this tempera-
ture for 16 h, then quenched with water. The mixture
was allowed to warm to room temperature and stirred
for 30 min, after separation of the layer, the aqueous
phase was further extracted with ethyl acetate (3×50
mL). The combined organic extracts were washed suc-
cessively with 2N sodium hydroxide solution, 2N
aqueous hydrogen chloride and brine, dried over anhy-
drous sodium sulfate and evaporated, the crude
product was purified by column chromatography to
afford the alcohol 1 (390 mg, 89%), [h]2D0 +14.4 (c 5.5,
CHCl3, d.e.>91%).
1
CHCl3). H NMR l 1.450 (d, 3H, J=6.8 Hz), 2.398 (s,
3H), 3.077–3.250 (m, 1H), 3.469–3.665 (m, 2H), 7.186
(s, 4H). MS (EI): m/z 214, 212, 133, 119 and 91.
3.5. (7S,9R)-(+)-Bisacumol, 1 and (7S,9S)-(+)-bisacu-
mol, epi-1
Under an atmosphere of Ar, a solution of bromide 6
(2.0 g, 9.4 mmol) together with iodomethane (1.6 g,
11.3 mmol) in dry ethyl ether (30 mL) was added
dropwise to magnesium powder (600 mg, 25 mmol) in
dry ethyl ether (10 mL). The mixture was stirred under
reflux for 3 h, and then cooled to −20°C, 3-methyl
crotonaldehyde (2.0 g, 24 mmol) was added slowly, the
mixture was stirred at this temperature for 2 h, and rt
for another 2 h, then quenched with saturated ammo-
nium chloride. After separation of the organic layer, the
aqueous phase was further extracted with ethyl acetate
(3×50 mL), The combined organic extracts were dried
over anhydrous sodium sulfate and evaporated to give
a pair of diastereoisomers. This crude product was
purified by column chromatography to afford (7S,9R)-
(+)-bisacumol, 1 (0.68 g, 33%) and (7S,9S)-(+)-bisacu-
mol, epi-1 (0.72 g, 35%), respectively.
Acknowledgements
We are grateful to the National Science Foundation of
China (NO. 20172023) for financial support.
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