Total synthesis of (R)- and (S)-turmerone and (7S,9R)-bisacumol by an efficient chemoenzymatic approach

Article abstract of DOI:10.1016/j.tetasy.2009.05.006

An enantioselective synthesis of (R)-, (S)-turmerone and (7S,9R)-bisacumol is described. The enantiomerically pure key intermediates, a substituted butanoate ester and acid are utilized in the synthesis of both enantiomers of turmerone. The lipase catalyzed resolution studies of the acetate of bisacumol have been exploited towards the total synthesis of the naturally occurring cytotoxic sesquiterpene, (7S,9R)-bisacumol with high diastereoselectivity (94% de).

Full text of DOI:10.1016/j.tetasy.2009.05.006

Tetrahedron: Asymmetry 20 (2009) 1267–1271
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Total synthesis of (R)- and (S)-turmerone and (7S,9R)-bisacumol
by an efficient chemoenzymatic approach
*
Ahmed Kamal , M. Shaheer Malik, Shaik Azeeza, Shaik Bajee, Ahmad Ali Shaik
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantioselective synthesis of (R)-, (S)-turmerone and (7S,9R)-bisacumol is described. The enantiome-
rically pure key intermediates, a substituted butanoate ester and acid are utilized in the synthesis of both
enantiomers of turmerone. The lipase catalyzed resolution studies of the acetate of bisacumol have been
exploited towards the total synthesis of the naturally occurring cytotoxic sesquiterpene, (7S,9R)-bisacu-
mol with high diastereoselectivity (94% de).
Received 24 March 2009
Accepted 8 May 2009
Available online 8 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
routes for biologically active compounds and their intermediates,12
we herein report the enantioselective synthesis of both forms of
Biocatalysis has increasingly become a useful tool for organic
chemists in the synthesis of biologically active natural and unnat-
ural products.1 The sesquiterpenoid class of natural products pos-
sessing a bisabolane framework are interesting synthetic targets
because they exhibit a diverse range of biological activities.2 Cur-
cuphenol 1 is an important member of this class of compounds
and its individual isomers display different biological effects.3
The target sesquiterpene, (S)-(+)-ar-turmerone 2 is one of the pri-
mary constituents of essential oils obtained from the rhizomes of
Curcuma longa and is reported to exhibit cytotoxic, anti-inflamma-
tory inhibition of platelet aggregation, and anti-venom properties.4
It is a significantly more potent platelet inhibitor than aspirin
against platelet aggregation induced by collagen.5 Its unnatural
isomer (R)-2 has been utilized as a demonstration target in the
development of new synthetic methodologies6 and is also a precur-
sor for other sesquiterpenes such as (R)-ar-himachalene 3, a sex
pheromone produced by the male flea beetle Aphthona flava.7
(7S,9R)-Bisacumol 4, another sesquiterpene, is isolated from the
rhizomes of Curcuma xanthorrhiza, Curcuma zedaria and the leaves
of Baccharis dracunculifolia,8 and exhibits potent cytotoxic activity,
particularly against leukaemia (Fig. 1).9
turmerone, as well as the total synthesis of (7S,9R)-bisacumol in
high enantiopurity.
2. Results and discussion
2.1. Synthesis of enantiomerically pure (R)- and (S)-ar-
turmerone
Herein, for the synthesis of the target sesquiterpenoids, the
enantiomerically pure substituted butanoate ester and acid were
obtained by lipase-mediated resolution as reported12c in our previ-
ous studies. The kinetic resolution of the racemic butanoate 5 was
performed by the lipase from Pseudomonas cepacia immobilized on
ceramic particles (PS-C) at a neutral pH to provide acid (S)-6 in 99%
ee and ester (R)-5 in 92% ee (Scheme 1).
The enantiomerically pure acid (S)-6 was reduced to the pri-
mary alcohol (S)-7 by employing lithium aluminium hydride as
the reducing agent in quantitative yield. The oxidation of (S)-7 to
aldehyde (S)-8 was carried out by a Swern oxidation protocol in
good yields. The nucleophilic addition of the Grignard reagent, 2-
methyl-1-propenyl magnesium bromide to aldehyde (S)-8 pro-
vides a diastereomeric mixture of bisacumol 4. The oxidation of
4 using oxalyl chloride and dimethyl sulfoxide affords the target
compound (S)-turmerone 1. Similarly, the enantiomerically pure
ester (R)-5 was subjected to reduction, followed by oxidation and
nucleophilic addition to provide (R)-turmerone 1 in good yield.
The direct reduction of acid (S)-6 and ester (R)-5 to the aldehyde
(S)-8 was found to be sluggish and low yielding. In the literature,
(R)-1 has been utilized in the synthesis of (R)-ar-himachalene 5,
which is a male pheromone component produced by the flea
A. flava (Scheme 2).
Several racemic and some stereoselective syntheses of turmer-
one 2 have already been reported.2,10 Usually, asymmetric ap-
proaches either employ environmentally unsustainable metal-
based catalysts or microbial processes to provide the single
isomeric form. To the best of our knowledge, there is only one re-
port on the synthesis of (7S, 9R)-4.11 In a continuation of our earlier
investigations towards the development of chemoenzymatic
* Corresponding author. Tel.: +91 40 27193157; fax: +91 40 27193189.
E-mail address: ahmedkamal@iict.res.in (A. Kamal).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.05.006

1268
A. Kamal et al. / Tetrahedron: Asymmetry 20 (2009) 1267–1271
OMe
O
OH
OH
(S)-2
(7S,9R)-4
(7S,9S)-4
(S)-1
O
(R)-3
(R)-2
Figure 1.
O
O
O
O
i
OH
O
+
5
6
(S)- ; 99% ee
(R)-5 ; 92% ee
Scheme 1. Reagents and conditions: (i) lipase PS-C, phosphate buffer, pH 7, 30 °C.
2.2. Lipase-mediated kinetic resolution: synthesis of (7S,9R)-
bisacumol
Herein, eight commercially available lipases from different
sources have been screened for the hydrolysis of the racemic ace-
tate of bisacumol 9, as the selection of the lipase plays an impor-
tant role in the development of an efficient resolution protocol.
Some of the results obtained are summarized in Table 1. It has been
observed that for the hydrolysis of racemic acetate 9, all the en-
zymes screened provide the acetate (7S,9S)-9 in low enantioselec-
tivity with enantiomeric excesses in the range of 25–62% after
incubation for 7 days. The lipase from Pseudomonas fluorescens
(AK-20) and the immobilized form of Candida antartica (CAL-B)
afforded the alcohol in around 85% de and the acetate in 54% de
and 43% de, respectively. The rate of hydrolysis for the lipase from
Candida rugosa (AYS) is comparatively higher but it provides the re-
quired alcohol in lower enantiopurity. The lipases from P. cepacia
(PS) and its immobilized forms PS-C and PS-D (immobilized on
The diastereomeric mixture of bisacumol 4 has been subjected
to lipase-mediated kinetic resolution to obtain the naturally occur-
ring (7S,9R)-bisacumol 4. Lipases from different sources were
screened for the transesterification of bisacumol (7S)-4 using iso-
propenyl acetate as acyl donor in diisopropyl ether at temperatures
up to 45 °C. However, even after a prolonged reaction time (7–
8 days), little conversion (5–7%) was observed. This prompted us
to investigate the lipase-catalyzed hydrolysis of bisacumol acetate
9 in order to achieve an effective kinetic resolution. Acetate 9 was
synthesized in good yield by the acetylation of (7S)-4 with acetic
anhydride, employing triethyl amine as the base in a catalytic
amount of 4-dimethylaminopyridine (Scheme 3).
O
i
ii
O
OH
OH
(S)-8
(S)-6
(S)-7
ii
iii
(S)-8
OH
O
(7S)-4
(S)-2
O
ref. 7
O
i, ii, iii, ii
O
(R)-5
3
(R)-2
Scheme 2. Reagents and conditions: (i) LAH; THF, rt; (ii) (COCl)2, DMSO, TEA, CH2Cl2, ꢀ78 °C; (iii) 2-methyl-1-propenyl magnesium bromide, THF, ꢀ60 °C.

A. Kamal et al. / Tetrahedron: Asymmetry 20 (2009) 1267–1271
1269
+
OAc
OH
i
(7S, 9R)-9
(7S, 9S)-4
ii
OH
(7S)-4
OAc
(
7S)-9
Scheme 3. Reagents and conditions: (i) lipase, IPA, DIPE, 45 °C; (ii) Ac2O, Et3N, DMAP, CH2Cl2.
Table 1
Lipase-mediated hydrolysis of bisacumol acetate 9a
Entry
Lipase
Timeb
Alcohol (7S,9R)-4 dec (%)
Acetate (7S,9S)-9 ded (%)
ce (%)
1
2
3
4
5
6
7
8
PS
PS-C
7
7
7
7
7
7
7
7
91
94
88
60
85
84
82
75
60
62
42
85
54
43
25
28
40
41
32
57
39
34
23
27
PS-D
AYS
AK-20
CAL-B
PPL
Lipozyme
a
Conditions: 30 mg of acetate 9, 15 mg of lipase (50% w/w), 3 mL of 0.1 M phosphate buffer NaH2PO4–Na2HPO4 (pH 7), temperature 35 °C.
Time taken for the acetate hydrolysis in days.
Determined by HPLC analysis employing Daicel Chiralcel AD-H column (0.46 ꢁ 25 cm); eluent: n-hexane:2-propanol = 90:10; flow rate: 0.5 mL/min; detector: 230 nm.
Determined by HPLC analysis employing Daicel Chiralcel OB-H column (0.46 ꢁ 25 cm); eluent: n-hexane:2-propanol = 99:1; flow rate: 0.25 mL/min; detector: 230 nm.
Conversion (c) is calculated from the enantiomeric excess of the substrate acetate (des) and product alcohol (dep) using the formula: c = des/(des + dep).
b
c
d
e
ceramic particles and diatomaceous earth, respectively) give better
results with respect to the enantiopurity of the required alcohol.
Amongst them, lipase PS and PS-D provide the alcohol in 91% de
and 88% de, respectively, whereas the acetate was obtained in
60% de and 42% de, respectively. However, the lipase PS-C afforded
the naturally occurring bisacumol (7S,9R)-4 in 94% de and its ace-
tate (7S,9S)-9 in 62% de. Increasing the reaction time caused the
enantiopurity of the required bisacumol to decrease.
Based on the above investigations, the lipase-mediated kinetic
resolution of the racemic acetate of bisacumol 9 was performed
with the lipase from P. cepacia immobilized on ceramic particles
(PS-C) in 0.1 M phosphate buffer (pH 7.0) at 35 °C. The conversion
and enantiopurity of the ester and acid were analyzed at regular
intervals by employing chiral columns on HPLC and the reaction
was stopped at around 40% conversion. The naturally occurring
bisacumol (7S,9R)-4 was obtained in 94% diastereomeric excess
and the remaining acetate (7S,9S)-9 in 62% de. Acetate (7S,9S)-9
was deacetylated by employing anhydrous potassium carbonate
in refluxing methanol to afford (7S,9S)-epi-bisacumol 4 in lower
enantiopurity (Scheme 4).
3. Conclusion
In conclusion, we have developed an efficient chemoenzymatic
route for the synthesis of both enantiomers of ar-turmerone, (7S,
9R)-bisacumol and (7S, 9S)-epi-bisacumol in high enantiopurity.
In addition to the total synthesis of the target compounds, this pro-
tocol provides an alternative route for the synthesis of related
members of the bisabolene family such as (R)-ar-himachalene, a
male pheromone component produced by the flea A. flava.
4. Experimental
4.1. Material and methods
Enzymatic reactions were carried out on an ‘Innova-4080 incu-
bator-shaker’ at 200 rpm. Infrared spectra of neat samples are re-
ported in wave numbers (cmꢀ1). 1H NMR spectra were recorded
as solutions in CDCl3 and chemical shifts are reported in parts
per million (PPM, d) on a 300 MHz instrument. Coupling constants
are reported in hertz (Hz). LSIMS mass spectra were recorded on
i
+
OH
OAc
OAc
(7S)-9
(7S,9R)-3
(7S,9S)-9
ii
(7S,9S)-3
Scheme 4. Reagents and conditions: (i) lipase PS-C, phosphate buffer, pH 7, 30 °C; (ii) and. K2CO3, MeOH.

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A. Kamal et al. / Tetrahedron: Asymmetry 20 (2009) 1267–1271
Autospec M with 7 KV acceleration voltage and 25 kV gun voltage.
HPLC analysis was performed on an instrument that consisted of a
Shimadzu SCL-10A system controller, SPA-M10A Diode array
detector. Specific rotations were recorded on SEPA-300 Horiba high
sensitive polarimeter, fixed with sodium lamp of wavelength
589 nm.
4.6. (S)-3-(4-Methylphenyl)butanal 8
To a stirred solution of oxalyl chloride (0.87 mL, 10.1 mmol) in
15 mL of dry dichloromethane at –78 °C, dimethyl sulfoxide
(0.81 mL, 11.4 mmol) dissolved in 10 mL of dry DCM was added
dropwise and stirred for over 15 min. To the resulting system, (S)-
7 (1.5 g, 9.1 mmol) dissolved in 5 mL of dry DCM was added drop-
wise and the reaction mixture was stirred for 1.5–2 h at –78 °C,
followed by addition of triethylamine (3.04 mL, 22.7 mmol). The
system was warmed to 0 °C and quenched with addition of water.
The aqueous layer was extracted with dichloromethane, washed
with brine solution, dried over anhydrous Na2SO4 and evaporated
under reduced pressure. The residue was purified on column chro-
matography to give 1.22 g of aldehyde (S)-8 as colourless liquid.
4.2. Chemicals and enzymes
Lithium aluminium hydride, oxalyl chloride, dimethyl sulfoxide,
2-methyl-1-propenyl magnesium bromide and solvents were ob-
tained commercially and used without purification. P. cepacia li-
pase immobilized on ceramic particles (PS-C) was purchased
from Amano (Nagoya, Japan).
Yield: 83%; ½a 2D5
ꢂ
¼ þ41:9 (c 1.0, CHCl3), {lit10c
½
a 2D0
ꢂ
¼ þ39:6 (c 1.0,
CHCl3)}; IR (neat): 2926, 1698, 1047 cmꢀ1
;
1H NMR (300 MHz,
4.3. Lipase-mediated hydrolysis of ethyl 3-(4-methylphenyl)
butanoate 5
CDCl3): d 1.25 (3H, d, J = 7.1 Hz), 2.34 (3H, s), 2.52–2.79 (2H, m),
3.22–3.41 (1H, m), 7.04 (4H, s), 9.68 (1H, s); EIMS (m/z): 162 (M+);
Anal. Calcd for C11H14O: C, 81.44; H, 8.70. Found: C, 81.40; H, 8.65.
To a solution of racemic ester 5 (5.0 g, 24.2 mmol) in 50 mL of
0.1 M phosphate buffer, pH 7.0, 1.5 g of lipase PS-C was added.
The reaction was performed at room temperature with magnetic
stirring. The pH of the reaction mixture was adjusted to 7.0 with
a pH meter by concomitant addition of 0.05 M NaOH solution.
The reaction was stopped at around 45% conversion and purified
to give 1.94 g of acid (S)-6 as a white solid. Yield: 45%; mp:
95 °C; 99% ee [determined by the HPLC analysis using Chiralcel
AD-H column (n-hexane:2-propanol:TFA = 95:5:0.1) with 0.5 mL/
4.7. (R)-3-(4-Methylphenyl)butanal 8
Prepared from (R)-7 by the same procedure described for (S)-8.
Yield: 85%; ½a 2D5
ꢂ
¼ ꢀ35:2 (c 1.0, CHCl3), {lit6a
½
a 2D0
ꢂ
¼ ꢀ58:0 (c 0.84,
CHCl3)}.
4.8. (7S)-Bisacumol 4
min flow rate (tmajor = 13.75, tminor = 14.74 min); ½a D25
ꢂ
¼ þ34:2 (c
To a stirred solution of aldehyde (S)-8 (1.0 g, 6.2 mmol) in 10 mL
of dry THF, 2-methyl-1-propenyl magnesium bromide solution
(12.3 mmol, in 0.5 M solution of THF) was added dropwise at
ꢀ60 °C and stirred for 1 h. The reaction was quenched by adding
saturated ammonium chloride solution and the aqueous layer
was extracted with diethyl ether. The ether layer was washed with
brine solution, dried over anhydrous Na2SO4 and evaporated under
reduced pressure. The residue was purified on column chromatog-
raphy to give 0.96 g of a diastereomeric mixture of (7S)-4 as a col-
1.0, CHCl3)]; IR (neat): 2966, 1701, 960 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 1.30 (3H, d, J = 6.9 Hz), 2.31 (3H, s), 2.42–
2.69 (2H, m), 3.11–3.32 (1H, m), 7.06 (4H, s); EIMS (m/z): 178
(M+); Anal. Calcd for C11H14O2: C, 74.13; H, 7.92. Found: C,
74.09; H, 7.88%. In addition to the acid, 2.58 g of unreacted ester
(R)-5 was recovered. Yield: 52%; 92% ee [determined by the HPLC
analysis using Chiralcel AD-H column (n-hexane:2-propa-
nol = 99.5:0.5) with 0.5 mL/min flow rate (tminor = 11.54,
tmajor = 12.23 min); ½a D25
ꢂ
¼ ꢀ26:2 (c 3.5, CHCl3)]; IR (neat): 1735,
ourless liquid. Yield: 72%; IR (neat): 3352, 2924, 1448, 1054 cmꢀ1
;
1166, 816 cmꢀ1
; d 1.19 (3H, t,
1H NMR (300 MHz, CDCl3):
1H NMR (300 MHz, CDCl3): d 1.24 (3H, d, J = 7.3 Hz), 1.55 and 1.58
(3H, s, diastereomeric), 1.73 and 1.78 (3H, s, diastereomeric), 1.75–
1.86 (1H, m), 1.89–1.98 (1H, m), 2.31 and 2.32 (3H, s, diastereo-
meric), 2.67–2.92 (1H, m), 4.14–4.25 (1H, m), 5.15 (1H, d,
J = 10.2 Hz), 7.05–7.13 (4H, m); EIMS (m/z): 218 (M+); Anal. Calcd
for C15H22O: C, 82.52; H, 10.16. Found: C, 82.50; H, 10.13.
J = 7.0 Hz), 1.27 (3H, d, J = 7.0 Hz), 2.31 (3H, s), 2.37–2.62 (2H,
m), 3.11–3.31 (1H, m), 4.05 (2H, q, J = 7.0 Hz), 7.06 (4H, s); EIMS
(m/z): 206 (M+); Anal. Calcd for C13H18O2: C, 75.69; H, 8.79.
Found: C, 75.63; H, 8.74.
4.4. (S)-3-(4-Methylphenyl)-1-butanol 7
4.9. (7R)-Bisacumol 4
To a stirred suspension of lithium aluminium hydride (0.4 g,
10.6 mmol) in 10 mL of dry THF was added a solution of (S)-6
(1.9 g, 10.6 mmol) in 20 mL of THF at 0 °C and stirred at room
temperature for 2 h. The reaction was quenched by the addition
of saturated Na2SO4 in an ice bath and the slurry was filtered over
a Celite pad. The aqueous layer was extracted with ethyl acetate,
washed with brine solution, dried over anhydrous Na2SO4 and
evaporated under reduced pressure. The residue was chromato-
graphed on silica gel to give 1.62 g of alcohol (S)-7 as a colourless
Prepared from (R)-8 by the same procedure described for (7S)-4
to provide diastereomeric mixture of (7R)-4. Yield: 73%.
4.10. (S)-Turmerone 2
To a stirred solution of oxalyl chloride (0.11 mL, 1.3 mmol) in 2–
3 mL of dry dichloromethane at –78 °C, dimethyl sulfoxide
(0.10 mL, 1.4 mmol) in 1–2 mL of dry DCM was added dropwise
and stirred for over 15 min. To the resulting system, a diastereo-
meric mixture of (7S)-4 (0.25 g, 1.1 mmol) dissolved in 2 mL of
dry DCM was added dropwise and the reaction mixture was stirred
for 1.5–2 h at –78 °C, followed by the addition of triethylamine
(0.26 mL, 2.8 mmol). The system was warmed to 0 °C and
quenched with addition of water. The aqueous layer was extracted
with dichloromethane, washed with brine solution, dried over
anhydrous Na2SO4 and evaporated under reduced pressure. The
residue was purified on column chromatography to give 0.13 g of
the target molecule (S)-2 as a colourless liquid. Yield: 53%;
liquid after purification. Yield: 93%; ½a D25
¼ þ30:1 (c 1.0, CHCl3);
ꢂ
IR (neat): 3352, 1514, 1044 cmꢀ1 1H NMR (300 MHz, CDCl3): d
;
1.25 (3H, d, J = 7.3 Hz), 1.72–1.86 (2H, m), 2.31 (3H, s), 2.72–
2.92 (1H, m), 3.38–3.60 (2H, m), 7.04 (4H, s); EIMS (m/z): 164
(M+); Anal. Calcd for C11H16O: C, 80.44; H, 9.82. Found: C, 80.4;
H, 9.79.
4.5. (R)-3-(4-Methylphenyl)-1-butanol 7
Prepared from (R)-5 by the same procedure described for (S)-7.
Yield: 91%; ½a 2D5
¼ ꢀ28:6 (c 1.0, CHCl3).
ꢂ
½
a 2D5
ꢂ
¼ þ80:2 (c 1.2, CHCl3), {lit11
½
a 2D0
ꢂ
¼ þ82:7 (c 6.8, CHCl3)}; IR

A. Kamal et al. / Tetrahedron: Asymmetry 20 (2009) 1267–1271
1271
(neat): 2960, 1692, 1517, 816 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d
for C15H22O: C, 82.52; H, 10.16. Found: C, 82.55; H, 9.89. 0.32 g of
unreacted acetate (7S,9S)-9 was recovered. Yield: 55%; 62% de
[determined by the HPLC analysis using Chiralcel OB-H column
(n-hexane:2-propanol = 99:1) with 0.25 mL/min flow rate (tma-
1.24 (3H, d, J = 7.0 Hz), 1.87 (3H, s), 2.02 (3H, s), 2.32 (3H, s),
2.53–2.79 (2H, m), 3.21–3.36 (1H, m), 6.02 (1H, s), 7.02 (4H, s);
13C NMR (75 MHz, CDCl3): d 20.66, 20.92, 21.98, 27.51, 35.21,
52.70, 124.42, 126.74, 129.12, 135.48, 144.02, 155.62, 199.94;
EIMS (m/z): 216 (M+); Anal. Calcd for C15H20O: C, 83.29; H, 9.32.
Found: C, 83.21; H, 9.26.
jor = 21.22, tminor = 23.13 min); ½a D25
¼ ꢀ21:4 (c 1.0, CHCl3). The
ꢂ
spectroscopic data of the acetate were identical to that of 9.
4.14. (7S,9S)-epi-Bisacumol 4
4.11. (R)-Turmerone 2
To (7S,9S)-9 (0.2 g, 0.7 mmol) in methanol (20 mL), anhydrous
K2CO3 (0.3 g, 2.1 mmol) was added and stirred at room tempera-
ture for 2 h. Potassium carbonate was removed by filtration
through a Celite pad and the solvent evaporated under reduced
pressure. The residue was purified by column chromatography to
afford 0.15 g of (7S, 9S)-4 as colourless liquid. Yield: 92%,
Prepared from the diastereomeric mixture of (7R)-4 by the
same procedure described for (S)-2. Yield: 52%; ½a D25
¼ ꢀ67:8 (c
ꢂ
1.0, CHCl3), {Lit6a
½
a 2D0
ꢂ
¼ ꢀ58:0 (c 6.8, CHCl3)}.
4.12. (7S)-Bisacumol acetate 9
½
a 2D5
ꢂ
¼ þ4:1 (c 1.0, CHCl3), {lit11
½
a 2D0
ꢂ
¼ þ9:4 (c 9.7, CHCl3)}. IR
A solution of a diastereomeric mixture of alcohol (7S)-4 (0.50 g,
1.7 mmol) in CH2Cl2 (8 mL) was treated with triethylamine
(1.15 mL, 8.2 mmol) and acetic anhydride (0.51 mL, 5.5 mmol) at
0 °C in a catalytic amount of DMAP. The reaction mixture was stir-
red at room temperature for 3 h and quenched with the addition of
water followed by extraction with CH2Cl2. The organic layer was
washed with sodium bicarbonate solution, followed by a brine
solution and dried over anhydrous Na2SO4. The residue obtained
on removal of solvent under reduced pressure was purified by col-
umn chromatography to provide 0.65 g of pure acetate (7S)-9.
(neat): 3352, 2925, 1446, 1054 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
d 1.25 (3H, d, J = 7.1 Hz), 1.57 (3H, s), 1.75 (3H, s), 1.75–1.86 (1H,
m), 1.89–1.98 (1H, m), 2.33 (3H, s), 2.69–2.91 (1H, m), 4.18–4.26
(1H, m), 5.14 (1H, d, J = 10.0 Hz), 7.05–7.12 (4H, s). The other spec-
troscopic data were identical to that of (7S, 9R)-4.
Acknowledgements
The authors (MSM, SA, SB and AAS) are thankful to CSIR, New
Delhi, for the award of research fellowship.
Yield: 92%; IR (neat): 2926, 1734, 1241, 816 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 1.21 and 1.25 (3H, d, J = 7.5 Hz, diastereo-
meric), 1.55 and 1.60 (3H, s, diastereomeric), 1.68 and 1.72 (3H,
s, diastereomeric), 1.74–2.02 (2H, m), 1.92 and 1.99 (3H, s, diaste-
reomeric), 2.31 (3H, s), 2.57–2.77 (1H, m), 4.99–5.11 (1H, m), 5.24–
5.42 (1H, m), 7.02–7.12 (4H, m); EIMS (m/z): 260 (M+); Anal. Calcd
for C17H24O2: C, 78.42; H, 9.29. Found: C, 78.36; H, 9.24.
References
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4.13. Lipase-mediated hydrolysis: Synthesis of (7S,9R)-
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bisacumol 4
To a solution of acetate (7S)-9 (0.6 g, 2.3 mmol) in 5 mL of 0.1 M
phosphate buffer, pH 7.0, was added 0.2 g of lipase PS-C. The reac-
tion was performed at 35 °C with magnetic stirring. The pH of the
reaction mixture was adjusted to 7.0 by the concomitant addition
of 0.05 M NaOH solution with a pH meter. The progress of the reac-
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drous Na2SO4, evaporated under reduced pressure and the residue
obtained was purified by column chromatography. The enantio-
pure products were analyzed by HPLC and compared with the cor-
responding racemic products. Then, 0.24 g of naturally occurring
bisacumol (7S, 9R)-4 was obtained as a colourless liquid. Yield:
40%; 94% de [determined by the HPLC analysis using Chiralcel
AD-H column (n-hexane: 2-propanol = 90:10) with 0.5 mL/min
´
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flow rate (tmajor = 9.89, tminor = 10.79 min); ½a D25
¼ þ14:8 (c 1.0,
ꢂ
CHCl3), {lit11
½
a 2D0
ꢂ
¼ þ15:6 (c 8.4, CHCl3)}; IR (neat): 3353, 2925,
1447, 1054 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 1.24 (3H, d,
J = 7.1 Hz), 1.55 (3H, s), 1.73 (3H, s), 1.75–1.86 (1H, m), 1.89–1.98
(1H, m), 2.31 (3H, s), 2.67–2.92 (1H, m), 4.14–4.25 (1H, m), 5.15
(1H, d, J = 10.2 Hz), 7.05–7.13 (4H, s); 13C NMR (75 MHz, CDCl3):
d 18.20, 20.92, 22.91, 25.62, 35.62, 45.89, 66.85, 126.86, 128.06,
128.99, 133.82, 135.35, 143.98; EIMS (m/z): 218 (M+); Anal. Calcd