Enantioselective synthesis of (R)- and (S)-curcumene and curcuphenol: an efficient chemoenzymatic route

Article abstract of DOI:10.1016/j.tetasy.2007.10.019

An efficient enantioselective synthesis of curcumene and curcuphenol is described. The key intermediates, substituted butanoates 7a and 7b and their acids 8a and 8b are obtained in high enantiopurity (>99% ee) by a lipase-catalyzed kinetic resolution proc

Full text of DOI:10.1016/j.tetasy.2007.10.019

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2547–2553
Enantioselective synthesis of (R)- and (S)-curcumene and curcuphenol:
an efficient chemoenzymatic route
Ahmed Kamal,* M. Shaheer Malik, Ahmad Ali Shaik and Shaik Azeeza
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 27 August 2007; accepted 10 October 2007
Abstract—An efficient enantioselective synthesis of curcumene and curcuphenol is described. The key intermediates, substituted butano-
ates 7a and 7b and their acids 8a and 8b are obtained in high enantiopurity (>99% ee) by a lipase-catalyzed kinetic resolution process.
The enantiopure intermediates thus obtained were utilized for the total synthesis of the target compounds.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
corals, exhibits antibacterial activity.4 Recently, dimers of
curcuphenols (e.g., 3) have been isolated and assessed for
their biological activities.5 The difficulty in the introduction
of a benzylic stereogenic centre in these compounds and
their varied biological activities has made them challenging
as well as attractive synthetic targets. Several non-racemic
syntheses have been reported based on new asymmetric
methodologies6 and microbial approaches.7 Since the bio-
logical activity of bisabolene enantiomers varies consider-
ably,4c,d this underlines the need for methods to provide
access to both enantiomers. In continuation of our efforts
towards the development of chemoenzymatic routes for
biologically active compounds,8 we herein report the prep-
aration of the target compounds in high enantiopurity.
Isolated from diverse natural sources, bisabolene sesquiter-
penes are an important class of compounds showing a wide
range of biological activities that vary with stereochemis-
try.1 They are characterized by a benzylic stereogenic cen-
tre, and often carry a methyl group at this position.
Amongst the numerous bisabolene sesquiterpenoids, the
simplest (+)-curcumene 1 has been isolated from rhizomes
of Curcuma aromatica salisb and is recognized as an odour
component of distantly related corals, along with other
members.2 The phenolic sesquiterpene (+)-curcuphenol 2
is a major metabolite in different sponge genera and is
known to possess potent H/K-ATPase inhibitory, antiplas-
OH
OH
(S)-1
(S)-2
OH
3
modial and cytotoxic activities.3 Interestingly, its enantio-
2. Results and discussion
mer, (ꢀ)-curcuphenol, which is isolated from gorgorian
Our synthetic approach to these sesquiterpenoids starts
with commercially available substituted acetophenones
such as 4-methyl-2-hydroxy acetophenone 4 and 4-methyl
*
Corresponding author. Tel.: +91 40 27193157; fax: +91 40 27193189;
e-mail: ahmedkamal@iict.res.in
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.10.019

2548
A. Kamal et al. / Tetrahedron: Asymmetry 18 (2007) 2547–2553
O
ii
ii
R
O
R
O
5a
O
iii
O
OH
O
OCH3O
i
7a R = H
7b R = OCH3
6a R = H
6b R = OCH3
5b
4
Scheme 1. Reagents: (i) Me2SO4, K2CO3, acetone; (ii) NaH, (EtO)2 POCH2CO2Et, THF; (iii) H2, 10% Pd–C, MeOH.
acetophenone 5a. Compound 4 is protected as a methyl
ether using dimethyl sulfonate and potassium carbonate un-
der refluxing conditions to provide 5b. These acetophenones
5a and 5b are converted to their a,b-unsaturated esters 6a
and 6b by a Horner–Wadsworth–Emmons reaction using
triethylphosphonoacetate and sodium hydride. The reduc-
tion of the olefinic bond of the unsaturated esters by
catalytic hydrogenation provides the required key interme-
diates 7a and 7b as depicted in Scheme 1.
(immobilized on ceramic particles and diatomaceous earth,
respectively) and lipase from Pseudomonas fluorescens
(AK-20, Amano) provided encouraging results, with
respect to conversion and enantioselectivity. Amongst them,
lipase PS-D and PS have been found to provide the acid
with 96% ee and 90% ee and the ester with 72% ee and
81% ee, respectively. However, excellent enantiopurity of
the acid (99% ee) has been obtained from lipase PS-C
and AK-20 with 92% ee and 86% ee of the ester,
respectively.
These intermediates have been investigated for their resolu-
tion by employing lipases. In the development of an effi-
cient resolution protocol, the selection of the lipase plays
an important role. Therefore, in the present study, ten com-
mercially available lipases obtained from different sources
have been screened for the hydrolysis of the racemic
3-substituted butanoates 7a and 7b. Some of the results
obtained are summarized in Table 1. It has been observed
that for the hydrolysis of racemic ester 7a, lipases from
Candida cylindracea (CCL), porcine pancreatic lipase
(PPL), Candida rugosa (CRL) have shown low enantio-
selectivity, whereas papain (latex from Carica papaya),
lipozyme (Mucor miehei) have shown no significant conver-
sion after prolonged reaction time. The lipase from Pseudo-
monas cepacia (PS) and its immobilized forms PS-C, PS-D
In the screening of lipases for the hydrolysis of ester 7b,
similar results have been obtained. Lipases such as CRL,
PPL, CCL and lipozyme were found to exhibit lower
enantioselectivities while lipases PS-D and AK-20 have
provided the acid with high enantiopurity (99% ee) and
the ester with 76% ee and 83% ee, respectively. However,
excellent enantiopurities of the acid (>99% ee) have been
obtained from lipase PS-C and PS with 94% ee and 90%
ee of the ester, respectively (Scheme 2). Moreover, this
process is also useful in the preparation of enantiomerically
enriched b-aryl carboxylic acids and in the literature where
one of the methods describes the resolution of 3-phenyl
methyl butanoate by lipase-catalyzed enantioselective
hydrolysis.9
Table 1. Lipase-mediated hydrolysis of ester ( )-7a and ( )-7ba
Entry
Lipase
Timeb (h)
ee (%)
Esterc (R)-7a
ce (%)
Timeb (h)
ee (%)
Esterf (R)-7b Acidd (S)-8b
>99
ce (%)
Acidd (S)-8a
1
2
3
4
5
6
7
8
PS-C
PS-D
PS
AK-20
CCL
PPL
CRL
Lipozyme
15
18
18
15
24
24
24
—
92
72
81
86
20
18
—
—
99
96
90
99
62
61
55
—
48
42
44
46
24
23
—
—
16
17
17
16
24
24
24
36
94
76
90
83
17
16
9
48
43
47
45
21
21
13
16
99
>99
99
56
58
69
12
60
a Conditions: 30 mg of ( )-7a, or 7b, 15 mg of lipase (50% w/w), 3 mL of 0.1 M phosphate buffer NaH2PO4–Na2HPO4 (pH 7), temperature 30 ꢁC.
b Time taken for ester hydrolysis.
c Determined by chiral HPLC analysis employing Daicel Chiralcel AD-H column (0.46 · 25 cm); eluent: hexane/2-propanol = 95:0.5; flow rate: 0.5 mL/
min; detector: 220 nm.
d Determined by chiral HPLC analysis employing Daicel Chiralcel AD-H column (0.46 · 25 cm); eluent: hexane/2-propanol/trifluoroacetic
acid = 95:5:0.1; flow rate: 0.5 mL/min; detector: 220 nm.
e Conversion (c) is calculated from enantiomeric excess of substrate esters 7a, 7b (ees) and product acid 8a, 8b (eep) using the formula c = ees/(ees + eep).
f Determined by chiral HPLC analysis employing Daicel Chiralcel AS-H column (0.46 · 25 cm); eluent: hexane/2-propanol = 99.5:0.5; flow rate: 0.5 mL/
min; detector: 220 nm.

A. Kamal et al. / Tetrahedron: Asymmetry 18 (2007) 2547–2553
2549
R
O
R
O
R
O
OH
i
O
O
+
(R,S)-7a R = H
(R)-7a R = H
(S)-8a R = H
(R,S)-7b R = OCH3
(R)-7b R = OCH3
(S)-8b R = OCH3
Scheme 2. Reagents: (i) Lipase PS-C, phosphate buffer pH 7.
Based on the above investigations, the lipase-catalyzed
hydrolysis of the racemic substituted ethyl butanoates 7a
and 7b was performed with the lipase from P. cepacia
immobilized on ceramic particles (PS-C) in 0.1 M
phosphate buffer (pH 7.0) at 30 ꢁC. The conversion and
enantiopurity of the esters and acids were analyzed at reg-
ular intervals with chiral HPLC and the reactions were
stopped at about 50% of conversion. The required acids
(S)-8a and (S)-8b were obtained in high enantiopurity
(>99% ee) and the remaining esters (R)-7a and (R)-7b with
92% ee and 94% ee, respectively. However, in a previous
report, the chiral synthons required in the synthesis of curcu-
phenol were obtained in enantiomeric excesses of up to
90% by sequential lipase-mediated hydrolysis and acetyl-
ation processes in two steps.7c
(S)-12 was carried out by using boron tribromide to
provide the desired curcuphenol (S)-2 (Scheme 3).
The other enantiomers of the target compounds, (R)-1 and
(R)-2, were also synthesized from (R)-7a and (R)-7b follow-
ing the same sequential route.
3. Conclusion
In conclusion, we have developed a simple and efficient
chemoenzymatic route for the synthesis of enantiomeric
pairs of curcumene and curcuphenol employing lipase-
mediated kinetic resolution process in high enantiopurity.
This protocol also provides an alternative route for the syn-
thesis of related members of the bisabolene family.
The enantiomerically pure acids (S)-8a and (S)-8b obtained
by lipase-mediated resolution were reduced to the corre-
sponding primary alcohols (S)-9a, (S)-9b by treatment with
lithium aluminium hydride, which were then transformed
to tosyl sulfonates (S)-10a and (S)-10b under mild condi-
tions using tosyl chloride with triethyl amine as base. The
cross coupling of tosylates with 2-methyl-1-propenyl
magnesium bromide was catalyzed by copper bromide-
dimethyl sulfide complex to provide the target compound
curcumene (S)-1 and methylated curcuphenol (S)-11. This
copper reagent has been previously utilized for the SN2
displacement of tosylates in the total synthesis of
bisabolol.10 Finally, cleavage of curcuphenol methyl ether
4. Experimental
4.1. Materials and methods
Enzymatic reactions were carried out on an ‘Innova-4080
incubator-shaker’ at 200 rpm. Infrared spectra of neat sam-
ple are reported 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 Autospec
R
O
R
R
i
ii
OH
OH
OTs
(S)-9a R = H
(S)-9b R = OCH3
(S)-10a R = H
(S)-10b R = OCH3
(S)-8a R = H
(S)-8b R = OCH3
OH
OMe
iii
iv
iii
(S)-10b
;
(S)-10a
(S)-1
(S)-11
(S)-2
i, ii
(R)-7a R = H; (R)-7b R = OCH3
(R)-10a R = H; (R)-10b R = OCH3
iii, iv
iii
;
(R)-10b
(R)-10a
(R)-1
(R)-2
Scheme 3. Reagents: (i) LAH, THF; (ii) TsCl, TEA, DMAP, CH2Cl2; (iii) (CH3)2C@CHMgBr, CuBrÆMe2S, THF; (iv) BBr3, CH2Cl2.

2550
A. Kamal et al. / Tetrahedron: Asymmetry 18 (2007) 2547–2553
M. with 7 kV acceleration voltage and 25 kV gun voltage.
HPLC analysis was performed on an instrument that con-
sisted of a Shimadzu SCL-10A system controller, SPA-
M10A Diode array detector. The pH was checked by Cole
parmer pH/ORP, 5652-10. Specific rotations were recorded
on a SEPA-300 Horiba high sensitive polarimeter, fixed
with a sodium lamp of wavelength 589 nm.
5.84 (1H, d, J = 1.5 Hz), 7.06–7.12 (4H, m); EIMS (m/z):
204 (M+); Anal. Calcd for C13H16O2: C, 76.44; H, 7.89.
Found: C, 76.41; H, 7.86.
4.3.2. Ethyl (E,Z)-3-(2-methoxy-4-methylphenyl)-2-buteno-
ate 6b. To a stirred suspension of NaH (60% in mineral
oil, 0.87 g, 21.9 mmol) in dry THF (25 mL) at 0 ꢁC, triethyl
phosphonoacetate (4 mL, 20.1 mmol) was added dropwise
under nitrogen over a period of 30 min and left for 15 min.
To the resulting mixture, ketone 5b (3 g, 18.3 mmol) was
added slowly and the reaction mixture was refluxed for
2 h. The reaction mixture was quenched with a saturated
NH4Cl and extracted with ethyl acetate. The organic layer
was washed with brine, dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue obtained
was chromatographed on silica gel to afford 3 g of pure es-
ter E-6b as a colourless liquid. Yield: 72%; IR (neat): 1717,
1628, 1172 cmꢀ1; 1H NMR (300 MHz, CDCl3): d 1.29 (3H,
t, J = 7.3 Hz), 2.34 (3H, s), 2.43 (3H, d, J = 1.4 Hz), 3.79
(3H, s), 4.15 (2H, q, J = 7.3 Hz), 5.81 (1H, s), 6.63 (1H,
s), 6.67 (1H, d, J = 7.3 Hz), 6.98 (1H, d, J = 7.3 Hz); EIMS
(m/z): 234 (M+); Anal. Calcd for C14H18O3: C, 71.77; H,
7.74. Found: C, 71.71; H, 7.72. The last eluted fractions
gave 0.68 g of ester Z-6b as a colourless liquid. Yield:
4.2. Chemicals and enzymes
Substituted acetophenones 4 and 5a, triethyl phosphono-
acetate, LAH, tosyl sulfonyl chloride, 2-methyl-1-propenyl
magnesium bromide, copper iodide-dimethyl sulfide com-
plex (used from new Aldrich bottle) and solvents were
obtained commercially and used without purification. P.
cepacia lipase immobilized on ceramic particles (PS-C)
was purchased from Amano (Nagoya, Japan).
4.3. 4-Methyl-5-methoxy acetophenone 5b
To a solution of 4-methyl-5-hydroxy acetophenone 4
(3.5 g, 23.3 mmol) and anhydrous K2CO3 (8 g, 58.3 mmol)
in 40 mL of dry acetone was added dimethyl sulfate
(2.45 mL, 25.6 mmol) after which it was refluxed overnight.
The reaction mixture was filtered through a Celite pad,
after which acetone was evaporated under reduced pressure
followed by the addition of water and extraction by ethyl
acetate. The organic layer was washed with brine solution
and dried over anhydrous Na2SO4. The solvent was evap-
orated and residue purified by silica gel column chromato-
graphy to give 3.5 g of protected phenol 5b as a pale yellow
16%; IR (neat): 1725, 1609, 1150 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 1.10 (3H, t, J = 7.0 Hz), 2.13 (3H,
d, J =1.5 Hz), 2.36 (3H, s), 3.78 (3H, s), 3.97 (2H, q,
J = 7.0 Hz), 5.88 (1H, d, J = 1.5 Hz), 6.66 (1H, s), 6.71
(1H, d, J = 7.8 Hz), 6.86 (1H, d, J = 7.8 Hz); EIMS (m/
z): 234 (M+); Anal. Calcd for C14H18O3: C, 71.77; H,
7.74. Found: C, 71.71; H, 7.72.
liquid. Yield: 92%; IR (neat): 1669, 1606, 1258, 814 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 2.38 (3H, s), 2.56 (3H, s),
3.90 (3H, s), 6.71 (1H, s), 6.77 (1H, d, J = 7.5 Hz), 7.64
(1H, d, J = 7.5 Hz); EIMS (m/z): 164 (M+); Anal. Calcd
for C10H12O2: C, 73.15; H, 7.37; O, 19.49. Found: C,
73.01; H, 7.21.
4.3.3. Ethyl 3-(4-methylphenyl)butanoate 7a. The unsatu-
rated esters E,Z-6a (3.75 g, 18.3 mmol) were dissolved in
methanol (35 mL) and stirred under a hydrogen atmo-
sphere (1 atm) in the presence of 10% Pd/C (0.8 g) for
3 h. The catalyst was removed by filtration on a Celite
pad and the filtrate was concentrated and purified by col-
umn chromatography to give 3.56 g of 7a as a colourless
4.3.1. Ethyl (E,Z)-3-(4-methylphenyl)-2-butenoate 6a. To
a stirred suspension of NaH (60% in mineral oil, 1.06 g,
26.8 mmol) in dry THF (25 mL) at 0 ꢁC, triethyl phospho-
noacetate (4.8 mL, 26.8 mmol) was added dropwise under
nitrogen over a period of 30 min and left for 15 min. To
the resulting mixture, ketone 5a (3 g, 22.3 mmol) was
added slowly and the reaction mixture was refluxed for
2 h. The reaction mixture was quenched with a saturated
NH4Cl and extracted with ethyl acetate. The organic layer
was washed with brine, dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue obtained
was chromatographed on silica gel to afford 3.69 g of pure
ester E-6a as a colourless liquid. Yield: 81%; IR (neat):
1713, 1627, 1160, 816 cmꢀ1;1H NMR (300 MHz, CDCl3):
d 1.31 (3H, t, J = 7.2 Hz), 2.37 (3H, s), 2.55 (3H, d,
J = 1.6 Hz), 4.17 (2H, q, J = 7.2 Hz), 6.07 (1H, d,
J = 1.6 Hz ), 7.12 (2H, d, J = 8.0 Hz), 7.35 (2H, d, J =
8.0 Hz); EIMS (m/z): 204 (M+); Anal. Calcd for
C13H16O2: C, 76.44; H, 7.89. Found: C, 76.39; H, 7.85.
The last eluted fractions gave 0.45 g of ester Z-6a as a col-
ourless liquid. Yield: 10%; IR (neat): 1712, 1627, 1162,
816 cmꢀ1;1H NMR (300 MHz, CDCl3): 1H NMR
(300 MHz, CDCl3): d 1.12 (3H, t, J = 6.7 Hz), 2.16 (3H,
d, J = 1.511 Hz) 2.36 (3H, s), 3.99 (2H, q, J = 6.7 Hz),
1
liquid. Yield: 95%; IR (neat): 1735, 1166, 816 cmꢀ1; H
NMR (300 MHz, CDCl3): d 1.19 (3H, t, 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.
4.3.4. Ethyl 3-(2-methoxy-4-methylphenyl)butanoate 7b.
The unsaturated esters E,Z-6b (3.2 g, 13.6 mmol) were dis-
solved in methanol (30 mL) and stirred under a hydrogen
atmosphere (1 atm) in the presence of 10% Pd/C (0.7 g)
for 3 h. The catalyst was removed by filtration on a Celite
pad and the filtrate was concentrated and purified by col-
umn chromatography to give 3.13 g of 7b as a pale yellow
1
liquid. Yield: 97%; IR (neat): 1735, 1259, 1039 cmꢀ1; H
NMR (300 MHz, CDCl3): d 1.22–1.29 (6H, m), 2.33 (3H,
s), 2.44 (1H, dd, J = 8.6 Hz, J = 15.1 Hz), 2.63 (1H, dd,
J = 5.7 Hz, J = 15.1 Hz), 3.47–3.65 (1H, m), 3.84 (3H, s),
4.08 (2H, q, J = 7.2 Hz), 6.62 (1H, s), 6.67 (1H, d,
J = 7.9 Hz), 7.00 (1H, d, J = 7.9 Hz); EIMS (m/z): 236
(M+); Anal. Calcd for C14H20O3: C, 71.16; H, 8.53. Found:
C, 71.09; H, 8.49.

A. Kamal et al. / Tetrahedron: Asymmetry 18 (2007) 2547–2553
2551
4.4. General procedure for the lipase-mediated hydrolysis of
ethyl 3-(4-methylphenyl)butanoate 7a
6.60 (1H, s), 6.66 (1H, d, J = 7.5 Hz), 6.99 (1H, d,
J = 7.5 Hz); LC–MS (m/z): 231 (M+Na)+; Anal. Calcd
for C12H16O3: C, 69.21; H, 7.74. Found: C, 69.17; H,
7.72. Unreacted ester (R)-7b (1.61 g) was recovered. Yield:
54%; 94% ee [determined by the HPLC analysis using Chi-
ralcel AS-H column (hexane/2-propanol = 99.5:0.5) with
To a solution of the racemic ester (3 g, 14.5 mmol) in
40 mL of 0.1 M phosphate buffer, pH 7.0, was added
0.9 g of lipase PS-C. The reaction was performed at room
temperature 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 reaction was monitored by chiral HPLC and after
approximately 45% conversion, the reaction mixture was
filtered and extracted with ethyl acetate. The aqueous layer
was acidified with a 2% HCl solution, saturated with so-
dium chloride solution and extracted with ethyl acetate.
The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, and evaporated under reduced
pressure after which the residue was purified by column
chromatography. The enantiopure products were analyzed
by HPLC and compared with the corresponding racemic
products. Acid (S)-8a (1.17 g) was obtained as a white col-
oured solid. Yield: 45%; mp: 95 ꢁC; 99% ee [determined by
the HPLC analysis using Chiralcel AD-H column (hexane/
0.5 mL/min flow rate (tmajor = 13.06, tminor = 14.12 min);
25
½aꢁD ¼ ꢀ2:7 (c 1.0, CHCl3)].
4.4.2. (S)-3-(4-Methylphenyl)-1-butanol 9a. To a stirred
suspension of lithium aluminium hydride (0.2 g, 5.6 mmol)
in 5 mL of dry THF was added a solution of (S)-8a (1 g,
5.6 mmol) in 15 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 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 chromatographed on silica
gel to give 0.85 g of alcohol (S)-9a as a colourless liquid.
25
Yield: 93%; ½aꢁD ¼ þ30:1 (c 1.0, CHCl3); IR (neat): 3352,
1514, 1044 cmꢀ1 1H NMR (300 MHz, CDCl3): d 1.25
;
2-propanol/TFA = 95:5:0.1) with 0.5 mL/min flow rate
(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.
25
(tmajor = 13.87, tminor = 14.74 min); ½aꢁD ¼ þ34:2 (c 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. Unreacted ester
(1.64 g) was recovered. Yield: 55%; 92% ee {determined
by the HPLC analysis using Chiralcel AD-H column
4.4.3. (R)-3-(4-Methylphenyl)-1-butanol 9a. Prepared
from (R)-7a by the same procedure described for (S)-9a.
25
Yield: 91%; ½aꢁD ¼ ꢀ29:6 (c 1.0, CHCl3).
(hexane/2-propanol = 99.5:0.5) with 0.5 mL/min flow rate
4.4.4. (S)-3-(2-Methoxy-4-methylphenyl)-1-butanol 9b. To
a stirred suspension of lithium aluminium hydride (0.2 g,
5.2 mmol) in 5 mL of dry THF was added a solution of
(S)-8b (1.1 g, 5.2 mmol) in 15 mL of THF at 0 ꢁC and stir-
red 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 Celite pad. The aque-
ous layer was extracted with ethyl acetate, washed with
brine solution, dried over anhydrous Na2SO4 and evapo-
rated under reduced pressure. The residue was chromato-
25
(tmajor = 11.92, tminor = 12.87 min); ½aꢁD ¼ ꢀ26:2 (c 3.5,
CHCl3)}.
4.4.1. General procedure for the lipase-mediated hydrolysis
of ethyl 3-(2-methoxy-4-methylphenyl)butanoate 7b. To a
solution of racemic ester (3 g, 12.7 mmol) in 40 mL of
0.1 M phosphate buffer, pH 7.0, was added 0.9 g of lipase
PS-C. The reaction was performed at room temperature
with magnetic stirring. The pH of the reaction mixture
was adjusted to 7.0 by concomitant addition of 0.05 M
NaOH solution with a pH meter. The progress of the reac-
tion was monitored by chiral HPLC and after approxi-
mately 46% conversion, the reaction mixture was filtered
and extracted with ethyl acetate. The aqueous layer was
acidified with a 2% HCl solution, saturated with sodium
chloride solution and extracted with ethyl acetate. The
combined organic layers were washed with brine, dried
over anhydrous Na2SO4, and evaporated under reduced
pressure after which the residue was purified by column
chromatography. The enantiopure products were analyzed
by HPLC and compared with the corresponding racemic
products. Acid (S)-8b (1.21 g) was obtained as a viscous
liquid. Yield: 46%; 99% ee [determined by the HPLC
analysis using Chiralcel AD-H column (hexane/2-propa-
graphed on silica gel to give 0.9 g of alcohol (S)-9b as a
25
colourless liquid. Yield: 92%; ½aꢁD ¼ þ21:6 (c 1.0, CHCl3);
IR (neat): 3422, 1505, 1040 cmꢀ1 1H NMR (300 MHz,
;
CDCl3): d 1.17 (3H, d, J = 6.9 Hz), 1.48–1.86 (2H, m),
2.26 (3H, s), 3.19–3.32 (3H, m), 3.37–3.46 (1H, m), 3.76
(3H, s), 6.57 (1H, s), 6.64 (1H, d, J = 7.7 Hz), 6.95 (1H,
d, J = 7.7 Hz); LC–MS (m/z): 217 (M+Na)+; Anal. Calcd
for C12H18O2: C, 74.19; H, 9.34. Found: C, 74.12; H, 9.30.
4.4.5. (R)-3-(4-Methylphenyl)-1-butanol 9b. Prepared
from (R)-7b by the same procedure described for (S)-9b.
25
Yield: 92%; ½aꢁD ¼ ꢀ20:2 (c 1.0, CHCl3).
4.4.6. (S)-3-(4-Methylphenyl)butyl 4-methyl-1-benzenesulfo-
nate 10a. A solution of alcohol (S)-9a (0.75 g, 4.5 mmol)
in CH2Cl2 (10 mL) was treated with triethylamine
(0.79 mL, 5.7 mmol) and tosyl chloride (0.94 g, 4.9 mmol)
nol/TFA = 95:5:0.1) with 0.5 mL/min flow rate (tmajor
=
25
13.97, tminor = 14.94 min); ½aꢁD ¼ þ16:2 (c 2.5, CHCl3)];
IR (neat): 1707, 1506, 810 cmꢀ1 1H NMR (300 MHz,
;
in
a
catalytic amount of 4-dimethylaminopyridine
CDCl3): d 1.27 (3H, d, J = 7.5 Hz), 2.31 (3H, s), 2.47
(1H, dd, J = 9.0 Hz, J = 15.8 Hz), 2.67 (1H, dd,
J = 9.0 Hz, J = 15.8 Hz), 3.48–3.63 (1H, m), 3.81 (3H, s),
(DMAP). The reaction mixture was stirred at room tem-
perature for 6 h, quenched with the addition of water and
extracted with ethyl acetate. The organic layer was washed

2552
A. Kamal et al. / Tetrahedron: Asymmetry 18 (2007) 2547–2553
with brine solution, dried over anhydrous Na2SO4 and
evaporated under reduced pressure. The residue was puri-
fied by column chromatography to afford 1.19 g of tosyl-
(m/z): 202 (M+); Anal. Calcd for C15H22: C, 89.04; H,
10.96. Found: C, 89.01; H, 10.92.
ated product (S)-10a as a pale yellow liquid. Yield: 82%;
4.4.11. (R)-Curcumene 1. Prepared from (R)-10a by the
25
½aꢁD ¼ þ37:7 (c 1.0, CHCl3); IR (neat): 2961, 1360,
same procedure described for (S)-1. Yield: 65%;
1
1176 cmꢀ1; H NMR (200 MHz, CDCl3): d 1.21 (3H, d,
25
½aꢁD ¼ ꢀ39:8 (c 1.2, CHCl3).
J = 6.7 Hz), 1.73–2.02 (2H, m), 2.30 (3H, s), 2.46 (3H, s),
2.67–2.90 (1H, m), 3.70–4.02 (2H, m), 6.85–7.07 (4H, m),
7.30 (2H, d, J = 7.6 Hz), 7.73 (2H, d, J = 7.6 Hz); EIMS
(m/z): 318 (M+); Anal. Calcd for C18H22O3S: C, 67.90;
H, 6.96. Found: C, 67.86; H, 6.92.
4.4.12. (S)-Methylated curcuphenol 11. A suspension of
copper bromide-dimethyl sulfide complex (0.23 g,
1.5 mmol) in 10 mL dry THF was treated with 2-methyl-
1-propenyl magnesium bromide solution (15 mmol, in
0.5 M solution of THF) at ꢀ60 ꢁC. 1.05 g of (S)-10b
(3 mmol) as a solution in 5 mL of THF was added drop-
wise and then warmed to 0 ꢁC to room temperature and
stirred for 3–4 h. Saturated NH4Cl solution was added
and the aqueous layer was extracted with diethyl ether.
The ether layer was washed with brine, dried over anhy-
drous Na2SO4 and concentrated under reduced pressure.
The residual mass was chromatographed on silica gel to
afford 0.5 g of methylated curcuphenol (S)-11. Yield: 72%;
4.4.7. (R)-3-(4-Methylphenyl)butyl 4-methyl-1-benzenesulfo-
nate 10a. Prepared from (R)-9a by the same procedure
25
described for (S)-10a. Yield: 83%; ½aꢁD ¼ ꢀ35:5 (c 1.0,
CHCl3).
4.4.8. (S)-3-(2-Methoxy-4-methylphenyl)butyl 4-methyl-1-
benzenesulfonate 10b.
A solution of alcohol (S)-9b
(0.75 g, 3.8 mmol) in CH2Cl2 (10 mL) was treated with tri-
ethylamine (0.67 mL, 4.8 mmol) and tosyl chloride (0.79 g,
4.1 mmol) in a catalytic amount of DMAP. The reaction
mixture was stirred at room temperature for 6 h, quenched
with the addition of water and extracted with ethyl acetate.
The organic layer was washed with brine solution, dried
over anhydrous Na2SO4 and evaporated under reduced
pressure. The residue was purified by column chromatogra-
25
20
½aꢁD ¼ þ7:1 (c 1.0, CHCl3), {lit.7a ½aꢁD ¼ þ7:8 (c 1.0,
CHCl3)}; IR (neat): 1611, 1505, 1463 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d 1.16 (3H, d, J = 6.6 Hz), 1.33–1.76
(2H, m), 1.53 (3H, s), 1.67 (3H, s), 1.79–1.99 (2H, m),
2.31 (3H, s), 3.02–3.20 (1H, m), 3.79 (3H, s), 5.08 (1H, t),
6.62 (1H, s), 6.68 (1H, d, J = 7.3 Hz), 6.99 (1H, d,
J = 7.3 Hz); 13C NMR (75 MHz, CDCl3): d 17.57, 21.09,
21.36, 25.70, 26.27, 31.40, 37.15, 55.27, 111.43, 121.08,
124.88, 126.52, 131.00, 132.80, 136.15, 156.13; EIMS
(m/z): 232 (M+); Anal. Calcd for C16H24O: C, 82.70; H,
10.41. Found: C, 82.67; H, 10.36.
phy to afford 1.12 g of tosylated product (S)-10b as a pale
25
yellow liquid. Yield: 84%; ½aꢁD ¼ þ14:2 (c 3.6, CHCl3); IR
(neat): 2960, 1359, 1176 cmꢀ1
;
1H NMR (300 MHz,
CDCl3): d 1.16 (3H, d, J = 6.9 Hz), 1.79–2.01 (2H, m),
2.30 (3H, s), 2.44 (3H, s), 3.11–3.24 (1H, m), 3.76 (3H, s),
3.86–3.94 (2H, m), 6.57 (1H, s), 6.62 (1H, d, J = 7.5 Hz),
6.87 (1H, d, J = 7.5 Hz), 7.27 (1H, d, J = 7.9 Hz), 7.71
(1H, d, J = 7.9 Hz); EIMS (m/z): 348 (M+); Anal. Calcd
for C19H24O4S: C, 65.49; H, 6.94. Found: C, 65.39; H, 6.89.
4.4.13. (R)-Methylated curcuphenol 11. Prepared from
(R)-10b by the same procedure described for (S)-11. Yield:
25
74% ½aꢁD ¼ ꢀ5:8 (c 1.0, CHCl3).
4.4.14. (S)-Curcuphenol 2. To a solution of (S)-11 (0.45 g,
1.9 mmol) in 10 mL of dry THF was added boron tribro-
mide (0.23 mL, 2.4 mmol) under nitrogen at ꢀ78 ꢁC and
warmed to room temperature and stirred for 1 h. The reac-
tion mixture was poured in ice-cold water and stirred for
half an hour. The aqueous layer was extracted with
CH2Cl2, washed with brine solution, dried with anhydrous
Na2SO4. The organic solvent was evaporated under re-
duced pressure and the residue obtained was chromato-
graphed to provide 0.31 g of (S)-curcuphenol 2. Yield:
4.4.9. (R)-3-(2-Methoxy-4-methylphenyl)butyl 4-methyl-1-
benzenesulfonate 10b. Prepared from (R)-9b by the same
procedure
½aꢁD ¼ ꢀ13:6 (c 1.0, CHCl3).
described
for
(S)-10b.
Yield:
82%;
25
4.4.10. (S)-Curcumene 1. A suspension of copper bro-
mide-dimethyl sulfide complex (0.24 g, 1.1 mmol) in
10 mL of dry THF was treated with a 2-methyl-1-propenyl
magnesium bromide solution (11.7 mmol, in 0.5 M solu-
tion of THF) at ꢀ60 ꢁC. 0.75 g of (S)-10a (2.3 mmol) as
a solution in 5 mL of THF was added dropwise and then
warmed to 0 ꢁC to room temperature and stirred for 3–
4 h. Saturated NH4Cl solution was added and the aqueous
layer was extracted with diethyl ether. The ether layer was
washed with brine, dried over anhydrous Na2SO4 and con-
centrated under reduced pressure. The residual mass was
25
20
68%; ½aꢁD ¼ þ23:5 (c 1.3, CHCl3), {lit.3c ½aꢁD ¼ þ24:6 (c
1
1.0, CHCl3)}; IR (neat): 3453, 1618, 1583, 1451 cmꢀ1; H
NMR (300 MHz, CDCl3): d 1.21 (3H, d, J = 6.9 Hz),
1.51 (3H, s), 1.54–1.65 (2H, m), 1.67 (3H, s), 1.84–1.96
(2H, m), 2.26 (3H, s), 2.84–3.03 (1H, m), 4.60 (1H, br s),
5.03–5.12 (1H, m), 6.56 (1H, s), 6.64 (1H, d, J = 7.9 Hz),
6.98 (1H, d, J = 7.9 Hz); 13C NMR (75 MHz, CDCl3): d
17.6, 20.9, 21.1, 25.7, 26.2, 31.5, 37.3, 116.2, 121.7, 124.7,
126.9, 130.0, 131.9, 136.5 152.9; EIMS (m/z): 218 (M+);
Anal. Calcd for C15H22O: C, 85.52; H, 10.16. Found: C,
85.47; H, 10.07.
chromatographed on silica gel to afford 0.32 g of (S)-cur-
25
cumene 1. Yield: 67%; ½aꢁD ¼ þ42:7 (c 1.0, CHCl3), {lit.2c
20
½aꢁD ¼ þ43:5 (c 1.0, CHCl3)}; IR (neat): 2859, 1513,
1
1451 cmꢀ1; H NMR (300 MHz, CDCl3): d 1.24 (3H, d,
J = 7.1 Hz), 1.55 (3H, s), 1.57–1.68 (2H, m), 1.69 (3H, s),
1.82–1.98 (2H, m), 2.34 (3H, s), 2.56–2.74 (1H, m), 5.13-
5.05 (1H, m), 7.03–7.12 (4H, m); 13C NMR (100 MHz,
CDCl3): d 17.67, 20.92, 22.49, 25.73, 26.18, 38.46,
39.00,124.55, 126.88, 128.93, 131.36, 135.13, 144.63; EIMS
4.4.15. (R)-Curcuphenol 2. Prepared from (R)-11 by the
same procedure described for (S)-2. Yield: 65%;
25
½aꢁD ¼ ꢀ20:9 (c 1.0, CHCl3).

A. Kamal et al. / Tetrahedron: Asymmetry 18 (2007) 2547–2553
2553
1661; (d) Bohlman, F.; Lonitz, M. Chem. Ber. 1978, 111,
843.
Acknowledgement
5. Cichewicz, R. H.; Clifford, L. J.; Lassen, P. R.; Cao, X.;
Freedman, T. B.; Nafie, L. A.; Deschamps, J. D.; Kenyon, V.
A.; Flanary, J. R.; Holman, T. R.; Crews, P. Bioorg. Med.
Chem. Lett. 2005, 13, 5600.
Authors (M.S.M., A.A.S. and S.A.) are thankful to CSIR,
New Delhi for the award of a research fellowship.
6. (a) Meyers, A. I.; Stoianova, D. J. Org. Chem. 1997, 62, 5219;
(b) Hagiwara, H.; Okabe, T.; Ono, H.; Kamat, V. P.; Hoshi,
T.; Suzuki, T.; Ando, M. J. Chem. Soc., Perkin Trans. 1 2002,
895; (c) Harmata, M.; Hong, X.; Barnes, C. L. Tetrahedron
Lett. 2003, 44, 7261; (d) Schmalz, H. G.; de Koning, C. B.;
Bernicke, D.; Siegel, S.; Pfletschinger, A. Angew. Chem., Int.
Ed. 1999, 38, 1620; (e) Takano, S.; Yanase, M.; Sugihara, T.;
Ogasawara, K. J. Chem. Soc., Chem. Commun. 1988, 1538; (f)
Tamao, K.; Hayashi, T.; Matsumoto, H.; Yamamato, H.;
Kumada, M. Tetrahedron Lett. 1979, 20, 2155; (g) Sugahara,
T.; Ogasawara, K. Tetrahedron: Asymmetry 1998, 9, 2215; (h)
Lu, J.; Xie, X.; Chen, B.; She, X.; Pan, X. Tetrahedron:
Asymmetry 2005, 16, 1435.
7. (a) Fuganti, C.; Serra, S. J. Chem. Soc., Perkin Trans. 1 2000,
3758; (b) Fuganti, C.; Serra, S.; Dulio, A. J. Chem. Soc.,
Perkin Trans. 1 1999, 279; (c) Fuganti, C.; Serra, S. Synlett
1998, 1252; (d) Ono, M.; Ogura, Y.; Hatogai, K.; Akita, H.
Tetrahedron: Asymmetry 1995, 6, 1829; (e) Ono, M.; Yama-
moto, Y.; Akita, H. Chem. Pharm. Bull. 1995, 43, 553.
8. (a) Kamal, A.; Krishnaji, T.; Khan, M. N. A. J. Mol. Catal. B
2007, 47, 1; (b) Kamal, A.; Shaik, A. A.; Azeeza, S.; Malik, M.
S.; Sandbhor, M. Tetrahedron: Asymmetry 2006, 17, 2890; (c)
Kamal, A.; Shaik, A. A.; Sandbhor, M.; Malik, M. S.; Azeeza,
S. Tetrahedron: Asymmetry 2006, 17, 2876; (d) Kamal, A.;
Ramana, K. V.; Rao, M. V. J. Org. Chem. 2001, 66, 997.
9. Varadharaj, G.; Hazell, K.; Reeve, C. D. Tetrahedron:
Asymmetry 1998, 9, 1191.
References
1. (a) Heathcock, C. H. In The Total Synthesis of Natural
Products; ApSimon, J. W., Ed.; Wiley: New York, 1973; Vol.
2, p 197; (b) Heathcock, C. H.; Graham, S. L.; Pirrung, M.
C.; Plavac, F.; White, C. T. In The Total Synthesis of Natural
Products; ApSimon, J. W., Ed.; Wiley and Sons: New York,
1981; Vol. 5, p 35; (c) Pirrung, M. C.; Morehead, A. T. In The
Total Synthesis of Natural Products; Goldsmith, D., Ed.;
Wiley and Sons: New York, 1997; Vol. 10, p 29.
2. (a) Simonsen, S. J.. In The Terpenes; Cambridge University
Press, 1952; Vol. III, p 18, 202; (b) Honwad, V. K.; Rao, A. S.
Tetrahedron 1965, 21, 2593; (c) McEnroe, F.; Fenical, W.
Tetrahedron 1978, 34, 1661.
3. (a) Butler, M. S.; Capon, R. J.; Nadeson, R.; Beveridge, A. A.
J. Nat. Prod. 1991, 54, 619; (b) El Sayed, K. A.; Yousaf, M.;
Hamann, M. T.; Avery, M. A.; Kelly, M.; Wipf, P. J. Nat.
Prod. 2002, 65, 1547; (c) Wright, A. E.; Pomponi, S. A.;
McConnell, O. J.; Kohmoto, S.; McCarthy, P. J. J. Nat.
Prod. 1987, 50, 976; (d) Fusetani, N.; Sugano, M.; Matsu-
naga, S.; Hashimoto, K. Experientia 1987, 43, 1234; (e)
´
Rodrıguez, A. D.; Vera, B. J. Org. Chem. 2001, 66, 6364; (f)
Peng, J.; Franzblau, S. G.; Zhang, F.; Hamann, M. T.
Tetrahedron Lett. 2002, 43, 9699.
4. (a) Armas, H. T. D.; Mootoo, B. S.; Reynolds, W. F. J. Nat.
Prod. 2000, 63, 1593; (b) Freyer, A. J.; Patil, A. D.; Killmer,
L.; Zuber, G.; Myers, C.; Johnson, R. K. J. Nat. Prod. 1997,
60, 309; (c) McEnroe, F.; Fenical, W. Tetrahedron 1978, 34,
10. Makita, N.; Hoshino, Y.; Yamamoto, H. Angew. Chem., Int.
Ed. 2003, 42, 941.