Chemoenzymatic synthesis of enantiomerically enriched kavalactones

Article abstract of DOI:10.1016/j.tetlet.2006.09.155

Lipase-mediated kinetic resolution of methyl-3-hydroxy-5-phenylpentanoate and (6E)-ethyl 5-hydroxy-3-oxo-7-phenylhept-6-enoate is described in high enantiomeric excess and good yields. The effect of different lipases in different solvents has been screened using different acylating agents. This protocol has been extended for the preparation of enantiomerically pure biologically important kavalactones.

Full text of DOI:10.1016/j.tetlet.2006.09.155

Tetrahedron Letters 47 (2006) 8657–8660
Chemoenzymatic synthesis of enantiomerically enriched
kavalactones
*
Ahmed Kamal, Tadiparthi Krishnaji and G. B. Ramesh Khanna
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 11 August 2006; revised 19 September 2006; accepted 28 September 2006
Available online 20 October 2006
Abstract—Lipase-mediated kinetic resolution of methyl-3-hydroxy-5-phenylpentanoate and (6E)-ethyl 5-hydroxy-3-oxo-7-phenyl-
hept-6-enoate is described in high enantiomeric excess and good yields. The effect of different lipases in different solvents has been
screened using different acylating agents. This protocol has been extended for the preparation of enantiomerically pure biologically
important kavalactones.
Ó 2006 Elsevier Ltd. All rights reserved.
Kavalactones are a class of a-pyrones and 5,6-dihydro-
pyrones isolated from the kava plant Piper methysticum
associated with the use of kava-containing dietary sup-
plements. These findings suggest the need for detailed
investigations on the individual kavalactones as well as
their structurally related analogues.
(
Piperaceae), which grows widely in the South Pacific
1
islands including Fiji and Hawaii. The extracts of its
root and stem are used as a folk medicine or as a cere-
monial drink in this region. Various structurally related
analogues such as kavain (1c), methylstian (1d) and
dihydrokavain-5-ol (1e) possess significant biological
There are several reports on the synthesis of kavain, and
its analogues, in particular, those involving asymmetric
3
reduction. However, in this investigation a chemoenzy-
2
a
2b
activities including anticonvulsive, muscle-relaxing,
matic synthetic strategy for kavalactones has been devel-
oped. In continuation of our earlier efforts towards the
preparation of biologically important compounds or
sedative, analgesic and antithrombotic,2d and have
attracted attention in both the pharmaceutical and
chemical research sectors. Some clinical studies indicate
that the kavalactones have demonstrable anxiety-reduc-
ing effects. However, the FDA and CDC have issued
warnings about the severe cause of liver injury probably
2c
4
their intermediates by the application of enzymes, we
herein report an efficient and facile synthesis of optically
pure (+)- and (ꢀ)-dihydrokavain (1a, 1b) and (R)-(+)-
kavain (1c) using a lipase catalyzed protocol (Fig. 1).
O
O
O
O
O
O
OMe
OMe
OMe
(+)-dihydrokavain 1a
(-)-dihydrokavain 1b
(+)-kavain 1c
O
O
O
O
O
O
OMe
OMe
OH
methylstian 1d
dihydrokavain-5-ol 1e
Figure 1. Kavain based compounds.
*
0
Corresponding author. Tel.: +91 40 27193157; fax: +91 40 27193189; e-mail addresses: ahmedkamal@iict.res.in; ahmedkamal@ iictnet.org
040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.155

8658
A. Kamal et al. / Tetrahedron Letters 47 (2006) 8657–8660
Enantiopure dihydrokavain has been synthesized by
chromatography (EtOAc–hexane, 8:2). After separation
alcohol (R)-5 was treated with lithium diisopropylamide
(LDA) and following addition of t-butyl acetate, hydr-
oxy b-keto ester (R)-6 was obtained. This was lactonized
with TFA to give (R)-7 which upon treatment with di-
methyl sulfate in acetone in the presence of potassium
employing b-keto ester 4 as the starting material. b-Keto
5
,3g
ester 4 has previously been prepared
by the alkyl-
ation of the dianion of methylacetoacetate 3 with benzyl
bromide 2. Reduction to b-hydroxy ester 5 was achieved
using sodium borohydride in methanol. The racemic
b-hydroxy ester 5 was resolved enzymatically using dif-
ferent lipases. Amongst all the lipases screened, Pseudo-
monas cepacia lipase immobilized on modified ceramic
particles (PS–C) gave good yields and high enantiomeric
excess (Table 1). The effect of different solvents was also
examined employing lipase PS–C. Among the solvents
investigated, diisopropyl ether and hexane provided
good conversions with high enantiomeric excess (Table
24
carbonate afforded (R)-(+)-dihydrokavain (R)-1a ½aꢁ
D
2
D
5
ꢀ26.6 (c 4.5, CHCl ); [Ref. 7 ½aꢁ ꢀ28 (c 1.92, EtOH)].
3
(S)-(ꢀ)-Dihydrokavain (S)-1b was obtained using the
same procedure after hydrolysis of acetate (S)-5
using potassium carbonate in methanol (Scheme 1)
2
D
4
10
D
½aꢁ +28.0 (c 1.5, CHCl ); [Ref. 7 ½aꢁ +30 (c 1, EtOH)].
3
Racemic 10 was obtained as a pale yellow liquid by reac-
tion of cinnamaldehyde 8 with the dianion of ethyl ace-
toacetate 9. Racemic 10 was resolved using lipases PS–C
and PS–D with different acylating agents. Amongst the
acylating agents examined, vinyl acetate gave low yields
as well as low conversion rates. However, isopropenyl
acetate and vinyl chloroacetate gave good yields and
high enantiomeric excess. Amongst the solvents em-
2
). During the course of this study a report on the enzy-
6
matic resolution of b-hydroxy esters appeared, how-
ever, there are no reports on the lipase-mediated
resolution of substrate 5.
The resolution of 5 gave (S)-acetate (S)-5 and (R)-alco-
hol (R)-5. These two products were separated by column
Table 1. Transesterification of methyl 3-hydroxy-5-phenylpentanoate 5 and (6E)-ethyl 5-hydroxy-3-oxo-7-phenylhept-6-enoate 10 with various
lipases in diisopropyl ether
a
b
Entry
Ester
Lipase
Acylating agent
Time (h)
Alcohol
Acetate
E
c
d
c
d
Yield (%)
Ee (%)
Yield (%)
Ee (%)
1
2
3
4
5
6
7
8
9
5
PS–C
PS–D
PS
CRL
AYS
PS–C
PS–D
PS–C
PS–D
PS
A
A
A
A
A
B
18
24
240
240
240
20
30
30
35
46
45
35
98
90
42
40
42
40
60
35
32
>99
>99
30.4
46
45
33
—
—
42
40
43
40
20
30
30
>99
>99
>99
—
1055
1055
339
—
5
5
5
5
—
—
10
10
10
10
10
10
10
>99
96
>99
94
80.2
82
80
>99
>99
>99
>99
>99
90
1055
751
1055
646
501
B
C
C
C
A
A
1
1
1
0
1
2
PS–C
PS–D
24
30
48.6
21
79.5
a
Pseudomonas cepacia lipase immobilized on modified ceramic particles (PS–C), Pseudomonas cepacia lipase immobilized on diatomite (PS–D),
Pseudomonas cepacia (PS) from (Amano Pharmaceutical company, Japan), Candida rugosa lipase (AYS) Candida rugosa lipase (CRL) from Sigma.
A = vinyl acetate, B = vinyl chloroacetate, C = isopropenyl acetate.
Isolated yields.
Determined by chiral HPLC (chiral column AS–H; Diacel) employing hexane–isopropanol (90:10) as mobile phase at 0.5 mL/min and monitored
by UV (254 nm).
b
c
d
Table 2. Effect of solvents on the transesterification of methyl 3-hydroxy-5-phenylpentanoate (5) and (6E)-ethyl 5-hydroxy-3-oxo-7-phenylhept-6-
a
enoate (10) using lipase PS–C
b
Entry
Ester
Solvent
Log P
Acylating agent
Time (h)
Alcohol
Acetate
E
c
d
c
d
Yield (%)
Ee (%)
Yield (%)
Ee (%)
1
2
3
4
5
6
7
8
9
5
Hexane
3.5
1.9
NA
2.5
0.85
1.9
3.5
3.5
1.9
A
A
A
A
A
B
B
C
C
20
18
24
48
48
20
30
28
34
45
46
31
41
44
42
40
42
40
>99
>99
59.2
>96
>99
96
94.4
>99
94
45
46
>99
>99
>99
>99
>99
>99
>99
>99
98.4
1055
1055
358
1055
1055
751
646
1055
356
5
Diisopropyl ether
t-Butyl methyl ether
Toluene
Diethyl ether
Diisopropyl ether
Hexane
5
5
38
44
40
39
43
40
5
10
10
10
10
Hexane
Diisopropyl ether
a
b
c
Pseudomonas cepacia lipase immobilized on modified ceramic particles (PS–C) (Amano Pharmaceutical company).
A = vinyl acetate, B = vinyl chloroacetate, C = isopropenyl acetate.
Isolated yields.
Determined by chiral HPLC (chiral column AS–H; Diacel) employing hexane–isopropanol (90:10) as mobile phase at 0.5 mL/min and monitored
by UV (254 nm).
d

A. Kamal et al. / Tetrahedron Letters 47 (2006) 8657–8660
8659
O
O
OH O
O
O
(
i)
(ii)
OMe
Br
OMe
+
OMe
8
5%
80%
2
3
4
5
OH
O
OAc O
OH
O
(
iii)
OMe
OMe
OMe
+
(S
)-5
5
(R
)-5
(v)
8
5%
(iv) 90%,
(
v) 85%
OH
O
O
OH
O
O
t
t
O -Bu
O -Bu
(S
)-6
vi)
(
R
)-6
vi)
(
(
O
O
O
O
O
O
(
R
)-7
(S)-7
(
vii)
(vii)
76% for 2 steps
76% for 2 steps
O
O
O
O
OMe
OMe
(
R
)-1a
(S)-1b
Scheme 1. Reagents and conditions: (i) NaH, n-BuLi, THF, 0 °C; (ii) NaBH
4
, MeOH, 0 °C–rt; (iii) Lipase PS–C, vinyl acetate (6 equiv), diisopropyl
t
ether; (iv) K
2
CO
3
, MeOH; (v) MeCO
2
Bu , LDA (3 equiv), THF, ꢀ78 °C; (vi) TFA, CH Cl , 10 h; (vii) K CO , acetone, (MeO) SO
2
2
2
3
2
2
.
ployed, diisopropyl ether led to good results compared
with hexane. The acetate obtained after enzymatic reso-
lution with vinyl acetate and isopropenyl acetate could
not be hydrolyzed. Therefore, vinyl chloroacetate was
used as the acylating agent in this enzymatic resolution.
Chloroester (R)-11 obtained after enzymatic resolution
was readily hydrolyzed to d-hydroxy b-ketoester (R)-
b-ketoester (R)-10 was lactonized using potassium car-
bonate in methanol and the solvent was evaporated.
The residue was dissolved in acetone and dimethylsul-
fate and stirred for 10 h at room temperature to afford
(R)-(+)-kavain 1c as a white crystalline solid following
purification by column chromatography (Scheme 2).
The structure elucidation of (R)-kavain 1c was carried
1
1
0 using 25% aq ammonia in methanol. The d-hydroxy
out by spectral and physical methods ( H NMR, melting
OH
O
O
O
O
O
(
i)
+
OEt
OEt
80%
8
9
10
O
Cl
OH
O
O
OH
O
O
O
R
O
O
(
ii)
+
OEt
OEt
OEt
(S)-10
(
)-11
iii)
10
(
O
O
OH
O
O
(
iv)
OMe
OEt
8
0%
for 2 steps
(R
)-1c
(R)-10
Scheme 2. Reagents and conditions: (i) NaH, n-BuLi, THF, 0 °C; (ii) lipase, vinyl chloroacetate (10 equiv), diisopropyl ether, 20 h; (iii) aq NH
25%), MeOH; (iv) (a) K CO , MeOH, rt., 3 h; (b) acetone, (MeO) SO , rt, 10 h.
3
(
2
3
2
2

8
660
A. Kamal et al. / Tetrahedron Letters 47 (2006) 8657–8660
(c) Klohs, M. W.; Keller, F.; Williams, R. E. J. Org. Chem.
point) and also by comparison of the optical rotation
values of previously reported results with those of
the natural product.
8
,7
1959, 24, 1829; (d) Izawa, T.; Mukaiyama, T. Chem. Lett.
1975, 161; (e) Israili, Z. H.; Smissman, E. E. J. Org. Chem.
1976, 41, 4070; (f) Dziadulewicz, E.; Giles, M.; Moss, W.
O.; Gallagher, T.; Harman, M.; Hursthouse, M. B. J.
Chem. Soc., Perkin Trans. 1 1989, 1793; (g) Spino, C.;
Mayes, N.; Desfoss e´ s, H.; Sotheeswaran, S. Tetrahedron
Lett. 1996, 37, 6503; (h) Pierres, C.; George, P.; Hijfte, L.
V.; Ducep, J.-B.; Hibert, M.; Mann, A. Tetrahedron Lett.
In conclusion, we have developed a simple and efficient
approach for the enantiopure preparation of both forms
of dihydrokavain and (R)-(+)-kavain employing a lipase
mediated resolution process.
2
2
003, 44, 3645; (i) Du, H.; Zhao, D.; Ding, K. Chem. Eur. J.
004, 10, 5964; (j) Smith, T. E.; Djang, M.; Velander, A. J.;
Acknowledgements
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We are thankful to the Department of Science and Tech-
nology, New Delhi, for the financial assistance of the
Grants-in-Aid project under SERC (No. SR/S1/OC-
4
. (a) Kamal, A.; Khanna, G. B. R. Tetrahedron: Asymmetry
001, 12, 405; (b) Kamal, A.; Khanna, G. B. R.; Ramu, R.
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Lett. 2003, 44, 4783; (d) Kamal, A.; Khanna, G. B. R.;
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New Delhi, for the award of research fellowships.
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