A new chemoenzymatic Baylis-Hillman approach for the synthesis of enantiomerically enriched umbelactones

Article abstract of DOI:10.1016/j.tetlet.2007.07.139

An efficient and convenient strategy for the enantioselective synthesis of enantiomerically enriched umbelactones is described utilizing a lipase-mediated resolution protocol, Baylis-Hillman reaction and ring closing metathesis as key steps. The lipase-re

Full text of DOI:10.1016/j.tetlet.2007.07.139

Tetrahedron Letters 48 (2007) 7232–7235
A new chemoenzymatic Baylis–Hillman approach
for the synthesis of enantiomerically enriched umbelactones
Ahmed Kamal,* Tadiparthi Krishnaji and P. Venkat Reddy
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 29 March 2007; revised 2 July 2007; accepted 18 July 2007
Available online 27 July 2007
Abstract—An efficient and convenient strategy for the enantioselective synthesis of enantiomerically enriched umbelactones is
described utilizing a lipase-mediated resolution protocol, Baylis–Hillman reaction and ring closing metathesis as key steps. The
lipase-resolution is carried out using several lipases from various sources in different solvents to afford the required intermediate
8 in good yield and high enantioselectivity.
Ó 2007 Elsevier Ltd. All rights reserved.
The butenolide ring system is found in natural products
and is also featured in intermediates used for the syn-
thesis of biologically important compounds.1 Buteno-
lides have shown to exhibit a wide range of biological
activities themselves such as insecticidal, bactericidal,
fungicidal, antibiotic, anticancer, anti-inflammatory,
antiallergic and antipsoriasis, together with cyclo-oxy-
genase and phospholipase A2 inhibition.2 Different
routes to these compounds have been reported.3 (R)-
Umbelactone-1 is one example of a naturally occurring
c-(hydroxymethyl)-a,b-butenolide which has been iso-
lated from Memycelon umbelatum Brum.4 The crude
extracts of this plant have shown various biological
activities including antiviral (activity against Ranikhet
disease virus), antiamphetory and spasmolytic. Thus
various synthetic approaches for umbelactones have
been reported (Fig. 1).5
In continuation of our activity6 in the development of
chemoenzymatic syntheses for molecules of biological
interest, we describe herein a new and efficient synthesis
of both optically pure forms of umbelactones utilizing
a lipase-catalyzed resolution, a Baylis–Hillman protocol
and ring-closing metathesis (RCM) as key steps. To the
best of our knowledge, this is the first chemoenzymatic
report describing the synthesis of both forms of the
umbelactones. A retrosynthetic analysis is outlined in
Scheme 1. Enantiomerically pure (R)-(+)-1 and (S)-(ꢀ)-
1 could be synthesized from (R)-8 and (S)-8 which in turn
could be obtained by lipase-catalyzed resolution of allylic
alcohol 8, which itself, could be obtained from 3.
Accordingly, the syntheses of 1 commenced from ester 3
as a precursor, which was prepared in quantitative yield
from aldehyde 2 upon treatment with methyl acrylate
and quinuclidine using the Baylis–Hillman strategy.7
The hydroxyl group of 3 was protected as the TBS ether
using TBSCl and imidazole to give 4 in high yield. a,b-
Unsaturated ester 4 was reduced8 to the allylic alcohol 5
with DIBAL-H in CH2Cl2 at ꢀ78 °C in 95% yield,
which on subsequent tosylation with tosyl chloride and
triethylamine in CH2Cl2 (in the presence of a catalytic
amount of DMAP) gave tosyl ether 6 in 75% yield.
Next, 6 was reduced using LiAlH4 in THF to produce
7, and upon TBS deprotection using TBAF in THF,
the required intermediate 1-benzyloxy-3-methylbut-3-
en-2-ol 8 was obtained.
O
O
O
O
(R)-(+)-1
HO
HO
umbelactones
(S)-(-)-1
Figure 1.
Keywords: Baylis–Hillman; Lipase-resolution; Ring-closing metathesis.
*
Corresponding author. Tel.: +91 40 27193157; fax: +91 40
27193189; e-mail addresses: ahmedkamal@iict.res.in; ahmedkamal@
iictnet.org
Having successfully completed the synthesis of 8, our
focus was to develop a lipase-catalyzed transesterification
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.139

A. Kamal et al. / Tetrahedron Letters 48 (2007) 7232–7235
7233
OH
(S)-1
(R)-1
BnO
(S)-8
OH
O
OH
BnO
BnO
OMe
OH
8
3
BnO
(R)-8
Scheme 1. Retrosynthesis of umbelactones.
of the allylic alcohol system to obtain enantiomerically
pure acetate (R)-9 and alcohol (S)-8, which are required
for the synthesis of enantiomerically enriched umbelac-
tones (R)-1 and (S)-1 (Scheme 2). In the first series of
experiments, the efficiency of various commercially
available lipases obtained from different sources was
investigated for the transesterification of 8. Amongst
all the lipases screened, Burkholderia cepacia (PS-C)
and CAL-B gave the best conversions and high enantio-
meric excesses as shown in Table 1. It is well known that
different solvents affect the enantiotopic selectivity as
well as the reaction rate for the lipase-catalyzed kinetic
resolutions. Therefore, the affect of different solvents
was examined on the resolution of substrate 8 employ-
ing lipase PS-C. A quantitative measurement of the
solvent can be determined by the parameter P, the
partition coefficient of the solvent between octanol and
water, and the corresponding logP values for the
solvents examined are given in Table 2. The catalytic
activity was low in polar solvents having logP < 2, mod-
erate in solvents having logP between 2 and 4, and was
high in apolar solvents having logP > 4. Hydrophobic
solvents such as hexane, toluene and diisopropyl ether
gave better results compared to hydrophilic solvents
including acetone and THF. From these results, hexane
appeared to be the solvent of choice for this transesteri-
fication with respect to yields and enantiomeric excess
(Table 2). The enantiomeric excess was calculated from
the enantiomeric ratios obtained by HPLC employing a
chiral OB-H column (Daicel).
O
O
OR
OR
O
OH
a)
b)
c)
BnO
BnO
BnO
BnO
OMe
H
OR'
OMe
90%
96%
95%
4
3
2
5
R' = H
e)
88%
d)
75%
R = TBDMS
R' = Tosyl 6
OAc
OH
OR
g)
+
BnO
BnO
46% (S)-8
BnO
45%
(R)-9
N
N
Mes
Mes
h) 90%,
i) 85%
i) 85%
Cl
Cl
R = TBDMS 7
R = H 8
f)
85%
Ru
Ph
PCy3
O
O
II
O
O
+
BnO
BnO
(R)-10
(S)-10
j) 65%
j) 65%
O
O
k)
90%
k)
90%
O
O
(S)-(-)-1
(R)-(+)-1
BnO
BnO
(R)-(+)-11
(S)-(-)-11
Scheme 2. Reagents and conditions: (a) Methyl acrylate, quinuclidine, MeOH, 8 h; (b) TBDMSCl, imidazole, CH2Cl2, DMAP, 0 °C to rt, 6 h;
(c) DIBAL-H, CH2Cl2, ꢀ78 °C, 1 h; (d) TsCl, Et3N, CH2Cl2, DMAP, rt, 4 h; (e) LiAlH4, THF, 1 h; (f) TBAF, THF, 0 °C to rt, 2 h; (g) Lipase PS-C,
vinyl acetate, hexane, 6 h; (h) K2CO3, MeOH, 0 °C to rt, 1 h; (i) Acryloyl chloride, Et3N, CH2Cl2, DMAP, 0 °C to rt, 30 min; (j) II, CH2Cl2, 35 °C,
48 h; (k) TiCl4, CH2Cl2,0 °C to rt, 10 min.

7234
A. Kamal et al. / Tetrahedron Letters 48 (2007) 7232–7235
Table 1. Transesterification of 1-benzyloxy-3-methyl-but-3-en-2-ol 8 with various lipasesa in hexane
Entry
Lipase
Time
(h)
Yieldb
(%)
Alcohol
eec (%)
Yieldb
(%)
Acetate
eec (%)
Conversion
(%)
Enantiomeric
ratio E
1
2
3
4
5
6
7
8
PS-C
CAL-B
PS-D
PS
CCL
CRL
P
4
10
24
46
45
64
80
82
82
85
88
98
96
80
21
20
—
—
—
45
44
31
15
7
5
6
4
>99
>99
98
97
97
—
—
—
0.49
0.49
0.45
0.18
0.17
—
782
782
221
79.6
81.8
—
48
120
120
120
120
—
—
—
—
MML
a Pseudomonas cepacia lipase immobilized on modified ceramic particles (PS-C), Pseudomonas cepacia lipase immobilized on diatomite (PS-D),
Pseudomonas cepacia (PS) obtained form Amano pharmaceutical company Japan, lipase immobilized from Mucor meihei (MML), Pseudomonas
fluorescens lipase immobilized in Sol–Gel-AK on sintered glass (P), Candida antartica lipase immobilized in Sol–Gel-AK on sintered glass (CAL B)
from Fluka, Candida cyclindracea lipase (CCL) and Candida rugosa lipase (CRL) (Sigma).
b Isolated yields.
c Determined by HPLC (chiral column OB-H; Daicel) employing hexane:n-propanol (95:5) as the mobile phase at 0.5 mL/min and monitored by UV
(254 nm).
Table 2. Effect of different solvents on the transesterification of 1-benzyloxy-3-methyl-but-3-en-2-ol 8 by lipase PS-Ca
Entry
Solvent
LogP
Time
(h)
Alcohol
yieldb (%)
eec
(%)
Acetate
yieldb (%)
eec (%)
Conversion
(%)
Enantiomeric
ratio E
1
2
3
4
5
6
7
8
9
Hexane
Toluene
3.5
2.5
4
10
24
45
48
55
60
80
85
85
88
—
98
90
88
75
59.5
55
—
—
—
45
32
30
25
10
6
6
5
—
>99
>99
98
95
94.5
90
—
—
—
0.49
0.48
0.47
0.44
0.38
0.38
—
782
599.2
312.5
8.8
693
33
—
—
—
Diisopropyl ether
t-Butyl methyl ether
Acetonitrile
Acetone
Tetrahydrofuran
Chloroform
Dioxane
ꢀ1.9
—
36
ꢀ0.33
ꢀ0.23
0.49
2.0
240
240
240
240
240
—
—
ꢀ1.1
a Pseudomonas cepacia lipase immobilized on modified ceramic particles (PS-C) purchased from Amano Pharmaceutical Co., Japan.
b Isolated yields.
c Determined by HPLC (chiral column OB-H; Daicel) employing hexane:n-propanol (95:5) as the mobile phase at 0.5 mL/min and monitored by UV
(254 nm).
After about 50% conversion of 8, as monitored by
HPLC, the two products (S)-8 and (R)-9 were separated
by column chromatography. Alcohol (S)-8 upon esteri-
fication9 using acryloyl chloride and triethylamine in
CH2Cl2 furnished acryl ester (S)-10 in a high yield,
which upon ring-closing metathesis (RCM)10 with
Grubbs’ 2nd generation catalyst II gave a,b-unsaturated
lactone (S)-11. Finally, (S)-11, upon debenzylation11
Acknowledgements
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-
36/2003). The authors T.K. and P.V.R. are thankful to
CSIR and UGC, New Delhi, respectively, for the award
of research fellowships.
using TiCl4 in CH2Cl2, gave the required enantiomeri-
25
cally pure umbelactone (S)-(ꢀ)-1 {½aꢁD ꢀ10.5 (c 1.0,
25
CHCl3), lit.5e ½aꢁD ꢀ9.5 (c 1.0, CHCl3)} in 90% yield.
Supplementary data
In a similar manner (R)-(+)-1 was obtained by hydroly-
sis of (R)-9 using K2CO3 in MeOH followed by esterifi-
cation (85%), RCM (65%) and debenzylation (90%)
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2007.07.139.
25
25
{½aꢁD +9.81 (c 1.75, CHCl3), lit.5e ½aꢁD +9.5 (c 1.0,
CHCl3)}.
In conclusion, we have developed a simple and efficient
method for the preparation of both forms of enantiome-
rically pure umbelactones employing a lipase-mediated
resolution protocol, Baylis–Hillman reaction and ring-
closing metathesis as the key steps. This lipase-catalyzed
transesterification of 8 has been optimized with respect
to different lipases and solvents.
References and notes
1. (a) Takahashi, S.; Maeda, K.; Hirota, S.; Nakata, T. Org.
Lett. 1999, 1, 2025; (b) Chia, Y. C.; Chang, F.; Wu, Y. F.
Tetrahedron Lett. 1999, 40, 7513; (c) Siddiqui, B. S.;
Afshan, F.; Ghiasuddin, F. S.; Naqvi, S. N. H.; Tariq, R.
M. J. Chem. Soc., Perkin Trans. 1 1999, 2367; (d) Cortez,

A. Kamal et al. / Tetrahedron Letters 48 (2007) 7232–7235
7235
D. A. G.; Fernandes, J. B.; Vieria, P. C.; Silva, M. F. G. F.;
Ferreira, A. G.; Cass, Q. B.; Pirani, J. R. Phytochemistry
1998, 49, 2493; (e) Otsuka, H.; Kotani, K.; Bando, M.;
Kido, M.; Takeda, Y. Chem. Pharm. Bull. 1998, 46, 1180.
2. (a) Ducharme, Y.; Gauthier, J. Y.; Prasit, P.; Leblanc, Y.;
Wang, Z.; Leger, S.; Therien, M. PCT Int. Appl. WO 95
00,501, 1995; Chem. Abstr. 1996, 124, 55954y; (b) Lee, G.
C. M.; Garst, M. E. PCT Int. Appl. WO 91 16,055, 1991;
Chem. Abstr. 1992, 116, 59197m; (c) Brima, T. S. U.S.
Patent 4968,817, 1990; Chem. Abstr. 1991, 114, 185246y.
3. (a) Yoneda, E.; Kaneko, T.; Zhang, S.; Onitsuka, K.;
Takahashi, S. Org. Lett. 2000, 2, 441; (b) Yu, W. Y.;
Alper, H. J. Org. Chem. 1997, 62, 5684; (c) Xiao, W. J.;
Alper, H. J. Org. Chem. 1997, 62, 3422, and references
cited therein.
J. Tetrahedron 1987, 43, 2199; (c) Sato, T.; Okumura, Y.;
Itai, J.; Fujisawa, T. Chem. Lett. 1988, 17, 1537; (d)
Gibson, C. L.; Handa, S. Tetrahedron: Asymmetry 1996, 7,
1281; (e) Liu, H.; Zhang, T.; Li, Y. Chirality 2006, 18,
223; (f) Huawei, L.; Li, Y. Chin. Chem. Lett. 2005, 16,
716.
6. (a) Kamal, A.; Krishnaji, T.; Khan, M. N. A. J. Mol.
Catal. B: Enzym. 2007, 47, 1; (b) Kamal, A.; Krishnaji, T.;
Khanna, G. B. R. Tetrahedron Lett. 2006, 47, 8657.
7. (a) Hine, J.; Chen, Y. J. J. Org. Chem. 1987, 52, 2091; (b)
Varinder, K. A.; Ingo, E.; Sarah, Y. F. J. Org. Chem.
2003, 68, 692; (c) Basavaiah, D.; Rao, A. J.; Satyanara-
yana, T. Chem. Rev. 2003, 103, 811.
8. Daniewski, A. R.; Wojciechowska, W. J. Org. Chem.
1982, 47, 2993.
4. Agarwal, S. K.; Rastogi, R. P. Phytochemistry 1978, 17,
1663.
5. (a) Caine, D.; Frobese, A. S.; Ukachukwu, V. C. J. Org.
Chem. 1983, 48, 740; (b) Ortuno, R. M.; Bigorra, J.; Front,
9. Herz, W.; Juo, R. R. J. Org. Chem. 1985, 50, 618.
10. Grubbs, R. J.; Chang, S. Tetrahedron 1998, 54, 4413.
11. Hiroshi, H.; Yoshihiro, N.; Hiroshi, O.; Hiroshi, M. J.
Org. Chem. 1989, 54, 1346.