Synthesis of substituted butenolides by the ring closing metathesis of two electron deficient olefins: a general route to the natural products of paraconic acids class

Article abstract of DOI:10.1016/j.tetlet.2007.01.053

A variety of allyl acrylates possessing electron-withdrawing groups undergo RCM using the second generation Grubbs' catalyst in the presence of a Lewis acid resulting in diverse butenolides in high isolated yields. This methodology provides a general rout

Full text of DOI:10.1016/j.tetlet.2007.01.053

Tetrahedron Letters 48 (2007) 2021–2024
Synthesis of substituted butenolides by the ring closing metathesis
of two electron deficient olefins: a general route to the
natural products of paraconic acids classI
N. Selvakumar,* P. Kalyan Kumar, K. Chandra Shekar Reddy and B. Chandra Chary
Department of Discovery Chemistry, Discovery Research, Dr. Reddy’s Laboratories Ltd., Miyapur, Hyderabad 500 049, India
Received 16 October 2006; revised 2 January 2007; accepted 10 January 2007
Available online 14 January 2007
Abstract—A variety of allyl acrylates possessing electron-withdrawing groups undergo RCM using the second generation Grubbs’
catalyst in the presence of a Lewis acid resulting in diverse butenolides in high isolated yields. This methodology provides a general
route to the natural products of paraconic acids class, exemplified by a total synthesis of ( )-phaseolinic acid.
Ó 2007 Elsevier Ltd. All rights reserved.
Paraconic acids are a group of highly substituted
CO2H
CO2H
c-butyrolactones isolated from different species of moss,
lichens, fungi and cultures of Penicillium sp. (Fig. 1).1
They possess either a methyl or a methylene group at
the a-position and a carboxyl group at the b-position
of the butyrolactone ring. However, they vary structur-
ally with respect to the groups attached at the c-posi-
tion. The paraconic acids exhibit interesting biological
activities such as antitumor, antifungal, and antibacte-
rial.2 Consequently, the synthesis of paraconic acids
has attracted wide attention from synthetic chemists.3
Herein, we report our initial efforts in this area culminat-
ing in an efficient and a general route to natural prod-
ucts of this class.
O
O
O
O
5
1
CO2Et
C5H11
O
CO2Et
C5H11
O
O
O
6
7
Scheme 1. Retrosynthesis of compound 1.
accessed via ring closing metathesis (RCM) of appropriate
dienes (Scheme 1).4 Since phaseolinic acid 1 had been
prepared by methylating carboxylic acid 5,3e we planned
to obtain acid 5 from butenolide 6, which in turn would
be assembled from diene 7 using RCM as the key step.
Diene 7 would be readily accessible by the acryloylation
of the corresponding alcohol, which in turn would be
available using a Baylis–Hillman reaction.5 A literature
search revealed that a b-carboxylated c-butyrolactone
had not been prepared using the RCM reaction.
We envisioned that the b-carboxylated c-butyrolactone
skeleton in paraconic acids could conceivably be
CO2H
R
CO2H
R
O
O
O
O
1: R = C5H11, phaseolinic acid
3: R = C11H23, nephrosteranic acid
2: R = C13H27, nephromopsinic acid 4: R = C13H27, roccellaric acid
Figure 1.
In order to test the feasibility of a RCM reaction on the
electron-deficient diene 7, we turned our attention
initially to cyclising the unsubstituted diene 9 as a model
system (Scheme 2). Diene 9 was prepared by acryloyla-
tion of the known Baylis–Hillman adduct 8.5c The prep-
aration of 4,5-dialkyl butenolides has been reported
Keywords: Ring closing metathesis; Baylis–Hillman reaction.
q DRL Publication No. 516A.
*
Corresponding author. Tel.: +91 40 2304 5439; fax: +91 40 2304
5438; e-mail: selvakumarn@drreddys.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.053

2022
N. Selvakumar et al. / Tetrahedron Letters 48 (2007) 2021–2024
recently using the first generation Grubbs’ catalyst 11 of
Cl
the appropriate dienes wherein the dienes possess an al-
kyl group on one of the double bonds.6 However,
employing similar conditions for the RCM of diene 9,
with electron-withdrawing groups on the double bonds,
did not result in even a trace of cyclisation product. In
addition, attempted RCM of diene 9 using the second
generation Grubbs’ catalyst 12 also resulted in recovery
of the starting material. At this stage, prompted by some
literature reports that Lewis acids such as titanium tetra-
isopropoxide promote the RCM of many substrates,7 we
tried to perform the RCM in the presence of a Lewis
acid. To that end, employing 10 mol % of Grubbs’
second generation catalyst along with 10 mol % of
Ti(OiPr)4 in dichloromethane, RCM of diene 9 resulted
in the required cyclisation product 10 in 90% isolated
yield.8
O
HO
O
CO2Me
CO2Me
Et3N, 92%
O
9
8
CO2Me
12 (10 mol%)
Ti(OiPr)4, CH2Cl2
reflux, 90%
O
O
10
PCy3
N
N
Cl
Mes
Ph
Mes
Ru
Cl
Cl
Ph
Ru
PCy3
Cl
PCy3
12
11
Scheme 2.
Table 1. Syntheses of 5-substituted butenolides
Entry
Starting material
Butenolide product
Yield (%)
84
CO2Me
O
CO2Me
1
O
O
O
13
15
14
CO2Me
O
O
CO2Me
CO2Me
2
3
4
5
6
87
88
84
77
0
O
O
O
O
16
CO2Me
O
O
17
18
CO2Et
O
O
CO2Et
O
Ph
O
O
Ph
19
O
20
CO2Me
R
CO2Me
O
O
R
R = 4-nitrophenyl
R = 4-nitrophenyl
21
22
O
CO2Me
No RCM
O
O
23
COMe
O
COMe
7
8
78
0
O
Ph
O
O
Ph
24
O
25
O
CN
No RCM
26

N. Selvakumar et al. / Tetrahedron Letters 48 (2007) 2021–2024
2023
Having identified appropriate experimental conditions,
CO2Et
C5H11
CO2Et
CuI, DIBALH
86%
we turned our attention to substituted electron-deficient
dienes in order to generalise the RCM method (Table
1).9 Dienes 13 and 15 underwent a smooth RCM result-
ing in the corresponding alkyl substituted butenolides 14
and 16, respectively. Likewise, the cyclohexyl substi-
tuted diene 17 gave 18 in a high yield. Successful closure
was possible with aromatic substituents (entries 4 and
5), however, the double bond in the resultant buteno-
lides 20 and 22 was found to have migrated to the b,c-
position presumably due to the extended conjugation.
In order to bring further diversity at C-5, the RCM with
the furan substituted diene 23 was attempted, but no
trace of cyclisation product was found. Next, we ex-
plored the RCM reaction on dienes possessing different
electron-withdrawing groups such as ketone and nitrile
in place of the ester. Thus, keto-diene 24, gave the
required product 25 in good yield. However, all our
attempts with diene 26, possessing a nitrile group as
the electron-withdrawing group, resulted only in recov-
ery of starting material.
O
O
C5H11
O
O
6
29
Scheme 4.
the cis vicinal protons in the isomer 28, which provided
further evidence for the identity of isomers 28 and 29.11
After considerable efforts to improve the ratio of the iso-
mers in favour of the cis isomer 28, we discovered that
transfer hydrogenation with ammonium formate re-
sulted in an acceptable ratio of 4:1. The total synthesis
of phaseolinic acid was completed following the re-
ported protocol.3e Thus, cis diastereomer 28 was con-
verted to ( )-phaseolinic acid 1 by hydrolysis followed
by methylation. The spectral data of the synthetic mate-
rial were comparable to that of reported values.3a
It is interesting to note that other natural products of the
paraconic acids class could be synthesised following a
similar sequence. Thus, the total synthesis of nephroster-
anic acid 3 could be achieved from the trans alcohol
analogous to 29 obtained using dodecanal as the alde-
hyde in the Baylis–Hillman reaction instead of hexanal
(Scheme 3).12 In a similar way, using tetradecanal as
the aldehyde would pave the way for the total synthesis
of roccellaric acid 4. As the syntheses of these natural
products 3 and 4 require the trans alcohol analogous
to 29, we wished to identify a method to obtain the trans
alcohol exclusively. To that end, after considerable
attempts, we discovered that a 1,4-hydrogen addition
using DIBAL-H in toluene afforded the required trans
isomer exclusively (Scheme 4). The total syntheses of
nephrosteranic acid 3 and roccellaric acid 4 will be the
subject of future publications from our laboratory.
Having generalised the RCM reaction of the electron
deficient dienes, we turned our attention to the synthesis
of phaseolinic acid 1 (Scheme 3). The known Baylis–
Hillman adduct 27,5b obtained from ethyl acrylate and
hexanal, was acryloylated to afford diene 7, which
underwent a smooth RCM reaction leading to the cycli-
sation product 6.10 Catalytic hydrogenation of buteno-
lide 6 using Pd/C in ethyl acetate resulted in a 1:2
diastereomeric mixture of cis and trans butyrolactones
28 and 29, respectively, which was easily separated by
column chromatography. Apart from the spectral data,
1D NOE experiments revealed a strong interaction for
HO
CHO
b
a
CO2Et
In conclusion, the RCM reaction of highly electron-defi-
cient dienes has been achieved resulting in diverse bute-
nolides possessing electron-withdrawing groups at C-4.
It is important to note that dienes having two elec-
tron-deficient olefins underwent smooth RCM under
the identified experimental conditions. One such buteno-
lide product 6 served as the starting material for the
total synthesis of ( )-phaseolinic acid 1.
27
CO2Et
c
O
CO2Et
O
O
d
O
6
7
CO2Et
C5H11
CO2Et
Acknowledgements
+
O
O
C5H11
O
O
We thank Dr. Javed Iqbal and Dr. R. Rajagopalan for
their continued encouragement. We appreciate the ser-
vices extended by the Analytical Research department
of Discovery Research, Dr. Reddy’s Laboratories Ltd.
for this Letter.
29
28
4:1 ratio
CO2H
C5H11
CO2H
e
f
28
O
O
O
O
1
5
References and notes
Scheme 3. Reagents and conditions: (a) Ref. 5b; (b) acryloyl chloride,
Et3N, CH2Cl2, 0 °C to rt, 95%; (c) 12, Ti(OiPr)4, 50 °C, 87%; (d) 10%
Pd–C, H2, EtOAc, 84% (combined yield, 1:2 ratio) or 10% Pd–C,
ammonium formate, MeOH, reflux, 83% (combined yield, 4:1 ratio);
(e) 6 N HCl, dioxane, reflux, 91%; (f) NaN(TMS)2, MeI, THF,
À78 °C.
1. (a) Mahato, S. B.; Siddiqui, K. A. I.; Bhattacharya, G.;
Ghoshal, T.; Miyahara, K.; Sholichin, M.; Kawasaki, T.
J. Nat. Prod. 1987, 50, 245–247; (b) Petragnani, N.;
Ferraz, H. M. C.; Silva, G. V. J. Synthesis 1986, 157–183;
(c) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed.

2024
N. Selvakumar et al. / Tetrahedron Letters 48 (2007) 2021–2024
Engl. 1985, 24, 94–110; (d) Cavallito, C. J.; Fruehauf, D.
(0.01 M) in dry DCM followed by titanium tetraisoprop-
oxide (10 mol %) under argon. To this solution was added
dropwise a 0.01 M solution of catalyst 12 (10 mol %) in
dry DCM over 12 h at reflux using a syringe pump. The
mixture was stirred at reflux for a further 24 h. The
reaction mixture was allowed to cool and then washed
with water, brine and dried. The solvent was removed in
vacuo and the residue was purified by silica gel chroma-
tography to separate the desired cyclisation product from
the recovered starting material.
M.; Bailey, J. H. J. Am. Chem. Soc. 1948, 70, 3724–3726;
(e) Zopf, W. Liebigs Ann. Chem. 1902, 324, 39–78, and
references cited therein.
2. (a) Park, B. K.; Nakagawa, M.; Hirota, A.; Nakayama,
M. J. Antibiot. 1988, 41, 751–758; (b) Muller, K. Appl.
Microbiol. Biotechnol. 2001, 56, 9–56, and references cited
therein.
3. (a) Amador, M.; Ariza, X.; Garcia, J.; Ortiz, J. J. Org.
Chem. 2004, 69, 8172–8175; (b) Chhor, R. B.; Nosse, B.;
Sorgel, S.; Bohm, C.; Seitz, M.; Reiser, O. Chem. Eur. J.
2003, 9, 260–270; (c) Bella, M.; Margarita, R.; Orlando,
C.; Orsini, M.; Parlanti, L.; Piancatelli, G. Tetrahedron
Lett. 2000, 41, 561–565; (d) Masaki, Y.; Arasaki, h.; Itoh,
A. Tetrahedron Lett. 1999, 40, 4829–4832; (e) Drioli, S.;
Felluga, F.; Forzato, C.; Nitti, P.; Pitacco, G.; Valentin, E.
J. Org. Chem. 1998, 63, 2385–2388; (f) Zhang, Z.; Lu, X.
Tetrahedron: Asymmetry 1996, 7, 1923–1928; (g) Jacobi, P.
A.; Herradura, P. Tetrahedron Lett. 1996, 46, 8297–8300,
and references cited therein.
9. The starting dienes for entries 1–6 were prepared from the
corresponding acrylates and appropriate aldehydes using
Baylis–Hillman reactions followed by acryloylation. Fol-
lowing the same sequence, the dienes in entries 7 and 8
were prepared from methyl vinyl ketone and acrylonitrile,
respectively.
10. Selected spectral data for compound 6: (oil) 1H NMR
(CDCl3, 400 MHz): d 6.64 (d, J = 1.9 Hz, 1H), 5.21 (ddd,
J = 8.1, 3.0 and 2.2 Hz, 1H), 4.38–4.30 (m, 2H), 2.16–2.08
(m, 1H), 1.69–1.60 (m, 1H), 1.36 (t, J = 7.2 Hz, 3H), 1.45–
1.25 (m, 6H), 0.90–0.87 (m, 3H). 13C NMR (CDCl3,
50 MHz): d 171.0, 161.0, 157.7, 126.6, 82.6, 62.1, 32.4,
31.3, 24.3, 22.3, 14.0, 13.9. IR (neat): 1769, 1728, 1223,
4. For some recent reviews related to RCM reactions, see: (a)
Dieters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199–
2238;; (b) Grubbs, R. H.; Trnka, T. M. Acc. Chem. Res.
2001, 34, 18–29.
1156 cmÀ1
.
5. For some selected references related to the Baylis–Hillman
reaction, see: (a) Basavaiah, D.; Rao, A. J.; Satyanara-
yana, T. Chem. Rev. 2003, 103, 811–891; (b) Krishna, P.
R.; Manjuvani, A.; Kannan, V.; Sharma, G. V. M.
Tetrahedron Lett. 2004, 45, 1183–1185; (c) Yu, C.; Liu, B.;
Hu, L. J. Org. Chem. 2001, 66, 5413–5418, and the
references cited therein.
6. Bassetti, M.; D’Annibale, A.; Fanfoni, A.; Minissi, F. Org.
Lett. 2005, 7, 1805–1808.
7. (a) Yang, Q.; Xiao, W. J.; Yu, Z. Org. Lett. 2005, 7, 871–
874; (b) You, Z. W.; Wu, Y. Y.; Qing, F. L. Tetrahedron
Lett. 2004, 45, 9479–9481; (c) Gosh, A. K.; Liu, C. Chem.
Commun. 1999, 1743–1744.
11. The spectral data of compounds 28 and 29 were identical
to reported values. Drioli, S.; Felluga, F.; Forzato, C.;
Nitti, P.; Pitacco, G.; Valentin, E. Chem. Commun. 1996,
1289–1290.
weak
noe
strong
noe
H
O
H
O
E
E
H
H
O
C5H11
O
C5H11
29
28
E = CO2Et
8. General experimental procedure for RCM: A two-neck
flask equipped with a condenser was flame dried in vacuo
and charged successively with a solution of the diene
12. For a synthesis of nephrosteranic acid 3, see: Barros, M.
T.; Maycock, C. D.; Ventura, M. R. Org. Lett. 2003, 5,
4097–4099.