'One-pot' four-step synthesis of cerpegin

Article abstract of DOI:10.1016/j.tetlet.2005.03.176

Cerpegin (1) was synthesized through a 'one-pot' reaction in 71% overall yield. Lithiation of commercially available 2-methoxynicotinic acid (2) as its lithium salt using LTMP, followed by addition of acetone at low temperature and a specific acidic treatment of the intermediate 3 thus obtained, gave the 1,1-dimethyl-3,4-dioxo-1,3,4,5-tetrahydrofuro[3,4-c]pyridine (4). The latter was finally selectively alkylated using methyl iodide and caesium carbonate to afford cerpegin (1).

Full text of DOI:10.1016/j.tetlet.2005.03.176

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3811–3813
ÔOne-potÕ four-step synthesis of cerpegin
´
Jalal Lazaar, Christophe Hoarau, Florence Mongin, Francois Trecourt, Alain Godard,
*
´
Guy Queguiner and Francis Marsais
´ ´ ´
Laboratoire de Chimie Organique Fine et Heterocyclique, CNRS UMR 6014, IRCOF, Universite et INSA de Rouen,
Place E. Blondel, BP 08, 76131 Mont-Saint-Aignan Cedex, France
Received 8 March 2005; revised 26 March 2005; accepted 29 March 2005
Available online 14 April 2005
Abstract—Cerpegin (1) was synthesized through a Ôone-potÕ reaction in 71% overall yield. Lithiation of commercially available 2-
methoxynicotinic acid (2) as its lithium salt using LTMP, followed by addition of acetone at low temperature and a specific acidic
treatment of the intermediate 3 thus obtained, gave the 1,1-dimethyl-3,4-dioxo-1,3,4,5-tetrahydrofuro[3,4-c]pyridine (4). The latter
was finally selectively alkylated using methyl iodide and caesium carbonate to afford cerpegin (1).
Ó 2005 Elsevier Ltd. All rights reserved.
Ceropegia juncea Roxb. is used in traditional indian
medicine as tranquillizer, anti-inflammatory, analgesic
and antiulcer.1 Cerpegin (1) is a rare naturally occurring
pyridinone alkaloid isolated from this plant and respon-
sible for some of its pharmacological actions;2 its struc-
ture was established in 1991.1,2a
We here report a new convenient Ôone-potÕ four-step
synthesis of cerpegin, which proceeds in a good overall
yield of 71%, starting from commercially available
2-methoxynicotinic acid. The work is an extension of
our studies on the directed lithiation of unprotected
pyridinecarboxylic acids11 to the synthesis of a natural
compound.
The deprotonation of 2-methoxynicotinic acid (2) was
carried out using 3 equiv of lithium 2,2,6,6-tetrameth-
ylpiperidide (LTMP) in THF at À75 °C after in situ for-
mation of its lithium salt with 1 equiv of BuLi (Scheme
1).12 The ring deprotonation step time was optimized by
O
O
N
O
1
1
recording the H NMR spectra of samples treated with
D2O. Trapping the intermediate dilithio derivative with
acetone furnished the expected 4-substituted lithium
nicotinate 3 as the major product. To reach the expected
furo[3,4-c]pyridine structure, we had to find the ade-
quate acidic conditions, which will allow the three-step
sequence including neutralization, lactonization and
conversion to the pyridinone. In the first experiment at-
tempted, the dilithium salt 3 was treated by a mixture of
hydrochloric and acetic acids in refluxing ethanol.13
After removal of the solvent and extraction with hot
dichloromethane, the lactopyridinone 4 was isolated in
only 48% yield, due to surprising formation of the
2-chloropyridolactone 514 in 38% yield (Scheme 1). In
the same way, we noticed that the 2-bromopyridolac-
tone 615 was produced in a good yield of 76% when
hydrobromic acid was used in place of hydrochloric acid
in the above acidic treatment of dilithium salt 3.16,17 The
Our laboratory reported in 1992 the first synthesis of
cerpegin (1) in six synthetic steps and 28% overall yield.3
Three syntheses of cerpegin employing three and four
synthetic steps in moderate overall yields of 21%,4
15%5 and 34%6 have been published. Villemin and Liao
documented in 1996 a really improved method consist-
ing of a Ôone-potÕ three-step preparation of cerpegin
in 75% overall yield.7 Three other laborious and low
yielding syntheses (17%,8 27%9 and 15%10) in five and
seven synthetic steps have since been reported.
Keywords: Cerpegin; Lithiation; Pyridines; Carboxylic acid.
*
Corresponding author. Tel.: +33 (0)2 35 52 24 75; fax: +33 (0)2 35 52
29 62; e-mail: francis.marsais@insa-rouen.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.176

3812
J. Lazaar et al. / Tetrahedron Letters 46 (2005) 3811–3813
THF (15 mL) at À78 °C under argon. The mixture
OLi
1. nBuLi (1 equiv.)
LTMP (3 equiv.)
THF, -78°C
O
O
was stirred for 30 min at the same temperature before
dried acetone (3 mL) was added dropwise. After
30 min at À78 °C, the mixture was allowed to reach rt
before hydrolysis with water (0.5 mL). After removal
of the solvents under reduced pressure, EtOH (30 mL),
H2SO4 (2 mL, 96%) and glacial AcOH (3 mL) were
added to the crude material and the resulting solution
was heated at reflux for 3 h. EtOH and AcOH were then
removed under reduced pressure and the residue was
dissolved in EtOH (30 mL). Caesium carbonate (2.1 g,
6.6 mmol) and CH3I (3 mL) were added and the mixture
was stirred for 48 h at rt. After evaporation of the
solvents under reduced pressure, hot CH2Cl2 (10 mL)
was added and the resulting solution was filtered. The
organic phase was dried over Na2SO4. After concentra-
tion, the crude material was chromatographed on a sil-
ica gel column using CH2Cl2/MeOH (9:1) as eluent to
give cerpegin (1, 2.1 g, 71%) as a beige solid.18
H2SO4 / AcOH
OH
OLi
OMe
EtOH, ∆, 3h
O
2.
N
OMe
N
3
2
Cs2CO3 (2 equiv.)
CH3I (15 equiv.)
O
O
Cerpegin
EtOH, rt, 24h
N
H
O
4
O
O
O
O
N
Br
N
Cl
6
5
Scheme 1. ÔOne-potÕ four-step synthesis of 1.
halopyridolactones 5 and 6 result from surprising direct
substitution of the methoxy group by the halide.17
References and notes
1. Sivakumar, K.; Eswaramurthy, S.; Sabramanian, K.;
Natarajan, S. Acta Crystallogr. 1990, C46, 839–841.
2. (a) Adibatti, N. A.; Thirugnanasambantham, P.; Kuilo-
thungan, C.; Viswanathan, S.; Kameswean, L.; Bala-
krishna, K.; Sukumar, E. Phytochemistry 1991, 30, 2449–
2450; (b) Sukumar, E.; Gopal, R. H.; Rao, R. B.;
Viswanathan, S.; Thirugnanasambantham, P.; Vijayasek-
aran, V. Fitoterapia 1995, 66, 403–406.
3. Guillier, F.; Nivoliers, F.; Bourguignon, J.; Dupas, G.;
´
Marsais, F.; Godard, A.; Queguiner, G. Tetrahedron Lett.
1992, 33, 7355–7356.
4. Kelly, T. R.; Walsh, J. J. Org. Chem. 1992, 57, 6657–
6658.
In order to counter the formation of the halopyridolac-
tone we decided to use the non-nucleophilic strong acid
H2SO4. We observed in this case by H NMR spectro-
1
scopy monitoring the total conversion of dilithium salt
3 to the desired lactopyridone 4 a 3 h reflux period.
Faced with the difficulty to extract the lactopyridone 4
from ethanol, it was decided to simply remove the sol-
vent and acetic acid under reduced pressure, and to finish
cerpegin synthesis before purification. This was effected
by adding to the residue an excess of methyl iodide and
caesium carbonate, the latter allowing neutralization of
residual H2SO4 and catalyzing the methylation of the
nitrogen atom.7 Cerpegin (1) was then isolated after re-
moval of the solvent, extraction and purification by flash
chromatography in 71% overall yield.
5. (a) Maisuo, K.; Arase, T. Chem. Pharm. Bull. 1995, 43,
2091–2094; (b) Maisuo, K.; Arase, T. Chem. Pharm. Bull.
1994, 42, 715–717.
6. Hong, H.; Comins, D. L. J. Org. Chem. 1996, 61, 391–
392.
In conclusion, as in three of the previously described
syntheses of cerpegin, our strategy utilizes lithiation as
key step. However, unlike our first synthesis3 and that
of Kelly and Walsh,4 the method we here described
avoids masking the lithium carboxylic group since the
lithium carboxylate was directly used as a directed met-
allation group. Starting with 2-methoxypyridine and
employing as key step a Ôone-potÕ dilithiation of the pyr-
idine ring at C3 then C4 positions, the CominsÕ synthesis
stays certainly the most elegant strategy based upon
directed lithiation of pyridine but it suffers from a
modest 38% overall yield. Our present Ôone-potÕ synthe-
sis of cerpegin from commercially available 2-meth-
oxynicotinic acid is a really improved way towards
cerpegin, as efficient as the VilleminÕs Ôone-potÕ judicious
procedure, which is based upon a condensation of eth-
oxycarbonyl-a,b-insaturated-c-lactone with triazine
leading directly to cerpegin skeleton.7
7. Villemin, D.; Liao, L. Tetrahedron Lett. 1996, 37, 8733–
8734.
8. Matsuo, K.; Kobayashi, M.; Sugimoto, K.-I. Heterocycles
1997, 45, 1191–1195.
9. Tarasov, E. V.; Henckens, A.; Ceulemans, E.; Dehaen, W.
Synlett 2000, 625–626.
10. Sarkar, T. K.; Basak, S. Org. Lett. 2004, 6, 2925–
2927.
´
11. (a) Mongin, F.; Trecourt, F.; Queguiner, G. Tetrahedron
Lett. 1999, 40, 5483–5486; (b) Lazaar, J.; Rebstock, A.-S.;
´
´
Mongin, F.; Godard, A.; Trecourt, F.; Marsais, F.;
Queguiner, G. Tetrahedron 2002, 58, 6723–6728.
´
12. These conditions were successful for 2-chloronicotinic
acid; see Ref. 11.
13. After the dilithium salts 3 were hydrolyzed by adding water
(0.5 mL), THF was removed under reduced pressure. A
2 M aqueous solution of HCl (0.5 mL), AcOH (5 mL) and
EtOH (10 mL) were then added to the crude material and
the resulting solution was heated at reflux for 3 h.
1
14. Spectral data of 5: H NMR (300 MHz, CDCl3): 8.58 (s,
1H, H6), 7.34 (s, 1H, H5), 1.62 (s, 6H, 2Me); m/z (EI): 197–
Typical one-pot four-step synthesis of cerpegin 1: 2-
Methoxynicotinic acid (2, 0.5 g, 3.2 mmol) was added
to a solution of BuLi (5.2 mL, 2.5 M in hexane) and
2,2,6,6-tetramethylpiperidine (1.2 mL, 9.8 mmol) in
199 (70%), 182–184 (100%).
15. Spectral data of 6: H NMR (300 MHz, DMSO): 7.83 (d,
1
1H, H6, J = 5.3 Hz), 6.80 (d, 1H, H5, J = 5.3 Hz), 1.41 (s,
6H, 2Me); m/z (EI): 241–243 (10%), 226–228 (100%).

J. Lazaar et al. / Tetrahedron Letters 46 (2005) 3811–3813
3813
16. After the dilithium salts 3 was first hydrolyzed by adding
water (0.5 mL), THF was removed under reduced
pressure. A 33% acetic solution of HBr (10 mL) was then
added to the crude material and the resulting solution was
heated at reflux for 3 h.
17. We here described a new example of direct substitution of a
methoxy group at C2 position of pyridine by an halide. This
transformation is generally achieved directly by treating the
2-halopyridine by a halogenating agent, see: Ukita, T.;
Nakamura, Y.; Kubo, A.; Yamamoto, Y.; Moritani, Y.;
Saruta, K.; Higashijima, T.; Kotera, J.; Fujishige, K.;
Takagi, M.; Kikkawa, K.; Omori, K. Bioorg. Med. Chem.
2003, 13, 2341–2345, and references cited therein.
18. Cerpegin 1: mp 268–269 °C (lit.1 mp 268–270 °C); 1H
NMR (300 MHz, CDCl3) 7.68 (d, 1H, H6, J = 6.9 Hz);
6.24 (d, H5, J = 6.9 Hz); 3.64 (s, 3H, Me); 1.60 (s, 6H,
2Me); 1H NMR (300 MHz, DMSO) 8.19 (d, 1H, H6,
J = 6.6 Hz); 6.63 (d, 1H, H5, J = 6.6 Hz); 3.46 (s, 3H, Me);
1.52 (s, 6H, 2Me); 13C NMR (75 MHz, DMSO): 172.3,
166.7, 157.4, 148.1, 110.2, 98.7, 82.5, 37.2, 25.8. The 1H
NMR data in CDCl3 are in agreement with those
previously described.4