A three-step synthesis of cerpegin

Full text of DOI:10.1021/jo951612i

J . Org. Chem. 1996, 61, 391-392
391
A Th r ee-Step Syn th esis of Cer p egin
Sch em e 1
Hao Hong and Daniel L. Comins*
Department of Chemistry, North Carolina State University,
Raleigh, North Carolina 27695-8204
Received September 5, 1995
The pyridone natural product cerpegin (1) was isolated
from Ceropegia juncea, a plant used in traditional Indian
medicine for its tranquilizer, anti-inflammatory, analge-
sic, and antiulcer properties.1 Three syntheses of cer-
pegin have been reported, employing five to six synthetic
steps.3 Because of our interest in the directed lithiation
,2
4
of pyridines and its utility in the synthesis of natural
5
products, we have developed a concise route to cerpegin
from commercially available 2-methoxypyridine (2).
iodide at 140 °C as reported by Kelly3b to give cerpegin
1) in 90% yield. The mp and spectral data for 1 were in
agreement with reported data for naturally derived and
synthetic cerpegin.3 The overall yield of this three-step
synthesis was 34%.
(
1
Exp er im en ta l Section
1
,1-Dim eth yl-4-m eth oxy-3-h yd r oxy-1,3-d ih yd r ofu r o[3,4-
c]p yr id in e (5). Cerium chloride heptahydrate (5.0 g, 13.4
mmol) was placed in a dry 100-mL round-bottomed flask and
heated at 145-150 °C under vacuum (0.25 mmHg) for 24 h.
Lithiation of 2 at C-3 was effected using mesityllithium
as the metalating agent4 (Scheme 1). Addition of N-
formyl-N,N′,N′-trimethylethylenediamine6 (3) gave an
R-amino alkoxide in situ, which was treated with n-
butyllithium to effect a directed lithiation5 giving dian-
ion 4. The dianion 4 proved to be too basic to add to an
enolizable ketone in acceptable yield. When acetone was
added to 4, 2-methoxy-3-pyridinecarboxaldehyde was
isolated as the major product. Previous work from our
laboratories5b has demonstrated that dianions of the type
a
Under a N
room temperature and suspended in THF (35 mL). The result-
ing slurry was vigorously stirred under N overnight. Im-
mediately prior to use, the CeCl slurry was titrated with tert-
2 3
atmosphere, the dry CeCl powder was cooled to
,7
2
3
9
butyllithium until a light orange coloration was achieved.
To a solution of tert-butyllithium (2.5 M/pentane, 6 mL, 15
mmol) in 35 mL of THF at -78 °C was added 0.91 mL (5.9 mmol)
of 2-bromomesitylene. After stirring at -78 °C for 1 h, a white
heterogeneous mixture resulted. To this mixture was added
2-methoxypyridine (0.56 mL, 5.35 mmol), and stirring was
continued at -78 °C for 1 h, at -23 °C for 1 h, and at room
temperature for 1 h. The mixture was cooled to -78 °C, and
4
will add to enolizable ketones if first treated with
8
CeCl
3
.
3
Addition of 4 to a slurry of anhydrous CeCl in
THF resulted in a homogeneous solution, which on
treatment with acetone provided lactol 5 as a low-melting
solid in 46% yield. Oxidation of 5 to lactone 6 was
effected in an 83% yield using PCC. The final step of
the synthesis was carried out by heating 6 in methyl
6
N-formyl-N,N′,N′-trimethylethylenediamine (0.75 mL, 7 mmol)
was added dropwise. After stirring at -78 °C for 1 h, the
mixture was warmed to -23 °C, and n-butyllithium (2.5 M/hex-
ane, 3.2 mL, 8 mmol) was added. The mixture was stirred at
-23 °C for 2 h to give a dark solution, which was transferred
via a double-tipped needle to the CeCl
3
slurry in THF at -23
°
C. After stirring at -23 °C for 2 h, the homogeneous solution
(1) (a) Sivakumar, K.; Eswaramurthy, S.; Subramanian, K.; Nat-
arajan, S. Acta. Crystallogr. 1990, C46, 839. (b) Adibatti, N. A.;
Thirugnanasambantham, P.; Kulothungan, C.; Viswanathan, S.; Ka-
meswaran, L.; Balakrishna, K.; Sukumar, E. Phytochemistry 1991, 30,
was cooled to -78 °C, and anhydrous acetone (1.2 mL, 16 mmol)
was added in one portion. The mixture was stirred at -78 °C
for 1 h and at -23 °C for 30 min. Glacial acetic acid (0.8 mL)
was added at -23 °C, and stirring was continued for 10 min.
2
449.
(2) (a) Usman, A. S.; Narayanaswamy, V. J . Res. Indian Med. 1970,
After addition of 30 mL of saturated aqueous NaHCO
the mixture was extracted with CH Cl
(3 × 30 mL). The
combined organic layers were washed with water and brine and
then dried over MgSO . Concentration under reduced pressure
gave 2.08 g of crude product, which was purified by radial PLC
silica gel, 15-50% EtOAc/hexanes) to give 482 mg (46%) of 1,1-
dimethyl-4-methoxy-3-hydroxy-1,3-dihydrofuro[3,4-c]pyridine (5)
as a semisolid: 1H NMR (300 MHz, CDCl
) δ 8.16 (d, 1 H, J )
.25 Hz), 6.74 (d, 1 H, J ) 5.25 Hz), 6.25 (s, 1 H), 4.36 (br s, 1
3
solution,
5
, 10. (b) Adibatti, N. A. Ph.D. Thesis, University of Madras, 1985.
2
2
(3) (a) Guiller, F.; Nivoliers, F.; Bourguignon, J .; Dupas, G.; Marsais,
F.; Godard, A.; Queguiner, G. Tetrahedron Lett. 1992, 33, 7355. (b)
Kelly, T. R.; Walsh, J . J . J . Org. Chem. 1992, 57, 6657. (c) Matsuo, K.;
Arase, T. Chem. Pharm. Bull. 1994, 42, 715.
4
(
4) (a) Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett. 1988, 29,
(
7
73. (b) Comins, D. L.; Killpack, M. O. J . Org. Chem. 1990, 55, 69. (c)
For a recent review on the directed metalation of pyridines and
π-deficient aza aromatics, see: Queguiner, G.; Marsais, F.; Sneickus,
V.; Epsztajn, J . Adv. Heterocycl. Chem. 1991, 52, 187.
3
5
1
3
(
5) (a) Comins, D. L.; Baevsky, M. F.; Hong, H. J . Am. Chem. Soc.
H), 4.02 (s, 3 H), 1.63 (s, 6 H); C NMR (75 MHz, CDCl
3
) δ 159.9,
1
992, 114, 10971. (b) Comins, D. L.; Hong, H.; Saha, J . K.; J ianhua,
148.2, 120.1, 98.1, 86.1, 53.6, 30.1, 28.1; IR (KBr) 3387, 1613,
G. J . Org. Chem. 1994, 59, 5120. (c) Comins, D. L.; Hong, H.; J ianhua,
G. Tetrahedron Lett. 1994, 35, 5331.
-1
1
591, 1453 cm ; HRMS calcd 195.0895, found 195.0899.
,1-Dim eth yl-4-m eth oxyfu r o[3,4-c]p yr id in -3(1H)-on e (6).
To a stirred solution of 5 (118 mg, 0.5 mmol) in CH Cl (6 mL)
was added PCC (118 mg, 0.55 mmol) at room temperature. After
stirring for 6 h, the mixture was diluted with CH Cl (10 mL)
1
(
(
6) Einhorn, J .; Luche, J . L. Tetrahedron Lett. 1986, 27, 1791.
7) For review of R-amino alkoxide directed lithiations, see:
2
2
a
Comins, D. L. Synlett 1992, 615.
8) Organocerium reagents are known to undergo addition to a wide
(
2
2
range of enolizable carbonyl compounds; see: (a) Imamoto, T.; Kusu-
moto, T.; Tawarayama, Y.; Sugiura, Y.; Mita, T.; Hatanaka, Y.;
Yokoyama, M. J . Org. Chem. 1984, 49, 3904. (b) Imamoto, T.;
Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya, Y. J . Am. Chem.
Soc. 1989, 111, 4392. (c) Imamoto, T. Pure Appl. Chem. 1990, 62, 747.
and washed with 5-mL portions of cold 10% aqueous HCl, water,
and brine. The aqueous layers were combined and extracted
with CH
2
Cl
2
(2 × 10 mL). The combined organic extracts were
(d) Bunnelle, W. H.; Narayanan, B. A. Org. Synth. 1990, 69, 89.
(9) Paquette, L. A.; Thompson, R. C. J . Org. Chem. 1993, 58, 4952.
0
022-3263/96/1961-0391$12.00/0 © 1996 American Chemical Society

3
92 J . Org. Chem., Vol. 61, No. 1, 1996
Notes
1
dried over MgSO
under reduced pressure was purified by radial PLC (silica gel,
4
.
The residue obtained from concentration
269 °C (lit.1b mp 268-270 °C); H NMR (300 MHz, CDCl
3
) δ 7.66
(d, 1 H, J ) 7.02 Hz), 6.22 (d, 1 H, J ) 7.02 Hz), 3.63 (s, 3 H),
1.59 (s, 6 H). These NMR data are in agreement with the
1
4
5-50% EtOAc/hexanes) to give 97 mg (83%) of 1,1-dimethyl-
-methoxyfuro[3,4-c]pyridin-3(1H)-one (6) as a white crystalline
3b
corrected spectral data.
3
b
1
solid: mp 112-113 °C (lit. mp 111-113 °C); H NMR (300
MHz, CDCl ) δ 8.39 (d, 1 H, J ) 5.15 Hz), 6.94 (d, 1 H, J ) 5.15
Hz), 4.14 (s, 3 H), 1.63 (s, 6 H); C NMR (75 MHz, CDCl
3
1
3
3
) δ
04.8, 167.9, 152.7, 109.3, 99.1, 84.0, 72.2, 54.4, 26.7; IR (KBr)
746, 1613, 1592, 1475 cm-1
Cer p egin (1). Following a literature procedure, a solution
Ack n ow led gm en t. We gratefully acknowledge the
support of this work by Glaxo Wellcome Inc. NMR and
mass spectra were obtained at NCSU instrumentation
laboratories, which were established by grants from the
North Carolina Biotechnology Center and the National
Science Foundation (Grant CHE-9121380).
2
1
.
3
b
of 6 (103 mg) in iodomethane (1 mL) was heated at 140 °C in a
sealed tube for 24 h. The resulting red mixture was diluted with
CH
2
Cl
2
, washed successively with 10% HCl and brine, dried over
MgSO
4
, and concentrated to yield 93 mg (90%) of 1 as a light
1
yellow solid, which was pure as judged by H NMR: mp 267-
J O951612I