New Pyridone Approach: Total Synthesis of Mappicine Ketone (Nothapodytine B)

Article abstract of DOI:10.1021/jo0003448

A novel synthesis of mappicine ketone, which possesses strong selective activity against the herpes viruses HSV-1 and HSV-2, including those Acyclovir-resistant, and human cytomegalovirus (HCMV) has been efficiently accomplished. The synthesis highlights a new pyridone approach that effectively combines a double, intramolecular Michael addition in a conjugated ester-conjugated amide with oxidation-decarboxylation of the resulting piperidone.

Full text of DOI:10.1021/jo0003448

5212
J . Org. Chem. 2000, 65, 5212-5215
New P yr id on e Ap p r oa ch : Tota l Syn th esis of Ma p p icin e Keton e
(Noth a p od ytin e B)†
Khalid Mekouar, Yves Ge´nisson,‡ Stefanie Leue, and Andrew E. Greene*
Chimie Recherche (LEDSS), Universite´ J oseph Fourier de Grenoble, 38041 Grenoble Cedex, France
Andrew.Greene@ujf-grenoble.fr
Received March 10, 2000
A novel synthesis of mappicine ketone, which possesses strong selective activity against the herpes
viruses HSV-1 and HSV-2, including those Acyclovir-resistant, and human cytomegalovirus (HCMV)
has been efficiently accomplished. The synthesis highlights a new pyridone approach that effectively
combines a double, intramolecular Michael addition in a conjugated ester-conjugated amide with
oxidation-decarboxylation of the resulting piperidone.
Sch em e 1
Mappicine ketone (or nothapodytine B, 1) has been
isolated in low yield from Nothapodytes foetida1 and
shown to possess strong, selective activity against the
herpes viruses HSV-1 and HSV-2, including those
Acyclovir-resistant, and human cytomegalovirus
(HCMV).2 While degradation of natural camptothecin (2)
provides an alternative means of securing mappicine
ketone,3 the cost and the analogue limitations inherent
in such an approach combine to make total synthesis
more attractive.4 In this paper, we report a conceptually
new and efficient approach to this important natural
alkaloid.
visioned for accessing the indolizino quinoline ring
system directly from an appropriate 2,3-disubstituted
quinoline. The Meth-Cohn quinolinecarboxaldehyde 3,
easily prepared and available commercially,5 appeared
to be the ideal starting material for this endeavor. As
will be seen, the success of this synthetic approach
ultimately proved to be critically dependent on the nature
of the X group.
In our initial effort, the Meth-Cohn quinolinecarbox-
aldehyde 3 was converted in good yield into amine 4c
via the known6 dibromide 4a and the azide 4b (Scheme
2). Acylation of this amine with (E)-2-methyl-2-hexenoyl
chloride to give 5a was followed by Stille coupling with
methyl (E)-3-(tributylstannanyl)acrylate7 to provide the
desired 2,3-disubstituted quinoline 5b. To our satisfac-
tion, this material underwent efficient double Michael
The approach, shown retrosynthetically in Scheme 1,
was based on the premise that an efficient piperidone to
pyridone transformation with concomitant or subsequent
removal of the EWG could be accomplished following an
intramolecular double Michael addition, which was en-
* To whom correspondence should be addressed. Telephone: (33)
4-76-51-46-86. FAX: (33) 4-76-51-44-94.
† This paper is dedicated to Professor Andre´ Rassat on the occasion
of his retirement.
‡ Present address: Universite´ de Toulouse 3, 118 Route de Nar-
bonne, 31062 Toulouse Cedex, France.
(1) Wu, T.-S.; Chan, Y.-Y.; Leu, Y.-L.; Chern, C.-Y.; Chen, C.-F.
Phytochemistry 1996, 42, 907-908. The corresponding alcohol, map-
picine, has been found in Mapia foetida Miers (now Nothapodytes
foetida). See: Govindachari, T. R.; Ravindranath, K. R.; Viswanathan,
N. J . Chem. Soc., Perkin Trans. 1 1974, 1215-1217. Reference 3c.
(2) Pendrak, I.; Barney, S.; Wittrock, R.; Lambert, D. M.; Kingsbury,
W. D. J . Org. Chem. 1994, 59, 2623-2625. Pendrak, I.; Wittrock, R.;
Kingsbury, W. D. J . Org. Chem. 1995, 60, 2912-2615.
(3) (a) Kingsbury, W. D. Tetrahedron Lett. 1988, 29, 6847-6850.
(b) Fortunak, J . M. D.; Mastrocola, A. R.; Mellinger, M.; Wood, J . L.
Tetrahedron Lett. 1994, 35, 5763-5764. (c) Das, B.; Madhusudhan,
P.; Kashinatham, A. Bioorg. Med. Chem. Lett. 1998, 8, 1403-1406.
(4) For total syntheses of mappicine ketone, see: (a) Kametani, T.;
Takeda, H.; Nemoto, H.; Fukumoto, K. Heterocycles 1975, 3, 167-170.
Kametani, T.; Takeda, H.; Nemoto, H.; Fukumoto, K. J . Chem. Soc.,
Perkin Trans. 1 1975, 1825-1828. (b) Comins, D. L.; Saha, J . K. J .
Org. Chem. 1996, 61, 9623-9624. (c) J osien, H.; Curran, D. P.
Tetrahedron 1997, 53, 8881-8886. (d) Boger, D. L.; Hong, J . J . Am.
Chem. Soc. 1998, 120, 1218-1222. (e) Yadav, J . S.; Sarkar, S.;
Chandrasekhar, S. Tetrahedron 1999, 55, 5449-5456.
(5) Meth-Cohn, O.; Narine, B.; Tarnowski, B. J . Chem. Soc., Perkin
Trans. 1 1981, 1520-1530. This aldehyde is also available from the
Aldrich Chemical Co.
(6) (a) Comins, D. L.; Baevsky, M. F.; Hong, H. J . Am. Chem. Soc.
1992, 114, 10971-10972. See also: Lyle, R. E.; Portlock, D. E.; Kane,
M. J .; Bristol, J . A. J . Org. Chem. 1972, 37, 3967-3968. (b) The alcohol
precursor was obtained as previously described: Srivastava, R. P.;
Seth, M.; Bhaduri, A. P.; Bhatnagar, S.; Guru, P. Y. Indian J . Chem.,
Sect. B 1989, 28, 562-573. Narasimhan, N. S.; Sunder, N. M.;
Ammanamanchi, R.; Bonde, B. D. J . Am. Chem. Soc. 1990, 112, 4431-
4435. Ciufolini, M. A.; Roschangar, F. Tetrahedron 1997, 53, 11049-
11060.
(7) Go´mez, A. M.; Lo´pez, J . C.; Fraser-Reid, B. J . Chem. Soc., Perkin
Trans.
1 1994, 1689-1695. See also: Zhang, H. X.; Guibe´, F.;
Balavoine, G. J . Org. Chem. 1990, 55, 1857-1867. For a review of the
Stille reaction, see: Farina, V.; Krishnamurthy, V.; Scott, W. J . Org.
React. 1997, 50, 1-652.
10.1021/jo0003448 CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/21/2000

Total Synthesis of Mappicine Ketone
J . Org. Chem., Vol. 65, No. 17, 2000 5213
Sch em e 2
Sch em e 3
addition in the presence of tert-butyldimethylsilyl triflate8
to give the desired indolizino quinoline derivative 6 as a
mixture of epimers.9 On exposure to dichlorodicyano-
benzoquinone (DDQ) in refluxing benzene, this derivative
suffered dehydrogenation to afford pyridone 7a , albeit in
poor yield, which in hot hydrobromic acid10 was cleanly
converted into deoxo mappicine ketone 7b. Unfortu-
nately, however, no procedure could be found, despite
considerable effort, for effecting the requisite side-chain
oxidation. For this approach to be successful, it appeared
that a γ oxygen substituent, or latent oxygen substituent,
would have to be present prior to cyclization (i.e., in the
acylating derivative).
of triethylamine in dichloromethane, clean cyclization
ensued to produce the desired tetracycle 11a as a mixture
of epimers in 84% yield. Carefully controlled ozonolysis
of 11a then unveiled the keto function to provide 11b,
but now DDQ entirely failed to effect oxidation to the
corresponding pyridone.
It was soon discovered, however, that 10% palladium
on carbon in refluxing p-cymene12 was capable of deliver-
ing the corresponding pyridone in a remarkable 79%
purified yield (11b f 12, eq 2).13 Even better, though, the
Thus, the keto, acetal, and silyl ether derivatives 8a -c
were prepared as above; to our dismay, however, none
of these derivatives could be coaxed into cyclizing (eq 1).
corresponding acid under the same conditions engendered
directly mappicine ketone in 60% yield after purification!14
(Scheme 3). This was particularly gratifying since both
(11) For the efficient preparation of the corresponding ester, see:
Negishi, E.; Okukado, N.; King, A. O.; Van Horn, D. E.; Spiegel, B. I.
J . Am. Chem. Soc. 1978, 100, 2254-2256. The acid reacted also with
azide 4b in the presence of triphenylphosphine to provide more directly
the same amide, but in lower yield (60%) than achieved in the two-
step conversion (82%). For this synthetic method, see: Garcia, J .; Urpi,
F.; Vilarrasa, J . Tetrahedron Lett. 1984, 25, 4841-4844.
(12) These conditions have previously been used to effect the
conversion of a terpenoid enol lactone into the corresponding R-pyrone.
See: Rosenthal, D.; Grabowich, P.; Sabo, E. F.; Fried, J . J . Am. Chem.
Soc. 1963, 85, 3971-3979.
(13) That the presence of the keto function was not critical in this
transformation was demonstrated by the transformation of i to ii. (For
comparison, DDQ provided ii in only 20% yield.)
In the belief that the additional oxygen substituents
might be affording new coordination sites and in this way
interfering with the desired course of the reaction, it was
concluded that olefin 10b could be a worthwhile substrate
to examine (Scheme 3). This substrate could readily be
secured from amine 4c by acylation with (E,E)-4-ethyl-
2-methyl-2,4-heptadienoic acid11 to afford amide 10a ,
followed by Stille coupling. Pleasingly, on treatment of
10b with tert-butyldimethylsilyl triflate in the presence
(8) See: Ihara, M.; Kirihara, T.; Kawaguchi, A.; Tsuruta, M.;
Fukumoto, K.; Kametani, T. J . Chem. Soc., Perkin Trans. 1 1987,
1719-1726. A Diels-Alder reaction of the silyl imino ether is also
possible.
(9) In
a closely related model system, it was found that a p-
tolylsulfonyl group could not be used in place of the methoxycarbonyl
in this cyclization.
(10) Shen, W.; Coburn, C. A.; Bornmann, W. G.; Danishefsky, S. J .
J . Org. Chem. 1993, 58, 611-617.
(14) The mixture of minor stereoisomers formed in the cyclization
of ester 10b was also converted, in the same manner and with an
identical overall yield, into mappicine ketone.

5214 J . Org. Chem., Vol. 65, No. 17, 2000
Mekouar et al.
5.53 (t, J ) 7.2 Hz, 1 H), 2.26-2.06 (m, 4 H), 1.97 (d, J ) 1.6
Hz, 3 H), 1.01 (t, J ) 7.2 Hz, 3 H), 0.96 (t, J ) 7.8 Hz, 3 H).
ester 12 and the corresponding acid resisted transforma-
tion into mappicine ketone under a variety of conditions,
including those used above. The synthetic mappicine
ketone so obtained was identical (mp, mmp, MS, IR,
NMR) with a sample derived3c from natural camptoth-
ecin.
To a stirred suspension of 1.08 g (4.56 mmol) of amine (4c)
and 90 mg (0.74 mmol) of DMAP in 22 mL of dichloromethane
at 5 °C was added 1.04 g (5.04 mmol) of dicyclohexylcarbodi-
imide (DCC), followed by a solution of 850 mg (5.06 mmol) of
the above acid in 6 mL of dichloromethane. The reaction
mixture was then stirred at 20 °C for 60 h, after which time
20 mL of ether was added and the resulting precipitate was
removed by filtration through Celite. The filtrate was evapo-
rated under reduced pressure, and the crude product was
purified by dry column silica gel chromatography with 4%
ether in dichloromethane to provide 1.57 g (89%) of amide
10a : IR (film) 3363, 1656 cm-1; 1H NMR (CDCl3, 200 MHz) δ
8.18 (s, 1 H), 7.99 (d, J ) 8.6 Hz, 1 H), 7.80 (d, J ) 7.8 Hz, 1
H), 7.69 (ddd, J ) 8.4, 7.0, 1.7 Hz, 1 H), 7.54 (ddd, J ) 8.0,
7.0, 1.4 Hz, 1 H), 6.78 (br s, 1 H), 6.49 (br s, 1 H), 5.36 (t, J )
7.6 Hz, 1 H), 4.68 (2 s, 2 H), 2.14 (q, J ) 7.6 Hz, 4 H), 1.99 (d,
J ) 1.7 Hz, 3 H), 0.98 (t, J ) 7.6 Hz, 3 H), 0.93 (t, J ) 7.8 Hz,
3 H); 13C NMR (CDCl3, 50.3 MHz) δ 169.7, 147.5, 143.1, 138.1,
137.9, 136.9, 134.3, 131.5, 130.3, 129.0, 128.1, 127.7, 127.3,
127.3, 43.4, 23.4, 21.1, 14.2, 14.1, 13.4.
In summary, a novel synthesis of mappicine ketone
from the readily available amino quinoline 4c has been
accomplished in six steps and 20% overall yield. The
synthesis of this biologically important substance high-
lights a new pyridone approach that effectively combines
a double, intramolecular Michael addition in a conjugated
ester-conjugated amide8 with oxidation-decarboxylation
of the resulting piperidone. Application of this approach15
for the preparation of related alkaloids is currently under
study.
Exp er im en ta l Section
The reaction mixture was generally poured into water, and
the separated aqueous phase was then thoroughly extracted
with the specified solvent. After being washed with 10%
aqueous HCl and/or NaHCO3 (if required), water, and satu-
rated aqueous NaCl, the combined organic phases were dried
over anhydrous Na2SO4 or MgSO4 and then filtered and
concentrated under reduced pressure on a Bu¨chi Rotovapor
to yield the crude reaction product. Dioxane and ether were
distilled from sodium-benzophenone, and dichloromethane,
dimethylformamide, benzene, and triethylamine were distilled
from calcium hydride.
3-(Azid om eth yl)-2-br om oqu in olin e (4b). To a stirred
solution of 3.69 g (12.3 mmol) of 2-bromo-3-bromomethylquino-
line (4a )6a in 65 mL of dimethylformamide under argon at 20
°C was added 4.0 g (62 mmol) of sodium azide. After being
stirred for 17 h, the crude product was isolated with dichloro-
methane in the usual way and purified by dry column silica
gel chromatography with 5% ethyl acetate in cyclohexane to
afford 2.63 g (82%) of azide 4b: mp 54-56 °C; IR (Nujol) 1706
cm-1; 1H NMR (CDCl3, 200 MHz) δ 8.06 (s, 1 H), 7.99 (dd, J )
8.2, 1.4 Hz, 1 H), 7.78 (dd, J ) 7.9, 1.4 Hz, 1 H), 7.68 (ddd, J
) 8.2, 7.0, 1.4 Hz, 1 H), 7.55 (ddd, J ) 7.9, 7.0, 1.4 Hz, 1 H),
4.60 (s, 2 H); 13C NMR (CDCl3, 50.3 MHz) δ 147.7, 142.2, 136.8,
130.7, 129.4, 128.3, 127.6, 127.5, 127.0, 53.7. Anal. Calcd for
Anal. Calcd for C20H23BrN2O: Mr, 386.0994. Found: Mr
(mass spectrum, EI), 386.0998.
Meth yl (E)-3-(3-(((E,E)-4-Eth yl-2-m eth yl-2,4-h ep ta d ien -
a m id o)-m eth yl)qu in olin -2-yl)a cr yla te (10b). A mixture of
1.47 g (3.80 mmol) of amide 10a and 120 mg (0.13 mmol) of
tris(dibenzylideneacetone)dipalladium in 59 mL of dry dioxane
under argon at 20 °C was stirred for 15 min (with brief periods
of sonication for homogeneity) and then treated with 162 mg
(0.53 mmol) of triphenylarsine. After being stirred for 30 min
(again with brief periods of sonication), 2.28 g (6.08 mmol) of
(E)-methyl 3-(tributylstannyl)acrylate in 10 mL of dioxane was
added, followed by a few crystals of BHT, and the resulting
reaction mixture was heated at 80 °C for 7 h. After being
permitted to cool to ambient temperature, the mixture was
treated with a few drops of aqueous potassium fluoride (2:1),
stirred for 10 min, and then processed with dichloromethane
in the usual manner to give the crude product. Purification of
this material by dry silica gel chromatography with ether in
dichloromethane gave 1.10 g (74%) of ester 10b : mp 119-
121 °C; IR (film) 3371, 1716, 1656 cm-1; 1H NMR (CDCl3, 200
MHz) δ 8.12 (s, 1 H), 8.08-7.96 (m, 1 H), 7.77 (d, J ) 7.8 Hz,
1 H), 7.69 (t, J ) 7.2 Hz, 1 H), 7.64 (ABq, δa ) 8.03, δb ) 7.25,
J ab) 15.2 Hz, 2 H), 7.51 (t, J ) 7.2 Hz, 1 H), 6.74 (br s, 1 H),
6.13 (br s, 1 H), 5.36 (t, J ) 7.6 Hz, 1 H), 4.79 (2 s, 2 H), 3.83
(s, 3 H), 2.19-2.06 (m, 4 H), 1.98 (s, 3 H), 1.02 (t, J ) 7.6 Hz,
3 H), 0.92 (t, J ) 7.9 Hz, 3 H); 13C NMR (CDCl3, 50.3 MHz) δ
169.8, 167.0, 151.1, 147.3, 139.1, 137.6, 136.9, 136.3, 134.3,
130.2, 130.0, 129.5, 129.2, 128.1, 127.4, 127.3, 125.0, 51.9, 41.0,
23.4, 21.2, 14.2, 14.1, 13.4. Anal. Calcd for C24H28N2O3: C,
73.44; H, 7.19; N, 7.14. Found: C, 73.54; H, 7.39; N, 7.16.
C
10H7BrN4: C, 45.65; H, 2.68; N, 21.30; Mr, 261.9854. Found:
C, 45.75; H, 2.70; N, 20.96; Mr (mass spectrum, EI), 261.9860.
3-(Am in om eth yl)-2-br om oqu in olin e (4c). A mixture of
1.02 g (3.88 mmol) of azide 4b and 30 mg (0.13 mmol) of
platinum oxide in 110 mL of 95% ethanol under hydrogen was
stirred for 2 h at 20 °C. The hydrogen was then replaced with
argon, and the mixture was filtered through Celite and the
filtrate concentrated to provide 863 mg (94%) of amine 4c: IR
Meth yl 7-(1-Eth yl-1-bu ten yl)-8-m eth yl-5b,6,7,8-tetr a h y-
d r o-11H -in d olizin o[1,2-b]q u in olin -9-on e-6-ca r b oxyla t e
(11a ). A stirred solution of 340 mg (0.87 mmol) of ester 10b
and 600 µL (436 mg, 4.30 mmol) of triethylamine in 9 mL of
dichloromethane at 10 °C under argon was treated with 590
µL (679 mg, 2.57 mmol) of tert-butyldimethylsilyl trifluoro-
methanesulfonate. After being stirred at 10 f 20 °C for 3.5 h,
the reaction mixture was processed with dichloromethane in
the usual way and the crude product was purified by dry
column silica gel chromatography with 4-10% ether in di-
chloromethane to afford 240 mg of a major isomer and then
45 mg of a mixture of minor isomers (84% combined yield).
1
(KBr) 3338, 1614 cm-1; H NMR (CDCl3, 200 MHz) δ 8.11 (s,
1 H), 7.99 (d, J ) 8.2 Hz, 1 H), 7.78 (dd, J ) 7.9, 1.4 Hz, 1 H),
7.66 (ddd, J ) 8.2, 7.0, 1.4 Hz, 1 H), 7.53 (ddd, J ) 7.9, 7.0,
1.4 Hz, 1 H), 4.04 (s, 2 H); 13C NMR (CDCl3, 50.3 MHz) δ 147.4,
143.5, 136.2, 135.6, 129.9, 128.2, 127.6, 127.4, 127.2, 45.8.
Anal. Calcd for C10H9BrN2: Mr, 235.9949. Found: Mr (mass
spectrum, EI), 235.9954.
(E,E)-N-(2-Br om oqu in olin -3-ylm eth yl)-4-eth yl-2-m eth -
yl-2,4-h ep t a d ien a m id e (10a ). A stirred solution of 1.58 g
(8.67 mmol) of methyl (E,E)-4-ethyl-2-methyl-2,4-heptadi-
enoate11 in 17 mL of methanol was treated with 10.8 mL (10.8
mmol) of 1 N aqueous sodium hydroxide and then refluxed
for 30 min. After being allowed to cool to ambient temperature,
the solution was processed in the usual way to afford 1.20 g
1
The major isomer: IR (film) 3061, 1739, 1649 cm-1; H NMR
(CDCl3, 300 MHz) δ 8.05 (s, 1 H), 7.98 (d, J ) 8.5 Hz, 1 H),
7.79 (d, J ) 8.0 Hz, 1 H), 7.66 (ddd, J ) 8.5, 6.9, 1.5 Hz, 1 H),
7.52 (ddd, J ) 8.1, 7.0, 1.3 Hz, 1 H), 5.22-5.08 (m, 2 H), 4.93
(ABq, δa ) 5.12, δb ) 4.73, J ab) 16.4 Hz, 2 H), 3.88 (s, 3 H),
3.16-2.76 (m, 3 H), 2.10-1.73 (m, 4 H), 1.10 (d, J ) 7.2 Hz, 3
H), 0.93 (t, J ) 7.0 Hz, 3 H), 0.90 (t, J ) 7.6 Hz, 3 H); 13C
NMR (CDCl3, 50.3 MHz) δ 173.4, 172.7, 160.5, 149.0, 138.0,
130.7, 130.2, 129.5, 129.3, 127.8, 127.7, 127.6, 126.7, 63.0, 51.9,
49.2, 48.4, 48.1, 38.5, 23.5, 21.0, 14.4, 13.5, 13.5; mass
(82%) of the expected acid: IR (film) 3249, 1678, 1627 cm-1
;
1H NMR (CDCl3, 200 MHz) δ 10.4 (br s, 1 H), 7.20 (br s, 1 H),
(15) Mekouar, K.; Ge´nisson, Y.; Leue, S.; Greene, A. E. Fr Appl 99/
06757, 28 May 1999. See also: Toyota, M.; Komori, C.; Ihara, M.
Heterocycles 2000, 52, 591-593.

Total Synthesis of Mappicine Ketone
J . Org. Chem., Vol. 65, No. 17, 2000 5215
spectrum (CI), m/z 393 (MH+). Anal. Calcd for C24H28N2O3: C,
73.44; H, 7.19; N, 7.13. Found: C, 73.25; H, 7.42; N, 7.16.
Meth yl 8-Meth yl-7-p r op ion yl-5b,6,7,8-tetr a h yd r o-11H-
in d olizin o[1,2-b]qu in olin -9-on e-6-ca r boxyla te (11b). A
stirred solution of 100 mg (0.25 mmol) of the above olefin
(major isomer)14 in 14 mL of dichloromethane-methanol (6:
1) at -78 °C was carefully treated with ozone until complete
consumption of the starting material (TLC). After the excess
ozone was removed with a stream of oxygen, 2 mL of dimethyl
sulfide was added to the reaction mixture, and overnight the
temperature was allowed reach 20 °C. The solvents were then
removed under reduced pressure, and the residue was proc-
essed with dichloromethane in the usual way to give the crude
reaction product. Purification of this material by dry column
silica gel chromatography with 15% ether in dichloromethane
yielded 56 mg (60%) of keto ester 11b: mp 178-181 °C; IR
7.89 (d, J ) 7.9 Hz, 1 H), 7.77 (ddd, J ) 8.4, 6.8, 1.4 Hz, 1 H),
7.62 (ddd, J ) 8.1, 6.9, 1.4 Hz, 1 H), 5.25 (2 s, 2 H), 4.04 (s, 3
H), 2.86 (q, J ) 7.3 Hz, 2 H), 2.17 (s, 3 H), 1.23 (t, J ) 7.3 Hz,
3 H). Anal. Calcd for C21H18N2O4: Mr, 362.1267. Found: Mr
(mass spectrum, EI), 362.1282.
8-Meth yl-7-p r op ion yl-11H-in d olizin o[1,2-b]qu in olin -9-
on e (Ma p p icin e Keton e) (1). A solution of 100 mg (0.27
mmol) of keto ester 11b in 4 mL of dichloromethane and 0.9
mL of methanol was treated with 0.47 mL (0.94 mmol) of 2 N
sodium hydroxide. After being stirred for 65 h at 20 °C, the
reaction mixture was diluted with 8 mL of water, acidified to
pH 2-2.5 with concentrated hydrochloric acid, and then
processed with dichloromethane in the usual way. The result-
ing crude acid was heated at reflux in 4 mL of cymene in the
presence of 75 mg of 10% Pd-C with stirring under argon for
1.5 h. After being allowed to cool to ambient temperature, the
reaction mixture was subjected directly to dry silica gel
chromatography with 0-2% methanol in dichloromethane to
give essentially pure 1, which on trituration with cold metha-
nol provided 50 mg (60%) of pure mappicine ketone (1):14 mp
236-237 °C (lit. 237-238 °C,4a 230-231 °C4d); IR (KBr) 3094,
1
(film) 1730, 1657 cm-1; H NMR (CDCl3, 200 MHz) δ 8.04 (s,
1 H), 7.96 (d, J ) 8.2 Hz, 1 H), 7.79 (dd, J ) 8.1, 1.4 Hz, 1 H),
7.66 (ddd, J ) 8.4, 6.8, 1.4 Hz, 1 H), 7.52 (ddd, J ) 8.1, 6.8 1.4
Hz, 1 H), 5.33-5.08 (m, 2 H), 4.93 (ABq, δa ) 5.15, δb ) 4.72,
J ab) 15.9 Hz, 2 H), 3.90 (s, 3 H), 3.60-3.44 (m, 1 H), 3.10-
2.92 (m, 1 H), 2.47 (dq, J ) 7.2, 1.4 Hz, 2 H), 1.16 (d, J ) 7.2
Hz, 3 H), 1.01 (t, J ) 7.2 Hz, 3 H);13C NMR (CDCl3, 50.3 MHz)
δ 209.5, 173.1, 170.5, 160.0, 149.1, 130.2, 129.5, 129.4, 127.8,
127.6, 127.5, 126.8, 62.2, 53.5, 52.4, 48.6, 45.3, 37.1, 36.1, 13.8,
7.3; mass spectrum (CI), m/z 367 (MH+). Anal. Calcd for
1
1703, 1651, 1600 cm-1; H NMR (CDCl3, 300 MHz) δ 8.34 (s,
1 H), 8.17 (d, J ) 8.6 Hz, 1 H), 7.90 (d, J ) 7.9 Hz, 1 H), 7.79
(ddd, J ) 8.4, 6.9, 1.6 Hz, 1 H), 7.62 (ddd, J ) 8.1, 6.8, 1.2 Hz,
1 H), 7.23 (s, 1 H), 5.27 (2 s, 2 H), 2.89 (q, J ) 7.2 Hz, 2 H),
2.28 (s, 3 H), 1.22 (t, J ) 7.2 Hz, 3 H); 13C NMR (CDCl3, 75.5
MHz) δ 205.5, 161.7, 152.8, 148.8, 148.1, 143.3, 131.0, 130.4,
129.5, 128.5, 128.1, 128.0, 127.7, 127.0, 97.8, 50.2, 36.0, 13.6,
7.7; mass spectrum (CI), m/z 305 (MH+). Anal. Calcd for
C19H16N2O2: C, 74.98; H, 5.30; N, 9.20; Mr, 304.1212. Found:
C, 74.53; H, 5.23; N, 8.86 Mr (mass spectrum, EI), 304.1235.
C
21H22N2O4: C, 68.84; H, 6.05; N, 7.65. Found: C, 68.90; H,
6.10; N, 7.53.
Meth yl 8-Meth yl-7-p r op ion yl-11H-in d olizin o[1,2-b]qu i-
n olin -9-on e-6-ca r b oxyla t e (6-Met h oxyca r b on ylm a p p i-
cin e Keton e) (12). A 23-mg (0.06 mmol) sample of keto ester
11b was heated at reflux in 1.2 mL of p-cymene in the presence
of 18 mg of 10% Pd-C with stirring under argon for 3.5 h.
After being allowed to cool to ambient temperature, the
reaction mixture was subjected directly to dry silica gel
chromatography with 0-20% ether in dichloromethane to
afford 18 mg (79%) of 6-(methoxycarbonyl)mappicine ketone
Ack n ow led gm en t . We thank Prof. Y. Yalle´e and
Dr. P. Le´on for their interest in our work. Financial
support from Rhoˆne-Poulenc Rorer and the CNRS (UMR
5616) are gratefully acknowledged.
(12): IR (film) 3053, 1717, 1656, 1624, 1605 cm-1
;
1H NMR
(CDCl3, 200 MHz) δ 8.33 (s, 1 H), 8.09 (d, J ) 8.5 Hz, 1 H),
J O0003448