J . Org. Chem. 2001, 66, 7873-7874
7873
Sch em e 1. P la n for Syn th esis of Six-Mem ber ed
Syn th esis of P u m iliotoxin e C fr om
Molecu la r Nitr ogen a s a Nitr ogen Sou r ce
Heter ocycles
Masaya Akashi, Yoshihiro Sato, and Miwako Mori*
Graduate School of Pharmaceutical Sciences,
Hokkaido University, Sapporo 060-0812, J apan
mori@pharm.hokudai.ac.jp
Received April 20, 2001
Sch em e 2. Syn th esis of Six-Mem ber ed
Heter ocycles
Nitrogen fixation is a very attractive and useful process
in synthetic organic chemistry.1 We have already re-
ported the synthesis of indole derivatives2f using a
titanium-nitrogen complex, which was synthesized from
TiCl4 or Ti(OiPr)4, Li, and TMSCl under an atmosphere
of nitrogen.2 In this reaction, a 2-substituted indole
derivative was obtained in high yield from keto-alkyne,
which has the electron-withdrawing group on the alkyne.
If keto-alkyne I having the carbomethoxy group on the
alkyne was reacted with titanium-nitrogen complexes,
six-membered heterocycles would be formed. We report
here the synthesis of (()-pumiliotoxine C from ketoalkyne
and molecular nitrogen. Our plan for the synthesis of the
quinoline derivative is shown in Scheme 1.
When a THF solution of keto-alkyne 1a (1 equiv) was
added to a THF solution of titanium-nitrogen complexes,
prepared from Ti(OiPr)4 (1.25 equiv), Li (12.5 equiv), and
TMSCl (20 equiv) under nitrogen gas (1 atm), and the
solution was stirred at room-temperature overnight, the
desired quinoline derivative 2a was obtained in 66% yield
(Scheme 2).
Sch em e 3. Retr osyn th etic An a lysis of
P u m iliotoxin C
The result of an NOE experiment indicated that a
Z-isomer was formed due to the stability of the hydrogen
bond with carbonyl oxygen. In a similar manner, the
desired piperidine derivative 2b was obtained from keto-
alkyne 1b in 63% yield. These results are very interesting
not only because molecular nitrogen was incorporated
into the organic compounds in good yields but also
because titanium-nitrogen complexes act as an agent for
the introduction of an N-1 unit in the synthesis of
heterocycles.
On the basis of these results, we attempted to synthe-
size (()-pumiliotoxine C, which was isolated3 from skin
extracts of the Panamanian poisonous frog Dendrobates
pumilio4 as the first member of one major class of
dendrobatid alkaloids.5 Pumiliotoxin C has a cis-decahy-
droquinoline skeleton. Our retrosynthetic analysis is
shown in Scheme 3. Pumiliotoxin C would be synthesized
from quinoline derivatives 3, which should be able to be
synthesized from keto-alkyne 4 and molecular nitrogen
using our method. From commercially available 3-meth-
ylcyclohexenone 5, keto-alkyne 4 would be synthesized.
Ketalization of compound 6, which was obtained from
5,5 followed by hydroboration afforded alcohol 7. Oxida-
tion of 7 with PCC followed by treatment with CBr4 and
PPh3 gave 8. Treatment of 8 with BuLi gave lithium
(3) For reports on the syntheses of racemic pumiliotoxine C, see:
(a) Ibuka, T.; Masaki, N.; Saji, I.; Tanaka, K.; Inubushi, Y.; Chem.
Pharm. Bull. 1975, 23, 2779. Ibuka, T.; Mori, Y.; Inubushi, Y. Chem.
Pharm. Bull. 1978, 26, 2442. For recent reports on (()-pumiliotoxin
C, see: (b) Comins, D. L.; Dehghani, A.; Tetrahedron Lett. 1991, 32,
5697. (c) Polniszek, R. P. Dillard, L. D.; J . Org. Chem. 1992, 57, 4110.
(d) Brandi, A.; Cordero, F. M.; Goti, A.; Guarna, A. Tetrahedron Lett.
1992, 33, 6697. (e) Meyers, A. I.; Milot, G.; J . Am. Chem. Soc. 1993,
115, 6652. For the chiral syntheses of (-)-pumiliotoxin C, see: (f)
Oppolzer, W.; Flaskamp, E. Helv. Chim. Acta 1977, 60, 204. (g) Bonin,
M.; Royer, J .; Grierson, D. S.; Husson, H.-P. Tetrahedron Lett. 1986,
27, 1569. (h) Murahashi, S.; Sasano, S.; Saito, E.; Naota, T. J . Org.
Chem. 1992, 57, 2521. Murahashi, S.; Sasano, S.; Saito, S.; Naota, T.
Tetrahedron 1993, 49, 8805. (i) Commins, D. L.; Dehghani, A. J . Chem.
Soc., Chem. Commun. 1993, 1838. (j) Naruse, M.; Aoyagi, S.; Kibayashi,
C. Tetrahedron Lett. 1994, 35, 9213. Naruse, M.; Aoyagi, S.; Kibayashi,
C. J . Chem. Soc., Perkin Trans. 1 1996, 1113. (k) Back, T. G.; Nakajima,
K. J . Org. Chem. 1998, 63, 6566. For recent reports on the syntheses
of (+)-pmiliotoxin C, see: (l) Toyota, M.; Asoh, T.; Fukumoto, K.
Tetrahedron Lett. 1996, 37, 4401. (m) Toyota, M.; Asoh, T.; Fukumoto,
K. J . Org. Chem. 1996, 61, 8687.
(1) Hidai, M.; Mizobe Y. Chem. Rev. 1995, 95, 1115.
(2) (a) Kawaguchi, M.; Hamaoka, S.; Mori, M. Tetrahedron Lett.
1993, 34, 6907. Mori, M.; Kawaguchi, M.; Hori, M.; Hamaoka, S.
Heterocycles 1994, 39, 729. (b) Hori, M.; Mori, M.; J . Org. Chem. 1995,
60, 1480. (c) Mori, M.; Hori, K.; Akashi, M.; Hori, M.; Sato, Y.; Nishida,
M. Angew. Chem., Int. Ed. 1998, 37, 636. (d) Hori, K.; Mori, M. J . Am.
Chem. Soc. 1998, 120, 7651. (e) Mori, M.; Hori, M.; Sato, Y. J . Org.
Chem. 1998, 63, 4832. (f) Akashi, M.; Nishida, M.; Mori, M. Chem.
Lett. 1999, 465. (g) Ueda, K.; Sato, Y.; Mori, M. J . Am. Chem. Soc.
2000, 122, 10723.
10.1021/jo0104072 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/16/2001