Synthesis of pumiliotoxine C from molecular nitrogen as a nitrogen Source

Full text of DOI:10.1021/jo0104072

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

7874 J . Org. Chem., Vol. 66, No. 23, 2001
Notes
Sch em e 4. Syn th esis of Ketoa lk yn ea
Sch em e 5. Syn th esis of P u m iliotoxin C
a
Key: (i) (CH2OH)2, PPTS; (ii) (Sia)2BH, then H2O2, NaOH;
(iii) PCC; (iv) CBr4, PPh3; (v) BuLi, then ClCO2Me; (vi) 5% HCl.
F igu r e 1.
acetylide, which was reacted with methyl chloroformate
followed by deketalization to give keto-alkyne 4. Synthe-
sis of quinoline 3 was successfully achieved by the
reaction of keto-alkyne 4 with titanium-nitrogen com-
plexes using nitrogen gas in high yield. Dry air could be
used for this reaction, and the desired quinoline deriva-
tive 3 was obtained in 58% yield. Hydrogenation and
deprotection of compound 3 was carried out using 5 mol
% of palladium on charcoal (STD-type).3h,6 Protection of
the secondary amine with carbobenzyloxy chloride af-
forded 9a and 9b in 57% yields in a ratio of 7 to 1.7 The
reason the desired product 9a was obtained as a main
product is thought to be that hydrogen approached from
the convex face of 3′, which is in a state of equilibrium
with 3 in MeOH, as shown in Figure 1.
The major isomer 9a was treated with DIBALH
followed by reaction with a Wittig reagent to give
compound 11. Hydrogenation of 11 with 5% palladium
on charcoal followed by treatment with Et2O‚HCl af-
forded pumiliotoxine C hydrochloride, whose spectral
data agreed with those reported in the literature.3a
The fact that the stereochemistry of the synthetic
product, which was confirmed by X-ray chrystallogra-
phy,8,9 agreed with that of the natural product indicated
that we had succeeded in the synthesis of pumiliotoxin
C from keto-alkyne and molecular nitrogen, namely,
nitrogen gas or an atmospheric nitrogen.
sphere. THF and TMSCl were distilled just before using from
sodium benzophenone (THF) and CaH2 (TMSCl). Other solvents
and reagents were purified when necessary using standard
procedures. Column chromatography was performed on silica
gel 60 (70-230 mesh), and flash column chromatography was
performed on silica gel 60 (230-400 mesh) using the indicated
solvent. Melting points are uncorrected.
(E)-(5-Meth yl-octa h yd r oqu in olin -2-ylid en e)a cetic Acid
Meth yl Ester (3). A solution of titanium-nitrogen complexes
prepared from Li (70.4 mg, 10.1 mmol), Ti(OiPr)4 (0.30 mL, 1.02
mmol), and TMSCl (2.0 mL, 15.8 mmol) in THF (15 mL) under
nitrogen was added to the THF (6.0 mL) suspension of 4 (176.9
mg, 0.796 mmol) and CsF (742.6 mg, 4.89 mmol) at -78 °C, and
the whole mixture was stirred at room temperature for 20 h.
Saturated aqueous NaHCO3 was added at 0 °C, and the mixture
was stirred at room temperature until the black precipitate
disappeared. The mixture was filtered through Celite, and the
filtrate was extracted with Et2O. The organic layer was washed
with brine, dried over Na2SO4, and concentrated. The residue
was purified by column chromatography on silica gel (hexane/
Et3N ) 100/3) to give 3 (138.8 mg, 79%) as a colorless oil: IR
(neat) 3280 1658, 1612 cm-1; 1H NMR (CDCl3, 270 MHz) δ 0.95
(d, J ) 6.8 Hz, 3 H), 1.32 (m, 1 H), 1.53-1.64 (m, 2 H), 1.91 (m,
1 H), 1.97-2.04 (m, 3 H), 2.10-2.22 (m, 2 H), 2.37 (ddd, J )
15.6, 6.6, 6.6 Hz, 1 H), 2.45 (ddd, J ) 15.6, 10.5, 5.4 Hz, 1 H),
3.61 (s, 3 H), 4.47 (s, 1 H), 9.25 (brs, 1 H); 13C NMR (CDCl3, 68
MHz) δ 19.3, 19.6, 22.6, 27.1, 29.0, 31.1, 32.0, 50.1, 82.3, 114.0,
128.1, 156.7, 170.6; EI-LRMS m/z 221 (M+), 206; EI-HRMS calcd
for C13H19NO2 221.1416, found 221.1414.
Ack n ow led gm en t. We thank the Mitsubishi Foun-
dation for their support to this work, and we also thank
the J apan Society for the Promotion of Science (J SPS)
Research Fellowships for Young Scientists (to M.A.).
Exp er im en ta l Section
All manipulations were performed under an argon atmo-
sphere. Ti(OiPr)4 was distilled and stored under argon atmo-
Su p p or tin g In for m a tion Ava ila ble: The spectral data
and experimental procedure of 2a ,b, 4, 7, 8, 9a , 11, and
pumiliotoxin‚HCl. This material is available free of charge via
the Internet at http://pubs.acs.org.
(4) (a) Daly, J . W.; Tokuyama, T.; Habermehl, G.; Karle, I. L.;
Witkop, B.; Liebigs Ann. Chem. 1969, 729, 198. (b) Tokuyama, T.;
Tsujita, T.; Shimada, A.; Garaffo, H. M.; Spande, T. F.; Daly, J . W.
Tetrahedron 1991, 47, 5401.
(5) Caine, D.; Chao, T.; Smith, A. Organic Syntheses; Wiley: New
York, 1973; Collect. Vol. VI, p 51.
(6) Palladium-charcoal was purchased from N.E. CHEMCAT Co.
(7) The stereochemistry of minor product 9b was not determined.
(8) The melting point of the synthetic product [mp 246-248 °C (from
EtOH-AcOEt)] did not agree with that (mp 232 °C) reported in the
literature.3a
J O0104072
(9) Crystallographic data for the structural analysis have been
deposited with the Cambridge Crystaallographic Data Centre, CCDC
no. 165162 for pumiliotoxine C‚HCl.