Synthesis of highly oxidized quinolizidine via reduction of acylpyridinium cations, and total syntheses of quinolizidines 207I and 1-epi-207I

Article abstract of DOI:10.1021/ol300541u

A new strategy for synthesizing quinolizidine skeletons by reductive cyclization via acylpyridinium cations was developed. Several functional groups, including carbonyl, silyl, and acetal, were tolerated under mild reaction conditions. The reaction was successfully extended to a one-pot synthesis of a bicyclic compound, and the synthetic strategy was applied to concise total syntheses of quinolizidines 207I and 1-epi-207I, without protecting groups.

Full text of DOI:10.1021/ol300541u

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1902–1905
Synthesis of Highly Oxidized Quinolizidine
via Reduction of Acylpyridinium Cations,
and Total Syntheses of Quinolizidines 207I
and 1-epi-207I
Chihiro Tsukano, Atsuko Oimura, Iderbat Enkhtaivan, and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku,
Kyoto, 606-8501, Japan
takemoto@pharm.kyoto-u.ac.jp
Received March 2, 2012
ABSTRACT
A new strategy for synthesizing quinolizidine skeletons by reductive cyclization via acylpyridinium cations was developed. Several functional
groups, including carbonyl, silyl, and acetal, were tolerated under mild reaction conditions. The reaction was successfully extended to a one-pot
synthesis of a bicyclic compound, and the synthetic strategy was applied to concise total syntheses of quinolizidines 207I and 1-epi-207I, without
protecting groups.
Quinolizidine is a 6,6-bicyclic scaffold with a bridgehead
nitrogen atom. Various types of quinolizidine alkaloids,
from simple bicyclic to polycyclic compounds, have been
isolated from bacteria, fungi, plants, invertebrates, and
vertebrates.1 Although there is no common biosynthetic
pathway, these compounds often have significant biologi-
cal activities, and some of them are major components of
traditional medicines. Because of their promising struc-
tures with respect to biological activities, chemists and
pharmacists are interested in the quinolizidine skeleton.
Various synthetic methods for quinolizidines have
been developed. The skeletons are generally constructed
from piperidine derivatives by formation of the second
six-membered ring using nitrogen nucleophilic substitu-
tion, intramolecular reductive amination, or ring-closing
metathesis.1,2 Comins et al. accomplished the total synthe-
ses of quinolizidine natural products from N-acyl-1,2-
dihydropyridines and N-acyl-2,3-dihydro-4-pyridinones,
which were prepared by nucleophilic addition to N-acyl-
pyridinium salts.3 Synthesis via iminium intermediates is
another route to this skeleton.4 Direct conversion of a
pyridinium salt fused with a six-membered ring has
also been reported, but this required a relatively stable
pyridinium cation.5 Recently, Charette et al. described
an intramolecular pyridine activationÀdearomatization
(3) (a) Comins, D. L.; Zheng, X.; Goehring, R. R. Org. Lett. 2002, 4,
1611. (b) Comins, D. L.; Thakker, P. M.; Baevsky, M. F. Tetrahedron
1997, 53, 16327. (c) Comins, D. L.; Hong, H. J. Am. Chem. Soc. 1993,
115, 8851. (d) Al-awar, R. S.; Joseph, S. P.; Comins, D. L. J. Org. Chem.
1993, 58, 7732. (e) Comins, D. L.; LaMunyon, D. H. J. Org. Chem. 1992,
57, 5807 and references therein.
(4) For recent reviews, see: (a) Speckamp, W. N.; Moolenaar, M. J.
Tetrahedron 2000, 56, 3817. (b) Royer, J.; Bonin, M.; Micouin, L. Chem.
Rev. 2004, 104, 2311. For recent examples, see: (c) Yang, D.; Micalizio,
G. C. J. Am. Chem. Soc. 2009, 131, 17548. (d) Amorde, S. M.; Jewett,
I. T.; Martin, S. F. Tetrahedron 2009, 65, 3222.
(1) (a) Michael, J. P. The Alkaloids; Academic Press: New York, 2001;
Vol. 55, p 91. (b) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139 and
references therein.
(2) Recent examples: (a) Wong, H.; Garnier-Amblard, E. C.; Lie-
beskind, L. S. J. Am. Chem. Soc. 2011, 133, 7517. (b) Ying, Y.; Kim, H.;
Hong, J. Org. Lett. 2011, 13, 796. (c) Kawahara, R.; Fujita, K.;
Yamaguchi, R. J. Am. Chem. Soc. 2010, 132, 15108. (d) Airiau, E.; T.
Spangenberg, R.; Girard, N.; Breit, B.; Mann, A. Org. Lett. 2010, 12,
528. (e) Dalton, D. M.; Oberg, K. M.; Yu, R. T.; Lee, E. E.; Perreault, S.;
Oinen, M. E.; Pease, M. L.; Malik, G.; Rovis, T. J. Am. Chem. Soc. 2009,
131, 15717. (f) Cui, L.; Peng, Y.; Zhang, L. J. Am. Chem. Soc. 2009, 131,
8394.
(5) Selected examples: (a) Ciufolini, M. A.; Roschangar, F. J. Am.
Chem. Soc. 1996, 118, 12082. (b) Kutney, J. P.; Fortes, C. C.; Honda, T.;
Murakami, Y.; Preston, A.; Ueda, Y. J. Am. Chem. Soc. 1977, 99, 964.
r
10.1021/ol300541u
Published on Web 03/22/2012
2012 American Chemical Society

strategy via a N-pyridinium imidate.6 In their paper,
quinolizidine ring formation, dearomatization of pyridine,
and CÀC bond formation were accomplished in one pot.
Although dearomatization strategies are powerful, they
would be difficult to apply to substrates with carbonyl
functionalities because they require strong nucleophiles
such as Grignard reagents. We therefore focused on
reducing reagents as mild nucleophiles. If the quinolizidine
skeleton is constructed by one-pot activationÀreduction
via an unstable pyridinium cation, this synthetic strategy
can be applied to a broader range of substrates. Using
pyridine instead of piperidine would make the synthesis
simple and free from protecting groups.7 In this paper, we
report a new strategy for the synthesis, without protecting
groups, of quinolizidine skeletons via reduction of acyl-
pyridinium cations and its application to total syntheses of
related natural products.
reduction of alkoxycarbonylpyridinium cation 5 and al-
kylpyridinium cation 6;3,5,11À14 Charette et al. focused on
nucleophilic addition to N-pyridinium imidates.15 How-
ever, there have been few reports of reduction of acylpyr-
idinium cation 4.16 Also, the reported yields were often
low, and specific functional groups were required because
the lability of 4, unlike 5 and 6, would hamper reduction
under these conditions. To realize our strategy, we needed
mild reducing agents.
Scheme 1. Synthetic Strategy for Highly Oxidized Quinolizi-
dines
For the initial survey, a model compound717 was usedto
examine reductive cyclization using an activator and a
reductant (Table 1). After treatment of 7 with oxalyl
chloride and a catalytic amount of DMF, we tried several
reagents for reduction of the resultant acylpyridinium
intermediate 8. Reduction using NaBH4, LiBH4, DIBAL-
H, and Et3SiH did not proceed and only the starting
Figure 1. Quinolizidine alkaloids.
We devised a synthesis of quinolizidine 3, bearing in
mind natural products with carbonyl functionalities and
carbon side chains, for example A58365B8 and GB179
(Figure 1, Scheme 1). Because 3 contains amide and ketone
groups, it would also be a useful intermediate for substi-
tuted quinolizidine derivatives such as quinolizidine
207I.10 The quinolizidine skeleton could be constructed
by reduction of acylpyridinium cation 2, which is obtained
by activation of carboxylic acid 1, as shown in Scheme 1.
There are many examples of nucleophilic addition and
carboxylic acid was recovered. In the case of BH3 THF
3
and Bu3SnH, 9b was obtained via 1,2-reduction (Table 1,
entries 1 and 2). In contrast, the reaction using Comins’
conditions16a gave 1,2-dihydropyridine as a 1:0.7 mixture
of isomers 9c (entry 3). When a Hantzsch ester 1018,19 was
(13) For recent examples of reduction of alkoxy carbonylpyridinium
cation 5 and alkyl pyridinium cation 6, see: (a) Donohoe, T. J.;
Connolly, M.; Rathi, A. H.; Walton, L. Org. Lett. 2011, 13, 2074.
(b) Shaw, A. P.; Ryland, B. L.; Franklin, M. J.; Norton, J. R.; Chen,
J. Y.-C.; Hall, M. L. J. Org. Chem. 2008, 73, 9668. (c) Donohoe, T. J.;
Johnson, D. J.; Mace, L. H.; Bamford, M. J.; Ichihara, O. Org. Lett.
2005, 7, 435.
(14) For related examples of nucleophilic addition and reduction of
other pyridinium cations, see: (a) Gutsulyak, D. V.; van der Est, A.;
Nikonov, G. I. Angew. Chem., Int. Ed. 2011, 50, 1384. (b) Legault, C. Y.;
Charette, A. B. J. Am. Chem. Soc. 2005, 127, 8966. (c) Legault, C.;
Charette, A. B. J. Am, Chem. Soc. 2003, 125, 6360.
(15) (a) Charette, A. B.; Grenon, M.; Lemire, A.; Pourashraf, M.;
Martel, J. J. Am. Chem. Soc. 2001, 123, 11829. (b) Alexandre, L.;
Charette, A. B. Org. Lett. 2005, 7, 2747. (c) Charette, A. B.; Mathieu,
S.; Martel, J. Org. Lett. 2005, 7, 5401. (d) Focken, T.; Charette, A. B.
Org. Lett. 2006, 8, 2985.
(6) Barbe, G.; Pelletier, G.; Charett, A. B. Org. Lett. 2009, 11, 3398.
(7) (a) Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193. (b)
Hoffmann, R. W. Synthesis 2006, 3531.
(8) (a) Mynderse, J. S.; Samlaska, S. K.; Fukuda, D. S.; Du Bus,
R. H.; Baker, P. J. J. Antibiot. 1985, 38, 1003. (b) Hunt, A. H.; Mynderse,
J. S.; Samlaska, S. K.; Fukuda, D. S.; Maciak, G. M.; Kirst, H. A.;
Occolowitz, J. L.; Swartzendruber, J. K.; Jones, N. D. J. Antibiot. 1988,
41, 771.
(9) Mander, L. N.; Willis, A. C.; Herlt, A. J.; Taylor, W. C. Tetra-
hedron Lett. 2009, 50, 7089.
(10) Proposed structure: (a) Jain, P.; Garraffo, H. M.; Yeh, H. J. C.;
Spande, T. F.; Daly, J. W. J. Nat. Prod. 1996, 59, 1174. (b) Revised
structure: Toyooka, N.; Tanaka, K.; Momose, T.; Daly, J. W.; Garraffo,
M. Tetrahedron 1997, 53, 9553.
(16) (a) Comins, D. L.; Abdullah, A. H. J. Org. Chem. 1984, 49, 3392.
(b) Obika, S.; Nishiyama, S.; Tatematsu, S.; Nishimoto, M.; Miyashita,
K.; Imanishi, T. Heterocycles 1997, 44, 537. (c) Schroif-Gregoire, C.;
Travert, N.; Zaparucha, A.; Al-Mourabit, A. Org. Lett. 2006, 8, 2961.
(17) Compound 7 was prepared from methyl picolinate by modifying
our previous report: Tsukano, C.; Zhao, L.; Takemoto, Y.; Hirama, M.
Eur. J. Org. Chem. 2010, 4198. Also see Supporting Information.
(18) Hantzsch, A. Justus Liebigs Ann. Chem 1882, 215, 1.
(19) For selected recent examples, see: (a) Barbe, G.; Charette, A. B.
J. Am. Chem. Soc. 2008, 130, 18. (b) Pelletier, G.; Bechara, W. S.;
Charette, A. B. J. Am. Chem. Soc. 2010, 132, 12817. (c) Li, L.; Chua,
K. W. S. Tetrahedron Lett. 2011, 52, 1392.
(11) For selected reviews, see: (a) Bull, J. A.; Mousseau, J. J.;
Pelletier, G.; Charette, A. B. Chem. Rev. 2012DOI: 10.1021/cr200251d.
(b) Poddubnyi, I. S. Chem. Heterocycl. Compd. 1995, 31, 682. (c) Stout,
D. M.; Meyers, A. I. Chem. Rev. 1982, 82, 223.
(12) For recent examples of nucleophilic addition to pyridinium
cation, see: (a) Nadeau, C.; Aly, S.; Belyk, K. J. Am. Chem. Soc.
2011, 133, 2878. (b) Wolfe, B. H.; Libby, A. H.; Al-awar, R. S.; Foti,
C. J.; Comins, D. L. J. Org. Chem. 2010, 75, 8564. (c) Fernandex-
Izbanez, M. A.; Macia, B.; Pizzuti, M. G.; Minnaard, A. J.; Feringa,
B. L. Angew. Chem., Int. Ed. 2009, 48, 9339. (d) Donohoe, T. J.;
Connolly, M. J.; Walton, L. Org. Lett. 2009, 11, 5562. (e) Arnott, G.;
Brice, H.; Clayden, J.; Blaney, E. Org. Lett. 2008, 10, 3089.
Org. Lett., Vol. 14, No. 7, 2012
1903

used as the reducing reagent, 1,4-reduction proceeded,
giving 9a as a single isomer along with recovered starting
material 7 (entry 4). Considering the obtained yields,
10 was used for further investigations. To obtain a full
conversion of 7, several reagents were investigated
for carboxylic acid activation (entries 5À7). It was found
that 1-chloro-N,N,2-trimethyl-1-propenylamine (Ghosez’s
reagent), which is used under mild and neutral conditions,20
Table 2. Substrate Scopes and Limitationsa
˚
gave good yields, and addition of MS4 A resulted in
excellent conversion (entry 8). It should be noted that the
1,4-dihydropyridine 9a was unstable; for example, lengthy
exposure to silica gel caused decomposition of the cyclized
1,4-dihydropyridine.
Table 1. Reduction of Acylpyridinium Cation
yield (%)a
entry
conditions A
conditions B
9aÀc
7
1
2
3
4
5
6
7
8
(COCl)2, cat. DMF BH3 THFb
(COCl)2, cat. DMF Bu3SnHc
(COCl)2, cat. DMF Li(tBuO)3AlH, CuBr 9c 33%d 0%
(COCl)2, cat. DMF Hantzsch ester (10) 9a 60%e 18%
(SOCl)2, cat. DMF Hantzsch ester (10) 9a 54%e 36%
9b 47% 0%
9b 32% 53%
3
BzCl, Et3N
Hantzsch ester (10) 9a 23%e 48%
Hantzsch ester (10) 9a 89%e trace
Hantzsch esterf
Ghosez’s reagent
Ghosez’s reagent
9a 96%e 0%
a Isolated yield. b THF was used as a cosolvent. c À78 °C. d The ratio
of mixture was 1:0.7. e Isolated yield based oxidized Hantzsch ester. f MS
˚
4 A was added.
Next we investigated the scope and limitations of the
optimized reaction conditions. Treatment of 11a with a
methyl group on the pyridine ring with Ghosez’s reagent
following treatment with Hantzsch ester 10 gave the
cyclized product 12a in 87% yield (Table 2, entry 1). In
the case of a phenyl substituent, the reaction proceeded
smoothly to give 12b (entry 2). Electron-withdrawing
groups, such as bromine and trifluoromethyl, on the
pyridine ring were tolerated under these conditions
(entries 3 and 4). The reaction of 11e, bearing a methoxy
group, resulted in decomposition of the starting material,
probably because of the instability of the intermediate
(entry 5). The sterically hindered carboxylic acid 11f could
be used for this cyclization (entry 6). The double bond was
a
˚
Conditions: 11 (1 equiv), Ghosez’s reagent (1.5 equiv), and MS 4 A
were stirred for 20 min at 0 °C, and then Hantzsch ester (3 equiv) was
added. b Isolated yield based oxidized Hantzsch ester.
not essential for this reductive cyclization, although the
yield was slightly decreased (entry 7). Acetal and tert-
butyldimethylsilyl (TBS) groups were compatible under
these conditions (entries 8 and 9). In contrast, the reaction
of 11j afforded only trace amounts of 12j (entry 10). These
results indicated that the ketone moiety was essential for
increasing product stability.
To show that our strategy is powerful for preparing
quinolizidine skeletons, the total syntheses of quino-
lizidines 207I (13) and 1-epi-207I (14) were performed
(20) Devos, A.; Remion, J.; Frisque-Hesbain, A.-M.; Colens, A.;
Ghosez, L. J. Chem. Soc., Chem. Commun. 1979, 1180.
1904
Org. Lett., Vol. 14, No. 7, 2012

(Scheme 2). 207I was isolated in trace quantities from skin
extractsof aMadagascanmantelline frog,Mantella baroni,
by Daly et al.10a It was first assigned as the C1 epimer (i.e.,
1-epi-207I) using GC-FTIR and GC-MS, but this was
revised after the syntheses of 207I and 1-epi-207I.10b,21a
The first total synthesis of racemic 207I, involving 17 steps,
was reported by Michel and Rassat.21a,b Toyooka et al.
determined the absolute stereochemistry of 207I using
their 23-step enantioselective synthesis.21c Interestingly,
Scheme 2. Total Synthesis of Quinolizidine 207I
1-epi-207I selectively blocks R7 nicotinic receptors (IC50
=
0.6 μM), but 207I is less potent than 1-epi-207I and shows
noselectivityforR4β2nicotinic receptors.22 Conciseroutes
to both quinolizidines are important for further biological
studies.
Our syntheses commenced with construction of the
quinolizidine skeleton by reductive cyclization. The cou-
pling of trimethylsilylpyridine and succinic anhydride,
using Thames’s procedure,23 was followed by cyclization
under the developed conditions to give 16 in 89% yield
without isolation of intermediate 15. The bicyclic core
was readily obtained by a one-pot synthesis based on an
extension of our method. After hydrogenation of 16,
we tried to install an ethyl group at the C1 position. After
several investigations, ketone 1724 was converted to diene
18 by formation of an enol triflate and Stille coupling.
Hydrogenation of 18 gave a 5:2 mixture of diastereomers
19 and 20 under medium pressure. After separation by
HPLC, products 19 and 20 were each treated with allyl
magnesium chloride and then sodium cyanoborohydride
in one pot3a,25 to giveracemic 207I (13) and 1-epi-207I (14),
respectively; 207I and 1-epi-207I were the only observed
products in each one-pot reduction and cyclization. The
1H NMR, 13C NMR, and high-resolution MS data were
identical to previously reported data.10,21 This seven-step
synthetic route using no protecting groups is more concise
compared to previous syntheses.
In summary, we have developed reduction of acylpyr-
idinium cations under mild conditions as a one-pot
synthesis of quinolizidine skeletons. Several functional
groups, including silyl and acetal, were tolerated under
these conditions. The method was successfully applied to
the seven-step syntheses of quinolizidine alkaloids 207I
and 1-epi-207I, without protecting groups. Because the
cyclized products are highly oxidized quinolizidines con-
taining enamide and R,β-unsaturated ketone functional-
ities, these compounds have the potential for conversion to
more-substituted quinolizidines. Extension of the strategy
and its application to syntheses of related quinolizidine
natural products are now underway.
(21) Total synthesis of 207I: (a) Rassat, A.; Michel, P. Chem.
Commun. 1999, 2281. (b) Michel, P.; Rassat, A.; Daly, J. W.; Spande,
T. F. J. Org. Chem. 2000, 65, 8909. (c) Toyooka, N.; Nemoto, H.
Tetrahedron Lett. 2003, 44, 569. Synthesis of 1-epi-207I: (d) Kinderman,
S. S.; Gelder, R.; Maarseveen, J. H.; Schoemaker, H. E.; Hiemstra, H.;
Rutjes, F. P. J. T. J. Am. Chem. Soc. 2004, 126, 4100.
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Young Scientists (Start-up) (C.T.) from
the Japan Society for the Promotion of Science.
(22) Tsuneki, H.; You, Y.; Toyooka, N.; Kagawa, S.; Kobayashi, S.;
Sasaoka, T.; Nemoto, H.; Kimura, I.; Dani, J. A. Mol. Pharmacol. 2004,
66, 1061.
(23) Pinkerton, F. H.; Thames, S. F. J. Organomet. Chem. 1970, 24,
623.
(24) (a) Huang, P.-Q.; Guo, Z.-Q.; Ruan, Y.-P. Org. Lett. 2006, 8,
1435. (b) Chen, B. F.; Tasi, M.-R.; Yang, C.-Y.; Chang, J.-K.; Chang,
N.-C. Tetrahedron 2004, 60, 10223. (c) Wijtdeven, M. A.; Wijtmans, R.;
van den Berg, R. J. F.; Noorduin, W.; Schoemaker, H. E.; Sonke, T.; van
Delft, F. L.; Blaauw, R. H.; Fitch, R. W.; Spande, T. F.; Daly, J. W.;
Rutjes, F. P. J. T. Org. Lett. 2008, 10, 4001.
Supporting Information Available. Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
ꢀ
(25) Gracias, V.; Zeng, Y.; Desai, P.; Aube, J. Org. Lett. 2003, 5,
4999.
The authors declare no competing financial interest.
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