Asymmetric synthesis of (+)-isofebrifugine and (-)-sedacryptine from a common chiral nonracemic building block

Article abstract of DOI:10.1021/ol8013864

(Chemical Equation Presented) The stereoselective syntheses of 2-substituted and 2,6-disubstituted 3-hydroxypiperidine alkaloids, (+)-isofebrifugine and (-)-sedacryptine, from a common, functionalized nonracemic bicyclic building block are achieved, demon

Full text of DOI:10.1021/ol8013864

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3869-3872
Asymmetric Synthesis of
(+)-Isofebrifugine and (-)-Sedacryptine
from a Common Chiral Nonracemic
Building Block
Andrew G. H. Wee* and Gao-Jun Fan
Department of Chemistry and Biochemistry, UniVersity of Regina, Regina,
Saskatchewan, Canada S4S 0A2
andrew.wee@uregina.ca
Received June 19, 2008
ABSTRACT
The stereoselective syntheses of 2-substituted and 2,6-disubstituted 3-hydroxypiperidine alkaloids, (+)-isofebrifugine and (-)-sedacryptine,
from a common, functionalized nonracemic bicyclic building block are achieved, demonstrating the flexibilty of the approach.
Piperidine alkaloids have diverse structures with interesting
stereochemistries and are widespread in nature.1 A subgroup
of these alkaloids possessing the 3-hydroxypiperidine moiety
as their core structure, exemplified by 1-5 (Figure 1), are
also frequently found in nature. Many of these alkaloids show
a wide range of biological activities1a,c,2 which have potential
applications in medicine and in the design of new drugs.3
These attributes have stimulated intense efforts directed at
the development of synthetic approaches and methods4 for
use in the synthesis of piperidine intermediates enroute to
alkaloids. In spite of the advancements achieved to date,
versatile and stereoselective routes are still highly desired.
We recently reported5 the synthesis of the functionalized
chiral nonracemic intermediate 6 (Figure 1) and described
its use in the synthesis of an indolizidine alkaloid. The cis-
bicyclic structure also provides a stereochemical bias for
(1) (a) Strunz, G. M.; Findlay, J. A. The Alkaloids; Brossi, A., Ed.;
Academic: New York, 1985; Vol. 26, p 89. (b) Numata, A.; Ibuka, T. The
Alkaloids; Brossi, A., Ed.; Academic: New York, 1987; Vol. 31, p 194. (c)
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2003, 59, 2953. (c) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003,
3693. Recent representative piperidine synthetic methods: (d) Goodenough,
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207. (e) Wang, X.; Dong, Y.; Sun, J.; Xu, X.; Li, R.; Hu, Y. J. Org. Chem.
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D.; Kirchoff, J. H. Synthesis 2000, 2099.
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Jenkins, P. R. Planta Med. 1999, 65, 161. (c) Tawara, J. N.; Blokhin, A.;
Foderaro, T. A.; Stermitz, F. R. J. Org. Chem. 1993, 58, 4813, and references
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10.1021/ol8013864 CCC: $40.75
Published on Web 08/02/2008
2008 American Chemical Society

(+)-Isofebrifugine (1) and (+)-febrifugine (Scheme 1) are
two antimalarial compounds isolated from the roots of the
Scheme 1. Retrosynthesis of (+)-Isofebrifugine (1)
Chinese herbal plant Dichroa febrifuga Lour. and related
hydrangea plants.8 There is renewed interest in these two
alkaloids and their synthetic analogues due to the increasing
resistance of the malarial parasite toward quinine and
synthetic antimalarial drugs such as chloroquine.9 From a
chemical standpoint, these two compounds show an interest-
ing interconversion; it was found that (+)-febrifugine was
converted10a to (+)-1 by heating the former compound in
refluxing aqueous HCl, whereas (+)-1 was converted to (+)-
febrifugine when it was refluxed in methanol10a (or water10b).
On the basis of the ease of conversion of (+)-isofebrifugine
to (+)-febrifugine, we chose the former as our synthetic
target. There have been two racemic11a,b and six asymmetric
syntheses10a,b,11c-f of (+)-1 to date; our approach is funda-
mentally different from those reported.
Figure 1
block 6.
. Representative 3-hydroxypiperidine alkaloids and building
reactions that are carried out on 6 facilitating the stereose-
lective installation of substituents on the bicycle. In connec-
tion with this work, we now report the enantioselective
syntheses of (+)-isofebrifugine (1) and (-)-sedacryptine (2)
starting from 6. The successful syntheses of 1 and 2 highlight
the utility of 6 as a nonracemic building block6 and
demonstrate the flexibility of the approach which provides
ready access to both 2-substituted and 2,6-disubstituted
3-hydroxypiperidine alkaloids.7
(6) (a) Chiral building block approaches: Toyooka, N.; Nemoto, H.
Studies in Natural Products Chemistry: BioactiVe Natural Products (Part
J); Atta-ur-Rahman, Ed.; Elsevier: New York, NY, 2003; Vol. 29, pp 419.
(b) Meyers, A. I.; Brengel, G. P. Tetrahedron 2000, 56, 9843. (c) Husson,
H.-P.; Royer, J. Chem. Soc. ReV. 1999, 28, 383.
The retrosynthesis of (+)-1 is shown in Scheme 1. The
epoxide unit in 7 will serve as an hydroxyethyl carbocation
equivalent to permit its coupling to 4-quinazolinone and
installation of the secondary alcohol unit that is destined to
be a ketone carbonyl function. Compound 7 will be derived
from the alkene 8, which in turn will be prepared from
building block 6.
(7) Review: 3-Piperidinol alkaloid synthesis: (a) Zhou, W.-S.; Lu, Z.-
H.; Xu, Y.-M.; Liao, L.-X.; Wang, Z.-M. Tetrahedron 1999, 55, 11959.
(b) Ciufolini, M. A.; Hermann, C. Y. W.; Dong, Q.; Shimizu, T.;
Swaminathan, S.; Xi, N. Synlett 1998, 105. Recent representative methods:
(c) Andres, J. M.; Pedrosa, R.; Perez-Encabo, A. Eur. J. Org. Chem. 2007,
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Lett. 2004, 6, 4029. (g) Randl, S.; Blechert, S. Tetrahedron Lett. 2004, 45,
1167. (h) Makabe, H.; Kong, L. K. Org. Lett. 2003, 5, 27. (i) Ma, D.; Ma,
N. Tetrahedron Lett. 2003, 44, 3963. (j) Aoyagi, S.; Kibayashi, C. Org.
Lett. 2003, 5, 3839. (k) Lee, H. K.; Chun, J. S.; Pak, C. S. Tetrahedron
2003, 59, 6445. (l) Singh, R.; Ghosh, S. K. Tetrahedron Lett. 2002, 43,
7711. (m) Dransfield, P. J.; Gore, P. M.; Shipman, M.; Slawin, A. M. Z.
Chem. Commun. 2002, 150. (n) Cossy, J.; Willis, C.; Bellosta, V.;
BouzBouz, S. J. Org. Chem. 2002, 67, 1982. (o) Sengupta, S.; Mondal, S.
Tetrahedron 2002, 58, 7983. (p) Herdeis, C.; Tesler, J. Eur. J. Org. Chem.
1999, 1407, and references cited therein. (q) Toyooka, N.; Yoshida, Y.;
Yotsui, Y.; Momose, T. J. Org. Chem. 1999, 64, 4914.
The synthesis began with the chemoselective reduction5
of the lactone carbonyl in 6 with RedAl to obtain the lactol
9 in 94% yield (Scheme 2). Wittig olefination of 9 followed
by protection of the secondary alcohol as the methoxymethyl
ether gave lactam 10. Reduction of the lactam carbonyl with
(11) (a) Racemic 1: Takeuchi, Y.; Hattori, M.; Abe, H.; Harayama, T.
Synthesis 1999, 1814. (b) Sugiura, M.; Kobayashi, S. Org. Lett. 2001, 3,
477. (+)-1: (c) Huang, P.-Q.; Wei, B.-G.; Ruan, Y.-P. Synlett 2003, 1663.
(d) Takeuchi, Y.; Azuma, K.; Takakura, K.; Abe, H.; Kim, H.-S.; Wataya,
Y.; Harayama, T. Tetrahedron 2001, 57, 1213. (e) Sugiura, M.; Hago, H.;
Hirabayashi, R.; Kobayashi, S. J. Am. Chem. Soc. 2001, 123, 12510. (f)
Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.; Kim, H.-S.; Wataya, Y.
J. Org. Chem. 1999, 64, 6833. (-)-1: (g) Katoh, M.; Matsune, R.; Honda,
T. Heterocycles 2006, 67, 189.
(8) (a) Koepfli, J. B.; Mead, J. F.; Brockman, J. A., Jr. J. Am. Chem.
Soc. 1947, 69, 1837. (b) Koepfli, J. B.; Mead, J. F.; Brockman, J. A., Jr.
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II; Williams, J. H. J. Org. Chem. 1952, 17, 14.
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R.; Hariguchi, N.; Matsumoto, M.; Oshima, Y. J. Med. Chem. 2006, 49,
4698, and references cited therein. (b) Jiang, S.; Zeng, Q.; Gettayacamin,
M.; Tungtaeng, A.; Wannaying, S.; Lim, A.; Hansukjariya, P.; Okunji, C. O.;
Zhu, S.; Fang, D. Antimicrob. Agents Chemother. 2005, 49, 1169. (c)
Kikuchi, H.; Tasaka, H.; Hirai, S.; Takaya, Y.; Iwabuchi, Y.; Ooi, H.;
Hatakeyama, S.; Kim, H.-S.; Wataya, Y.; Oshima, Y. J. Med. Chem. 2002,
45, 2563.
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318.
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63, 2564.
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Chem. 2000, 65, 8651.
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Abe, H.; Harayama, T. Chem. Commun. 2000, 1643.
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3870
Org. Lett., Vol. 10, No. 17, 2008

Since its isolation, there have been four reported syntheses,19
two of which described the asymmetric synthesis of se-
dacryptine. Our retrosynthesis of (-)-sedacryptine is shown
in Scheme 3.
Scheme 2. Synthesis of (+)-Isofebrifugine
Scheme 3. Retrosynthesis of (-)-Sedacryptine (2)
The intermediate 15 is derived from the vinylogous amide
16, which in turn is to be assembled from the thiolactam
17, using the Eschenmoser sulfide contraction method.20
Thiolactam 17 is to be prepared from 6 via chemoselective
thionation of the lactam carbonyl group.
Thus, treatment of 6 with Lawesson’s reagent21 proceeded
efficiently (Scheme 4) to give the corresponding thiolactam
17 in excellent yield. Alkylation of 17 with phenacyl bromide
followed by Ph3P gave the vinylogous amide 16 in 67%
yield. We found that the use of 1-methylpiperidine22 as the
base was beneficial because, with Et3N, the yield of 16 was
52%.
Hydrogenation of 16 catalyzed by Adams’ catalyst gave
a 98% yield of the phenyl ketone as a 90:10 ratio of
diastereomers 18a,b. The major diastereomer was assigned
structure 18a on the basis that hydrogenation would pref-
erentially occur from the less hindered convex side of the
bicycle. The stereochemistry of the phenylacetonyl side chain
in 18a was confirmed after installation of the side-chain
benzylic carbinol stereocenter (cf. 15, vide infra).
LiAlH4 gave the piperidine intermediate in 93% yield.
Acylative N-debenzylation using R-chloroethyl chlorofor-
mate12 followed by N-carbamoylation using Boc2O gave the
alkene intermediate 11 in an overall yield of 92%. The
epoxidation of the terminal double bond in 11 turned out
not to be trivial. Epoxidation using m-CPBA was unproduc-
tive, and starting 11 was recovered (86%); m-CPBA oxida-
tion in the presence of K2CO313 led to a low yield (38%) of
the desired epoxide 12, and 50% of 11 was recovered. The
use of DCC/H2O214 gave no epoxide 12 and a low recovery
(56%) of alkene 11. Gratifyingly, it was found that MeReO3
(MTO)-catalyzed epoxidation using H2O2 as co-oxidant in
the presence of 3-cyanopyridine15 was efficient and yielded
the desired epoxide 12 in 80% yield and as an inseparable
mixture of diastereomers. Base-mediated coupling of 12 with
4-quinazolinone16 yielded a diastereomeric mixture of the
secondary alcohol 13. The stereochemistry of the carbinol
center was inconsequential to the synthesis as it will be
converted to a ketone carbonyl in 14. This was accomplished
in 92% yield by oxidation using Dess-Martin periodinane.17
Acid hydrolysis of 14 effected deprotection of the hydroxyl
and amino groups to furnish (+)-isofebrifugine (1). Our
Subsequent N-debenzylation of 18a under catalytic transfer
hydrogenation using Pearlman’s catalyst gave the corre-
sponding piperidine intermediate, which was not purified but
was immediately reacted with methyl chloroformate to
furnish 19 in 63% yield over two steps. Reduction of the
(19) (()-2: (a) Sugiura, M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S.
J. Am. Chem. Soc. 2001, 123, 12510. (b) Natsume, M.; OgawaHeter, M.
Heterocycles 1983, 20, 601. (-)-2: (c) Akiyama, E.; Hirama, M. Synlett
1996, 100(+)-2: (d) Plehiers, M.; Hootele, C. Can. J. Chem. 1996, 74, 2444.
(20) Roth, M.; Dubs, P.; Gotschi, E.; Eschenmoser, A. HelV. Chim. Acta
1971, 54, 710.
synthetic (+)-1 showed [R]22 ) +120.8 (c 0.30, CHCl3)
D
[lit.10b [R]22 ) +124.3 (c 0.50, CHCl3), lit.11c [R]23
)
D
D
+123 (c 0.30, CHCl3), lit.11e [R]23 ) +128.9 (c, 0.31,
D
1
CHCl3)], and its H and 13C NMR data are in accord with
(21) Review Ozturk, T.; Ertas, E.; Mert, O. Chem. ReV. 2007, 107, 5210.
(22) Honda, T.; Kimura, M. Org. Lett. 2000, 2, 3925.
literature data.10a,11e,f
(23) (a) Corey, E. J.; Bakshi, R.; Shibata, S.; Chen, C. P.; Shing, V. K.
J. Am. Chem. Soc. 1987, 109, 7925. Review: Walbaum, S.; Martens, J.
Tetrahedron: Asymmetry 1992, 3, 1475.
The use of building block 6 in the synthesis of (-)-
sedacryptine (2), a 2,6-disubstituted 3-hydroxypiperidine
alkaloid, was next pursued. Sedacryptine is a minor alkaloid
that was isolated, along with sedinine, from Sedum acre.18
Its structure was solved by X-ray crystallographic analysis.
(24) (a) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112,
6392. (b) Dollinger, L. M.; Ndakala, A. J.; Hashemzadeh, M.; Wang, G.;
Wang, Y.; Martinez, I.; Arcari, J. T.; Galluzzo, D. J.; Howell, A. R.;
Rheingold, A. R.; Figuero, J. S. J. Org. Chem. 1999, 64, 7080.
Org. Lett., Vol. 10, No. 17, 2008
3871

Protection of the secondary alcohol in 15 (R ) Me) was
accomplished in high yield using t-BuMe2SiOTf to give 20.
Methylenation of the γ-lactone carbonyl using Petasis’
reagent24 proceeded chemoselectively to give the corre-
sponding cyclic methylidene ether, which was not purified
but treated immediately with dry methanol in the presence
of a catalytic amounts of PPTS. The resultant cyclic ketal
was obtained in a respectable 57% overall yield. Reduction
of the carbamate group of the cyclic ketal with LiAlH4 gave
the N-methylpiperidine derivative 21 (74%).
Scheme 4. Synthesis of (-)-Sedacryptine
Desilylation of 21 followed by hydrolysis of the cyclic
ketal in refluxing aqueous 0.1 M HCl gave sedacryptine (2).
We found it useful to let a methanolic solution of 2 to stand
at rt for 36 h before purification and recrystallization from
cyclohexane.19d Synthetic (-)-2 showed [R]25D ) -13.5 (c
0.74, CHCl3); for (+)-sedacryptine:19d [R]20D ) +14 (c 0.54,
CHCl3). Its spectroscopic data agreed with reported19a,d
literature values.
In summary, we have demonstrated the versatility of the
nonracemic building block 6 in the asymmetric synthesis of
two structurally different 3-hydroxypiperidine alklaoids, (+)-
isofebrifugine and (-)-sedacryptine. The use of 6 provides
flexibility in our approach. Further studies in the use of 6 in
alklaoid synthesis are continuing.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council, Canada, and the University
of Regina for financial support.
ketone group in 19 with BH3·SMe2 catalyzed by (R)-
2MeCBS23 gave a high yield of the corresponding alcohol
15 (R ) Me; Scheme 3) with the desired S-configuration at
the carbinol center. The epimeric alcohol was not detected.
The assigned stereochemistries of the benzylic carbinol
center in 15 (R ) Me) and of the phenylacetonyl side chain
in 18a were established by 1D NOESY experiment on the
cyclic carbamate 22.
Supporting Information Available: Experimental pro-
cedures and data for the preparation of 10-14, (+)-1, 16-21,
(-)-2, and 22, NMR data for compounds 10-14, (+)-1, 16,
18a,b, 19-22, and (-)-2, and 1D NOESY spectra for 22.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL8013864
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Org. Lett., Vol. 10, No. 17, 2008