A diastereocontrolled synthesis of (+)-febrifugine: a potent antimalarial piperidine alkaloid.

Article abstract of DOI:10.1021/ol006384f

A diastereocontrolled synthesis of (+)-febrifugine, a potent antimalarial piperidine alkaloid, has been achieved using a chiral block having a bicyclo[3.2.1]octane framework which exhibits inherent convex-face selectivity.

Full text of DOI:10.1021/ol006384f

ORGANIC
LETTERS
2000
Vol. 2, No. 20
3193-3195
A Diastereocontrolled Synthesis of
(+)-Febrifugine: A Potent Antimalarial
Piperidine Alkaloid
Takahiko Taniguchi and Kunio Ogasawara*
Pharmaceutical Institute, Tohoku UniVersity, Aobayama, Sendai 980-8578, Japan
konol@mail.cc.tohoku.ac.jp
Received July 26, 2000
ABSTRACT
A diastereocontrolled synthesis of (+)-febrifugine, a potent antimalarial piperidine alkaloid, has been achieved using a chiral block having a
bicyclo[3.2.1]octane framework which exhibits inherent convex-face selectivity.
Although (+)-febrifugine 1 and (+)-isofebrifugine 2, con-
stituents of the Chinese medicinal plant Dichroa febrifuga
Lour. (Chinese name: Chang Shan), were isolated more than
a half century ago as active principles against malaria,1 their
absolute structures have just been determined quite recently
as shown2 (Figure 1). Their antimalarial activity as well as
(+)-febrifugine 1 exhibits comparable activity in vivo to the
clinically used drug chloroqine.1f,2b,3 Since its racemate and
natural (+)-isofebrifugine 2 as well as the enantiomers of
the natural products were found to exhibit much less activity
than natural (+)-febrifugine 1 and since febrifugine 1 could
be epimerized to isofebrifugine 2, development of efficient
enantio- and diastereocontrolled preparation of natural (+)-
febrifugine 1 is most important for extensive biological
investigation. If we look at (+)-febrifugine 1 retrosyntheti-
cally, presuming the construction of its piperidine moiety
by a ring-closing metathesis (RCM) reaction,4 we can reach
to the 4-allylamino-3-heptene-3,7-diol 4 which in turn can
be connected to the chiral building block5,6 (-)-5 having a
dioxabicyclo[3.2.1]octane framework. This building block
was readily prepared either by catalytically5 or enzymatically6
from frufural in enantiomerically pure forms and utilized for
Figure 1.
their chemistry was reinvestigated which revealed their high
activity against Plasmodium Malaria parasite. In particular,
(2) (a) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H. Tetrahedron
Lett. 1999, 40, 2175. (b) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.;
Kim, H.-S.; Wataya, Y. J. Org. Chem. 1999, 64, 6833.
(3) Takaya, Y.; Tasaka, H.; Chiba, T.; Uwai, K.; Tanitsu, M.; Kim, H.-
S.; Wataya, Y.; Miura, M.; Takeshita, M.; Oshima, Y. J. Med. Chem. 1999,
42, 3163.
(4) For pertinent reviews, see: Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413. Roy, R.; Das, S. K. Chem. Commun. 2000, 519.
(5) Takeuchi, M.; Taniguchi, T.; Ogasawara, K. Synthesis 1999, 341.
(6) Taniguchi, T.; Takeuchi, M.; Kadota, K.; ElAzab, A. S.; Ogasawara,
K. Synthesis 1999, 1325.
(1) (a) Koepeli, J. B.; Mead, J. F.; Brockman, Jr. J. Am. Chem. Soc.
1947, 69, 1836. (b) Koepeli, J. B.; Mead, J. F.; Brockman, Jr. J. Am. Chem.
Soc. 1949, 69, 1048. (c) Jang, C. S.; Fu, F. Y.; Wang, C. Y.; Huang, K. C.;
Lu, G.; Thou, T. C. Science 1946, 103, 59. (d) Frederick, A. K., Jr.; Spencer,
C. F.; Folkers, K. J. Am. Chem. Soc. 1948, 70, 2091. (e) Barringer, D. F.;
Berkelhammer, G.; Wayne, R. S. J. Org. Chem. 1973, 38, 1937. (f) Murata,
K.; Takano, F.; Fushiya, S.; Oshima, Y. J. Nat. Prod. 1998, 61, 729.
10.1021/ol006384f CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/07/2000

the diastereocontrolled construction of aldohexoses5,7 and
other natural products8 on the basis of its inherent convex-
face selectivity and high functionality. In this paper, we report
its utilization for a diastereocontrolled synthesis of (+)-
febrifugine 1 on the retrosynthetic analysis shown (Scheme
1).
via the primary alcohol 11 (X ) OH), [R]28 +77.5 (c 1.0,
D
CHCl3), by a sequence of reactions involving desilylation,
mesylation, and substitution. The iodide 11 (X ) I), [R]26
D
+33.9 (c 1.1, CHCl3), thus obtained was then treated with
zinc to give the hemiacetal 12 which was further reduced to
afford the dihydroxydiene 13, [R]27D +13.1 (c 1.0, CHCl3).
Upon RCM reaction in the presence of Grubbs’ catalyst10
(5 mol %), 13 furnished the dedihydropiperidine 14 (4,5-
dehydro) in 89% yield, which was hydrogenated to give the
piperidinediol 14, [R]30D -31.3 (c 1.4, CHCl3), corresponding
to the retron 4 (Scheme 3).
Scheme 1
Scheme 3
Enantiopure enone (-)-5 was first converted diastereo-
selectively into the endo-allyl alcohol 6, [R]26D +2.8 (c 1.1,
CHCl3), by convex-face selective 1,2-reduction,9 which was
hydrogenated to give the saturated alcohol 7, [R]28 +17.2
D
(c 1.1, CHCl3). Replacement of the hydroxy functionality
of 7 by an azide was carried out in an acceptable overall
yield through the mesylate 8 which afforded the exo-azide
9, [R]26D +11.8 (c 2.1, CHCl3), on reflux with sodium azide
in DMF. Having installed the nitrogen functionality with the
requisite stereochemistry, the azide 9 was next transformed
into the carbamate 10, [R]30D +17.3 (c 1.0, CHCl3), by one-
pot reduction and carbamoylation. Overall yield of 10 from
the chiral block (-)-5 was 63% in six steps (Scheme 2).
To connect the quinazoline moiety required for (+)-
febrifugine 1, the diol 14 was transformed regioselectively
into the primary sulfide 15 (R ) H), [R]29 -19.5 (c 1.0,
D
CHCl3), on reaction with diphenyl disulfide in pyridine in
the presence of tributylphosphine.11,12 A similar reaction
using o-nitrophenyl selenocyanate13 in place of diphenyl
disulfide proceeded in nonregioselective way. After ben-
zylation of the secondary hydroxy functionality, the benzyl
ether 15 (R ) Bn), [R]27 -29.1 (c 1.1, CHCl3), obtained
D
was converted into the sulfoxide which was refluxed in
diphenyl ether in the presence of calcium carbonate14 to
furnish the terminal olefin 16, [R]28D -45.1 (c 1.0, CHCl3),
in acceptable overall yield. Since direct epoxidation with a
Scheme 2
(8) Utilization of the chiral building block for enantiocontrolled synthesis
of other natural products, see: (a) (+)-noviose: Takeuchi, M.; Taniguchi,
T.; Ogasawara, K. Tetrahedron Lett. 2000, 41, 2609. (b) FK-506 frag-
ment: Takeuchi, M.; Taniguchi, T.; Ogasawara, K. Tetrahedron: Asymmetry
2000, 11, 1601. (c) (-)-Shikimic acid: Takeuchi, M.; Taniguchi, T.;
Ogasawara, K. Synthesis 2000, 1375. (d) (-)-Physostigmine and (-)-
physovenine: ElAzab, A. S.; Taniguchi, T.; Ogasawara, K. Org. Lett. 2000,
2, 2757.
(9) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
(10) Bis(tricyclohexylphosphine)benzylideneruthenium(IV) dichloride
was purchased from Strem Chemicals and used without further purification.
(11) Nakagawa, I.; Hata, T. Tetrahedron Lett. 1975, 1409. Nakagawa,
I.; Aki, K.; Hata, T. J. Chem. Soc., Perkin Trans. 1 1983, 1315.
(12) Takano, S.; Goto, E.; Ogasawara, K. Tetrahedron Lett. 1982, 23,
5567.
(13) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485.
(14) Trost, B. M.; Saltzmann, T. N. J. Am. Chem. Soc. 1973, 95, 6840.
(15) Diastereomeric ratio could not be determined by spectroscopically
(1H NMR).
To construct the piperidine moiety of (+)-febrifugine 1,
the secondary carbamate 10 was first N-allylated to give the
tertiary carbamate 11 (X ) OTBS), [R]28 +37.6 (c 1.1,
D
CHCl3), whose siloxy functionality was replaced by iodine
(16) Cruickshank, P. A.; Fishman, M. J. Org. Chem. 1969, 34, 4060.
(17) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(7) Takeuchi, M.; Taniguchi, T.; Ogasawara, K. Chirality 2000, 12, 338.
3194
Org. Lett., Vol. 2, No. 20, 2000

inseparable mixture of two diastereomers,15 by sequential
dihydroxylation, monotosylation, and base-induced cycliza-
tion. The mixture was then reacted with the potassium salt16
generated from 4-quinazolone to furnish the secondary
alcohol 18 as an inseparable mixture of two diastereomers,15
which was oxidized with the Dess-Martin reagent17 to give
Scheme 4
the protected febrifugine 19, [R]31 -22.0 (c 1.0, CHCl3),
D
as a single product. Finally 19 was refluxed with 6 N
hydrochloric acid to afford (+)-febrifugine 1, mp 152-153
°C, [R]31D +27.5 (c 0.3, EtOH) [natural1b: mp 139-140 °C;
[R]25D +28 (c 0.5, EtOH)], after basic workup, by concurrent
removal of the nitrogen and the oxygen protecting groups.
Overall yield of (+)-febrifugine 1 from the chiral building
block 5 was 11% in 24 steps (Scheme 4).
In conclusion, we have demonstrated an alternative utiliza-
tion of the chiral building block which is developed for the
construction of the aldohexoses by a diastereocontrolled
synthesis of (+)-febrifugine.
Acknowledgment. We thank Professor Yoshiteru Oshi-
ma, Pharmaceutical Institute, Tohoku University, for kindly
providing us with natural (+)-febrifugine for comparison and
helpful discussions.
peracid proceeded very slowly, 16 was converted sequentially
into the epoxide 17 corresponding to the retron 3, as an
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