A concise enantioselective synthesis of antimalarial febrifugine alkaloids.

Article abstract of DOI:10.1021/ol015655z

Reaction of (S)-2-(tert-butyldiphenylsilyloxy)-5-(mesyloxy)pentanal with hydroxylamine in allyl alcohol brought about simultaneous 1,3-dipolar cycloaddition of the resulting nitrone to allyl alcohol to give three diastereoisomeric adducts, from which (+)-febrifugine and (+)-isofebrifugine, potent antimalarial alkaloids, were synthesized.

Full text of DOI:10.1021/ol015655z

ORGANIC
LETTERS
2001
Vol. 3, No. 6
953-955
A Concise Enantioselective Synthesis of
Antimalarial Febrifugine Alkaloids
Hidenori Ooi, Ayumi Urushibara, Tomoyuki Esumi, Yoshiharu Iwabuchi, and
Susumi Hatakeyama*
Faculty of Pharmaceutical Sciences, Nagasaki UniVersity, Nagasaki 852-8521, Japan
susumi@net.nagasaki-u.ac.jp
Received February 5, 2001
ABSTRACT
Reaction of (S)-2-(tert-butyldiphenylsilyloxy)-5-(mesyloxy)pentanal with hydroxylamine in allyl alcohol brought about simultaneous 1,3-dipolar
cycloaddition of the resulting nitrone to allyl alcohol to give three diastereoisomeric adducts, from which (+)-febrifugine and (+)-isofebrifugine,
potent antimalarial alkaloids, were synthesized.
Febrifugine (1) and isofebrifugine (2) are active principals
against malaria, occurring in the roots of Dichroa febrifuga
(Chinese name: Cha´ng Shan)1 and related hydrangea plants.2
The absolute structures of these alkaloids were elucidated
by the asymmetric total synthesis achieved by Kobayashi
and co-workers.3 Recently, Oshima and co-workers reported4
that analogue 3, prepared by Mannich reaction of 1 with
Plasmodium falciparum with good therapeutic selectivity as
well as comparable activity in vivo to that of chloroquine.
This finding as well as its low availability from natural
sources has spurred much research on the synthesis of
febrifugine and its analogues with the aim of developing a
new antimalarial drug.3,5
We now wish to report an efficient synthesis of (+)-
febrifugine (1) and (+)-isofebrifugine (2) in naturally oc-
curring forms based on a new strategy, which relies on 1,3-
dipolar cycloaddition6 of nitrone 4 to allyl alcohol.
(2) (a) Ablondi, F.; Gordon, S.; Morton, J.; II.; Williams, J. H. J. Org.
Chem. 1952, 17, 14. (b) Kato, M.; Inaba, M.; Itahana, H.; Ohara, E.;
Nakamura, K.; Uesato, S.; Inouye, H.; Fujita, T. Shoyakugaku Zasshi 1990,
44, 288.
(3) (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.
(4) 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.
(5) (a) Takeuchi, Y.; Abe, H.; Harayama, T. Chem. Pharm. Bull. 1999,
47, 905. (b) Takeuchi, Y.; Hattori, M.; Abe, H.; Harayama, T. Synthesis
1999, 1814. (c) Okitsu, O.; Suzuki, R.; Kobayashi, S. Synlett 2000, 989.
(d) Takeuchi, Y.; Azuma, K.; Takakura, K.; Abe, H.; Harayama, T. J. Chem.
Soc., Chem. Commun. 2000, 1643. (e) Taniguchi, T.; Ogasawara, K. Org.
Lett. 2000, 2, 3193.
acetone, exhibits potent antimalarial activity against both
chloroquine-sensitive and chloroquine-resistant strains of
(1) (a) Koepeli, J. B.; Mead, J. F.; Brockman, J. A., Jr. J. Am. Chem.
Soc. 1947, 69, 1837. (b) Koepeli, J. B.; Mead, J. F.; Brockman, J. A., Jr.
J. Am. Chem. Soc. 1949, 71, 1048.
(6) For a review on asymmetric 1,3-dipolar cycloaddition reactions,
see: Gothelf, K. V.; Jørgensen, K. A. Chem. ReV. 1998, 98, 863.
10.1021/ol015655z CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/24/2001

Tufariello and co-worker7 reported that 1,3-dipolar cy-
cloaddition of 2,3,4,5-trahydropyridine-1-oxide to allyl al-
cohol took place with perfect regioselectivity and high exo-
selectivity to produce the corresponding cycloadduct in
excellent yield. This report prompted us to envisage the
synthesis of febrifugine alkaloids by employing a 1,3-dipolar
cycloaddition reaction of chiral nitrone 4 with allyl alcohol
as a key reaction despite uncertainty of the regio- and
stereoselectivity (Scheme 1).8 In this approach, the stereo-
Scheme 2
Scheme 1
selectivity of the key cycloaddition is not a serious problem
because, as long as the regioselectivity is perfect, all
stereoisomers of 5 would be converted to either febrifugine
(1) or isofebrifugine (2) via 6 and isofebrifugine (2) can be
isomerized to febrifugine (1) through equilibration via 7.4,5d
Our synthesis started with kinetic resolution of racemic
propargylic alcohol 89 by lipase-mediated acetylation (Scheme
2). Thus, reaction10 of 8 with vinyl acetate in the presence
of Novozym 435 in tert-butyl methyl ether at room temper-
ature gave (S)-acetate 9 (91% ee)11 and (R)-8 (78% ee) in
43% and 54% yields, respectively. Lindlar semi-hydrogena-
tion followed by in situ methanolysis and silylation converted
9 into olefin 10 in 80% yield. Upon reductive removal of
the benzyl ether using lithium naphthalenide12 and mesyla-
tion, 10 gave mesylate 11 in 93% yield. After ozonolysis of
11, the resulting aldehyde 12 was directly reacted13 with
hydroxylamine hydrochloride in the presence of triethylamine
in allyl alcohol at room temperature. As a result, nitrone 14
was generated in situ via oxime 13 which underwent
simultaneous 1,3-dipolar cycloaddition to allyl alcohol to give
15, 16, and 17 in a ratio of 64:10:26 in 74% yield from 11.
The stereostructures of these diastereomers were determined
by NOE experiments of the corresponding acetates. The
optical purity (>90% ee) of the acetates11 allowed us to
conclude that no racemization occurred during formation of
the nitrone and the cycloaddition. Interestingly, 1,3-dipolar
cycloaddition of 14 to allyl acetate also occurred at room
temperature with perfect regioselectivity, and the acetates
of 15, 16, and 17 were quantitatively produced in exactly
the same ratio as observed in the reaction of 14 with allyl
alcohol. These results tell us that both cycloadditions
occurred with 90:10 exo/endo-selectivity, 74:26 diastereo-
facial selectivity, and perfect regioselectivity.
Although the above-mentioned 1,3-dipolar cycloadducts
were separable by silica gel column chromatography, the
following reactions were carried out without separation. The
diastereoisomeric mixture of adducts was subjected to
hydrogenolytic N-O bond fission and tert-butoxycarbony-
lation to give diol 18 in 94% yield. Reaction of 18 with
N-tosylimidazole14 in the presence of NaH afforded epoxide
19, which was then reacted5e with the potassium salt
(7) Tufariello, J. J.; Ali, A. A. Tetrahedron Lett. 1978, 4647.
(8) Goti et al. reported that reaction of 3-(tert-butyldimethylsilyl)oxy-
1-pyrroline-1-oxide, a five-membered ring nitrone, with allyl alcohol
occurred with perfect regioselectivity but poor stereoselectivity: Goti, A.;
Cicci, S.; Fedi, V.; Nannelli, L.; Brandi, A. J. Org. Chem. 1997, 62, 3119.
(9) Prepared from 1,4-butanediol in 70% yield by a three-step sequence
involving benzylation (PhCH2Br, NaH, DMF), Swern oxidation, and
addition of acetylene (C2HMgBr, THF, 0 °C).
(10) For lipase-catalyzed resolution of racemic propargylic alcohols,
see: (a) Ohtani, T.; Kikuchi, K.; Kamezawa, M.; Hamatani, H.; Tachibana,
H.; Totani, T.; Naoshima, Y. J. Chem. Soc., Perkin Trans. 1 1996, 961. (b)
Ohtani, T.; Nakatsukasa, H.; Kamezawa, M.; Tachibana, H.; Naoshima, Y.
J. Mol. Catal. B.: Enzym. 1998, 4, 53. (c) Morishita, K.; Kamezawa, M.;
Ohtani, T.; Tachibana, H.; Kawase, M.; Kishimoto, M.; Naoshima, Y. J.
Chem. Soc., Perkin Trans. 1 1999, 513.
(13) Obtained via modification of the procedure for substituted pyrroline-
1-oxides: see ref 8 and Closa, M.; Wightman, R. H. Synth. Commun. 1998,
28, 3443.
(11) Determined by HPLC analysis using a chiral column (Chiralcel OD).
(12) Liu, H.-J.; Yip, J.; Shia, K.-S. Tetrahedron Lett. 1997, 38, 2253.
(14) Cink, R. D.; Forsyth, C. J. J. Org. Chem. 1995, 60, 8122.
954
Org. Lett., Vol. 3, No. 6, 2001

generated from 4-quinazolone to give alcohol 20 in 71%
overall yield (Scheme 3). Dess-Martin oxidation15 of 20
corresponding natural specimens by spectroscopic and
chromatographic comparisons. The ratio of 1 and 2 (67:33)
produced tells us that isomerization between these alkaloids
occurred through a reversible Michael reaction process under
the above-mentioned acidic hydrolysis conditions (reflux, 4
h). Prolonged reaction times (reflux, 12 h) led to a 62:38
mixture of 1 and 2. Furthermore, after separation, 21 and
22 were subjected to acidic hydrolysis under the exact
conditions as used above, respectively. As a result, it was
found that 21 provided a 84:16 mixture of 1 and 2 while 22
gave only 2. These results suggest that, under acidic
conditions, febrifugine (1) can undergo this isomerization
but isofebrifugine (2) cannot.16 Isofebrifugine (2) thus
obtained was converted to febrifugine (1) in 50% yield by
isomerization under neutral conditions (MeOH, reflux) as
reported by Oshima and co-workers.4
Scheme 3
In conclusion, (+)-febrifugine (1) and (+)-isofebrifugine
(2) were synthesized from easily available chiral building
block 9 in 12 steps in 21% and 10% overall yields,
respectively. The convergent route established herein should
enable us to synthesize a variety of interesting analogues.
Acknowledgment. We thank Professor Yoshiteru Oshi-
ma, Pharmaceutical Institute, Tohoku University, for kindly
providing us with natural febrifugine and isofebrifugine and
their spectra. This work was supported in part by a Grant-
in-Aid for Scientific Research on Priority Areas (No.
11147225) from the Ministry of Education, Science, Sports
and Culture of Japan.
afforded a 78:22 separable mixture of 21 and 22 in almost
quantitative yield. Finally, this epimeric mixture was sub-
jected to acid hydrolysis in boiling hydrochloric acid to
24
furnish (+)-febrifugine (1), [R]D +28.0° (c 0.30, EtOH),
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
31
mp 152-154 °C [lit.5e mp 152-153 °C, [R]D +27.5° (c
0.30, EtOH)], and (+)-isofebrifugine (2), [R]D22 +130.0° (c
23
0.30, CHCl3), mp 152-154 °C [lit.1 mp 129-130 °C, [R]D
+131° (c 0.35, CHCl3)], in 58% and 27% yields, respec-
tively. The synthetic 1 and 2 were identical with the
OL015655Z
(16) Takeuchi and co-workers also reported that isofebrifugine (2) did
not isomerize under acidic conditions; see ref 5d.
(15) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
Org. Lett., Vol. 3, No. 6, 2001
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