Asymmetric synthesis of antimalarial alkaloids (+)-febrifugine and (+)-isofebrifugine

Article abstract of DOI:10.1055/s-2003-40988

Diastereoselective α,-amidoalkylation of N,O-acetal, derivated from controlled regio and diastereoselective reduction of (S)-N-(4-methoxybenzyl)-3-silyloxyglutarimide provided two diastereomeric 6-allyl-5-silyloxy-2-piperidinones in 76:24 selectivity. The transformation of the major diastereomer into a known advanced intermediate allowed the synthesis of (+)-febrifugine and (+)-isofebrifugine.

Full text of DOI:10.1055/s-2003-40988

LETTER
1663
Asymmetric Synthesis of Antimalarial Alkaloids (+)-Febrifugine and
(+)-Isofebrifugine
Asymmetric
S
e
ynthesisof
i
A
ntim
-
A
Q
lkaloids iang Huang,* Bang-Guo Wei, Yuan-Ping Ruan
Department of Chemistry, Xiamen University, Xiamen, Fujian 361005, China
Fax +86(592)2186400; E-mail: pqhuang@xmu.edu.cn
Received 13 June 2003
OH
N
O
N
O
O
Abstract: Diastereoselective a-amidoalkylation of N,O-acetal, de-
O
OH
rivated from controlled regio and diastereoselective reduction of
N
N
N
N
H
(S)-N-(4-methoxybenzyl)-3-silyloxyglutarimide provided two dia-
stereomeric 6-allyl-5-silyloxy-2-piperidinones in 76:24 selectivity.
H
The transformation of the major diastereomer into a known ad-
vanced intermediate allowed the synthesis of (+)-febrifugine and
(+)-isofebrifugine.
2. isofebrifugine
1. febrifugine
O
OH
O
N
Br
Cl
O
N
Key words: piperidines, alkaloids, allylations, N,O-acetal, asym-
metric synthesis
H
OH
N
N
N
.HBr
H
O
N
3. halofuginone hydrobromide
(+)-Febrifugine (1) and (+)-isofebrifugine (2)1 are two al-
kaloids isolated from Chinese medicinal plants Dichroa
febrifuga Lour. (Chang Shan)2,3 and related hydrangea
arten.4 The structures of febrifugine and isofebrifugine
have puzzled chemists for decades,4,5 and were unambig-
uously determined in 1999 by Kobayashi et al via asym-
metric total synthesis.6 The antimalarial activity2,3,7
exhibits by these two compounds have stimulated inten-
sive chemical and biological studies, which has led to the
development of halofuginone (3) as an antiparasitic feed
additive,8a which has recently been shown to inhibit col-
lagen production and is currently under clinical trials for
treatment of scleroderma in human.8b Recent studies also
led to the isolation of hydrachine A (4) as a novel alka-
loid,9 and led to the discovery of several febrifugine ana-
logues,10 which show potent antimalarial activity
(Figure 1). In addition, crude drug Dichroa febrifuga
Lour. also exhibits bioactivity of enhancement of NO pro-
duction in activated macrophages in vivo.2c Although the
synthetic activities directed towards febrifugine and
isofebrifugine have lasted for decades,11 not until very re-
cently have their total asymmetric synthesis been
achieved.6,12 In continuation of our ongoing program
aimed at the development of a general approach to bioac-
tive 2-substituted 3-piperidinols and 2-substituted 3-ami-
nopiperidines,13 we now report a new asymmetric
synthesis of febrifugine and isofebrifugine.
4. hydrachine A
Figure 1
ed form) as the key advanced intermediates in the asym-
metric synthesis of febrifugine and isofebrifugine, these
diastereomers were chosen as the key intermediates in our
approach to febrifugine and isofebrifugine (Scheme 1).
Piperidine derivatives 5 and 6 could be accessible from
appropriately protected 6-allyl-5-hydroxy-2-piperidi-
nones such as 7 or 8, which in turn was considered to be
prepared from 9 or 10.
OP2
OTBDMS
O
from 5, ref.12a,d
from 6, ref. 12c
1, 2
X
N
O
N
P
H
P1
5. P1=Cbz, P2=H, X=2H, β-H
9. P=Bn
10. P=PMB
6. P1=Cbz, P2=Bn, X=2H, α-H
7. P1=Bn, P2=TBDMS, X=O
8. P1=PMB, P2=TBDMS, X=O
Scheme 1
As a first attempt, we chosen to explore N-benzyl protect-
ed 2-piperidinone 7 as a ready precursor to 5/6. Thus, lac-
tone-amide 11 was prepared from (S)-glutamic acid13 via
the one-pot diazodation – acid chloride formation14 and
amidation in an overall yield of 85% (Scheme 2). Treat-
ment of lactone-amide 11 with t-BuOK in THF at –78 °C
resulted in the expected ring expansion13 product (–)-12 in
90% yield. Protection of the hydroxy group provided the
desired N-benzyl-3-silyoxyglutarimide 9. Controlled
regioselective C-2 carbonyl reduction of 9 to hydroxy lac-
tam 13 was achieved using sodium borohydride in meth-
anol at low temperature as described previously13 and
as documented for malimides.15 It is to note that when
In previous studies,13 we showed that N-protected 3-hy-
droxyglutarimide could be served as a valuable chiral
building block for the asymmetric synthesis of 3-piperi-
dinols via an intramolecular phenyl migration. In view of
the success use of both cis and trans N-carbamoyl 2-allyl-
3-piperidinol 512a,d and 612c (the later in O-benzyl protect-
Synlett 2003, No. 11, Print: 02 09 2003. Web: 05 08 2003.
Art Id.1437-2096,E;2003,0,11,1663,1667,ftx,en;U11503ST.pdf.
DOI: 10.1055/s-2003-40988
© Georg Thieme Verlag Stuttgart · New York

1664
P.-Q. Huang et al.
LETTER
the reduction was performed at temperature between –14 Attempt reduction of the amide carbonyl of cis-7 with
to –10 °C, a good balance of C-2 regioselectivity (11:1) lithium aluminum hydride (LiAlH4, 7 molar equiv., 40 °C,
and chemical yield (80%) was obtained. In all cases, a 2.5 h) resulted in the desired piperidine derivative 17 in
mixture of two diastereomers was obtained, which with- 57% yield and the concomitant formation of desilylated
out further separation was treated with methanol in the product 18 in 28% yield (Scheme 4). This observation led
presence of montmorillonite clay (K-10)16 to give N,O-ac- us to consider an one-pot carbonyl reduction–desilylation
etal 14 as the sole diastereomer (yield, 90%). The stere- protocol. Indeed, when heating a suspension of cis-7 and
ochemistry of 14 was not determined.17 Standard 9 molar equivalents of LAH in THF at 60 °C for 5 hours,
acetylation of 13 resulted in an inseparable diastereomeric 3-piperidinol 18 was formed in 74% yield. Unfortunately,
mixture of 15. On the other hand, treatment of 13 using after several attempts, we were unable to realize the key
Ley’s conditions18 (CaCl2, PhSO2H, CH2Cl2, r.t.) yielded one-pot debenzylative–carbamoylation20 (CbzCl, THF,
sulfone 16 as a separable diastereomeric mixture in 91:9 reflux)11g for the conversion of 17 to 19. At this stage, the
ratio (combined yield, 86%).
change of N-protective group from benzyl (in 7 and 9) to
4-methoxybenzyl (in 8 and 10) appeared to be an attrac-
tive solution to our approach, because PMB is a well-
known complementary protective group to benzyl21 in the
sense that the former is removable under mild oxidative
conditions.22
NH2
H
t-BuOK, THF
1. ref. 14
O
CONH
–78 oC to –40 o
90%
C
2. SOCl2
3. BnNH2
85 %
O
HOOC COOH
Bn
(S)-11
(S)-Glu
OH
O
OTBDMS
OH
OTBDMS
NaBH4
TBDMSCl
LiAlH4, 7 equiv.
+
MeOH, –14 to –10 o
80%
C
cis-7
40 oC, 2.5 h; or
LiAlH4, 9 equiv.
60 oC, 5 h;
imid., CH2Cl2
95%
O
N
O
N
O
N
N
Bn
(S)-12
Bn
(S)-9
Bn
18
P
(17 57% + 18 28%
or 18 74%)
17. P=Bn
19. P=Cbz
OTBDMS
OTBDMS
OH
K10, MeOH, r.t.
or
Ac2O, CH2Cl2
or
Scheme 4
O
N
X
O
N
Bn
For this purpose, known N-(p-methoxybenzyl)-3-
hydroxyglutarimide (S)-20,13 easily prepared from (S)-
glutamic acid (Scheme 1) as described previously,13 was
silylated (TBDMSCl, DMAP, imidazole, r.t., overnight)
to give O-silylated product (S)-10 {colorless solid. Mp
Bn
PhSO2H, CaCl2
14. X=OMe, 90%
15. X=OAc, 96%
16. X=SO2Ph, 86%
13
Scheme 2
20
63–64 °C. [a]D –19.2 (c 1.1, CHCl3)} in 95% yield
With synthetic equivalents (14–16) of N-acyliminium19 in
hands, we investigated Lewis acid induced allylation of
14–16. Thus, treatment of N,O-acetal 14 with allyltrime-
thylsilane in the presence of BF3·OEt2 yielded a disap-
pointing 50:50 mixture of cis-7 and trans-7 (combined
yield, 96%), which were separable by flash chromatogra-
phy (Scheme 3). When starting from acetate 15 and using
TiCl4 as a Lewis acid the trans–cis ratio was 34:66. Reac-
tion of sulfone 16 with allyltrimethylsilane or allyltributyl
stannane in the presence of anhydrous ZnCl2 gave similar
low ratio’s of 51:49 and 57:43, respectively, the major
isomer was tentatively assigned as cis based on the mech-
anistic considerations.15c This was partially confirmed by
comparing the silica gel chromatographic behavior of the
two diastereomers cis-7 and trans-7 with that of 8 and 23,
trans-diastereomers being faster eluting diastereomers.
(Scheme 5). Regio and stereoselective reduction of imide
(S)-10 C-2 carbonyl furnished predominantly hydroxy
amide 21 in 88:12 regioselectivity and as a diastereomeric
mixture (combined yield, 82%). In the light of the above-
mentioned studies on N-benzyl series, acetate 22 was se-
lected as the substrate for the stereoselective allylation.
Thus, acetylation of the diastereomeric mixture of 21 gave
acetate 22 as a partially separable diastereomeric mixture.
Repeated flash chromatography allowed to obtain a sam-
ple of pure major diastereomer, which showed a J5,6 = 3.5
Hz.
OTBDMS
NaBH4 , CH3OH
OH
O
TBDMSCl, DMAP,
imid., CH2Cl2
0 oC-r.t., overnight
>95 %
O
N
O
N
O
–15 oC, 25 min,
82 %
PMB
PMB
(S)-20
(S)-10
OTBDMS
OTBDMS
OAc
OTBDMS
OTBDMS
Lewis acid
AllR3M
CH2Cl2, –78 oC;
Ac2O , Et3N ,
14–16
+
DMAP, r.t. 3 h
97 %
O
N
O
N
O
N
O
N
OH
then r.t.
PMB
Bn
Bn
PMB
cis-7
trans-7
21
22
Scheme 3
Scheme 5
Synlett 2003, No. 11, 1663–1667 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of Antimalarial Alkaloids (+)-Febrifugine and (+)-Isofebrifugine
1665
For the allylation of 22, after several trials, it was found febrifugine (+)-1, which was characterized as its dihydro-
that when the reaction was conducted by very slow addi- chloride {colorless solid, mp 217–219 °C (dec.); lit.12d
tion of a CH2Cl2 solution of freshly distillated TiCl4 to a 218–219 °C; lit.4a 223–225 °C. [a]D20 +12.5 (c 0.2, H2O);
cooled (–78 °C) CH2Cl2 solution of 22 and allyltrimethyl- lit.12d [a]D29 +13.3 (c 1.01, H2O); lit.4a [a]D31 +12.8 (c 0.85,
silane, and keeping the reaction at –78 °C for 4 hours be- H2O)}.
fore warming up, a 76:24 stereoselectivity, in favor of cis-
Next, the possibility for the conversion of the minor dia-
stereomer (23) resulted from the allylation of 22 to anoth-
isomer 8 was achieved23 (both the stereoselectivity and
the cis versus trans diastereoisomer attribution were de-
er key intermediate for (+)-febrifugine (1) was examined.
duced from the followed step, Scheme 6). Although the
Thus as outlined in Scheme 7, treatment of 25 with an ex-
cess of lithium aluminum hydride followed by reaction of
the resultant trans-2-allyl-3-piperidinol with Cbz-Cl fur-
allylation products 8 and its isomer 23 are only partially
separable, we were delight to find that the two diastereo-
mers were easily separable after removal of N-protective
nished 26 in an overall yield of 67%. O-Benzylation of 26
group (PMB) under oxidative conditions (CAN, MeCN/
under standard conditions afforded known 6 {[a]D28 –47.8
1
H2O, r.t., 25 min., 63%).22 Moreover, well resolute H
20
(c 1.0, CHCl3); lit.12c [a]D –45.1 (c 1.0, CHCl3)} in a
NMR spectra of both 2424 and its stereoisomer 2524 al-
yield of 87%. Since 6 has previously been converted to
lowed an easy assignment of stereochemistry.17 Thus, the
(+)-febrifugine (1),12c the simple transformations showed
major isomer (24) showing a vicinal coupling constants:
in Scheme 7 not only allowed to confirm the stereochem-
J
5,6 = 2.8 Hz, was assigned as cis-isomer (24), and the mi-
istry of 25, but also constituted a formal synthesis of (+)-
febrifugine (1), and thus justified the utility of the minor
diastereomer 23.
nor isomer with a vicinal coupling constants J5,6 = 6.5 Hz,
was assigned to trans-isomer (25).
OTBDMS
OTBDMS
OP
AllMe3Si, TiCl4
1. LAH, 60 oC, 6 h;
(+)-febrifugine 1
+
22
25
CH2Cl2, –78 oC,
4 h; r.t., 10 h
O
N
P
O
N
P
ref. 12c
N
2. CbzCl, NEt3, r.t.
67 %
(76:24)
Cbz
26. P= H
6. P=Bn
95%
8. P=PMB
24. P=H
CAN, MeCN/H2O
r.t., 25 min., 63 %
23. P=PMB
25. P=H
BnBr, NaH
THF, 87%
OH
i. LiAlH4, THF, 60 oC, 6 h;
Scheme 7
4 steps,
overall yield 27.6 %
24
N
ref. 12a,d
ii. CbzCl, Et3N, DMAP,
CH2Cl2, 68 %
In conclusion, we have demonstrated that (S)-1-(p-meth-
oxybenzyl)-3-silyloxyglutarimide is a valuable chiral
building block, which could be used in the asymmetric
synthesis of natural enantiomers of (+)-febrifugine and
(+)-isofebrifugine. Investigation is in progress for the
application of this new chiral 3-piperidinol synthon in the
asymmetric synthesis of other 3-piperidinol-based alka-
loids.
Cbz
(2S, 3S)-5
i. H2O, 80 oC, 15 min.
(+)-febrifugine 1
(+)-isofebrifugine 2
ii. 10 % HCl,
68 %
Scheme 6
The cis stereochemistry of 24 was later and unambiguous-
ly confirmed by its conversion to known compounds
(2S,3S)-5, isofebrifugine (2) and febrifugine (1)
(Scheme 6). The transformation of 24 to (2S,3S)-5 was
achieved via an one-pot amide reduction-desilylation
(vide infra) by an excess of lithium aluminum hydride in
refluxing tetrahydrofuran for 6 hours, followed by reac-
tion with Cbz-Cl. The overall yield from 24 to 5 was 68%.
Acknowledgement
The authors are grateful to the National Science Fund for Distin-
guished Young Investigators, the NNSF of China, (29832020;
20072031; 20272048; 203900505) and the Fund for doctoral sites
of the Ministry of Education for financial support.
20
Compound (2S,3S)-5 {colorless oil. [a]D +77.1 (c 1.0,
References
24
20
EtOH); lit.12a [a]D +76.2 (c 1.0, EtOH); lit.12d [a]D
(1) b-Dichroine and a-dichroine are two names once been
proposed to two of three isomeric alkaloids isolated from
Dichroa febrifuga Lour., which were correlated with
febrifugine and isofebrifugine respectively, see ref.2b,3b
(2) (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. J. Am. Chem. Soc. 1949, 71, 1048.
(c) Murata, K.; Takeno, F.; Fushiya, S.; Oshima, Y. J. Nat.
Prod. 1998, 61, 729.
+78.5 (c 1.00, EtOH), 97% ee} showed the same spectral
data as reported. Chiral HPLC analysis on a chiral column
showed that the ee of thus synthesized (2S,3S)-5 was
97.18%.25 Following Takeuchi’s four-step procedure,12a,d
(2S,3S)-5 was converted, in an overall yield of 27.6%, into
isofebrifugine (+)-2 {white solid, mp 126–128 °C; lit.2b,12d
27
mp 129–130 °C. [a]D20 +123 (c 0.30, CHCl3); lit.12d [a]D
+124.3 (c 0.5, CHCl3); lit.12i [a]D +128.9 (c 0.319,
20
(3) (a) Chou, T. Q.; Jang, C. S.; Fu, F. Y.; Kao, Y. S.; Huang, K.
C. Science (Chinese) 1947, 29, 49. (b) Chou, T.-Q.; Fu, F.
Y.; Kao, Y. S. J. Am. Chem. Soc. 1948, 70, 1765.
CHCl3); lit.2b [a]D23 +131 (c 0.35, CHCl3)}. Finally, heat-
ing an aqueous solution of isofebrifugine (+)-2 at 80 °C
for 15 minutes afforded the desired epimerized product
Synlett 2003, No. 11, 1663–1667 © Thieme Stuttgart · New York

1666
P.-Q. Huang et al.
LETTER
(4) (a) Ablondi, F.; Gordon, S.; Morton, J. II; Williams, J. H. J.
Org. Chem. 1952, 17, 14. (b) Hutchings, B. L.; Gordon, S.;
Ablondi, F.; Wolf, C. F.; Williams, J. H. J. Org. Chem. 1952,
17, 19.
(15) (a) Chamberlin, A. R.; Chung, J. Y. L. J. Am. Chem. Soc.
1983, 105, 3653. (b) Klaver, W. J.; Hiemstra, H.; Speckamp,
W. N. J. Am. Chem. Soc. 1989, 111, 2588. (c) Bernardi, A.;
Micheli, F.; Potenza, D.; Scolastico, C.; Villa, R.
(5) (a) Koepfli, J. B.; Brockman, J. A.; Moffat, J. J. Am. Chem.
Soc. 1950, 72, 3323. (b) Baker, B. R.; McEvoy, F. J.;
Schaub, R. E.; Joseph, J. P.; Williams, J. H. J. Org. Chem.
1953, 18, 178. (c) Takeuchi, Y.; Azuma, K.; Abe, H.;
Sasaki, K.; Harayama, T. Chem. Pharm. Bull. 2002, 50,
1011. (d) Takeuchi, Y.; Azuma, K.; Oshige, M.; Abe, H.;
Nshioka, H.; Sasaki, K.; Harayama, T. Tetrahedron 2003,
59, 1639.
(6) (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.
(7) (a) Jang, C. S.; Fu, F. Y.; Wang, C. Y.; Huang, K. C.; Lu, G.;
Thou, T. C. Science 1946, 103, 59. (b) Frederick, A. K. Jr.;
Spencer, C. F.; Folkers, K. J. Am. Chem. Soc. 1948, 70,
2091.
(8) (a) Waletzky, E.; Berkelhammer, G.; Kantor, S. U. S. Patent
3320124, 1967. (b) Elkin, M.; Reich, R.; Nagler, A.;
Aingorn, E.; Pines, M.; De Groot, N.; Hochberg, A.;
Vlodavsky, I. Clin. Cancer Res. 1999, 5, 1982.
Tetrahedron Lett. 1990, 31, 4949.
(16) For a review on clay and clay-supported reagents in organic
synthesis, see: Varma, R. S. Tetrahedron 2002, 58, 1235.
(17) There is not a general rule for determining the relative
stereochemistry of 5,6-disubstituted 2-piperidinones by 1H
NMR vicinal coupling constants (J5,6). However, during the
course of this work, we were able to observed that for N-
unsubstituted 6-substituted 5-alkoxy- or 5-silyloxy-2-
piperidinones, trans-isomers generally show larger J5,6
(J5,6>3 Hz) than those of cis-isomers (J5,6<3 Hz). Two
literature precedents listed below are in support of this
argument: (a) Boudreault, N.; Ball, R. G.; Bayly, C.;
Bermstein, M. A. Tetrahedron 1994, 50, 7947. (b)Bach,T.;
Bergmann, H.; Brummerhop, H.; Lewis, W.; Harms, K.
Chem.–Eur. J. 2001, 7, 4512.
(18) Brown, D. S.; Charreau, P.; Hansson, T.; Ley, S. V.
Tetrahedron 1991, 47, 1311.
(19) For a recent review on a-amidoalkylation of N-acyliminium,
see: Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000,
56, 3817.
(9) Patnam, R.; Chang, F.-R.; Chen, C.-Y.; Kuo, R. Y.; Lee, Y.
H.; Wu, Y. C. J. Nat. Prod. 2001, 64, 948.
(20) Campbell, A. L.; Pilipauqkas, D. R.; Khanna, I. K.; Rhodes,
R. A. Tetrahedron Lett. 1987, 28, 2331.
(10) (a) 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. (b) 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.
(21) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Chemistry, 2nd ed.; Wiley: New York, 1991, 401.
(22) (a) Yamaura, M.; Suzuki, T.; Hashimoto, H.; Yoshimura, J.;
Okamoto, T.; Shin, C. Bull. Chem. Soc. Jpn. 1985, 58, 1413.
(b) Yoshimura, J.; Yamaura, M.; Suzuki, T.; Hashimoto, H.
Chem. Lett. 1983, 1001.
(11) (a) Baker, B. R.; Schaub, R. E.; McEvoy, F. J.; Williams, J.
H. J. Org. Chem. 1952, 17, 132. (b) Baker, B. R.; Schaub,
R. E.; McEvoy, F. J.; Williams, J. H. J. Org. Chem. 1953, 18,
153. (c) Baker, B. R.; McEvoy, F. J.; Schaub, R. E.; Joseph,
J. P.; Williams, J. H. J. Org. Chem. 1953, 18, 178. (d) See
also: Baker, B. R.; McEvoy, F. J. J. Org. Chem. 1955, 20,
118. (e) Baker, B. R.; McEvoy, F. J. J. Org. Chem. 1955, 20,
136. (f) Hill, R. K.; Edwards, A. G. Chem. Ind. 1962, 858.
(g) Barringer, D. F. Jr.; Beakelhammer, G. B.; Wayne, R. S.
J. Org. Chem. 1973, 38, 1937. (h) Burgess, L. E.; Gross, E.
K. M.; Jurka, J. Tetrahedron Lett. 1996, 37, 3255.
(i) Takeuchi, Y.; Hattori, M.; Abe, H.; Harayama, T.
Synthesis 1999, 1814.
(12) (a) Takeuchi, Y.; Azuma, K.; Takakura, K.; Abe, H.;
Harayama, T. Chem. Commun. 2000, 1643. (b) Okitsu, O.;
Suzuki, R.; Kobayashi, S. Synlett 2000, 989. (c) Taniguchi,
T.; Ogasawara, K. Org. Lett. 2000, 2, 3193. (d) Takeuchi,
Y.; Azuma, K.; Takakura, K.; Abe, H.; Kim, H.-S.; Wataya,
Y.; Harayama, T. Tetrahedron 2001, 57, 1213. (e) Ooi, H.;
Urushibara, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S.
Org. Lett. 2001, 3, 953. (f) Sugiura, M.; Kobayashi, S. Org.
Lett. 2001, 3, 477. (g) Sugiura, M.; Hagio, H.; Hirabayashi,
R.; Kobayashi, S. Synlett 2001, 1225. (h) Okitsu, O.;
Suzuki, R.; Kobayashi, S. J. Org. Chem. 2001, 66, 809.
(i) Sugiura, M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S. J.
Am. Chem. Soc. 2001, 123, 12510.
(23) To a cooled (–78 °C) solution of 22 (348 mg, 0.85 mmol) in
anhyd CH2Cl2 (10 mL) was added dropwise allyltrimethyl-
silane (0.270 mL, 1.71 mmol). After being stirred for 5 min,
a solution of TiCl4 (0.14 mL, 1.283 mmol) in anhyd CH2Cl2
(2 mL) was added over a period of 40 min. The mixture was
stirred for 4 h at the same temperature and then allowed to
warm to r.t. and stirred for 10 h. After which, a sat. aq
NaHCO3 (1 mL) and brine (2 mL) were slowly added. The
organic layer was separated and the aq phase was extracted
with CH2Cl2 (2 × 2 mL). The combined organic layers were
dried over anhyd Na2SO4 and concentrated. The crude was
purified by chromatography on silica gel (EtOAc/PE) to give
pure (5S,6S)-8 (86 mg), pure (5S, 6R)-23 (38 mg), and a
mixture of un-separated (5S,6S)-8 and (5S,6R)-23 (191 mg)
in a combined yield of 95%. Major diastereomer (5S,6S)-8:
colorless oil. [a]D20 +56.5 (c 1.0, CHCl3). IR(neat): nmax
=
3075, 2952, 2929, 1642,1513, 1463, 1248, 1175 cm–1. 1H
NMR (500 MHz, CDCl3): d = 7.08 (m, 2 H, Ar-H), 6.83 (m,
2 H, Ar-H), 5.87 (m, 1 H, CH=), 5.40 (d, J = 14.6 Hz, 1 H,
NCH2), 5.13 (m, 1 H, =CH2), 5.09 (m, 1 H, =CH2), 3.94–3.88
(m, 1 H, H-5), 3.91 (s, 3 H, OCH3), 3.88 (d, J = 14.6 Hz, 1
H, NCH2), 3.23 (vrt. dt, J = 6.6, 4.7 Hz, 1 H, H-6), 2.63 (m,
2 H, =CCH2) 2.50 (ddd, J = 8.0, 8.8, 17.0 Hz, 1 H, H-3), 2.27
(ddd, J = 7.4, 8.2, 17.0 Hz, 1 H, H-3), 1.94 (m, 1 H, H-4),
1.81 (m, 1 H, H-4), 0.9 (s, 9 H, t-Bu), 0.18 (s, 3 H, SiCH3),
0.08 (s, 3 H, Si-CH3) ppm. 13C NMR (125 MHz, CDCl3): d
= 169.39 (C=O), 158.99 (Ar), 136.11 (CH=), 129.44 (Ar),
129.37 (2 C, Ar), 117.44 (=CH2), 114.01 (2 C, Ar), 68.38 (C-
6), 59.39 (C-5), 55.32 (OCH3), 48.23 (N-CH2), 33.62 (=CH-
CH2), 28.96 (C-3), 25.77 (C-4), 25.68 (3C, t-Bu), 17.97
(SiCMe3), –4.90 (Si-CH3), –5.13 (SiCH3) ppm. MS (ESI):
m/z (%) = 390(100) [M + H+], 412 (11) [M + Na+]. HRMS
calcd for [C22H35NO3Si + H]+: 390.2464. Found: 390.2463.
(5S,6R)-Minor diastereomer 23: colorless oil. [a]D20 –51.4 (c
1.0, CHCl3). 1H NMR (500 MHz, CDCl3): d = 7.09 (m, 2 H,
(13) Huang, P.-Q.; Liu, L.-X.; Wei, B.-G.; Ruan, Y.-P. Org. Lett.
2003, 5, 1927.
(14) Gringore, O. H.; Rouessac, F. P. In Org. Synth., Coll. Vol.
VII; Freeman, J. P., Ed.; John Wiley and Sons: New York,
1990, 99.
Synlett 2003, No. 11, 1663–1667 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of Antimalarial Alkaloids (+)-Febrifugine and (+)-Isofebrifugine
1667
Ar-H), 6.80 (m, 2 H, Ar-H), 5.67 (m, 1 H, CH=), 5.44 (d,
56.43 (C-6), 36.96 (C-4), 28.15 (CH2-CH=), 26.37 (C-3),
25.76 (3 C, t-Bu), 18.11 (SiCMe3), –4.39 (SiCH3), –4.94
(SiCH3) ppm. MS (ESI): m/z (%) = 270, (100) [M + H+], 292
(20) [M + Na+]. HR-ESI-MS calcd for [C14H27NO2Si + H]+:
270.1889. Found: 270.1907. Minor diastereomer (5S, 6R)-
25: white solid. Mp 67–68 °C. [a]D20 +15.3 (c 0.98, CHCl3).
IR(film): nmax = 3190, 1682 cm–1. 1H NMR (500 MHz,
CDCl3): d = 5.74 (m, 1 H, CH=), 5.70 (m, 1 H, NH), 5.21
(dd, J = 0.8, 14.7 Hz, 1 H, =CH2), 5.18 (dd, J = 0.8, 14.7 Hz,
1 H, =CH2), 3.66 (ddd, J = 3.3, 6.5, 9.3 Hz, 1 H, H-5,
irradiation at H-6 gave dd, J = 3.3, 9.3 Hz), 3.23 (ddd,
J = 9.5, 6.5, 4.5 Hz, 1 H, H-6), 2.53 (ddd, J = 5.8, 6.2, 17.8
Hz, 1 H, H-3), 2.34 (ddd, J = 6.5, 9.4, 17.8 Hz, 1 H, H-3),
2.12–1.92 (m, 1 H, CH2CH=), 1.84–1.78 (m, 2 H, H-4), 0.9
(s, 9 H, t-Bu), 0.56 (s, 3 H, SiCH3), 0.50 (s, 3 H, SiCH3) ppm.
13C NMR (125 MHz, CDCl3): d = 171.28 (C=O), 133.41
(CH=), 119.67 (CH2=), 69.11 (C-5), 58.11 (C-6), 38.55 (C-
4), 28.46 (C-3), 28.30 (CH2-CH=), 25.71 (3 C, t-Bu), 17.95
(SiCMe3), –4.27 (SiCH3), –4.75 (SiCH3) ppm. MS (ESI):
m/z (%) = 270 (100) [M + H+], 292 (3) [M + Na+]. HR-ESI-
MS calcd for [C14H27NO2Si + H]+: 270.1889. Found:
270.1890.
J = 14.9 Hz, 1 H, NCH2), 5.12 (m, 1 H, =CH2), 5.09 (m, 1 H,
=CH2), 3.95 (m, 1 H, H-5), 3.78 (s, 3 H, OCH3), 3.77 (d,
J = 14.9 Hz, 1 H, NCH2), 3.21 (vrt. ddt, J = 9.8, 3.4, 2.0 Hz,
1 H, H-6), 2.70 (ddd, J = 7.2, 12.3, 18.5 Hz, 1 H, H-3), 2.52
(m, 1 H, =CCH2), 2.37 (ddd. J = 1.4, 6.5, 18.5 Hz, 1 H, H-3),
2.09 (m, 1 H, =CCH2), 2.01 (m, 1 H, H-4), 1.74 (m, 1 H, H-
4), 0.8 (s, 9 H, t-Bu), 0.08 (s, 3 H, SiCH3), 0.05 (s, 3 H,
SiCH3) ppm. 13C NMR (125 MHz, CDCl3): d = 169.68
(C=O), 158.79 (Ar), 133.85 (CH=), 129.24 (Ar), 129.20 (2
C, Ar), 118.32 (=CH2), 113.94 (2 C, Ar), 65.78 (C-6), 61.86
(C-5), 55.30 (OCH3), 46.60 (NCH2), 36.65 (=CHCH2),
26.89 (C-3), 25.68 (3 C, t-BuC), 24.17 (C-4), 17.92
(SiCMe3), –4.94 (2 C, SiCH3) ppm. MS (ESI): m/z (%) =
390.1 (100) [M + H+], 412.2 (19) [M + Na+]. HRMS calcd
for [C22H35NO3Si + H]+: 390.2464. Found: 390.2463.
(24) Major diastereomer (5S, 6S)-24: white solid. Mp 67–68 °C.
[a]D20 –4.5 (c 1.05, CHCl3). IR(film): nmax = 3222, 1669
cm–1. 1H NMR (500 MHz, CDCl3): d = 5.73 (m, 1 H, =CH),
5.61 (brs, 1 H, NH), 5.22 (m, 1 H, =CH2), 5.19 (m, 1 H,
=CH2), 4.0 (m, 1 H, H-5), 3.36 (ddd, J = 2.8, 3.6, 9.7 Hz, 1
H, H-6, decoupling H-5, J = 3.6, 9.7 Hz), 2.57 (ddd, 6.4,
12.1, 18.6 Hz, 1 H, H-3), 2.32 (m, 2 H, =CH-CH2), 2.20
(ddd, J = 9.0, 9.8, 18.6 Hz, 1 H, H-3), 1.97 (m, 1 H, H-4),
1.84 (m, 1 H, H-4), 0.90 (s, 9 H, t-Bu), 0.08 (s, 3 H, SiCH3),
0.02 (s, 3 H, SiCH3) ppm. 13C NMR (125 MHz, CDCl3): d =
171.54 (C=O), 133.63 (CH=), 119.54 (CH2=), 65.96 (C-5),
(25) The ee was determined by HPLC analysis using a Chiracel®
OJ-H column (0.46 cm × 25 cm; column temperature: r.t.;
eluent: hexane/isopropyl alcohol = 37:3; flow rate = 1.0 mL/
min; wavelength: 240 and 260 nm, tR = 11.50 and 16.39
min).
Synlett 2003, No. 11, 1663–1667 © Thieme Stuttgart · New York