A convergent total synthesis of (+)-febrifugine

Article abstract of DOI:10.1055/s-2008-1072736

Febrifugine was synthesized in ten steps from N-Boc 4-aminobutan-1-ol by a convergent approach. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072736

1216
LETTER
A Convergent Total Synthesis of (+)-Febrifugine
Total
Synthesis
o
o
f
(+)-Febrifu
r
gine a Sieng, Oscar Lozano Ventura, Véronique Bellosta, Janine Cossy*
Laboratoire de Chimie Organique, ESPCI, CNRS, 10 Rue Vauquelin, 75231 Paris Cedex 05, France
Fax +33(1)40794660; E-mail: janine.cossy@espci.fr
Received 22 January 2008
70 °C, 5 h) afforded phosphonium salt 2 which was depro-
tonated (K2CO3, MeOH–H2O, r.t., 45 min) to furnish the
corresponding ylide 3 in a global yield of 95% (for the two
steps).9 This ylide was then converted into 5 by treatment
with 4-hydroxyquinazoline 4 under basic conditions (KH,
DMF, reflux, 1 h, 98% yield) (Scheme 2).
Abstract: Febrifugine was synthesized in ten steps from N-Boc 4-
aminobutan-1-ol by a convergent approach.
Key words: total synthesis, allyltitanation, Wittig reaction, febri-
fugine, antimalarial activity
Malaria is one of the most severe tropical diseases in
many tropical and subtropical regions causing 1–3 mil-
lions deaths annually as the malaria parasite has become
resistant to the best antimalarial drugs.1,2 Futhermore, in
the last 25 years, very few new antimalarial compounds
have been developed and a few of them are currently in
the stage of clinical development. Therefore, compounds
based on a novel mode of action are needed to overcome
the emergence of resistance and to control epidemics
caused by malaria parasite.
OH
N
O
N
N
H
O
(+)-febrifugine
O
N
O
N
(PG)2N
OR'
In China, the roots of Dichroa febrifuga have been em-
ployed for centuries by the local people as a traditional an-
timalarial drug. The quinazolinone-type alkaloids,
febrifugine and its stereoisomer isofebrifugine, have been
identified as the active components of these roots.3 Febri-
fugine acts by impairing haemazoin formation required
for maturation of the parasite at the trophozoite stage.4
However, preclinical researches have found that febrifug-
ine possesses strong liver toxicity and it has therefore
been precluded as an antimalarial drug.5,6 Due to the po-
tent antimalarial activity of febrifugine, chemists were
stimulated to synthesize febrifugine by using versatile
strategies in order to get access to derivatives which may
provide valuable leads for novel drugs.7,8
A
N
O
O
O
Ph3P
+
N
(PG)2N
H
OR'
B
C
5
H
OH
(PG)2N
BocHN
O
6
Scheme 1
In our retrosynthetic analysis of febrifugine, the construc- The preparation of the protected hydroxy aldehyde of type
tion of the substituted piperidine was envisaged by using B was then investigated. The hydroxy group of the com-
an intramolecular 1,4-addition of an amine on an a,b-un- mercially available N-Boc 4-aminobutan-1-ol 6 was oxi-
saturated ketone. The required w-amino unsaturated dized under the Swern conditions to the corresponding
ketone A would be obtained by condensing heterocycle 5 aldehyde 7 (Scheme 3).10
with amino aldehyde of type B. This compound would be
synthesized by using an enantioselective allyltitanation
applied on aldehyde C which would be obtained from the
The aldehyde 7 was directly treated with the highly face-
selective allyltitanium complex (S,S)-Ti-I11 to afford the
homoallylic alcohol 8 which was isolated in an overall
commercially available N-Boc 4-aminobutan-1-ol (6),
yield of 67% (from 6), with an enantiomeric excess of
(Scheme 1).
92%.12 Protection of secondary alcohol 8 (MOMCl,
In order to obtain a,b-unsaturated w-amino ketone A, DIPEA, DMAP, MeCN, reflux, 6 h) afforded the corre-
ylide 5 has to be prepared. This compound was obtained sponding methoxymethyl ether 9. In order to transform
in three steps from dichloroketone 1. Addition of triphen- homoallylic ether 9 to aldehyde 11, an isomerization13 of
ylphosphine to 1,3-dichloropropan-2-one (1) (THF, the double bond by treatment with the Grubbs second-
generation catalyst Ru-II14 in the presence of N-allyl-N-
tritylamine and diisopropylethylamine in refluxing tolu-
ene (4 h) was achieved and the desired allylic ether 10 was
isolated in 90% yield. After oxidative cleavage of the
SYNLETT 2008, No. 8, pp 1216–1218
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1072736; Art ID: G02508ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
8

LETTER
Total Synthesis of (+)-Febrifugine
1217
O
O
effected in order to obtain aldehyde 16 (Scheme 4).
Monocarbamate 9 was transformed to biscarbamate 14
(Boc2O, DMAP, MeCN, 60% yield).16 In order to get the
desired aldehyde 16, the same sequence of transforma-
tions, as previously described, were applied to 14. After
isomerization of the double bond to afford 1513,17 (Ru-II,
DIPEA, N-allyl-,N-tritylamine, toluene, reflux, 6 h, 94%
yield), followed by oxidative cleavage of the double bond
in 15 (OsO4, NMO, acetone–H2O, r.t., 20 h; then NaIO4,
THF–H2O) the desired aldehyde 16 was isolated in 77%
yield. The protected a-hydroxy aldehyde 16 was then
transformed to the target molecule in three steps. After a
Wittig reaction applied to aldehyde 16 using ylide 5 (tol-
uene, reflux, 8 h), the expected a,b-unsaturated enone 1718
was isolated (45% yield) and transformed to the substitut-
ed piperidine 18 by a two-step one-pot sequence by treat-
ing with trifluoroacetic acid (3.3 equiv) at room
temperature for 12 h in CH2Cl2. Under these conditions,
the monodeprotection of the amino group occurred and
the intramolecular 1,4-addition of the resulting mono-
protected N-Boc amine to the a,b-unsaturated ketone took
place leading to the formation of the piperidine ring in
82% yield as a mixture of cis- and trans-isomers which
were directly engaged in the next step. After simultaneous
deprotection of the amine and hydroxy group utilizing 6 N
HCl (H2O, reflux, 4 h), (+)-febrifugine was obtained, ac-
companied by isofebrifugine19 in a ratio of 80:20 deter-
mined by 1H NMR (Scheme 4).
Ph3P
Cl
Cl
Ph3P
Cl
Cl
THF, 70 °C, 5 h
1
2
K2CO3
MeOH–H2O
r.t., 45 min
95%
(2 steps)
N
N
N
O
4
O
O
OH
Ph3P
Ph3P
N
Cl
KH, DMF
∆, 1 h
98%
5
3
Scheme 2
(ClCO)2, DMSO
Et3N, CH2Cl2
OH
H
O
BocHN
BocHN
6
7
(S,S)-Ti-I
Et2O
–78 °C, 4 h
67%
(2 steps)
MOMCl
DIPEA, DMAP
BocHN
BocHN
CH2Cl2
84%
MOMO
OH
9
8
NHCPh3
toluene
reflux, 4 h
DIPEA
Ru-II
90%
Boc2O, DMAP
O
BocHN
(Boc)2N
1) OsO4
NMO
MeCN
60%
MOMO
MOMO
14
3
BocHN
H
BocHN
9
2) NaIO4
THF, H2O
MOMO
MOMO
NHCPh3
10
11
toluene
reflux, 6 h
90% (2 steps)
DIPEA
Ru-II
N
O
94%
N
O
Ar =
O
1) OsO4
NMO
Ph3P
Ar
O
OMOM
OH
(Boc)2N
(Boc)2N
H
O
5
2) NaIO4
Ar
MOMO
MOMO
3
BocHN
toluene
∆, 20 h
13%
THF, H2O
N
16
15
MOMO
77% (2 steps)
Boc
12
N
13
toluene
∆, 8 h
Ph3P
Ar
N
Ar =
O
5
45%
Ti
O
Ph
Ph
OMOM
O
N
N
TFA
(3.3 equiv)
O
O
Ph
Cl
Cl
Ar
Ru
Ph
Ar
O
O
(Boc)2N
MOMO
17
3
CH2Cl2, r.t.
82%
Ru-II
Ph
(S,S)-Ti-I
N
PCy3
Boc
18
Scheme 3
6 N HCl
4 h, ∆
46%
double bond (OsO4, NMO, acetone–H2O, r.t., 20 h; then
NaIO4, THF–H2O, r.t., 1 h, 90%),15 the expected aldehyde
11 was not observed, and the hemiaminal 12 was isolated
instead. This latter compound revealed to be poorly reac-
tive towards 5 as enone 13 was only produced in 13%
yield (Scheme 3).
OH
N
O
N
O
O
OH
O
+
N
N
N
N
H
H
20:80
isofebrifugine
febrifugine
To avoid the formation of the nonreactive hemiaminal 12,
the synthesis of the bis-N-Boc homoallylic ether 14 was
Scheme 4
Synlett 2008, No. 8, 1216–1218 © Thieme Stuttgart · New York

1218
B. Sieng et al.
LETTER
(10) Aqueous workup has to be precluded. The treatment of 6
After purification by silica gel chromatography, (+)-febri-
25
under Swern conditions followed by classical aqueous
workup lead only to the formation of the hemiaminal which
is then totally unreactive with allyltitanium complex (S,S)-
Ti-I.
fugine was isolated in 38% yield {mp 137–139 °C, [a]D
+26.9 (c 0.26, EtOH); natural product:3b mp 139–140 °C,
25
1
[a]D +28 (c 0.5, EtOH)}. The melting point, H NMR
and 13C NMR data, and optical rotation for the synthe-
sized (+)-febrifugine are in agreement with the reported
values.8a,f
(11) The allyltitanium complex (S,S)-Ti-I was prepared
according to: Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs,
G.; Rothe-Streit, P.; Schwarzenbach, F. J. Am. Chem. Soc.
1992, 114, 2321.
In conclusion, we were able to develop a short convergent
synthesis of febrifugine in ten steps from N-Boc 4-ami-
nobutan-1-ol by using an enantioselective allyltitanation
to control the C3 stereogenic center, an intramolecular
1,4-addition of an amine onto an a,b-unsaturated ketone
to build the piperidine ring, and a Wittig reaction to intro-
duce the b-keto 4-hydroxyquinazoline. This strategy can
be applied to the synthesis of derivatives that can be used
for the study of structure–reactivity relationship.
(12) Preparation of 8
Allylmagnesium chloride (1.47 mL, 2 M in THF, 2.93
mmol, 1.1 equiv) was added at 0 °C to a mixture of
cyclopentadienyl[(4S,trans)-2,2-dimethyl-a,a,a¢,a¢-
tetraphenyl-1,3-dioxolane-4,5-dimethanolato-O,O¢]titanium
chloride (2.12 g, 3.46 mmol, 1.3 equiv) in anhyd Et2O (30
mL). The orange mixture was stirred for 2 h at 0 °C and
cooled to –78 °C. To this mixture was added dropwise a
solution of the crude aldehyde 7 (498 mg, 2.66 mmol, 1
equiv) in Et2O (2.4 mL) via cannula. After 4 h at –78 °C,
H2O (14 mL) was added and the mixture was stirred
overnight at r.t. and then filtered through Celite. The organic
phase was washed with brine (2 × 40 mL), dried over
MgSO4, and concentrated in vacuo. The crude residue was
purified on silica gel (PE–EtOAc, 7:3) to afford 8 (408 mg,
1.78 mmol, 67% for two steps) as a yellow oil.
References and Notes
(1) Winstanley, P. A. Parasitol. Today 2000, 16, 146.
(2) Zhu, S.; Hudson, T. H.; Kyle, D. E.; Lin, A. J. Med. Chem.
2002, 45, 3491.
(3) (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.
(4) WHO Report, Meeting on Antimalarial Drug Development,
Shangai, China, 16-17 November 2001.
(5) Chien, P. L.; Cheng, C. C. J. Med. Chem. 1970, 13, 867.
(6) Pharmacology and Applications of Chinese Material
Medecine; Chang, H. M.; But, P. P. H., Eds.; World
Scientific Publishing: Singapore, 1986-1987.
(7) For racemic syntheses of febrifugine, see: (a) Baker, B. R.;
McEvoy, F. J.; Schaub, R. E.; Joseph, J. P.; Williams, J. H.
J. Org. Chem. 1953, 18, 178. (b) Burgess, L. E.; Gross, E.
K. M.; Jurka, J. Tetrahedron Lett. 1996, 37, 3255.
(c) Takeuchi, Y.; Hattori, M.; Abe, H.; Harayama, T.
Synthesis 1999, 1814. (d) Takeuchi, Y.; Oshige, M.; Azuma,
K.; Abe, H.; Harayama, T. Chem. Pharm. Bull. 2005, 53,
868.
(8) For syntheses of (+)-febrifugine, see: (a) Kobayashi, S.;
Ueno, M.; Suzuki, R.; Ishitani, H.; Kim, H.-S.; Wataya, Y.
J. Org. Chem. 1999, 64, 6833. (b) Takeuchi, Y.; Azuma, K.;
Takakura, K.; Abe, H.; Harayama, T. Chem. Commun. 2000,
1643. (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) Okitsu, O.; Suzuki, R.; Kobayashi, S. J. Org.
Chem. 2001, 66, 809. (f) Ooi, H.; Urushibara, A.; Esumi, T.;
Iwabuchi, Y.; Hatakeyama, S. Org. Lett. 2001, 3, 953.
(g) Huang, P.-Q.; Wei, B.-G.; Ruan, Y.-P. Synlett 2003,
1663. (h) Katoh, M.; Matsune, R.; Nagase, H.; Honda, T.
Tetrahedron Lett. 2004, 45, 6221. (i) Ashoordazeh, A.;
Caprio, V. Synlett 2005, 346. (j) Katoh, M.; Matsune, R.;
Honda, T. Heterocycles 2006, 67, 189.
The ee of 8 was determined by 1H NMR after derivatization
with (S)- and (R)-methoxyphenylacetic acids. See: (a) Dale,
J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(b) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P.
G.; Balkovec, J. M. J. Org. Chem. 1986, 51, 2370. (c)Seco,
J. M.; Quiňoà, E.; Riguera, R. Tetrahedron: Asymmetry
2001, 12, 2915.
(13) Wipf, P.; Rector, S. R.; Takahashi, H. J. Am. Chem. Soc.
2002, 124, 14848.
(14) Scholl, M.; Ding, S.; Woo Lee, S.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
(15) A better yield was observed for the oxidative cleavage of the
double bond when performed in two separated steps.
(16) The yield for 14 corresponds to the isolated yield but the
protection did not reach completion (71% conversion).
(17) A cross-metathesis reaction using methyl vinyl ketone and
the protected allylic alcohol 15, in the presence of the
Grubbs–Hoveyda catalyst failed.
(18) Compound 17: [a]D25 –22.1 (c 1.17, CHCl3). IR (neat): 2979,
1678, 1612, 1365, 1118, 1028, 775, 734, 697 cm–1. 1H NMR
(400 MHz, CDCl3): d = 8.29 (dd, J = 8.0, 1.5 Hz, 1 H), 7.90
(s, 1 H), 7.80–7.73 (m, 2 H), 7.51 (ddd, J = 8.0, 6.8, 1.6 Hz,
1 H), 6.94 (dd, J = 16.0, 5.8 Hz, 1 H), 6.46 (dd, J = 16.0, 1.3
Hz, 1 H), 4.99 (d, J = 1.6 Hz, 2 H), 4.65 (dABsyst, J = 6.9 Hz,
1 H), 4.63 (dABsyst, J = 6.9 Hz, 1 H), 4.30, (m, 1 H), 3.61 (br
t, J = 6.8 Hz, 2 H), 3.39 (s, 3 H), 1.76–1.60 (m, 4 H), 1.51 (s,
18 H). 13C NMR (100 MHz, CDCl3): d = 191.0 (s), 160.9 (s),
152.8 (2 s), 148.6 (d), 148.2 (s), 146.4 (d), 134.4 (d), 127.6
(d), 127.4 (d), 126.8 (d), 126.3 (d), 121.9 (s), 95.1 (t), 82.3
(2s), 75.2 (q), 55.8 (d), 52.6 (t), 45.9 (t), 31.8 (t), 28.1 (6 q),
24.6 (t).
(19) Efficient isomerization of isofebrifugine into febrifugine by
heating in water has been reported by Takeuchi et al., see ref.
8d.
(9) Hudson, R. F.; Chopard, P. A. J. Org. Chem. 1963, 28, 2446.
Synlett 2008, No. 8, 1216–1218 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.