Stereocontrolled synthesis of a potent antimalarial alkaloid, (+)-febrifugine

Article abstract of DOI:10.1016/j.tetlet.2004.06.100

A novel and stereocontrolled synthetic path to a potential antimalarial piperidine alkaloid, (+)-febrifugine, was established by employing a reductive deamination of a proline derivative with samarium diiodide, as a key step. A novel and stereocontrolled

Full text of DOI:10.1016/j.tetlet.2004.06.100

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6221–6223
Stereocontrolled synthesis of a potent antimalarial alkaloid,
(+)-febrifugine
Miho Katoh, Ryuichiro Matsune, Hiromasa Nagase and Toshio Honda*
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41, Shinagawa, Tokyo 142-8501, Japan
Received 25 May 2004; revised 24 June 2004; accepted 28 June 2004
Abstract—A novel and stereocontrolled synthetic path to a potential antimalarial piperidine alkaloid, (+)-febrifugine, was estab-
lished by employing the reductive deamination and simultaneous recyclization of a proline derivative with samarium diiodide, as
a key step.
Ó 2004 Elsevier Ltd. All rights reserved.
Febrifugine 1 and isofebrifugine 2, isolated from the
SmI2
´
roots of Dichroa febriguga Lour. (Chinese name: Chang
THF-HMPA
Shan),1 are recognized as active principles against ma-
laria.2 These alkaloids were approximately 100 times
as effective as quinine against Plasmodia lophurae in
ducks.1a It is also known that there is an equilibrium
between those alkaloids under acidic conditions.3 More-
over, isofebrifugine was transformed into febrifugine by
heating.1a Due to their attractive biological activity,
a number of racemic and chiral syntheses of these
compounds have been established to date (Fig. 1).4
R
R
N
P
proton source
NHP
O
O
P = H, alkyl; R = OR', alkyl
Figure 2. Sml2-promoted reductive deamination.
ested in developing an effective and stereocontrolled
synthesis of febrifugine starting from readily accessible
(+)-4-hydroxyproline.
Recently, we have developed a general carbon–nitrogen
bond cleavage reaction of a-amino carbonyl compounds
by using samarium diiodide as a one-electron reducing
agent, as shown in Figure 2.5 As an extension of our
ongoing program utilizing this reaction in the synthesis
of biologically active natural products,6 we are inter-
N-Boc-(4S)-tert-butyldimethylsiloxy-L-proline methyl
ester 3 was prepared from the commercially available
(4R)-hydroxy-L-proline according to the literature.7
The silyl ether 3 was then oxidized with ruthenium tetr-
oxide to give the desired lactam 4.7 Although a number
of strategies for stereoselective introduction of a side
chain at the 5-position have so far been developed,8
some of them were found to suffer from limitations, in
terms of the nucleophile species, conversion yield,
reaction conditions, and stereoselectivity. Thus, we
attempted to develop an alternative procedure for
introduction of an alkyl side chain at the 5-position stereo-
selectively, and we were able to establish a facile proce-
dure by applying a tandem Horner–Emmons–Michael
reaction,9 for this purpose, as follows.
HO
N
O
N
O
H+
O
HO
O
N
N
N
H
N
H
1. Febrifugine
2. Isofebrifugine
Figure 1. Structures of febrifugine and isofebrifugine.
Reduction of the lactam 4 with lithium triethylborohy-
dride, followed by treatment of the resulting aminal 5
with triethyl phosphonoacetate in the presence of NaH
gave the ester 6, stereoselectively, as the sole product.
Keywords: Febrifugine; Isofebrifugine; Tandem Horner–Emmons–
Michael reaction; Samarium diiodide; Antimalarial activity.
*
Corresponding author. Tel.: +81-3-5498-5791; fax: +81-3-3787-
0036; e-mail: honda@hoshi.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.100

6222
M. Katoh et al. / Tetrahedron Letters 45 (2004) 6221–6223
The stereochemistry at the 5-position would be control-
led during the Michael addition of the nitrogen to the
a,b-unsaturated ester, generated by the Horner–Em-
mons reaction, where the addition took place from the
sterically less hindered side of the substrate (Scheme 1).
without further purification was subjected to samarium
diiodide-promoted reductive deamination reaction in
the presence of MeOH as the proton source to furnish
the d-lactam 12,12 where carbon–nitrogen bond cleavage
reaction and subsequent recyclization took place simul-
taneously, as expected (Scheme 3).
Using diethyl (N-methoxy-N-methylcarbamoylmethyl)-
phosphonate under similar reaction conditions, the
amide 7 was also obtained, in good yield. The amide 7
seems to be a versatile precursor for further modification
of the side chain. The stereochemistry of the amide 7
was unambiguously determined by the X-ray crystallo-
graphic analysis of the corresponding NH compound 8
(Scheme 2).10
Lithium aluminum hydride reduction of the lactam 12
afforded the corresponding hydroxy-amine 13 which,
on treatment with CbzCl, gave the desired carbamate
14. After protection of the secondary hydroxy group
as its benzyl ether, the resulting benzyl ether 15 was con-
verted to the methyl ketone 16 by ozonolysis (Scheme 4).
Finally, bromination of 16 by treatment with trimethyl-
silyl triflate and subsequently with NBS, resulted in the
formation of the a-bromoketone which, without purifi-
cation, was further coupled with 4-hydroxyquinazoline
in the presence of potassium hydride to furnish the pro-
tected febrifugine 17. The spectroscopic data of the syn-
Treatment of the amide 7 with methylmagnesium bro-
mide afforded the methyl ketone 9, which on methylena-
tion with the Wittig reagent gave the olefin 10, in 43%
yield. The yield of the olefination of the ketone 9 could
be improved by using TebbeÕs reagent11 providing 10 in
81% yield.
thesized compound were identical with those reported,
31
[a]D ꢀ36.0 (c 0.51, CHCl3), {lit.4h ½aꢁD ꢀ22.0 (c 1.0,
Selective removal of the Boc group of 10 was carried out
by using zinc bromide providing the amine 11, which
CHCl3)}. Deprotection of 17 with 6N HCl gave febrifu-
gine 1, mp 139–140°C; [a]D +16.0 (c 0.4, MeOH) {lit.1b
TBSO
TBSO
O
TBSO
b
a
CO2Me
CO2Me
HO
CO2Me
CO2Me
N
N
N
Boc
Boc
Boc
3
4
5
TBSO
TBSO
c
R1
CO2Me
N
O
Z
HN
Boc
R2
6 R1 = CO2Et, R2 = Boc
7 R1 = CON(OMe)Me, R2 = Boc
8 R1 = CON(OMe)Me, R2 = H
Z = OEt or N(OMe)Me
d
Scheme 1. Reagents and conditions: (a) RuO2 (cat), NaIO4, AcOEt/H2O, rt (86%); (b) LiEt3BH, THF, ꢀ78°C; (c) (EtO)2P(O)CH2CO2Et or
(EtO)2P(O)CH2CON(Me)OMe, NaH, THF, rt (6: 62% from 4, 7: 83% from 4); (d) TFA, CH2Cl2, 0°C to rt (56%).
TBSO
O
TBSO
O
a
b
CO2Me
N
Me
N
OMe
CO2Me
N
Boc
Boc
9
7
TBSO
TBSO
TBSO
d
CO2Me
CO2Me
N
R
N
H
O
NH2
10 R = Boc
11 R = H
12
c
Scheme 2. Reagents and conditions: (a) MeMgBr, THF, 0°C (88%); (b) TebbeÕs reagent, THF, ꢀ40°C to rt (81%) (c) ZnBr2, CH2Cl2, rt; (d) Sml2,
THF–HMPA, MeOH, 0°C to rt (90% from 10).

M. Katoh et al. / Tetrahedron Letters 45 (2004) 6221–6223
6223
Chiba, M.; Uwai, K.; Tanitsu, M.; Kim, H.-S.; Wataya,
Y.; Miura, M.; Takeshita, M.; Oshima, Y. J. Med. Chem.
1999, 42, 3163; (e) 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; (f) Hirai, S.; Kikuchi, H.; Kim, H.-S.; Begum, K.;
Wataya, Y.; Tasaka, H.; Miyazawa, Y.; Yamamoto, K.;
Oshima, Y. J. Med. Chem. 2003, 46, 4351.
TBSO
BnO
O
R2O
d
a
N
H
O
N
N
Cbz
R1
13 R1 = R2 = H
16
12
b
c
14 R1 = Cbz, R2 = H
15 R1 = Cbz, R2 = Bn
3. Barringer, D. F., Jr.; Berkelhemmer, G.; Carter, S. D.;
Goldman, L.; Lanzilotti, A. E. J. Org. Chem. 1973, 38,
1933.
Scheme 3. Reagents and conditions: (a) LiAlH4, THF, 65°C; (b)
CbzCl, TEA, DMAP, CH2Cl2, rt (95% from 12); (c) BnBr, NaH,
DMF, 0°C (90%); (d) O3, MeOH, ꢀ78°C then Me2S (92%).
4. For recent syntheses of febrifugine and/or isofebrifugine,
see: (a) Burgess, L. E.; Gross, E. K. M.; Jurka, J.
Tetrahedron Lett. 1996, 37, 3255; (b) Kobayashi, S.; Ueno,
M.; Suzuki, R.; Ishitani, H. Tetrahedron Lett. 1999, 40,
2175; (c) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani,
H.; Kim, H.-S.; Wataya, Y. J. Org. Chem. 1999, 64, 6833;
(d) Takeuchi, Y.; Abe, H.; Harayama, T. Chem. Pharm.
Bull. 1999, 47, 905; (e) Takeuchi, Y.; Hattori, M.; Abe, H.;
Harayama, T. Synthesis, 1999, 1814; (f) Takeuchi, Y.;
Azuma, K.; Takakura, K.; Abe, H.; Harayama, T. Chem.
Commun., 2000, 1643; (g) Okitsu, O.; Suzuki, R.; Ko-
bayashi, S. Synlett, 2000, 989; (h) Taniguchi, T.; Ogasaw-
ara, K. Org. Lett. 2000, 2, 3193; (i) Takeuchi, Y.; Azuma,
K.; Takakura, K.; Abe, H.; Kim, H.-S.; Wataya, Y.;
Harayama, T. Tetrahedron 2001, 57, 1213; (j) Ooi, H.;
Urushibara, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S.
Org. Lett. 2001, 3, 953; (k) Sugiura, M.; Kobayashi, S.
Org. Lett. 2001, 3, 477; (l) Sugiura, M.; Hagio, H.;
Hirabayashi, R.; Kobayashi, S. J. Org. Chem. 2001, 66,
809; (m) Sugiura, M.; Hagio, H.; Hirabayashi, R.;
Kobayashi, S. J. Am. Chem. Soc. 2001, 123, 12510; (n)
Huang, P.-Q.; Wei, B.-G.; Ruan, Y.-P. Synlett, 2003,
1663.
BnO
O
BnO
O
a
b
Br
N
N
Cbz
Cbz
16
BnO
O
HO
N
O
N
O
c
N
N
N
N
H
Cbz
O
17
(+)-febrifugine
Scheme 4. Reagents and conditions: (a) 1. TMSOTf, DIPEA, CH2Cl2,
rt; 2. NBS, rt; (b) 4-hydroxyquinazoline, KH, DMF, 70°C (57% from
16); (c) 6N HCl, reflux (92%).
mp 139–140°C; lit.4b mp 138–139°C; lit.1c [a]D +13.0 (c
0.65, MeOH)}.
5. Honda, T.; Ishikawa, F. Chem. Commun. 1999, 1065.
6. Honda, T.; Kimura, M. Org. Lett. 2000, 2, 3925.
7. Zhang, X.; Schmitt, A. C.; Jiang, W. Tetrahedron Lett.
2001, 42, 5335.
In summary, we were able to establish an alternative
stereoselective chiral synthesis of febrifugine 1 by
employing reductive deamination of an a-amino carbo-
nyl compound as a key reaction. In this synthesis, we
found that the intramolecular Michael addition of the
nitrogen to the a,b-unsaturated carbonyl compound
proceeded stereoselectively to give the desired product
as the sole product. This methodology is obviously
applicable for the introduction of a side chain at the 5-
position of the substituted pyrrolizidine ring system.
´
8. Najera, C.; Yus, M. Tetrahedron: Asymmetry 1999, 10,
2245, and references cited therein.
9. (a) Collado, I.; Ezquerra, J.; Vaquero, J. J.; Pedregal, C.
Tetrahedron Lett. 1994, 35, 8037; (b) Mulzer, J.; Schulz-
¨
chen, F.; Bats, J.-W. Tetrahedron 2000, 56, 4289.
10. Crystal data for 8: mp 89–91°C (recrystallized from
n-hexane). C16H32N2O5Si, M=360.52, monoclinic, space
˚
group P21, a=6.7052(5), b=7.6518(7), c=20.608(2) A,
3
˚
b=91.043(7)°, V=1057.2(2) A , Z=2, Dcalcd =1.129
g/cm3. The data were collected at a temperature of
25 1°C using the x scan technique to a maximum 2h
values of 136.6°. Of the 5762 reflections that were
collected, 2073 were unique (Rint =0.036); equivalent
reflections were merged. The intensities of three repre-
sentative reflections were measured after every 150 reflec-
tions. No decay correction was applied. The structure was
solved using SIR92. R=0.045, Rw=0.039.
Acknowledgements
This work was supported in part by a grant from the
Ministry of Education, Culture, Sports, Science and
Technology of Japan.
11. Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem.
Soc. 1978, 100, 3611.
References and notes
12. Selected data for 12: colorless oil. [a]D +12.0 (c 1.0,
CHCl3). 1H NMR (CDCl3) d 0.08 (6H, s), 0.89 (9H, s),
1.72 (3H, s), 1.93–1.99 (1H, m), 1.90 (1H, dd, J=10.4,
13.7Hz), 1.77–1.86 (1H, m), 2.34 (1H, ddd, J=6.4, 10.0,
18.0Hz), 2.47–2.55 (2H, m), 3.26 (1H, ddd, J=3.0, 6.9,
10.4Hz), 3.59 (1H, ddd, J=3.6, 6.9, 10.0Hz), 4.80 (1H, s),
4.93 (1H, s), 5.62 (1H, br s); 13C NMR (CDCl3) d ꢀ4.8,
ꢀ4.2, 17.9, 21.7, 25.6, 28.7, 28.8, 42.7, 55.9, 69.9, 114.9,
140.8, 170.9; IR (thin film) 3220, 2960, 2960, 2860, 1670,
1090, 840, 770cmꢀ1; EIMS (m/z) 283 (M+); Anal. Calcd
for C15H29NO2Si: C, 63.55; H, 10.31; N, 4.94. Found: C,
63.51; H, 10.32, N; 4.97.
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