Concise asymmetric synthesis of antimalarial alkaloid (+)-febrifugine

Article abstract of DOI:10.1055/s-0029-1217713

An asymmetric total synthesis of antimalarial alkaloid (+)-febrifugine is accomplished in 23% overall yield over 14 steps from readily available starting materials. The synthesis features a SmI₂-mediated reductive cross-coupling of chiral N-ter

Full text of DOI:10.1055/s-0029-1217713

LETTER
2301
Concise Asymmetric Synthesis of Antimalarial Alkaloid (+)-Febrifugine
S
ynthesisof
Anti
u
malarial
A
lk
i
aloid(+)-Feb
W
r
ifugine ang,a Kai Fang,a Bing-Feng Sun,a Ming-Hua Xu,*a,b Guo-Qiang Lin*a
a
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P. R. of China
Fax +86(21)64166263; E-mail: lingq@mail.sioc.ac.cn
b
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. of China
Received 17 April 2009
O
S
R1
O
S
Abstract: An asymmetric total synthesis of antimalarial alkaloid
(+)-febrifugine is accomplished in 23% overall yield over 14 steps
from readily available starting materials. The synthesis features a
SmI2-mediated reductive cross-coupling of chiral N-tert-butane-
sulfinyl imine with aldehyde.
O
SmI2, t-BuOH
THF, –78 °C
HO
N
t-Bu
+
N
t-Bu
R2
H
H
R2
R1
H
R1 = aryl, alkyl;
R2 = alkyl
Key words: antimalarial, asymmetric synthesis, febrifugine, cross-
coupling
Scheme 1
As depicted in Scheme 2, retrosynthetically (+)-febrifu-
gine (1) could be derived from 4-quinazolone and piperi-
dine epoxide 3.4e,g Containing all the necessary functional
groups with defined stereochemistry, the key intermediate
b-amido alcohol 4 would be a proper precursor for 3.
Amido alcohol 4 could be derived from N-tert-butane-
sulfinyl imine 5 and aldehyde 6 by employing SmI2-medi-
ated reductive cross-coupling. Based on our previous
findings, chiral imine 5 with S-configuration at the sulfur
atom was to be utilized in the cross-coupling reaction in
order to generate b-amido alcohol 4 with the desired abso-
lute configurations at the two newly formed carbon cen-
ters. It is worth mentioning that the N-sulfinyl group as a
powerful chiral directing group5 could be used to domi-
nate over the isolated unsymmetrical acetonide moiety in
determining the stereochemical outcome of the reaction.6
(+)-Febrifugine (1) and (+)-isofebrifugine (2, Figure 1),
structurally related quinazolinone alkaloids isolated from
the roots of Dichroa febrifuga Lour (Chinese name:
Cháng Shan) and related hydrangea plants, were identi-
fied as the principles showing potent antimalarial activi-
ty.1a–c Structures of these alkaloids had been elusive1d–f
ever since their isolation in 1947 until being unambigu-
ously elucidated by Kobayashi and co-workers in 1999
via asymmetric total synthesis.2 Although febrifugine was
precluded from being a potential clinical drug owing to its
strong liver toxicity and other adverse side effects,3 re-
newed efforts have been exerted from synthetic commu-
nity aiming at developing efficient synthetic pathways
which could provide valuable leads for antimalarial drug
discoveries.2,4
N
OH
N
O
t-Bu
OP
O
OH
S
N
O
1
N
O
NH
O
N
N
H
N
H
O
O
P
O
TBDPSO
3
(+)-febrifugine (1)
(+)-isofebrifugine (2)
OH
4
t-Bu
S
Figure 1
SmI2-mediated
cross-coupling
O
O
N
O
O
OTBDPS
+
H
Recently, our laboratory developed a highly efficient and
practical approach for the synthesis of enantiomerically
pure b-amino alcohol by SmI2-mediated reductive cross-
coupling of chiral N-tert-butanesulfinyl imines with alde-
hydes, with the newly formed hydroxyl group and amido
group being in anti orientation (Scheme 1).5 As a part of
our continuing program applying this methodology in
syntheses of bioactive natural products, herein we present
an efficient enantioselective synthesis of (+)-febrifugine
(1) by taking advantage of this methodology.
H
5
6
Scheme 2 Retrosynthesis of (+)-febrifugine (1)
Our synthesis started with the preparation of segment 5
from readily available inexpensive materials (Scheme 3).
Alcohol 7 (prepared from L-malic acid through known
procedures)7was subjected to oxidation under Swern’s
conditions8 to afford crude aldehyde which, without fur-
ther purification, was treated with Ellman’s reagent9 to af-
ford imine 5 in 85% overall yield. Aldehyde 6 was readily
obtained by Swern oxidation of monoprotected butane-
SYNLETT 2009, No. 14, pp 2301–2304
Advanced online publication: 29.07.2009
x
x
.x
x
.2
0
0
9
DOI: 10.1055/s-0029-1217713; Art ID: W05609ST
© Georg Thieme Verlag Stuttgart · New York

2302
R. Wang et al.
LETTER
t-Bu
S
t-Bu
S
1) Swern oxidation
2) Ellman's reagent
CuSO4 (anhyd)
MCPBA
NaH, BnBr
OH
O
O
O
NH
O
O
N
O
4
O
THF, 50 °C
83%
CH2Cl2
96%
+
6
O
O
85% (2 steps)
TBDPSO
H
7
8
5
OBn
t-BuO2S
1) TBAF,THF
2) MsCl, Et3N,
–78 °C
SmI2, t-BuOH
THF, –78 °C
85%, dr: see text
NH
O
TBDPSO
3) NaH,THF
OBn
89% (3 steps)
9
t-Bu
S
O
NH
O
OBn
O
O
O
TBDPSO
N
OH
4
SO2t-Bu
Scheme 3 Synthesis of amido alcohol 4
10
Scheme 4 Synthesis of sulfonamide 10
1,4-diol. With imine 5 and aldehyde 6 in hand, we moved
on to the crucial SmI2-mediated reductive cross-coupling
reaction (Scheme 3). Initial attempts afforded the
coupling product amido alcohol 4 in good yield, however,
with varying diastereoselectivity as high as
86.0:11.8:2.0:0.2, which was determined by HPLC-MS
since 1H NMR of the product did not afford differentiable
signals belonging to each diastereomers. To our delight,
after numerous trials we found that, to obtain consistently
high diastereoselectivity, it was crucial to keep the inter-
nal low temperature for sufficiently long time. This en-
tailed slow addition of the substrates mixture solution to
SmI2 at –78 °C and subsequent maintenance of the reac-
tion mixture at the same temperature for several hours.
Furthermore, freshly prepared substrates, compared to the
aged ones, were found to give higher diastereoselectivity
in the coupling reaction. Eventually, the cross-coupling
reaction proceeded to furnish 4 in 85% yield with typical
93.5:4.0:2.0:0.5 diastereoselectivity when the coupling
reaction was performed with freshly prepared imine 5 and
aldehyde 6 under –78 °C for 7 hours.15 Thus, the two re-
quired stereocenters were established successfully.
With compound 10 in hand, efforts were continued to-
ward the total synthesis of (+)-febrifugine (1, Scheme 5).
Acetonide 10 was then exposed to p-toluenesulfonic acid
in methanol to give diol 11, which was converted to ep-
oxide 12 in 91% yield by sequential monotosylation11 and
then base-induced cyclization. An alternative one-step
procedure involving N-tosylimidazole12 in the presence of
NaH could convert 11 into 12 in 85% yield. Epoxide 12
was then reacted with 4-quinazolone potassium salt13 to
give alcohol 13 in 84% yield, which in turn was treated
with Dess–Martin periodinane14 to furnish 14 in 86%
yield. Finally, 14 was subjected to global deprotection in
refluxing 6 N hydrochloric acid4e to produce (+)-febrifu-
gine (1) in 79% yield.15 The 1H NMR, 13C NMR, melting
point, and optical rotation for the synthesized 1 are in well
agreement with the reported data.2b,4g It’s worth mention-
ing that, thanks to the anti orientation of the hydroxyl and
the amido group in amido alcohol 4, and hence the trans
substitution pattern in piperidine 14, (+)-febrifugine (1)
was isolated as the major product in good yield in the
deprotection step.4c,g
The next task was to elaborate amido alcohol 4 into the pi-
peridine derivative. As shown in Scheme 4, the newly
formed hydroxyl group in amido alcohol 4 was first con-
verted into benzyl ether 8 in 83% yield by treatment with
NaH/BnBr in THF. Surprisingly, additive TBAI was
found to be unbeneficial, leading to a less clean reaction
and decreased yield. Subsequent exposure of sulfinamide
8 to MCPBA delivered sulfonamide 9 in 96% yield, which
was then elaborated into the piperidine derivative 10 by a
three-step reaction sequence. Removal of the silyl group
with TBAF, mesylation of the resulting free hydroxyl
group with MeSO2Cl/Et3N followed by treatment with
NaH in THF provided N-sulfonyl piperidine 10 in 89%
yield over 3 steps. Oxidation of 8 to 9 proved necessary
since 8, when subjected to the above identical reaction se-
quence, failed to undergo a clean mesylation due to the
competitive mesylation of the nucleophilic oxygen of the
sulfinyl group,10 which rendered the subsequent base-
mediated cyclization complicated.
In conclusion, we have accomplished the asymmetric syn-
thesis of (+)-febrifugine in a concise and practical manner
from readily available inexpensive starting materials with
23% overall yield. The synthetic route features the SmI2-
mediated reductive cross-coupling of chiral N-tert-
butanesulfinyl imine with aldehyde developed by our
group, and can be easily adapted to permit rapid access to
various febrifugine analogues by using diversified N-tert-
butanesulfinyl imines and/or aldehydes and various sub-
stituted quinazolone as the reaction substrates. Further en-
deavors applying this methodology in synthesizing
febrifugine analogues and other natural products are cur-
rently under way.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2009, No. 14, 2301–2304 © Thieme Stuttgart · New York

LETTER
Synthesis of Antimalarial Alkaloid (+)-Febrifugine
2303
OBn
OH
OBn
1) TsCl, Bu2SnO
O
OH
Et3N, CH2Cl2
TsOH
N
N
10
MeOH
88%
2) DBU, CH2Cl2
91%
12
SO2t-Bu
SO2t-Bu
11
4-quinazolone
KH, DMF, reflux
84%
OR2
N
O
OBn
OH
N
O
Dess–Martin
N
periodinane
N
N
R1
N
86%
O
SO2t-Bu
6 M HCl
reflux
79%
14 R1 = SO2t-Bu, R2 = Bn
(+)-febrifugine (1)
13
Scheme 5 Completion of the synthesis of (+)-febrifugine (1)
K.; Horoiwa, S.; Hirai, S.; Kasahara, R.; Hariguchi, N.;
Matsumoto, M.; Oshima, Y. J. Med. Chem. 2006, 49, 4698.
(q) Sieng, B.; Ventura, O. L.; Bellosta, V.; Cossy, J. Synlett
2008, 1216. (r) Wee, A. G. H.; Fan, G.-J. Org. Lett. 2008,
10, 3869.
Acknowledgment
Financial support from the Major State Basic Research Develop-
ment Program (2006CB806106), and the Chinese Academy of Sci-
ences
(KSCX2-YW-R-23,
07JC140063)
is
gratefully
acknowledged.
(5) (a) Zhong, Y.-W.; Dong, Y.-Z.; Fang, K.; Isumi, K.; Xu,
M.-H.; Lin, G.-Q. J. Am. Chem. Soc. 2005, 127, 11956.
(b) Zhong, Y.-W.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2004, 6,
3953. (c) Zhong, Y.-W.; Isumi, K.; Xu, M.-H.; Lin, G.-Q.
Org. Lett. 2004, 6, 4747.
(6) Indeed, a preliminary study, which utilized aldehyde A and
imine B (Scheme 6) as the substrates to investigate the
impact of a stereocenter adjacent to the reaction site, has
established that the N-sulfinyl group determines the
stereochemistry of the product C, whose structure was
confirmed by X-ray crystallography (CCDC deposit no.
724597). These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
References and Notes
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O
t-Bu
S
SmI2, t-BuOH
–78 °C
S
HN
t-Bu
OBn
O
O
+
O
N
O
O
O
OBn
69%
H
H
OH
A
C
B
single isomer (by 1H NMR)
.
Scheme 6
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Synlett 2009, No. 14, 2301–2304 © Thieme Stuttgart · New York

2304
R. Wang et al.
LETTER
(15) Selected Experiment and Spectroscopic Data
Preparation of Compound 4
MHz, CDCl3): d = 8.26 (m, 1 H), 7.98 (s, 1 H), 7.81–7.73 (m,
2 H), 7.51 (m, 1 H), 7.32–7.24 (m, 5 H), 4.96 (d, J = 17.6 Hz,
1 H), 4.75 (d, J = 17.6 Hz, 1 H), 4.63–4.52 (m, 2 H), 4.42 (s,
1 H), 3.62–3.59 (m, 2 H), 3.11–3.03 (m, 2 H), 2.75 (m, 1 H),
2.05–1.92 (m, 2 H), 1.62–1.47 (m, 2 H), 1.38–1.33 (m, 9 H).
13C NMR (100 MHz, CDCl3): d = 200.67, 160.95, 148.33,
146.60, 138.18, 134.44, 128.26, 127.70, 127.61, 127.54,
127.29, 126.67, 121.86, 74.29, 70.81, 61.98, 54.80, 54.70,
43.16, 42.05, 24.10, 23.24, 19.62. FT-IR (thin film): 2928,
2870, 1308, 936 cm–1. ESI-MS: m/z = 512.4 [M + H]+, 534.4
[M + Na]+. ESI-HRMS: m/z calcd for C27H34N3O5S [M +
H]+: 512.2214; found: 512.2232.
To the solution of SmI2 (4.0 mmol in 20 mL of THF) the
solution of imine 5 (480 mg, 1.90 mmol), aldehyde 6 (1.14
g, 3.80 mmol) and t-BuOH (380 mL, 4.0 mmol) in 20 mL of
THF was dropped in slowly under argon at –78 °C.
The mixture was stirred vigorously for 7 h at the same
temperature and then quenched by 10 mL sat. Na2S2O3 aq
solution. The organic layer was separated, and the aqueous
layer was extracted with EtOAc. The combined organic
extracts were washed by sat. brine and then dried over anhyd
MgSO4, filtered, and concentrated under vacuum. After
flash silica gel chromatography, 952 mg (85%) of the pure
product 4 was obtained as yellow oil.
Compound 1: mp 137–139 °C; [a]D26 +27.3 (c 0.45, EtOH)
[lit.1b mp 139–140 °C; [a]D25 +28.0 (c 0.5, EtOH)]. 1H NMR
(500 MHz, CDCl3): d = 8.28 (m, 1 H), 7.89 (s, 1 H), 7.77–
7.72 (m, 2 H), 7.52 (t, J = 6.7 Hz, 1 H), 4.90 (d, J = 17.7 Hz,
1 H), 4.81 (d, J = 17.7 Hz, 1 H), 3.28 (br s, 1 H), 3.11 (dd,
J = 15.9, 3.9 Hz, 1 H), 2.96 (d, J = 11.0 Hz, 1 H), 2.87 (br d,
J = 3.9 Hz, 1 H), 2.65 (dd, J = 15.9, 6.7 Hz, 1 H), 2.58 (m, 1
H), 2.08 (br d, J = 10.7 Hz, 1 H), 1.84 (br, 2 H), 1.70 (br d,
J = 12.4 Hz, 1 H), 1.52 (br d, J = 12.8 Hz, 1 H), 1.34 (br d,
J = 10.1 Hz, 1 H). 13C NMR (125 MHz, CDCl3): d = 202.64,
161.01, 148.23, 146.39, 134.54, 127.64, 127.44, 126.80,
121.88, 72.26, 60.18, 54.85, 45.97, 44.04, 34.48, 25.65. FT-
IR (thin film): 3304, 3287, 2941, 2931, 2858, 2814, 1722,
1674, 1614, 1475, 1363, 1084, 773, 698 cm–1. ESI-MS:
m/z = 302.2 [M + H]+, 324.2 [M + Na]+. ESI-HRMS: m/z
calcd for C16H20N3O3 [M + H]+: 302.1500; found: 302.1499.
Compound 4: [a]D28 +33.0 (c 2.70, CHCl3). 1H NMR (300
MHz, CDCl3): d = 7.65 (d, J = 6.9 Hz, 4 H), 7.45–7.26 (m, 6
H), 4.46 (d, J = 4.8 Hz, 1 H), 4.29 (m, 1 H), 4.12 (dd, J = 8.1,
5.7 Hz, 1 H), 3.74–3.67 (m, 3 H), 3.52 (t, J = 7.8 Hz, 1 H),
3.42 (m, 1 H), 3.05 (d, J = 4.8 Hz, 1 H), 1.89–1.52 (m, 6 H),
1.40 (s, 3 H), 1.36 (s, 3 H), 1.24 (s, 9 H), 1.05 (s, 9 H). 13
C
NMR (75 MHz, CDCl3): d = 135.48, 133.67, 129.55, 127.57,
109.57, 73.65, 72.59, 69.65, 63.79, 57.96, 55.57, 32.16,
29.77, 29.14, 26.83, 26.79, 25.73, 22.62, 19.11. FT-IR (thin
film): 3414, 3283, 2983, 2959, 2933, 2860, 1112, 1052 cm–1.
ESI-MS: m/z = 576.3 [M + H]+, 598.3 [M + Na]+. MALDI-
HRMS: m/z calcd for C31H49NO5SSiNa [M + Na]+:
598.2993; found: 598.3011.
Compound 14: [a]D25 +64.6 (c 0.60, CHCl3). 1H NMR (400
Synlett 2009, No. 14, 2301–2304 © Thieme Stuttgart · New York