Total synthesis of (-)-centrolobine

Article abstract of DOI:10.1016/j.tetlet.2008.08.102

Stereoselective synthesis of (-)-centrolobine, an anti-Leishmania agent, was accomplished via an intramolecular Barbier-type reaction of iodo-ester with n- or t-butyllithium followed by Lewis acid-promoted Et₃SiH reduction of the resulting hemi

Full text of DOI:10.1016/j.tetlet.2008.08.102

Tetrahedron Letters 49 (2008) 6462–6465
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Tetrahedron Letters
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Total synthesis of (ꢀ)-centrolobine
Toshiharu Takeuchi, Miyuki Matsuhashi, Tadashi Nakata
*
Department of Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective synthesis of (ꢀ)-centrolobine, an anti-Leishmania agent, was accomplished via an intra-
molecular Barbier-type reaction of iodo-ester with n- or t-butyllithium followed by Lewis acid-promoted
Et3SiH reduction of the resulting hemiacetal.
Received 1 August 2008
Revised 25 August 2008
Accepted 28 August 2008
Available online 31 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Butyllithium
2,6-syn-Tetrahydropyran
Cyclization
CBS reduction
Mitsunobu reaction
(ꢀ)-Centrolobine (1) is a natural product isolated from the
heartwood of Centrolobium robustum1 and from the stem of Brosi-
num potabile2 in the Amazon forest (Fig. 1). It exhibits activity
against Leishmania amazonensis promastigotes, a parasite associated
with leishmaniasis, which is a major health problem in Brazil.1c,3
Its structure, which contains 2,6-syn-tetrahydropyran, was eluci-
dated by the synthesis of racemic 11a,1b and the absolute structure
was determined in 2002 by the first enantioselective total synthe-
sis of (ꢀ)-1.4 Since then, a number of groups have reported the to-
tal synthesis of 1 in both racemic5 and optically active forms.6
We have recently reported that treatment of an acyclic iodo-es-
ter with n- or t-butyllithium effected intramolecular cyclization to
give the hemiacetal, which was reduced with Et3SiH in the pres-
ence of BF3ꢁEt2O to give 2,6-syn-tetrahydropyran.7 As an applica-
tion of this method to the synthesis of natural products, we
focused our attention on the synthesis of (ꢀ)-centrolobine (1). Ret-
rosynthetic analysis revealed two possible synthetic routes, A and
B, using iodo-esters 2 and 3, respectively (Fig. 2). We now report
our results using both synthetic routes A and B.
First, we examined route A using the iodo-ester 2 (Scheme 1).
Addition of Grignard reagent 5 to acid chloride 4 in the presence
of CuBr and LiBr in THF8 afforded ketone 65d in 98% yield. Asym-
metric reduction of 5 with BH3ꢁTHF in the presence of (R)-(+)-2-
methyl-CBS-oxazaborolidine 79 gave (S)-alcohol 85d in 96% yield.
Reduction of the ester 8 with LiAlH4 followed by TBS protection
afforded TBS ether 9 (99% ee)10 in 97% yield. Coupling of the alco-
hol 9 and carboxylic acid 1011 was carried out by Shiina’s method12
using 2-methyl-6-nitrobenzoic anhydride (MNBA) to give ester 11
in 98% yield. Removal of the TBS group followed by iodination with
I2 and Ph3P13 gave the required iodo-ester 2 in 87% yield. Upon
treatment of 2 with n- or t-butyllithium in THF at ꢀ78 °C, an intra-
molecular Barbier-type reaction14 took place to give an equilibrium
I
O
H
O
MeO
OBn
OBn
2
route A
O
H
H
(–)-Centrolobine (1)
MeO
OH
I
(–)-Centrolobine (1)
Figure 1. Structure of (ꢀ)-centrolobine (1).
route B
O
O
H
MeO
3
* Corresponding author.
E-mail address: nakata@rs.kagu.tus.ac.jp (T. Nakata).
Figure 2. Synthetic routes A and B.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.102

T. Takeuchi et al. / Tetrahedron Letters 49 (2008) 6462–6465
6463
Ph
MgBr
H
N
Ph
O
CO2Me
CO2Me
OH
1) LiAlH4
MeO
CuBr, LiBr
5
7
B
Et2O, 0 °C
O
BH3·THF
Me
CO2Me
100%
H
COCl
MeO
MeO
THF, rt
98%
toluene, –78 °C
2) TBSCl
pyridine, rt
97%
96%
4
6
8
HO2C
OTBS
OTBS
I
1) CSA, MeOH
CH2Cl2, 0 °C
10
OBn
O
OH
H
O
H
O
H
O
MNBA, DMAP, Et3N
CH2Cl2, rt
2) I2, imidazole
Ph3P, THF, rt
87% (2 steps)
MeO
OBn
MeO
MeO
OBn
9 (99% ee)
11
2
98%
O
H
H
OH
MeO
OBn
t
or
-BuLi
Et3SiH
BF3·Et2O
12a
n-BuLi
O
H
H
THF
–78 °C
MeCN
–78 ~ –40 °C
64%
MeO
OR
O
97% (for t-BuLi)
96% (for n-BuLi)
OH
H2, Pd/C
EtOH, EtOAc
rt, 91%
13: R = Bn
1: R = H
MeO
OBn
Scheme 1.
12b
O
BF3·Et2O
Et3SiH
OBn
OH
O
H
O
racemic 13
H
MeO
OBn
MeO
MeO
OBn
ii
12b
i
Figure 3. Mechanism for reaction of 12 with Et3SiH and BF3ꢁEt2O.
CO2H
1)
MeO
DEAD, Ph3P
benzene, 0 °C
18
BrMg
TBSO
TBSO
16
OBn
CuI
HO2C
CO2H
NH2
HO
H
THF, 0 °C
2) CSA, MeOH
CH2Cl2, 0 °C
90% (2 steps)
O
100%
OBn
14
15
17 (99% ee)
O
H
OH
HO
I
a)
b)
t
-BuLi (2.6 eq)
I2, Ph3P
imid.
MeO
MeO
OBn
OBn
20a
20b
n
-BuLi (1.8 eq)
O
O
O
H
O
H
THF, –78 °C
THF, rt
98%
MeO
OBn
MeO
OBn
O
19
3
HO
H
Et3SiH
BF3·Et2O
H2, Pd/C
O
H
O
H
H
H
MeCN
EtOH, EtOAc
rt, 88%
–78 ~ –40 °C
a) 50% (2 steps)
b) 67% (2 steps)
MeO
OBn
MeO
OH
13
(–)- 1
Scheme 2.

6464
T. Takeuchi et al. / Tetrahedron Letters 49 (2008) 6462–6465
Acid
HO
H
(–)-centrolobine (1)
chiral 13
OH OH
MeO
OBn
MeO
OBn
iii
iv
Figure 4. Synthetic plan for (ꢀ)-1 via cyclization of diol iii.
BF3·Et2O
MS 4A
LiAlH4
O
20
OH OH
H
H
MeCN, –40 °C
Et2O, 0 °C
50%
MeO
OBn
93%
MeO
OBn
(2 steps from 3)
13 (99% ee)
21
Scheme 3.
mixture of hemiacetal 12a and ketone 12b (ca. 1:1.8 ratio in CDCl3)
in 96% or 97% yield, respectively. Treatment of 12 with Et3SiH in
the presence of BF3ꢁEt2O15 effected reductive etherification to give
References and notes
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1970; (i) Lee, C.-H.; Loh, T.-P. Tetrahedron Lett. 2006, 47, 1641–1644; (j) Prasad,
K. R.; Anbarasan, P. Tetrahedron 2007, 63, 1089–1092; (k) Washio, T.;
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2007, 63, 12037–12046; (l) Dziedzic, M.; Furman, B. Tetrahedron Lett. 2008, 49,
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13513–13520.
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10. The enantiomeric excess (ee) was determined by HPLC (Daicel Chiralcel OD-H,
2-propanol/n-hexane = 1:15).
11. Lewin, A. H.; Szewczyk, J.; Wilson, J. W.; Carroll, F. I. Tetrahedron 2005, 61,
7144–7152.
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1830.
13. Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Chem. Commun. 1979, 978–
980.
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see: (a) Cooke, M. P., Jr.; Houpis, I. N. Tetrahedron Lett. 1985, 26, 4987–4990; (b)
Ohtsuki, K.; Matsuo, K.; Yoshikawa, T.; Moriya, C.; Tomita-Yokotani, K.;
Shishido, K.; Shindo, M. Org. Lett. 2008, 10, 1247–1250.
15. Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 4976–4978.
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Kihara, M.; Iguchi, S.; Imakuma, Y.; Kobayashi, S. Heterocycles 1989, 29, 1097–
1105.
2,6-syn-tetrahydropyran 13 in 64% yield. However, the [a] value
D
of 13 was 0; that is, the product 13 is unfortunately racemic. Thus,
hydrogenolysis of the benzyl ether 5 gave racemic centrolobine (1).
This racemization presumably takes place as follows ( Fig. 3).
Removal of the hydroxyl group of 12b with BF3ꢁEt2O would easily
proceed owing to the effect of the electron-donating MeO group;16
thus, the chirality of 12 would be lost at this stage. Then, the
carbonyl oxygen would attack the diene-oxonium ion i to give
tetrahydropyran oxonium ion ii. Subsequent reduction of the
oxonium ion ii with Et3SiH would provide racemic 13.
Next, we examined the other route B, in which no epimerization
was expected (Scheme 2). The synthesis commenced with the
known chiral epoxide 15,17 which was prepared starting from
L-glutamic acid (14). Coupling of the epoxide 15 and Grignard
reagent 16 in the presence of CuI in THF afforded (R)-alcohol 17
(99% ee),10 quantitatively.18 The Mitsunobu reaction19 of 17 with
p-methoxybenzoic acid (18) in the presence of DEAD and Ph3P
effected esterification accompanied with inversion of the hydroxyl
group to give an ester, which was treated with CSA in MeOH to give
alcohol 19 in 90% yield (2 steps). After iodination of 19 (98% yield),
treatment of the resulting 3 with n-BuLi or t-BuLi afforded an equi-
librium mixture of hemiacetal 20a and ketone 20b (ca. 1:1.1 ratio
in CDCl3), which was subjected to BF3ꢁEt2O-mediated Et3SiH reduc-
tion to give optically active 2,6-syn-tetrahydropyran 13 in 67% or
50% yield (2 steps), respectively. Finally, hydrogenolysis of 13 on
Pd/C in EtOH-EtOAc afforded (ꢀ)-centrolobine (1) (98% ee)20 in
88% yield. The spectral data of synthetic (–)-121 were identical with
those of natural centrolobine (1).
Treatment of 12b with BF3ꢁEt2O promoted removal of the hy-
droxyl group as shown in Figure 3. Thus, when diol iii, which
should be formed by reduction of 20, is treated with acid, removal
of the hydroxyl group and intramolecular addition of the hydroxyl
group in iv should proceed successively to give optically active 2,6-
syn-tetrahydropyran 13, from which (ꢀ)-centrolobine (1) can be
obtained ( Fig. 4). Therefore, this synthetic route was examined
(Scheme 3). LiAlH4 reduction of the mixture 20, prepared from 3
by n-BuLi treatment, afforded diol 21 in 50% yield (2 steps). After
several attempts at cyclization, it was found that treatment of diol
21 with BF3ꢁEt2O in the presence of MS 4A in MeCN at ꢀ40 °C affor-
ded optically active tetrahydropyran 13 (99% ee)22 in 93% yield.23
In summary, total synthesis of (ꢀ)-cetrolobine (1) was accom-
plished via an intramolecular Barbier-type cyclization of iodo-ester
3 with n- or t-BuLi, followed by BF3ꢁEt2O-mediated Et3SiH reduc-
tion of the resulting hemiacetal.
17. (a) Ravid, U.; Silverstein, R. M.; Smith, L. R. Tetrahedron 1978, 34, 1449–1452;
(b) Andreou, T.; Costa, A. M.; Esteban, L.; Gonzalez, L.; Mas, G.; Vilarrasa, J. Org.
Lett. 2005, 7, 4083–4086.
18. Pandey, S. K.; Kumar, P. Eur. J. Org. Chem. 2007, 369–373.
19. (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380–2382; (b)
Mitsunobu, O. Synthesis 1981, 1–28; (c) Hughes, D. L. Org. React. 1992, 42, 335–
656; (d) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017–3020.
20. The enantiomeric excess (ee) was determined by HPLC analysis (Daicel
Chiralpak AD-H, 2-propanol/n-hexane = 1:15).

T. Takeuchi et al. / Tetrahedron Letters 49 (2008) 6462–6465
6465
21. Recrystallization of synthetic (ꢀ)-1 from n-hexane–EtOAc gave colorless
1.26 (m, 1H); 13C NMR (100 MHz, CDCl3) d 158.7, 153.5, 135.9, 134.7, 129.5
(2C), 127.1 (2C), 115.1 (2C), 113.6 (2C), 79.1, 77.2, 55.3, 38.3, 33.3, 31.3, 30.7,
24.1; HRMS (ESI) calcd for C20H24O3Na (M+Na+) 335.1618, found 335.1618.
22. The enantiomeric excess (ee) was determined by HPLC analysis (Daicel
Chiralcel OD-H, 2-propanol/n-hexane = 1:99).
needles. mp 85.5–86.5 °C (100% ee)20 (lit.1 mp 84–86 °C); ½a 2D4
ꢂ
–91.7 (c 0.77,
CHCl3) [lit.1 a 2D0
½ ꢂ –92.1 (c 1, CHCl3)]; IR (KBr) 3387, 2925, 1610, 1511, 1451,
1300, 1244, 1088, 1036, 805, 568 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.32–7.29
;
(m, 2H), 7.06–7.02 (m, 2H), 6.89–6.86 (m, 2H), 6.73–6.70 (m, 2H), 4.29 (dd,
J = 11.2, 2.0 Hz, 1H), 3.80 (s, 3H), 3.47–3.40 (m, 1H), 2.74–2.61 (m, 2H), 1.95–
1.80 (m, 3H), 1.76–1.67 (m, 1H), 1.66–1.57 (m, 2H), 1.55–1.45 (m, 1H), 1.38–
23. In the first total synthesis of ( )-centrolobine,1b a similar cyclization was
carried out by treatment with ZnCl2.