6604
L. Boulard et al. / Tetrahedron Letters 45 (2004) 6603–6605
Our total synthesis of (ꢀ)-centrolobine involves the ini-
tial selective protection of 3-(4-hydroxyphenyl)-1-propa-
nol 1 to the corresponding monobenzyl ether 2 (90%
yield) by using benzylbromide (0.95equiv) [NaH
(0.95equiv), DMF, 50°C, 12h]. Two steps were neces-
sary to transform 2 into the optically active homoallylic
alcohol 3, a precursor of the tetrahydropyran ring of
(ꢀ)-centrolobine. After oxidation of 2 with PCC
(CH2Cl2, rt, quantitative), the resulting aldehyde was
treated with the highly face-selective enantioselective
allyltitanium complex (S,S)-I7 (Scheme 2). In this
manner, the homoallylic alcohol 3 was obtained in
61% yield with an enantiomeric excess superior to 95%.8
(ꢀ)-centrolobine in two steps. After treatment of 4 in
THF at ꢀ78°C for 1h with 4-methoxyphenylmagnesium
bromide (3.0equiv), lactol 5 was obtained in equilibrium
with the 5-hydroxyketone. The addition of Et3SiH
(4.0equiv), in the presence of BF3ÆEt2O (3.0equiv)
(CH2Cl2, ꢀ78°C then rt, 1h), to the crude lactol 5
afforded (ꢀ)-centrolobine with a nonoptimized 40%
overall yield from lactone 4. (ꢀ)-Centrolobine was thus
obtained in a 12% overall yield from 3-(4-hydroxyphen-
yl)-1-propanol 1. The analytical and spectroscopic data
of (ꢀ)-centrolobine thus obtained including IR, 1H
NMR and 13C NMR as well as the optical rotation
20
½aꢁ ꢀ94:0 (c 0.33, CHCl3) were in perfect agreement
D
with those previously reported in the literature
20
D
(½aꢁ ꢀ92:2 (c 1.0, CHCl3)).3d
a
HO
It is worth noting that a one-pot transformation of 4
into (ꢀ)-centrolobine, implying two successive one-pot
reactions, was also tested. Lactone 4 was transformed
into (ꢀ)-centrolobine by addition of 4-methoxyphenyl-
magnesium bromide (1M solution in THF, 4.0equiv,
CH2Cl2, ꢀ78°C), followed by the addition at ꢀ78°C
of TMSOTf (4.0equiv) and Et3SiH (4.0equiv). After this
successive one-pot reaction (ꢀ)-centrolobine was iso-
lated in 23% yield (Scheme 2).
HO
OH
OBn
1
2
b
Ph
OH
Ph
O
O
Ti
O
OBn
3
Ph
O
Ph
(S,S)-I
c
O
MesN
Cl
NMes
HO
O
The two reported synthetic approaches to (ꢀ)-centrolo-
bine are very short and efficient. By performing two suc-
cessive one-pot reactions, purification of the
intermediates was avoided and this is very attractive
for large scale preparations. As the reactions used are
quite versatile, an expeditious preparation of a small
library of analogues should be achieved in a straightfor-
ward manner. This work is ongoing in our laboratories
as well as the structure–activity relationship of the
libraries.
e
Ru
O
Cl
PriO
OH
II
4
5
OH
OMe
f
d
O
OH
(-)-Centrolobine
Acknowledgements
Scheme 2. Synthesis of (ꢀ)-centrolobine. (a) NaH, BnBr, DMF, reflux
90%; (b) i. PCC, CH2Cl2, rt, quantitative; ii. (S,S)-I, ether, ꢀ78°C,
61%; (c) acrylic acid (4.2equiv), II (3.7mol%), CH2Cl2, two days then
Pd/C (2.2mol%), H2, four days, 56%; (d) i. 4-methoxyphenylmagne-
sium bromide (4equiv) THF, ꢀ78°C, 1h; ii. TMSOTf (4equiv) and
Et3SiH (4equiv), ꢀ78°C then rt, 1h, 23%; (e) 4-methoxyphenylmag-
nesium bromide (3equiv) THF, ꢀ78°C, 1h; (f) BF3ÆEt2O (3equiv) and
Et3SiH (4equiv), CH2Cl2, ꢀ78°C then rt, 1h, 40% from 4.
M. dos Santos is acknowledged for his technical assis-
tance and we thank Dr. R. A. Fisher (Materia, Inc)
for a generous gift of catalyst II.
References and notes
1. Cossy, J.; Bargiggia, F.; Bouzbouz, S. Org. Lett. 2003, 5,
459.
The transformation of homoallylic alcohol 3 into lac-
tone 4 was achieved according to the one-pot procedure
that we have previously devised1 with the modification
of using the more commonly used Pd/C instead of
PtO2 in the hydrogenation step. After treating the
homoallylic alcohol 3 with acrylic acid (4.2equiv) in
the presence of the Hoveydaꢁs catalyst II (3.7mol%) in
CH2Cl2 for two days at rt, Pd/C (2.2mol%) was
added and the reaction mixture was placed under one
atmosphere of hydrogen for four days. Lactone 4 was
produced in 56% yield from homoallylic alcohol 3.9 This
transformation implies four one-pot reactions, a cross-
metathesis (CM), a hydrogenation, a lactonization and
a debenzylation. The use of Pd/C instead of PtO2
allowed us to improve the in situ debenzylation of the
phenol function. Lactone 4 was then transformed into
`
2. (a) Franck, X.; Figadere, B., unpublished results; (b)
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Marini-Bettolo, G. B. Gazz. Chim. Ital. 1964, 287; (b)
Galeffi, C.; Casinovi, C. G.; Marini-Bettolo, G. B. Gazz.
Chim. Ital. 1965, 95; (c) Craveiro, A. A.; Prado da Costa,
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´
4. (a) Colobert, F.; Des Mazery, R.; Solladie, G.; Carreno, M.
C. Org. Lett 2002, 4, 1723; (b) Carreno, M. C.; Des Mazery,
´
F.; Urbano, A.; Colobert, F.; Solladie, G. J. Org. Chem.
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Boulard, Lucie
