The efficient total synthesis of bis-glycosyl apigenin from naringenin: a greener way

Article abstract of DOI:10.1016/j.carres.2009.08.014

An efficient total synthesis of 7-O-β-d-glucopyranosyl-4′-O-α-l-rhamnopyranosyl apigenin (1) was developed in only four steps from naringenin. Compared with our previously reported first total synthesis route (six steps and 19.6% overall yield), this new

Full text of DOI:10.1016/j.carres.2009.08.014

Carbohydrate Research 344 (2009) 2245–2249
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
The efficient total synthesis of bis-glycosyl apigenin from naringenin:
a greener way
a
a
b
a,*
Jianli Chen , Wei Huang , Gaoyan Lian , Feng Lin
a
Shanghai Institute of Pharmaceutical Industry, 1111 Zhongshanbeiyi Road, Shanghai 200437, China
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, CAS, 354 Fenglin Road, Shanghai 200032, China
b
a r t i c l e i n f o
a b s t r a c t
0
Article history:
Received 7 May 2009
Received in revised form 7 August 2009
Accepted 11 August 2009
Available online 15 August 2009
An efficient total synthesis of 7-O-b-D-glucopyranosyl-4 -O-a-L-rhamnopyranosyl apigenin (1) was devel-
oped in only four steps from naringenin. Compared with our previously reported first total synthesis
route (six steps and 19.6% overall yield), this new route contained two steps of highly regioselective gly-
cosylation without any selective protection steps. 7,4 -di-O-b-
pared efficiently by this method. The method is environmentally friendly, economical, and provides a
greener method for flavonoid synthesis starting from an inexpensive flavanone.
Ó 2009 Elsevier Ltd. All rights reserved.
0
D-glucopyranosyl apigenin (2) was also pre-
Keywords:
Total synthesis
Flavonoid glycoside
PTC
Glycosylation
Glycosylated flavonoids occur widely in human food and drinks,
especially in fruits and vegetables,1 and exhibit a broad spectrum
the yield was poor (Table 1, entries 1–3), due to the poor solubility
of naringenin. However, in the case of Aliquat 336 (CH
,2
3
3
+
ꢀ
of interesting biological activities, such as activities against can-
(C H
8 17
)
3
N Cl ), the yield and regioselectivity were better. Because
and water (entry 3) is a suspen-
cer, cardiovascular, and neurodegenerative diseases.4 Flavonoids
,5
naringenin in a mixture of CHCl
3
also contribute to the pigment of petal and plants, providing a col-
sion, while naringenin could be readily dissolved in DMF–water
(1:1), DMF was added to improve the solubility of naringenin. This
change in solvent improved the reaction; using CHCl –DMF–water
3
1
orful nature.
0
The first total synthesis of 7-O-b-
D
-glucopyranosyl-4 -O-
a
-L
-
rhamnopyranosyl apigenin (1, Fig. 1) was recently reported by
1:1:1 (entry 6), 7-O-glucosyl flavonoid 5 was obtained in 47% yield.
However, the hydrolysis of bromide 4 into compound 4a still re-
mained as a main side reaction.
Preliminary studies showed that by changing the number of
equivalents of PTC from 0.5 to 0.1, the hydrolysis of bromide 4
was greatly decreased, while the glycosylation rate was not af-
fected. However, the concentration of bromide 4 affected the gly-
cosylation rate significantly. Further optimization of the number
6
our group. Because of its excellent inhibitory activity against hep-
7
,8
atitis B virus replication and remarkable anti-stroke activity, its
preparation in large scale was needed for further pharmacology
studies. During our process of research, a practical and much
cheaper method was developed, which provided 1 from naringenin
(
an inexpensive flavanone) in four steps without any selective pro-
0
tection steps. Using the same method, 7,4 -di-O-b-
D
-glucopyrano-
syl apigenin (2) was prepared, which is an important pigment
component contributing to the blue color of Salvia Patens’ petals.
2 3
of equivalents of K CO and Aliquat 336 led to a good result (entry
9
8), compound 5 was obtained in 71% yield. The hydrolysis of bro-
mide 4 was greatly reduced with 0.1 equiv of PTC, which helped
to maintain the concentration of bromide 4 and benefit the glyco-
sylation reaction.
In addition, the route developed employed reagents and conditions
that are both environmentally friendly and inexpensive.
Earlier work by Kondo and co-workers reported the direct gly-
9
cosylation of naringenin. Using these conditions, 7-O-glucosyl fla-
Interestingly, in some cases (Table 1, entries 2 and 5), a small
0
vonoid 5 was obtained in moderate yield, but a large amount of
amount of 7,4 -di-O-b-
D
-glucosyl flavonoid 6 was produced at the
1
Ag
2
CO
3
(1.5 equiv) and quinoline were needed, which is not ideal
early stage of reaction, which was isolated and confirmed by H
for large-scale reactions. The phase transfer-catalyzed (PTC) meth-
NMR spectroscopy. Our attempts to glycosylate compound 5 with
bromide 4 under the above PTC conditions failed, proving that the
4 -hydroxy group of naringenin is much more inert than the 7-hy-
1
0,11
od, which was successfully applied in flavonoid synthesis,
was
0
also tried for this direct glycosylation, but in initial experiments,
droxy group (Scheme 1). Based on this result, we thought that the
formation of 6 did not proceed in a stepwise PTC glycosylation via
compound 5, but required the formation of di-anion (where the
*
Corresponding author. Tel.: +86 21 65310547; fax: +86 21 65169893.
E-mail address: linfeng@mail.sioc.ac.cn (F. Lin).
0
008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.08.014

2
246
J. Chen et al. / Carbohydrate Research 344 (2009) 2245–2249
O
OH
O
O
OH
O
HO
HO
O
O
O
HO
HO
O
O
O
O
OH
O
OH
OH
OH
OH
HO
HO OH
HO
OH
OH
1
2
0
0
Figure 1. 7-O-b-
D
-Glucopyranosyl-4 -O-
a-
L
-rhamnopyranosyl apigenin (1) and 7, 4 -di-O-b-
D-glucopyranosyl apigenin (2).
Table 1
Study of selective direct glycosylation of naringenin
a
Entry
K
2
CO
3
(equiv)
PTC agent
Catalyst equiv
Solvent ratiob
Yield (%)
5
6
1
2
3
4
5
6
7
8
1.5
1.5
1.5
1.5
1.5
1.5
2.5
2
TBAB
TBAB
0.1
0.5
0.5
0.5
0.5
0.5
0.5
0.1
1:1:0
1:1:0
1:1:0
20:20:1
2:2:1
1:1:1
1:1:1
1:1:1
Trace
12.5%
23%
31%
42%
47%
61%
71%
—
7%
—
2%
4%
5%
5%
—
Aliquat336
Aliquat336
Aliquat336
Aliquat336
Aliquat336
Aliquat336
a
The reactions were vigorously stirred at 40 °C for 24 h.
Solvent ratio of H O–CHCl –DMF (v/v/v).
2 3
b
0
7
,4 -hydroxyl groups are both deprotonated). Such a species would
The solvent showed remarkable influence on the glycosylation:
the use of CH Cl gave the best results. Addition of DMF or aceto-
nitrile, which improves the solubility of compound 7, did not in-
crease the yield, due to the increased hydrolyzation of rhamnosyl
bromide (Table 3, entry 5 and 6). Similar results were obtained
when the equivalents of Aliquat 336 was raised to 1 equiv (entry
be more difficult to transfer into chloroform during the reaction. At
the early stage of the reaction, dianion was formed under the high
concentration of K
0.5 equiv, entry 7), the dianion could be transferred into chloro-
form, where they reacted with bromide 4 directly to provide prod-
uct 6. When a smaller amount (0.1 equiv) of PTC was used (entry
2
2
2 3
CO . When an effective amount of PTC was used
(
2 2
3). Interestingly, when the concentration of flavonoid 7 in CH Cl
8
), the concentration of di-anion in CHCl
3
was reduced greatly, this
was diluted to 0.05 mol/L, the yield improved remarkably (Table
3, entry 7). Global deprotection of compound 9 with sodium meth-
oxide provided flavonoid 1 in 93% yield.
reaction pathway was retarded.
Boron chelates were reported to improve the selectivity or reac-
tivity of aryl substitution reaction.12 Inspired by these reports, sev-
eral Lewis acids were tried to investigate the metal chelating effect
on glycosylation (Table 2). Unfortunately, none gave an improved
0
Using these optimized conditions, 4 -O-glycosylation of flavo-
noid 7 with tetrabenzoylglucosyl bromide proceeds smoothly
and compound 10 was obtained in 55% yield. Next, 2 was obtained
by the treatment with NaOMe. Although the yield of glycosylation
2 3
result, and a lower yield was obtained. When K CO was added,
9
there was a white flocculent solid that formed after 6 h, which
was carbonate, thus demonstrating that the Lewis acid hindered
the base-promoted glycosylation reaction (see Scheme 2).
Compound 5 could be oxidized with DDQ or iodine–pyridine to
compound 7 in good yield.13 The iodine–pyridine method was used
because of its mild conditions, better reproducibility, and easy
work-up, which showed great advantage in our scale-up attempts.
was lower than that of the reported fluoride case, the application
of much more easily accessed glycosyl bromide donor make this an
attractive synthetic route. These two synthetic cases demonstrated
0
that glycosyl bromides can be suitable donors for flavonoid 4 -O-
glycosylation, which has been reported to be difficult.
0
In conclusion, the synthesis of 7-O-b-
D-glucopyranosyl-4 -O-
a-
L-rhamnopyranosyl apigenin 1 was accomplished in four steps
0
The subsequent 4 -O-glycosylation has been reported to be
and 30% overall yield from inexpensive naringenin. This new route
contained two highly regioselective glycosylation steps without
any selective protection step, and improved remarkably our previ-
difficult. The success of this kind of glycosylation has been
achieved by using glucosyl fluorides with hindered base DTBMP
and TMG. Although the yield was good, the expensive donor and
9
6
ously reported first total synthesis of 1 (six steps and 19.6% overall
0
the reagents prompted us to find a cheaper glycosylation condition
yield) and was easy to scale up. 7,4 -di-O-b-
D
-glucopyranosyl api-
(
see Scheme 3).
genin 2 was also prepared efficiently by this method. The method
is environmentally friendly, economical, and provides a greener
method for flavonoid synthesis starting from an inexpensive
flavanone.
Table 2
a
Investigation of the metal chelating effect on glycosylation
Entry
Lewis acid
—
Equiv
Yield (%)
1
1
. Experimental section
1
2
3
4
5
6
—
1
1
0.8
1
1
61
33
37
36
43
42
ZnCl
AlCl
Yb(OTf)
MgCl
B(OCH
2
.1. General methods
3
3
2
Reagents and solvents were reagent grade and used without
3
)
3
further purification. Methylene dichloride was distilled from cal-
cium hydride. All reactions involving air or moisture sensitive
reagents or intermediates were performed under a nitrogen or
a
Reaction conditions: 2.5 equiv K
:1:1, vigorously stirred at 40 °C for 24 h.
2 3 2 3
CO , 0.5 equiv Aliquat 336, H O–CHCl –DMF
1

J. Chen et al. / Carbohydrate Research 344 (2009) 2245–2249
2247
OBz
O
OH
OH
BzO
BzO
OBz
O
BzO
HO
O
O
BzO
O
O
O
Br BzO
4
OBz
K CO , PTC
2
3
OH
OH
3
5
O
OBz
OBz
O
BzO
BzO
O
O
O
O
OBz
BzO
BzO
4
OBz
BzO
5
OH
4a
BzO
OBz
BzO
K CO , PTC
2
3
OH
O
6
Scheme 1. Reagents and conditions: K
2
CO
3
, PTC, H
2
O–DMF–CHCl
3
, 40 °C, 24 h.
OBz
O
OH
OH
BzO
BzO
OBz
O
δ+
BzO
Br BzO
HO
O
O
BzO
O
O
4
OBz
K CO , PTC
2
3
O
OH
O
5
M
3
+
Scheme 2. Reagents and conditions: Lewis acid, Aliquat 336, H
2
O–DMF–CHCl
3
, then K
2
CO
3
, 40 °C, 24 h.
OH
OH
OBz
O
OBz
O
BzO
BzO
a
BzO
BzO
O
O
O
O
O
O
OBz
OBz
OH
OH
5
7
Br
OBz
O
O
O
O
BzO
BzO
BzO
c
BzO
O
O
O
OBz
OBz
OBz
1
8
OBz
b
BzO
OH
9
OBz
O
BzO
BzO
O
OBz
O
BzO
BzO
BzO
O
O
O
O
OBz
OBz
Br
4
OBz
c
2
BzO
BzO
b
OH
1
0
Scheme 3. Reagents and conditions: (a) I
2
, py, 90 °C, 4 h, 90%; (b) K
2
CO
3
, Aliquat 336, H
2
O–CH
2
Cl
2
, 40 °C, 24 h, for 9: 52%, for 10: 55%; (c) NaOCH
3
, for 1: 93%, for 2: 91%.
Table 3
0
a
Study of 4 -O-rhamnosylation of flavonoid 7
Entry
Base (equiv)
PTC agent
Catalyst equiv
Solvent
Yield (%)
1
2
3
4
5
6
7
8
K
K
2
CO
CO
3
3
(2)
(2)
Aliquat336
TBAB
0.2
0.2
1
0.2
0.2
0.2
0.2
0.2
CHCl
CHCl
CHCl
3
3
3
13
2
Trace
Trace
25
Trace
18
NaOH (2)
Aliquat336
Aliquat336
Aliquat336
Aliquat336
Aliquat336
Aliquat336
K
K
K
K
K
2
CO
2
CO
2
CO
2
CO
2
CO
3
3
3
3
3
(2)
(2)
(2)
(2)
(2)
CH
2
CH
2
CH
2
CH
2
CH
2
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
/DMFb
/CH
3
CNb
c
52
31
d
a
b
c
Unless indicated, the reactions were vigorously stirred at 40 °C for 24 h, the concentration of flavonoid 7 in chloroform was 0.1 M.
Solvent ratio is CH Cl –X 2:1 (v/v).
2
2
The concentration of flavonoid 7 in CH
The concentration of flavonoid 7 in CH
2
Cl
Cl
2
was 0.05 M.
was 0.025 M.
d
2
2

2
248
J. Chen et al. / Carbohydrate Research 344 (2009) 2245–2249
argon atmosphere. Flash chromatography was performed on Qing-
dao Haiyang silica gel (300ꢀ400 mesh). Analytical TLC was per-
formed using 0.25 mm EM Silica Gel 60 F250 plates that were
9 (3.4 g, 52%) as a yellow solid. 1H NMR (400 MHz, CDCl
(3H, CH ), 4.34 (1H, m), 4.53 (3H, m), 4.80 (1H, d, J = 11.6 Hz),
5.66 (1H, d, J = 7.2 Hz), 5.86 (4H, m), 6.02 (2H, m), 6.35 (1H, m),
3
): d 1.42
3
13
visualized by irradiation (254 nm) or by staining with H
2
SO
OH solution. H and C NMR spectra were obtained using
00 MHz Bruker AM300 and 400 MHz Varian instruments.
4
–
6.62 (2H, m), 7.19–8.26 (39H, Ar), 12.71 (1H, s).
C NMR
1
13
CH
3
(100 MHz, CDCl ): 17.6, 63.0, 68.0, 69.3, 69.6, 70.4, 71.4, 71.5,
3
3
72.6, 73.0, 95.7, 98.2, 99.9, 100.1, 105.0, 105.9, 106.9, 116.9,
122.5, 125.4, 127.7, 128.2–133.9 (m, Ar), 158.8, 161.9, 162.1,
162.4, 162.4, 163.4, 163.8, 164.5, 164.9, 165.2, 165.5, 165.6,
Elemental analysis was performed on a Foss-Heraeus Vario EL
instrument. Mass spectra (ESI) were performed on Shimadzu
LCMS-2010EV. High resolution mass spectra (MALDI/DHB) were
performed on IonSpec 4.7 Tesla FTMS from Varian.
+
+
166.0, 182.30. ESI-MS (m/z): 1329.27 [M+Na] , 1345.28 [M+K] ,
1307.26 [M+H] .
+
0
1
.2. 7-O-(2,3,4,6-Tetra-O-benzoyl-b-
D-glucopyranosyl)-
1.5. 7,4 -Di-O-(2,3,4,6-tetra-O-benzoyl-b-
D
-glucopyranosyl)-
naringenin (5)
apigenin (10)
A solution of naringenin (19 g, 70 mmol) and K
44 mmol) in DMF (700 mL), H O (700 mL), was mixed with ali-
quat 336 (3 g, 7 mmol) and bromide 4 (72.5 g, 110 mmol) in CHCl
700 mL). The mixture was stirred vigorously at 45 °C for 24 h, the
organic phase was separated and the aqueous phase was extracted
with CH Cl . The organic extracts were combined, washed with
brine, dried (Na SO ), and concentrated. The residue was purified
by column chromatography (hexane–EtOAc 3:1, R = 0.26) to ob-
tain 5 (43.7 g, 70%) as yellow solid. 1H NMR (400 MHz, CDCl
): d
.76 (1H, m), 3.04 (1H, m), 4.40 (1H, m), 4.53 (1H, dd, J = 6.4,
2
CO
3
(20 g,
The procedure was the same as that for flavonoid 9, yielding 10
(1.9 g, 55%). H NMR (400 MHz, CDCl ): d 4.53 (4H, m), 4.75 (2H,
3
1
1
2
3
m), 5.54 (1H, d), 5.64 (1H, d, J = 7.6 Hz), 5.80 (4H, m), 6.05 (2H,
m), 6.48 (1H, s), 6.57 (2H, s), 7.09 (2H, d, J = 8.8 Hz), 7.44 (26H,
(
1
3
3
m), 7.98 (16H, m). C NMR (100 MHz, CDCl ): 63.0, 69.3, 69.6,
2
2
71.7, 72.6, 72.9, 73.0, 95.6, 98.2, 98.8, 99.8, 105.0, 106.9, 117.4,
125.8, 127.9, 128.3, 128.4–133.5 (m, Ar), 157.2, 159.4, 162.0,
162.5, 163.7, 165.0, 165.2, 165.3, 165.7 (2 C), 165.8, 166.0, 182.3.
2
4
f
+
+
3
ESI-MS (m/z):1449.31 [M+Na] , 1427.31 [M+K] .
2
1
1
0
2.0 Hz), 4.73 (1H, m), 5.27 (1H, m), 5.54 (1H, dd, J = 7.6,
1.2 Hz), 5.79 (2H, m), 6.02 (1H, t, J = 9.2 Hz), 6.15 (1H, m), 6.27
1.6. 7-O-b-
D
-Glucopyranosyl-4 -O-
a-
L-rhamnopyranosyl
apigenin (1)
(
(
1H, m), 6.90 (2H, m), 7.39 (14H, m), 7.97 (8H, m). 13C NMR
3
100 MHz, CDCl ): 42.8, 43.2, 63.1, 69.2, 71.4, 72.6, 72.9, 78.9,
2 2
A solution of 9 (6.5 g, 5 mmol) in CH Cl (100 mL) and MeOH
9
1
1
6.3, 96.4, 97.2, 97.9, 98.0, 104.3, 115.7, 127.7, 127.9, 128.3–
33.5 (m, Ar), 156.6, 162.8, 162.9, 163.9, 164.0, 164.3, 164.4,
(200 mL) with NaOMe (1 g, 20 mmol) was stirred for 4 h at rt.
The mixture was quenched by adding methanolic HCl (2 M) to
pH 6–7, and the solvent was removed under vacuum. The residue
65.0, 165.2, 165.8, 166.2, 196.4, 196.5. ESI-MS (m/z): 873.12
+
+
[
M+Na] , 889.10 [M+K] .
was purified by chromatography on silica gel (CH
2
Cl
2 3
–CH OH 3:1)
1
to give 1 (2.7 g, 93%). H NMR (400 MHz, C D N): d 8.07 (d, 2H,
6 6
1
.3. 7-O-(2,3,4,6-Tetra-O-benzoyl-b-
D-glucopyranosyl)-apigenin
J = 8.8 Hz), 7.45 (d, 2H, J = 8.8 Hz), 7.23 (d, 1H, J = 1.6 Hz), 7.07 (s,
1H), 6.96 (d, 1H, J = 2 Hz), 6.22 (s, 1H), 5.92 (d, 1H, J = 7.7 Hz),
4
(
7)
.74 (m, 2H), 4.36 (m, 8H), 1.67 (d, 3H, J = 6.2 Hz). 13C NMR
A solution of 5 (13.5 g, 16.2 mmol), and iodine (4 g, 16 mmol) in
6 6
(100 MHz, C D N): d 183.2, 164.8, 164.5, 160.5, 158.3, 159.6,
pyridine (140 mL) was heated to 90 °C for 4 h. The mixture was
cooled and poured into cold water. The precipitate was separated
and the mixture was extracted with EtOAc. The combined organic
phases were washed with saturated sodium thiosulfate and water,
129.1, 129.1, 125.1, 117.7, 117.7, 106.9, 105.3, 102.0, 101.2,
100.0, 96.0, 79.3, 78.4, 74.9, 73.8, 73.7, 72.5, 71.8, 71.5, 62.6,
18.9. ESI-MS (m/z): 601.1 [M+Na] , 613.1 [M+Cl] , HR-MS: m/z
+
ꢀ
calcd for C27
H
31
O14: 579.1714, found: 579.1708.
successively. Then, the organic layer was dried (Na
centrated. The residue was purified by silica gel column chroma-
tography (hexane–THF 3:2, R = 0.25) to obtain compound 7
12.1 g, 88%). H NMR (400 MHz, CDCl ): d 4.46 (1H, dd, J = 2.4,
2 4
SO ) and con-
0
1.7. 7,4 -Di-O-b-
D-glucopyranosyl apigenin 2
f
1
(
3
The procedure was the same as that for 1, giving 2 (2.9 g, 91%).
H NMR (400 MHz, CDCl ): d 4.53 (4H, m), 4.75 (2H, m), 5.54 (1H,
d), 5.64 (1H, d, J = 7.6 Hz), 5.80 (4H, m), 6.05 (2H, m), 6.48 (1H, s),
6.57 (2H, s), 7.09 (2H, d, J = 8.8 Hz), 7.44 (26 H, m), 7.98 (16H, m).
1
6
5
.8 Hz), 4.53 (1H, dd, J = 6.0, 6.4 Hz), 4.78 (1H, dd, J = 2.4, 9.6 Hz),
.58 (1H, d, 7.6 Hz), 5.81 (2H, m), 6.03 (1H, t, J = 9.2 Hz), 6.53
3
(
3H, m), 6.95 (1H, s), 6.97 (2H, s), 7.36 (8H, m), 7.51 (4H, m),
1
3
7
1
7
1
1
.69 (2H, d, J = 8.4 Hz), 7.91 (2H, d, J = 7.6 Hz), 7.99 (6H, m),
3
C NMR (100 MHz, CDCl ): 63.0, 69.3, 69.6, 71.7, 72.6, 72.9, 73.0,
1
3
2.73 (1H, s). C NMR (100 MHz, CDCl
3
): 63.0, 69.3, 71.6, 72.7,
95.6, 98.2, 98.8, 99.8, 105.0, 106.9, 117.4, 125.8, 127.9, 128.3,
128.4–133.5 (m, Ar), 157.2, 159.4, 162.0, 162.5, 163.7, 165.0,
165.2, 165.3, 165.7 (2C), 165.8, 166.0, 182.3. ESI-MS (m/
3.0, 95.6, 98.2, 99.8, 104.1, 106.8, 116.2 (2C), 123.0, 128.4,
28.5, 128.6, 128.9–133.6 (m, Ar), 157.2, 159.8, 161.9, 162.3,
+
+
64.6, 165.1, 165.2, 165.8, 166.2, 182.4. ESI-MS (m/z): 871.18
z):1449.31 [M+Na] , 1427.31 [M+K] .
+
[
M+Na]+, 849.20 [M+H] .
Acknowledgments
0
1
.4. 7-O-(2,3,4,6-Tetra-O-benzoyl-b-
D
-glucopyranosyl)-4 -O-
(
2,3,4-tri-O-benzoyl-
a
-
L
-rhamnopyranosyl) apigenin (9)
This work was supported by Innovation Research Grant of SIPI.
F.L. thanks the Open Grant of the State Key Lab of Bioorganic and
Natural Products Chemistry (SIOC, CAS).
2 3 2
A solution of K CO (1.38 g, 10 mmol) in H O (100 mL), was
mixed with acceptor 5 (4.2 g, 5 mmol), Aliquat 336 (0.4 g, 1 mmol)
and bromide 4 (5.4 g, 10 mmol) in CH Cl (100 mL). The mixture
was stirred vigorously at 45 °C for 24 h, the organic phase was sep-
arated and the aqueous phase was extracted with CH Cl . The or-
ganic extracts were combined, washed with brine, dried
Na SO ), and concentrated. The residue was purified by column
chromatography (hexane–THF–CH Cl 3:1:1, R = 0.19) to obtain
2
2
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