Facile synthesis of acacetin-7-O-β-d-galactopyranoside

Article abstract of DOI:10.1016/j.carres.2011.11.015

Acacetin-7-O-β-d-galactopyranoside (1), a natural flavonoid isolated from flower heads of Chrysanthemum morifolium, has been reported to inhibit the replication of HIV in H9 cells. We achieved the total synthesis of compound 1 by employing a one-pot synthesis of the aglycon. The key reactions in this approach include the modified Baker-Venkataraman reaction and regio- and stereoselective O-glycosylations.

Full text of DOI:10.1016/j.carres.2011.11.015

Carbohydrate Research 348 (2012) 91–94
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Carbohydrate Research
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Note
Facile synthesis of acacetin-7-O-b-D-galactopyranoside
⇑
James T. Zacharia, Masahiko Hayashi
Department of Chemistry, Graduate School of Science, Kobe University, Kobe 657-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 October 2011
Received in revised form 11 November 2011
Accepted 14 November 2011
Available online 8 December 2011
Acacetin-7-O-b-D-galactopyranoside (1), a natural flavonoid isolated from flower heads of Chrysanthe-
mum morifolium, has been reported to inhibit the replication of HIV in H9 cells. We achieved the total syn-
thesis of compound 1 by employing a one-pot synthesis of the aglycon. The key reactions in this approach
include the modified Baker–Venkataraman reaction and regio- and stereoselective O-glycosylations.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Acacetin-7-O-b-
Flavonoid
D-galactopyranoside
Aglycon
Glycosyl fluoride
O-glycosylation
Acacetin-7-O-b-
D
-galactopyranoside (1) was first isolated in
Synthesis of aglycon: 2-p-methoxybenzyl-5,7-
1994 by Lee and co-workers from a methanol extract of the flower
heads of Chrysanthemum morifolium1 along with several other
flavonoids. The flavonoids were evaluated for the inhibition of
HIV growth in H9 cells. A typical example of this group of flavo-
noids is acacetin-7-O-b-D-galactopyranoside 1, which is a glycoside
incorporating an aglycon moiety and a galactopyranoside sugar in
its structure.
It has recently become more apparent that most of the
important classes of drugs, especially those derived from natural
products, are glycosides having a sugar moiety linked to an agly-
con through an O- or C-glycosidic bond.2 In our continued efforts
to use natural products only as synthetic templates and thereby
replace the original plant sources with synthetic ones, we have
developed a synthetic approach providing access to acacetin-7-
dihydroxychromone (2)
Recently, one-pot syntheses of various kinds of flavones utiliz-
ing a modified Baker–Venkataraman rearrangement3,4 have re-
ceived considerable attention. Of particular relevance here is a
work by Boumendjel et al. who succeeded in the syntheses of flav-
ones by refluxing 2,6-dihydroxyacetophenone with one equivalent
of benzoyl chloride in the presence of K2CO3 in dry acetone, result-
ing in a moderate yield of the desired flavones (52%). However, the
reaction also produced a small amount of the corresponding phe-
nolic ester as a by-product.5
More interestingly, Buckle et al. have recently reported a one-
pot syntheses of flavones by heating 2-hydroxyacetophenone with
3 equiv of benzoyl chloride using a K2CO3/acetone system resulting
in an improved yield of the desired flavone to 65%. Nevertheless, a
3-benzoyl substituted flavone was produced in 20% yield as a by-
product of the reaction.6
Inspired by the two reports above, we embarked on the synthe-
sis of compound 1 with a vision to employ this one-pot strategy for
the synthesis of our desired aglycon 2. Gratifyingly, the K2CO3/ace-
tone system using 1.5 equiv of p-methoxybenzoyl chloride under
argon atmosphere gave us the best results as it led exclusively to
the desired aglycon 2 in a 72% yield. The structure of aglycon 2
was confirmed by 1H NMR and 13C NMR spectroscopies, and fur-
ther verified by MS and IR spectroscopic measurements. The mass
spectrum of 2 was characterized by a molecular ion peak at m/z
285.27 (M+1). The IR spectrum showed sharp peaks at
1737 cmꢀ1 and 1651 cmꢀ1 indicating the presence of a carbonyl
O-b-D-galactopyranoside in good yields. The approach is facile
and flexible and thus can be applied to the synthesis of other re-
lated flavonoids by simple substitution of the desired groups.
The starting materials used are simple and cheaply available
from commercial sources, thus making our approach economi-
cally effective.
⇑
Corresponding author.
E-mail address: mhayashi@kobe-u.ac.jp (M. Hayashi).
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.11.015

92
J. T. Zacharia, M. Hayashi / Carbohydrate Research 348 (2012) 91–94
group and carbon–carbon double bonds, respectively. A broader
peak at 3161 cmꢀ1 indicated the presence of –OH groups.
ture afforded the thermodynamically stable a anomer along with
the b anomer in an
a/b ratio of 96:4. On the other hand, treatment
OMe
OMe
HO
OH
O
K2CO3
acetone
65 o
72%
HO
O
+
O
C
Cl
OH
OH
O
2
Table 1
with DAST afforded the two anomers in an a/b ratio of 67:33 (Ta-
ble 1). The use of DAST as a fluorinating agent was particularly
important when the desired anomer was b because the procedure
allowed the isolation of the b anomer after recrystallization from
OAc
OAc
OAc
O
OAc
O
ethanol. The 1H NMR spectrum for the
a anomer featured a charac-
Fluorinating agent
teristic doublet signal of the anomeric proton at 5.87 ppm with a
coupling constant J = 2.8 Hz, which is typical for an equatorial–ax-
ial coupling of H-1–H-2, whereas the b anomer was characterized
by a doublet signal at 5.70 ppm, J = 8.4 Hz, signifying axial–axial
coupling of H-1–H-2. These observations are in agreement with
the reported data in the literature.8,9
AcO
OAc
AcO
OAc
OAc
F
3
Entry
Fluorinating agent
Solvent
Yielda (%)
a
/bb
Regio- and stereoselective O-glycosylation of aglycon 2 with
glycosyl fluoride 3
1
2
70% HF–pyridine
DAST
No solvent
CH2Cl2
82
87
96/4
67/33
a
Isolated yield.
b
Determined by 1H NMR analysis.
Aglycon 2 was treated with 1 equiv of acetylated 1-fluoro-D-
galactopyranoside 3 in the presence of 10 equiv (by weight) of
4 Å molecular sieves in dichloromethane. The reaction was cata-
lyzed by 0.1 equiv of Lewis acid to give the corresponding b glyco-
sides in good to high yields (Table 2). Glycosylation was found to
be highly regioselective with glycosylation at the –OH group on
C-7 predominating over glycosylation at the –OH on C-5. This reg-
ioselectivity for –OH on C-7 can be explained by both steric effects
as well as electronic effects. The –OH group at C-7 is less sterically
hindered compared with the –OH group at C-5, thus making it
more favorable toward glycosylation. Moreover, the –OH group
at C-7 is more electronically favored toward glycosylation owing
to the fact that the neighboring carbonyl group at C-4 renders
the –OH at C-5 less reactive toward glycosyl donors. Screening of
Lewis acids indicated that BF3ꢁEt2O and ZnCl2 were more effective
in catalyzing the reaction than others tested. The phenomenon that
b glycosyl donors are less stable, and hence more reactive, toward
glycosyl acceptors was observed. The stereochemistry of the
Synthesis of the glycosyl donor 3
Having succeeded in the synthesis of the desired glycosyl accep-
tor 2, the next task was to prepare the glycosyl donor to be used in
the glycosylation. Halogenated sugars are known and have been
applied successfully in various glycosylation reactions. In particu-
lar, fluorinated sugars are good candidates. The thermal and chem-
ical stabilities conferred by the strength of the carbon–fluorine
bond are advantageous, resulting in the successful employment
of fluorinated sugars as glycosyl donors under various reaction
conditions.7 With this concept in mind, we embarked on the
fluorination of 1,2,3,4,6-pentaacetylated-b-
The glycosyl fluorides were prepared using conventional methods
either by treating the O-pentaacetylated-b- -galactopyranoside
with 70% HF–pyridine or with diethylaminosulfur trifluoride
(DAST). Treatment with 70% HF–pyridine for 4 h at room tempera-
D-galactopyranoside.
D
Table 2
OMe
OAc
AcO
OAc
O
OMe
OAc
AcO
OAc
O
HO
O
O
O
O
O
+
F
Lewis acid
Solvent
OAc
OAc
-20 to -5 o
C
OH
OH
3
2
4
Entry
Anomeric config. of 3
Solvent
Lewis acid
Yielda (%)
a
/bb
1
2
3
4
5
a
a
b
b
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
BF3ꢁEt2O
SnCl4
ZnCl2
68
64
76
78
69
12:88
16:84
4:96
3:97
8:92
BF3ꢁEt2O
a
and b (1:1)
ZnCl2
a
Isolated yield after column chromatography.
Ratio was determined by 1H NMR analysis.
b

J. T. Zacharia, M. Hayashi / Carbohydrate Research 348 (2012) 91–94
93
Table 3
Comparison between the spectral data of acacetin-7-O-b-D-galactopyranoside obtained from natural sources and synthetic acacetin-7-O-b-D-galactopyranoside
OH
HO
OH
O
OMe
O
O
O
OH
OH
1
Parameter
Natural 11
Synthetic 1
Mp (°C)
254–256
Nd
446 (M+)
251–254
+32.37 (c1.0 CHCl3)
446.87 (M+H)+
1595, 1645, 2930
½ ꢂ
a DT
MS (m/z)
IR (cmꢀ1
)
Nd
Elemental analysis
Nd
Anal. Calcd for C22H22O10: C, 59.19; H, 4.97. Found: C, 58.98; H, 4.78
d 8.04 (2H, d, J = 8.8 Hz, H-20, 60), 7.14 (2H, d, J = 9.2 Hz, H-30, 50), 6.97
(1H, s, H-8), 6.86 (1H, s, H-6), 6.49 (1H, s, H-3),
5.7–3.7 (m, galactosy), 3.41 (3H, s, OCH3, 40)
d 22.51, 38.87, 40.13, 55.31, 113.38, 129.34, 161.58, 167.45, 171.53
1H NMR (DMSO)
d 8.04 (2H, d, J = 8.0 Hz, H-20, 60), 7.14 (2H, d, J = 8.0 Hz, H-30, 50), 6.97
(1H, d, J = 2.0 Hz, H-8), 6.86 (1H, d, J = 2.0 Hz, H-6), 6.44 (1H, s, H-3),
5.1–3.2 (m, galactosy), 3.86 (3H, s, OCH3, 40)
Nd
13C NMR (DMSO)
Nd = No data.
glycosides was established by proton NMR spectroscopy by the JH-
1–H-2 coupling constant. A doublet signal observed between 5.6 and
5.7 ppm in the anomeric proton region with a J = 8.4 Hz was char-
acteristic of a b-galactopyranoside, indicating the axial position of
the anomeric proton at the glycoside center. Conversely, the JH-1–H-2
MP-500D and were uncorrected. Mass spectra were measured on a
Thermo Quest LCQ DECA plus. FT-IR spectra were recorded using
Thermo Scientific, NICOLET iS5, iD5 ATR instrument. Elemental
analyses were performed on a Yanaco CHN Corder MT-5.
for the
a-galactopyranoside was 2.4 Hz in the region from 5.7 to
1.2. Synthesis of 4-methoxybenzoic acid
5.8 ppm, which is consistent with the H-1–H-2 equatorial–axial
anomeric coupling relationship. Regardless of the stereochemistry
of the starting sugar, glycosylation proceeded with good b selectiv-
ity, producing only a small amount of the
This may be the result of a neighboring group participation effect.
To a mixture of 4-hydroxybenzoic acid (1 g, 7.24 mmol) and
anhydrous K2CO3 (1.3 g, 13.03 mmol, 1.8 equiv) in anhydrous ace-
tone (15 mL) under argon atmosphere was added methyl iodide
(1.23 g, 8.69 mmol, 1.2 equiv) at room temperature. The mixture
was heated under reflux for 3 h. After cooling to room temperature
the undissolved K2CO3 was filtered off and the filtrate was evapo-
rated to a residue. The residue was dissolved in warm benzene and
the solution was filtered again and diluted with hexane. The ben-
zene–hexane solution was concentrated until recrystallization be-
gan. After cooling, the crystalline product was collected and
recrystallized from acetone–methanol as white crystals. Yield:
0.46 g (42%). Mp 180–185 °C. 1H NMR (400 MHz, DMSO) d 3.73
(s, 3H), 6.6–7.0 (d, 2H, J = 8.8 Hz), 7.6–8.0 (d, 2H, J = 7.6 Hz),
10.34 (s, 1H). 13C NMR (100.6 MHz, DMSO) d 38.88, 113.99,
115.33, 120.27, 131.41, 161.98.
a anomer glycosides.
Deacetylation
The synthesis of acacetin 7-O-b-D-galactopyranoside (1) was
accomplished by the removal of the acetyl groups from the sugar
moiety. The first reaction conditions used to deprotect the acetyl
groups with 0.1% NaOMe/MeOH for 17 h at room temperature
proved to be too strong, as cleavage of the formed glycosyl bond
occurred along with deprotection of the acetyl groups. We there-
fore investigated other mild conventional methods for deacetyla-
tion. The best result was obtained with 2 M NH3/MeOH10 at
room temperature for 24 h, which improved the yield to 78%.
The physical and spectroscopic data of 1 were similar in all cases
to those from natural sources (Table 3).
1.3. Synthesis of 4-methoxybenzoyl chloride
In conclusion, we have succeeded in the synthesis of acacetin-7-
O-b-D-galactopyranoside (1). Our strategy is versatile and facile
and can be applied to the synthesis of other similar flavonoids by
simple substitution of the desired groups. The key steps in our ap-
proach included the one-pot synthesis of the aglycon, regio- and
stereoselective O-glycosylations, and deacetylation.
4-Methoxybenzoic acid (1 g, 6.57 mmol) was dissolved in SOCl2
(8.61 g) and heated at 60 °C for 2 h. The excess SOCl2 was removed
and the residue was further made free from SOCl2 by dissolving it
in benzene and again taking it to dryness. The acid chloride was
recrystallized from benzene–petroleum ether at 2 °C. Yield:
0.61 g, (54%). 1H NMR (400 MHz, DMSO) d 3.82 (s, 3H), 6.9–7.1
(d, 2H, J = 7.2
H
Hz), 7.8–8.0 (d, 2H, J = 7.2 Hz). 13C NMR
1. Experimental
(100.6 MHz, DMSO) d 39.71, 55.54, 114.24, 131.45, 162.93, 167.06.
1.1. General procedures
1.4. Synthesis of 2-p-methoxybenzyl-5,7-dihydroxychromone
(2)
All starting materials were obtained from commercial sources
and used without further purification unless otherwise stated.
Reactions that required anhydrous conditions were carried out
using dehydrated solvents under argon atmosphere. 1H and 13C
NMR spectra (400 and 100.6 MHz, respectively) were recorded
on a JEOL JNM-LA 400 instrument using Me4Si as an internal
standard (0 ppm). All melting points were measured using Yanaco
To
a solution of 2,4,6-trihydroxyacetophenone (1.68 g, 10
mmol) in acetone under argon/open atmosphere, was added
K2CO3 (13.82 g, 100 mmol, 10 equiv). The mixture was stirred at
room temperature for 10 min and then 4-methoxybenzoyl chloride
(2.56 g, 15 mmol, 1.5 equiv) was added. The mixture was stirred
under reflux for 24 h. After cooling to room temperature the

94
J. T. Zacharia, M. Hayashi / Carbohydrate Research 348 (2012) 91–94
undissolved K2CO3 was filtered off, washed with acetone and evap-
orated under reduced pressure to a residue. The crude mixture was
extracted with ethyl acetate (30 mL ꢃ 3), washed with water,
brine, dried with anhydrous Na2SO4 and concentrated under re-
duced pressure to a residue. The residue was purified by silica
gel column chromatography using hexane/ethyl acetate (4:1) as
eluent. Yield: 2.05 g (72%). Rf 0.17. Mp 138–142 °C. 1H NMR
(400 MHz, DMSO) d 2.07 (s, 1H), 2.63 (s, 1H), 3.56 (s, 3H), 6.29 (s,
1H), 6.96–7.11 (m, 2 H), 7.88–7.92 (m, 2H), 8.02–8.09 (m, 2H).
13C NMR (100.6 MHz, DMSO) d 14.34, 30.79, 33.12, 40.13, 55.68,
60.51, 101.03, 108.68, 114.29, 130.25, 132.29, 156.56, 163.52,
204.59. MS (m/z): 285.27 (M + 1)+. Anal. Calcd for C16H12O5: C,
67.60; H, 4.25. Found: C, 67.49; H, 4.36.
atmosphere. The mixture was stirred for 1.5 h at ꢀ20 °C and then
for a further 2 h at ꢀ5 °C. The mixture was then quenched with a
saturated solution of NaHCO3 (20 mL) and extracted with chloro-
form (30 mL ꢃ 3). The combined organic layer was washed with
water, dried with anhydrous Na2SO4, and concentrated under re-
duced pressure to a residue. The residue was purified by silica
gel column chromatography using hexane/ethyl acetate (5:1) as
eluent. Yield: 0.69 g (78%). Rf 0.38. Mp 118–122 °C. 1H NMR
(400 MHz, DMSO) d 1.9–2.1 (m, 12H), 2.50 (s, 1H), 3.35 (s, 3H),
3.89 (dd, 2H, J = 2.8, 6.4 Hz), 4.01 (m, 1H), 4.41 (dd, 1H, J = 6.4,
6.4 Hz), 5.08 (dd, 1H, J = 2.0, 8.4 Hz), 5.33 (dd, 1H, J = 4.0, 6.8 Hz),
5.89 (d, 1H, J = 8.4 Hz), 6.31 (s, 1H), 7.14 (m, 2H), 8.10 (m, 4H).
13C NMR (100.6 MHz, DMSO) d 20.31, 39.71, 55.68, 61.23, 67.62,
69.93, 70.82, 91.27, 100.88, 114.34, 132.16, 162.89, 169.92. MS
(m/z): 614.99 (M+1)+. Anal. Calcd for C30H30O14: C, 58.63; H, 4.92.
Found: C, 58.41; H, 5.06.
1.5. Synthesis of glycosyl donor 3
1,2,3,4,6-Pentaacetylated-b-D-galactopyranoside (3.9 g, 10
mmol) was dissolved in 70% HF/pyridine (10 mL) in a sealed plastic
vial and stirred for 4 h at room temperature. The progress of the
reaction was monitored by TLC. After completion of the reaction,
the solution was diluted with dichloromethane (30 mL) and deion-
ized water (30 mL). Excess acid was neutralized by addition of
sodium carbonate until no gas evolution was visible and the pH
was adjusted to slightly above 7. The organic phase was separated
and the aqueous phase was extracted using dichloromethane
(30 mL ꢃ 3) and the combined organic phase was dried using
anhydrous Na2SO4, filtered and the solvent was evaporated under
reduced pressure to a residue. The residue was purified by silica
gel column chromatography using ethyl acetate/petroleum ether
1.7. Synthesis of acacetin-7-O-b-D-galactopyranoside (1)
A 20 mL portion of a 2 M NH3 solution in methanol was added
to 1.0 g (1.6 mmol) of glycoside 4 and the solution was stirred at
room temperature for 24 h. The solution was then evaporated un-
der reduced pressure to a residue. The residue was purified by sil-
ica gel column chromatography using hexane/ethyl acetate (5:1) as
an eluent. Yield: 0.59 g (82%). Rf 0.43. Mp 251–254 °C. (lit. 1, 254–
256 °C). [a]
D +32.37 (c1.0 CHCl3). 1H NMR (400 MHz, DMSO) d 2.50
(s, 1H), 3.34 (s, 3H), 3.75–3.91 (m, 4H), 3.99–4.04 (m, 1H), 5.65 (d,
1H, J = 6.4 Hz), 5.79 (d, 1H, J = 2.0, 8.4 Hz), 6.25 (d, 1H, J = 6.8 Hz),
6.49 (s, 1H), 6.97 (d, 1H, J = 8.8 Hz), 7.11, (d, 1H, J = 9.2 Hz), 7.89
(d, 2H, J = 9.2 Hz), 8.07 (d, 2H, J = 8.8 Hz). 13C NMR (100.6 MHz,
DMSO) d 22.51, 38.87, 40.13, 55.31, 113.38, 129.34, 161.58,
167.45, 171.53. MS (m/z): 446.87 (M+1)+. Anal. Calcd for
(1:2). 2.87 g (82%) as a mixture of
a and b-anomer (a/b = 96:4).
For
a
-anomer; Rf. 0.53, 1H NMR (400 MHz, CDCl3) d 1.96 – 2.17
(m, 12H), 4.09 – 4.19 (2dd, 2H, J = 6.8, 12.0 Hz), 4.41 (dd, 1H,
J = 6.4, 6.4 Hz), 5.14 – 5.24 (m, 1H), 5.38 (dd, 1H, J = 3.6, 7.2 Hz),
5.53 (d, 1H, J = 2.0 Hz), 5.88 (d, 1H, J = 2.8 Hz). 13C NMR
(100.6 MHz, CDCl3) d 20.47, 61.15, 67.22, 76.68, 103.05, 105.32,
C22H22O10: C, 59.19; H, 4.97. Found: C, 58.98; H, 4.78.
170.11. MS (m/z): 353.13 (M+H)+. ½a D31
ꢂ
+103.06 (c 1.0 CHCl3). Anal.
References
Calcd for C14H17FO9: C, 48.00; H, 5.47. Found: C, 47.73; H, 5.44. For
b-anomer; Rf 0.27. 1H NMR (400 MHz, CDCl3) d 1.96–2.33 (m, 12H),
4.05–4.08 (2dd, 2H, J = 6.0, 6.4 Hz), 4.10–4.19 (dd, 1H, J = 4.0,
6.4 Hz), 5.08 (d, 1H, J = 3.6 Hz), 5.09–5.33 (dd, 1H, J = 3.2, 8.0 Hz),
5.36 (d, 1H, J = 8.4 Hz), 5.72 (d, 1H, J = 8.4 Hz). 13C NMR
(100.6 MHz, CDCl3) d 20.60, 61.26, 67.34, 76.75, 103.17, 105.44,
1. Hu, C.-Q.; Chen, K.; Shi, Q.; Kilkuskie, R. E.; Cheng, Y.-C.; Lee, K.-H. J. Nat. Prod.
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5. Bois, F.; Beney, C.; Mariotte, A. M.; Boumendjel, A. Synlett 1999, 1480.
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170.25. MS (m/z): 353.13 (M+H)+. ½a D31
ꢂ
+97.71 (c 1.0 CHCl3). Anal.
Calcd for C14H17FO9: C, 48.00; H, 5.47. Found: C, 47.73; H, 5.44.
1.6. Synthesis of glycoside 4
8. Esmurziev, A.; Simic, N.; Sundbyb, E.; Hoff, B. H. Magn. Reson. Chem. 2009, 47,
449–452.
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B.; Pinto, B. M. Tetrahedron: Asymmetry 1994, 5, 2367–2396.
Boron trifluoride etherate complex (0.027 g, 0.19 mmol,
0.13 equiv) was added to a stirred solution of glycosyl donor 3
(0.5 g, 1.43 mmol, 1.0 equiv), 2-p-methoxybenzyl-5,7-dihydroxy-
chromone 2 (0.41 g, 1.43 mmol), and 10 equiv (by weight) of
molecular sieves 4 Å in dichloromethane (5 mL) under argon