Synthesis of pelargonidin 3-O-6″-O-acetyl-β-d-glucopyranoside, an acylated anthocyanin, via the corresponding kaempferol glucoside

Article abstract of DOI:10.1016/j.tetlet.2007.06.134

The first total synthesis of pelargonidin 3-O-6″-O-acetyl-β-d-glucopyranoside, an acylated anthocyanin of magenta-colored Verbena flowers, was successfully carried out. The key intermediate, protected kaemferol 3-O-glucoside, was constructed by the Baker-

Full text of DOI:10.1016/j.tetlet.2007.06.134

Tetrahedron Letters 48 (2007) 6005–6009
Synthesis of pelargonidin 3-O-600-O-acetyl-b-D-glucopyranoside,
an acylated anthocyanin, via the corresponding
kaempferol glucoside
Kin-ichi Oyama,a Satoshi Kawaguchi,b Kumi Yoshidac and Tadao Kondob,c,
*
aChemical Instrument Room, Research Center for Materials Science, Nagoya University, Chikusa, Nagoya 464-8601, Japan
bGraduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
cGraduate School of Information Science, Nagoya University, Chikusa, Nagoya 464-8601, Japan
Received 6 June 2007; accepted 19 June 2007
Available online 30 June 2007
Abstract—The first total synthesis of pelargonidin 3-O-600-O-acetyl-b-D-glucopyranoside, an acylated anthocyanin of magenta-col-
ored Verbena flowers, was successfully carried out. The key intermediate, protected kaemferol 3-O-glucoside, was constructed by the
Baker–Venkataraman rearrangement from a glucosyloxyacetophenone followed by Zn–Hg reduction to the corresponding acylated
anthocyanin.
Ó 2007 Elsevier Ltd. All rights reserved.
Glycosyl flavonoids, such as anthocyanins, flavonols,
and flavones, show a wide range of biological activities
such as flower color development,1 protection against
UV light,2 and insect stimulants.3 They also have medic-
inal properties as antioxidants,4 hepatoprotectant,5 and
inhibitors against influenza virus sialidase.6 Despite their
potential importance, the synthetic methodology of gly-
cosyl flavonoids was extremely limited.7,8 In particular,
the synthesis of acylated anthocyanin has never been
performed.7 Thus, we have focused our attention on
the synthesis of acylated anthocyanin and 3-O-glucosyl
flavonol as a precursor of acylated anthocyanin. There
are two critical points on the synthesis of glycosyl flavo-
noids. One is the formation of the flavonoid nucleus and
the other is regio and stereoselective glycosylation to the
nucleus. Direct glycosylation to the flavonoid skeleton is
a very powerful and useful method, but this method has
been limited because the preparation of suitably pro-
tected flavonoids is difficult and this glycosylation reac-
tion sometimes gives a low yield due to hydrogen
bonding. Therefore, only a few approaches for 3-O-glu-
cosyl flavonol using quercetin8b,c,e and kaempferol8f
have been reported. To overcome the problem, we stud-
ied the efficient and flexible synthesis of the flavonoid
skeleton via cyclization after glycosylation. Retrosyn-
thetic analysis of pelargonidin 3-O-600-O-acetyl-b-D-
glucopyranoside (1),9 an acylated anthocyanin of
magenta-colored Verbena flowers, is shown in Figure 1.
Our strategy has two challenging issues: [1] The effective
b-glucosylation of the low nucleophilic OH of 2-
hydroxyacetophenone (6) predicted by a hydrogen
bonding to the carbonyl group and [2] transformation
of the acylated flavonol 13 to the corresponding antho-
cyanin 1 by metal reduction.
We developed a high b-selective glucosylation of an a-
ketoalcohol 6 and realized the construction of 3-O-
glucosyl flavonol 11 and 13 using a building block hav-
ing a sugar moiety.10 By a direct metal reduction7c,e
of kaempferol 3-O-600-O-acetyl-b-D-glucopyranoside
(13),5b we could transform to the corresponding antho-
cyanin 1. Here we report the first total synthesis of
pelargonidin 3-600-O-acetyl-b-D-glucoside (1)9 (Scheme
1).
Tri-MOM ether 3 protected with MOMCl from phloro-
glucinol (2) (53%) was lithiated with n-BuLi, and then
condensed with benzyloxyacetoaldehyde to give alcohol
4 (77%). Alcohol 4 was oxidized with TPAP to give ace-
tophenone 5 (99%), which was converted by acidic
hydrolysis, selective silyl protection to the di-TBS, and
hydrogenolysis using Pd(OH)2 (6, 76%, three steps).
Keywords: Acylated anthocyanin; Pelargonidin 3-O-600-O-acetyl-b-D-
glucopyranoside; Kaempferol 3-O-600-O-acetyl-b-D-glucopyranoside.
*
Corresponding author. Tel./fax: +81 052 789 5638; e-mail: kondot@
info.human.nagoya-u.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.134

6006
K. Oyama et al. / Tetrahedron Letters 48 (2007) 6005–6009
3'
2'
OH
5'
OH
+
8
B
HO
O
HO
O
C
OH
OH
6'
A
HO
HO
OH
OH
6''
6
O
O
O
O
4
OH
OH
O
1''
AcO
AcO
13
1
Baker-Venkataraman
rearrangement
O
TBSO
OTBS
OBn
B
TBSO
O
BnO
O
OBn
OBn
A
OBn
O
BnO
O
OBn
OH
O
O
PMBO
TBSO
9b
O
8b
PMBO
TBSO
OTBS
HO
OH
.
2H2O
O
O
O
OH
H
6
H
phloroglucinol 2
Figure 1. Structure and retrosynthetic analysis for pelargonidin 3-O-600-O-acetyl-b-D-glucopyranoside (1).
MOMO
OMOM
HO
OH
2H2O
1) n-BuLi, TMEDA, THF
MOMCl
NaH, DMF (53%)
2)
H
OBn
OMOM
OH
2
O
(77%)
3
MOMO
OMOM
OBn
MOMO
OMOM
OBn
TPAP, NMO,
MS 4A, CH2Cl2, (99%)
MOMO
OH
MOMO
O
4
5
TBSO
OTBS
1) Dowex 50W-X8, MeOH/H2O, 50 °C
2) TBSCl, Et3N, CH2Cl2 (76%, 2 steps)
3) H2, Pd(OH)2/C, AcOEt/MeOH (quant.)
O
O
O
H
6
H
Scheme 1.
Glucosylation of 6 was examined using various glucosyl
imidates 7a–d in the presence of a catalytic amount of
TMSOTf and MS 4A (Table 1).11,12 The acetyl-pro-
tected sugar 7a gave no glucosylated product, but the
starting alcohol remained, while benzyl-protected sugar
7b, c gave glucoside 8a. Using acetonitrile or propio-
2).10c Compound 8a and p-O-benzyloxybenzoic acid
were mixed with EDCI and DMAP in the presence of
TsOH at rt to give ester 9a in 61% yield. Successively
9a was heated at 120 °C with pyridine and K2CO3.
The Baker–Venkataraman type sequential cyclization–
dehydration reaction occurred to give kaempferol 3-O-
glucoside derivative 10 (42%).10c Hydrogenolysis of 10
with H2–Pd(OH)2/C gave kaempferol 3-O-glucoside
(11) quantitatively.5b,14,15
nitrile as
a solvent the desired b-glucoside was
predominantly obtained in spite of no neighboring
participation.13 Because TBS-protecting groups were
partially removed during the glucosylation, re-silylated
reaction with TBSCl was carried out for work-up han-
dling. Although silylation of 8a,c was performed, one
hydroxyl group remained to be free. This might be due
to the strong hydrogen bond formation between the car-
bonyl group and phenolic hydroxyl group.
For the synthesis of 600-O-acetylated glucosyl flavonol,
we designed 7-O-p-methoxybenzyl-2,3,4-tri-O-benzyl-
glucosyl imidate (7d) (Table 1, entry 4). Compound 8b
was obtained by the glycosylation of 6 with 7d followed
by re-silylation giving 8b in 66% yield (b/a = 94/6).
According to the same process as for 9a,b was obtained
in 68% yield (Scheme 2), and then cyclization toward a
flavonol, re-silylation with TBSCl–Et3N, treatment with
Esterification of the free ortho-hydroxyl group was car-
ried out according to Wandless’s condition (Scheme

K. Oyama et al. / Tetrahedron Letters 48 (2007) 6005–6009
6007
Table 1. Glucosylation with imidates 7a–d in the presence of TMSOTfa
TBSO
OTBS
OBn
RO
1) donor 7a-d, TMSOTf, MS 4A
BnO
6
OBn
O
O
2) TBSCl, Et3N, CH2Cl3
OH
O
8a,b
Entry
Donor
Solvent
CH2CI2
Temperature
(°C)
Glucoside
—
Yieldb
(%)
a/bc
OAc
O
ꢀ78 to 0
0
—
AcO
AcO
1
AcO
O
O
CCl3
NH
7a
OBn
O
BnO
BnO
2
MeCN
ꢀ40
ꢀ40
8a
57
11/89
BnO
CCl3
NH
7b
OBn
O
BnO
BnO
3
EtCN
8a
65
11/89
BnO
O
SCH2R
NR
7c
R = p-CF3 C6H5
OPMB
O
BnO
BnO
4
MeCN
ꢀ40
8b
66
6/94
BnO
O
CCl3
NH
7d
a Compound 6 was used without purification, after hydrogenolysis.
b Isolated yield.
c a/b ratio was determined by 1H NMR spectra.
O
O
HO
TBSO
O
OBn
OBn
OBn
OBn
8a,b
O
BnO
EDCI, DMAP, TsOH.H2O,CH2Cl2
O
TBSO
O
9a: R = Bn (61%)
RO
9b: R = PMB (68%)
OBn
TBSO
O
OBn
K2CO3, pyridine, 120 °C
(42%)
BnO
OBn
O
O
OH
O
BnO
10 (from 9a)
3'
OH
2'
8
HO
O
H2, Pd(OH)2/C,
5'
OH
HO
6'
HO
AcOEt/MeOH (quant.)
OH
6''
6
O
O
OH
11
O
1''
Scheme 2.

6008
K. Oyama et al. / Tetrahedron Letters 48 (2007) 6005–6009
OBn
1) K2CO3, pyridine, 120 °C
2) TBSCl, Et3N, CH2Cl2
TBSO
O
O
OBn
AcO
9b
BnO
3) DDQ, H2O, CH2Cl2
O
OBn
O
OH
12
4) AcCl, pyridine (57%, 4 steps)
OH
HO
O
1) TBAF, THF (99%)
OH
2) H2, Pd(OH)2/C, AcOEt/MeOH (99%)
HO
3'
O
OH
O
OH
13
O
AcO
2'
OH
5'
+
8
HO
O
OH
1) Zn(Hg), 3% HCl/MeOH, 0 °C
2) TFA (10%, 2 steps)
6'
HO
OH
6''
6
O
O
4
OH
1''
AcO
1
Scheme 3.
Chapman & Hall: London, 1994; pp 565–588; (c) Ander-
son, O. M.; Jordheim, M. In Flavonoids Chemistry
Biochemistry and Applications; Anderson, Ø. M., Mark-
ham, K. R., Eds.; CRC Press: Boca Raton, 2006; pp 471–
551.
DDQ/H2O/CH2Cl2 for the removal of PMB, and acetyl-
ation gave acetate 1216,17 in an overall 57% yield for the
four steps (Scheme 3). Deprotection of TBS and benzyl
groups gave kaempferol 3-O-600-O-acetyl-b-D-glucopyr-
anoside (13)14,15a in quantitative yield. The product 13
was identical to that isolated from the flower of Arnica
chamissonis and the needles of Picea abies. Finally metal
reduction of 13 with Zn(Hg) in 3% HCl(gas) MeOH
solution gave the corresponding anthocyanin, pelargo-
nin 3-O-600-O-acetyl-b-D-glucopyranoside (1)9,14 in 10%
yield,18 which was found as a pigment in magenta Ver-
bena hybrida petals. Here, we succeeded in the first syn-
thesis of a natural acylated anthocyanin.
2. (a) Takahashi, A.; Takeda, K.; Ohnishi, T. Plant Cell
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Our synthetic route has flexibility to synthesize versatile
3-O-glycosyl-flavonols and anthocyanins by changing
the sugar moiety and/or the benzaldehyde structure.
In summary, we succeeded in the first total synthesis of
pelargonidin 3-O-600-O-acetyl-b-D-glucopyranoside (1),
an acylated anthocyanin of the Verbena flower, via the
corresponding kaempferol glucoside. This synthetic pro-
tocol might render a useful construction method for
other flavonoid glucosides including anthocyanins and
flavonol glucosides.
6. Nagai, T.; Miyaichi, Y.; Tomimori, T.; Suzuki, Y.;
Yamada, H. Chem. Pharm. Bull. 1990, 38, 1329–1332.
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Acknowledgments
This work was financially supported by the Ministry of
Education, Culture, Sports, Science, and Technology,
Japan ((B) No.16370021, the 21st Century COE Pro-
gram No.14COEB01-00, Creative Scientific Research
No.16GS0206, Priority Areas No. 18032037, and Young
Scientists (B) No. 18780086).
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1H, H-6 or H-8), 5.27 (d, J = 7.3 Hz, 1H, H-100), 3.73 (dd,
J = 11.9, 2.5 Hz, 1H, H-600), 3.57 (dd, J = 11.9, 5.5 Hz,
1H, H-600), 3.48 (dd, J = 9.1, 7.3 Hz, 1H, H-200), 3.45 (t,
J = 9.1, 1H, H-300), 3.35 (t, J = 9.1 Hz, 1H, H-400), 3.24
(ddd, J = 9.1, 5.5, 2.5 Hz, 1H, H-500); Data for 13: 1H
NMR (600 MHz, CD3OD) d 8.06 (d, J = 8.8 Hz, 2H, H-
20,60), 6.90 (d, J = 8.8 Hz, 2H, H-30,50), 6.44 (d,
J = 2.2 Hz, 1H, H-6 or H-8), 6.24 (d, J = 2.2 Hz, 1H, H-
6 or H-8), 5.20 (d, J = 7.3 Hz, 1H, H-100), 4.21 (dd,
J = 11.8, 2.2 Hz, 1H, H-600), 4.10 (dd, J = 11.8, 5.9 Hz,
1H, H-600), 3.48 (dd, J = 9.1, 7.3 Hz, 1H, H-200), 3.46 (t,
J = 9.1 Hz, 1H, H-300), 3.42 (ddd, J = 9.1, 5.9, 2.2 Hz, 1H,
H-500), 3.33 (t, J = 9.1 Hz, 1H, H-400), 1.87 (s, 3H, OAc).
15. (a) Slimestad, R.; Andersen, Ø. M.; Francis, G. W.;
Marston, A.; Hostettmann, K. Phytochemistry 1995, 40,
1537–1542; (b) Kazuma, K.; Noda, N.; Suzuki, M.
Phytochemistry 2003, 62, 229–237.
13. It is well known that glycosylation using MeCN as a
solvent has the tendency to give b-linked glucoside:
Ratcliffe, A. J.; Fraser-Reid, B. J. Chem. Soc., Perkin
Trans. 1 1990, 747–750.
16. A minor a-linked glucoside disappeared during the reac-
tion and the purification.
17. Data for 12: 1H NMR (600 MHz, CDCl3) d 12.59 (s, 1H),
8.01 (d, J = 8.8 Hz, 2H, H-20,60), 7.2–7.4 (m, 20H, Bn),
6.96 (d, J = 9.2 Hz, 2H, H-30,50), 6.38 (d, J = 1.6 Hz, 1H,
H-6 or H-8), 6.28 (d, J = 1.6 Hz, 1H, H-6 or H-8), 5.51 (d,
J = 7.7 Hz, 1H, H-100), 5.11 (d, 1H, J = 11.0 Hz, Bn), 5.10
(s, 2H, Bn), 4.99 (d, J = 10.7 Hz, 1H, Bn), 4.81 (d,
J = 11.0 Hz, 1H,Bn), 4.78 (d, J = 10.7 Hz, 1H, Bn), 4.77
(d, J = 11.0 Hz, 1H, Bn), 4.51 (d, J = 11.0 Hz, 1H, Bn),
4.09 (dd, J = 12.0, 2.2 Hz, 1H, H-600), 3.98 (dd, J = 12.0,
4.0 Hz, 1H, H-600), 3.76 (t, J = 9.1 Hz, 1H, H-300), 3.64 (dd,
J = 9.1, 7.7 Hz, 1H, H-200), 3.52 (t, J = 9.1 Hz, 1H, H-400),
3.39 (ddd, J = 9.1, 4.0, 2.2 Hz, 1H, H-500), 1.76 (s, 3H,
OAc), 0.98 (s, 9H, Sit-Bu), 0.25 (s, 6H, SiMe2).
14. The synthetic 1,9 11,15 and 1315a were identical to the
natural ones. For NMR analysis of 1, we found a
misassignment. The assignments of H-200 and H-300 should
be reversed.9 Data for 1: 1H NMR (500 MHz, 5%
CF3CO2D in DMSO-d6) d 8.83 (s, 1H, H-4), 8.55 (d,
J = 8.9 Hz, 1H, H-20,60), 7.02 (d, J = 8.9 Hz, 1H, H-30,50),
6.94 (d, J = 2.3 Hz, 1H, H-8), 6.70 (d, J = 2.3 Hz, 1H, H-
6), 5.35 (d, J = 8.0 Hz, 1H, H-100), 4.38 (dd, J = 12.0,
1.7 Hz, 1H, H-6a00), 3.98 (dd, J = 12.0, 8.0 Hz, 1H, H-
6b00), 3.75 (ddd, J = 9.0, 8.0, 1.7 Hz, 1H, H-500), 3.43 (dd,
J = 9.0, 8.0 Hz, 1H, H-200), 3.35 (t, J = 9.0 Hz, H-300), 3.17
(t, J = 9.0 Hz, H-400), 1.97 (s, 3H, OAc), HRMS (FAB)
calcd for C23H23O11 (M+) 475.1240. Found: 475.1244;
Data for 11: 1H NMR (600 MHz, CD3OD) d 8.09 (d,
J = 9.0 Hz, 2H, H-20,60), 6.93 (d, J = 9.0 Hz, 2H, H-30,50),
6.42 (d, J = 2.2 Hz, 1H, H-6 or H-8), 6.23 (d, J = 2.2 Hz,
18. The low yield was due to deacetylation. The main product
was pelargonidin 3-O-glucoside (yield: 15%), which was
identical to the natural one: Yoshida, K.; Sato, Y.; Okuno,
R.; Kameda, K.; Isobe, M.; Kondo, T. Biosci. Biotech.
Biochem. 1996, 60, 589–593.