Base-catalyzed oxidative dearomatization of multisubstituted phloroglucinols: An easy access to C-glucosyl 3,5,6-trihydroxycyclohexa-2,4-dienone derivatives

Article abstract of DOI:10.1016/j.carres.2019.107756

An efficient and simple method for the protecting group-free synthesis of C-glucosyl 3,5,6-trihydroxycyclohexa-2,4-dienone has been firstly established. This method is compatible with various functional groups, such as benzyl and phenethyl groups, affording a range of C-glucosyl 3,5,6-trihydroxycyclohexa-2,4-dienone derivatives.

Full text of DOI:10.1016/j.carres.2019.107756

Journal Pre-proof
Base-catalyzed oxidative dearomatization of multisubstituted phloroglucinols: An easy
access to C-glucosyl 3,5,6-trihydroxycyclohexa-2,4-dienone derivatives
Wan Gao, Zhong Chen, Yanan Yang, Jianshuang Jiang, Ziming Feng, Xu Zhang,
Xiang Yuan, Peicheng Zhang
PII:
S0008-6215(19)30251-4
DOI:
https://doi.org/10.1016/j.carres.2019.107756
CAR 107756
Reference:
To appear in: Carbohydrate Research
Received Date: 20 April 2019
Revised Date: 21 July 2019
Accepted Date: 26 July 2019
Please cite this article as: W. Gao, Z. Chen, Y. Yang, J. Jiang, Z. Feng, X. Zhang, X. Yuan, P. Zhang,
Base-catalyzed oxidative dearomatization of multisubstituted phloroglucinols: An easy access to C-
glucosyl 3,5,6-trihydroxycyclohexa-2,4-dienone derivatives, Carbohydrate Research (2019), doi: https://
doi.org/10.1016/j.carres.2019.107756.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Ltd.

Base-catalyzed oxidative dearomatization of multisubstituted
phloroglucinols: an easy access to C-glucosyl
3,5,6-trihydroxycyclohexa-2,4-dienone derivatives
Wan Gao, Zhong Chen, Yanan Yang, Jianshuang Jiang, Ziming Feng, Xu Zhang,
Xiang Yuan, Peicheng Zhang*

Carbohydrate Research
journal homepage: www.elsevier.com
Base-catalyzed oxidative dearomatization of multisubstituted phloroglucinols: an easy
access to C-glucosyl 3,5,6-trihydroxycyclohexa-2,4-dienone derivatives
Wan Gao, Zhong Chen, Yanan Yang, Jianshuang Jiang, Ziming Feng, Xu Zhang, Xiang Yuan, Peicheng
Zhang*
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College
and Chinese Academy of Medical Sciences, Beijing 100050, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and simple method for the protecting group-free synthesis of C-glucosyl
3,5,6-trihydroxycyclohexa-2,4-dienone has been firstly established. This method is compatible
with various functional groups, such as benzyl and phenethyl groups, affording a range of
C-glucosyl 3,5,6-trihydroxycyclohexa-2,4-dienone derivatives.
Available online
Keywords:
3,5,6-trihydroxycyclohexa-2,4-dienone
Oxidative dearomatization
Quinochalcone C-glucosides
*Corresponding author. E-mail address: pczhang@imm.ac.cn
1. Introduction
C-glucosides are an important class of bioactive compounds
most notable for their resistance to metabolic processing and
their prevalence in natural products. In the past decade, a subset
of these natural products bearing an unusual core of
3,5,6-trihydroxycyclohexa-2,4-dienone, named quinochalcone
C-glucosides, have been isolated from Carthamus tinctorius1
(safflower), which has been used in the treatment of strokes for at
least 2000 years in Oriental medicine.2 Representative examples
for such quinochalcone C-glucosides are shown in Figure 1. For
example, HSYA is the main chemical compoment of
hydroxysafflor yellow used for the treatment of ischemic
cardio-cerebrovascular disease in clinical medicine.3 Carthamin,
containing two C-glucosyl quinochalcone units, is used for
dyeing delicate Kimonos.4 Saffloquinoside A and C exhibit
moderate anti-inflammatory activity.1a Because of their
distinctive molecular architecture and extensive applications,
much effort has been devoted to their total synthesis.5 However,
the synthetic methods to produce them are relatively
underdeveloped due to formidable challenges posed by the
constructing C-glucosyl 3,5,6-trihydroxycyclohexa-2,4-dienone
unit.6
Figure 1. Representative natural products with C-glucosyl
3,5,6-trihydroxycyclohexa-2,4-dienone skeletons.
a). However, in this case, they failed in subsequent deacetylation
step after dearomatization. Second, Suzuki’s group5b tried to
construct this unit by treating C-per-O-acetylglucosyl 2,
4-dimethoxyphenol with bis(trifluoroacetoxy)iodobenzene in
wet acetonitrile in the presence of NaHCO3 (Scheme 1, b).
Nevertheless, in this manner, there are two major obstacles for
developing C-glucosyl 3,4,6-trihydroxycyclohexadienone unit:
(1) the hydroxy of phenol must be protected with methoxy
groups,
which
make
it
failure
to
form
3,5,6-trihydroxycyclohexa-2,4-dienone scaffold; (2) the glucose
must be protected with acetyl groups, which make it difficult to
remove the protecting groups after the oxidation of phenol due to
the instability of quinone unit. Third, Onodera’s group8 reported
an oxidative dearomatization reaction of 2,4,6-trihydroxy-3-
methyl-5-β-D-glucosylacetophenone catalyzed by pyridine in the
presence of O2. As a result, the glucose is unstable and the
hydroxyl group at position 2 of the glucoside readily undergoes
To date, three synthetic methodologies that are related to
assembling the C-glucosyl 3,5,6-trihydroxycyclohexa-2,4-
dienone unit have been reported, as shown in scheme 1. First, in
route (a), Sato7 and co-workers reported synthetic method for
preparing C-per-O-acetylglucosyl 3,5,6-trihydroxycyclohexa-2,4-
dienone
using
acetylbenzene-2,3,4,6-tetrol
with
acetobromoglucose in the presence of sodium hyride (Scheme 1,

condensation with the neighboring enol. This reaction is followed
by the opening of the pyranose ring due to the strain effect and
subsequently, recyclization takes place to form the
oxofuro[3,2-d]benzofuran ring (Scheme 1, c). Therefore, it is of
great importance to develop concise and efficient methods for the
synthesis of C-glucosyl 3,5,6-trihydroxycyclohexa-2,4-dienone.
Then, the reaction was further optimized employing
NH4Cl-NH3·H2O buffer salts with different pH values. The
oxidative dearomatization reaction of 1a was successful at pH
values between 7.5 and 9.0 and furnished desired
3,5,6-trihydroxycyclohexa-2,4-dienone derivative 2a (entries
10−13). However, when the pH was increased to 9.5, no 2a was
obtained (entry 14). It was also found that the yield of 2a was
highest at pH 8.0 (entry 11). In addition, the reaction time was
greatly reduced when the oxidation of 1a was carried out under
O2 instead of air (entry 15). Meanwhile, K2HPO4-KH2PO4 buffer
salt was also optimized. The yield of 2a was 35% at pH 7.5 and
49% at pH 8.0 (entries 16−17). Thus, it can be concluded that the
optimized reaction conditions involve NH4Cl-NH3·H2O buffer
salt with pH 8.0, room temperature, an O2 atmosphere and a
reaction time of 12 h.
Previous studies
AcO OAc
AcO
a)
OH
HO
OH
O
Acetylglucopyranosyl bromide
NaH, DMSO
O
AcO
OH
HO
O
OH
OH
O
b)
AcO
AcO OAc
AcO
AcO
OAc
O
AcO
MeO
O
PhI(OCOCF3)2, NaHCO3
MeCN-H2O
AcO
MeO
OH
OMe
OMe
Table 1. Optimization of the oxidative dearomatization of 1aa.
R
R
O
O
OH
O
OH
c)
OH
H
H
O
HO
HO
O
OH
Pyridine, O2
MeOH
HO
H
HO
HO
O
H
OH
O
O
OH
O
HO
OH
H
This study
d)
HO
OH
HO OH
HO
OH
entry
catalyst
pH
oxidant
time
(h)
24
24
24
24
24
24
24
24
24
24
24
24
24
24
12
12
12
yield
(%)j,k
0
HO
O
O
NH4Cl-NH3 H2O, pH = 8.0
HO
OH
1b
2c
Pyridine
Pyridine
-
-
air
HO
HO
O
OH
HO
HO
O
O
O
air or O2, rt
HO
HO
R
HO
HO
air
trace
15
0
R
OH
3d
4e
Pyridine
-
air
OH
OH
O
OH
Pb(OAc)2
-
O2
5e
Pb(OAc)2·Pb(OH)
PhI(OCOCF3)2
-
-
O2
0
Scheme 1. Previous works: (a, b) two methods for constructing
C-glucosyl cyclohexadienones in which the glucose must be
protected with an acetyl group; and (c) method for constructing
C-glucosyl cyclohexadienones without protecting groups. This study:
(d) new method for constructing C-glucosyl cyclohexa-2,4-dienone.
6f
-
air
0
7g
8h
9i
-
Ce(NH4)2(NO3)6
0
-
-
DDQ
air
air
air
air
air
air
O2
0
I2
-
0
10
11
12
13
14
15
16
17
NH4Cl-NH3·H2O
NH4Cl-NH3·H2O
NH4Cl-NH3·H2O
NH4Cl-NH3·H2O
NH4Cl-NH3·H2O
NH4Cl-NH3·H2O
K2HPO4-KH2PO4
K2HPO4-KH2PO4
7.5
8.0
8.5
9.0
9.5
8.0
7.5
8.0
31
84
62
36
0
2. Results and discussion
Our
strategy
for
the
synthesis
of
C-glucosyl
3,5,6-trihydroxycyclohexa-2,4-dienone involved the development
of a new oxidative dearomatization reaction that did not require
protecting groups. For this study, di-C-glucosylchalcone 1a, an
analog of HSYA, was chosen as the model substrate to explore
the feasibility of this oxidation step (Table 1). Inspired by Sato et
al.,8a the same reaction conditions, using pyridine as the catalyst
and methanol as the solvent, were applied first. As expected, a
similar by-product from the dehydration ring-closure of the
phenolic hydroxy group at the 5-position and the 2ʹʹ-hydroxy
group of the glucose moiety was produced (entry 1). To avoid the
dehydration reaction, we changed from methanol as the solvent
to H2O. Surprisingly, a trace amount of desired product 2a was
obtained (entry 2). Furthermore, when the amount of pyridine
was gradually increased, desired product 2a could be obtained in
a maximum yield of 15% (entry 3). In addition, many commonly
85
35
49
O2
O2
aReaction conditions: 1a (1.0 mmol), room temperature. bPyridine (2
c
d
equiv), CH3OH as solvent. Pyridine (2 equiv), H2O as solvent. Pyridine
(13 equiv), H2O as solvent. eCatalyst (1 equiv), CH3OH as solvent.
fPhI(OCOCF3)2 (1.5 equiv), CH3CN as solvent. CAN (3 equiv), CH3OH
g
h
i
as solvent. DDQ (1 equiv), CH3OH as solvent. I2 (1 equiv), CH3OH as
solvent. jDetermined by 500 MHz NMR and MS. kIsolated yield.
With the optimized conditions in hand, the scope of
di-C-glucosyldihydrochalcones
1 was examined. Model
substrates 1a−g were prepared according to previous
reports.11-12 The reactions of di-C-glucosyldihydrochalcones
1b−e, which have hydrogen, methoxy, methyl, or fluoro
substituents at the 4-position, afforded the corresponding
di-C-glucosyl 3,5,6-trihydroxycyclohexa-2,4-dienones 2b−e
in 72−86% yields. Similar results were observed with
substrates 1f−g, which bear chloro and methoxy groups at the
3-position, and these reactants gave 2f−g in 65−68% yields
(Scheme 2). Notably, 1h was also well-tolerated in the
oxidation reaction and gave 2h in 60% yield (Scheme 3).
used
dearomatization
reagents7
(Pb(OAc)2/O2,
Pb(OAc)2·Pb(OH)/O2, PhI(OCOCF3)2, Ce(NH4)2(NO3)6, DDQ,
and I2) were also examined, but none of these reagents were
suitable for the reaction due to serious side reactions or poor
reactivity of 1a (entries 4−9). After comprehensive analysis of
the above results, we speculated that the weak basicity of
pyridine promoted this reaction, and the pH of the solution also
affected the reaction pathway.10 Therefore, other weak aqueous
alkaline systems were examined. To our delight, vigorous stirring
of 1a in NH4Cl-NH3·H2O buffer salt (pH = 8.5) under an air
atmosphere at room temperature for 24 h afforded oxidized
products 2a in a total yield of 62% as an inseparable mixture of
stereoisomers.

Based on literature precedent,14-15 a plausible mechanism for
this oxidative dearomatization reaction is proposed as follows.
First, under basic catalysis and in the present of light, oxygen is
activated to form singlet oxygen (1O2). The generated 1O2 attacks
the double bond of the phloroglucinol substrate to form epoxide
intermediate A, which is not stable and is rapidly converted into
hydroperoxy intermediate B. Then, the cracking of peroxide B
leads to free radical C. Finally, radical C abstracts a hydrogen
free radical from the alkaline solution to afford the desired
3,5,6-trihydroxycyclohexa-2,4-dienone product (Scheme 4).
Scheme
2.
Oxidative
dearomatization
of
substituted
di-C-glucosyldihydrochalcones 1b−ga, b, c
.
HO
HO
OH
HO
O
HO
HO
HO
O
NH4Cl-NH3.H2O
R
HO
HO
OH
O
R
HO
HO
HO
O
OH
O
HO
HO
pH = 8.0
O
HO
HO
O2, rt, 12 h
OH
OH
OH
OH
O
1b-g
2b-g
HO
O
HO
HO
HO
HO
HO
HO
O
HO
HO
O
HO
HO
HO
HO
OH
O
HO
HO
OH
O
OH
O
HO
HO
OCH3
HO
CH3
O
O
HO
HO
O
HO
HO
HO
HO
OH
OH
OH
OH
O
OH
O
OH
O
2b 72%
HO
2c 86%
2d 81%
HO
HO
HO
HO
HO
HO
HO
HO
O
O
O
Cl
OCH3
HO
HO
HO
HO
HO
HO
OH
O
OH
O
OH
O
HO
HO
HO
F
O
O
O
HO
HO
HO
HO
HO
HO
OH
OH
OH
OH
O
OH
O
OH
O
2g 68%
2f 65%
2e 80%
aReaction conditions: 1 (1.0 mmol), NH4Cl-NH3·H2O (pH = 8.0, 30 mL), O2,
rt, 12 h. bDetermined by 500 MHz NMR and MS. cIsolated yields are shown.
Scheme 4. Plausible Mechanism.
3. Conclusion
In conclusion, we have developed an efficient and simple
method for the protecting group-free synthesis of C-glucosyl
3,5,6-trihydroxycyclohexa-2,4-dienone.
compatible with various functional groups, such as benzyl and
phenethyl groups, affording range of C-glucosyl
3,5,6-trihydroxycyclohexa-2,4-dienone derivatives 2 in 60−86%.
The absolute configuration of the
3,5,6-trihydroxycyclohexa-2,4-dienone unit was determined by
the comparison of experimental and calculated electronic circular
dichroism (ECD) spectra. A plausible mechanism involving a
singlet oxygen intermediate and a radical process is also
proposed. The advantages of the new oxidative dearomatization
reaction, including mild reaction conditions, broad substrate
scope, metal-free catalyst, satisfactory yields, and environmental
friendliness, make it applicable to the synthesis of related natural
C-glucosides.
This
method
is
Scheme 3. Oxidative dearomatization of 1h.
a
All
the
desired
oxidation
products,
3,5,6-trihydroxycyclohexa-2,4-dienone derivatives 2a−h, have a
stereogenic center at the 3-position. Each of the di-C-glucosyl
3,5,6-trihydroxycyclohexa-2,4-dienone derivatives was an
mixture of diastereomers that are inseparable by silica gel column
chromatography. To study the stereochemistry of the
cyclohexa-2,4-dienone derivatives, one pair of isomers (2c−1 and
2c−2) were separated from 2c using chiral HPLC (CHIRALPAK
AD-RH). Their absolute configurations were determined by
comparing their experimental electronic circular dichroism
(ECD) data to their ECD data calculated based on the MMFF94
force field and time-dependent density functional theory
(TDDFT) at the B3LYP/6-31G(d, p) level (Supporting
Information, S10).13 Over the entire range of wavelengths, the
calculated spectra of (6R)−2c and (6S)−2c matched the
experimental data of 2c−1 and 2c−2, respectively. Thus, the
structures of the compounds mentioned above were defined as
shown in Figure 2.
4. Experimental section
4.1. General method
All commercially available materials were purchased from
commercial sources and used without further purification.
Purification of the reaction products was carried out by column
chromatography using Silica Gel (200-300 mesh), unless
otherwise noted. Analytical TLC was performed on Silica-Gel
60-F254 plate. A Chiralpak AD-RH chiral column (250 mm×10
mm, 5 µm; Daicel Corp., Tokyo, Japan) was used for chiral
1
separation. The H NMR, 13C NMR, HSQC, and HMBC spectra
were recorded on a Bruker AVANCE III 500 spectrometer
(Bruker-Biospin, Billerica, MA, U.S.A.) using DMSO-d6,
CD3OD, and acetone-d6 as solvents and Me4Si as an internal
standard. Chemical shifts (δ) were reported in ppm and spin-spin
coupling constants (J) were given in Hz. The optical rotations
and ECD spectra were measured on JASCO P-2000 and JASCO
J-815 spectrometers (JASCO, Easton, MD), respectively.
HR-ESI-MS analyses were performed with an Agilent 1200
series LC/MSD TOF instrument.
HO
O
HO
O
HO
HO
HO
HO
OCH3
OCH3
HO
HO
HO
HO
OH
OH
HO
HO
O
O
O
O
O
O
HO
HO
HO
HO
OH
OH
OH
OH
4.2. General procedure for the synthesis of 1a-h
A mixture of dihydrochalcone S[11a] (10 mmol), D-glucose (50
mmol), and Sc(OTf)3 (4 mmol) in EtOH (20 mL)/H2O (10 mL)
2c-2
2c-1
Figure 2. The experimental and calculated ECD spectra of 2c.

was refluxed for 18 h. Then water (200 mL) was added to the
reaction mixture, and the suspension was passed through a
column of MCI GEL CHP20P (75–150 µm, Mitsubishi Chemical
Corp., 3.5 × 25 cm) loaded with water, and the gel was then
washed with water (300 mL), to remove nonabsorbed glucose
and Sc(OTf)3. The nonabsorbed components, which include the
unreactive glucose and Sc(OTf)3, was evaporated in vacuo to
give a colorless solid. The absorbed products were eluted from
the gel column with 50% aqueous MeOH (300 mL), and the
eluate was evaporated to dryness. The residue was then separated
by silica-gel column chromatography (Me2CO:EtOAc:H2O:
AcOH) to give 1.
White solid (2.74 g, 46%); Rf = 0.31, (Me2CO:EtOAc:H2O:
1
AcOH, 20:20:3:1); [α]D20 = +86.4 (c 0.2, MeOH); H NMR (500
MHz, CD3OD) δH: 7.08 (2H, m, H-2, 6), 7.05 (2H, m, H-3, 5),
4.94 (2H, d, J = 9.8 Hz, H-1ʹʹ, 1″ʹ), 3.83 (4H, m, H-6ʹʹ, 6ʹ″), 3.50
(2H, m, H-5ʹʹ, 5ʹ″), 3.50 (2H, m, H-4ʹʹ, 4″ʹ), 3.49 (2H, m, H-3ʹʹ,
3ʹ″), 3.42 (2H, m, H-α), 3.37 (2H, m, H-2ʹʹ, 2ʹ″), 2.91 (2H, m,
H-β) ppm. 13C NMR (125 MHz, CD3OD) δC: 206.9 (C-βʹ), 163.1
(C-4ʹ), 162.2 (C-2ʹ, 6ʹ), 139.9 (C-1), 129.9 (C-2, 6), 129.3 (C-3,
5), 106.1 (C-1ʹ), 104.3 (C-3ʹ, 5ʹ), 82.7 (C-5ʹʹ, 5ʹʹʹ), 79.0 (C-3ʹʹ,
3ʹʹʹ), 76.7 (C-1ʹʹ, 1ʹʹʹ), 74.1 (C-2ʹʹ, 2ʹʹʹ), 71.0 (C-4ʹʹ, 4ʹʹʹ), 61.8
(C-6ʹʹ, 6ʹʹʹ), 47.5 (C-α), 31.3 (C-β), 21.0 (CH3) ppm; HR-ESI-MS
m/z: [M+H]+ calcd. for C28H37O14 597.2105, found 597.2183.
4.2.1. 2ʹ,4,4ʹ,6ʹ-tetrahydroxy-3ʹ,5ʹ-di-C-β-D-glucopyranosyldihy-
drochalcone (1a)
4.2.5. 2ʹ,4ʹ,6ʹ-trihydroxy-4-fluro-3ʹ,5ʹ-di-C-β-D- glucopyranosyl
dihydrochalcone (1e)
White solid (3.48 g, 58%); Rf = 0.26, (Me2CO:EtOAc:H2O:
White solid (2.87 g, 48%); Rf = 0.25 (Me2CO:EtOAc:H2O:
AcOH, 20:20:3:1); [α]2D0 = +102.4 (c 0.2, MeOH); 1H NMR (500
MHz, CD3OD) δH: 7.02 (2H, d, J = 8.5 Hz, H-2, 6), 6.67 (2H, d, J
= 8.5 Hz, H-3, 5), 4.94 (2H, d, J = 9.8 Hz, H-1ʹʹ, 1″ʹ), 3.83 (4H,
m, H-6ʹʹ, 6″ʹ), 3.60 (2H, m, H-5ʹʹ, 5ʹʹʹ), 3.51 (2H, m, H-4ʹʹ, 4″ʹ),
3.49 (2H, m, H-3ʹʹ, 3ʹʹʹ), 3.43 (2H, m, H-α), 3.34 (2H, m, H-2ʹʹ,
2ʹʹʹ), 2.85 (2H, m, H-β) ppm; 13C NMR (125 MHz, CD3OD) δC:
207.1 (C-βʹ), 163.1 (C-4ʹ), 162.4 (C-4), 156.2 (C-2ʹ, 6ʹ), 133.8
(C-1), 130.4 (C-3, 5), 130.1 (C-2, 6), 106.2 (C-1ʹ), 104.4 (C-3ʹ,
5ʹ), 82.7 (C-5ʹʹ, 5″ʹ), 79.1 (C-3ʹʹ, 3ʹʹʹ), 76.7 (C-1ʹʹ, 1ʹʹʹ), 74.1 (C-2ʹʹ,
2ʹʹʹ), 71.1 (C-4ʹʹ, 4ʹʹʹ), 61.8 (C-6ʹʹ, 6ʹʹʹ), 47.8 (C-α), 31.0 (C-β)
ppm; HR-ESI-MS m/z: [M+H]+ calcd. for C27H35O15 599.1976,
found 599.1981.
1
AcOH, 20:20:3:1); [α]D20 = +90.7 (c 0.2, MeOH); H NMR (500
MHz, CD3OD) δH: 7.23 (2H, dd, J = 8.5, 5.5 Hz, H-2, 6), 6.96
(2H, dd, J = 8.5, 5.5 Hz, H-3, 5), 4.94 (2H, d, J = 9.8 Hz, H-1ʹʹ,
1ʹ″), 3.83 (4H, m, H-6ʹʹ, 6ʹ″), 3.60 (2H, m, H-5ʹʹ, 5ʹ″), 3.51 (2H,
m, H-4ʹʹ, 4ʹ″), 3.49 (2H, m, H-3ʹʹ, 3ʹ″), 3.43 (2H, m, H-α), 3.34
(2H, m, H-2ʹʹ, 2ʹ″), 2.93 (2H, m, H-β) ppm; 13C NMR (125 MHz,
CD3OD) δC: 206.6 (C-βʹ), 175.2 (C-4), 163.5 (C-4ʹ), 162.2 (C-2ʹ,
6ʹ) 138.9 (C-1), 131.1 (C-2, 6), 115.9 (C-3, 5), 106.1 (C-1ʹ),
104.3 (C-3ʹ, 5ʹ), 82.6 (C-5ʹʹ, 5″ʹ), 79.0 (C-3ʹʹ, 3ʹʹʹ), 76.7 (C-1ʹʹ,
1ʹʹʹ), 74.1 (C-2ʹʹ, 2ʹʹʹ), 71.0 (C-4ʹʹ, 4ʹʹʹ), 61.7 (C-6ʹʹ, 6ʹʹʹ), 47.4
(C-α), 30.9 (C-β) ppm; HR-ESI-MS m/z: [M+H]+ calcd. for
C27H34O14F601.1933, found 601.1927.
4.2.6. 2ʹ,4ʹ,6ʹ-trihydroxy-3-chloro-3ʹ,5ʹ-di-C-β-D-glucopyranosyl
dihydrochalcone (1f)
4.2.2. 2ʹ,4ʹ,6ʹ-trihydroxy-3ʹ,5ʹ-di-C-β-D-glucopyranosyldihydro-
chalcone (1b)
White solid (2.96 g, 48%); Rf = 0.25 (Me2CO:EtOAc:H2O:
1
AcOH, 20:20:3:1); [α]D20 = +80.1 (c 0.2, MeOH); H NMR (500
White solid (2.91 g, 50%); Rf = 0.30 (Me2CO:EtOAc:H2O:
1
AcOH, 20:20:3:1); [α]D20 = +64.7 (c 0.2, MeOH); H NMR (500
MHz, CD3OD) δH: 7.25 (1H, m, H-2), 7.22 (1H, m, H-4), 7.16
(2H, m, H-5, 6), 4.93 (2H, d, J = 9.8 Hz, H-1ʹʹ, 1″ʹ), 3.83 (4H, m,
H-6ʹʹ, 6ʹ″), 3.60 (2H, m, H-5ʹʹ, 5″ʹ), 3.50 (2H, m, H-4ʹʹ, 4ʹ″), 3.50
(2H, m, H-3ʹʹ, 3ʹ″), 3.43 (2H, m, H-2ʹʹ, 2ʹ″), 3.40 (2H, m, H-α),
2.96 (2H, m, H-β) ppm; 13C NMR (125 MHz, CD3OD) δC: 206.2
(C-βʹ), 163.1 (C-4ʹ), 162.2 (C-2ʹ, 6ʹ), 145.5 (C-3), 135.0 (C-1),
130.8 (C-2), 129.5 (C-4), 128.0 (C-6), 126.9 (C-5), 106.0 (C-1ʹ),
104.3 (C-3ʹ, 5ʹ), 82.6 (C-5ʹʹ, 5ʹʹʹ), 79.0 (C-3ʹʹ, 3ʹʹʹ), 76.7 (C-1ʹʹ,
1ʹʹʹ), 74.1 (C-2ʹʹ, 2ʹʹʹ), 71.0 (C-4ʹʹ, 4ʹʹʹ), 61.8 (C-6ʹʹ, 6ʹʹʹ), 46.9
(C-α), 31.2 (C-β) ppm; HR-ESI-MS m/z: [M+H]+ calcd. for
C27H34O14Cl 617.1637, found 617.1641.
MHz, CD3OD) δH: 7.24 (4H, m, H-2, 3, 5, 6), 7.16 (1H, m, H-4),
4.94 (2H, d, J = 9.6 Hz, H-1ʹʹ, 1″ʹ), 3.83 (4H, m, H-6ʹʹ, 6″ʹ), 3.62
(2H, m, H-5ʹʹ, 5ʹ″), 3.52 (2H, t, J = 7.2 Hz, H-α), 3.43 (2H, m,
H-2ʹʹ, 2″ʹ), 3.42 (2H, m, H-4ʹʹ, 4ʹ″), 3.37 (2H, m, H-3ʹʹ, 3ʹ″), 2.96
(2H, t, J = 7.2 Hz, H-β) ppm; 13C NMR (125 MHz, CD3OD) δC:
206.8 (C-βʹ), 163.1 (C-2ʹ, 6ʹ), 162.2 (C-4ʹ), 143.1 (C-1), 129.5
(C-2, 6), 129.3 (C-3, 5), 106.1 (C-1ʹ), 104.4 (C-3ʹ, 5ʹ), 82.9 (C-5ʹʹ,
5ʹʹʹ), 79.1 (C-3ʹʹ, 3ʹʹʹ), 76.7 (C-1ʹʹ, 1ʹʹʹ), 74.1 (C-2ʹʹ, 2ʹʹʹ), 71.0
(C-4ʹʹ, 4ʹʹʹ), 61.8 (C-6ʹʹ, 6ʹʹʹ), 47.5 (C-α), 31.8 (C-β) ppm;
HR-ESI-MS m/z: [M+H]+ calcd. for C27H35O14 583.2027, found
583.2029.
4.2.7. 2ʹ,4ʹ,6ʹ-trihydroxy-3-methoxy-3ʹ,5ʹ-di-C-β-D-glucopyranos-
yldihydrochalcone (1g)
4.2.3. 2ʹ,4ʹ,6ʹ-trihydroxy-4-methoxy-3ʹ,5ʹ-di-C-β-D-glucopyranos-
yldihydrochalcone (1c)
White solid (2.75 g, 45%); Rf = 0.28 (Me2CO:EtOAc:H2O:
1
AcOH, 20:20:3:1); [α]D20 = +75.4 (c 0.2, MeOH); H NMR (500
White solid (3.18 g, 52%); Rf = 0.28, (Me2CO:EtOAc:H2O:
1
AcOH, 20:20:3:1); [α]D20 = +57.6 (c 0.2, MeOH); H NMR (500
MHz, CD3OD) δH: 7.15 (1H, t, J = 7.8 Hz, H-6), 6.80 (2H, m,
H-2, 4), 6.70 (1H, m, H-5), 4.93 (2H, d, J = 9.8 Hz, H-1ʹʹ, 1ʹʹʹ),
3.83 (4H, m, H-6ʹʹ, 6ʹʹʹ), 3.62 (2H, m, H-5ʹʹ, 5ʹʹʹ), 3.51 (2H, m,
H-4ʹʹ, 4ʹʹʹ), 3.49 (2H, m, H-3ʹʹ, 3ʹʹʹ), 3.42 (2H, m, H-α), 3.34 (2H,
m, H-2ʹʹ, 2ʹʹʹ), 2.93 (2H, m, H-β) ppm; 13C NMR (125 MHz,
CD3OD) δC: 206.8 (C-βʹ), 163.1 (C-4ʹ), 162.3 (C-2ʹ, 6ʹ), 161.2
(C-3) 144.6 (C-1), 130.3 (C-5), 121.8 (C-6), 115.1 (C-4), 112.3
(C-2), 106.1 (C-1ʹ), 104.3 (C-3ʹ, 5ʹ), 82.6 (C-5ʹʹ, 5ʹʹʹ), 79.0 (C-3ʹʹ,
3ʹʹʹ), 76.7 (C-1ʹʹ, 1ʹʹʹ), 74.1 (C-2ʹʹ, 2ʹʹʹ), 71.0 (C-4ʹʹ, 4ʹʹʹ), 61.8
(C-6ʹʹ, 6ʹʹʹ), 47.3 (C-α), 31.8 (C-β) ppm; HR-ESI-MS m/z:
[M+H]+ calcd. for C28H37O15 613.2132, found 613.2135.
MHz, CD3OD) δH: 7.11 (2H, d, J = 8.6 Hz, H-2, 6), 6.80 (2H, d, J
= 8.6 Hz, H-3, 5), 4.94 (2H, d, J = 9.8 Hz, H-1ʹʹ, 1ʹ″), 3.83 (4H,
m, H-6ʹʹ, 6ʹ″), 3.62 (2H, m, H-5ʹʹ, 5″ʹ), 3.51 (2H, m, H-4ʹʹ, 4″ʹ),
3.49 (2H, m, H-3ʹʹ, 3ʹ″), 3.42 (2H, m, H-α), 3.34 (2H, m, H-2ʹʹ,
2″ʹ), 2.89 (2H, m, H-β) ppm; 13C NMR (125 MHz, CD3OD) δC:
207.0 (C-βʹ), 162.2 (C-4), 159.3 (C-2ʹ, 6ʹ), 135.0 (C-1), 130.4
(C-2, 6), 114.8 (C-3, 5), 106.1 (C-1ʹ), 104.3 (C-3ʹ, 5ʹ), 82.6 (C-5ʹʹ,
5ʹʹʹ), 79.0 (C-3ʹʹ, 3ʹʹʹ), 76.7 (C-1ʹʹ, 1ʹʹʹ), 74.1 (C-2ʹʹ, 2ʹʹʹ), 71.1
(C-4ʹʹ, 4ʹʹʹ), 61.8 (C-6ʹʹ, 6ʹʹʹ), 55.6 (OCH3), 47.4 (C-α), 30.9 (C-β)
ppm; HR-ESI-MS m/z: [M+H]+ calcd. for C28H37O15 613.2132,
found 613.2127.
4.2.8. 2-(4ʺ-methylphenyl)-2ʹ,4ʹ,6ʹ-trihydroxy-3ʹ,5ʹ-di-C-β-D-
glucopyranosyl acetophenone (1h)
4.2.4. 2ʹ,4ʹ,6ʹ-trihydroxy-4-methyl-3ʹ,5ʹ-di-C-β-D-glucopyranosyl
dihydrochalcone (1d)
White solid (3.60 g, 62%); Rf = 0.25 (Me2CO:EtOAc:H2O:
1
AcOH, 20:20:3:1); [α]D20 = +53.8 (c 0.2, MeOH); H NMR (500

MHz, CD3OD) δH: 7.09 (4H, m, H-2ʺ, 3ʺ, 5ʺ, 6ʺ), 4.93 (2H, d, J =
9.8 Hz, H-1ʹʹʹ, 1ʹʹʹʹ), 4.30 (2H, d, J = 15.7 Hz, H-2), 3.84 (4H, m,
H-6ʹʹʹ, 6ʹʹʹʹ), 3.62 (2H, m, H-5ʹʹʹ, 5ʹʹʹʹ), 3.51 (2H, m, H-4ʹʹʹ, 4ʹʹʹʹ),
3.49 (2H, m, H-3ʹʹʹ, 3ʹʹʹʹ), 3.42 (2H, m, H-2ʹʹʹ, 2ʹʹʹʹ), 2.28 (3H, s,
CH3) ppm; 13C NMR (125 MHz, CD3OD) δC: 205.6 (C-1), 175.3
(C-4ʹ) 163.2 (C-6ʹ), 162.5 (C-2ʹ), 137.0 (C-1ʺ), 133.8 (C-4ʺ),
130.8 (C-2ʺ, 6ʺ), 129.8 (C-3ʺ, 5ʺ), 106.0 (C-1ʹ), 104.4 (C-3ʹ, 5ʹ),
82.7 (C-5ʹʹʹ, 5ʹʹʹʹ), 79.0 (C-3ʹʹʹ, 3ʹʹʹʹ), 76.7 (C-1ʹʹʹ, 1ʹʹʹʹ), 74.1 (C-2ʹʹʹ,
2ʹʹʹʹ), 71.0 (C-4ʹʹʹ, 4ʹʹʹʹ), 61.8 (C-6ʹʹʹ, 6ʹʹʹʹ), 21.1 (CH3) ppm;
HR-ESI-MS m/z: [M+H]+ calcd. for C27H35O14 583.2027, found
583.2021.
diastereomers 2c (100 mg) was separated by preparative HPLC
with a chiral column (CHIRALPAK AD-RH, ADRHCG-VA001,
250 mm×10 mm, 5 µm; Daicel Corp., Tokyo, Japan) using
MeOH-H2O (17:83, HOAc 0.2%) as eluent to give 2c-1(45 mg,
45%) and 2c-2 (20 mg, 20%).
4.3.3.1.(6R)-2-(3-(4-methoxyphenyl)propanoyl)-3,5,6-trihydroxy-
4,6-di-C-β-D-glucopyranosylcyclohexa-2,4-dienone (2c-1)
[α]D20 = +23.9 (c 0.1, MeOH); ECD (5 × 10-4 M , MeOH) λext
1
(∆ε) 238 (−7.8), 310 (+1.7) nm; H NMR (500 MHz, DMSO-d6)
δH: 17.73 (1H, s, 3-OH), 7.15 (2H, d, J = 8.6 Hz, H-11, 15), 6.81
(2H, d, J = 8.6 Hz, H-12, 14), 4.12 (1H, d, J = 9.4 Hz, H-1ʹʹ),
4.13 (1H, m, H-2ʹʹ), 3.71 (3H, s, OCH3), 3.60 (1H, m, H1-6ʹʹ),
3.60 (1H, m, H1-6ʹ), 3.52 (1H, d, J = 9.4 Hz, H-1ʹ ), 3.32 (1H, m,
H2-6ʹ), 3.32 (1H, m, H2-6ʹʹ), 3.26 (1H, m, H-2ʹ), 3.09 (1H, m,
H-3ʹʹ), 3.09 (1H, m, H-3ʹ), 3.00 (3H, m, H- 4ʹʹ, 5ʹ, 5ʹʹ), 2.93 (1H,
m, H-4ʹ), 2.77 (2H, m, H-8), 2.67 (2H, m, H-9) ppm; 13C NMR
(125 MHz, DMSO-d6) δC: 195.8 (C-1), 193.5 (C-7), 190.4 (C-5),
182.6 (C-3), 157.9 (C-13), 134.8 (C-10), 129.8 (C-11, 15), 114.2
(C-12, 14), 104.3 (C-2), 98.6 (C-4), 85.8 (C-1ʹ), 85.3 (C-6), 81.4
(C-5ʹʹ), 81.0 (C-5ʹ), 79.8 (C-3ʹʹ), 78.8 (C-3ʹ), 74.4 (1ʹʹ), 71.7
(C-4ʹ), 70.8 (C-4ʹʹ), 70.6 (C-2ʹʹ), 69.1 (C-2ʹ), 62.3 (6ʹʹ), 61.9
(C-6ʹ), 55.6 (OCH3), 49.2 (C-8), 31.4 (C-9) ppm; HR-ESI-MS
m/z: [M+Na]+ calcd. for C28H36NaO16 651.1901, found 651.1873.
4.3. General procedure for the synthesis of 2a−h
A solution of 1 (1.0 mmol) in NH4Cl-NH3·H2O buffer salt (pH
= 8.0, 30 mL) was vigorously stirred at r.t. under O2 atmosphere
(balloon) for 12 h. The mixture was passed through a column of
MCI GEL CHP20P (75–150 µm, Mitsubishi Chemical Corp., 1.5
× 20 cm) loaded with water, and the gel was then washed with
water (100 mL), to remove nonabsorbed NH4Cl and NH3·H2O.
The absorbed products were eluted from the gel column with 100
mL of 30% aqueous MeOH, and the eluate was evaporated in
vacuo to give a light green solid that was then separated by
preparative HPLC with an ODS-A column (250 × 20 mm, 5 µm,
YMC Corp.) using MeOH-H2O as eluent to give 2.
4.3.1 2-(3-(4-hydroxyphenyl)propanoyl)-3,5,6-trihydroxy-4,6-di-
4.3.3.2. (6S)-2-(3-(4-methoxyphenyl)propanoyl)-3,5,6-trihydroxy-
4,6-di-C-β-D-glucopyranosylcyclohexa-2,4-dienone (2c-2)
[α]D20 = -48.8 (c 0.1, MeOH); ECD (5 × 10-4 M , MeOH) λext
C-β-D-glucopyranosylcyclohexa-2,4-dienone (2a)
Light yellow solid (520 mg, 85%); 1H NMR (500 MHz,
DMSO-d6) δH: 17.70 (1H, s, 3-OH), 9.06 (1H, brs, 5-OH), 7.00
(2H, d, H-10, J = 8.4 Hz, H-11, 15), 6.63 (2H, d, J = 8.4 Hz,
H-12, 14), 4.12 (2H, d, J = 10.0 Hz, H-1ʹʹ ), 4.10 (2H, m, H-2ʹ,
2ʹʹ), 3.58 (1H, m, H1-6ʹ), 3.56 (1H, m, H1-6ʹʹ), 3.52 (1H, d, J = 9.4
Hz, H-1ʹ ), 3.48 (1H, m, H2-6ʹ), 3.37 (1H, m, H2-6ʹʹ), 3.37 (2H, m,
H-8), 3.15 (1H, m, H-3ʹʹ), 3.08 (1H, m, H-4ʹʹ), 3.08 (1H, m, H-3ʹ),
3.00 (1H, m, H-4ʹ), 2.99 (1H, m, H-5ʹʹ), 2.90 (1H, m, H-5ʹ), 2.90
(1H, m, H1-9), 2.70 (1H, m, H2-9) ppm; 13C NMR (125 MHz,
DMSO-d6) δC: 195.3 (C-1), 193.5 (C-7) 190.2 (C-5), 182.3 (C-3),
155.6 (C-13), 132.8 (C-10), 129.5 (C-11, 15), 115.3 (C-12, 14),
103.9 (C-2), 98.3 (C-4), 85.7 (C-1ʹ), 85.1 (C-6), 81.2 (C-5ʹ), 81.2
(C-5ʹʹ), 79.6 (C-3ʹʹ), 78.6 (C-3ʹ), 74.2 (1ʹʹ), 71.4 (C-4ʹ), 70.5
(C-4ʹʹ), 69.0 (C-2ʹ), 62.1 (C-6ʹ), 62.1 (6ʹʹ), 49.1 (C-8), 31.3 (C-9)
ppm; HR-ESI-MS m/z: [M+Na]+ calcd. for C27H34NaO16
637.1745, found 637.1739.
1
(∆ε) 265 (+3.4), 304 (−4.2) nm; H NMR (500 MHz, DMSO-d6)
δH: δH: 17.64 (1H, s, 3-OH), 7.15 (2H, d, J = 8.5 Hz, H-11, 15),
6.81 (2H, d, J = 8.5 Hz, H-12, 14), 4. 20 (1H, d, J = 9.3 Hz,
H-1ʹʹ), 4.03 (1H, m, H-2ʹʹ), 3.71 (3H, s, OCH3), 3.60 (1H, m,
H1-6ʹʹ), 3.60 (1H, m, H1-6ʹ), 3.54 (1H, d, J = 9.2 Hz, H-1ʹ ), 3.44
(1H, m, H2-6ʹ), 3.44 (1H, m, H2-6ʹʹ), 3.26 (1H, m, H-2ʹ), 3.09
(1H, m, H-3ʹʹ), 3.09 (1H, m, H-3ʹ), 3.06-3.03 (3H, m, H- 4ʹʹ, 5ʹ,
5ʹʹ), 2.91 (1H, m, H-4ʹ), 2.81 (2H, m, H-8), 2.72 (2H, m, H-9)
ppm; 13C NMR (125 MHz, DMSO-d6) δC: 196.5 (C-1), 195.3
(C-7), 192.1 (C-5), 172.5 (C-3), 157.8 (C-13), 134.3 (C-10),
129.6 (C-11, 15), 114.1 (C-12, 14), 103.8 (C-2), 99.9 (C-4), 85.7
(C-1ʹ), 84.4 (C-6), 81.2 (C-5ʹʹ), 80.4 (C-5ʹ), 79.4 (C-3ʹʹ), 77.1
(C-3ʹ), 75.1 (1ʹʹ), 71.5 (C-4ʹ), 71.3 (C-4ʹʹ), 71.1 (C-2ʹʹ), 70.1
(C-2ʹ), 62.3 (6ʹʹ), 61.5 (C-6ʹ), 55.4 (OCH3), 42.5 (C-8), 31.3 (C-9)
ppm. HR-ESI-MS m/z: [M+H]+ calcd. for C28H37O16 629.2082,
found 629.2082.
4.3.2. 2-(3-phenylpropanoyl)-3,5,6-trihydroxy-4,6-di-C-β-D-
glucopyranosylcyclohexa-2,4-dienone (2b)
4.3.4. 2-(3-(4-methylphenyl)propanoyl)-3,5,6-trihydroxy-4,6-di-
1
Light yellow solid (430 mg, yield 72%); H NMR (500 MHz,
C-β-D-glucopyranosylcyclohexa-2,4-dienone (2d)
DMSO-d6) δH: 17.69 (1H, s, 3-OH), 7.26 (2H, m, H-11, 15), 7.25
(3H, m, H-12, 13, 14), 4.14 (1H, d, J = 9.4 Hz, H-1ʹʹ ), 4.12 (1H,
m, H- 2ʹʹ), 3.59 (1H, m, H1-6ʹʹ), 3.59 (1H, m, H1-6ʹ), 3.55 (1H, d,
J = 9.4 Hz, H-1ʹ ), 3.54 (1H, m, H-2ʹ), 3.32 (1H, m, H2-6ʹ), 3.32
(1H, m, H-3ʹʹ), 3.28 (1H, m, H2-6ʹʹ), 3.17 (2H, m, H-8), 3.09 (1H,
m, H-3ʹ), 3.00m (3H, m, H-4ʹ, 4ʹʹ, 5ʹ), 2.93 (1H, m, H-5ʹʹ), 2.85
(1H, m, H1-9), 2.75 (1H, m, H2-9) ppm. 13C NMR (125 MHz,
DMSO-d6) δC: 195.7 (C-1), 193.4 (C-7) 190.6 (C-5), 182.3 (C-3),
142.9 (C-10), 128.9 (C-11, 15), 128.7 (C-12, 14), 126.2 (C-13),
104.2 (C-2), 98.5 (C-4), 85.9 (C-1ʹ), 85.4 (C-6), 81.2 (C-5ʹʹ), 80.9
(C-5ʹ), 79.8 (C-3ʹʹ), 78.8 (C-3ʹ), 74.4 (1ʹʹ), 71.6 (C-4ʹ), 70.8
(C-4ʹʹ), 70.6 (C-2″), 69.2 (C-2ʹ), 62.3 (6ʹʹ), 61.9 (C-6ʹ), 49.2 (C-8),
32.3 (C-9) ppm; HR-ESI-MS m/z: [M+Na]+ calcd. for
C27H34NaO15 621.1795, found 621.1793.
Light yellow solid (495 mg, 81%); 1H NMR (500 MHz,
DMSO-d6) δH: 17.67 (1H, s, 3-OH), 7.10 (2H, d, J = 7.5 Hz,
H-11, 15), 7.04 (2H, d, J = 7.5 Hz, H-12, 14), 4.18 (1H, d, J = 9.9
Hz, H-1ʹʹ ), 4.12 (1H, m, H-2ʹʹ), 3.58 (1H, m, H1-6ʹʹ), 3.58 (1H,
m, H1-6ʹ), 3.49 (1H, d, J = 9.4 Hz, H-1ʹ ), 3.43 (1H, m, H2-6ʹ),
3.43 (1H, m, H2-6ʹʹ), 3.32 (1H, m, H-2ʹ), 3.09 (2H, m, H-3ʹ, 3ʹʹ),
3.08 (1H, m, 5ʹʹ), 3.00 (2H, m, H-5ʹ, 4ʹʹ), 2.93 (1H, m, H-4ʹ), 2.88
(2H, m, H-8), 2.68 (2H, m, H-9), 2.23 (3H, s, CH3) ppm; 13C
NMR (125 MHz, DMSO-d6) δC: 195.5 (C-1), 194.9 (C-7), 193.4
(C-5), 182.5 (C-3), 139.4 (C-10), 134.8 (C-13), 129.2 (C-12, 14),
128.6 (C-11, 15), 104.4 (C-2), 100.4 (C-4), 85.7 (C-6), 81.2
(C-1ʹ), 80.8 (C-5ʹ), 79.6 (C-5ʹʹ), 78.6 (C-3ʹʹ), 75.0 (C-3ʹ), 74.4
(C-1ʹʹ), 71.7 (C-4ʹ), 70.8 (C-4ʹʹ), 70.3 (C-2ʹʹ), 69.1 (C-2ʹ), 62.3
(C-6ʹʹ), 62.2 (C-6ʹ), 49.0 (C-8), 31.6 (C-9), 31.1 (CH3);
HR-ESI-MS m/z: [M+Na]+ calcd. for C28H36NaO15 635.1952,
found 635.1950.
4.3.3. 2-(3-(4-methoxyphenyl)propanoyl)-3,5,6-trihydroxy-4,6-di-
C-β-D-glucopyranosylcyclohexa-2,4-dienone (2c)
Light yellow solid (540 mg, 86%); The mixture of
4.3.5. 2-(3-(4-fluorophenyl)propanoyl)-3,5,6-trihydroxy-4,6-di-

C-β-D-glucopyranosylcyclohexa-2,4-dienone (2e)
79.6 (C-5ʹ), 78.9 (C-3ʹʹ), 77.9 (C-3ʹ), 73.3 (C-1ʹʹ), 69.8 (C-4ʹ),
69.5 (C-4ʹʹ), 69.3 (C-2ʹʹ), 68.8 (C-2ʹ), 61.0 (C-6ʹ), 60.7 (C-6ʹʹ),
42.9 (C-8), 20.2 (CH3) ppm; HR-ESI-MS m/z: [M+Na]+ calcd.
for C27H34NaO15 621.1795, found 621.1776.
Light yellow solid (490 mg, 80%); 1H NMR (500 MHz,
DMSO-d6) δH: 17.65 (1H, s, 3-OH), 7.28 (2H, m, H-12, 14), 7.07
(2H, m, H-11, 15), 4.32 (1H, d, J = 9.4 Hz, H-1ʹʹ), 4.12 (1H, m,
H-2ʹʹ), 3.60 (2H, m, H1-6ʹ, 6ʹʹ), 3.55 (1H, d, J = 9.4 Hz, H-1ʹ ),
3.32 (2H, m, H2-6ʹ, 6ʹʹ), 3.32 (1H, m, H-2ʹ), , 3.09 (2H, m, H-3ʹ,
3ʹʹ), 3.08 (1H, m, 5ʹʹ), 3.00 (1H, m, H-5ʹ), 3.00 (1H, m, H-4ʹʹ),
2.93 (1H, m, H-4ʹ), 2.84 (2H, m, H-8), 2.75 (2H, m, H-9) ppm;
13C NMR (125 MHz, DMSO-d6) δC: 195.5 (C-1), 193.0 (C-7),
190.4 (C-5), 182.0 (C-3), 138.8 (C-13), 130.4 (C-11, 15), 115.2
(C-12, 14), 104.0 (C-2), 98.3 (C-4), 85.7 (C-1ʹ), 85.2 (C-6), 81.2
(C-5ʹʹ), 80.8 (C-5ʹ), 79.6 (C-3ʹʹ), 78.6 (C-3ʹ), 74.1 (C-1ʹʹ), 71.5
(C-4ʹ), 70.6 (C-4ʹʹ), 70.4 (C-2ʹʹ), 69.0 (C-2ʹ), 62.1 (C-6ʹʹ), 61.7
(C-6ʹ), 49.0 (C-8), 31.2 (C-9) ppm; HR-ESI-MS m/z: [M+Na]+
calcd. for C27H33NaFO15 639.1701, found 639.1721.
Acknowledgments
This project was supported by the National Natural Science
Foundation of China (81673311) and CAMS Innovation Fund for
Medical Sciences (CIFMS) (No. 2017-I2M-3-010).
Supplementary Material
Experimental procedures, compound characterization data, and
spectral data
4.3.6. 2-(3-(3-chlorophenyl)propanoyl)-3,5,6-trihydroxy-4,6-di-
C-β-D-glucopyranosylcyclohexa-2,4-dienone (2f)
Notes and references
[1] (a) J. S. Jiang, J. He, Z. M. Feng, P. C. Zhang, Org. Lett. 12 (2010)
1196-1199; (b) K. Kazuma, T. Takahashi, K. Sato, H. Takeuchi, T.
Matsumoto, T. Okuno, Biosci. Biotechnol. Biochem. 64 (2000)
1588-1599; (c) H. B. Yin, Z. S. He, Tetrahedron Lett. 41 (2000)
1955-1958; (d) M. R. Meselhy, S. Kadota, Y. Momose, M. Hattori, T.
Namba, Chem. Pharm. Bull. 40 (1992) 3355-3357; (e) M. R. Meselhy,
S. Kadota, Y. Momose, N. Hatakeyama, A. Kusai, M. Hattori, T.
Namba, Chem. Pharm. Bull. 41 (1993) 1796-1802; (f) J. Onodera, H.
Obara, R. Hirose, S. Matsuba, N. Sato, S. Sato, M. Suzuki, Chem. Lett.
(1989) 1571-1574; (g) J. Onodera, H. Obara, M. Osone, Y. Maruyama,
S. Sato, Chem. Lett. (1981) 433–436; (h) Y. Takahashi, N. Miyasaka, S.
Tasaka, I. Miura, S. Urano, M. Ikura, K. Hikichi, T. Matsumoto, M.
Wada, Tetrahedron Lett. 23 (1982) 5163-5166.
[2] H. Z. Zhang, Z. H. Dong, J. She, Moderm Study of Traditional Chinese
Medicine, Vol. 3, Xue Yuan Press, Beijing, China, 1998, pp. 2057.
[3] Z. M. Feng, J. He, J. S. Jiang, Z. Chen, Y. N. Yang, P. C. Zhang, J. Nat.
Prod. 76 (2013) 270-274.
[4] A traditional Japanese kimono (Manyo-karano-izanai) dyed with Beni
(=carthamin), courtesy of Shirataka town, Yamagata.
Light yellow solid (410 mg, 65%); 1H NMR (500 MHz,
DMSO-d6) δH: 17.57 (1H, s, 3-OH), 7.29 (2H, m, H-11, 13), 7.20
(2H, m, H-14, 15), 4.31 (1H, d, J = 9.4 Hz, H-1ʹʹ), 4.11 (1H, m,
H-2ʹʹ), 3.60 (2H, m, H1-6ʹ, 6ʹʹ), 3.52 (1H, d, J = 9.4 Hz, H-1ʹ ),
3.26 (2H, m, H2-6ʹ, 6ʹʹ), 3.15 (2H, m, H-3ʹ, 3ʹʹ), 3.15 (1H, m,
H-2ʹ), 3.08 (1H, m, H-4ʹʹ), 3.06 (1H, m, H-4ʹ), 2.98 (2H, m, H-5ʹ,
5ʹʹ), 2.86 (2H, m, H-8), 2.75 (2H, m, H-9) ppm; 13C NMR (125
MHz, DMSO-d6) δC: 195.7 (C-1), 192.9 (C-7), 190.6 (C-5), 182.1
(C-3), 145.6 (C-12), 130.6 (C-10), 128.7 (C-15), 127.7 (C-14),
126.2 (C-13), 120.1 (C-11), 104.3 (C-2), 98.4 (C-4), 85.9 (C-6),
85.4 (C-1ʹ), 81.4 (C-5ʹʹ), 81.0 (C-5ʹ), 79.8 (C-3ʹʹ), 78.8 (C-3ʹ),
74.3 (C-1ʹʹ), 70.7 (C-4ʹ), 70.5 (C-4ʹʹ), 70.7 (C-2ʹʹ), 70.6 (C-4ʹ),
69.1 (C-2ʹ), 62.3 (C-6ʹ), 61.9 (C-6ʹʹ), 49.2 (C-8), 31.8 (C-9) ppm;
HR-ESI-MS m/z: [M+Na]+ calcd. for C27H33NaClO15 655.1406,
found 655.1410.
4.3.7. 2-(3-(3-methoxyphenyl)propanoyl)-3,5,6-trihydroxy-4,6-di-
[5] (a) S. Sato, T. Kumazawa, H. Watanabe, K. Takayanagi, S. Matsuba, J.
Onodera, H. Obara, K. Furuhata, Chem. Lett. 30 (2001) 1318-1319; (b)
T. Hayashi, K. Ohmori, K. Suzuki, Synlett. 27 (2016) 2345-2351; (c) T.
Hayashi, K. Ohmori, K. Suzuki, Org. Lett. 19 (2017) 866-869; (d) K.
Kitamura, Y. Ando, T. Matsumoto, K. Suzuki, Chem. Rev. 118 (2017)
1495-1598. (e) K. Azami, T. Hayashi, T. Kusumi, K. Ohmori, K.
Suzuki, Angew. Chem. Int. Ed. 58 (2019), 1-7.
[6] (a) T. Ho, H. Kamimura, K. Ohmori, K. Suzuki, Org. Lett. 18 (2016)
4488-4490; (b) H. Obara, H. Machida, S. Namai, J. Onodera, Chem.
Lett. (1985) 1393-1394; (c) S. Sato, H, Obara, T. Kumazawa, J.
Onodera, K. Furuhata, Chem. Lett. (1996) 833-834.
[7] S. Sato, T. Kumazawa, H. Watanabe, K. Takayanagi, S. Matsuba, J.
Onodera, H. Obara, K. Furuhata, Chem. Lett. 30 (2001) 1318-1319.
[8] (a) S. Sato, T. Nojiri, J. Onodera, Carbohydr. Res. 340 (2005) 389-393;
(b) T. Suzuki, M. Ishida, T. Kumazawa, S. Sato, Carbohydr. Res. 448
(2017) 52-56.
[9] (a) A. Sib, T. M. Gulder, Angew. Chem. Int. Ed. 56 (2017)
12888-12891; (b) T. Suzuki, M. Ishida, T. Kumazawa, S. Sato,
Carbohydr. Res. 448 (2017) 52-56; (c) T. Hayashi, K. Ohmori, K.
Suzuki, Synlett. 27 (2016) 2345-2351; (d) T. W. Cambell, G. M.
Copponger, J. Am. Chem. Soc. 73 (1951) 1849-1950; (e) E. Collons, G.
D. John, V. R. Shannon, J. C. S. Perkin trans I. 1 (1975) 94–101; (f) S.
Sata, H. Obara, J. Onoder, A. Endo, Bull. Chem. Soc. Jpn. 65 (1992)
452-457; (g) D. Magdziak, S. J. Meek, T. R. R. Pettus, Chem. Rev. 104
(2004) 1383-1429; (h) S. Barradas, G. H. Andez–Torres, A. Urbano, M.
C. Carreno, Org. Lett. 14 (2012) 5952-5955; (i) V. Zhdankin, Chem.
Rev. 108 (2008) 5299-5358.
C-β-D-glucopyranosylcyclohexa-2,4-dienone (2g)
Light yellow solid (425 mg, 68%); 1H NMR (500 MHz,
DMSO-d6) δH: 17.71 (1H, s, 3-OH), 7.17 (1H, m, H-14), 6.81
(2H, m, H-11, 13), 6.72 (1H, m, H-15), 4.19 (1H, d, J = 9.8 Hz,
H-1ʹʹ ), 4.12 (1H, m, H-2ʹʹ), 3.73 (3H, s, OCH3), 3.60 (2H, m,
H1-6ʹ, 6ʹʹ), 3.54 (1H, d, J = 9.4 Hz, H-1ʹ ), 3.32 (2H, m, H2-6ʹ, 6ʹʹ),
3.32 (1H, m, H-2ʹ), 3.09 (2H, m, H-3ʹ, 3ʹʹ), 3.08 (1H, m, H-5ʹʹ),
3.00 (1H, m, H-4ʹʹ), 3.00 (1H, m, H-5ʹ), 2.93 (1H, m, H-4ʹ), 2.85
(2H, m, H-8), 2.73 (2H, m, H-9) ppm; 13C NMR (125 MHz,
DMSO-d6) δC: 195.8 (C-1), 194.9 (C-7), 193.3 (C-5), 182.9 (C-3),
159.8 (C-12), 144.5 (C-14), 129.8 (C-10), 121.2 (C-15), 111.5
(C-11), 111.4 (C-13), 104.3 (C-2), 98.5 (C-4), 85.9 (C-1ʹ), 85.4
(C-6), 81.6 (C-5ʹʹ), 81.0 (C-5ʹ), 79.8 (C-3ʹʹ), 78.8 (C-3ʹ), 74.4
(C-1ʹʹ), 71.6 (C-4ʹ), 71.2 (C-4ʹʹ), 70.6 (C-2ʹʹ), 69.1 (C-2ʹ), 62.3
(C-6ʹ), 61.9 (C-6ʹʹ), 55.5 (OCH3), 49.2 (C-8), 32.2 (C-9) ppm;
HR-ESI-MS m/z: [M+Na]+ calcd. for C28H36NaO16 651.1901,
found 651.1875.
4.3.8. 2-(2-(4-methylphenyl)acetyl)-3,5,6-trihydroxy-4,6-di-C-β-
D-glucopyranosylcyclohexa-2,4-dienone (2h)
Light yellow solid (360 mg, 60%); 1H NMR (500 MHz,
acetone-d6) δH: 17.63 (1H, s, 3-OH), 7.16 (2H, d, J =7.9 Hz, H-10,
14), 6.98 (2H, d, J = 7.9 Hz, H-11, 13), 4.36 (1H, d, J = 9.4 Hz,
H-1ʹʹ), 4.13 (2H, m, H-8), 3.78 (1H, d, J = 9.4 Hz, H-1ʹ), 3.64
(2H, m, H1-6ʹ, 6ʹʹ), 3.53 (2H, m, H-4ʹ, 4ʹʹ), 3.50 (2H, m, H-2ʹ, 2ʹʹ),
3.36 (1H, m, H-3ʹ), 3.38 (1H, m, H-3ʹʹ), 3.18 (1H, m, H-5ʹ), 3.17
(1H, m, H-5ʹʹ), 2.16 (3H, s, CH3) ppm; 13C NMR (125 MHz,
acetone-d6) δC: 195.4 (C-1), 193.2 (C-7), 192.2 (C-5), 183.2
(C-3), 135.4 (C-9), 134.4 (C-12), 129.6 (C-11, 13), 128.6 (C-10,
14), 104.0 (C-2), 98.8 (C-4), 85.6 (C-1ʹ), 85.1 (C-6), 79.9 (C-5ʹʹ),
[10] (a) S. Y. Fung, K. W. M. Zuurbier, N. B. Paniego, J. J. C. Scheffer, R.
Verpoorte, Phytochemistry, 44 (1997) 1047-1053; (b) A. Sib, T. A. M.
Gulder, Angew. Chem. Int. Ed. 56 (2017) 12888-12891.
[11] (a) V. Siddaiah, C. Rao, S. Venkateswarlu, G. Subbaraju, Tetrahedron,
62 (2006) 841-846; (b) J. Z. Miao, H. Q. Cui, J. Jin, F. F. Lai, H. Wen,
X. Zhang, X. G. Chen, D. L. Yin, Chem. Commun. 51 (2015) 881-884.
[12] S. Sato, T. Akiya, T. Suzuki, J. Onodera, Carbohydr. Res. 339 (2004)
2611-2614.
[13] (a) D. Zheng, H. Zhang, C. W. Zheng, Y. Z. Lao, D. Q. Xu, L. B. Xiao,
H. X. Xu, Org. Chem. Front. 4 (2017) 2102-2108; (b) Y. Y. Fan, L. S.

Gan, H. C. Liu, L. Heng, C. H. Xu, J. P. Zuo, J. Ding, J. M. Yue, Org.
Lett. 19 (2017) 4580-4583; (c) S. Jurinovich, C. A. Guido, T. Bruhn, G.
Pescitell, B. Mennucci, Chem. Commun. 51 (2015) 10498-10501.
[14] (a) D. Gryglik, J. S. Miller, S. Ledakowicz, J. Hazard. Mater. 146 (2007)
502-507; (b) Y. You, E. J. Cho, H. Kwon, J. Hwang, S. E. Lee, Chem.
Commun. 52 (2016) 780-783.
[15] K. Ozoemena, N. Kuznetsova, J. Mol. Catal. A-Chem. 176 (2001)
29-40.

Highlights
1. An efficient and simple method for the protecting group-free synthesis of
C-glucosyl 3,5,6-trihydroxycyclohexa-2,4-dienones was firstly developed.
2. The absolute configuration of the 3,5,6-trihydroxycyclohexa-2,4-dienone unit was
determined by the comparison of experimental and calculated electronic circular
dichroism (ECD) spectra.
3. A plausible mechanism involving a singlet oxygen intermediate and a radical
process is proposed.