Total synthesis of three natural phenethyl glycosides

Article abstract of DOI:10.1080/10286020.2020.1724970

Phenethyl glycosides having phenolic or methoxy functions at benzene rings are substances widely occurring in nature. This kind of compounds has been shown to have anti-oxidant, anti-inflammatory, and anticancer activities. However, some of them are not naturally abundant, thus the synthesis of such molecules is desirable. In this paper, natural phenethyl glycosides 3 and 4 were first totally synthesized from easily available materials with overall yields of 50.5% and 40.1%, respectively. And a new synthetic route to obtain natural phenethyl glycoside 2 in 46.2% yield was also described.

Full text of DOI:10.1080/10286020.2020.1724970

Journal of Asian Natural Products Research
ISSN: 1028-6020 (Print) 1477-2213 (Online) Journal homepage: https://www.tandfonline.com/loi/ganp20
Total synthesis of three natural phenethyl
glycosides
Hong-Bo Dong, Jian Meng, Zhong-Quan Yao, Hong-Bing Luo, Jing-Xia Zhang,
Wei-Hong Du, Ke-Hui Tang & Sheng-Hua Cao
To cite this article: Hong-Bo Dong, Jian Meng, Zhong-Quan Yao, Hong-Bing Luo, Jing-Xia Zhang,
Wei-Hong Du, Ke-Hui Tang & Sheng-Hua Cao (2020): Total synthesis of three natural phenethyl
glycosides, Journal of Asian Natural Products Research, DOI: 10.1080/10286020.2020.1724970
To link to this article: https://doi.org/10.1080/10286020.2020.1724970
View supplementary material
Published online: 21 Feb 2020.
Submit your article to this journal
Article views: 2
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=ganp20

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
https://doi.org/10.1080/10286020.2020.1724970
Total synthesis of three natural phenethyl glycosides
Hong-Bo Donga, Jian Menga, Zhong-Quan Yao, Hong-Bing Luoa, Jing-Xia
Zhanga,b, Wei-Hong Dub, Ke-Hui Tanga and Sheng-Hua Caoa
aAntibiotics Research and Re-Evaluation Key Laboratory of Sichuan Province, Sichuan Industrial
b
Institute of Antibiotics, Chengdu University, Chengdu 610106, China; College of Pharmacy, Chengdu
University of Traditional Chinese Medicine, Chengdu 611137, China
ABSTRACT
ARTICLE HISTORY
Received 9 October 2019
Accepted 29 January 2020
Phenethyl glycosides having phenolic or methoxy functions at
benzene rings are substances widely occurring in nature. This
kind of compounds has been shown to have anti-oxidant, anti-
inflammatory, and anticancer activities. However, some of them
are not naturally abundant, thus the synthesis of such molecules
is desirable. In this paper, natural phenethyl glycosides 3 and 4
were first totally synthesized from easily available materials with
overall yields of 50.5% and 40.1%, respectively. And a new syn-
thetic route to obtain natural phenethyl glycoside 2 in 46.2%
yield was also described.
KEYWORDS
Total synthesis; phenethyl
glycosides; natural product
1. Introduction
Phenethyl glycosides having phenolic or methoxy functions at benzene rings are sub-
stances widely occurring in nature (Figure 1). The most famous compound among this
kind of natural products is salidroside 1, which is isolated from Rhodiola sachalinensis
A. Bor. Salidroside 1 has a wide range of pharmacological effects, such as anti-oxidant,
anti-inflammatory, anticancer, hepatoprotective, cardioprotective, neuroprotective, anti-
diabetic, and antiviral activities [1–5]. So the total syntheses of salidroside 1 employing
various chemical or enzymatic methods have been previously reported.
As shown in Figure 1, natural phenethyl glycosides 2 [(2R,3R,4S,5S,6R)-2-(4-
hydroxy-3-methoxyphenethoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol], 3
CONTACT Hong-Bo Dong
bloodwhenseeme@163.com
Antibiotics Research and Re-Evaluation Key Laboratory
of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052, China
Supplemental data for this article is available online at https://doi.org/10.1080/10286020.2020.1724970.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
H.-B. DONG ET AL.
Figure 1. Structures of salidroside 1 and natural products 2–4.
[(2R,3R,4S,5S,6R)-2-(3,4-dimethoxyphenethoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-
3,4,5-triol], and 4 [(2R,3R,4S,5S,6R)-2-(3-hydroxy-4-methoxyphenethoxy)-6-(hydroxy-
methyl)tetrahydro-2H-pyran-3,4,5-triol] have chemical structures similar to salidroside
1. They were first isolated from polar fraction of Saussurea genus (Asteraceae), leaves
of Forsythia suspensa (Lauraceae), and dried root of Scrophularia ningpoensis, respect-
ively [6–8]. These compounds have attracted scientific attention as a result of their
diverse biological activities, which include antibacterial [7], inhibiting nitric oxide pro-
duction [9], and cell protection [10]. However, all of these compounds have been iso-
lated in low yields from natural sources and synthesis of them are rarely reported [11,
12]. So far detailed pharmacological study of these compounds has been minimal.
Hence efficient synthetic routes to this potentially useful natural products are needed.
We herein report the first total syntheses of phenethyl glycosides 3 and 4 and a new
synthetic method to get phenethyl glycoside 2 from inexpensive materials also has
been developed.
2. Results and discussion
As shown in Scheme 1, the synthesis of compound 2 began with readily available 4-
hydroxyphenethyl alcohol 5. Using the known method [13], compound 5 was brom-
ized to generate compound 6 in 89% yield. The aryl bromide of 6 was displaced by
methoxide in the presence of CuBr to obtain 7. Then acetyl protection was used for
the aromatic hydroxy group of 7. Acetic anhydride was gradually added to a solution
of 7 and aqueous NaOH for 45 min with the pH maintained at 7–8 to obtain com-
pound 8 in good yield (78%) as the phenol hydroxyl group of reactant 7 could be
ionized in the weak alkali reaction medium, but the alcohol hydroxyl could not.
On the other hand, rhamnose donor 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl tri-
chloroacetimidate 13 was prepared from D-glucose in three steps according to a lit-
erature method (Scheme 2, 62% overall yield) [14]. Phenylethanol 8 was glycosylated
with rhamnose donor 13 in the presence of a catalytic amount of trimethylsilyl tri-
fluoromethane sulfonate (TMSOTf) at ꢀ78 ꢁC to give the b-linked monosaccharide
derivative 9 as the major product in 85% yield. Removal of all five acetyl groups
from compound 9 gave natural product 2 in quantity (Scheme 1).

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
3
Scheme 1. Synthetic route of compound 2. Reagent and conditions: (a) NaBr, Oxone, acetone,
H2O, 0 ꢁC, 1.5h; (b) CuBr, CH3ONa, DMF, 90 ꢁC, 3 h; (c) acetic anhydride, NaOH, H2O, 0–10 ꢁC,
40 min; (d) compound 13, 4 Å molecular sieves, TMSOTf, ꢀ78 ꢁC to 0 ꢁC, 30 min; (e) CH3ONa,
CH3OH, Amberlite IR 120, room temperature, 1.5 h.
Scheme 2. Synthetic route of compound 13. Reagent and conditions: (a) sodium acetate, acetic
anhydride, 90 ꢁC, 4 h; (b) hydrazine acetate, DMF, 50 ꢁC, 2 h; (c) trichloroacetonitrile, DBU, CH2Cl2,
room temperature, 2 h.
In 2013, Zheng and Guo et al. had reported a similar route to get phenethyl glycoside
2 [11]. In their strategy, benzyl group was used to protect phenol hydroxyl of compound
7. The product was glycosylated with rhamnose donor acetyl-1-bromoglucose under
Koenigs–Knorr conditions. Then acetyl and benzyl protection groups were removed by
CH3ONa/CH3OH and Pd/C systems in two steps, respectively. Compared to their work,
we represent a shorter and more convenient approach to obtain phenethyl glycoside 2.
As shown in Scheme 3, natural product 3 was readily obtained via a similar three-step
sequence including methylation, glycosylation, and deprotection from compound 6.
In an effort to promote the application of the above procedure, we sought to
exploit similar ways to get phenethyl glycoside 4 (Scheme 4). But to our surprise, key
intermediate 17 (17a or 17b) could not be got from protected phenyl ethanol 16 (16a
or 16b) under various conditions.
So we resorted to another route for phenethyl glycoside 4. Our new synthetic route
started from commercially available phenylpropionic acid 19. Treatment of 19 with SOCl2
in CH3OH yielded successfully methyl phenylacetate 20 in 84% yield. Then benzyl protec-
tion was taken to protect the aromatic hydroxy group of 20 to generate 21. Compound
21 was reduced with LiAlH4 (3 equiv.) to afford the corresponding alcohol 22 in 80%
yield. Afterward, compound 23 was obtained by Schmidt’s trichloroacetimidate procedure.

4
H.-B. DONG ET AL.
Scheme 3. Synthetic route of compound 3. Reagent and conditions: (a) NaH, CH3I, DMF, room
temperature, 10 min (b) compound 13, 4 Å molecular sieves, TMSOTf, ꢀ78 ꢁC to 0 ꢁC, 30 min; (c)
CH3ONa, CH3OH, Amberlite IR 120, room temperature, 1.5 h.
Scheme 4. Design of initial attempt to prepare compound 4.
In the last two steps, benzyl and acetyl protection groups of 23 were removed by Pd/C
and CH3ONa/CH3OH systems to get natural product 4 (Scheme 5).
In summary, the first total syntheses of the naturally occurring and biologically
interesting phenethyl glycosides 3 and 4 have been achieved. A new synthetic method
to get 4-hydroxy-3-methoxyphenethyl b-D-glucopyranoside (2) was also developed
from inexpensive commercially available materials. All reaction steps were carried out
by conventional reagents. The syntheses solve the problems of availabilities of the
phenethyl glycosides for potential biomedical applications, as they are also excellent
starting materials for the synthesis of other potential bioactive molecules.
3. Experimental
3.1. General experimental procedures
Melting points were measured on X-4 digital display microscopic melting point appar-
atus (Tianjin Xintian Optical Analytical Instruments Co. Ltd., Tianjin, China) and are
1
13
€
€
uncorrected. H and C NMR spectra were recorded on Bruker Avance 600 (Bruker
Co., Fallanden, Switzerland) instrument (using tetramethylsilane as the internal stand-
€
€
ard). HR–MS were obtained on a Bruker Apex II mass spectrometer (Bruker Co.,
Bremen, Germany). The solvents were analytical grade and newly distilled before usage.
3.2. General procedures for the synthetic compounds
3.2.1. Synthesis of 2-bromo-4-(2-hydroxyethyl)phenol (6)
To a solution of hydroxyphenethyl alcohol 5 (13.8 g, 0.1 mol) in acetone (150 ml), was
added NaBr (12.3 g, 12 mmol). Then a solution of Oxone in water (10 ml) was added
at 0 ꢁC in a period of 15 min. The reaction mixture was kept at 0 ꢁC and stirred for

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
5
Scheme 5. Synthetic route of compound 4. Reagent and conditions: (a) dichlorosulfoxide, CH3OH,
0 ꢁC, 6 h (b) K2CO3, BnBr, acetone, 60 ꢁC, 4 h; (c) LiAlH4, THF, 0 ꢁC, 3 h; (d) compound 13, 4 Å
molecular sieves, TMSOTf, ꢀ78 ꢁC to 0 ꢁC, 30 min; (e) 10% Pd/C, H2, THF, CH3OH, room tempera-
ture, 24 h; (f) CH3ONa, CH3OH, Amberlite IR 120, room temperature, 1.5h.
1.5 h. The reaction was quenched by Na2S2O3 and extracted with ethyl acetate
(3 ꢂ 100 ml). The combined organic layers were washed with brine (100 ml), dried
over Na2SO4, and evaporated in vacuo. The crude residue was crystallized from ethyl
acetate/n-hexane to give pure 6 as crystals (19.4 g, 89% yield), m.p. 88–90 ꢁC. flit.
1
[15] m.p. 91–93 ꢁCg. H NMR (600 MHz, CDCl3) d: 7.33 (d, J ¼ 2.1 Hz, 1H), 7.07
(dd, J ¼ 8.3, 2.1 Hz, 1H), 6.95 (d, J ¼ 8.3 Hz, 1H), 5.44 (s, 1H, –OH), 3.81 (dd,
J ¼ 12.3, 6.5 Hz, 2H), 2.77 (t, J ¼ 6.5 Hz, 2H); 13C NMR (150 MHz, CD3OD) d: 152.6,
133.4, 132.3, 129.6, 116.6, 109.6, 62.66, 38.1.
3.2.2. Synthesis of 4-(2-hydroxyethyl)-2-methoxyphenyl (7)
To a solution of compound 6 (15 g, 69.1 mmol) in DMF (20 ml) was added CuBr
(1.0 g, 6.9 mmol) and 1.5 ml solution of 25% CH3ONa/CH3OH. The reaction mixture
was heated at 90 ꢁC and kept under magnetic stirring for 3 h, quenched with 2 M
HCl, and diluted with H2O. The solution was extracted with ethyl acetate
(3 ꢂ 150 ml), and the organic layers were collected, washed with brine, dried over
Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography
using ethyl acetate/petroleum ether 1:4 as eluent to give pure 7 12.6 g, yield 87.6%,
1
m.p. 55–58 ꢁC. flit. [16] m.p. 62–65 ꢁCg. H NMR (600 MHz, CDCl3) d: 6.84 (d,
J ¼ 7.8 Hz, 1H), 6.71–6.70 (m, 2H), 5.64 (s, 1H, –OH), 3.86 (s, 3H), 3.81 (t,
J ¼ 6.5 Hz, 2H), 2.78 (t, J ¼ 6.5 Hz, 2H). 13C NMR (150 MHz, CDCl3) d: 146.7, 144.3,
130.3, 121.7, 114.6, 111.7, 63.9, 55.9, 38.8.

6
H.-B. DONG ET AL.
3.2.3. Synthesis of 4-(2-hydroxyethyl)-2-methoxyphenol acetate (8)
Compound 7 (2.76 g, 20 mmol) was added to a stirred solution of 6 ml 6 M NaOH.
Then the temperature of the system was decreased to 0 ꢁC, and acetic anhydride
(2.45 g, 24 mmol) was added slowly over 40 min under vigorously stirring with the
pH maintained at 7–8. The addition was exothermic, and the temperature was no
more than 10 ꢁC. The solution was extracted three times with EtOAc (3 ꢂ 20 ml), and
the combined organic solutions were washed with brine, dried over Na2SO4, and then
concentrated in vacuo to get a colorless oil compound 8 2.15 g (yield 78%) which is
1
pure enough for the next step. H NMR (600 MHz, CDCl3) d: 6.95 (d, J ¼ 8.0 Hz,
1H), 6.82 (d, J ¼ 1.9 Hz, 1H), 6.79 (dd, J ¼ 8.0, 1.9 Hz, 1H), 3.86–3.83 (m, 2H), 2.84
(t, J ¼ 6.5 Hz, 2H), 2.83 (s, 3H), 2.30 (s, 3H). 13C NMR (150 MHz, CDCl3) d: 169.6,
150.9, 138.2, 137.9, 122.7, 121.2, 113.3, 63.5, 55.9, 39.1, 20.8.
3.2.4. Synthesis of b-D-glucose pentaacetate (11)
A mixture of dextrose 10 (5.0 g, 27.7 mmol) and sodium acetate (6.83 g, 83.3 mmol)
was dissolved in acetic anhydride (43 ml, 0.46 mol). The reaction mixture was refluxed
for 4 h at 90 ꢁC. After the reaction time, the reaction mixture was cooled to r.t. and
then poured into the beaker containing crushed ice (250 ml) under stirring condi-
tions. The penta-acetate was precipitated. The precipitation was filtered and washed
with ice-cold water until the odor of the acetic acid disappeared. The crude product
was purified by recrystalization from MeOH to afford the title compound 11 (9.96 g,
92%) as a white crystalline solid, m.p. 130–135 ꢁC. flit. [17] m.p. 130–135 ꢁCg.
3.2.5. Synthesis of 2,3,4,6-tetra-O-acetyl-D-glucopyranose (12)
Hydrazine acetate (2.0 g, 22.6 mmol) was added to a solution of glucopyranoside 11
(8 g, 10.3 mmol) in N,N-dimethylformamide (DMF, 60 mL) at 50 ꢁC and the reaction
was stirred for 2 h under N2. Then the mixture was diluted with EtOAc, washed with
aqueous 5% NaCl and water, dried over anhydrous Na2SO4, and concentrated to give
yellow oil. This crude oil was subjected to silica gel column chromatography. The
residue was purified by flash chromatography using ethyl acetate/hexane 1:2 as eluent
to give 12 (92%, 6.5 g) as a colorless oil.
3.2.6. Synthesis of O-(2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl)trichloroacetimidate
(13)
Compound 12 (7 g, 20 mmol) was treated with trichloroacetonitrile (28.4 g, 200 mmol)
and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.5 ml, 20 mmol) in anhydrous CH2Cl2
(150 ml) and stirred for 2 h at r.t. After 2 h, the reaction mixture was concentrated
under reduced pressure and purified by silica gel column chromatography. The
required product was eluted in petroleum ether: EtOAc (4:1, v/v) solvent mixture,
and 13 was isolated as an yellow oil (7.3 g, 73%), [a]20 þ60.2 (c 1.5, CHCl3). flit.
D
[18] [a]20 þ67.2 (c 1.0, CHCl3)g. H NMR (600 MHz, CDCl3) d: 8.66 (s, 1H), 6.47
1
D
(d, J ¼ 3.7 Hz, 1H), 5.47 (t, J ¼ 9.9 Hz, 1H), 5.13–5.07 (m, 1H), 5.05 (dd, J ¼ 10.2,
3.7 Hz, 1H), 4.19 (dd, J ¼ 12.5, 4.2 Hz, 1H), 4.13 (ddd, J ¼ 10.3, 4.2, 2.2 Hz, 1H),
4.02–4.07 (m, 1H), 1.99 (s, 3H), 1.97 (s, 3H), 1.95 (s, 3H), 1.93 (s, 3H).

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
7
3.2.7. Synthesis of (2R,3R,4S,5R,6R)-2-(4-acetoxy-3-methoxyphenethoxy)-6-(acetoxy-
methyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (9)
A mixture of 8 (0.336 g, 1.6 mmol), 13 (1.47 g, 3 mmol), and 4 Å molecular sieves
(1.0 g) was added to dry CH2Cl2 (30 ml) under argon atmosphere at ꢀ78 ꢁC. The
mixture was stirred for 30 min and TMSOTf (cat., 10 ll) was added. Then the stirring
was continued for further 30 min after which the temperature was brought up to
0 ꢁC. The reaction mixture was neutralized by the addition of Et3N and concentrated.
The crude product was purified by column chromatography (petroleum ether: EtOAc
1
1:2 V/V) to give 9 (0.73 g, 85%) as a colorless oil, [a]20 ꢀ40.2 (c 1.3, CHCl3). H
D
NMR (600 MHz, CDCl3) d: 6.89 (d, J ¼ 8.0 Hz, 1H), 6.77 (d, J ¼ 1.8 Hz, 1H), 6.72 (dd,
J ¼ 8.0, 1.8 Hz, 1H), 5.14 (t, J ¼ 9.7 Hz, 1H), 5.05 (t, J ¼ 9.7 Hz, 1H), 4.96 (dd, J ¼ 9.7,
8.0 Hz, 1H), 4.45 (d, J ¼ 8.0 Hz, 1H), 4.24 (dd, J ¼ 12.3, 4.7 Hz, 1H), 4.14–4.09 (m,
2H), 3.80 (s, 3H), 3.68–3.63 (m, 1H), 3.63–3.59 (m, 1H), 2.85–2.83(m, 2H), 2.26 (s,
3H), 2.06 (s, 3H), 1.99 (s, 3H), 1.96 (s, 3H), 1.85 (s, 3H); 13C NMR (150 MHz,
CDCl3) d: 171.2, 170.8, 169.7, 169.2, 169.1, 150.8, 138.2, 137.8, 122.6, 121.1, 113.4,
96.8, 72.9, 69.8, 68.3, 66.8, 64.2, 63.2, 55.9, 36.1, 20.9, 20.8, 20.8, 20.7, 20.6.
3.2.8. Synthesis of (2R,3R,4S,5S,6R)-2-(4-hydroxy-3-methoxyphenethoxy)-6-(hydrox-
ymethyl)tetrahydro-2H-pyran-3,4,5-triol (2)
To a solution of 9 (0.73 g,1.35 mmol) in CH3OH (20 ml) was added the solution of
CH3ONa (150 mg, 3 mmol) at 0 ꢁC. The mixture was stirred at room temperature for
1.5 h. After the reaction was completed (detected by TLC), Amberlite IR 120 (3 g)
was added and stirred for another 20 min. Then the mixture was filtered and evapo-
rated to give a solid residue, which was recrystallized from alcohol to get white pow-
der compound 2 in 90% yield, m.p. 150–155 ꢁC, [a]20 ꢀ20.2 (c 1.0, CH3OH). flit.
D
[10] [a]25 ꢀ12.5 (c 0.13, CH3OH)g. 1H NMR (600 MHz, CD3OD) d: 6.85 (d,
D
J ¼ 1.8 Hz, 1H), 6.71 (d, J ¼ 8.0 Hz, 1H), 6.67 (dd, J ¼ 8.0, 1.8 Hz, 1H), 4.31 (d,
J ¼ 7.8 Hz, 1H), 4.02–4.07 (m, 1H), 3.87 (dd, J ¼ 11.9, 1.7 Hz, 1H), 3.83 (s, 3H),
3.80–3.60 (m, 2H), 3.42–3.15 (m, 4H), 2.92–2.78 (m, 2H); 13C NMR (150 MHz,
CD3OD) d: 148.8, 145.9, 131.6, 122.5, 116.1, 113.8, 104.3, 78.1, 77.9, 75.1, 72.0, 71.7,
62.8, 56.5, 36.9. HR-ESI-MS: m/z 331.1390 [M þ H]þ (calcd for C15H23O8, 331.1387).
3.2.9. Synthesis of 2-(3,4-dimethoxyphenyl)ethan-1-ol (14)
To a mixture of 7 (1.68 g, 10 mmol), NaH (0.24 g, 10 mmol) in 20 ml dry DMF, a
solution of CH3I (2.16 g, 15 mmol) in 10 ml DMF was added in 20 min. Then the stir-
ring was continued for further 10 min. The reaction was quenched by water (20 ml),
extracted with ethyl acetate (3 ꢂ 50 ml), and the organic layers were collected, washed
with brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by
flash chromatography using ethyl acetate/petroleum ether 1:4 as eluent, to give pure
1
14 (1.70 g, 93%) as a colorless oil. H NMR (600 MHz, CD3OD) d: 6.80–6.77 (m,
2H), 6.68–6.66 (m, 1H), 3.69 (s, 3H), 3.66 (s, 3H), 3.55 (t, J ¼ 7.3 Hz, 2H), 2.62 (t,
J ¼ 7.3 Hz, 2H); 13C NMR (150 MHz, CD3OD) d: 149.0, 147.6, 132.5, 121.2, 113.3,
112.3, 62.9, 56.0, 55.9, 39.2.

8
H.-B. DONG ET AL.
3.2.10. Synthesis of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(3,4-dimethoxyphene-
thoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (15)
The procedure was the same as compound 8 in Section 3.2.7 from compound 14 to
afford a light yellow solid 15 in 78% yield, m.p. 100–103 ꢁC, [a]20 ꢀ33.0 (c 0.8,
D
1
CHCl3). H NMR (600 MHz, CDCl3) d: 6.76–6.74 (m, 1H), 6.70–6.68 (m, 2H), 5.14
(t, J ¼ 9.5 Hz, 1H), 5.05 (t, J ¼ 8.0 Hz, 1H), 4.96 (dd, J ¼ 9.5, 8.0 Hz, 1H), 4.45 (d,
J ¼ 8.0 Hz, 1H), 4.23 (dd, J ¼ 12.3, 4.7 Hz, 1H), 4.12–4.04 (m, 2H), 3.84 (s, 3H), 3.81
(s, 3H), 3.65 (ddd, J ¼ 10.0, 4.6, 2.4 Hz, 1H), 3.60 (dt, J ¼ 9.5, 7.3 Hz, 1H), 2.79 (t,
J ¼ 6.8 Hz, 2H), 2.05 (s, 3H), 1.98 (s, 3H), 1.96 (s, 3H), 1.85 (s, 3H); 13C NMR
(150 MHz, CDCl3) d: 170.8, 170.4, 169.5, 169.2, 150.8, 138.2, 137.5, 122.5, 121.1 113.5,
100.9, 72.8, 71.9, 71.1, 70.6, 68.5, 62.0, 55.9, 55.9, 35.9, 20.8, 20.7, 20.7, 20.5.
3.2.11. Synthesis of (2R,3R,4S,5S,6R)-2-(3,4-dimethoxyphenethoxy)-6-(hydroxyme-
thyl)tetrahydro-2H-pyran-3,4,5-triol (3)
The procedure was the same as compound 2 in Section 3.2.8 from compound 15 to
afford a light yellow oil 3 in 90% yield, [a]20 ꢀ28.2 (c 1.0, CH3OH). flit. [7] [a]D
D
1
ꢀ20.1 (CH3OH)g H NMR (600 MHz, CD3OD) d: 6.85 (d, J ¼ 1.7 Hz, 1H), 6.79 (d,
J ¼ 8.2 Hz, 1H), 6.74 (dd, J ¼ 8.2, 1.7 Hz, 1H), 4.29 (d, J ¼ 7.8 Hz, 1H), 4.04 (dt,
J ¼ 9.4, 7.6 Hz, 1H), 3.85 (dd, J ¼ 11.9, 1.8 Hz, 1H), 3.76 (s, 3H), 3.73 (s, 3H),
3.72–3.63 (m, 2H), 3.38–3.19 (m, 4H), 2.85–2.82 (m, 2H); 13C NMR (150 MHz,
CD3OD) d: 148.9, 147.6, 131.7, 121.0, 112.7, 111.7, 103.0, 76.7, 76.5, 73.8, 70.5, 70.3,
61.5, 55.3, 55.2, 35.4. HR-ESI-MS: m/z 345.1541 [M þ H]þ (calcd for
C16H25O8, 345.1544).
3.2.12. Synthesis of methyl 2-(3-hydroxy-4-methoxyphenyl)acetate (20)
To a stirred solution of 3-(3-hydroxy-4-methoxyphenyl)propanoic acid 19 (5.0 g,
25.5 mmol) in 100 ml CH3OH was added dichlorosulfoxide (5 ml) at 0 ꢁC. After stir-
ring for 6 h at 0 ꢁC, the solution was diluted with ether (200 ml) and washed with
water (100 ml). The aqueous layer was then further extracted with ether (2 ꢂ 50 ml),
and the combined organic extracts were dried (Na2SO4), filtered, and concentrated in
1
vacuo to provide yellow oil 20 (4.8 g, 84%). H NMR (600 MHz, CDCl3) d: 6.85–6.84
(m, 1H), 6.77–6.71 (m, 2H), 3.80 (s, 3H), 3.65 (s, 3H), 3.51 (s, 2H); 13C NMR d:
172.4, 145.9, 145.7, 127.1, 120.8, 115.7, 110.9, 55.9, 52.0, 40.5.
3.2.13. Synthesis of methyl 2-(3-benzyloxy-4-methoxyphenyl)acetate (21)
To a stirred solution of compound 20 (1.5 g, 7.14 mmol) and K2CO3 (3.41 g,
24.7 mmol) in 20 ml acetone was added BnBr (1.41 ml, 11.7 mmol) dropwise at room
temperature. After stirring for 4 h at 60 ꢁC, the solution was diluted with CH2Cl2
(50 ml) and washed with water (50 ml). The aqueous layer was then further extracted
with CH2Cl2 (2 ꢂ 50 ml), and the combined organic extracts were dried (Na2SO4), fil-
tered, and concentrated in vacuo to get white solid compound 21 (2.3 g, 81%), m.p.
58–61 ꢁC. 1H NMR (600 MHz, CDCl3) d: 7.45–7.43 (m, 2H), 7.38–7.34 (m, 2H),
7.31–7.29 (m, 1H), 6.85–6.83 (m, 3H), 5.13 (s, 2H), 3.86 (s, 3H), 3.64 (s, 3H), 3.51 (s,
2H); 13C NMR (150 MHz, CDCl3) d: 172.2, 148.9, 148.2, 137.1, 128.5, 127.8, 127.4,
126.4, 122.0, 115.1, 111.9, 71.0, 56.1, 52.0, 40.7.

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
9
3.2.14. Synthesis of 2-(3-benzyloxy-4-methoxyphenyl)ethan-1-ol (22)
A mixture of 21 (1.5 g, 5 mmol) and LiAlH4 (0.57 g, 15 mmol) was added to dry THF
(30 ml) under argon atmosphere at 0 ꢁC. The mixture was stirred for 3 h. After reac-
tion was completed (detected by TLC), 20 ml water was added to quench the reaction.
Then the mixture was extracted with EtOAc (50 ml ꢂ3). The organic phase was com-
bined and washed with brine, dried over Na2SO4, evaporated under vacuum to give
compound 22 (1.03 g, 80% yield) as an colorless solid, m.p.70–72 ꢁC. flit. [19] m.p.
80–80.5 ꢁCg. 1H NMR (600 MHz, CDCl3) d: 7.43 (d, J ¼ 7.5 Hz, 2H), 7.35 (t,
J ¼ 7.5 Hz, 2H), 7.30–7.29 (m, 1H), 6.84 (d, J ¼ 8.0 Hz, 1H), 6.77–6.76 (m, 2H), 5.14
(s, 2H), 3.86 (s, 3H), 3.76 (q, J ¼ 6.3 Hz, 2H), 2.74 (t, J ¼ 6.3 Hz, 2H); 13C NMR
(150 MHz, CDCl3) d: 148.5, 148.2, 137.2, 130.9, 128.6, 127.9, 127.5, 121.7, 115.2,
112.1, 71.1, 63.8, 56.2, 38.7.
3.2.15. Synthesis of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-[3-(benzyloxy)-4-methoxy-
phenethoxy]tetrahydro-2H-pyran-3,4,5-triyl triacetate (23)
Compound 23 was get with a similar approach to compound 8 (yield 90%), m.p.
1
135–137 ꢁC, [a]20 ꢀ14.8 (c 0.7, CHCl3). H NMR (600 MHz, CDCl3) d: 7.44 (d,
D
J ¼ 7.4 Hz, 2H), 7.35 (t, J ¼ 7.4 Hz, 2H), 7.29 (d, J ¼ 7.4 Hz, 1H), 6.79 (d, J ¼ 8.0 Hz,
1H), 6.75–6.70 (m, 2H), 5.19–5.04 (m, 4H), 4.97 (dd, J ¼ 9.6, 8.0 Hz, 1H), 4.42 (d,
J ¼ 8.0 Hz, 1H), 4.25 (dd, J ¼ 12.3, 4.6 Hz, 1H), 4.11 (dd, J ¼ 12.2, 2.2 Hz, 1H), 4.04
(dt, J ¼ 9.4, 6.3 Hz, 1H), 3.84 (s, 3H), 3.65 (ddd, J ¼ 10.0, 4.6, 2.2 Hz, 1H), 3.56 (dt,
J ¼ 9.3, 7.4 Hz, 1H), 2.76 (t, J ¼ 6.5 Hz, 2H), 2.06 (s, 3H), 2.04 (s, 3H), 1.98 (s, 3H),
1.87 (s, 3H); 13C NMR (150 MHz, CDCl3) d: 170.8, 170.4, 169.5, 169.4, 148.3, 148.0,
137.3, 131.0, 128.6, 127.9, 127.5, 121.6, 115.2, 111.9, 100.9, 72.8, 71.9, 71.1, 71.0
(2 ꢂ C), 68.5, 62.0, 56.2, 35.5, 20.9, 20.7, 20.7, 20.6.
3.2.16. Synthesis of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(3-hydroxy-4-methoxy-
phenethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (24)
A suspension of 23 (100 mg, 0.17 mmol) and palladium (20 mg, 10 wt.% on activated
carbon) in THF (3 ml) and CH3OH (30 ml) was stirred at room temperature under
hydrogen gas atmosphere for 24 h. After the reaction was completed, the mixture was
filtered through a pad of Celite. The filtrate was then concentrated in vacuo to get
1
compound 24 (80 mg, 90%) as a colorless oil, [a]20 ꢀ28.8 (c 0.1, CHCl3). H NMR
D
(600 MHz, CDCl3) d: 6.75–6.73 (m, 2H), 6.64 (dd, J ¼ 8.1, 2.1 Hz, 1H), 5.16 (t,
J ¼ 9.5 Hz, 1H), 5.13–5.02 (m, 1H), 4.98 (dd, J ¼ 9.5, 8.0 Hz, 1H), 4.46 (d, J ¼ 8.0 Hz,
1H), 4.24 (dd, J ¼ 12.3, 4.7 Hz, 1H), 4.12 (dd, J ¼ 12.3, 2.4 Hz, 1H), 4.08–4.04 (m,
1H), 3.84 (s, 3H), 3.66 (ddd, J ¼ 10.0, 4.7, 2.4 Hz, 1H), 3.61 (dt, J ¼ 9.6, 7.3 Hz, 1H),
2.89–2.63 (m, 2H), 2.07 (s, 3H), 2.00 (s, 3H), 1.98 (s, 3H), 1.94 (s, 3H); 13C NMR
(150 MHz, CDCl3) d: 170.8, 170.4, 169.5, 169.5, 145.5, 145.2, 131.8, 120.5, 115.2,
110.7, 100.8, 72.9, 71.9, 71.2, 70.9, 68.5, 62.0, 56.0, 35.4, 20.8, 20.7, 20.7, 20.6.
3.2.17. Synthesis of (2R,3R,4S,5S,6R)-2-(3-hydroxy-4-methoxyphenethoxy)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (4)
Compound 4 was obtained with a similar approach to compound 2 (yield 91%) as a
colourless oil, [a]20 ꢀ17.3 (c 0.07, CH3OH), flit. [20] [a]31 ꢀ12.9 (0.33, CH3OH)g.
D
D

10
H.-B. DONG ET AL.
1H NMR (600 MHz, CD3OD) d: 6.83 (d, J ¼ 8.2 Hz, 1H), 6.75 (d, J ¼ 2.1 Hz, 1H), 6.70
(dd, J ¼ 8.2, 2.1 Hz, 1H), 4.31 (d, J ¼ 7.8 Hz, 1H), 4.08–4.04 (m, 1H), 3.88 (dd,
J ¼ 11.9, 2.1 Hz, 1H), 3.83 (s, 3H), 3.75–3.66 (m, 2H), 3.39–3.36 (m, 1H), 3.33–3.32
(m, 1H), 3.30–3.27 (m, 1H), 3.21 (dd, J ¼ 9.1, 7.9 Hz, 1H), 2.88–2.77 (m, 2H); 13C
NMR (150 MHz, CD3OD) d: 146.1, 146.0, 131.5, 119.8, 115.7, 111.5, 103.0, 76.7, 76.5,
73.7, 70.5, 70.2, 61.3, 55.1, 35.2. HR-ESI-MS: m/z 331.1395 [M þ H]þ (calcd for
C15H23O8, 331.1387).
Disclosure statement
No potential conflict of interest was reported by the author(s).
References
[1] G.X. Mao, H.B. Deng, L.G. Yuan, D.D. Li, Y.Y.Y. Li, and Z. Wang, Biomed. Environ.
Sci. 23, 161 (2010).
[2] J.F. Ouyang, J. Lou, C. Yan, Z.H. Ren, H.X. Qiao, and D.S. Hong, J. Pharm. Pharmacol.
62, 530 (2010).
[3] A. Bonanome, Nutr. Metab. Cardiovasc. Dis. 10, 111 (2000).
[4] S.N. Udintsev and V.P. Schakhov, Eur. J. Cancer 27, 1182 (1991).
[5] J. Zhang, A. Liu, R. Hou, J. Zhang, X. Jia, W. Jiang, and J. Chen, Eur. J. Pharm. 607, 6
(2009).
[6] D.G. Marina, F. Maria, F. Antonio, M. Pietro, and P. Lucio, Phytochemistry 49, 1299
(1998).
[7] K. Endo, T. Kazuhiro, A. Toyoko, and H. Hiroshi, Heterocycles 16, 1311 (1981).
[8] K. Tetsuya, H. Mitsuharu, S. Kayoko, and N. Toshihiro, Phytochemistry 28, 2701
(1989).
[9] C.Q. Fan and J.M. Yue, Bioorg. Med. Chem. 11, 703 (2003).
[10] S.D. Marino, N. Borbne, F. Zollo, A. Iannaro, P.D. Meglio, and M. Iorizzi, J. Agric.
Food Chem. 52, 7525 (2004).
[11] Z. Cheng, G. Yibing, M. Ying, D.S. Feng, S. Jian, and Y.Y. Min, Indian J. Chem. B 52,
654 (2013).
[12] G. Yibing, Z. Cheng, X. Wen, S. Yongxing, D. Sufeng, and Y. Yumin, Med. Chem. Res.
22, 2524 (2013).
[13] P. Bovicelli, F. Bottaro, C. Sappino, M. Tomei, V. Nardi, I. Proietti Silvestri, B. Macchi,
C. Frezza, and G. Righi, Synth. Commun. 46, 242 (2016).
[14] V. Srikanth, R.B.N. Prasad, Y. Poornachandra, V.S. Phani Babu, C. Ganesh Kumar, B.
Jagadeesh, and R.C.R. Jala, Eur. J. Med. Chem. 109, 134 (2016).
[15] S.I. Sviridov, A.A. Vasil’ev, N.L. Sergovskaya, M.V. Chirskaya, and S.V. Shorshnev,
Tetrahedron 62, 2639 (2006).
[16] S. Cardinal, J. Azelmat, D. Grenier, and N. Voyer, Bioorg. Med. Chem. Lett. 26, 440
(2016).
[17] N. Michihata, Y. Kaneko, Y. Kasai, K. Tanigawa, T. Hirokane, S. Higasa, and H.
Yamada, J. Org. Chem. 78, 4319 (2013).
[18] S.M. Andersen, M. Heuckendorff, and H.H. Jensen, Org. Lett. 17, 944 (2015).
[19] T. Fujii, M. Ohba, and J. Sakaguchi, Chem. Pharm. Bull. 35, 3628 (1987).
[20] Y. Kikuchi, Y. Miyaichi, Y. Yamaguchi, H. Kizu, and T. Tomimori, Chem. Pharm. Bull.
39, 1047 (1991).