First total syntheses of two natural glycosides

Article abstract of DOI:10.1016/j.carres.2020.108200

Isosyringinoside (1) and 3-(O-β-_D-glucopyranosyl)-α-(O-β-_D-glucopyranosyl)-4-hydroxy phenylethanol (2), the natural bioactive compounds contained unique structures, were first totally synthesized using easily available materials in short convenient routes with overall yields of 20.2% and 27.0%, respectively. An efficient total synthesis of 1 was developed in six steps, which contained two key steps of highly regioselective glycosylation without any selective protection steps. The seven-step synthesis of 2 involved two steps of regioselective glycosylations using BF₃–O(C₂H₅)₂ and TMSOTf as catalysts, respectively.

Full text of DOI:10.1016/j.carres.2020.108200

Journal Pre-proof
First total syntheses of two natural glycosides
Hongbo Dong, Weihong Du, Zhongquan Yao, Min Wu, Hongbing Luo, Yujiao He,
Shenghua Cao
PII:
S0008-6215(20)30571-1
DOI:
https://doi.org/10.1016/j.carres.2020.108200
CAR 108200
Reference:
To appear in: Carbohydrate Research
Received Date: 8 September 2020
Revised Date: 9 November 2020
Accepted Date: 11 November 2020
Please cite this article as: H. Dong, W. Du, Z. Yao, M. Wu, H. Luo, Y. He, S. Cao, First total syntheses of
two natural glycosides, Carbohydrate Research, https://doi.org/10.1016/j.carres.2020.108200.
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Graphical Abstrsct
Two
natural
bioactive
glycosides,
Isosyringinoside
(1)
and
3-(O-β-D-glucopyranosyl)-α-(O-β-D-glucopyranosyl)-4-hydroxy phenylethanol (2), were first
totally synthesized via 6-7 steps with overall yields of 20.2% and 27.0%, respectively.

First total syntheses of two natural glycosides
Hongbo Donga, Weihong Dua, Zhongquan Yaoa, Min Wub, Hongbing Luoa, Yujiao Hea, Shenghua
Caoa
aAntibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial
Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, 610052, China
bSchool of Food and Biological Engineering, Chengdu University, Chengdu, 610052, China
Abstract
Isosyringinoside
(1)
and
3-(O-β-D-glucopyranosyl)-α-(O-β-D-glucopyranosyl)-4-hydroxy
phenylethanol (2), the natural bioactive compounds contained unique structures, were first totally
synthesized using easily available materials in short convenient routes with overall yields of
20.2% and 27.0%, respectively. An efficient total synthesis of 1 was developed in six steps, which
contained two key steps of highly regioselective glycosylation without any selective protection
steps. The seven-step synthesis of 2 involved two steps of regioselective glycosylations using
BF3-O(C2H5)2 and TMSOTf as catalysts, respectively.
Key words
Total synthesis
Glycosides
Isosyringinoside
3-(O-β-D-glucopyranosyl)-α-(O-β-D-glucopyranosyl)-4-hydroxy phenylethanol
- 1 -

1. Introduction
The O-glycoside designates the structure with an aglycone moiety and sugar(s), which are
directly connected through the C−O bond linkage. It is an important kind of organic compounds
that exists widely in nature and encompasses a vast number of secondary metabolites. Members of
O-glycosides embody various range of biological activities, especially antitumor, anti-infective
and immunomodulatory effects [1]. The connection of bioactive aglycones to hydrophilic sugar
rings could improve their pharmacokinetic properties and bioavailabilities in physiological fluids
[2]. Depending on the different glycosidic bonds, the O-glycoside can be classified as phenolic
glycoside and alcoholic glycoside, which show diverse pharmacokinetic and pharmacodynamic
properties.
Figure 1. Structures of compounds 1 and 2
As
shown
in
Figure
1,
natural
products
isosyringinoside
(1)
and
3-(O-β-D-glucopyranosyl)-α-(O-β-D-glucopyranosyl)-4-hydroxy phenylethanol (2) contained
unique structures of both phenolic and alcoholic glycosides. Isosyringinoside (1) was first isolated
in 1993 from bark of Osmanthus asiaticus, which was not only an ornamental plant growing in
southwest China, but also a well-known traditional Chinese herbal medicine [3]. Isosyringinoside
(1) has also been obtained from the fruit of Lycium barbarum L. (Solanaceae) (goji or wolfberry)
[4] and other plants [5]. Due to its novel chemical structure, isosyringinoside (1) exhibited
significant super oxide anion scavenging activity [5e] and triglyceride-lowering effect [5a].
3-(O-β-D-glucopyranosyl)-α-(O-β-D-glucopyranosyl)-4-hydroxy phenylethanol (2) was first
isolated from aerial parts of Teucrium polium L. by Elmasri and co-workers in 2014 [6]. It also
has been obtained from the fruit parts of Chinese folk medicine Sambucus williamsii Hance [7], as
well as Aconitum tanguticum (Maxim) Stapf (Ranunculaceae) [8]. In 2015, Wang and Li
evaluated the anti-inflammatory activity of compound 2 by testing the inhibition of TNF-ɑ
- 2 -

production on LPS-stimulated RAW264.7 macrophages, and it showed certain inhibition activity
with IC50 of 38.18 [8].
Although natural products 1 and 2 exhibit a broad spectrum of interesting biological activities,
the detailed pharmacological studies of these compounds so far have been minimal. Such studies
are limited since glycosides 1 and 2 were isolated in low yields from natural sources, and
syntheses of them and their derivatives were rarely reported. Hence, short and efficient routes to
obtain 1 and 2 are urgently required. We herein report an efficient and scalable methodology to
synthesize natural products 1 and 2, which also can be applied for the synthesis of diverse
derivatives of these molecules in the future.
2. Results and discussion
Figure 2. Retrosynthetic approaches to compounds 1 and 2
Through investigating of their structures, we have noticed that both 1 and 2 contained three
main groups, including two β-D-glucose rings and one phenylpropanoid aglycone (for compound 1)
or phenylethanol aglycone (for compound 2). Hence, highly regioselective glycosylations of these
two different active aglycones would be the key steps of our devising synthetic routes (Figure 2).
As shown in Scheme 1, our strategy for total synthesis of glycoside 1 started from
commercially available Syringaldehyde (3). A 3-step synthesis that utilized Knoevenagel reaction,
ethyl esterification, and LiAlH4 reduction was taken to generate Sinapyl alcohol (6) following the
method that previously reported [9, 10]. With the key intermediate 6 in hand, our synthesis route
towards intermediate
7
was devised by coupling
6
and excess glycosyl donor
2,3,4,6-tetra-O-acetyl-ɑ-D-glucopyranosyl bromide (8), which was readily got in a 3-step sequence
from D-glucose, under Koenigs-Knorr conditions [11]. The reaction was conducted in dry CH2Cl2
for 10 h under dark in the presence of Ag2CO3 and powdered 4 Å MS (molecular sieve) that was
dried at 400 °C for 8 h before usage. However, the attempted double-glycosylation of acceptor 6
- 3 -

with an excessive amount of donor 9 (10 equiv.) provided a complex mixture, from which product
7 could not be isolated.
Scheme 1. Design of Initial Attempt to Prepare Compound 7. Reaction and Conditions: (a)
Malonic acid, pyridine, p-aminotoluene, piperazine, toluene, 80 ºC, 83.7%; (b) p-Toluenesulfonic
acid, alcohol, 75 ºC, 76.5%; (c) LiAlH4, BnCl, THF, room temperature, 82.8%; (d) 4Å MS,
Ag2CO3, CH2Cl2, r.t.
Then the synthetic route was modified. In the modified route, two separate glycosylation
steps were required in order to obtain 7 from 6. As phenolic hydroxyl of 6 could be ionized in the
weak alkali reaction medium while the alcoholic hydroxyl could not, the phenolic hydroxyl of 6
was selectively coupled to acetyl-1-bromoglucose (8) in the presence of K2CO3 and phase transfer
catalyst (PTC, tetrabutylammonium bromide, TBAB) in CH2Cl2-water solvent system without any
protective groups to generate compound 9 successfully [12]. Efforts to obtain 7 from 9 under
Koenigs-Knorr conditions described above, however, gave poor yields (31%). To improve the
yield, we next turned to Schmidt’s trichloroacetimidate procedure. Accordingly, glycosyl donor
trichloroacetimidate 10 was prepared from D-glucose following literature procedure [13].
TMSOTf-promoted glycosylation of compound 9 using 10 proceeded stereoselectively and the
β-anomer of glycoside 7 was obtained in 71.6% yield.
The final deprotection step involving the cleavage of all the acetyl groups by NaOCH3
1
afforded natural product 1 in high yield (75.0%). The H NMR and 13C NMR spectra of the
synthetic compound 1 matched the published data [3].
- 4 -

Scheme 2. Synthesis of Isosyringinoside (1). Reaction and Conditions: (a) Compound 8,
TBAB, K2CO3, CH2Cl2-H2O, r.t., 71.1%; (b) (i) Compound 10, 4Å MS, TMSOTf, CH2Cl2, -80 ºC,
71.6% or (ii) Compound 8, 4Å MS, Ag2CO3, CH2Cl2, r.t., 31.2%; (c) CH3ONa, CH3OH, 75.0%.
As shown in scheme 3, the first step of the total synthesis for natural product 2 was
bromination of 4-hydroxyphenethyl alcohol 11. Using a known method [14], compound 12 was
obtained in 89.4% yield. Then a Cu-catalyzed C-O bond-forming reaction of aryl bromide 12 and
benzyl alcohol was taken to get compound 13, which was subsequently converted to its benzoate
derivative 14 (77.5% yield) using benzoic acid anhydride. The glycosylation of protected
hydroxytyrosol 14 with trichloroacetimidate 10 processed stereoselectively, and the β-anomer of
glycoside 15 was isolated in satisfactory yield (74.0 %).
Scheme 3. Synthesis of 3-(O-β-D-glucopyranosyl)-α-(O-β-D-glucopyranosyl)-4-hydroxy
phenylethanol (2). Reaction and Conditions: (a) NaBr, Oxone, H2O, acetone, 0 ºC; 89.4%; (b) CuI,
K3PO4, 8-hydroxyquinoline, benzyl alcohol, 110 ºC, 85.7%; (c) Benzoic acid anhydride, DMAP,
Et3N, CH2Cl2, 0 ºC, 77.5%; (d) Compound 10, 4Å MS, TMSOTf, CH2Cl2, -78 ºC~-20 ºC, 74.0 %;
- 5 -

(e) 10% Pd/C, H2, CH3OH/THF, 95.8%; (f) Compound 10, 4Å MS, BF3-(CH3CH2O)2, CH2Cl2,
-78 ºC~-20 ºC, 75.6 %; (g) CH3ONa, CH3OH, 84.8%.
In the next step, Pd/C catalytic system under H2 atmosphere was used to deprotect benzyl
protection of phenol to obtain 16 successfully. However, our attempts to glycosylate compound 16
with bromide 4 under the above PTC conditions failed, proving that the hydroxy group of 16 was
much more inert than the phenolic hydroxyl of 6. Instead, compound 16 was treated with
trichloroacetimidate 10 in the presence of BF3-(C2H5)2O, which had been confirmed as a better
catalyst than TMSOTf for formation of phenolic O-glycosylatic bond [15], to get 17 in 75.6%
yield. Finally, the deprotection of the sugar moiety (acetate cleavages) and phenol
(benzoate cleavage) of compound 17 proceeded smoothly and the desired target glycoside 2 was
isolated in high yield (84.8%).
Based on the synthesis routes presented above, the key steps of the processes are different
O-glycosylations, including BF3-O(C2H5)2 and TMSOTf catalyzed glycosylations with 10 and
PTC promoted glycosylation with 8. The glycosylations of these receptors (compounds 6, 9, 14
and 16 ) with glycosyl donors (compounds 8 and 10) led to the desired β-O-glucosides (9, 7, 15
and 17) in complete stereoselectivity with good yields (71.1%-75.6%). The structures of all
β-anomers were confirmed by the presence of a doublet of the anomeric proton with characteristic
vicinal interaction constants (3J1,2 and 3J1’,2’) in the interval of 7.2-8.0 Hz in the 1H NMR spectra.
3. Conclusion
In summary, we have accomplished the first total syntheses of Isosyringinoside (1) and
3-(O-β-D-glucopyranosyl)-α-(O-β-D-glucopyranosyl)-4-hydroxy phenylethanol (2). Synthesis of 1
utilized a six-step sequence from commercially available Syringaldehyde (3) and gave 1 in an
overall yield of 20.2%. Compound 2 was obtained via a seven-step synthesis route in the overall
yield of 27.0%. This efficient and scalable methodology should be of benefit for further biological
investigations on this kind of natural products.
4. Experimental
4.1 General experimental procedure.
Melting points were measured on X-4 digital display microscopic melting point apparatus
1
(Tianjin Xintian Optical Analytical Instruments Co. Ltd. Tianjin, China) and are uncorrected. H
NMR and 13C NMR spectra were recorded on Bruker Avance 400 (Bruker Co., Fallanden,
- 6 -

Switzerland) instrument or JEOL Eclips-600 (Japan Electronics Co. Ltd. Tokyo, Japan). Optical
rotations were recorded on a Jasco P-1020 prolarimeter. HR-MS were obtained on Bruker Apex II
mass spectrometer (Bruker Co., Bremen, Germany). The solvents were analytical grade and newly
distilled before usage.
4.2 3-(4-Hydroxy-3,5-dimethoxyphenyl)acrylic acid (4)
A mixture of 4-hydroxy-3,5-dimethoxybenzaldehyde (3, 10 g, 54.9 mmol) , malonic acid
(6.29 g, 60.4 mmol), pyridine (3.62 g, 45.7 mmol), p-aminotoluene (0.59 g,0.55 mmol) and
piperazine (0.1 g, 1.1 mmol) in toluene (150 ml) was stirred at 80 ºC for 3 h. After the mixture
was cooled to room temperature, a solution of aq. 25% K2CO3 (75 ml) was added and the mixture
was stirred for another 10 min. Then separated, the aqueous layer was adjusted to pH 2.5 with
conc. HCl and the powder precipitated from the aqueous solution was collected by filtration and
washed with water to give the compound 4 (10.3 g, 83.7% yield) as a light yellow powder. M.p.
193.5-195.0 ºC. 1H NMR (DMSO-d6) δ: 12.16 (s, 1H, -COOH), 8.93 (s, 1H, Ph-OH), 7.49 (d, J =
15.8 Hz, 1H, -CH=CH-), 6.99 (s, 2H, -PhH), 6.42 (d, J = 15.8 Hz, 1H, -CH=CH-), 3.80 (s, 6H,
-OCH3). 13C NMR (DMSO-d6) δ: 167.9 (-CO), 147.9, 144.8 (-CH=CH-), 137.9, 124.5, 116.0
1
(-CH=CH-), 105.9, 56.0 (-OCH3). H NMR and 13C NMR are in agreement with the reported
values [10].
4.3 Ethyl 3-(4-hydroxy-3,5-dimethoxyphenyl)acrylate (5)
A solution of 4 (10.3 g, 45.9 mmol) and p-toluenesulfonic acid (0.79 g, 4.6 mmol) in alcohol
(100 ml) was heated at 75 ºC for 20 h. After the mixture was cooled to room temperature, alcohol
was removed by evaporation under reduced pressure. The residue was dissolved in EtOAc (200 ml)
and washed with aq. 5 % Na2CO3 and brine, then evaporated in vacuo and recrystallized from
EtOAc and n-hexane (V/V, 1:10) to afford compound 5 (8.8 g, 76.5% yield) as a white solid. M.p.
83.2-86.5 ºC. 1H NMR (CDCl3) δ: 7.60 (d, J = 15.9 Hz, 1H, -CH=CH-), 6.77 (s, 2H, Ph-H), 6.31
(d, J = 15.9 Hz, 1H, -CH=CH-), 4.26 (q, J = 7.1 Hz, 2H, -OCH2-), 3.91 (s, 6H, -OCH3), 1.34 (t, J
= 7.1 Hz, 3H, -CH3). 13C NMR (CDCl3) δ: 167.2 (-CO), 147.2, 144.9 (-CH=CH-), 137.1, 125.9,
1
115.9 (-CH=CH-), 105.0, 60.4 (-OCH2-), 56.3 (-OCH3), 14.4 (-CH3). H NMR and 13C NMR are
in agreement with the reported values [16].
4.4 4-(3-hydroxyprop-1-en-1-yl)-2,6-dimethoxyphenol (6)
- 7 -

To a stirred suspension of LiAlH4 (0.57 g, 15 mmol) in dry THF (40 ml), a solution of BnCl
(1.98 g, 15 mmol) in dry THF (10 ml) was added. After the suspension was stirred for 15 min. A
solution of 5 (2.52 g, 10 mmol) in dry THF (15 ml) was added dropwise at r.t. Then the reaction
mixture was stirred for 1.5 h. After reaction was completed (detected by TLC), 20 ml water was
added to quench the reaction. Then the mixture was extracted with EtOAc (50 ml ×3). The organic
phase was combined and washed with brine, dried over Na2SO4, evaporated under vacuum to give
crude product 6 (1.74 g, 82.8% yield) as an colourless oil. Compound 6 can be introduced to next
step without further purification.
4.5 (E)-4-(3-hydroxyprop-1-enyl)-2,6-dimethoxyphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosi
de (9)
To a solution of 6 (1.5 g, 7.1 moml) in CH2Cl2 (25 ml) was added aq. 20% K2CO3 (15 ml)
and TBAB (2.3 g, 7.1 mmol), then the mixture stirred vigorously at room temperature for 10 min.
After that compound 8 (4.4 g, 10.7 mmol) was added and stirred at room temperature for anther 5
h. The mixture was diluted with CH2Cl2 (100 ml), washed with brine, and dried over MgSO4. The
solvent was evaporated under vacuum. The residue was purified by chromatography on silica gel
(gradient eluent of EtOAc/petroleum ether, 1:1) to give compound 9 (2.7 g, 71.1% yield) as a light
1
yellow solid. M.p. 76.0-79.6 ºC. [ɑ]D -28 º (c = 0.11, CHCl3). H NMR (CDCl3) δ: 6.60 (s, 2H,
Ph-H), 6.53 (d, J = 15.9 Hz, 1H, -CH2=CH2-), 6.29 (dt, J = 15.9, 5.6 Hz, 1H, -CH2=CH2-),
5.41-5.20 (m, 3H, H-2, H-3, H-4), 5.07 (d, J = 7.2 Hz, 1H, H-1), 4.32 (d, J = 5.6 Hz, 2H,
-CH2OH), 4.26 (dd, J = 12.2, 5.0 Hz, 1H, H-6a), 4.12 (dd, J = 12.2, 2.5 Hz, 1H, H-6b), 3.83 (s, 6H,
-OCH3), 3.69 (ddd, J = 9.1, 5.0, 2.5 Hz, 1H, H-5), 2.04-2.03 (m, 12H, -Ac). 13C NMR (CDCl3) δ:
170.7 (-CO), 170.5 (-CO), 169.5(-CO), 169.4(-CO), 153.0, 134.1, 133.7, 130.5, 128.8, 103.7,
101.3 (C-1), 73.0, 72.0, 71.9, 68.5, 63.4, 62.3, 56.2 (-OCH3), 20.7 (-CH3), 20.7 (-CH3), 20.7
(-CH3), 20.6 (-CH3). 1H NMR and 13C NMR are in agreement with the reported values [17].
4.6 (E)-4-[3-(2,3,4,6-tetra-O-acetyl-D-glucopyranosyloxy)prop-1-enyl]-2,6-dimethoxyphenyl 2,3,
4,6-tetra-O-acetyl-β-D-glucopyranoside (7)
A mixture of trichloroacetimidate 10 1.82 g (3.7 mmol) and compound 9 1.32 g (2.4 mmol)
and activated 4 Å molecular sieves (2 g) in DCM (20 mL) was stirred for 30 min at −20 °C under
argon atmosphere, then cooled to −78 °C and TMSOTf (cat., 0.05 ml) was added and the stirring
was continued for further 30 min after which the temperature was brought up to −20 °C. The
- 8 -

reaction mixture was neutralized by addition of Et3N, washed with brine, dried with anhydrous
Na2SO4 and evaporated in vacuo. The crude product was purified by column chromatography
(EtOAc/petroleum ether, 1:2) to give a colourless oil 7 1.44 g (71.6%). [ɑ]D -13 º (c = 0.13,
1
CHCl3). ESIHRMS m/z 871.2847 [M+H]+ (calcd for C39H51O22+ 871.2866). H NMR (CDCl3) δ:
6.56 (s, 2H, Ph-H), 6.47 (d, J = 15.8 Hz, 1H, -CH2=CH2-), 6.12 (dt, J = 15.8, 5.6 Hz, 1H,
-CH2=CH2-), 5.33-5.16 (m, 4H, H-2, H-4, H-2’, H-4’,), 5.10 (t, J = 9.7 Hz, 1H, H-3), 5.05-5.03 (m,
2H, H-3’, H-1), 4.59 (d, J = 7.9 Hz, 1H, H-1’), 4.47 (m, 1H, H-6a’), 4.24-4.22 (m, 2H, H-6b’,
H-6a), 4.16-4.13 (m, 1H, H-6b), 4.11-4.08 (m, 2H, -CH2O-), 3.80 (s, 6H, -OCH3), 3.72-3.61 (m,
2H, H-5, H-5’), 2.06 (s, 3H, -Ac), 2.03 (s, 3H, -Ac), 2.02 (s, 3H, -Ac), 2.01 (s, 3H, -Ac), 2.01 (s,
6H, -Ac), 2.00 (s, 3H, -Ac), 1.99 (s, 3H, -Ac). 13C NMR (CDCl3) δ: 170.8 (-CO), 170.7 (-CO),
170.5 (-CO), 170.4 (-CO), 169.5 (-CO), 169.5 (-CO), 169.4 (-CO), 169.4 (-CO), 153.1, 134.5,
133.4, 132.7, 124.7, 103.9, 101.4 (C-1), 99.8 (C-1’), 73.1, 72.9, 72.0, 71.9, 71.4, 69.9, 68.5, 68.4,
62.3, 62.0, 60.5, 56.4, 20.8 (3 × C, -Ac), 20.8 (-Ac), 20.8 (-Ac), 20.7 (-Ac), 20.7 (-Ac), 20.7 (-Ac).
4.7 Isosyringinoside (1)
To a solution of CH3ONa (0.32 g, 6 mmol) in 100 ml CH3OH was added compound 7 (0.65 g,
0.75 mmol). The mixture stirred at room temperature for 1.5 h. After the reaction was completed
(detected by TLC), Amberlite IR 120 (5 g) was added and stirred for another 20 min. Then the
mixture was filtered and evaporated to give a solid residue, which was recrystallized from alcohol
to get compound 1 0.30 g (75.0% yield) as a white powder. M.p. 190.1-196.3 ºC. [α]D = - 44 (c
0.16, MeOH). ESIHRMS m/z 557.1840 [M+Na]+ (calcd for C23H34NaO14+ 557.1845). H NMR
1
(CD3OD) δ: 6.77 (s, 2H, Ph-H), 6.62 (t, J = 15.9 Hz, 1H, -CH2=CH2-), 6.34 (dt, J = 15.9, 6.1 Hz,
1H, -CH2=CH2-), 4.87 (d, 1H, J = 7.3 Hz, H-1), 4.52 (dd, J = 14.0, 5.0 Hz, 1H, one hydrogen atom
of -CH2O-), 4.37 (d, J = 7.8 Hz, 1H, H-1’), 4.33 (dd, J = 14.0, 6.5 Hz, 1H, one hydrogen atom of
-CH2O-), 3.86 (s, 6H, -OCH3), 3.90-3.85 (m, 1H, H-6a’), 3.80-3.76 (m, 1H, H-6a), 3.70-3.64 (m,
2H, H-6b, H-6b’), 3.48-3.34 (m, 4H, H-2, H-3, H-4, H-2’), 3.29-3.20 (m, 4H, H-5, H-3’, H-4’,
H-5’). 13C NMR (CD3OD) δ: 154.4, 136.0, 135.3, 133.6, 127.0, 105.7, 105.4 (C-1), 103.4 (C-1’),
78.4, 78.2, 78.1, 77.9, 75.8, 75.3, 71.8, 71.3, 71.0, 62.9, 62.5, 57.3 (-OCH3).
4.8 2-Bromo-4-(2-hydroxyethyl)phenol (12)
To a solution of hydroxyphenethyl alcohol 11 (13.8 g，0.1 mol) in acetone (150 ml) were
added NaBr (12.3 g, 12 mmol). Then a solution of Oxone in water (10 ml) was added at 0 ºC in a
- 9 -

period of 15 min. The reaction mixture was kept at 0 ºC and stirred for 1.5 h. The reaction was
quenched by Na2S2O3 and extracted with ethyl acetate (3 × 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 12 as crystals (19.4 g, 89.4% yield). M.p.
90.0-94.0 ºC. 1H NMR (CDCl3) δ: 7.33 (d, J = 2.1 Hz, 1H, Ph-H), 7.07 (dd, J = 8.3, 2.1 Hz, 1H,
Ph-H), 6.95 (d, J = 8.3 Hz, 1H, Ph-H), 5.44 (s, 1H, -OH), 3.81 (dd, J = 12.3, 6.5 Hz, 2H, -CH2OH),
2.77 (t, J = 6.5 Hz, 2H, Ph-CH2-). 13C NMR (CD3OD) δ: 152.6, 133.4, 132.3, 129.6, 116.6, 109.6,
62.66 (-CH2OH), 38.1 (-CH2-). 1H NMR and 13C NMR are in agreement with the reported values
[18].
4.9 2-(Benzyloxy)-4-(2-hydroxyethyl)phenol (13)
A mixture of compound 12 (5.0 g, 23.0 mmol), CuI 0.22 g (1.2 mmol, 5 mol%),
8-hydroxyquinoline 1.0 g (2.3 mmol, 10 mol %), and K3PO4 (9.7 g, 46.7 mmol) were added to a
screw-capped Schlenk tube under argon. The tube was then evacuated and back filled with argon
(3 cycles). Benzyl alcohol 23 ml were added by syringe at room temperature. The reaction mixture
was stirred at 110 °C for 24 h then allowed to reach room temperature and diluted with
dichloromethane (100 ml). The slurry was filtered and the filter cake was washed with 100 mL of
dichloromethane. The solvent was removed in vacuo, and the residue was purified by column
chromatography on silica gel with ethyl acetate/petroleum ether 1:4 as eluent, to afford the desired
product 13 4.8 g (85.7 %) as a white solid. M.p. 110.1-116.3 °C. ESIHRMS m/z 245.1169
+
[M+H]+ (calcd for C15H17O3 245.1172). 1H NMR (CDCl3) δ: 7.50-7.29 (m, 5H, Ph-H), 6.88 (d, J
= 8.0 Hz, 1H, Ph-H), 6.80 (d, J = 1.8 Hz, 1H, Ph-H), 6.73 (dd, J = 8.0, 1.8 Hz, 1H, Ph-H), 5.72 (s,
1H, -OH), 5.08 (s, 2H, PhCH2O-), 3.78 (m, 2H, -CH2OH), 2.76 (t, J = 6.5 Hz, 2H, -CH2-). 13C
NMR (CDCl3) δ: 145.9, 144.6, 136.4, 130.3, 128.8, 128.6, 128.0, 122.1, 114.9, 113.1, 71.2
(PhCH2O-), 63.9 (-CH2OH), 38.8 (-CH2-).
4.10 2-(benzyloxy)-4-(2-hydroxyethyl)phenyl benzoate (14)
A 500 ml flask was charged with 13 5.0 g (20.5 mmol), CH2Cl2 (150 ml), Et3N (40 mmol, 5.5
ml) and DMAP (4 mmol, 0.5 g), benzoic acid anhydride 3.9 ml (4.7 g, 21 mmol) in 50 ml CH2Cl2
was added dropwise to the mixture at 0 °C. The mixture was allowed to stir at room temperature
for 10 min until all of the starting material disappeared. Then, the mixture was poured into water
(100 mL), extracted with EtOAc (150 ml), washed with 1 N HCl (100 ml) and brine (100 ml), and
- 10 -

dried over Na2SO4. The crude organic phase was concentrated in vacuo and purified with column
chromatography (silica gel, ethyl acetate/petroleum ether = 5:1) to afford the corresponding
product 14 (5.5 g, 77.5%) as a white solid. M.p. 41.0-44.0 °C. ESIHRMS m/z 349.1430 [M+H]+
1
(calcd for C22H21O4+ 349.1434). H NMR (CDCl3) δ: 8.21 (dd, J = 8.5, 1.5 Hz, 2H, Ph-H),
7.63-7.60 (m, 1H, Ph-H), 7.50-7.48 (m, 2H, Ph-H), 7.31-7.29 (m, 2H, Ph-H), 7.26-7.20 (m, 3H,
Ph-H), 7.12 (d, J = 8.1 Hz, 1H, Ph-H), 6.91 (d, J = 2.3 Hz, 1H, Ph-H), 6.86 (dd, J = 8.1, 2.3 Hz,
1H, Ph-H), 5.10 (s, 2H, PhCH2O-), 3.81 (t, J = 6.8 Hz, 2H, -CH2OH), 2.83 (t, J = 6.8 Hz, 2H,
-CH2-). 13C NMR (CDCl3) δ: 165.2 (C=O), 150.3, 139.2, 137.7, 136.7, 133.6, 130.4, 128.6, 128.5,
127.8, 127.0, 123.0, 121.8, 115.3, 70.7 (PhCH2O-), 63.6 (-CH2OH), 39.2 (-CH2-).
4.11 2-(4-Benzoyloxy-3-benzyloxyphenyl)ethyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (15)
A mixture of 14 (3.48 g, 10 mmol), 10 (7.39 g, 15 mmol), and 4Å molecular sieves (6.0 g)
were added to dry CH2Cl2 (300 ml) under argon atmosphere at -78 °C. The mixture was stirred for
30 min and TMSOTf (cat., 0.1 ml) 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
addition of Et3N and concentrated. The crude product was purified by column chromatography
(petroleum ether: EtOAc 1:2 V/V) to give 15 (5.02 g, 74.0%) as colourless oil. [ɑ]D -33.8 (c = 0.4,
1
CHCl3). ESIHRMS m/z 679.2369 [M+H]+ (calcd for C36H39O13+ 679.2385). H NMR (CDCl3) δ:
8.18 (dd, J = 8.3, 1.2 Hz, 2H, Ph-H), 7.61-7.46 (m, 3H, Ph-H), 7.31-7.22 (m, 5H, Ph-H), 7.08 (d, J
= 8.1 Hz, 1H, Ph-H), 6.89 (d, J = 1.8 Hz, 1H, Ph-H), 6.82 (dd, J = 8.1, 1.8 Hz, 1H, Ph-H),
5.19-4.98 (m, 5H, H-2, H-3, H-4, PhCH2O-), 4.45 (d, J = 8.0 Hz, 1H, H-1), 4.26 (dd, J = 12.3, 4.7
Hz, 1H, H-6a), 4.14-4.12 (m, 2H, H-6b, one hydrogen atom of -CH2O-), 3.68 (ddd, J = 10.0, 4.7,
2.4 Hz, 1H, H-5), 3.63 (m, 1H, one hydrogen atom of -CH2O-), 2.87-2.85 (m, 2H, -CH2-), 2.08 (s,
3H, -Ac), 2.01 (s, 3H, -Ac), 1.99 (s, 3H, -Ac), 1.91 (s, 3H, -Ac). 13C NMR (CDCl3) δ: 170.8,
170.4, 169.6, 169.5, 165.0, 150.1, 139.1, 137.5, 136.9, 133.5, 130.3, 129.6, 128.6, 128.4, 127.7,
127.0, 122.8, 121.6, 115.3, 100.9 (C-1), 72.8, 71.9, 71.1, 70.7, 70.6, 68.5, 62.0, 36.0, 20.9, 20.7,
20.7, 20.6.
4.12 2-(4-Benzoyloxy-3-hydroxyphenyl)ethyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (16)
A suspension of 15 (2 g, 2.9 mmol) and palladium (100 mg, 10 wt % on activated carbon) in
a mixture of THF : CH3OH = 1 : 1 (100 ml) was stirred at room temperature under H2 atmosphere
- 11 -

for 24 h. The reaction mixture was filtered through a pad of Celite. The filtrate was then
concentrated in vacuo to generate crude product 16 (1.63 g, 95.8%) as a white solid.
4.13 2-[4-Benzyloxy-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)]ethyl 2,3,4,6-tetra-O-acet
yl-β-D-glucopyranoside (17)
A mixture of trichloroacetimidate 10 2.0 g (4.1 mmol) and compound 16 1.24 g (2.1 mmol)
and activated 4 Å molecular sieves (1.0 g) in dry DCM (50 ml) was stirred for 30 min at −20 °C
under argon atmosphere, then cooled to −78 °C and TMSOTf (cat., 0.05 ml) was added and the
stirring was continued for further 30 min after which the temperature was brought up to −20 °C.
The reaction mixture was neutralized by addition of Et3N, washed with brine, dried with
anhydrous Na2SO4 and evaporated in vacuo. The crude product was purified by column
chromatography (EtOAc/petroleum ether, 1:2) to give 17 2.8 g (75.6%) as colourless oil. [ɑ]D -21
1
(c = 0.2, CHCl3). ESIHRMS m/z 919.2848 [M+H]+ (calcd for C43H51O22+ 919.2867). H NMR
(CDCl3) δ: 8.13 (d, J = 7.1 Hz, 2H, Ph-H), 7.64 (t, J = 7.4 Hz, 1H, Ph-H), 7.51 (t, J = 7.7 Hz, 2H,
Ph-H), 7.07 (d, J = 8.1 Hz, 1H, Ph-H), 6.99 (d, J = 1.8 Hz, 1H, Ph-H), 6.93 (dd, J = 8.2, 1.8 Hz,
1H, Ph-H), 5.41-4.83 (m, 7H, H-2, H-3, H-4, H-1’, H-2’, H-3’, H-4’), 4.47 (d, J = 7.9 Hz, 1H,
H-1), 4.36-4.08 (m, 5H, one hydrogen atom of -CH2O-, H-6, H-6’), 3.97 (ddd, J = 10.0, 4.8, 2.3
Hz, 1H, H-5’), 3.77-3.56 (m, 2H, H-5, one hydrogen atom of -CH2O-), 2.88 (t, J = 6.0 Hz, 2H,
-CH2-), 2.10 (s, 3H, -Ac), 2.06 (s, 3H, -Ac), 2.04 (s, 3H, -Ac), 2.03 (s, 3H, -Ac), 2.02 (s, 3H, -Ac),
1.92 (s, 3H, -Ac), 1.89 (s, 3H, -Ac), 1.76 (s, 3H, -Ac). 13C NMR (CDCl3) δ: 170.7, 170.6, 170.3,
170.2, 169.6, 169.5, 169.4, 169.0, 164.7, 148.0, 138.9, 137.9, 133.6, 130.3, 129.2, 128.5, 123.7,
123.2, 117.8, 100.7 (C-1), 98.4 (C-1’), 72.9, 72.6, 71.9, 71.8, 70.9, 70.8, 70.2, 68.5, 68.2, 68.1,
61.9, 35.9, 20.8, 20.7, 20.7, 20.6 (2 × C), 20.5, 20.5, 20.2.
4.14 3-(O-β-D-glucopyranosyl)-α-(O-β-D-glucopyranosyl)-4-hydroxy phenylethanol (2)
Compound 17 0.63 g (0.69 mmol) was dissolved in 60 ml of a mixture of CH3OH/THF
(50:50). Then CH3Na 120 mg was added. When the deprotection was completed, the solution was
neutralized by adding 5 g of an ion-exchange resin. The agitation was maintained for 10 min, and
then the filtered. The methanol was eliminated by vacuum evaporation to afford a white solid,
which was recrystallized from alcohol to get compound 2 (0.28 g, 84.8%). M.p. 73.2-78.6 °C. [α]D
= -45 (c 0.12, MeOH). ESIHRMS m/z 501.1581 [M+Na]+ (calcd for C20H30NaO13+, 501.1579). 1H
NMR (CD3OD) δ: 7.10 (d, J = 1.9 Hz, 1H, Ph-H), 6.79 (dd, J = 8.1, 1.9 Hz, 1H, Ph-H), 6.74 (d, J
- 12 -

= 8.1 Hz, 1H, Ph-H), 4.76 (d, J = 7.4 Hz, 1H, H-1), 4.27 (d, J = 7.8 Hz, 1H, H-1’), 4.08-4.03 (m,
1H, one hydrogen atom of -CH2O-), 3.90 (dd, J = 12.1, 2.2 Hz, 1H, H-6a), 3.86 (dd, 12.1, 2.3 Hz,
1H, H-6a’), 3.70-3.65 (m, 3H, H-6b, H-6b’, one hydrogen atom of -CH2O-), 3.50-3.47 (m, 2H,
H-2, H-3’), 3.45-3.42 (m, 1H, H-5’), 3.39-3.33 (m, 2H, H-4, H-5), 3.30-3.29 (m, 1H, H-4’),
3.27-3.25 (m, 1H, H-3), 3.17 (dd, J = 9.2, 7.8 Hz, 1H, H-2’), 2.82 (t, J = 7.4 Hz, 2H, -CH2-). 13
C
NMR (150 MHz, CD3OD) δ: 146.6, 146.4, 131.7, 125.1, 119.4, 116.8, 104.3 (C-1’), 104.2 (C-1),
78.2, 78.0, 77.8, 77.6, 75.0, 74.8, 71.7, 71.6, 71.4, 62.7, 62.5, 36.4.
Acknowledgments
We thank the National Natural Science Foundation of China (82003619, 21702022) and
Sichuan Science and Technology Program (2018JY0222) for the funding support.
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The total syntheses of two natural bioactive glycosides, Isosyringinoside (1) and
3-(O-β-D-glucopyranosyl)-α-(O-β-D-glucopyranosyl)-4-hydroxy phenylethanol (2), were firstly
reported in short, convenient routes.

Conflict of interest
We declare that we do not have any commercial or associative interest that represents a
conflict of interest in connection with the work submitted.
Hongbo Dong,
Weihong Du,
Zhongquan Yao,
Min Wu,
Hongbing Luo,
Yujiao He,
Shenghua Cao
2020.9.8