Synthesis and comparative structure-activity study of carbohydrate-based phenolic compounds as α-glucosidase inhibitors and antioxidants

Article abstract of DOI:10.3390/molecules24234340

Twenty-one natural and unnatural phenolic compounds containing a carbohydrate moiety were synthesized and their structure-activity relationship (SAR) was evaluated for α-glucosidase inhibition and antioxidative activity. Varying the position of the galloyl unit on the 1,5-anhydro -D-glucitol (1,5-AG) core resulted in changes in the α-glucosidase inhibitory activity and notably, particularly strong activity was demonstrated when the galloyl unit was present at the C-2 position. Furthermore, increasing the number of the galloyl units significantly affected the α-glucosidase inhibition, and 2,3,4,6-tetra-galloyl-1,5-AG (54) and 2,3,4,6-tetra-galloyl-d-glucopyranose (61) exhibited excellent activities, which were more than 13-fold higher than the α-glucosidase inhibitory activity of acertannin (37). Moreover, a comparative structure-activity study suggested that a hemiacetal hydroxyl functionality in the carbohydrate core and a biaryl bond of the 4,6-O-hexahydroxydiphenoyl (HHDP) group, which are components of ellagitannins including tellimagrandin I, are not necessary for the α-glucosidase inhibitory activity. Lastly, the antioxidant activity increased proportionally with the number of galloyl units.

Full text of DOI:10.3390/molecules24234340

molecules
Article
Synthesis and Comparative Structure–Activity Study
of Carbohydrate-Based Phenolic Compounds
as α-Glucosidase Inhibitors and Antioxidants
Shota Machida, Saki Mukai, Rina Kono, Megumi Funato, Hiroaki Saito and Taketo Uchiyama *
School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan;
phsh18002@g.nihon-u.ac.jp (S.M.); phsa12222@g.nihon-u.ac.jp (S.M.); rinachammm1026ml@icloud.com (R.K.);
mgm27.04f@ezweb.ne.jp (M.F.); saito.hiroaki@nihon-u.ac.jp (H.S.)
* Correspondence: uchiyama.taketo@nihon-u.ac.jp; Tel.: +81-47-465-6290
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Received: 7 November 2019; Accepted: 25 November 2019; Published: 27 November 2019
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: Twenty-one natural and unnatural phenolic compounds containing a carbohydrate moiety
were synthesized and their structure–activity relationship (SAR) was evaluated for
inhibition and antioxidative activity. Varying the position of the galloyl unit on the 1,5-anhydro
-d-glucitol (1,5-AG) core resulted in changes in the -glucosidase inhibitory activity and notably,
particularly strong activity was demonstrated when the galloyl unit was present at the C-2 position.
Furthermore, increasing the number of the galloyl units significantly affected the -glucosidase
inhibition, and 2,3,4,6-tetra-galloyl-1,5-AG (54) and 2,3,4,6-tetra-galloyl-d-glucopyranose (61) exhibited
excellent activities, which were more than 13-fold higher than the -glucosidase inhibitory activity
α-glucosidase
α
α
α
of acertannin (37). Moreover, a comparative structure-activity study suggested that a hemiacetal
hydroxyl functionality in the carbohydrate core and a biaryl bond of the 4,6-O-hexahydroxydiphenoyl
(HHDP) group, which are components of ellagitannins including tellimagrandin I, are not necessary
for the α-glucosidase inhibitory activity. Lastly, the antioxidant activity increased proportionally with
the number of galloyl units.
Keywords: 1,5-AG; tellimagrandin I; acertannin; maplexin; ginnalin; polyphenol; α-glucosidase;
antioxidant
1. Introduction
Impaired glucose tolerance increases the risk of vascular events such as atherosclerotic coronary
artery disease [ ]. Particularly, postprandial hyperglycemia is a serious risk factor for cardiovascular
diseases and is believed to be the cause of oxidative stress that leads to vascular events [ ]. Thus,
controlling postprandial hyperglycemia is an important target to prevent diabetes as well as diabetic
complications. In clinical medicine, -glucosidase inhibitors such as acarbose, miglitol, and voglibose,
belong to the class of antidiabetic drugs used for improving postprandial hyperglycemia [ 11].
Currently, natural products and their derivatives constitute more than half of the drugs in the
clinic [12 15]. Therefore, finding inspiration in nature to develop more efficient and effective medicines
1,2
3–7
α
8
–
–
has attracted significant interest.
Trees belonging to the Acer species have been used as traditional medicinal plants for many
years and are widely known for their sap, which can be concentrated to produce maple syrup [16].
It has been demonstrated that Acer extracts display various bioactivities such as anti-cancer [17
antioxidant [19 22], and antihyperglycemic effects [23 24]. A. Honma et al. identified a compound
from Acer saccharum extracts able to suppress hyperglycemia, namely acertannin, and revealed that
its effects are a consequence of potent inhibitory activity toward -glucosidase [25]. The structural
components of acertannin include the characteristic 1,5-anhydro-d-glucitol (1,5-AG) sugar moiety,
,18],
–
,
α
Molecules 2019, 24, 4340; doi:10.3390/molecules24234340
www.mdpi.com/journal/molecules

Molecules 2019, 24, 4340
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which lacks the hemiacetal hydroxyl group present in d-glucose, as the carbohydrate core, and two
gallic acid functionalities as the phenolic units (Figure 1) [26]. However, only a few plants belonging
to the Acer genus produce the 1,5-AG core containing polyphenols [27
and ginnalin A–C have been isolated and characterized. The molecules possess varying numbers
and positions of the phenol units esterified with the 1,5-AG core [29 32]. These polyphenols were
shown to exhibit different bioactivities such as -glucosidase inhibition and antioxidant activity. It is
,28]. To date, maplexin A–J
–
α
noteworthy that different numbers, positions, and types of the phenol units on the 1,5-AG core display
non-identical bioactivities [32–36].
HO
OH
OH
O
O
O
O
HO
HO
H
H
O
OH
OH
HO
Figure 1. Structure of acertannin.
Tellimagrandin I, which belongs to ellagitannins, has also been demonstrated to be an α-glucosidase
inhibitor and to show antioxidant activity [37,38]. The molecule is characterized by the presence
of a hexahydroxydiphenoyl (HHDP) group, two galloyl units and the d-glucose core possesses
a hemiacetal hydroxyl functionality (Figure 2) [39]. The HHDP group provides structural diversity
in polyphenols, and the macro-lactone structure is considered to be the element responsible for the
pharmacological activity [40]. Nonetheless, to our knowledge, no reports on the evaluation of the
synthesis and/or bioactivity of compounds comprising the HHDP functionality on the 1,5-AG core
have been reported so far. Furthermore, the hemiacetal hydroxyl group is a fundamental moiety in the
carbohydrate chemistry; however, its effects on the bioactivity remain largely unexplored.
HO
OH
HO
HHDP group
OH
HO
HO
O
O
O
O
O
Carbohydrate core
O O
OH
O
O
HO
HO
Galloyl units
Phenolic hydroxyl groups
OH
HO
OH
HO
Figure 2. The structural components of tellimagrandin I. HHDP, hexahydroxydiphenoyl.

Molecules 2019, 24, 4340
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In the present study, we report the synthesis of a series of 21 carbohydrate-based phenolic
compounds to investigate the structure–activity relationship (SAR). -glucosidase inhibition and
α
antioxidant activity were examined by studying the effects of (1) the position and number of galloyl
units, (2) the type of phenol units, (3) the existence the 4,6-O-HHDP group, and (4) the presence of the
hemiacetal hydroxyl group.
2. Results
2.1. Syntheses of 1,5-AG-Based Polyphenols
2.1.1. Syntheses of Galloylated 1,5-AGs
Recently, A. Kamori et al. reported the synthesis of various natural and unnatural acertannin
derivatives and evaluated their SAR against ceramidase and ceramide synthase enzymes [35].
In addition, we have also previously reported a facile method for the preparation of 1,5-anhydroalditol
via treatment of per-O-TMS-glycopyranosyl iodide with LiBH4 [41]. In total, 1,5-AG, which can be
easily synthesized from d-glucose on multi-gram scale in three days, possesses four hydroxyl groups;
hence, 15 different combinations are possible for mono-, di-, tri-, and tetra-galloylation of 1,5-AG. In the
current study, we attempted the synthesis of all of these galloylated compounds starting from 1,5-AG.
Firstly, 4,6-O-benzylidene-1,5-AG (
NaH to afford di-benzylated compound 2 [42]. However, reacting
(DCM)/5% NaOH system with BnBr, NaI, and tetra-n-butylammonium hydrogen sulfate provided the
3-OH analog 35] and the 2-OH analog 35] as a mixture of products, which could be separated by
column chromatography (C.C.) (Scheme 1) [43].
1
) [42] was protected with benzyl (Bn) group using BnBr and
1
in a 2-phase dichloromethane
3
[
4 [
Scheme 1. Selective protection of 1,5-AG.
Subsequently, the 4,6-O-benzylidene groups on the 1,5-AG derivatives
corresponding hydroxyl moieties using an acid or reducing reagent (Scheme 2). Compounds
then deprotected with 80% acetic acid/H2O solution to give the corresponding diol analogs
Reduction of , and by BH3/THF and trimethylsilyl trifluoromethanesulfonate (TMSOTf) [44],
and reduction of by diisobutylaluminium hydride (DIBAL-H) [45] resulted in the formation of the
6-OH derivatives 11 35 46 47]. Moreover, compounds were treated with triethylsilane and
trifluoroacetic acid (TFA) [48] to afford the 4-OH derivatives 12 15 35 49]. Esterification of these
1–
4
were converted to the
were
35 42].
2–4
5
–7
[
,
1
,
3
4
2
8–
[
,
,
1–4
–
[ ,
-OH derivatives with Bn-protected gallic acid (16) [50] using N,N-dimethyl-4-aminopyridine (DMAP)
and triethylamine (TEA), as well as 2-chloro-1-methylpyridinium iodide as the condensing reagent,
provided 1,5-AG-based galloylated derivatives 17–30. Finally, hydrogenolysis using Pd(OH)2 as the
catalyst in a MeOH/THF solvent mixture gave 14 types of the 1,5-AG core containing polyphenol
analogs 31–44 (Scheme 3).

Molecules 2019, 24, 4340
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2
5
3
6
4
7
HO
HO
R2O
80% AcOH
80 °C, 5 h
O
2, 3, 4
R1 Bn
R2 Bn
Bn
H
H
OR1
Bn
5 7 (76-95%)
1
8
3
9
4
10
HO
O
BH3/THF, TMSOTf
BnO
1, 3, 4
R2O
DCM, 0 °C ~ rt
4 10 h
R1
R2
H
H
Bn
H
H
OR1
Bn
8 10 (61-82%)
HO
O
DIBAL-H
BnO
2
BnO
Toluene, rt
20 h
OBn
11 (95%)
1
12
2
13
3
14
4
15
BnO
HO
Triethylsilane, TFA
O
1, 2, 3, 4
R2O
R1
R2
H
H
Bn
Bn
Bn
H
H
DCM, 0 °C ~ rt
4 16 h
OR1
Bn
12 15 (58-62%)
Scheme 2. Deprotection of 1–4.
Scheme 3. Synthesis of galloylated 1,5-AGs.

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2.1.2. Synthesis of Maplexin J Analogs
Maplexin J (54) [32,50], which is per-galloylated 1,5-AG, could be easily synthesized from
1,5-AG. Therefore, we attempted to synthesize of maplexin J analogs, which in addition to the galloyl
moiety, contained different numbers of phenolic groups at various positions intending to elucidate
the effect of this functionality on the bioactivity. Phenol derivatives 45
in 2-steps from commercially available methyl esters (Scheme 4). Subsequently, 1,5-AG was condensed
with 16 50], and 45 48 using DMAP, TEA, and 2-chloro-methylpyridinium iodide to obtain the
corresponding Bn-protected 1,5-AG analogs 49 53. Deprotection under hydrogenolysis conditions
provided compounds 54 58 (Scheme 5). However, esterification of benzyl glucoside 59 54] with 16
–48 [51–53] were prepared
[
–
–
–
[
using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and DMAP resulted in the formation
of intermediate 60. Following hydrogenolysis, tetra-galloylated d-glucopyranose 61 containing
a hemiacetal moiety was formed. Notably, the structure of 61 [55] is analogous to tellimagrandin I;
however, the biaryl bond of the HHDP group is missing (Scheme 6).
Scheme 4. Preparation of the Bn-protected phenol units 45–48.
Scheme 5. Synthesis of maplexin J analogs 54–58.

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Scheme 6. Synthesis of tellimagrandin I analog 61.
2.1.3. Synthesis of a 1,5-AG-Based Tellimagrandin I Analog
To consider the effect of the hemiacetal group on the activity of tellimagrandin I, we also focused
on the synthesis of the 1-deoxy analog 67. Deprotection of benzylidene acetal in 21 in a methanol/DCM
solvent system using iodine, according to the method reported by Feldman et al. [56], gave diol 62
in a high yield of 93% (Scheme 7). Intermediate 62 was then condensed with the gallic acid derivative
63
[57] to afford the galloylated compound 64. The subsequent removal of the methoxymethyl (MOM)
protecting groups provided 65 in 93% yield.
Scheme 7. Synthesis of the 1,5-AG-based tellimagrandin I analog 67.
The construction of the HHDP group was performed in accordance with the approach previously
reported by Yamada et al. [57
–
60]. Compound 65 was treated with n − BuNH2 and CuCl2 to provide
the biaryl derivative 66. Finally, hydrogenation of 66 in MeOH/THF with Pd(OH)2 as the catalyst gave
the desired 1,5-AG-based tellimagrandin I analog 67.

Molecules 2019, 24, 4340
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2.2. Evaluation of α-Glucosidase Inhibition and Antioxidant Activity
2.2.1. The α-Glucosidase Inhibitory Activity
The
FUJIFILM
in H2O) or acarbose (0.5–8
buffer (100 mM, pH = 6.0), and 25
at 37 ◦C for 30 min. Subsequently, 400
mixture was boiled for 3 min to deactivate
LabAssay glucose (mutarotase-GOD method). In total, 100
α
-glucosidase inhibitory activity of all samples was assayed utilizing a commercially available
-glucosidase inhibitory activity assay kit. In total, 25 L of each sample (25–2000 g/mL
g/mL in H2O), 50 L of 18.5 mM maltose diluted in maleic anhydride
L of the rat -glucosidase solution were incubated in a micro-tube
L of purified water was added to the solution and the reaction
-glucosidase. The generated glucose was measured by
L of the reaction solution and 150
α
µ
µ
µ
µ
µ
α
µ
α
™
µ
µL
of the coloring solution were incubated in 96-well plates at 37 ◦C for 10 min, and the absorbance was
recorded at 505 nm using a microplate reader (Bio-Rad, Model 680). The inhibition percentage was
calculated using the following Equation:
As − Ab
Inhibition percentage (%) = 1 −
× 100
Ac
where As is the absorbance of the analyzed sample, Ab is the absorbance of the blank (immediate
deactivation), and Ac is the absorbance of the control (without
the positive control.
α-glucosidase). Acarbose was used as
2.2.2. Evaluation of Antioxidant Activity
The antioxidant activity was assessed by employing the 2,2-diphenyl-1-picrylhydrazyl (DPPH)
radical scavenging assay, according to the previously published method [61]. In total, 100 L of each
sample (1000–10 g/mL in 50%EtOH/H2O) or trolox (160–0 M in 50% EtOH/H2O), and 50
of 2-(N-morpholino)ethanesulfonic acid (MES)-NaOH buffer (200 mM, pH = 6.0), and 50 L of an
800 M DPPH diluted in 99.5% EtOH were mixed in 96-well plates. Following shaking the microplate
µ
µ
µ
µL
µ
µ
for 15 min in the dark, the absorbance was recorded at 520 nm using a microplate reader (Bio-Rad,
Model 680). Effective percentages (%) were calculated as follows:
As
Ab
Effective percentages (%) = 1 −
× 100
where As is the absorbance of the sample and Ab is the absorbance of the blank (without samples,
50% EtOH/H2O solution was used instead).
In addition, correlation of the absorbance on the y-axis and the concentrations on the x-axis resulted
in the formation of an approximately straight-line plot. The trolox-equivalent (sample-mol/trolox-mol)
was calculated as follows:
mol − trolox
Ss
St
Trolox − equivalent (
) =
mol − sample
where Ss is the slope of the sample and St is the slope of trolox.
3. Discussion
The results of the biological evaluation of the 21 synthesized compounds considering the
α-glucosidase inhibitory and antioxidant activities are summarized in Table 1.

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Table 1. α-Glucosidase inhibitory and antioxidant activities.
α-Glucosidase
IC50 (µM) a
Antioxidant
Compounds
EC50 (µM) b
Trolox-eq b
Mono-
2-galloyl (Ginnalin C) [31] 31
3-galloyl (Maplexin A) [29] 32
4-galloyl (Maplexin B) [29] 33
6-galloyl (Ginnalin B) [31] 34
Di-
95.1 ± 0.22
137.9 ± 1.50
143.9 ± 0.52
127.1 ± 0.88
19.40 ± 1.02
20.50 ± 2.05
20.80 ± 1.54
22.90 ± 1.61
2.04 ± 0.08
2.38 ± 0.24
2.09 ± 0.19
2.13 ± 0.12
2,3-galloyl (Maplexin C) [29] 35
2,4-galloyl (Maplexin D) [29] 36
2,6-galloyl (Acertannin) [25] 37
3,4-galloyl 38 c
20.50 ± 0.50
48.30 ± 1.25
35.60 ± 2.58
91.40 ± 6.56
55.00 ± 8.84
26.60 ± 2.37
11.30 ± 0.98
14.30 ± 0.29
15.20 ± 0.53
14.80 ± 0.56
11.90 ± 0.71
13.00 ± 1.12
4.29 ± 0.23
3.36 ± 0.13
3.32 ± 0.37
3.55 ± 0.42
3.67 ± 0.19
3.78 ± 0.33
3,6-galloyl 39
4,6-galloyl 40
Tri-
2,3,4-galloyl 41
6.72 ± 0.21
5.34 ± 0.55
9.34 ± 0.99
12.60 ± 0.61
7.94 ± 0.39
8.09 ± 0.41
10.30 ± 0.76
8.48 ± 0.21
5.59 ± 0.26
5.75 ± 0.18
4.31 ± 0.35
5.36 ± 0.20
2,3,6-galloyl (Maplexin F) [30] 42
2,4,6-galloyl (Maplexin E) [29] 43
3,4,6-galloyl 44
Tetra-
2,3,4,6-galloyl (Maplexin J) [32] 54
30,40-dihydroxybenzoyl 55 c
30,50-dihydroxybenzoyl 56 c
30-hydroxybenzoyl 57 c
40-hydroxybenzoyl 58 c
1-OH-2,3,4,6-galloyl 61
2,3-galloyl-4,6-HHDP 67 c
Tellimagrandin I
2.56 ± 0.10
3.28 ± 0.16
9.34 ± 0.02
6.61 ± 0.68
6.99 ± 0.11
70<
6.77 ± 0.63
6.54 ± 0.15
n.d e
n.d e
d
78<
78<
−
n.d e
d
−
1.68 ± 0.21
3.22 ± 0.51
3.37 ± 0.04
90.50 ± 6.97
300<<
5.60 ± 0.28
6.79 ± 0.21
6.31 ± 0.27
19.60 ± 0.11
21.10 ± 1.08
n.d e
8.33 ± 0.49
6.44 ± 0.24
7.04 ± 0.37
2.42 ± 0.27
2.20 ± 0.05
n.d e
Methyl gallate
Methyl 3,4-dihydroxybenzoate
Methyl 3,5-dihydroxybenzoate
Methyl 3-hydroxybenzoate
Methyl 4-hydroxybenzoate
Acarbose
300<<
660<<
660<<
n.d e
n.d e
n.d e
n.d e
0.11 ± 0.02
-
-
-
Trolox
-
49.40 ± 3.87
a
b
c
IC50 data represents mean
±
S.D. of n = 2. EC50 and trolox-eq data represents mean
±
S.D. of n = 3. Novel
d
e
compound. Did not dissolve in water. n.d.: not detected.
The comparison of the 1,5-AG-based polyphenol analogs 31–44 and 54 revealed that the α-glucosidase
inhibitory activity significantly increased with the number of the galloyl units in the compounds and the
highest inhibition was observed for tetra-O-galloyl-1,5-AG (maplexin J) 54 (IC50 = 2.56 M). This result is
in accordance with the previous reports [32]. In addition, different the position of the galloyl unit on
the 1,5-AG core appeared to influence the -glucosidase inhibitory activity, even for the compounds
with the same number of these moieties. Analogous outcomes were noted for 2-galloyl-1,5-AG (31
and methyl gallate (IC50 = 95.1, 90.5 M, respectively). Conversely, differing -glucosidase inhibitory
activities were obtained for mono-galloyl analogs 32 34, which are weaker inhibitors than methyl
gallate (IC50 = 127.1–143.9 M). Furthermore, compound 33 (galloyl unit at the C-4 position) exhibited
lowest activity (IC50 = 143.9 M). Higher inhibitory activity was detected for di-galloylated analogs
M), which possessed the galloyl unit at the C-2 position than for analogs
M). In particular, compound 35 that contains esterified galloyl units at the
µ
α
)
µ
α
–
µ
µ
35
38
–
–
37 (IC50 = 20.5–48.3
40 (IC50 = 26.6–91.4
µ
µ
C-2 and C-3 positions exhibited three-times higher inhibitory activity than gallic acid. Moreover,
analog 38, galloylated at the C-3 and C-4 positions, displayed significantly lower activity (IC50 = 91.4).
Among the tri-galloyllated analogs, compound 42 without a galloyl unit at the C-4 position showed
stronger inhibitory activity (IC50 = 5.34 µM) than analogs 41, 43, and 44 (IC50 = 6.72, 9.34, and 12.6 µM,

Molecules 2019, 24, 4340
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respectively). In addition, analog 44 without a galloyl moiety at the C-2 position displayed weak
activity. Thus, our results suggested that a galloyl unit at the C-2 position considerably increases the
α
-glucosidase inhibitory activity, while the presence of this group at the C-4 position causes a decrease
in the activity.
Subsequently, we compared maplexin J (54) and its analogs (55 and 56) to elucidate the effect
of the phenolic hydroxyl group. The 30,40-di-hydroxybenzoyl analog 55 exhibited good inhibitory
activity, whereas the 30,50-di-hydroxybenzoyl analog 56 was a weaker inhibitor of the
-glucosidase
enzyme (IC50 = 3.28, 9.34 M, respectively). Consequently, these results implied that the presence
α
µ
of two adjacent phenolic hydroxyl groups is essential for the desired activity. We then focused on
the evaluation of the influence of the hemiacetal hydroxyl and the HHDP functionalities against the
α
-glucosidase inhibitory activity. The effect of the hemiacetal hydroxyl moiety can be observed by
the comparison of the activity of maplexin J (54) and its analog 61 (IC50 = 1.68, 2.56 M, respectively).
Furthermore, tellimagrandin I and 67 showed analogous inhibitory activity (IC50 = 3.37, 3.22 M,
respectively). Therefore, the obtained outcomes suggested that the presence of a hemiacetal hydroxyl
group did not have a significant effect on the -glucosidase inhibitory activity. Lastly, to examine the
µ
µ
α
influence of the HHDP group, the results for maplexin J (54) and the 4,6-O-HHDP analog 67 were
compared and it transpired that maplexin J (54) displayed marginally higher activity than its analog
67 (IC50 = 2.56, 3.22
the activity of analog 61 without the HHDP group revealed that 61 was a stronger inhibitor than
tellimagrandin I (IC50 = 3.37, 1.68 M, respectively). Intriguingly, our results suggested that the
µM, respectively). Likewise, the assessment of the tellimagrandin I activity and
µ
4,6-O-HHDP group has a weakening effect on the α-glucosidase inhibitory activity [38,62].
Meanwhile, we also investigated the antioxidant activity of these polyphenols and their analogs.
Firstly, the mono-galloylated analogs 31
gallate (EC50 = 19.4–22.9 M, TE = 2.04–2.42). Moreover, the activity improved as the number of galloyl
units increased, with di-galloylated analogs (EC50 = 11.9–15.2 M, TE = 3.32–4.29) exhibiting lower
activity than the tri-galloylated analogs (EC50 = 7.94–10.3 M, TE = 4.31–5.75) and the tetra-galloylated
analogs 54 61 displaying the highest activity (EC50 = 5.60, 6.61 µM, TE = 8.33, 6.77, respectively).
Unlike the significant increase observed for the -glucosidase inhibitory activity, the antioxidant
–34 showed nearly equivalent antioxidative activity with methyl
µ
µ
µ
,
α
activity increased proportionally to the number of galloyl units. Moreover, the antioxidant activity was
not affected by the position of the galloyl units on the carbohydrate core. In addition, the comparison
of compounds 54, 61, and 67 with tellimagrandin I revealed similar activity (EC50 = 6.61, 5.60, 6.79,
and 6.31 M, TE = 6.77, 8.33, 6.44, and 7.04, respectively). This implied that the antioxidative
µ
activity was not influenced by the presence of a hemiacetal hydroxyl and the 4,6-O-HHDP groups.
The presence of the phenolic hydroxyl groups in 3,4-dihydroxybenzoyl analogs 55 and methyl
3,4-dihydroxybenzoate appeared to result in improved antioxidative activity (EC50 = 6.99
µM,
TE = 6.54); however, no antioxidant activity was observed for 3,5-dihydroxybenzoyl analog 56 and the
monohydroxybenzoyl analogs (57 and 58). Likewise, the activity of methyl 3,4-dihydroxybenzoate was
comparable with methyl gallate (EC50 = 21.1 µM, TE = 2.20), whereas methyl 3,5-dihydroxybenzoate,
methyl 3- and 4-hydroxybenzoate did not exhibit any notable activity. This data therefore suggested
that the presence of two adjacent phenolic hydroxyl groups is necessary for the antioxidant activity,
as was the case with α-glucosidase inhibitory activity.
4. Conclusions
We synthesized 21 carbohydrate-based phenolic analogs including a series of compounds
containing all possible combinations of galloylation on 1,5-AG. The
antioxidant activities of these compounds were further studied to evaluate the SAR. Our results
suggested that the -glucosidase inhibitory activity; 1) is significantly enhanced with the increasing
α-glucosidase inhibition and
α
number of galloyl units, and changing the position of the galloyl moiety substitution on the 1,5-AG
unit tends to affect the activity; particularly, the presence of this functionality at the C-2 position
improves the α-glucosidase inhibition, whereas substitution at the C-4 position reduces it, 2) requires

Molecules 2019, 24, 4340
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two adjacent phenolic hydroxyl groups, 3) is not affected by the presence of the biaryl bond on the
4,6-O-HHDP group, 4) is not influenced by the hemiacetal hydroxyl functionality on the carbohydrate
unit. Moreover, the following trends were determined for the antioxidant activity; 1) the activity is
dependent on the number of galloyl units; however, it is not affected by their position, 2) the presence
of two adjacent phenolic hydroxyl groups is significant, 3) the activity is not affected by the HHDP
group or the hemiacetal hydroxyl group. The α-glucosidase inhibitory activity is undoubtedly affected
by the position of the galloyl group on 1,5-AG. This outcome indicates that the carbohydrate core is
not only a store unit for the galloyl moiety but can also act as a carrier to the biological targets. Thus,
derivatives modified at the C-2 or C-4 positions on the carbohydrate unit, which is not d-glucose,
have the potential to exhibit stronger antidiabetic activity. The synthesis and profiling of further
analogs will be reported in due course.
5. Materials and Methods
5.1. General Information
Proton nuclear magnetic resonance (1
spectrometers. Chemical shifts are reported relative to internal standard (tetramethylsilane; δH 0.00,
CDCl3 δH 7.26). Data are presented as follows: chemical shift ( , ppm), multiplicity (s = singlet,
H NMR) spectra were recorded on JEOL JNM-ECX600
;
δ
d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant and integration. Carbon nuclear
magnetic resonance (13C NMR) spectra were recorded on JEOL JNM-ECX600 (150 MHz) spectrometers.
The following internal reference was used: (tetramethylsilane:
δ
0.00, CDCl3 δ 77.0, Acetone − d6
;
δ
29.8, CD3OD 49.0). Optical rotations were measured on a JASCO P-1030 digital polarimeter at the
; δ
sodium D line (589 nm). Electron impact (EI) mass analyses and fast atom bombardment (FAB) mass
analyses were carried out with a JEOL JMS-GCMATE. C.C. was carried out on Kanto Silica gel 60N
spherical (63–210 mesh). Analytical thin-layer chromatography (TLC) was carried out using Merck
Kieselgel 60 F254 plates with visualization by ultraviolet light or stained by 8% H2SO4/EtOH solution
on hot-plate. Tellimagrandin I was purchased from Nagara Science (Gifu, Japan). Methyl gallate,
methyl 3,4-dihydroxybenzoate, methyl 3,5-dihydroxybenzoate, methyl 3-hydroxybenzoate, methyl
4-hydroxybenzoate, Trolox and MES were purchased from TOKYO CHEMICAL INDUSTRY CO., LTD
(Tokyo, Japan). DPPH was purchased from Sigma-Aldrich Japan (Tokyo, Japan).
5.2. Chemical Synthesis
2-O-Benzyl-4,6-O-benzylidene-1,5-anhydro-d-glucitol (
3) [35] and 3-O-Benzyl-4,6-O-benzylidene-1,5
-anhydro-d-glucitol ( ) [35]; Compound (2.5 g, 10 mmol) and TBAHSO4 (0.68 g, 2.0 mmol) in 160 mL
4
1
of DCM and 14 mL of 5% NaOH was stirred at rt. Then, BnBr (2.1 mL, 17 mmol) was slowly added, and
the mixture was refluxed for 30 h. After the addition 50 mL of water, the mixture was extracted with
DCM (3
concentrated under reduced pressure. The crude product was separated by C.C (Hex/EtOAc = 4/1
to obtain 2-O-Bn compound (2.0 g, 59%) as colorless needles and 3-O-Bn compound (1.0 g, 30% yield)
as a white solid. Compound NMR (CDCl3, 600 MHz)
: m.p. 163 ◦C; [α]D20 3.16 (c 1.0, CHCl3); 1
7.49–7.47 (m, 2H), 7.38–7.29 (m, 8H), 5.50 (s, 1H), 4.76, 4.67 (ABq, J = 11.7 Hz, 2H), 4.30 (dd, J = 10.5
5.0 Hz, 1H), 4.01 (dd, J = 11.3, 5.5 Hz, 1H), 3.84 (m, 1H), 3.65 (t, J = 10.3 Hz, 1H), 3.59–3.55 (m, 1H),
3.45 (t, J = 9.3 Hz, 1H), 3.35 (m, 1H), 3.30 (t, J = 11.0 Hz, 1H); 13
NMR (CDCl3, 150 MHz) 138.02,
137.05, 129.23, 128.56, 128.33, 128.03, 127.89, 126.29, 101.88, 81.05, 77.74, 74.81, 73.43, 70.91, 68.79, 68.45.
Compound NMR (CDCl3, 600 MHz) 7.50–7.48 (m, 2H),
: m.p. 137 ◦C; [α]D20 = +5.3 (c 1.0, CHCl3); 1
7.41–7.29 (m, 8H), 5.58 (s, 1H), 5.03, 4.72 (ABq, J = 11.3 Hz, 2H), 4.34 (dd, J = 10.5, 5.0 Hz, 1H), 4.06
×
100). The combined organic layers were washed with brine, dried over Na2SO4, filtered and
)
3
4
3
=
−
H
δ
,
C
δ
4
H
δ
(
(
dd, J = 11.2, 5.7 Hz, 1H), 3.80–3.76 (m, 1H), 3.72 (t, J = 10.3 Hz, 1H), 3.66 (t, J = 9.1 Hz, 1H), 3.58
t, J = 8.8 Hz, 1H), 3.44–3.40 (m, 1H), 3.34 (t, J = 10.8 Hz, 1H); 13
C
NMR (CDCl3, 150 MHz) 138.30,
δ
137.32, 129.00, 128.61, 128.30, 128.13, 128.01, 125.98, 101.21, 82.66, 82.13, 74.71, 71.53, 69.91, 69.79, 68.88.

Molecules 2019, 24, 4340
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2,3-Di-O-benzyl-1,5-anhydro-d-glucitol (
5
) [42]; Compound
2
(0.86g, 2.0 mmol) in 10 mL of 80%
AcOH/H2O solution was stirred at 80 ◦C for 5 h. After the addition 5 mL of saturated aq. NaHCO3
,
the reaction solution was extracted by EtOAc (3
dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by
recrystallization (EtOAc/Hex) to obtain 10.4
(0.65 g, 95%) as colorless needles. m.p. 129 ◦C; [α]D20
(c 1.00, CHCl3); 1
NMR (CDCl3, 600 MHz) 7.43–7.29 (m, 10H), 5.03, 4.70 (ABq, J = 11.7 Hz, 2H),
4.64, 4.03 (ABq, J = 11.3, 2H), 3.86–3.82 (m, 1H), 3.72–3.68 (m, 1H), 3.63–3.59 (m, 1H), 3.50–3.44 (m, 2H),
3.28–3.23 (m, 2H); 13
NMR (CDCl3, 150 MHz) 138.54, 137.97, 128.67, 128.53, 127.98, 127.93, 127.83,
85.30, 79.53, 78.29, 75.10, 73.07, 70.45, 67.94, 62.89.
1,5-Anhydro-2-O-benzyl-d-glucitol ( ) [35]; Compound
AcOH/H2O solution was stirred at 80 ◦C for 5 h. By the same procedure previously described for the
preparation of compound , compound
(503 mg, 76%) was obtained as colorless needles. m.p. 131 ◦C;
[α]2D0 = +8.4 (c 1.00, MeOH); 1H NMR (CD3OD, 600 MHz);
7.40–7.36 (m, 2H), 7.33–7.31 (m, 2H),
×
30). The organic layer was washed with brine,
5
=
−
H
δ
C
δ
6
3 (860 mg, 2.5 mmol) in 10 mL of 80%
5
6
δ
7.28–7.25 (m, 1H), 4.75, 4.64 (ABq, J = 11.7 Hz, 2H), 3.96 (dd, J = 11.0, 5.2 Hz, 1H), 3.81 (dd, J = 11.9,
2.2 Hz, 1H), 3.59 (dd, J = 11.9, 6.0 Hz, 1H), 3.43 (t, J = 8.9 Hz, 1H), 3.39–3.35 (m, 1H), 3.26–3.22 (m, 1H),
3.15–3.11 (m, 2H); 13
C
NMR (CD3OD, 150 MHz);
δ
140.09, 129.37, 129.05, 128.76, 82.42, 79.31, 79.27,
74.14, 71.92, 68.95, 63.07.
1,5-Anhydro-3-O-benzyl-d-glucitol (
7
); Compound 4
(680 mg, 2.0 mmol) in 10 mL of 80% AcOH/H2O
solution was stirred at 80 ◦C for 5 h. By the same procedure previously described for the preparation
of compound
(c 1.00, MeOH); 1
4.90 (overlap, 2H), 3.89 (dd, J = 11.3, 5.5 Hz, 1H), 3.83 (dd, J = 11.9, 2.2 Hz, 1H), 3.62–3.57 (m, 2H), 3.37
dd, J = 18.0, 8.71 Hz, 1H), 3.31–3.28 (overlap, 1H), 3.22–3.16 (m, 2H); 13C NMR (CD3OD, 150 MHz);
140.53, 129.20, 129.09, 128.49, 88.20, 82.68, 76.10, 71.67, 71.54, 71.09, 63.05. HRMS (ESI, m/z): [M + Na]+
calcd for [C13H18O5 Na]+: 277.1052; found 277.1052.
1,5-Anhydro-4-O-benzyl-d-glucitol ( ) [35]; Compound
5
, compound
7
(410 mg, 80%) was obtained as colorless needles. m.p. 153 ◦C; [α]D20 = +28.6
7.44 (m, 2H), 7.32–7.30 (m, 2H), 7.26–7.23 (m, 1H),
H
NMR (CD3OD, 600 MHz);
δ
(
δ
,
8
1 (0.76 g, 3.0 mmol) in 15 mL of DCM was
stirred at 0 ◦C. Then, 15 mL of borane-THF (ca. 1M THF solution) and TMSOTf (0.11 mL, 0.60 mmol)
were successively added to the mixture. The mixture was allowed to stir for 4 h and added MeOH
carefully. After the addition 1 mL of saturated aq. NaHCO3, the reaction solution was extracted with
DCM (5
under reduced pressure. The crude product was purified by C.C. (CHCl3/MeOH = 8/1) to obtain
(0.64 g, 74%) as a white solid. [α]2D0 = +27.7 (c 0.45, CHCl3); 1
NMR (CD3OD, 600 MHz) 7.38–7.25
×
40 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated
8
H
δ
(m, 5H), 4.94, 4.64 (ABq, J = 11.0 Hz, 2H), 3.89 (dd, J = 13.3, 5.4 Hz, 1H), 3.78 (dd, J = 12.0, 2.1 Hz, 1H),
3.60 (dd, 1H, J = 11.4, 5.73 Hz,), 3.49–3.46 (m, 2H), 3.33–3.30 (overlap, 1H), 3.20 (ddd, J = 9.7, 5.2, 2.1 Hz,
1H), 3.14 (t, J = 10.7, 1H); 13
C
NMR (CD3OD, 150 MHz);
δ
140.09, 129.33, 129.14, 128.70, 81.75, 80.43,
79.50, 75.90, 71.77, 70.93, 62.72.
2,4-Di-O-benzyl-1,5-anhydro-d-glucitol (
9
) [46]; Compound (1.0 g, 3.0 mmol) in 15 mL of DCM
3
was successively added 15 mL of borane-THF (ca. 1M THF solution) and TMSOTf (0.11 mL, 0.6 mmol)
at 0 ◦C. The mixture was allowed to stir at rt for 10 h and added 1 mL of MeOH carefully. After the
addition 1 mL of saturated aq. NaHCO3, the mixture was extracted with DCM (3
layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure.
The crude was purified by recrystallization (Hex/EtOAc) to obtain (820 mg, 82%) as colorless needles.
m.p. 112 ◦C; [α]2D0 = +34.6 (c 1.00, CHCl3); 1
NMR (CDCl3, 600 MHz) 7.37–7.28 (m, 10H), 4.86, 4.70
×
40 mL). The organic
9
H
δ
(ABq, J = 11.3 Hz, 2H), 4.65 (s, 2H), 3.99 (dd, J = 11.3, 5.2 Hz, 1H), 3.84 (ddd, J = 11.8, 5.8, 2.7 Hz, 1H),
3.74 (td, J = 8.9, 2.1 Hz, 1H), 3.68–3.64 (m, 1H), 3.45–3.41 (m, 1H), 3.41 (t, J = 9.2 Hz, 1H), 3.26 (ddd,
J = 9.6, 4.5, 2.7 Hz, 1H), 3.19 (t, J = 10.8 Hz, 1H); 13
C
NMR (CDCl3, 150 MHz)
128.56, 128.09, 127.98, 127.85, 79.34, 78.18, 77.97, 77.39, 74.74, 73.05, 67.44, 62.27.
3,4-Di-O-benzyl-1,5-anhydro-d-glucitol (10) [47]; Compound (850 g, 2.5 mmol) in 15 mL of DCM
was successively added 12.5 mL of borane-THF (ca. 1M THF solution) and TMSOTf (90 L, 0.5 mmol)
at 0 ◦C. The mixture was allowed to stir at rt for 7 h and added 5 mL of MeOH carefully. After the
δ 138.18, 138.00, 128.60,
4
µ

Molecules 2019, 24, 4340
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addition 1 mL of saturated aq. NaHCO3, the mixture was extracted with DCM (3
layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure.
×
40 mL). The organic
The crude was purified by recrystallization (Hex/EtOAc) to obtain 10 (523 mg, 61%) as colorless needles.
m.p. 99 ◦C; [α]D20 = +48.3 (c 1.40, CHCl3); 1H NMR (CDCl3, 600 MHz)
δ 7.38–7.30 (m, 10H), 4.97, 4.77
(ABq, J = 11.3 Hz, 2H), 4.86, 4.68 (ABq, J = 11.0 Hz, 2H), 3.98 (dd, J = 11.2, 5.3 Hz, 1H), 3.84 (ddd,
J = 11.9, 5.5, 2.6 Hz, 1H), 3.71–3.65 (m, 2H), 3.52 (t, J = 9.1 Hz, 1H), 3.47 (t, J = 8.8 Hz, 1H), 3.32–3.29
(m, 1H), 3.23 (t, J = 10.8 Hz, 1H); 13
C
NMR (CDCl3, 150 MHz)
127.86, 86.73, 79.92, 77.79, 75.25, 74.95, 70.16, 69.30, 61.99.
2,3,4-Tri-O-benzyl-1,5-anhydro-d-glucitol (11) [46]; Compound
δ
138.45, 137.84, 128.71, 128.56, 128.02,
2
(860 mg, 2.0 mmol) in 10 mL
of toluene was stirred at rt. The reaction solution was added DIBAL-H (ca. 1M toluene solution,
6 mL) and stirred at rt for 20 h. The reaction solution was slowly added 4.2 mL of MeOH and 7.2 mL
of 30% Rochelle salt solution and stirred for 1 h. After the addition 20 mL of EtOAc, the mixture
was extracted with 30% Rochelle salt solution (3
×
15 mL). The organic layer was washed with brine,
dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by C.C.
(Hex/EtOAc = 4/1–2/1) to obtain 11 (760 mg, 90% yield) as colorless needles. m.p. 83 ◦C; [α]D20 = +8.9
(c 0.90, CHCl3); 1
H
NMR (CDCl3, 600 MHz)
5.2 Hz, 1H), 3.84–3.81 (m, 1H), 3.67–3.58 (m, 3H), 3.48 (t, J = 9.3 Hz, 1H), 3.29–3.25 (m, 1H), 3.23
t, J = 10.8 Hz, 1H); 13
NMR (CDCl3, 150 MHz) 138.61, 138.09, 138.01, 128.48, 128.41, 128.05, 127.89,
127.83, 127.64, 86.17, 79.69, 78.55, 77.57, 75.55, 75.13, 73.34, 67.96, 62.25.
δ 7.37–7.28 (m, 15H), 4.98–4.64 (m, 6H), 3.99 (dd, J = 11.3,
(
C
δ
1,5-Anhydro-6-O-benzyl-d-glucitol (12) [35]; Compound 1 (760 mg, 3.0 mmol) in 15 mL of DCM was
added triethylsilane (2.4 mL, 15 mmol) and trifluoracetic acid (1.2 mL, 15 mmol) at 0 ◦C. The reaction
solution was stirred at rt for 8 h. After the addition 10 mL of saturated aq. NaHCO3, the mixture was
extracted with DCM (5
×
30 mL). The combined organic layer was dried over Na2SO4, filtered and
concentrated under reduced pressure. The crude was purified by C.C (CHCl3/MeOH = 100/1–10/1)
to obtain 12 (471 mg, 62%) as a colorless oil. [α]2D0 = +8.9 (c 0.30, CHCl3); 1H NMR (CDCl3, 600 MHz)
δ
7.35–7.25 (m, 5H), 4.55 (d, J = 2.1 Hz, 2H), 3.88 (dd, J = 11.0, 5.5 Hz, 1H), 3.77 (dd, J = 10.8, 1.9 Hz,
1H), 3.60 (dd, J = 10.8, 5.7 Hz, 1H), 3.48–3.42 (m, 1H), 3.32–3.24 (overlap, 3H), 3.15 (t, J = 10.8 Hz, 1H);
13C NMR (CDCl3, 150 MHz)
139.57, 129.34, 128.90, 128.67, 81.38, 79.95, 74.48, 71.85, 71.31, 71.19, 70.95.
2,3,6-Tri-O-benzyl-1,5-anhydro-d-glucitol (13) [49]; Compound (860 mg, 2.0 mmol) in 10 mL
of DCM was added triethylsilane (1.6 mL, 10 mmol) and tifluoroacetic acid (0.8 mL, 10 mmol) at 0 ◦C.
The reaction solution was stirred at rt for 15 h. After the addition 5 mL of saturated aq. NaHCO3
the mixture was extracted with DCM (3 30 mL). The organic layer was washed with brine, dried
over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified
by C.C. (Hex/EtOAc = 4/1) to obtain 13 (505 mg, 59%) as a colorless oil. [α]D20
7.0 (c 1.00, CHCl3);
1H NMR (CDCl3, 600 MHz)
7.37–7.25 (m, 15H), 5.00, 4.76 (ABq, J = 11.5 Hz, 2H), 4.69, 4.63 (ABq,
δ
2
,
×
=
−
δ
J = 11.7 Hz, 2H), 4.58, 4.54 (ABq, J = 12.2 Hz, 2H), 4.04 (dd, J = 11.3, 5.2 Hz, 1H), 3.70 (dd, J = 10.5,
3.3 Hz, 1H), 3.64–3.60 (m, 2H), 3.54 (td, J = 9.2, 2.1 Hz, 1H), 3.44 (t, J = 8.9 Hz, 1H), 3.37–3.34 (m, 1H),
3.23 (t, J = 11.0 Hz, 1H); 13
C
NMR (CDCl3, 150 MHz)
δ 138.64, 138.05, 137.84, 128.58, 128.48, 128.39,
127.95, 127.90, 127.87, 127.83, 127.77, 127.70, 85.40, 78.75, 78.04, 75.10, 73.65, 73.05, 70.87, 69.98, 68.06.
2,6-Di-O-benzyl-1,5-anhydro-d-glucitol (14); Compound
was added triethylsilane (2.0 mL, 12.5 mmol) and tifluoroacetic acid (1.0 mL, 12.5 mmol) at 0 C.
3
(860 mg, 2.5 mmol) in 15 mL of DCM
◦
The reaction solution was stirred at rt for 8 h. After the addition 10 mL of saturated aq. NaHCO3
,
the mixture was extracted with DCM (3 40 mL). The organic layer was washed with brine, dried
×
over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by
C.C. (CHCl3/MeOH = 8/1) to obtain 14 (500 mg, 58%) as a white solid. [α]2D0 = +17.4 (c 1.00, CHCl3);
1H NMR (CDCl3, 600 MHz)
(
δ
7.36–7.27 (m, 10H), 4.64 (s, 2H), 4.59, 4.54 (ABq, J = 12.0 Hz, 2H), 4.02
dd, J = 11.2, 5.0 Hz, 1H), 3.69 (dd, J = 10.5, 3.6 Hz, 1H), 3.65 (dd, J = 10.5, 5.0 Hz, 1H), 3.55 (td, J = 8.8,
2.1 Hz, 1H), 3.50 (td, J = 9.0, 2.6 Hz, 1H), 3.47–3.43 (m, 1H), 3.37–3.34 (m, 1H), 3.19 (t, J = 10.8 Hz, 1H);
13C NMR (CDCl3, 150 MHz)
137.96, 137.71, 128.59, 128.46, 128.07, 127.90, 127.81, 78.31, 77.74, 77.41,
δ

Molecules 2019, 24, 4340
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73.68, 72.95, 71.34, 70.01, 67.70. HRMS (ESI, m/z): [M + Na]+, calcd for [C20H24O5 Na]+: 367.1521;
found 367.1521.
1,5-Anhydro-3,6-di-O-benzyl-d-glucitol (15); Compound 4 (680 mg, 2.0 mmol) in 15 mL of DCM was
added triethylsilane (1.6 mL, 10 mmol) and trifluoroacetic acid (0.80 mL, 10 mmol) at 0 ◦C. The reaction
solution was stirred at rt for 4 h. After the addition 10 mL of saturated aq. NaHCO3, the mixture
was extracted with DCM (3
×
40 mL). The combined organic layer was washed with brine, dried
over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified
by C.C. (CHCl3/MeOH = 8/1) to obtain 15 (420 mg, 62%) as a white solid. [α]2D0 = +22.7 (c 1.00,
CHCl3); 1
H
NMR (CDCl3, 600 MHz)
ABq, J = 12.2 Hz, 2H), 3.96 (dd, J = 11.2, 5.3 Hz, 1H), 3.72–3.66 (m, 3H), 3.61 (dt, J = 9.1, 2.6 Hz, 1H),
3.39–3.36 (m, 1H), 3.31 (t, J = 8.8 Hz, 1H), 3.21 (t, J = 10.8 Hz, 1H); 13
NMR (CDCl3, 150 MHz) 138.60,
δ 7.39–7.27 (m, 10H), 4.91, 4.83 (ABq, J = 11.7 Hz, 2H), 4.59, 4.54
(
C
δ
137.61, 128.70, 128.47, 128.02, 127.93, 127.86, 127.82, 86.47, 78.47, 74.87, 73.74, 72.11, 70.38, 69.79, 69.57.
HRMS (ESI, m/z): [M + Na]+, calcd for [C20H24O5 Na]+: 367.1521; found 367.1522.
1,5-Anhydro-2-O-(30,40,50-tribenzyloxybenzoyl)-3-O-benzyl-4,6-O-benzylidene-d-glucitol (17); Compound
3
(340 mg, 1.0 mmol), compound 16
(380 mg, 1.5 mmol), DMAP (37 mg, 0.30 mmol), TEA (416
rt for 20 h. After the addition 100 mL of saturated aq. NH4Cl, the reaction solution was extracted with
DCM (3 60 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and
concentrated under reduced pressure. The crude was purified by C.C. (DCM/MeOH = 500/1 − 200/1
to obtain 17 (350 mg, 41%) as a colorless amorphous oil. [α]2D0 = +8.4 (c 1.04, CHCl3); 1
NMR (CDCl3
600 MHz) 7.53–7.11 (m, 29H), 5.61 (s, 1H), 5.27–5.20 (m, 1H), 5.15 (s, 2H), 5.09 (s, 4H), 4.86, 4.71 (ABq,
J = 12.0 Hz, 2H), 4.36 (dd, J = 10.3, 4.8 Hz, 1H), 4.19 (dd, J = 11.0, 5.8 Hz, 1H), 3.87 (t, J = 9.1 Hz, 1H),
3.79–3.74 (m, 2H), 3.45 (td, J = 9.7, 4.9 Hz, 1H), 3.36 (t, J = 10.8 Hz, 1H); 13
NMR (CDCl3, 150 MHz)
[39] (650 mg, 1.5 mmol), 2-chloro-1-methylpyridinium iodide
µL, 3.0 mmol) in 15 mL of DCM was stirred at
×
)
H
,
δ
C
δ
165.06, 152.55, 142.74, 138.10, 137.31, 137.28, 136.56, 129.03, 128.57, 128.30, 128.25, 128.22, 128.07, 128.02,
127.89, 127.58, 127.47, 126.02, 124.50, 109.41, 101.32, 81.96, 79.12, 75.14, 74.33, 71.50, 71.30, 68.76, 67.68;
HRMS (ESI, m/z): [M + Na]+, calcd for [C48H44O9 Na]+: 787.2883; found 787.2881.
1,5-Anhydro-2-O-benzyl-3-O-(30,40,50-tribenzyloxybenzoyl)-4,6-O-benzylidene-d-glucitol (18); Compound
2
(0.51 g, 1.5 mmol), compound 16 (1.0 g, 2.3 mmol), 2-chloro-1-methylpyridinium iodide (0.59 g,
2.3 mmol), DMAP (28 mg, 0.23 mmol), TEA (0.62 mL, 4.5 mmol) in 20 mL of DCM was stirred at rt for
20 h. By the same procedure previously described for the preparation of compound 17, compound
18 (0.87 g, 68%) was obtained as a colorless amorphous oil. [α]D20
(
=
−
45.6 (c 0.95, CHCl3); 1
CDCl3, 600 MHz) δ 7.24–7.44 (m, 24H), 7.20–7.14 (m, 5H), 5.53 (t, J = 9.3 Hz, 1H), 5.46 (s, 1H), 5.15–5.10
H NMR
(m, 6H), 4.55, 4.46 (ABq, J = 12.4 Hz, 2H), 4.35 (dd, J = 10.5, 5.0 Hz, 1H), 4.13 (dd, J = 11.3, 5.5 Hz, 1H),
3.76–3.72 (m, 1H), 3.70 (t, J = 10.3 Hz, 1H), 3.65 (t, J = 9.5 Hz, 1H), 3.51 (td, J = 9.7, 4.8 Hz, 1H), 3.48
(t, J = 11.0 Hz, 1H); 13
C NMR (CDCl3, 150 MHz) δ 165.16, 152.47, 142.58, 137.53, 137.39, 136.69, 128.95,
128.54, 128.38, 128.21, 128.16, 128.02, 127.98, 127.87, 127.53, 126.14, 125.05, 109.55, 101.35, 79.18, 75.62,
75.15, 74.94, 72.97, 71.48, 71.33, 68.80, 68.74; HRMS (ESI, m/z): [M + Na]+, calcd for [C48H44O9 Na]+
:
787.2883; found 787.2882.
1,5-Anhydro-2,3,6-tris-O-benzyl-4-O-(30,40,50-tribenzyloxybenzoyl)-d-glucitol (19); Compound 13
(340 mg, 0.78 mmol), compound 16 (530 mg, 1.2 mmol), 2-chloro-1-methylpyridinium iodide (307 mg,
1.2 mmol), DMAP (95 g, 0.78 mmol), TEA (315
2 d. By the same procedure previously described for the preparation of compound 17, compound 19
(607 mg, 91%) was obtained as a colorless amorphous oil. [α]2D0 32.0 (c 0.95, CHCl3); 1H NMR
CDCl3, 600 MHz) 7.44–7.26 (m, 20H), 7.23–7.15 (m, 7H), 7.11–7.03 (m, 5H), 5.18–5.15 (m, 3H),
5.13–5.07 (m, 4H), 4.76, 4.54 (ABq, J = 11.3 Hz, 2H), 4.74, 4.65 (ABq, J = 11.7 Hz, 1H), 4.45 (s, 2H), 4.08
dd, J = 11.3, 5.2 Hz, 1H), 3.75–3.71 (m, 1H), 3.65 (t, J = 9.1 Hz, 1H), 3.59–3.56 (m, 1H), 3.50 (dd, J = 10.8
2.6 Hz, 1H), 3.45 (dd, J = 10.7, 5.8 Hz, 1H), 3.29 (t, J = 11.0 Hz, 1H); 13
NMR (CDCl3, 150 MHz)
µL, 2.3 mmol) in 15 mL of DCM was stirred at rt for
=
−
(
δ
(
,
C
δ
164.83, 152.41, 142.58, 138.03, 137.58, 137.37, 136.62, 128.57, 128.50, 128.23, 128.14, 128.06, 128.01, 127.94,
127.86, 127.83, 127.58, 127.49, 127.45, 124.67, 109.34, 83.08, 78.18, 78.08, 75.13, 74.94, 73.67, 73.40, 71.24,
69.47, 68.23; HRMS (ESI, m/z): [M + Na]+, calcd for [C55H52O9 Na]+: 879.3509; found 879.3511.

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1,5-Anhydro-2,3,4-tris-O-benzyl-6-O-(30,40,50-tribenzyloxybenzoyl)-d-glucitol (20); Compound 11
(0.43 g, 1.0 mmol), compound 16 (0.66 g, 1.5 mmol), 2-chloro-1-methylpyridinium iodide (0.38 g,
1.5 mmol), DMAP (0.18 g, 1.5 mmol), TEA (0.42 mL, 3.0 mmol) in 20 mL of DCM was stirred at rt for
2 d. By the same procedure previously described for the preparation of compound 17, compound
20 (0.50 g, 58%) was obtained as a colorless amorphous oil. [α]2D0 = +27.9 (c 1.00, CHCl3); 1
H
NMR
(CDCl3, 600 MHz) δ 7.43–7.18 (m, 32H), 5.14–5.10 (m, 6H), 5.03, 4.88 (ABq, J = 10.7 Hz, 2H), 4,85, 4.53
(ABq, J = 11.8 Hz, 2H), 4.74, 4.67 (ABq, J = 11.7 Hz, 2H), 4.52 (dd, J = 12.0, 2.1 Hz, 1H), 4.37 (dd, J = 12.0
,
4.5 Hz, 1H), 4.03 (dd, J = 11.3, 5.2 Hz, 1H), 3.69 (t, J = 8.8 Hz, 1H), 3.66–3.62 (m, 1H), 3.52–3.49 (m, 1H),
3.46 (t, J = 8.9 Hz, 1H), 3.23 (t, J = 10.8 Hz, 1H); 13
C NMR (CDCl3, 150 MHz) δ 165.82, 152.41, 142.46,
138.55, 138.04, 137.69, 137.37, 136.65, 128.59, 128.53, 128.48, 128.46, 128.20, 128.08, 128.01, 127.96, 127.93,
127.85, 127.76, 127.45, 124.91, 109.30, 86.33, 78.48, 77.83, 77.57, 75.73, 75.23, 75.09, 73.29, 71.17, 68.12,
63.86; HRMS (ESI, m/z): [M + Na]+, calcd for [C55H52O9 Na]+: 879.3509; found 879.3509.
1,5-Anhydro-2,3-bis-O-(30,40,50-tribenzyloxybenzoyl)-4,6-O-benzylidene-d-glucitol (21); Compound
1
(380 mg, 1.5 mmol), compound 16 (2.0 g, 4.5 mmol), 2-chloro-1-methylpyridinium iodide (1.2 g,
4.5 mmol), DMAP (0.55 g, 4.5 mmol), TEA (1.3 mL, 9.0 mmol) in 20 mL of DCM was stirred at rt for
2 d. By the same procedure previously described for the preparation of compound 17, compound 21
(1.6 g, 88%) was obtained as a colorless amorphous oil. [α]2D0 = +46.4 (c 1.00, CHCl3); 1
H
NMR ( CDCl3
7.44–7.42 (m, 6H), 7.34–7.31 (m, 26H), 7.25–7.22 (m, 4H), 5.80 (t, J = 9.5 Hz, 1H), 5.56 (s, 1H),
5.27–5.23 (m, 1H), 5.11–4.93 (m, 12H), 4.45–4.41 (m, 2H), 3.87 (t, J = 16.0 Hz, 1H), 3.82 (t, J = 17.0 Hz,
1H), 3.65–3.62 (m, 1H), 3.55 (t, J = 10.5 Hz, 1H); 13
NMR (CDCl3, 150 MHz) 165.6, 165.4, 152.6, 142.9,
,
600 MHz)
δ
C
δ
142.8, 137.4, 136.8, 136.5, 129.1, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.5, 126.2, 109.3, 109.1, 101.6,
78.8, 75.1, 73.0, 71.9, 71.2, 71.2, 71.1, 68.7, 67.7; HRMS (ESI, m/z): [M + Na]+, calcd for [C48H44O9 Na]+
:
1119.3932; found 1119.3901.
1,5-Anhydro-2,4-bis-O-(30,40,50-tribenzyloxybenzoyl)-3,6-bis-O-benzyl-d-glucitol (22); Compound 15
(0.30 mg, 0.87 mmol), compound 16 (1.3 g, 3.0 mmol), 2-chloro-1-methylpyridinium iodide (0.77 g,
3.0 mmol), DMAP (0.37 g, 3.0 mmol), TEA (0.83 mL, 6.0 mmol) in 20 mL of DCM was stirred at rt for
2 d. By the same procedure previously described for the preparation of compound 17, compound
22 (0.93 g, 77%) was obtained as a colorless amorphous oil. [α]2D0 = +7.87 (c 1.00, CHCl3); 1
H
NMR
7.58–7.14 (m, 45H), 7.08–6.95 (m, 5H), 5.32–5.25 (m, 2H), 5.19–5.08
(m, 13H), 4.61–4.45 (m, 4H), 4.29 (dd, J = 11.3, 5.5 Hz, 1H), 3.94 (t, J = 9.1 Hz, 1H), 3.72–3.68 (m, 1H),
3.58–3.53 (m, 2H), 3.39 (t, J = 10.8 Hz, 1H); 13C NMR (CDCl3, 150 MHz)
164.87, 164.71, 152.61, 152.51,
1H NMR (CDCl3, 600 MHz)
δ
δ
142.88, 142.79, 137.54, 137.52, 137.32, 137.27, 136.56, 136.49, 128.59, 128.57, 128.55, 128.28, 128.24, 128.22,
128.16, 128.10, 128.05, 128.02, 127.85, 127.76, 127.65, 127.53, 127.49, 124.51, 109.43, 80.72, 78.29, 75.16,
74.16, 73.72, 72.12, 71.35, 71.32, 69.44, 67.03; HRMS (ESI, m/z): [M + Na]+, calcd for [C76H68O13 Na]+
:
1211.4558; found 1211.4554.
1,5-Anhydro-2,6-bis-O-(30,40,50-tribenzyloxybenzoyl)-3,4-bis-O-benzyl-d-glucitol (23); Compound 10
(0.45 g, 1.3 mmol), compound 16 (1.8 g, 4.0 mmol), 2-chloro-1-methylpyridinium iodide (1.0 g, 4.0 mmol),
DMAP (0.49 g, 4.0 mmol), TEA (1.1 mL, 8.0 mmol) in 30 mL of DCM was stirred at rt for 2 d. By the
same procedure previously described for the preparation of compound 17, compound 23 (1.4 g, 92%)
was obtained as a colorless amorphous oil. [α]2D0 = +51.2 (c 1.00, CHCl3); 1
δ
H
NMR (CDCl3, 600 MHz)
7.43–7.18 (m, 44H), 5.27–5.21 (m, 1H), 5.17–5.07 (m, 12H), 4.82, 4.52 (ABq, J = 11.0 Hz, 2H), 4.77,
4.70 (ABq, J = 11.3 Hz, 2H), 4.56 (m, 1H), 4.42–4.39 (m, 1H), 4.19 (dd, J = 11.2, 5.7 Hz, 1H), 3.85–3.82
(m, 1H), 3.60–3.56 (m, 2H), 3.31 (t, J = 10.7 Hz, 1H); 13
NMR (CDCl3, 150 MHz) 165.80, 165.05, 152.56,
C
δ
152.43, 142.76, 142.47, 137.88, 137.49, 137.37, 137.28, 136.66, 136.53, 128.62, 128.60, 128.57, 128.51, 128.39,
128.21, 128.12, 128.06, 128.01, 127.88, 127.80, 127.40, 127.37, 124.80, 124.49, 109.32, 109.25, 84.32, 77.91,
77.42, 75.45, 75.26, 75.13, 75.09, 72.22, 71.26, 71.15, 67.11, 63.52; HRMS (ESI, m/z): [M + Na]+, calcd for
[C76H68O13 Na]+: 1211.4558; found 1211.4550.
1,5-Anhydro-2,6-bis-O-benzyl-3,4-bis-O-(30,40,50-tribenzyloxybenzoyl)-d-glucitol (24); Compound 14
(380 mg, 1.1 mmol), compound 16 (1.5 g, 3.3 mmol), 2-chloro-1-methylpyridinium iodide (0.84 g,
3.3 mmol), DMAP (0.91 g, 3.3 mmol), TEA (0.91 mL, 6.6 mmol) in 30 mL of DCM was stirred at rt for

Molecules 2019, 24, 4340
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2 d. By the same procedure previously described for the preparation of compound 17, compound 24
(1.2 g, 92%) was obtained as a colorless amorphous oil. [α]2D0 80.8 (c 1.00, CHCl3); 1
NMR (CDCl3
600 MHz) 7.41–7.14 (m, 44H), 5.58 (t, J = 9.5 Hz, 1H), 5.31 (t, J = 9.8 Hz, 1H), 5.09–5.00 (m, 12H),
4.54, 4.48 (ABq, J = 12.2 Hz, 2H), 4.52, 4.47 (ABq, J = 12.0 Hz, 2H), 4.19 (dd, J = 11.5, 5.3 Hz, 1H), 3.79
=
−
H
,
δ
(
(
td, J = 9.9, 5.2 Hz, 1H), 3.73 (m, 1H), 3.59 (dd, J = 10.7, 2.4 Hz, 1H), 3.51 (dd, J = 10.8, 5.3 Hz, 1H), 3.46
t, J = 11.0 Hz, 1H); 13
C
NMR (CDCl3, 150 MHz) 165.62, 165.18, 152.43, 142.67, 142.53, 137.56, 137.48,
δ
137.43, 137.39, 136.57, 136.56, 128.49, 128.41, 128.38, 128.36, 128.27, 128.16, 127.98, 127.89, 127.87, 127.84,
127.65, 127.55, 124.67, 124.20, 109.15, 77.99, 76.35, 75.22, 75.10, 75.08, 73.70, 72.96, 71.12, 70.07, 69.06,
68.30; HRMS (ESI, m/z): [M + Na]+, calcd for [C76H68O13 Na]+: 1211.4558; found 1211.4558.
1,5-Anhydro-2,4-bis-O-benzyl-3,6-bis-O-(30,40,50-tribenzyloxybenzoyl)-d-glucitol (25); Compound
9
(0.52 mg, 1.5 mmol), compound 16 (2.0 g, 4.5 mmol), 2-chloro-1-methylpyridinium iodide (1.2 g,
4.5 mmol), DMAP (0.55 g, 4.5 mmol), TEA (1.2 mL, 9.0 mmol) in 20 mL of DCM was stirred at rt for
2 d. By the same procedure previously described for the preparation of compound 17, compound
25 (1.6 g, 91%) was obtained as a colorless amorphous oil. [α]2D0 = +16.1 (c 1.00, CHCl3); 1H NMR
(CDCl3, 600 MHz) δ 7.43–7.24 (m, 34H), 7.18–7.05 (m, 10H), 5.50 (t, J = 9.3 Hz, 1H), 5.19–5.08 (m, 12H),
4.56, 4.43 (ABq, J = 12.4 Hz, 2H), 4.55 (dd, J = 12.0 Hz, 2.0 Hz, 1H), 4.45 (dd, J = 12.0, 5.5 Hz, 1H) 4.41
(s, 2H), 4.11 (dd, J = 11.3, 5.2 Hz, 1H), 3.67–3.62 (m, 2H), 3.54 (t, J = 9.5 Hz, 1H), 3.36 (t, J = 11.0 Hz, 1H);
13C NMR (CDCl3, 150 MHz)
δ 165.84, 165.22, 152.49, 142.66, 137.65, 137.31, 136.99, 136.59, 128.56, 128.36,
128.22, 128.16, 128.05, 127.94, 127.83, 127.52, 127.47, 124.96, 124.88, 109.54, 109.51, 78.19, 77.87, 76.42,
75.26, 75.13, 74.68, 72.63, 71.32, 67.97, 63.91; HRMS (ESI, m/z): [M + Na]+, calcd for [C76H68O13 Na]+
:
1211.4558; found 1211.4557.
1,5-Anhydro-2,3-bis-O-benzyl-4,6-bis-O-(30,40,50-tribenzyloxybenzoyl)-d-glucitol (26); Compound
5
(0.34 g, 1.0 mmol), compound 16 (1.3 g, 3.0 mmol), 2-chloro-1-methylpyridinium iodide (0.77 g,
3.0 mmol), DMAP (0.37 g, 3.0 mmol), TEA (0.83 mL, 6.0 mmol) in 20 mL of DCM was stirred at rt for
2 d. By the same procedure previously described for the preparation of compound 17, compound 26
(1.0 g, 87%) was obtained as a colorless amorphous oil. [α]2D0 = +13.7 (c 1.00, CHCl3); 1
H NMR (CDCl3,
600 MHz) δ 7.45–7.21 (m, 39H), 7.12–7.03 (m, 5H), 5.32 (t, J = 9.5 Hz, 1H), 5.15–5.08 (m, 8H), 5.03–5.01
(m, 4H), 4.79, 4.58 (ABq, J = 11.5, 2H), 4.76, 4.66 (ABq, J = 11.5 Hz, 2H), 4.63 (dd, J = 12.0, 2.8 Hz, 1H),
4.12 (dd, J = 12.2, 5.3 Hz, 1H), 4.07 (dd, J = 11.5, 5.0 Hz, 1H), 3.70–3.68 (m, 2H), 3.70 (t, J = 8.9 Hz, 1H),
3.30 (t, J = 10.8 Hz, 1H); 13
C NMR (CDCl3, 150 MHz) δ 165.80, 164.76, 152.48, 152.44, 142.77, 142.42,
137.98, 137.91, 137.47, 137.37, 136.73, 136.56, 128.53, 128.50, 128.47, 128.20, 128.17, 128.07, 128.03, 128.01,
127.94, 127.84, 127.60, 127.53, 124.75, 124.54, 109.40, 109.14, 82.95, 78.22, 76.56, 75.15, 75.08, 73.47, 71.24,
71.06, 70.96, 68.32, 63.44; HRMS (ESI, m/z): [M + Na]+, calcd for [C76H68O13 Na]+: 1211.4558; found
1211.4553.
1,5-Anhydro-2,3,4-tris-O-(30,40,50-tribenzyloxybenzoyl)-6-O-benzyl-d-glucitol (27); Compound 12
(180 mg, 0.70 mmol), compound 16 (1.4 g, 3.2 mmol), 2-chloro-1-methylpyridinium iodide (0.82 g,
3.2 mmol), DMAP (0.39 g, 3.2 mmol), TEA (0.89 mL, 6.4 mmol) in 20 mL of DCM was stirred at rt for
2 d. By the same procedure previously described for the preparation of compound 17, compound
27 (0.94 g, 91%) was obtained as a colorless amorphous oil. [α]D20
CDCl3, 600 MHz)
=
−
4.9 (c 0.65, CHCl3); 1H NMR
7.43–7.16 (m, 56H), 5.82 (t, J = 9.6 Hz, 1H), 5.55 (t, J = 10.0 Hz, 1H), 5.29 (td, J = 10.0,
(
δ
5.5 Hz, 1H), 5.13–4.96 (m, 14H), 4.90 (s, 4H), 4.58, 4.53 (ABq, J = 12.0, 2H), (dd, J = 10.2, 5.6 Hz, 1H),
3.88–3.84 (m, 1H), 3.67 (dd, J = 11.0, 2.4 Hz, 1H), 3.61 (dd, J = 10.8, 5.3 Hz, 1H), 3.57 (t, J = 10.8 Hz,
1H) 13
C NMR (CDCl3, 150 MHz) δ 165.92, 165.17, 165.02, 152.54, 152.50, 142.88, 142.82, 142.71, 137.44,
137.34, 136.49, 136.45, 136.36, 128.55, 128.51, 128.39, 128.32, 128.27, 128.17, 128.15, 128.10, 128.06, 128.02,
127.95, 127.92, 127.89, 127.81, 127.72, 127.56, 127.52, 124.08, 124.03, 109.20, 109.11, 109.02, 78.36, 75.12,
75.09, 75.07, 74.65, 73.77, 71.18, 71.10, 71.02, 70.75, 69.71, 69.00, 67.26; HRMS (ESI, m/z): [M + Na]+
calcd for [C97H84O17 Na]+: 1543.5606; found 1543.5601.
,
1,5-Anhydro-2,3,6-tris-O-(30,40,50-tribenzyloxybenzoyl)-4-O-benzyl-d-glucitol (28); Compound
8 (0.38 mg,
1.5 mmol), compound 16 (3.0 g, mmol), 2-chloro-1-methylpyridinium iodide (1.8 g, 7.0 mmol), DMAP
(0.12 g, 1.0 mmol), TEA (1.9 mL, 14 mmol) in 30 mL of DCM was stirred at rt for 1 d. By the same procedure

Molecules 2019, 24, 4340
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previously described for the preparation of compound 17, compound 28 (1.0 g, 45% yield) was obtained
as a colorless amorphous oil. [α]2D0 = +47.2 (c 0.40, CHCl3); 1
NMR (CDCl3, 600 MHz) 7.47–7.19
H
δ
(m, 51H), 7.11–7.05 (m, 5H), 5.75 (t, J = 9.1 Hz, 1H), 5.19–5.03 (m, 15H), 5.00, 4.92 (ABq, J = 11.7 Hz
,
,
4H), 4.60–4.53 (m, 2H), 4.45 (s, 2H), 4.41 (dd, J = 11.3, 5.5 Hz, 1H), 3.75–3.70 (m, 2H), 3.46 (t, J = 10.8 Hz
1H); 13
C NMR (CDCl3, 150 MHz) δ 165.84, 165.51, 165.41, 152.59, 152.54, 142.94, 142.75, 142.65, 137.35,
137.32, 137.27, 136.86, 136.62, 136.51, 136.39, 128.60, 128.54, 128.46, 128.44, 128.38, 128.22, 128.18, 128.14,
128.08, 128.06, 128.01, 127.97, 127.90, 127.61, 127.50, 127.43, 124.81, 124.40, 124.05, 109.54, 109.29, 109.03,
78.11, 76.54, 76.04, 75.14, 75.11, 75.09, 74.96, 71.34, 71.20, 71.06, 70.81, 67.07, 63.58; HRMS (ESI, m/z):
[M + Na]+, calcd for [C97H84O17 Na]+: 1543.5606; found 1543.5604.
1,5-Anhydro-2,4,6-tris-O-(30,40,50-tribenzyloxybenzoyl)-3-O-benzyl-d-glucitol (29); Compound
7 (0.33 mg,
1.3 mmol), compound 16 (2.6 g, 6.0 mmol), 2-chloro-1-methylpyridinium iodide (1.5 g, 6.0 mmol), DMAP
(0.73 g, 6.0 mmol), TEA (1.7 mL, 12 mmol) in 20 mL of DCM was stirred at rt for 2 d. By the same
procedure previously described for the preparation of compound 17, compound 29 (1.3 g, 65% yield)
was obtained as a colorless amorphous oil. [α]2D0 = +26.7 (c 0.95, CHCl3); 1
H NMR (CDCl3, 600 MHz) δ
7.46–7.21 (m, 49H), 7.07–6.96 (m, 5H), 5.48 (t, J = 9.5 Hz, 1H), 5.34–5.29 (m, 1H), 5.17–5.07 (m, 14H), 5.04
(s, 4H), 4.68 (dd, J = 12.0, 3.1 Hz, 1H), 4.62, 4.54 (ABq, J = 11.7 Hz, 2H), 4.30 (dd, J = 11.2, 5.7 Hz, 1H),
4.22 (dd, J = 12.2, 5.0 Hz, 1H), 3.99 (t, J = 9.1 Hz, 1H), 3.90–3.87 (m, 1H), 3.42 (t, J = 10.8 Hz, 1H); 13
C
NMR (CDCl3, 150 MHz) δ 165.81, 164.83, 164.61, 152.63, 152.55, 152.46, 142.94, 142.49, 137.46, 137.41,
137.33, 137.24, 136.67, 136.50, 136.46, 128.57, 128.53, 128.51, 128.46, 128.21, 128.19, 128.14, 128.10, 128.06,
128.02, 127.95, 127.85, 127.80, 127.62, 127.56, 127.47, 124.64, 124.41, 124.38, 109.47, 109.44, 109.13, 80.62,
76.53, 75.16, 75.08, 74.34, 72.02, 71.35, 71.30, 71.05, 70.98, 67.05, 63.33; HRMS (ESI, m/z): [M + Na]+
calcd for [C97H84O17 Na]+: 1543.5606; found 1543.5599.
,
1,5-Anhydro-2-O-benzyl-3,4,6-tris-O-(30,40,50-tribenzyloxybenzoyl)-d-glucitol (30); Compound
6 (0.38 g,
1.5 mmol), compound 16 (3.0 g, 6.8 mmol), 2-chloro-1-methylpyridinium iodide (1.7 g, 6.8 mmol), DMAP
(0.83 g, 6.8 mmol), TEA (2.0 mL, 14 mmol) in 30 mL of DCM was stirred at rt for 2 days. By the same
procedure previously described for the preparation of compound 17, compound 30 (2.0 g, 89% yield)
was obtained as a colorless amorphous oil. [α]D20
= H NMR (CDCl3, 600 MHz) δ
36.2 (c 1.00, CHCl3); 1
−
7.42–7.14 (m, 54H), 5.67 (t, J = 9.6 Hz, 1H), 5.41 (t, J = 9.8 Hz, 1H), 5.13–4.94 (m, 18H), 4.69 (dd, J = 12.2,
2.9 Hz, 1H), 4.59, 4.51 (ABq, J = 12.4 Hz, 2H), 4.23 (dd, J = 12.4, 5.5 Hz, 1H), 4.19 (dd, J = 11.5, 5.3 Hz,
1H) 3.92 (m, 1H), 3.83 (td, J = 9.8, 5.3 Hz, 1H), 3.48 (t, J = 11.0 Hz, 1H); 13
C NMR (CDCl3, 150 MHz) δ
165.68, 165.65, 165.29, 152.51, 152.48, 152.40, 142.87, 142.66, 142.53, 137.54, 137.43, 137.38, 136.63, 136.46,
128.51, 128.46, 128.43, 128.38, 128.29, 128.15, 128.11, 127.98, 127.92, 127.89, 127.87, 127.80, 127.78, 127.57,
127.52, 124.65, 124.53, 123.97, 109.18, 76.69, 76.16, 75.17, 75.08, 72.95, 71.13, 71.03, 70.20, 68.38, 63.54;
HRMS (ESI, m/z): [M + Na]+, calcd for [C97H84O17 Na]+: 1543.5606; found 1543.5607.
1,5-Anhydro-2-O-(30,40,50-trihydroxybenzoyl)-d-glucitol (31) [31]; Pd(OH)2 on C (20 wt.%, 20 mg)
was added to a solution of 17 (270 mg, 0.35 mmol) in 10 mL of MeOH and 10 mL of THF under the
argon. After the replaced argon atmosphere to hydrogen gas, the suspension was stirred at rt for
6 h. The reaction mixture was filtered and concentrated under reduced pressure to obtain purple
amorphous oil. The purple amorphous oil was dissolved by 2 mL acetone and filtered through
a whatman
amorphous oil dissolved with 2 mL of MeOH and added acidic resin until becoming a clear solution.
After the filtered through the whatman puradisc 0.1 m TF, the solution was concentrated under
reduced pressure to give 31 (106 mg, 96%) as pale yellow amorphous oil. [α]2D0 = +58.5 (c 0.70, MeOH);
1H NMR (CD3OD, 600 MHz)
7.08 (d, J = 5.5 Hz, 2H), 4.87–4.83 (overlap, 1H), 4.08 (dd, J = 10.5, 5.5 Hz,
1H), 3.86 (dd, J = 11.9, 2.2 Hz, 1H), 3.66–3.63 (m, 2H), 3.36 (t, J = 9.5 Hz, 1H), 3.29 (t, J = 10.7 Hz, 1H),
™ puradisc 0.1 µM TF and concentrated under reduced pressure. In addition, the purple
™
µ
δ
3.24 (ddd, J = 9.7, 5.9, 2.3 Hz, 1H). 13
C NMR (CD3OD, 150 MHz) δ 167.80, 146.42, 139.92, 121.14, 110.25,
82.56, 77.06, 73.28, 71.97, 67.84, 62.93; HRMS (ES−, m/z): [M − H]−, calcd for [C13H15O9]−: 315.0716;
found 315.0718. Please find 1
Supplementary Materials.
H C NMR spectra of compounds 31–44, 54–58, 61 and 67 in the
NMR, 13

Molecules 2019, 24, 4340
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1,5-Anhydro-3-O-(30,40,50-trihydroxybenzoyl)-d-glucitol (32) [29]; Pd(OH)2 on C (20 wt.%, 20 mg)
was added to a solution of compound 18 (270 mg, 0.35 mmol) in 10 mL of MeOH and 10 mL of THF
under the argon. By the same procedure previously described for the preparation of compound 31
desired compound 32 (110 mg, quant.) was obtained as a colorless amorphous oil. [α]2D0 = +24.8
c 1.0 MeOH); 1H NMR CD3OD, 600 MHz)
7.13 (s, 2H), 5.04 (t, J = 9.3 Hz, 1H), 3.97 (dd, J = 11.3, 5.5 Hz,
1H), 3.85 (dd, J = 11.9, 2.2 Hz, 1H), 3.73–3.69 (m, 1H), 3.66 (dd, J = 12.0, 5.8 Hz, 1H), 3.51 (t, J = 9.5 Hz
,
(
δ
,
1H), 3.31–3.27 (overlap, 2H). 13
C NMR (CD3OD, 150 MHz) δ 168.50, 146.39, 139.64, 121.88, 110.34, 82.51,
81.20, 70.95, 69.98, 69.89, 62.75; HRMS (ES−, m/z): [M − H]−, calcd for [C13H15O9]−: 315.0716; found
315.0721.
1,5-Anhydro-4-O-(30,40,50-trihydroxybenzoyl)-d-glucitol (33) [29]; Pd(OH)2 on C (20 wt.%, 20 mg)
was added to a solution of compound 19 (280 mg, 0.33 mmol) in 10 mL of MeOH and 10 mL of THF
under the argon. By the same procedure previously described for the preparation of compound 31
desired compound 33 (100 mg, 96%) was obtained as a colorless amorphous oil. [α]D20
5.7 (c 0.90,
MeOH); 1
7.14 (s, 2H), 4.88 (t, J = 9.3 Hz, 1H), 3.94 (dd, J = 11.2,
,
=
−
H
NMR (Acetone − d6, 600 MHz)
δ
5.3 Hz, 1H), 3.68 (t, J = 8.9 Hz, 1H), 3.64–3.60 (m, 1H), 3.57 (dd, J = 12.0, 2.1 Hz, 1H), 3.51–3.44 (m, 2H),
3.25 (t, J = 10.8 Hz, 1H); 13C NMR (Acetone − d6 , 150 MHz) δ 166.59, 145.90, 138.86, 121.46, 110.07,
80.56, 77.44, 72.70, 71.38, 70.45, 62.54; HRMS (ES−, m/z): [M − H]−, calcd for [C13H15O9]−: 315.0716;
found 315.0718.
1,5-Anhydro-6-O-(30,40,50-trihydroxybenzoyl)-d-glucitol (34) [31]; Pd(OH)2 on C (20 wt.%, 20 mg)
was added to a solution of compound 20 (210 mg, 0.25 mmol) in 10 mL of MeOH and 10 mL of THF
under the argon. By the same procedure previously described for the preparation of compound 31
desired compound 55 (74 mg, 96%) was obtained as a colorless amorphous oil. [α]2D0 = +30.3 (c 1.00,
MeOH); 1
NMR (CD3OD, 600 MHz) 7.09 (s, 2H), 4.54 (dd, J = 11.9, 1.9 Hz, 1H), 4.35 (dd, J = 12.0,
5.5 Hz, 1H), 3.93 (dd, J = 11.2, 5.3 Hz, 1H), 3.51–3.55 (m, 1H), 3.48–3.45 (m, 1H), 3.40 (t, J = 8.6 Hz,
,
H
δ
1H), 3.37 (t, J = 8.6 Hz, 1H), 3.23 (t, J = 10.8 Hz, 1H). 13
C NMR (CD3OD, 150 MHz) δ 168.32, 146.36,
139.71, 121.26, 110.09, 79.91, 79.63, 71.59, 71.20, 70.86, 65.02; HRMS (ES−, m/z): [M − H]−, calcd for
[C13H15O9]−: 315.0716; found 315.0718.
1,5-Anhydro-2,3-bis-O-(30,40,50-trihydroxybenzoyl)-d-glucitol (35) [29]; Pd(OH)2 on C (20 wt.%, 50 mg)
was added to a solution of compound 21 (210 mg, 0.25 mmol) in 10 mL of MeOH and 10 mL of THF
under the argon. By the same procedure previously described for the preparation of compound 31
desired compound 35 (313 mg, quant.) was obtained as a colorless amorphous oil. [α]2D0 = +139.7
(c 1.00, MeOH); 1H NMR (CD3OD, 600 MHz)
7.05 (s, 2H), 6.96 (s, 2H), 5.41 (t, J = 9.5 Hz, 1H), 5.08
(td, J = 10.1, 5.3 Hz, 1H), 4.20 (dd, J = 11.0, 5.5 Hz, 1H), 3.90 (dd, J = 11.9, 2.2 Hz, 1H), 3.74–3.69 (m, 2H),
3.45 (t, J = 10.8 Hz, 1H), 3.40 (ddd, J = 9.6, 5.5, 2.1 Hz, 1H); 13
NMR (CD3OD, 150 MHz) 168.18,
,
δ
C
δ
167.38, 146.38, 146.34, 140.08, 139.85, 121.29, 120.55, 1−10.30, 110.25, 82.65, 77.91, 71.39, 69.83, 67.81, 62.57;
HRMS (ES−, m/z): [M − H]−, calcd for [C20H19O13] : 467.0826; found 467.0831.
1,5-Anhydro-2,4-bis-O-(30,40,50-trihydroxybenzoyl)-d-glucitol (36) [29]; Pd(OH)2 on C (20 wt.%,
50 mg) was added to a solution of compound 22 (680 mg, 0.57 mmol) in 20 mL of MeOH and
20 mL of THF under the argon. By the same procedure previously described for the preparation
of compound 31, desired compound 36 (267 mg, quant.) was obtained as a colorless amorphous
oil. [α]2D0 = +11.3 (c 0.70, MeOH); 1
H
NMR (Acetone − d6, 600 MHz)
δ 7.17 (s, 2H), 7.14 (dd, J = 9.8,
4.0 Hz, 2H), 5.04 (t, J = 9.5 Hz, 1H), 5.01–4.97 (m, 1H), 4.15–4.11 (m, 2H), 3.63–3.54 (m, 3H), 3.41
(
t, J = 10.8 Hz, 1H); 13C NMR (Acetone − d6 , 150 MHz) δ 166.39, 166.21, 146.00, 145.98, 138.99, 138.94,
121.43, 121.38, 110.15, 110.09, 80.72, 74.30, 73.19, 72.73, 67.38, 62.49; HRMS (ES−, m/z): [M − H]−, calcd
for [C20H19O13]−: 467.0826; found 467.0827.
1,5-Anhydro-2,6-bis-O-(30,40,50-trihydroxybenzoyl)-d-glucitol (37) [26]; Pd(OH)2 on C (20 wt.%, 50 mg)
was added to a solution of compound 23 (440 mg, 0.37 mmol) in 20 mL of MeOH and 20 mL of THF
under the argon. By the same procedure previously described for the preparation of compound
31, desired compound 37 (170 mg, quant.) was obtained as a yellow amorphous oil. [α]2D0 = +19.4
(c 1.00 in MeOH); 1H NMR (Acetone − d6, 600 MHz)
δ 7.16 (s, 2H), 7.14 (s, 2H), 4.92–4.88 (m, 1H),

Molecules 2019, 24, 4340
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4.57 (d, J = 10.7 Hz, 1H), 4.41–4.35 (m, 1H), 4.07 (dd, J = 10.8, 5.3 Hz, 1H), 3.83–3.78 (m, 1H), 3.61–3.57
(m, 2H), 3.37 (t, J = 10.7 Hz, 1H); 13C NMR (Acetone − d6 , 150 MHz) δ 166.63, 166.30, 146.02, 145.96,
138.89, 1−38.77, 121.74, 121.46, 110.07, 109.85, 79.47, 76.57, 72.94, 71.60, 67.45, 64.54; HRMS (ES−, m/z):
[M − H] , calcd for [C20H19O13]−: 467.0826; found 467.0831.
1,5-Anhydro-3,4-bis-O-(30,40,50-trihydroxybenzoyl)-d-glucitol (38); Pd(OH)2 on C (20 wt.%, 50 mg)
was added to a solution of compound 24 (710 mg, 0.60 mmol) in 20 mL of MeOH and 20 mL of THF
under the argon. By the same procedure previously described for the preparation of compound 31
desired compound 38 (280 mg, quant.) was obtained as a yellow amorphous oil. [α]D20
78.2 (c 1.00,
MeOH); 1
NMR (Acetone − d6, 600 MHz) 7.06 (s, 2H), 7.04 (s, 2H), 5.40 (t, J = 9.5 Hz, 1H), 5.16
,
=
−
H
δ
(
t, J = 9.6 Hz, 1H), 4.06 (dd, J = 11.3, 5.5 Hz, 1H), 3.98–3.93 (m, 1H), 3.71–3.64 (m, 2H), 3.58 (dd, J = 12.5,
5.7 Hz, 1H), 3.45 (t, J = 10.8 Hz, 1H); 13C NMR (Acetone − d6 , 150 MHz) δ 166.41, 166.12, 145.83,
145.72, 139.04,−138.66, 121.52, 120.78, 110.05, 110.01, 80.29, 78.04, 70.50, 70.17, 69.50, 62.25; HRMS (ES−
,
m/z): [M − H] , calcd for [C20H19O13]−: 467.0826; found 467.0829.
1,5-Anhydro-3,6-bis-O-(30,40,50-trihydroxybenzoyl)-d-glucitol (39) [35]; Pd(OH)2 on C (20 wt.%, 50 mg)
was added to a solution of compound 25 (800 mg, 0.67 mmol) in 20 mL of MeOH and 20 mL of THF
under the argon. By the same procedure previously described for the preparation of compound 31
desired compound 39 (310 mg, quant.) was obtained as a yellow amorphous oil. [α]2D0 = +28.7 (c 0.60,
MeOH); 1
7.17 (s, 2H), 7.16 (s, 2H), 5.11 (t, J = 9.1 Hz, 1H), 4.57
,
H
NMR (Acetone − d6, 600 MHz)
δ
(dd, J = 11.9, 1.9 Hz, 1H), 4.40 (dd, J = 11.9, 5.3 Hz, 1H), 3.99 (dd, J = 11.0, 5.5 Hz, 1H), 3.84–3.79 (m, 1H),
3.72 (t, J = 9.5 Hz, 1H), 3.65–3.63 (m, 1H), 3.38 (t, J = 10.8 Hz, 1H); 13C NMR (Acetone − d6 , 150 MHz)
δ
166.90, 166.63, 145.97, 145.82, 138.71, 138.52, 122.16, 121.76, 110.10, 109.85, 81.10, 79.61, 70.73, 69.66,
69.46, 64.54; HRMS (ES−, m/z): [M − H]−, calcd for [C20H19O13]−: 467.0826; found 467.0828.
1,5-Anhydro-4,6-bis-O-(30,40,50-trihydroxybenzoyl)-d-glucitol (40) [35]; Pd(OH)2 on C (20 wt.%, 50 mg)
was added to a solution of compound 26 (430 mg, 0.36 mmol) in 20 mL of MeOH and 20 mL of THF
under the argon. By the same procedure previously described for the preparation of compound 31
desired compound 40 (160 mg, 95%) was obtained as a yellow amorphous oil. [α]2D0 = +41.7 (c 0.60,
MeOH); 1
NMR (Acetone − d6, 600 MHz) 7.15 (s, 2H), 7.14 (s, 2H), 5.09 (t, J = 9.5 Hz, 1H), 4.41
,
H
δ
(
dd, J = 12.0, 2.1 Hz, 1H), 4.13 (dd, J = 12.0, 5.8 Hz, 1H), 3.97 (dd, J = 11.2, 5.3 Hz, 1H), 3.82–3.79 (m, 1H),
3.75 (t, J = 9.1 Hz, 1H), 3.71–3.66 (m, 1H), 3.33 (t, J = 10.8 Hz, 1H); 13C NMR (Acetone − d6 , 150 MHz)
δ
166.47, 166.13, 145.92, 138.90, 138.77, 121.53−, 121.38, 110.12, 109.91, 77.56, 77.42, 72.24, 71.28, 70.51,
69.79, 63.98, 55.32; HRMS (ES−, m/z): [M − H] , calcd for [C20H19O13]−: 467.0826; found 467.0829.
1,5-Anhydro-2,3,4-tris-O-(30,40,50-trihydroxybenzoyl)-d-glucitol (41) [35]; Pd(OH)2 on C (20 wt.%,
50 mg) was added to a solution of compound 27 (520 mg, 0.34 mmol) in 20 mL of MeOH and 20 mL
of THF under the argon. By the same procedure previously described for the preparation of compound
31, desired compound 41 (210 mg, quant.) was obtained as a yellow amorphous oil. [α]D20
=
−
4.8 (c 1.00,
MeOH); 1H NMR (Acetone − d6, 600 MHz)
δ 7.07 (d, J = 3.8 Hz, 4H), 7.01 (d, J = 3.8 Hz, 2H), 5.77
(t, J = 9.6 Hz, 1H), 5.36 (t, J = 9.8 Hz, 1H), 5.23 (td, J = 10.1, 5.4 Hz, 1H), 4.28 (dd, J = 11.2, 5.7 Hz, 1H),
3.83–3.80 (m, 1H), 3.72 (dd, J = 12.4, 2.1 Hz, 1H), 3.62–3.65 (m, 2H); 13C NMR (Acetone − d6 , 150 MHz)
δ
166.12, 165.91, 165.89, 145.80, 145.65, 139.00, 138.76, 120.93, 120.70, 120.62, 110.03, 109.96, 109.91, 80.37,
74.46, 70.83, 69.96, 67.27, 61.99; HRMS (ES−, m/z): [M − H]−, calcd for [C27H23O17]−: 619.0935; found
619.0934.
1,5-Anhydro-2,3,6-tris-O-(30,40,50-trihydroxybenzoyl)-d-glucitol (42) [30]; Pd(OH)2 on C (20 wt.%,
50 mg) was added to a solution of compound 28 (410 mg, 0.27 mmol) in 20 mL of MeOH and
20 mL of THF under the argon. By the same procedure previously described for the preparation
of compound 31, desired compound 42 (170 mg, quant.) was obtained as a yellow amorphous oil.
[α]2D0 = +80.9 (c 0.70, MeOH); 1
H
NMR (Acetone − d6, 600 MHz)
δ 7.19 (s, 2H), 7.10 (s, 2H), 7.04 (s, 2H),
5.50 (t, J = 9.5 Hz, 1H), 5.13–5.09 (m, 1H), 4.60 (dd, J = 11.9, 1.9 Hz, 1H), 4.47 (dd, J = 12.0, 4.8 Hz,
1H), 4.20 (dd, J = 11.0, 5.5 Hz, 1H), 3.93 (t, J = 9.5 Hz, 1H), 3.79–3.77 (m, 1H), 3.56 (t, J = 10.8 Hz,
1H) 13C NMR (Acetone − d6 , 150 MHz) δ 166.60, 166.39, 166.03, 146.05, 145.96, 145.87, 139.15, 138.86,

Molecules 2019, 24, 4340
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138.81, 121.64,−121.56, 120.75, 110.06, 110.00, 109.89, 79.67, 77.07, 70.84, 69.60, 67.44, 64.23; HRMS (ES−
1,5-Anhydro-2,4,6-tris-O-(30,40,50-trihydroxybenzoyl)-d-glucitol (43) [29]; Pd(OH)2 on C (20 wt.%,
50 mg) was added to a solution of compound 29 (480 mg, 0.32 mmol) in 20 mL of MeOH and
20 mL of THF under the argon. B By the same procedure previously described for the preparation
of compound 31, desired compound 37 (200 mg, quant.) was obtained as a yellow amorphous oil.
,
m/z): [M − H] , calcd for [C27H23O17]−: 619.0935; found 619.0931.
[α]2D0 = +36.3 (c 1.00, MeOH); 1
H
NMR (Acetone − d6, 600 MHz)
δ 7.17 (s, 2H), 7.16 (s, 2H), 7.15 (s, 2H),
5.25 (dd, J = 10.0, 9.3 Hz, 1H), 5.07–5.03 (m, 1H), 4.46 (dd, J = 12.2, 1.9 Hz, 1H), 4.20–4.16 (m, 3H),
3.95–3.92 (m, 1H), 3.50 (t, J = 10.8 Hz, 1H); 13C NMR (Acetone − d6 , 150 MHz) δ 166.44, 166.19, 165.95,
145.98, 138.98, 138.83, 121.56, 121.35, 121.31, 110.20, 1−10.11, 109.96, 77.63, 74.27, 72.96, 72.22, 67.45, 63.76;
HRMS (ES−, m/z): [M − H]−, calcd for [C27H23O17] : 619.0935; found 619.0934.
1,5-Anhydro-3,4,6-tris-O-(30,40,50-trihydroxybenzoyl)-d-glucitol (44) [35]; Pd(OH)2 on C (20 wt.%,
50 mg) was added to a solution of compound 30 (765 mg, 0.50 mmol) in 20 mL of MeOH and 20 mL of THF
under the argon. By the same procedure previously described for the preparation of compound 31
desired compound 37 (310 mg, quant.) was obtained as a colorless amorphous oil. [α]D20
6.12 (c 0.80,
MeOH); 1
NMR (Acetone − d6, 600 MHz) 7.20 (s, 2H), 7.07 (s, 2H), 7.06 (s, 2H), 5.46 (t, J = 9.5 Hz
1H), 5.34 (t, J = 9.8 Hz, 1H), 4.47 (dd, J = 12.4, 2.1 Hz, 1H), 4.27 (dd, J = 12.2, 5.3 Hz, 1H), 4.12 (dd, J = 11.3
,
=
−
H
δ
,
,
5.5 Hz, 1H), 4.04–4.00 (m, 2H), 3.55 (t, J = 10.8 Hz, 1H) 13C NMR (Acetone − d6 , 150 MHz) δ 166.39,
166.35, 165.72, 145.83, 145.73, 145.66, 138.98, 138.74, 138.64, 121.44, 121.38, 120.67, 110.05, 109.97, 109.94,
77.86, 77.41, 70.54, 69.73, 69.41, 63.52; HRMS (ES−, m/z): [M − H]−, calcd for [C27H23O17]−: 619.0935;
found 619.0941.
3,4-bis(Benzyloxy)benzoic acid (45) [51]; Methyl 3,4-dihydroxybenzoate (2.5 g, 15 mmol) and K2CO3
(8.2 g, 60 mmol) and KI (2.0 g, 12 mmol) in 100 mL of acetone was stirred at rt. The reaction suspension
was slowly added BnCl (4.2 mL, 36 mmol) and refluxed for 7 h. TLC indicated full conversion of the
start material, added MeOH and stirred 1 h. The reaction mixture was filtered by celite and filtrate was
evaporated under reduced pressure. The residue was purified by recrystallization with hexane, and the
mother liquid was purified by C.C (Hex/EtOAc = 100/1–4/1) to afford methyl ester of 45 (total 5.0 g,
97%) as a white solid. Further on, methyl ester of 45 (3.0 g, 9.0 mmol), KOH (5.0 g, 90 mmol) in
90 mL of 1,4-dioxane and 30 mL of MeOH was stirred at 85 ◦C for 2 h. TLC indicated full conversion
of the start material, the reaction mixture was cooled to 0 ◦C and slowly added 6 M HCl until pH = 1
.
The precipitating muddy suspension was filtrated, and the white residue was washed by water and
MeOH until pH = 7. The white solid was dried in vacuo, purified by recrystallizing with MeOH
to obtain desired compound 45 (2.4 g, 79%) as colorless needles. m.p. 211 ◦C; 1
H
NMR (DMSO-d6,
166.88,
600 MHz)
δ
7.56–7.15 (m, 13H), 5.22 (s, 2H), 5.18 (s, 2H); 13
C
NMR (DMSO − d6, 150 MHz)
δ
151.94, 147.50, 136.93, 136.62, 128.36, 128.30, 127.82, 127.71, 127.46, 127.34, 123.36, 123.22, 114.43, 112.97,
69.87, 69.73.
3,5-bis(Benzyloxy)benzoic acid (46) [53]; Methyl 3,5-dihydroxybenzoate (2.5 g, 15 mmol) and K2CO3
(8.2 g, 60 mmol) and KI (2.0 g, 12 mmol) in 100 mL of acetone was stirred at rt. The reaction suspension
was slowly added BnCl (4.2 mL, 36 mmol) and refluxed for 9 h. By the same procedure previously
described for the preparation of compound 45, methyl ester of 46 (5.2 g, quant.) was obtained as a white
solid. Further on, methyl ester of 46 (3.0 g, 9.0 mmol), KOH (5.0 g, 90 mmol) in 90 mL of 1,4-dioxane
and 30 mL of MeOH was stirred at 85 ◦C for 2 h. By the same procedure previously described for the
preparation of compound 45, desire compound 46 (2.5 g, 81%) was obtained as colorless needles. m.p.
185 ◦C; 1
5.15 (s, 4H); 13
107.87, 106.43, 69.38.
H
NMR (DMSO − d6, 600 MHz)
δ
7.46–7.30 (m, 11H), 7.19–7.16 (m, 2H), 6.93–6.93 (m, 1H),
166.80, 159.30, 136.64, 132.80, 128.36, 127.79, 127.58,
C
NMR (DMSO − d6, 150 MHz)
δ
3-(Benzyloxy)benzoic acid (47) [52]; Methyl 3-hydroxybenzoate (2.3 g, 15 mmol) and K2CO3 (4.2 g,
30 mmol) and KI (1.0 g, 6.0 mmol) in 100 mL of acetone was stirred at rt. The reaction suspension
was slowly added BnCl (2.1 mL, 18 mmol) and refluxed for 10 h. By the same procedure previously
described for the preparation of compound 45, methyl ester of 47 (3.7 g, 95%) was obtained as a white

Molecules 2019, 24, 4340
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solid. Further on, methyl ester of 47 (1.9 g, 7.4 mmol), KOH (4.2 g, 74 mmol) in 90 mL of 1,4-dioxane
and 30 mL of MeOH was stirred at 85 ◦C for 2 h. By the same procedure previously described for the
preparation of compound procedure described for previously 45 preparation, desire compound 47
(1.4 g, 85%) was obtained as colorless needles. m.p. 136 ◦C; 1
(m, 2H), 7.48–7.39 (m, 5H), 7.35–7.32 (m, 1H), 7.28–7.26 (m, 1H), 5.17 (s, 2H); 13
H
NMR (600 MHz, DMSO-d6)
δ 7.57–7.53
C
-NMR (150 MHz,
DMSO-d6) δ 167.12, 158.34, 136.84, 132.23, 129.79, 128.50, 127.92, 127.70, 121.82, 119.77, 114.89, 69.35.
4-(Benzyloxy)benzoic acid (48) [51]; Methyl 4-hydroxybenzoate (2.3 g, 15 mmol) and K2CO3 (4.2 g,
30 mmol) and KI (1.0 g, 6.0 mmol) in 100 mL of acetone was stirred at rt. The reaction suspension
was slowly added BnCl (2.1 mL, 18 mmol) and refluxed for 9 h. By the same procedure previously
described for the preparation of compound 45, methyl ester of 48 (3.6 g, quant.) was obtained as a white
solid. Further on, methyl ester of 48 (2.3 g, 9.0 mmol), KOH (5.0 g, 90 mmol) in 90 mL of 1,4-dioxane
and 30 mL of MeOH was stirred at 85 ◦C for 2 h. By the same procedure previously described for the
preparation of compound procedure described for previously 45 preparation, desired compound 48
(1.4 g, 85%) was obtained as colorless needles. m.p. 192 ◦C; 1
(m, 2H), 7.48–7.46 (m, 2H), 7.42–7.40 (m, 2H), 7.36–7.34 (m, 1H), 7.12–7.09 (m, 2H), 5.19 (s, 2H); 13
H
NMR (600 MHz, DMSO-d6)
δ
7.95–7.90
-NMR
C
(150 MHz, DMSO-d6) δ 166.90, 161.83, 136.43, 131.27, 128.40, 127.92, 127.73, 123.09, 114.50, 69.35.
1,5-Anhydro-2,3,4,6-tetrakis-O-(30,40,50-tribenzyloxybenzoyl)-d-glucitol (49) [50]; 1,5-AG (82 mg,
0.50 mmol), compound 16 (1.1 g, 2.4 mmol), 2-chloro-1-methylpyridinium iodide (0.61 g, 2.4 mmol),
DMAP (0.29 g, 2.4 mmol), TEA (0.67 mL, 4.8 mmol) in 20 mL of DCM was stirred at rt for 2 d. By the
same procedure previously described for the preparation of compound 17, desire compound 49 (0.86 g,
92%) was obtained as a colorless amorphous oil. [α]2D0 = +7.0 (c 1.00, CHCl3); 1
CHLOROFORM-D)
(m, 1H), 5.18–4.94 (m, 22H), 4.88–4.84 (m, 4H), 4.76 (dd, J = 12.2, 2.9 Hz, 1H), 4.52 (dd, J = 11.3, 5.5 Hz,
1H), 4.30 (dd, J = 12.4, 5.2 Hz, 1H), 4.06–4.03 (m, 1H), 3.60 (t, J = 10.8 Hz, 1H); 13C NMR (CDCl3
150 MHz) 165.91, 165.71, 165.14, 165.10, 152.54, 152.43, 143.06, 142.93, 142.79, 142.62, 137.41, 137.31,
H
NMR (600 MHz,
δ
7.56–7.07 (m, 68H), 5.89 (t, J = 9.8 Hz, 1H), 5.63 (t, J = 9.8 Hz, 1H), 5.35–5.31
,
δ
136.59, 136.44, 136.35, 136.25, 128.54, 128.45, 128.44, 128.37, 128.27, 128.23, 128.14, 128.11, 128.08,
128.02, 128.00, 127.95, 127.90, 127.87, 127.81, 127.55, 127.52, 124.56, 123.95, 123.79, 109.22, 109.14, 109.03,
75.10, 75.06, 74.53, 71.18, 71.11, 71.05, 70.51, 69.78, 67.31, 63.36 HRMS (ESI, m/z): [M + Na]+, calcd for
[C118H100O21 Na]+: 1875.6644; found 1875.6653.
1,5-Anhydro-2,3,4,6-tetrakis-O-(30,40-dibenzyloxybenzoyl)-d-glucitol (50); 1,5-AG (0.12 g, 0.7 mmol),
compound 45 (1.4 g, 4.2 mmol), 2-chloro-1-methylpyridinium iodide (1.1 g, 4.2 mmol), DMAP (0.52 g,
4.2 mmol), TEA (1.1 mL, 8.0 mmol) in 20 mL of DCM was stirred at rt for 2 d. By the same procedure
previously described for the preparation of compound 17, desired compound 50 (0.61 g, 72%) was
obtained as a colorless amorphous oil. [α]2D0 = +18.8 (c 0.90, CHCl3); 1
H
NMR (CDCl3, 600 MHz)
δ
7.65–7.23 (m, 48H), 6.89–6.86 (m, 2H), 6.82–6.80 (m, 1H), 6.77–6.75 (m, 1H), 5.81 (t, J = 9.8 Hz, 1H), 5.56
(t, J = 9.6 Hz, 1H), 5.29 (td, J = 10.1, 5.5 Hz, 1H), 5.22–5.03 (m, 14H), 4.99 (s, 2H), 4.63 (dd, J = 12.4
,
2.7 Hz, 1H), 4.43 (dd, J = 11.3, 5.5 Hz, 1H), 4.29 (dd, J = 12.4, 5.2 Hz, 1H), 3.97–3.94 (m, 1H), 3.53
(
t, J = 10.8 Hz, 1H); 13
C NMR (CDCl3, 150 MHz) δ 165.83, 165.69, 165.17, 164.91, 153.26, 153.14, 152.96,
148.27, 148.17, 136.87, 136.68, 136.51, 136.38, 128.57, 128.53, 128.46, 128.40, 127.94, 127.86, 127.46, 127.41,
127.09, 127.01, 126.98, 124.36, 124.25, 121.79, 115.37, 115.20, 113.01, 76.91, 73.90, 71.07, 71.04, 70.95, 70.70,
70.64, 70.16, 69.38, 67.29, 63.16; HRMS (ESI, m/z): [M + Na]+, calcd for [C62H56O13 Na]+: 1451.4980;
found 1451.4977.
1,5-Anhydro-2,3,4,6-tetrakis-O-(30,50-dibenzyloxybenzoyl)-d-glucitol (51); 1,5-AG (0.15 g, 0.9 mmol),
compound 46 (1.8 g, 5.4 mmol), 2-chloro-1-methylpyridinium iodide (1.3 g, 5.4 mmol), DMAP (0.66 g,
5.4 mmol), TEA (1.5 mL, 10.8 mmol) in 20 mL of DCM was stirred at rt for 2 d. By the same procedure
previously described for the preparation of compound 17, desired compound 51 (0.69 g, 63%) was
obtained as a colorless amorphous oil. [α]2D0 = +8.3 (c 0.90, CHCl3); 1H NMR (CDCl3, 600 MHz)
δ
7.45–7.18 (m, 48H), 6.79–6.76 (m, 2H), 6.72–6.69 (m, 2H), 5.89 (t, J = 9.6 Hz, 1H), 5.62 (t, J = 9.8 Hz, 1H),
5.37 (td, J = 10.1, 5.6 Hz, 1H), 5.06–4.98 (m, 8H), 4.95–4.84 (m, 8H), 4.66 (dd, J = 12.2, 2.9 Hz, 1H), 4.49
(dd, J = 11.3, 5.5 Hz, 1H), 4.40 (dd, J = 12.2, 5.3 Hz, 1H), 4.04–4.01 (m, 1H), 3.58 (t, J = 10.8 Hz, 1H);

Molecules 2019, 24, 4340
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13C NMR (CDCl3, 150 MHz)
δ
165.84, 165.80, 165.20, 165.06, 159.76, 159.75, 159.70, 136.44, 136.31, 136.26,
136.22, 131.45, 130.91, 130.87, 130.71, 128.60, 128.57, 128.51, 128.09, 128.06, 127.59, 127.57, 108.53, 108.49,
108.41, 108.11, 107.74, 107.70, 107.51, 74.28, 70.41, 70.23, 70.19, 69.73, 67.21, 63.51; HRMS (ESI, m/z):
[M + Na]+, calcd for [C62H56O13 Na]+: 1451.4980; found 1451.4980.
1,5-Anhydro-2,3,4,6-tetrakis-O-(30-benzyloxybenzoyl)-d-glucitol (52); 1,5-AG (0.10 g, 0.6 mmol),
compound 47 (0.82 g, 3.6 mmol), 2-chloro-1-methylpyridinium iodide (0.81 g, 3.6 mmol), DMAP (0.44 g,
3.6 mmol), TEA (1.0 mL, 7.2 mmol) in 20 mL of DCM was stirred at rt for 2 d. By the same procedure
previously described for the preparation of compound 17, desire compound 52 (0.56 g, 92%) was
obtained as a colorless amorphous oil. [α]2D0 = +22.7 (c 1.00, CHCl3); 1
H NMR (CDCl3, 600 MHz) δ
7.68–7.05 (m, 36H), 5.90 (t, J = 9.6 Hz, 1H), 5.65 (t, J = 9.8 Hz, 1H), 5.40 (td, J = 10.1, 5.6 Hz, 1H), 5.02–5.13
(m, 4H), 5.00 (s, 2H), 4.96 (s, 2H), 4.65 (dd, J = 12.0, 2.7 Hz, 1H), 4.48 (dd, J = 11.2, 5.7 Hz, 1H), 4.42
(
dd, J = 12.2, 5.3 Hz, 1H), 4.02–4.05 (m, 1H), 3.59 (t, J = 10.8 Hz, 1H); 13
C NMR (CDCl3, 150 MHz) δ
166.03, 165.85, 165.34, 165.11, 158.66, 136.57, 136.37, 130.91, 130.30, 130.12, 129.56, 129.49, 128.61, 128.56,
128.13, 127.62, 127.58, 122.52, 121.12, 120.85, 120.71, 120.53, 115.16, 115.12, 115.00, 114.84, 76.89, 74.07,
70.27, 70.12, 69.50, 67.21, 63.31; HRMS (ESI, m/z): [M + Na]+, calcd for [C62H56O13 Na]+: 1027.3306;
found 1027.3301.
1,5-Anhydro-2,3,4,6-tetrakis-O-(40-benzyloxybenzoyl)-d-glucitol (53); 1,5-AG (0.16 g, 1.0 mmol),
compound 48 (1.4 g, 6.1 mmol), 2-chloro-1-methylpyridinium iodide (1.4 g, 6.0 mmol), DMAP
(0.73 g, 6.0 mmol), TEA (1.7 mL, 12 mmol) in 30 mL of DCM was stirred at rt for 2 d. By the same
procedure previously described for the preparation of compound 17, desire compound 53 (0.99 g, 98%)
was obtained as a colorless amorphous oil. [α]2D0 = +38.2 (c 0.90, CHCl3); 1
H
NMR (CDCl3, 600 MHz)
8.06–7.96 (m, 2H), 7.92–7.86 (m, 6H), 7.44–7.17 (m, 20H), 6.93–6.78 (m, 8H), 5.89 (t, J = 9.5 Hz, 1H), 5.63
(t, J = 9.8 Hz, 1H), 5.40 (td, J = 10.0, 5.7 Hz, 1H), 5.02–4.85 (m, 8H), 4.61–4.59 (m, 1H), 4.41 (td, J = 12.5
5.4 Hz, 2H), 3.99–3.96 (m, 1H), 3.54 (t, J = 10.8 Hz, 1H); 13
NMR (CDCl3, 150 MHz) 165.83, 165.55,
δ
,
C
δ
165.15, 164.86, 162.78, 162.62, 162.57, 136.22, 136.07, 131.93, 131.86, 128.63, 128.61, 128.17, 127.46, 127.41,
127.19, 122.30, 121.65, 121.59, 121.46, 114.52, 114.47, 114.43, 114.38, 73.69, 69.96, 69.90, 69.24, 67.23, 63.05;
HRMS (ESI, m/z): [M + Na]+, calcd for [C62H56O13 Na]+: 1027.3306; found 1027.3304.
2,3,4,6-tetrakis-O-(30,40,50-Trihydroxybenzoyl)-d-glucitol (54) [50]; Pd(OH)2 on C (20 wt.%, 50 mg)
was added to a solution of compound 50 (860 mg, 0.46 mmol) in 20 mL of MeOH and 20 mL of THF
under the argon. By the same procedure previously described for the preparation of compound 31
desired compound 54 (321 mg, 90%) was obtained as a yellow amorphous oil. [α]2D0 = +58.0 (c 1.04,
MeOH); 1
7.19 (s, 2H), 7.06 (s, 2H) 2, 6.99 (s, 2H), 5.81 (t, J = 9.6 Hz,
,
H
NMR (Acetone − d6, 600 MHz)
δ
×
1H), 5.50 (t, J = 9.8 Hz, 1H), 5.28–5.24 (m, 1H), 4.49 (dd, J = 12.4, 2.1 Hz, 1H), 4.33–4.29 (m, 2H),
4.17–4.15 (m, 1H), 3.72 (t, J = 10.8 Hz, 1H); 13C NMR (Acetone − d6 , 150 MHz) δ 166.36, 166.05, 165.90,
165.63, 146.00, 145.97, 145.92, 145.80, 139.22, 138.97, 138.90, 121.50, 120.90, 120.63, 110.17, 110.08, 110.01,
109.98, 77.57, 74.31, 70.74, 69.61, 67.44, 63.32; HRMS-ESI (m/z): [M + Na]+, calcd for [C34H28O21 Na]+
:
795.1021; found 795.1019.
1,5-Anhydro-2,3,4,6-tetrakis-O-(30,40-dihydroxybenzoyl)-d-glucitol (55); Pd(OH)2 on C (20 wt.%,
50 mg) was added to a solution of compound 50 (365 mg, 0.30 mmol) in 10 mL of MeOH and 10 mL
of THF under the argon. By the same procedure previously described for the preparation of compound
31, desired compound 55 (196 mg, 92%) was obtained as a colorless amorphous oil. [α]2D0 = +48.3
(c 0.65, MeOH); 1
H
NMR (Acetone − d6, 600 MHz);
δ 7.56 (d, J = 2.1 Hz, 1H), 7.49 (dd, J = 8.4, 1.9 Hz,
1H), 7.43–7.33 (m, 6H), 6.90 (d, J = 8.2 Hz, 1H), 6.84 (dd, J = 11.3, 8.2 Hz, 2H), 6.76 (d, J = 8.2 Hz, 1H),
5.85 (t, J = 9.6 Hz, 1H), 5.55 (t, J = 9.8 Hz, 1H), 5.30 (td, J = 10.1, 5.4 Hz, 1H), 4.52 (dd, J = 12.0, 2.4 Hz,
1H), 4.37–4.32 (m, 2H), 4.20–4.17 (m, 1H), 3.75 (t, J = 10.8 Hz, 1H); 13C NMR (Acetone − d6 , 150 MHz)
δ
166.22, 166.00, 165.76, 165.56, 151.21, 151.01, 145.55, 145.39, 123.78, 123.71, 123.62, 122.53, 121.96,
121.74, 117.41,−117.29, 117.19, 117.09, 115.74, 115.68, 77.53, 74.40, 70.78, 69.87, 67.48, 63.52; HRMS (ES−
,
m/z): [M − H] , calcd for [C34H27O17]−: 707.1248; found 707.1255.
1,5-Anhydro-2,3,4,6-tetrakis-O-(3,5-dihydroxybenzoyl)-d-glucitol (56); Pd(OH)2 on C (20 wt.%, 50 mg)
was added to a solution of compound 51 (365 mg, 0.30 mmol) in 20 mL of MeOH and 20 mL of THF

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under the argon. By the same procedure previously described for the preparation of compound 31
desired compound 56 (210 mg, quant.) was obtained as a colorless amorphous oil. [α]2D0 = +39.1 (c 0.50,
MeOH); 1
7.09 (s, 2H), 6.95 (d, J = 1.4 Hz, 4H), 6.89 (d, J = 1.7 Hz,
,
H
NMR (Acetone − d6, 600 MHz);
δ
2H), 6.63–6.49 (m, 4H), 5.90 (t, J = 9.6 Hz, 1H), 5.59 (t, J = 9.6 Hz, 1H), 5.37 (td, J = 10.0, 5.6 Hz, 1H), 4.55
(d, J = 12.4 Hz, 1H), 4.43 (dd, J = 12.2, 4.6 Hz, 1H), 4.37 (dd, J = 11.3, 5.5 Hz, 1H), 4.25 (dd, J = 9.8, 4.3 Hz,
1H), 3.80 (t, J = 10.8 Hz, 1H) 13C NMR (Acetone − d6 , 150 MHz) δ 166.33, 166.13, 165.82, 165.67, 159.36,
159.31, 159.24, 132.73, 132.10, 131.91, 129.67, 128.96, 108.81, 108.74, 108.65, 108.39, 108.24, 108.08, 77.25,
74.65, 70.85, 69.79, 67.25, 63.45; HRMS (ES−, m/z): [M − H]−, calcd for [C34H27O17]−: 707.1248; found
707.1255.
1,5-Anhydro-2,3,4,6-tetrakis-O-(3-hydroxybenzoyl)-d-glucitol (57); Pd(OH)2 on C (20 wt.%, 50 mg)
was added to a solution of compound 52 (300 mg, 0.30 mmol) in 20 mL of MeOH and 20 mL of THF under
the argon. By the same procedure previously described for the preparation of compound 31, desired
compound 57 (181 mg, 94%) was obtained as a colorless amorphous oil. [α]2D0 = +36.4 (c 0.70, MeOH); 1
H
NMR (Acetone − d6, 600 MHz);
δ 7.55–6.97 (m, 20H), 5.94 (t, J = 9.5 Hz, 1H), 5.65 (t, J = 9.6 Hz, 1H), 5.41
(td, J = 10.1, 5.4 Hz, 1H), 4.57 (dd, J = 12.2, 2.6 Hz, 1H), 4.47 (dd, J = 12.4, 4.8 Hz, 1H), 4.39 (dd, J = 11.2
,
5.7 Hz, 1H), 4.29–4.26 (m, 1H), 3.83 (t, J = 10.8 Hz, 1H); 13C NMR (Acetone − d6 , 150 MHz) δ 166.38,
166.23, 165.90, 165.82, 158.46, 158.25, 132.14, 131.57, 131.43, 130.49, 130.44, 130.40, 129.72, 129.00, 126.08,
121.43, 121.39, 121.21, 121.08, 117.04, 116.93, 1−16.88, 116.73, 77.23, 74.83, 70.96, 70.23, 67.33, 63.83; HRMS
(ES−, m/z): [M − H]−, calcd for [C34H27O13] : 643.1452; found 643.1459.
1,5-Anhydro-2,3,4,6-tetrakis-O-(4-hydroxybenzoyl)-d-glucitol (58); Pd(OH)2 on C (20 wt.%, 50 mg)
was added to a solution of compound 54 (288 mg, 0.29 mmol) in 15 mL of MeOH and 15 mL of THF
under the argon. By the same procedure previously described for the preparation of compound 31
desired compound 58 (190 mg, quant.) was obtained as a colorless amorphous oil. [α]2D0 = +45.3 (c 0.50,
MeOH); 1
7.93–7.76 (m, 8H), 6.92–6.77 (m, 8H), 5.89 (t, J = 9.6 Hz,
,
H
NMR (Acetone − d6, 600 MHz);
δ
1H), 5.61 (t, J = 9.8 Hz, 1H), 5.34 (td, J = 10.0, 5.3 Hz, 1H), 4.55 (dd, J = 12.4, 2.7 Hz, 1H), 4.41–4.35
(m, 2H), 4.23–4.20 (m, 1H), 3.77 (t, J = 10.8 Hz, 1H); 13C NMR (Acetone − d6 , 150 MHz) δ 166.17,
165.99, 165.69, 165.54, 163.17, 163.13, 162.88, 162.82, 132.75, 132.68, 132.61, 132.58, 121.99, 121.44, 121.2−1,
121.19, 116.09, 116.05, 116.00, 115.94, 77.45, 74.47, 70.76, 70.05, 67.50, 63.65; HRMS (ES−, m/z): [M − H]
calcd for [C34H27O13]−: 643.1452; found 643.1459.
,
Benzyl 2,3,4,6-tetrakis-O-(30,40,50-tribenzyloxybenzoyl)-
(211 mg, 0.78 mmol), EDC
α,
β
-d-glucopyranoside (60); Compound 59
[43]
·
HCl (1.2 g, 6.3 mmol), compound 16 (2.06 g, 4.7 mmol), DMAP (47.7 mg,
0.39 mmol) in 30 mL of DCM was stirred at rt for overnight. After the addition 20 mL of water,
the reaction mixture was extracted with DCM (20 mL). The combined organic layer was washed with
water (30 mL
The crude was purified by C.C (CHCl3/MeOH = 200/1) to obtain desired compound 60 (791 mg, 52%) as
a colorless amorphous oil. [α]2D0 = +18.1 (c 1.00, CHCl3); 1
NMR (CDCl3, 600 MHz) (assigned for the
major anomer; 7.42–7.16 (m, 80H), 6.21 (t, J = 10.0, 1H), 5.69 (t, J = 10.0 Hz, 1H), 5.45 (d, J = 3.8 Hz
1H), 5.12–4.95 (m, 16H), 4.73 (dd, J = 3.1, 12.4 Hz, 1H), 4.54–4.51 (m, 1H), 4.73 (dd, J = 3.1, 12.4 Hz, 1H);
13C NMR (CDCl3, 150 MHz) (assigned for the major anomer;
165.68, 165.16, 152.55, 152.52, 152.49,
×
4) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure.
H
α
)
δ
,
α) δ
143.00, 142.86, 142.69, 142.64, 137.41, 137.36, 137.32, 136.56, 136.53, 136.48, 136.40, 136.29, 128.54, 128.46,
128.38, 128.29, 128.24, 128.16, 128.12, 128.09, 128.05, 127.98, 127.94, 127.92, 127.88, 127.81, 127.58, 127.54,
127.52, 124.64, 124.15, 124.02, 123.85, 109.23, 109.16, 109.01, 95.27, 75.11, 75.09, 75.06, 72.17, 71.18, 71.15,
71.05, 70.16, 69.96, 67.96, 63.17. HRMS (ESI, m/z): [M + Na]+, calcd for [C125H106O22 Na]+: 1981.7073;
found 1981.7067.
2,3,4,6-tetrakis-O-(30,40,50-Trihydroxybenzoyl)-
α,β-d-glucopyranose (61) [55]; Pd(OH)2 on C (20 wt.%,
20 mg) was added to a solution of compound 54 (100 mg, 0.51 mmol) in 10 mL of MeOH and 10 mL
of THF under the argon. By the same procedure previously described for the preparation of compound
31, desire compound 58 (34 mg, 85%) was obtained as a colorless amorphous oil. [α]2D0 = +54.4 (c 0.30,
MeOH); 1
H
NMR (CDCl3, 600 MHz)
δ [α-form] 7.20 (s, 2H), 7.09 (s, 2H), 7.07 (s, 2H), 7.00 (s, 2H), 6.11
(t, J = 9.6 Hz, 1H), 5.62 (d, J = 3.4 Hz, 1H), 5.56 (t, J = 10.2 Hz, 1H), 5.16 (dd, J = 10.3, 3.5 Hz, 1H), 4.47

Molecules 2019, 24, 4340
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(dd, J = 2.4, 11.4 Hz, 1H), 4.35 (dd, J = 12.6, 4.8 Hz, 1H), 4.32–4.29 (m, 1H); [
β-form] 7.19 (s, 2H), 7.08
(s, 2H), 7.05 (s, 2H), 6.95 (s, 2H), 5.80 (t, J = 9.6 Hz, 1H), 5.51 (t, J = 9.6 Hz, 1H), 5.29 (t, J = 9.0 Hz, 1H),
5.24 (d, J = 9.0 Hz, 1H), 4.50 (d, J = 1.7, 11.4 Hz, 1H), 4.31 (m, 2H); 13C NMR (Acetone − d6 , 150 MHz)
(assigned for the major anomer; α) δ 166.48, 166.22, 165.99, 165.73, 146.04, 145.99, 145.84, 139.27, 139.24,
139.00, 138.93, 121.61, 121.02, 120.78, 120.67, 110.21, 110.17, 110.06, 110.01, 91.04, 73.02, 70.70, 69.88,
68.55, 63.27; HRMS (ESI, m/z): [M + Na]+, calcd for [C62H56O13 Na]+: 811.0970; found 811.0970.
1,5-Anhydro-2,3-bis-O-(30,40,50-tribenzyloxybenzoyl)-d-glucitol (62); Compound 21 (3.5 g, 3.2 mmol),
◦
iodine (0.71 g, 5.6 mmol) in 100 mL of DCM and 50 mL of MeOH was stirred at 70 C for 7 days.
The reaction mixture was washed with sodium thiosulfate solution and brine. The crude product
was purified by C.C (DCM/MeOH = 4/1) to obtain desired compound 62 (3.0 g, 93%) as a white solid.
[α]2D0 = +80.3 (c 1.06, CHCl3); 1
H
NMR (CDCl3, 600 MHz)
5.28–5.26 (m, 1H), 5.07–4.97 (m, 12H), 4.35–4.32 (m, 1H), 4.00–3.99 (m, 1H), 3.91–3.88 (m, 2H), 3.51–3.48
(m, 2H), 3.07 (d, J = 4.0 Hz, 1H), 2.01 (t, J = 6.0 Hz, 1H); 13
NMR (CDCl3, 150 MHz) 167.2, 165.3,
δ 7.38–7.21 (m, 32H), 5.34 (t, J = 9.0 Hz, 1H),
C
δ
152.6, 143.1, 142.9, 137.3, 136.5, 136.4, 128.5, 128.4, 128.2, 128.1, 128.0, 127.7, 127.5, 109.3, 109.1, 80.4, 78.5,
75.1, 71.1, 67.0, 69.8, 66.9, 62.4; HRMS-ESI (m/z): [M + Na]+, calcd for [C62H56O13 Na]+: 1031.3612;
found 1031.3619.
1,5-Anhydro-2,3-bis-O-(30,40,50-tribenzyloxybenzoyl)-4,6-bis-O-(30,50-dimetoxymetoxy-40-benzyloxybenzoyl)
-d-glucitol (64); Compound 62 (2.5 g, 2.5 mmol), 63
DMAP (0.15 g, 1.2 mmol) in 15 mL of DCM was stirred at rt for 18 h. After the addition 30 mL of water,
the reaction mixture was extracted with EtOAc (3 50 mL). The combined organic layer was washed
[
46] (2.5 g, 6.2 mmol), EDC·HCl (1.4 g, 7.2 mmol),
×
with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was
purified by C.C (CHCl3/acetone = 100/1) to obtain 64 (2.3 g, 55% yield) as a colorless amorphous oil.
[α]2D0 = +24.7 (c 2.15 in CHCl3); 1H NMR (CDCl3, 600 MHz)
(
δ
7.58 (s, 2H), 7.46–7.25 (m, 50H), 5.85
t, J = 10Hz, 1H), 5.61 (t, J = 10.0Hz, 1H), 5.28–5.26 (m, 1H), 5.22–4.93 (m, 24H), 4.73–4.71 (m, 1H),
4.50–4.47 (m, 1H), 4.35–4.32 (m, 1H), 4.06–4.03 (m, 1H), 3.56 (t, J = 11.0 Hz, 1H), 3.48 (s, 6H), 3.42(s, 6H);
13C NMR (CDCl3, 150 MHz)
165.7, 165.5, 165.1, 164.8, 152.5, 150.9, 150.8, 143.7, 143.4, 142.8, 142.7,
δ
137.4, 137.3, 137.2, 136.5, 136.4, 132.4, 130.8, 128.7, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8,
127.6, 127.5, 125.1, 124.2, 124.1, 124.0, 112.4, 112.3, 109.1, 109.0, 95.4, 75.2, 75.1, 75.0, 74.4, 71.1, 71.0, 70.6,
69.3, 68.1, 67.1, 63.3, 56.4; HRMS-ESI (m/z): [M + Na]+, calcd for [C98H92O25 Na]+: 1691.5824; found
1691.5825.
1,5-Anhydro-2,3-bis-O-(30,40,50-tribenzyloxybenzoyl)-4,6-bis-O-(30,50-dihydroxy-40-benzyloxybenzoyl)
-d-glucitol (65); Compound 64 (2.0 g, 1.2 mmol) in 8 mL of THF solution was added 8.8 mL of 2-propanol
and 0.2 mL of conc. HCl solution, and the mixture was stirred at 60 ◦C for 6 h. After the addition
3 mL of NaHCO3, the mixture was extracted with EtOAc (3
was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure.
×
100 mL). The combined organic layer
The crude was purified by C.C (CHCl3/MeOH = 1000/1–500/1) to obtain 65 (1.7 g, 93% yield) as a white
amorphous oil. [α]2D0 = +26.8 (c 2.36, CHCl3); 1
H
NMR (CDCl3, 600 MHz)
(s, 4H), 5.82 (t, J = 9.5 Hz, 1H), 5.59 (t, J = 9.5 Hz, 1H), 5.37–5.30 (m, 1H), 5.10–4.82 (m, 16H), 4.70–4.68
(m, 1H), 4.54–4.52 (m, 1H), 4.45–4.42 (m, 1H), 3.97–3.95 (m, 1H), 3.57 (t, J = 10.5 Hz, 1H); 13
NMR
CDCl3, 150 MHz) 166.2, 165.8, 165.5, 165.2, 152.5, 149.0, 148.9, 142.8, 142.7, 138.2, 137.8, 137.3, 137.2,
δ 7.43–7.14 (m, 48H), 6.00
C
(
δ
136.6, 136.4, 136.2,128.8, 128.7, 128.5, 128.4, 128.3, 128.1, 128.0, 127.9, 127.7, 127.5, 124.5, 123.9, 123.8,
109.9, 109.8, 109.1, 108.9, 77.6, 75.2, 75.1, 75.0, 74.3, 71.1, 71.0, 70.7, 69.7, 68.6, 67.3, 62.6; HRMS-ESI (m/z):
[M + Na]+, calcd for [C90H76O21 Na]+: 1515.4775; found 1515.4777.
Benzyl protected 1,5-AG-tellimagrandin analog (66); To a solution of CuCl2 (135 mg, 1.0 mmol)
in 10 mL of MeOH was added n-butylamine (400 µL, 4.0 mmol). After the stirred at rt for 1.5 h,
the mixture was added to solution of compound 65 (500 mg, 0.34 mmol) in 20 mL of 1,2-dichloroethane
(DCE) and stirred at rt for 30 min. The reaction mixture was diluted with 50 mL of diethyl ether,
and 50 mL of 5M aq. HCl and 50 mL of diethyl ether were added. The separating organic layer washed
with water, NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated
under reduced pressure. The crude was purified by C.C (DCM/MeOH = 250/1) and HPLC (column,

Molecules 2019, 24, 4340
24 of 27
FNED01048, 250
×
20 mm, SG80–5
µ
m, eluant DCM/MeOH = 200/1) to afford 66 (237 mg, 48%) as
a peal yellow amorphous oil. [α]2D0 = +69.5 (c 1.43, CHCl3); 1
H NMR (CDCl3, 600 MHz) δ 7.43–7.23
(m, 50H), 6.75 (s, 1H), 6.67 (s, 1H), 5.67 (t, J = 10.0 Hz, 1H), 5.37–5.34 (m, 1H), 5.29 (t, J = 10.0 Hz, 1H),
5.25–5.24 (m, 1H), 5.13–4.85 (m, 16H), 4.47–4.45 (m, 1H), 3.98 (d, J = 12.5 Hz, 1H), 3.96–3.94 (m. 1H),
3.46 (t, J = 11.0 Hz, 1H); 13C NMR (CDCl3 , 150 MHz) δ 167.1, 166.6, 165.8, 165.2, 152.5, 149.0, 147.0,
142.8, 137.4, 137.3, 136.5, 136.4, 136.3, 136.2, 135.7, 135.5, 130.3, 129.6, 129.0, 128.9, 128.6, 128.5, 128.4,
128.3, 128.1, 128.0, 127.9, 127.8, 127.6, 127.5, 123.9, 113.7, 113.2, 109.2, 108.4, 107.9, 75.6, 75.1, 75.0, 74.4,
71.1, 71.0, 70.8, 70.1, 67.7, 63.6; HRMS-ESI (m/z): [M + Na]+, calcd for [C90H74O21 Na]+: 1513.4619;
found 1513.4620.
1,5-Anhydro-2,3-bis-O-(30,40,50-trihydroxybenzoyl)-4,6-O-hexahydroxydiphenyl-d-glucitol (67); Pd(OH)2
on C (20 wt.%, 20 mg) was added to a solution of compound 66 (60 mg, 0.40 mmol) in 2 mL of MeOH
and 2 mL of THF under the argon. By the same procedure previously described for the preparation
of compound procedure described for previously 31 preparation, desired compound 67 (32 mg,
quant.) was obtained as a peal yellow amorphous oil. [α]2D0 = +113.3 (c 0.29, MeOH); 1H NMR
(
CD3OD, 600 MHz)
(m, 2H), 5.03 (t, J = 10.0 Hz, 1H), 4.25–4.22 (m, 1H), 4.08–4.07 (m, 1H), 3.80 (t, J = 13.0 Hz, 1H), 3.54
t, J = 11.0 Hz, 1H); 13
NMR (CD3OD, 150 MHz); 171.1, 170.7, 168.8, 168.3, 150.6, 147.6, 147.1, 144.6,
δ 7.00 (s, 2H), 6.95 (s, 2H), 6.60 (s, 1H), 6.40 (s, 1H), 5.61 (t, J = 9.5 Hz, 1H), 5.27–5.19
(
C
143.5, 141.8, 139.7, 126.8, 126.7, 126.3, 120.7, 120.3, 120.1, 119.4, 111.1, 110.8, 108.3, 107.7, 78.7, 78.5, 76.2,
72.1, 72.0, 71.8, 71.4, 71.3, 69.4, 68.7, 64.7; HRMS (ESI, m/z): [M + Na]+, calcd for [C34H26O21 Na]+
:
793.0864; found 793.0865.
Supplementary Materials: The following are available online 1H NMR, 13C NMR spectra of compounds 31
54–58, 61 and 67.
–44,
Author Contributions: Experiment: S.M. (Shota Machida), S.M. (Saki Mukai), R.K. and M.F.; Writing—Original
Draft preparation: S.M. (Shota Machida); Writing—Review and Editing: S.M. (Shota Machida), H.S. and T.U.;
project administration: T.U.
Funding: This study was partly supported by Japan Society for the Promotion of Science (JSPS), 18K06725 (T.U.)
and Nihon University Mutidisciplinary Research Grant for 2019 (19-016).
Acknowledgments: We thank Koichi Metori (Chemical Analysis Center, School of Pharmacy, Nihon University)
for performing mass measurements.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are not available from the authors.
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2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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(CC BY) license (http://creativecommons.org/licenses/by/4.0/).