Improved Synthesis of 1-Glycosyl Thioacetates and Its Application in the Synthesis of Thioglucoside Gliflozin Analogues

Article abstract of DOI:10.1002/ejoc.202100357

An improved method to synthesize 1-glycosyl thioacetates was developed, where per-O-acetylated glycoses were allowed to directly react with potassium thioacetate (KSAc) in the presence of BF₃ ? Et₂O in ethyl acetate under mild conditions. This method not only overcomes the disadvantage of the traditional one-step method, which is that the odorous and toxic thioacetic acid has to be used, but also overcomes the disadvantage of the traditional two-step method, which is that the unstable intermediate, glycosyl halide, has to be synthesized from the per-O-acetylated glycose in advance. Based on this, the per-O-acetylated glucosyl disulfide and the per-O-acetylated glucosyl 1-thiol were efficiently synthesized in high yields (91 % and 90 % respectively) starting from per-O-acetylated glycoses in two-step without the need to isolate intermediate products. Through metal-catalyzed cross-coupling of per-O-acetylated glucosyl 1-thiol with aryl-iodide under very mild conditions, two thioglucoside gliflozin analogues were efficiently synthesized in high yields for the first time. These two thioglucoside gliflozin analogues were further confirmed to be stable to hydrolysis of β-glucosidase.

Full text of DOI:10.1002/ejoc.202100357

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Improved Synthesis of 1-Glycosyl Thioacetates and Its
Application in the Synthesis of Thioglucoside Gliflozin Analogues
Authors: Guang-Jing Feng, Shuangshuang Wang, Jian Lv, Tao Luo,
Yuzhou Wu, and Hai Dong
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100357
Link to VoR: https://doi.org/10.1002/ejoc.202100357
01/2020

10.1002/ejoc.202100357
European Journal of Organic Chemistry
FULL PAPER
Improved Synthesis of 1-Glycosyl Thioacetates and Its Application
in the Synthesis of Thioglucoside Gliflozin Analogues
Guang-Jing Feng, [a] Shuang-Shuang Wang, [a] Jian Lv, [a] Tao Luo, [a] Yuzhou Wu, [a] and Hai Dong*[a]
Abstract: An improved method to synthesize 1-glycosyl thioacetates
was developed, where per-O-acetylated glycoses were allowed to
directly react with potassium thioacetate (KSAc) in the presence of
.
BF3 Et2O in ethyl acetate under mild conditions. This method not only
overcomes the disadvantage of the traditional one-step method,
which is that the odorous and toxic thioacetic acid has to be used, but
also overcomes the disadvantage of the traditional two-step method,
which is that the unstable intermediate, glycosyl halide, has to be
synthesized from the per-O-acetylated glycose in advance. Based on
this, the per-O-acetylated glucosyl disulfide and the per-O-acetylated
Figure 1. Comparison of thioglucoside gliflozin analogues with gliflozins.
glucosyl 1-thiol were efficiently synthesized in high yields (91% and
90% respectively) starting from per-O-acetylated glycoses in two-step
without the need to isolate intermediate products. Through metal-
Recently, the reaction between glycosyl thiols and aryl-iodides
catalyzed cross-coupling of per-O-acetylated glucosyl 1-thiol with
catalyzed by PdG3-XantPhos under very mild conditions has been
aryl-iodide under very mild conditions, two thioglucoside gliflozin
reported.[6] Thus, the thioglucoside analogues of canagliflozin and
analogues were efficiently synthesized in high yields for the first time.
dapagliflozin should be efficiently synthesized from glucosyl 1-
These two thioglucoside gliflozin analogues were further confirmed to
thiol and aryl-iodides. Glycosyl 1-thioacetates are usually
be stable to hydrolysis of β-glucosidase.
precursors of glycosyl 1-thiols.[7] The synthesis of 1-glycosyl
thioacetates has attracted the most attention[8] because glycosyl
1-thiols can be used to synthesize various thioglycoside
derivatives by alkylation,[9] thiol-ene coupling reaction,[10] and
metal catalysed cross-coupling reactions.[11] Auranofin and its
Introduction
analogs were synthesized by the use of glycosyl 1-thiols and
phosphine ligands, showing potential antimicrobial activities.[7a-c]
Various methods for the synthesis of glycosyl thioacetates (Figure
2a) have been reported. The one-step method involves the use of
anomeric acetates and thioacetate acid (HSAc) under Lewis
Thioglycosides, such as thio-linked glycopetide, glycolipids and
oligosaccharides, have drawn increasing attention due to their
importance in extensive biological studies.[1] Thioglycoside
derivatives have unique advantages as mimetics of biologically
active O-glycosides, because they are more stable than their O-
glycosides analogs to hydrolysis under both acidic and enzymatic
conditions[2] and display higher conformational flexibility.[3]
Therefore, the thiosugar moiety has been found in inhibitors of
enzymes, various drugs, natural products and medicinal active
agents.[4] Canagliflozin and dapagliflozin are antidiabetic drugs of
the gliflozin class or subtype 2 sodium-glucose cotransporter 2
(SGLT2) inhibitors for patients with type-2 diabetes, developed
from phlorizin (Figure 1).[5] Phlorizin is easily hydrolyzed by β-
glucosidase since it is an O-glycoside. We speculated that
thioglucoside analogues of canagliflozin and dapagliflozin should
be stable to hydrolysis under enzymatic conditions, and thus have
the potential to become the antidiabetic drugs.
.
acidic conditions (BF3 Et2O usually), which is less common due to
the malodor and toxicity of HSAc.[12] The two-step method
involving the treatment of glycosyl halides (glycosyl bromides
usually) with potassium thioacetate (KSAc) in acetone, is more
frequently employed, due to avoiding the use of HSAc.[13]
However, the synthesis of glycosyl bromides involves the use of
anomeric acetates and hydrobromic acid (HBr in acetic acid), and
glycosyl bromides are generally unstable and difficult to store.
Then per-O-acylated glycosyl 1-thiols can be obtained by
selective deacetylation.[7] For example, by the use of DTT-
mediated selective deacetylation method,[7c] the per-O-acetylated
glucosyl 1-thiol was obtained in 86% yield after 3 steps of reaction,
separation and purification starting from the per-O-acetylated
glucose. In the present study, in order to efficiently synthesize
thioglucoside analogues of canagliflozin and dapagliflozin, we
have developed an improved method to synthesize glycosyl
thioacetates (Figure 2b). In the method, per-O-acetylated
glycoses were allowed to directly react with KSAc in the presence
[a]
G-J. Feng, S-S. Wang, J. Lv, T. Luo, Prof. Y-Z. Wu, Prof. H. Dong
Key Laboratory of Material Chemistry for Energy Conversion and
Storage, Ministry of Education, School of Chemistry & Chemical
Engineering, Huazhong University of Science & Technology, Luoyu
Road 1037, Wuhan, 430074, PR China, E-mail:
.
of BF3 Et2O in ethyl acetate under mild conditions, yielding
hdong@mail.hust.edu.cn
http://faculty.hust.edu.cn/donghai/en/index/1380857/list/index.htm
Hubei Key Laboratory of Bioinorganic Chemistry and Materia
Medica, Huazhong University of Science & Technology, Luoyu Road
1037, Wuhan, 430074, PR China
glycosyl thioacetates in the improved yields (65 - 95%). Based on
this method, the per-O-acetylated glycosyl disulfides and the per-
O-acetylated glycosyl 1-thiols have been efficiently synthesized in
high yields (91% for the glucosyl disulfide and 90% for the
glucosyl 1-thiol respectively) starting from per-O-acetylated
glycoses in two-step without the need to isolate intermediate
[b]
Supporting information and for this article is given via a link at the
end of the document.
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10.1002/ejoc.202100357
European Journal of Organic Chemistry
FULL PAPER
increased to 91% on the conditions that 2 equiv of KSAc reacted
products (Figure 2c). With this convenient approach for obtaining
the glucosyl 1-thiol in hand, thioglucoside analogues of
canagliflozin and dapagliflozin have been synthesized in high
yields for the first time (Figure 2d).
.
with 1 in the presence of 4 equiv of BF3 Et2O at 50 oC for 4 hours.
We guessed that the higher temperature is beneficial to increase
the solubility of KSAc in the solvent, thereby facilitating the
reaction. However, although DMF and acetonitrile were better
solvents for KSAc, no 2 was formed in DMF and only 40% yield
of 2 was obtained in acetonitrile (Entries 5 and 6 in Table 1).
These results indicated that the solubility of thioacetate was not
the key factor in this one-step method. Further experiments
(Entries 7 – 10 in Table 1) indicated that ethyl acetate (EtOAc)
was the best solvent for the reaction, by which the optimal yield
of 2 reached 95% (Entry 7 in Table 1). Under optimal conditions,
.
the use of TMSOTf instead of BF3 Et2O led to 87% yield of 2 (Entry
11 in Table 1) and the use of TBASAc instead of KSAc led to 29%
yield of 2 (Entry 12 in Table 1). EtOAc is a much greener solvent
than CH2Cl2. The solvent could be easily recycled by simple
distillation (Entry 13 in Table 1). In addition, since the high
reaction conversion rate facilitates the isolation of 2, we chosen 2
.
equiv of KSAc, 4 equiv of BF3 Et2O and 4 hours’ reaction in EtOAc
at 50 oC as the optimal conditions due to the highest conversion
rate (Entry 7 in Table 1).
Table 1. Comparison of results under various conditions[a]
Entry
Various Conditions, reagents (equiv)
[c] Yield (%)
1
BF3.Et2O (2), TBASAc/KSAc (1.5), DCM, rt, 24h
BF3.Et2O (4), KSAc (2), DCM, W/O AcOH, rt, 4h
BF3.Et2O (2), KSAc (1.5/2), DCM, 50 oC, 4h
BF3.Et2O (3/4), KSAc (2), DCM, 50 oC, 4h
BF3.Et2O (4), KSAc (2), DMF, 50 oC, 4h
0/30
69/62
73/78
87/91
0
2
Figure 2. Improved method for synthesis of 1-glycosyl thioacetates and thiols
and its application in the synthesis of thioglucoside gliflozin analogues.
3
4
5
Results and Discussion
6
BF3.Et2O (4), KSAc (2), MeCN, 50 oC, 4h
BF3.Et2O (4), KSAc (2), EtOAc, 50 oC, 4h
BF3.Et2O (4), KSAc (2), EtOAc, 40 oC, 24h
BF3.Et2O (3), KSAc (2/3), EtOAc, 50 oC, 4h
BF3.Et2O (2), KSAc (2/1.5), EtOAc, 50 oC, 4h
TMSOTf (4), KSAc (2), EtOAc, 50 oC, 4h
BF3.Et2O (4), TBASAc (2), EtOAc, 50 oC, 4h
BF3.Et2O (4), KSAc (2), [b] EtOAc, 50 oC, 4h
BF3.Et2O (4), KSAc (2), AcOH (1), EtOAc, 50 oC, 4h
BF3.Et2O (4), KSAc (2), TBABr (1), EtOAc, 50 oC, 4h
40
We have often synthesized glycosyl thioacetates in our lab.[14] We
hated both the use of HSAc in the one-step method and the
inevitable synthesis of glycosyl halide in the two-step method. We
started to think why KSAc cannot be used instead of HSAc in the
one-step method. The reason must be the solubility of KSAc in
organic solvents. The solvent is dichloromethane (DCM) in the
one-step method, while it is DMF or acetone in the two-step
method. KSAc should have a good solubility in DMF or acetone,
but a poor solubility in DCM. It is known that tetrabutylammonium
thioacetate (TBASAc) has a good solubility in DCM. Therefore,
we speculated that we should be able to use TBASAc instead of
HSAc in the one-step method to synthesize glycosyl thioacetates
though KSAc cannot be used. In order to testify this, we did a
comparative experiment, where per-O-acetylated glucopyranose
1 was treated with 1.5 equiv of TBASAc or KSAc, respectively, in
7
95
8
82
9
93/93
87/84
87
10
11
12
13
14
15
29
90
67
.
the presence of 2 equiv of BF3 Et2O in DCM at room temperature
20
for 24 hours. Unexpectedly, the use of TBASAc led to no or trace
of glucosyl thioacetate 2, but the use of KSAc led to 30% yield of
2 (Entry 1 in Table 1). The further experiment indicated that the
[a]
[b]
Reaction conditions: substrate 1 (100 mg), solvent (1.5 mL).
solvent. [c] Isolated yields.
Recycled
.
use of 2 equiv of KSAc and 4 equiv of BF3 Et2O led to 69% yield
of 2 after 4 hours’ reaction (Entry 2 in Table 1). Then we tried to
improve the yield by the addition of 0.5 equiv of acetic acid
(AcOH), because we thought that ion exchange should occur
between AcOH and KSAc to form HSAc. However, contrary to the
expectation, the yield of 2 decreased to 62% (Entry 2 in Table 1).
An interesting question is why good results can be achieved with
KSAc in this method, but not with TBASAc, although the solubility
of TBASAc in organic solvents is much better than that of KSAc.
The principle of hard-soft acid-base (HSAB) may provide an
explanation (Figure 3). In light of HSAB principle, AcS- is a soft
.
By the optimization of the used amounts of KSAc and BF3 Et2O in
DCM (Entries 3 and 4 in Table 1), we found that the yield of 2
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10.1002/ejoc.202100357
European Journal of Organic Chemistry
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base and AcO- is a hard base. BF3, H+ and K+ are hard acid and
TBA+ is a soft acid. AcO- might be produced under the action of
BF3 from 1 (Eqs. 1). When HSAc or KSAc encounters a hard base
AcO-, the hard acid H+ or K+ preferentially coordinates to AcO- to
form the soft base AcS- and stable AcOH or AcOK (Eqs. 2). Then
AcS- attacks the glucosyl cation to form 1-thioglucoside 2 (Eqs. 4).
Particularly, AcOK may precipitate out of the solvent more easily
than KSAc, leading to a shift of the reaction equilibrium towards
the formation of 2. However, when TBASAc encounters a hard
base AcO-, the coordination of soft acid TBA+ to AcO- is
disadvantageous, leading to a shift of the reaction equilibrium
towards lack of AcS- (Eqs. 3). As a result, 2 is hard to form due to
lack of AcS-. Since the reaction equilibrium tends to the formation
of 2 from 1 due to poorer solubility of AcOK than KSAc in the
solvent, either the addition of AcOH (Entry 14 in Table 1) or the
addition of TBABr (Entry 15 in Table 1) shifts the reaction
equilibrium towards 1, leading to poor yield of 2.
Scheme 1. Improved method for the synthesis of per-O-acylated glycosyl
thioacetates. Reaction conditions: substrate (100 mg), KSAc (2.0 equiv),
.
.
BF3 Et2O (4.0 equiv), EtOAc (1.5 mL), 50 oC, 4 h. [a] KSAc (3.0 equiv), BF3 Et2O
(6.0 equiv), EtOAc (1.5 mL), 60 oC, 20 h. KSAc (2.0 equiv), BF3.Et2O (6.0
equiv), EtOAc (1.5 mL), 75 oC, 16 h.
[b]
With the improved method for the synthesis of glycosyl
thioacetates in hand, we started to try this method for the
improved synthesis of per-O-acetylated glycosyl disulfides and
per-O-acetylated glycosyl 1-thiols. We have previously found that
glycosyl thioacetates could be oxidized by nitrite in DMF to form
per-O-acetylated glycosyl disulfides, and could be selectively
.
deacetylated by hydrazine hydrate (N2H4 H2O) in DMF to form
Figure 3. Proposed mechanism by the HSAB principle.
per-O-acetylated glycosyl thiols.[15] For this new method, ethyl
acetate and BF3 Et2O can be easily removed by distillation so that
.
the resulting glycosyl thioacetates can be easily transferred into
DMF. Based on these, we envisioned that glycosyl disulfides and
thiols be efficiently synthesized starting from corresponding per-
O-acetylated glycoses through a two-step reaction without the
need to isolate the intermediate products, glycosyl thioacetates.
Therefore, per-O-acetylated glycoses 1, 11, 27 and 29 were
selected for experiments to verify the possibility of the tentative
idea (Scheme 2). After the reaction of 1, 11, 27 or 29 with KSAc
(shown in Scheme 1), the reaction mixture was neutralized by
TEA at room temperature, followed filtering the crystalized salts.
Then, the solvent was removed from the organic phase by
distillation and the residue was dissolved in DMF. At this time,
when KNO2 (2 equiv) was added to this residue in DMF and the
reaction proceeded at 50 oC for 4 – 8 h, disulfide 2a, 12a, 28a or
30a was isolated in 91%, 72%, 74% or 60% yield (based on per-
The applicability of this method on various substrates was then
examined (Scheme 1). Starting from per-O-acylated sugars 3, 5,
7, 9, 11, 13, 15 and 17, 1-glycosyl thioacetates 4, 6, 8, 10, 12, 14,
16 and 18 were produced in 76 - 94% isolation yields under the
optimal conditions. The per-O-acetylated rhamnopyranose 19
and disaccharides 21, 23 and 25 showed poor reactivity under the
conditions. Reactions with them had to be performed in the
.
presence of 3 equiv of KSAc and 6 equiv of BF3 Et2O at 60 oC for
16 h, leading to 72 - 86% yields of 1-glycosyl thioacetates 20, 22,
24 and 26. Furthermore, per-O-acetylated mannopyranose 27
and glucosamine 29 showed the poorest reactivity in the method.
Reactions with them had to be performed in the presence of 2
.
equiv of KSAc and 6 equiv of BF3 Et2O at 75 oC for 20 h, leading
to an 81% yield of 1-thiomannoside 28, and a 65% yield of 1-
thioglucosamine 30. We guessed that the poor reactivity should
be caused by the strong neighboring group participation of the
axial 2-acetate of 27 and the 2-acetamido of 29. Starting from per-
O-benzoylated glucopyranose 31 and galactopyranose 33, only
28% yield of 1-glycosyl thioacetate 32 and 21% yield of 1-glycosyl
thioacetate 34 were obtained under the conditions. We compared
the yields of 1-glycosyl thioacetates obtained by this method with
those obtained by traditional one-step[12] and two-step[13] methods.
It can be seen (Table S1 in Supporting Information), the yields we
obtained were much better than those obtained by traditional
methods in all cases.
.
O-acetylated glycoses) for two steps; when N2H4 H2O (1.3 – 1.5
equiv) was added to this residue in DMF and the reaction
proceeded at room temperature for 2 min, glycosyl 1-thiol 2b, 12b,
28b or 30b was isolated in 90%, 73%, 70% or 61% yield (based
on per-O-acetylated glycoses) for two steps. In comparison with
this, in a method developed by Wan’s group to synthesize per-O-
acetylated glycosyl 1-thiols,[7c] 2b, and 30b was obtained in 86%,
and 56% yield (traditional two-step method: yields based on
glycosyl halides), and 28b was obtained in 53% yield (traditional
two-step method: yields based on per-O-acetylated
mannopyranose).
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10.1002/ejoc.202100357
European Journal of Organic Chemistry
FULL PAPER
at room temperature for 1h, gave the thioglucoside analogue of
canagliflozin 36 in a 89% yield. When the coupling of acetylated
β-thioglucose 2b with 38 was performed under the same
conditions, the desired product 39 was obtained 91% within 2h.
Deprotection of 36 and 39 with NaOH/MeOH gave high yields of
the thioglucoside canagliflozin analogue 37 (TCA) and the
thioglucoside dapagliflozin analogue 40 (TDA).
Scheme 2. Synthesis of per-O-acetylated glycosyl disulfides and thiols starting
from corresponding per-O-acetylated glycoses via two-step reaction without
intermediates isolation. Reaction conditions: [a] Per-O-acetylated glycoses (100
mg), KNO2 (2 equiv), DMF (1 mL), 50 oC, 4 – 8 h, 60 - 91% yields for two steps.
.
[b] Per-O-acetylated glycoses (100 mg), N2H4 H2O (1.3 – 1.5 equiv), DMF (1 mL),
rt, 2 min, 61 - 90% yields for two steps. [c] yields reported in ref. 7c.
Scheme 4. Improved method for the synthesis of auranofin.
It was reported that auranofin had been synthesized in 89% yield
starting from per-O-acetylated glucosyl thiol 2b and PEt3AuCl.[7a-
c]
PEt3AuCl was synthesized by the reaction of KAuCl4 and
triethylphosphine (PEt3).[7b] Since glycosyl disulfides could be
reduced to glycosyl thiols by triethylphosphine (PEt3),[14a] we
wondered if we could synthesize auranofin starting from glucosyl
disulfide 2a and KAuCl4 in the presence of PEt3 in one pot. Firstly,
we confirmed the above idea, and obtained an 87% yield of
auranofin (Scheme 4a). The yield for auranofin based on per-O-
acetylated glucose 1 was improved due to the high yield of 2a by
this method. Next, we further tested whether the formation of
PEt3AuCl, the reduction of disulfide 2a, and the following
formation of auranofin can be carried out in one pot (Scheme 4b).
Thus, a small amount of acetone containing 2.2 equiv of
triethylphosphine were dropped into an aqueous solution of 4,4'-
dihydroxydiphenyl sulfide (2.2 equiv) and KAuCl4 at 0 oC. After the
reaction proceeded for 3 h, 0.6 equiv of disulfide 2a dissolved in
CH2Cl2 were added and the reaction further proceeded in the
presence of 1.2 equiv of K2CO3 for 2 h at room temperature.
Auranofin was isolated in a 70% yield (calculation based on
KAuCl4). Comparing the synthesis of disulfide 2a with the
synthesis of thiol 2b (Scheme 2), the synthesis of 2b was
obviously more efficient though KNO2 might be a greener reagent
Scheme 3. Synthesis of thioglucoside analogues of canagliflozin and
dapagliflozin
We then synthesized glucosyl thioacetate 2 and thiol 2b by this
method in a large-scale reaction (Scheme 3a). Per-O-acetylated
glucopyranose 1 (2 g) was reacted with 2 equiv of KSAc in the
.
presence of 4 equiv of BF3 Et2O in EtOAc (20 mL) at 50 oC for 4
h, giving 2 in a 95% yield. When 2 had not been isolated, after the
reaction mixture was neutralized, filtered and concentrated, the
.
residue was reacted with 1.3 equiv of N2H4 H2O in DMF (20 mL)
at room temperature for 2 min, giving 2b in an 88% yield. With the
highly efficient method to obtain per-O-acetylated glucosyl 1-thiol
2b in hand, we started to synthesize the thioglucoside analogues
of canagliflozin and dapagliflozin (Scheme 3b). The reaction of 2b
(1 equiv) with aryl-iodide 35 (1 equiv) in the presence of 0.04
equiv of Pd-G3-XantPhos precatalyst and 1 equiv of Et3N in THF
.
than N2H4 H2O. Therefore, we started to conceive a one-pot
reaction in which 2b was used instead of 2a in the route shown in
Scheme 3a, and 2b was obtained by simple extraction without
purification. This idea has also proved to be successful (Scheme
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10.1002/ejoc.202100357
European Journal of Organic Chemistry
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4c), and auranofin was isolated in a 72% yield (calculation based
on KAuCl4) finally. In contrast, the isolation yields of auranofin
based on KAuCl4 were around 61-62% in light of the reported
methods. [7a-c] Obviously, our methods have great practical value
since the multi-step intermediate separation process is omitted.
per-O-acetylated glucosyl disulfides and glucosyl 1-thiols have
been used to improve the synthesis of auranofin. More importantly,
the thioglucoside analogues of dapagliflozin and canagliflozin
(TDA and TCA) have been efficiently synthesized starting from
per-O-acetylated glucosyl 1-thiol for the first time. TDA and TCA
showed good stability to β-glucosidase. Compared with the
synthesis of gliflozin compounds, the synthesis of their
thioglucoside analogues is much easier and more efficient. Thus,
we will have provided a new approach to discover new drugs for
the treatment of type 2 diabetes if the modified thioglucoside
gliflozin analogues prove to be good SGLT2 inhibitors in future
biological studies.
With the TDA and the TCA in hand, we evaluated their stability to
hydrolysis under the action of β-glucosidase. We treated β-
glucosidase with 4-nitrophenyl β-D-glucopyranoside, TDA and
TCA respectively under the same conditions. The reaction results
were analyzed by both TLC (SI) and HPLC (Figure 4). The
retention time of 4-nitrophenyl β-D-glucopyranoside is about 14
min (Figure 4a). Under the action of β-glucosidase, 4-nitrophenyl
β-D-glucopyranoside was completely hydrolyzed to form glucose
and 4-nitrophenol within 24 hours. 4-Nitrophenol was detected by
HPLC and its retention time is about 23 min (Figure 4b). However,
neither TDA nor TCA has been hydrolyzed by β-glucosidase even
for 15 days (Figure 4c and 4d). Next, we treated β-glucosidase
with a mixture of 4-nitrophenyl β-D-glucopyranoside and TDA (1:1
Experimental Section
General methods: All reagents were acquired as reagent grade and used
without further purification. Chemical reactions were monitored with thin-
layer chromatography using precoated silica gel 60 (0.25 mm thickness)
plates. The spots on TLC were visualized by warming 10% H2SO4 (10%
mole ratio) and with
a
mixture of 4-nitrophenyl β-D-
glucopyranoside and TCA (1:1 mole ratio). It could be observed
from HPLC detection, in the presence of TDA, only a small
amount of 4-nitrophenyl β-D-glucopyranoside have been
hydrolyzed for 15 days (Figure 4e); and in the presence of TCA,
4-nitrophenyl β-D-glucopyranoside has not been hydrolyzed at all
for 15 days (Figure 4f). These results indicated that both TDA and
TCA were not only stable to hydrolysis of β-glucosidase but also
good inhibitors of β-glucosidase.
H2SO4 in ethanol) sprayed plates on
a hot plate. Flash column
chromatography was performed on silica gel 60 (SDS 0.040−0.063 mm).
1H NMR spectra were recorded at 298 K in CDCl3 / CD3OD, using the
residual signals from CHCl3 (1H = 7.26 ppm) / CD3OD (1H = 3.31 ppm)as
internal standard. Unless mentioned, all organic chemistry experiments
were executed under an oxygen-free atmosphere of nitrogen using
standard techniques. β-glucosidase (135 kDa, activity ≥ 6 units/mg) from
almonds was purchased from Real-Times (Beijing) Biotechnology Co., Ltd.
All the reactions with enzyme were analyzed using RP-HPLC (Shanghai
Wufeng Scientific Instrument Co. Ltd) using
a H2O-CH3CN (with
0.01%TFA) line gradient from 100-0% to 65-35% to 5-95%. The column
type: Suzhou Kesheng C18 10*250nm,10um.
General Procedure for the synthesis of per-acetylated 1-glycosyl
thioacetates by reaction of per-O-acetylated glycosides with KSAc:
potassium thioacetate (2 – 3 equiv) was added into a solution of a per-O-
acetyl glycoside (100 mg) in ethyl acetate (1.5 mL), and stirred for 2
minutes. After the addition of BF3·Et2O (4 – 6 equiv) to the mixture, the
reaction was allowed to proceed at 50 – 75 ℃ for 4 – 20 h. When TLC
indicated full conversion of the starting material, the resulting mixture was
diluted with water, then extracted with CH2Cl2. The combined organic
phases were dried with MgSO4, and concentrated in vacuo. The crude
material was purified by silica gel chromatography.
※
Figure 4. The stability of TDA and TCA to hydrolysis of β-glucosidase. 4-
Nitrophenyl β-D-glucopyranoside (retention time: 14 min). ☆ 4-Nitrophenol (the
hydrolysis product of 4-Nitrophenyl β-D-glucopyranoside, retention time: 23
min). ☼ TDA (retention time: 27 min). # TCA (retention time: 32 min).
2,3,4,6-Tetra-O-acetyl-1-S-acetyl-1-thio-β-D-glucopyranose
(2):[7c]
Conclusions
Following the general procedure, the reaction was carried out with per-O-
acetylated glucopyranoside 1 (100 mg, 0.26 mmol) and potassium
thioacetate (2.0 equiv) in the presence of BF3·Et2O (4.0 equiv) at 50 ℃ for
4 h. The crude material was purified by flash column chromatography
(petroleum/EtOAc 2:1), afforded 2 as a white solid (98.7 mg, 95% yield).
1H NMR (400 MHz, CDCl3): δ 5.29-5.24 (m, 2H, H-3, H-1), 5.15-5.08 (m,
2H, H-2, H-4), 4.26 (dd, 1H, H-6a), 4.09 (dd, 1H, H-6b), 3.83 (ddd, 1H, H-
5), 2.38 (s, 3H, SCOCH3), 2.07, 2.03, 2.02, 2.00 (4 × s, 12H, COCH3). 13
NMR (151 MHz, CDCl3) δ 192.0, 170.6, 170.1, 169.4, 169.3, 80.2, 76.4,
74.0, 69.0, 67.9, 61.7, 30.9, 20.7, 20.6, 20.6.
We have developed a one-step method to synthesize glycosyl
thioacetates by the direct reaction of per-O-acetylated glycoses
with KSAc in the presence of BF3 Et2O in ethyl acetate under mild
.
conditions. Compared with the traditional one-step method and
two-step method, the yields of glycosyl thioacetates obtained by
this method are much higher in most cases. This method is
relatively green due to avoiding the use of the odorous and toxic
HSAc and avoiding the synthesis of intermediate products,
glycosyl halides. Ethyl acetate is a green solvent and can be
recycled through simple distillation. This method was further
applied to improve the synthesis of per-O-acetylated glycosyl
disulfides and glycosyl thiols starting from per-O-acetylated
glycoses. The obtained yields are higher due to the two-step
reaction without the requirement of intermediate isolation. The
C
Large-scale: Following the general procedure, the reaction was carried out
with per-O-acetylated glucopyranoside 1 (2.0 g, 5.12 mmol) and potassium
thioacetate (2.0 equiv) in the presence of BF3·Et2O (4.0 equiv) in ethyl
acetate (15 mL) at 50 ℃ for 4 h. The crude material was purified by flash
column chromatography (petroleum/EtOAc 2:1), afforded 2 as a slight
yellow solid (1.98 g, 95% yield).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100357
European Journal of Organic Chemistry
FULL PAPER
2,3,4,6-Tetra-O-acetyl-1-S-acetyl-1-thio-β-D-galactopyranose (4):[7c]
Following the general procedure, the reaction was carried out with per-O-
acetylated galacopyranoside 3 (200 mg, 0.51 mmol) and potassium
thioacetate (2.0 equiv) in the presence of BF3·Et2O (4.0 equiv) in ethyl
acetate (2.0 mL) at 50 ℃ for 4 h. The crude material was purified by flash
column chromatography (petroleum/EtOAc 2:1), afforded 4 as a white
solid (195 mg, 94% yield). 1H NMR (400 MHz, CDCl3): δ 5.45 (d, 1H, H-4),
5.32 (m, 1H, H-2), 5.25 (d, 1H, H-1), 5.10 (dd, 1H, H-3), 4.15-4.04 (m, 3H,
H-5, H-6a, H-6b), 2.39 (s, 3H, SCOCH3), 2.15, 2.04, 2.03, 1.98 (4 × s, 12H,
COCH3). 13C NMR (151 MHz, CDCl3) δ 192.1, 170.4, 170.2, 169.9, 169.6,
80.6, 75.0, 71.9, 67.2, 66.4, 61.2, 30.9, 20.7, 20.7, 20.7, 20.6.
acetylated arabinofuranoside 13 (102 mg, 0.32 mmol) and potassium
thioacetate (2.0 equiv) in the presence of BF3·Et2O (4.0 equiv) in ethyl
acetate (1.5 mL) at 50 ℃ for 4 h. The crude material was purified by flash
column chromatography (petroleum/EtOAc 3:1), afforded 14 as a colorless
oil (99 mg, 92% yield). [α]D21= the range (α < 0.04°) beyond the limit (c =
0.35, CHCl3); 1H NMR (600 MHz, CDCl3): δ 5.79 (d, J = 4.1 Hz, 1H, H-1),
5.36 (dd, J = 5.0, 4.1 Hz, 1H, H-2), 5.26 (dd, J = 5.7, 5.0 Hz, 1H, H-3), 4.31
– 4.27 (m, 2H, H-5), 4.07 (m, 1H, H-4), 2.35 (s, 3H), 2.09, 2.08, 2.06 (3 ×
s, 9H). 13C NMR (101 MHz, CDCl3) δ 192.9, 170.4, 169.7, 169.4, 83.8,
79.8, 74.6, 71.0, 63.0, 31.0, 20.8, 20.5, 20.5. HRMS (ESI-TOF) m/z:
[M+Na] + calcd for: C13H18NaO8S 357.0615; Found 357.0616.
2,3,4-Tri-O-acetyl-1-S-acetyl-1-thio-α/β-L-fucopyranose
Following the general procedure, the reaction was carried out with per-O-
acetylated fucopyranoside (100 mg, 0.3 mmol) and potassium
(6):[13g]
2,3-di-O-acetyl-5-deoxy-1-S-acetyl-1-thio-β-D-arabinofuranose (16):
Following the general procedure, the reaction was carried out with per-O-
acetylated arabinofuranoside 15 (100 mg, 0.38 mmol) and potassium
thioacetate (2.0 equiv) in the presence of BF3·Et2O (4.0 equiv) in ethyl
acetate (1.5 mL) at 50 ℃ for 4 h. The crude material was purified by flash
column chromatography (petroleum/EtOAc 3:1), afforded 16 as a colorless
oil (90 mg, 85% yield). [α]D21= the range (α < 0.04°) beyond the limit (c =
0.5, CHCl3); 1H NMR (600 MHz, CDCl3): δ 5.73 (d, J = 4.2 Hz, 1H, H-1),
5.37 (dd, J = 4.2, 5.1 Hz, 1H, H-2), 4.98 (dd, J = 6.0, 5.1 Hz, 1H, H-3), 4.19
(m, 1H, H-4), 2.37 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H), 1.33 (d, J = 6.4 Hz,
3H, H-5). 13C NMR (151 MHz, CDCl3) δ 193.2, 169.9, 169.5, 83.2, 78.3,
75.2, 74.7, 31.0, 20.6, 20.6, 19.2. HRMS (ESI-TOF) m/z: [M+Na] + calcd
for: C11H16NaO6S 299.0560; Found 299.0561.
5
thioacetate (2.0 equiv) in the presence of BF3·Et2O (4.0 equiv) in ethyl
acetate (1.5 mL) at 50 ℃ for 4 h. The crude material was purified by flash
column chromatography (petroleum/EtOAc 2:1), afforded 6 as a white
solid (93.3 mg, α/β = 1:4, 89% yield). 1H NMR (400 MHz, CDCl3): δ 5.21-
5.29 (m, 3H, H-4, H-2, H-1), 5.09 (dd, 1H, H-3), 3.95 (qd, 1H, H-5), 2.37
(s, 3H, SCOCH3), 2.16, 2.02, 1.97 (3 × s, 9H, COCH3), 1.19 (d, 3H, CH3-
6). 13C NMR (151 MHz, CDCl3) δ 192.6, 170.6, 170.0, 169., 80.3, 73.8,
72.3, 70.3, 66.5, 30.9, 20.7, 20.7, 20.6, 16.3.
2,3,4-Tri-O-acetyl-1-S-acetyl-1-thio-α-L-arabinopyranose
(8):[7c]
Following the general procedure, the reaction was carried out with per-O-
acetylated arabinopyranoside 7 (104 mg, 0.33 mmol) and potassium
thioacetate (2.0 equiv) in the presence of BF3·Et2O (4.0 equiv) in ethyl
acetate (1.5 mL) at 50 ℃ for 4 h. The crude material was purified by flash
column chromatography (petroleum/EtOAc 3:1), afforded 8 as a colorless
oil (95.0 mg, 87% yield). 1H NMR (400 MHz, CDCl3): δ 5.39 (d, 1H, H-1),
5.30 (m, 1H, H-4), 5.23 (t, 1H, H-2), 5.15 (dd, 1H, J = 3.6 Hz, H-3), 3.99
(dd, 1H, J = 4.8 Hz, H-5a), 3.78 (dd, 1H, H-5b), 2.38 (s, 3H, SCOCH3), 2.11,
2.07, 2.06 (3 × s, 9H, COCH3). 13C NMR (151 MHz, CDCl3) δ 192.5, 170.1,
169.7, 169.5, 80.1, 70.0, 67.9, 67.1, 65.4, 30.9, 20.9, 20.8, 20.7.
2,3,5-Tri-O-benzoyl-1-S-acetyl-1-thio-β-D-arabinofuranose
(18):
Following the general procedure, the reaction was carried out with per-O-
acetylated arabinofuranoside 17 (100 mg, 0.2 mmol) and potassium
thioacetate (2.0 equiv) in the presence of BF3·Et2O (4.0 equiv) in ethyl
acetate (1.5 mL) at 50 ℃ for 4 h. The crude material was purified by flash
column chromatography (petroleum/EtOAc 3:1), afforded 18 as a colorless
oil (97 mg, 93% yield). [α]D21= the range (α < 0.04°) beyond the limit (c =
1
0.31, CHCl3); H NMR (400 MHz, CDCl3): δ 8.11 – 7.91 (m, 6H), 7.59 –
7.33 (m, 9H), 6.11 (d, J = 3.7 Hz, 1H, H-1), 5.87 – 5.79 (m, 2H, H-2, H-3),
4.74 – 4.68 (m, 2H, H-5), 4.52 (m, 1H, H-4), 2.37 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 192.8, 166.1, 165.3, 165.1, 133.6, 133.6, 133.3, 129.9,
3,4,6-Tri-O-acetyl-2-deoxy-1-S-acetyl-1-thio-α/β-D-arabino-
hexopyranose (10):[7c] Following the general procedure, the reaction was
carried out with per-O-acetylated arabino-hexopyranose 9 (100 mg, 0.30
mmol) and potassium thioacetate (2.0 equiv) in the presence of BF3·Et2O
(4.0 equiv) in ethyl acetate (1.5 mL) at 50 ℃ for 4 h. The crude material
was purified by flash column chromatography (petroleum/EtOAc 2:1),
afforded 10 as a white solid (93 mg, α/β = 2.5:1, 88% yield). 1H NMR (400
MHz, CDCl3): δ 6.09 (m, 2.5H), 5.29 (d, 1H ), 4.32-4.24 (m, 3.5H), 4.05 –
3.91 (m, 6H), 4.05-3.91 (m, 6H), 3.73 (m, 1H), 2.37 (s, 7.5H), 2.34 (m,
3.5H), 2.26(m, 3.5H), 2.05, 2.02, 2.00 (3 × s, 31.5H), 1.98-1.73(m, 3.5H).
13C NMR (151 MHz, CDCl3) δ 192.3, 192.3, 170.8, 170.7, 170.2, 170.2,
169.8, 169.7, 78.6, 76.7, 76.5, 71.8, 71.7, 69.9, 68.8, 68.3, 62.2, 62.0, 35.8,
35.6, 31.3, 30.7, 20.9, 20.9, 20.8, 20.7, 20.7, 20.7.
129.9, 129.8, 129.5, 128.9, 128.7, 128.5, 128.5, 84.2, 80.2, 75.3, 72.0,
+
63.7, 31.0. HRMS (ESI-TOF) m/z: [M+Na]
543.1084; Found 543.1082.
calcd for: C28H24NaO8S
2,3,4-Tri-O-acetyl-1-S-acetyl-1-thio-α/β-L-rhamnopyranose
(20):[7c]
Following the general procedure, the reaction was carried out with per-O-
acetylated rhamnopyranoside 19 (101 mg, 0.3 mmol) and potassium
thioacetate (3.0 equiv) in the presence of BF3·Et2O (6.0 equiv) in ethyl
acetate (1.5 mL) at 60 ℃ for 20 h. The crude material was purified by flash
column chromatography (petroleum/EtOAc 2:1), afforded 20 as a colorless
oil (76.2 mg, α/β = 13:1, 72% yield). 1H NMR (400 MHz, CDCl3): δ 5.88 (d,
1H, H-1), 5.31 (dd, 1H, H-2), 5.11 (m, 1H, H-4), 5.04 (dd, 1H, H-3), 3.78
(dq, 1H, H-5), 2.41 (s, 3H, SCOCH3), 2.17, 2.05, 1.98 (3 × s, 9H, COCH3),
1.22 (d, 3H, CH3-6). 13C NMR (151 MHz, CDCl3) δ 191.0, 170.0, 169.9,
169.8, 80.1, 71.3, 70.8, 70.6, 69.8, 31.3, 20.9, 20.8, 20.6, 17.5.
2,3,4-Tri-O-acetyl-1-S-acetyl-1-thio-β-D-xylopyranose
(12):[7c]
Following the general procedure, the reaction was carried out with per-O-
acetylated xylopyranoside 11 (102 mg, 0.32 mmol) and potassium
thioacetate (2.0 equiv) in the presence of BF3·Et2O (4.0 equiv) in ethyl
acetate (1.5 mL) at 50 ℃ for 4 h. The crude material was purified by flash
column chromatography (petroleum/EtOAc 3:1), afforded 12 as a white
solid (81.4 mg, 76% yield). 1H NMR (400 MHz, CDCl3): δ 5.36 (d, 1H, H-
1), 5.19 (t, 1H, H-3), 5.00 (t, 1H, H-2), 4.92 (m, 1H, H-4), 4.14 (dd, 1H, H-
5a), 3.53 (dd, 1H, H-5b), 2.37 (s, 3H, SCOCH3), 2.05, 2.05, 2.04 (3 × s, 9H,
COCH3). 13C NMR (151 MHz, CDCl3) δ 192.3, 169.8, 169.7, 169.4, 80.2,
71.4, 68.9, 68.1, 65.6, 30. 9, 20.8, 20.7, 20.7.
2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl(1→4)-2,3,6-Tri-O-acetyl-
l-S-acetyl-1-thio-β-D-glucopyranose (22):[7c] Following the general
procedure, the reaction was carried out with per-O-acetylated lactoside 21
(102 mg, 0.15 mmol) and potassium thioacetate (3.0 equiv) in the
presence of BF3·Et2O (6.0 equiv) in ethyl acetate (1.5 mL) at 60 ℃ for 20
h. The crude material was purified by flash column chromatography
(petroleum/EtOAc 1:1), afforded 22 as a white solid (83.6 mg, 80% yield).
1H NMR (400 MHz, CDCl3): δ 5.33 (dd, 1H, H-4'), 5.24 (m, 1H, H-3), 5.20
(d, 1H, H-1), 5.09 (dd, 1H, H-2'), 5.03 (dd, 1H, H-2), 4.93 (dd, 1H, H-3'),
4.46 (d, 1H, H-1'), 4.44 (dd, 1H, H-6'a), 4.14 – 4.04 (m, 3H, H-6a, H-6b, H-
6'b), 3.86 (m, 1H, H-5'), 3.80 (d, 1H, H-4), 3.74 (ddd, 1H, H-5), 2.36 (s, 3H,
2,3,5-Tri-O-acetyl-1-S-acetyl-1-thio-β-D-arabinofuranose
(14):
Following the general procedure, the reaction was carried out with per-O-
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100357
European Journal of Organic Chemistry
FULL PAPER
SCOCH3), 2.14, 2.10, 2.06, 2.03, 2.03, 2.01, 1.95 (7 × s, 21H, COCH3).
13C NMR (151 MHz, CDCl3) δ 191.9, 170.4, 170.3, 170.2, 170.1, 169.6,
169.6, 169.0, 100.9, 80.0, 77.2, 75.7, 73.7, 71.0, 70.8, 69.3, 69.0, 66.7,
62.0, 60.9, 30.8, 20.9, 20.8, 20.6, 20.6, 20.5.
2,3,4,6-Tetra-O-benzoyl-1-S-acetyl-1-thio-β-D-glucopyranose (32):[7c]
Following the general procedure, the reaction was carried out with per-O-
benzoylated glucopyranose 31 (205 mg, 0.32 mmol) and potassium
thioacetate (2.0 equiv) in the presence of BF3·Et2O (6.0 equiv) in ethyl
acetate (1.5 mL) at 75 ℃ for 16 h. The crude material was purified by flash
column chromatography (petroleum/EtOAc 3:1), afforded 32 as a white
solid (58.8 mg, 28% yield). 1H NMR (400 MHz, CDCl3): δ 8.05-7.25 (m,
20H, Ar-H), 5.98 (m, 1H, H-3), 5.75-5.61 (m, 3H, H-4, H-2, H-1), 4.60 (dd,
1H, H-6a), 4.46 (dd, 1H, H-6b), 4.31 (ddd, 1H, H-5), 2.32 (s, 3H, SCOCH3).
13C NMR (151 MHz, CDCl3) δ 192.2, 166.1, 165.7, 165.2, 165.1, 133.6,
133.5, 133.3, 133.1, 130.0, 129.9, 129.9, 129.8, 129.6, 128.7, 128.7, 128.5,
128.4, 128.4, 128.3, 80.7, 76.9, 74.2, 69.9, 69.1, 62.9, 30.9.
2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl(1→4)-2,3,6-Tri-O-acetyl-l-
S-acetyl-1-thio-β-D-glucopyranose (24):[7c] Following the general
procedure, the reaction was carried out with per-O-acetylated maltoside
23 (104 mg, 0.15 mmol) and potassium thioacetate (3.0 equiv) in the
presence of BF3·Et2O (6.0 equiv) in ethyl acetate (1.5 mL) at 60 ℃ for 20
h. The crude material was purified by flash column chromatography
(petroleum/EtOAc 1:1), afforded 24 as a colorless oil (91.5 mg, 86% yield).
1H NMR (400 MHz, CDCl3): δ 5.38 (d, 1H, H-1'), 5.36-5.28 (m, 2H, H-3', H-
3), 5.27 (d, 1H, H-1), 5.03 (t, 1H, H-4'), 4.96 (dd, 1H, H-2), 4.84 (dd, 1H,
H-2'), 4.43 (dd, 1H, H-6a), 4.24-4.17 (m, 2H, H-6'a, H-6b), 4.02-3.96 (m, 2H,
H-6'b, H-4), 3.91 (m, 1H, H-5'), 3.81 (ddd, 1H, H-5), 2.36 (s, 3H, SCOCH3),
2.11, 2.08, 2.04, 2.01, 1.99, 1.98, 1.98 (7 ×s, 21H, COCH3). 13C NMR (151
MHz, CDCl3) δ 191.8, 170.6, 170.5, 170.5, 170.0, 169.9, 169.6, 169.5, 95.7,
79.8, 76.6, 76.3, 72.6, 70.0, 69.8, 69.3, 68.6, 68.0, 62.7, 61.5, 30.8, 20.9,
20.8, 20.7, 20.6, 20.6, 20.6.
2,3,4,6-Tetra-O-benzoyl-1-S-acetyl-1-thio-β-D-galactopyranose
(34):[7c] Following the general procedure, the reaction was carried out with
per-O-benzoylated galactopyranose 33 (205 mg, 0.32 mmol) and
potassium thioacetate (2.0 equiv) in the presence of BF3·Et2O (6.0 equiv)
in ethyl acetate (1.5 mL) at 75 ℃ for 16 h. The crude material was purified
by flash column chromatography (petroleum/EtOAc 3:1), afforded 34 as a
white solid (44.1 mg, 21% yield). 1NMR (400 MHz, CDCl3): δ 8.08-7.22 (m,
20H, Ar-H), 6.07 (m, 1H, H-4), 5.91 (m, 1H, H-2), 5.73 (dd, 1H, H-3), 5.64
(d, 1H, H-1), 4.62 (dd, 1H, H-6a), 4.50 (m, 1H, H-5), 4.38 (dd, 1H, H-6b),
2.34 (s, 3H, SCOCH3). 13C NMR (151 MHz, CDCl3) δ 192.1, 166.0, 165.5,
165.4, 165.3, 133.7, 133.6, 133.3, 133.3, 130.0, 129.9, 129.9, 129.8, 129.4,
129.0, 128.8, 128.7, 128.7, 128.5, 128.4, 128.3, 81.0, 75.8, 72.7, 68.3,
67.5, 62.1, 30.9.
2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl(1→4)-2,3,6-Tri-O-acetyl-l-
S-acetyl-1-thio-β-D-glucopyranose (26):[7c] Following the general
procedure, the reaction was carried out with per-O-acetylated cellobioside
25 (101 mg, 0.15 mmol) and potassium thioacetate (3.0 equiv) in the
presence of BF3·Et2O (6.0 equiv) in ethyl acetate (1.5 mL) at 60 ℃ for 20
h. The crude material was purified by flash column chromatography
(petroleum/EtOAc 1:1), afforded 26 as a white solid (83.7 mg, 81% yield).
1H NMR (400 MHz, CDCl3): δ 5.22 (d, 1H, H-3), 5.18 (d, 1H, H-1), 5.11 (d,
1H, H-3'), 5.06 – 5.00 (m, 2H, H-4, H-4'), 4.90 (dd, 1H, H-2'), 4.48-4.44 (m,
2H, H-1', H-6a), 4.34 (dd, 1H, H-6b), 4.07 (dd, 1H, H-6'a), 4.02 (dd, 1H, H-
6'b), 3.78 (m, 1H, H-2), 3.73 (ddd, 1H, H-5), 3.63 (ddd, 1H, H-5'), 2.35 (s,
3H, SCOCH3), 2.10, 2.07, 2.02, 2.00, 2.00, 1.99, 1.96 (7 × s, 21H, COCH3).
13C NMR (151 MHz, CDCl3) δ 191.9, 170.5, 170.3, 170.2, 169.6, 169.6,
169.3, 169.0, 100.6, 80.1, 77.2, 76.0, 73.5, 72.9, 72.0, 71.5, 69.2, 67.8,
61.9, 61.6, 30.8, 20.9, 20.7, 20.6, 20.5, 20.5.
General procedure for the application of this method to synthesize
per-O-acetylated
glycosyl
disulfides
without
intemediates
purification:Potassium thioacetate (2 – 3 equiv) was added into a solution
of a per-O-acetyl glycoside (100 mg) in ethyl acetate (1.5 mL), and stirred
for 2 minutes. After the addition of BF3·Et2O (4 – 6 equiv) to the mixture,
the reaction was allowed to proceed at 50 – 75 ℃ for 4 – 20 h. When TLC
indicated full conversion of the starting material, the resulting mixture was
treated with TEA. After filtered to remove potassium salts, the reaction
mixture was concentrated in vacuo and the residue was disolved in DMF
(1 mL). Potassium nitrite (2 equiv) was added into the solution and the
reaction was allowed to proceed at 50 ℃ for 4 – 8 h. Then the reaction
mixture was extracted with CH2Cl2 and water. The combined organic
phases were dried with MgSO4, and concentrated in vacuo. The crude
material was purified by silica gel chromatography.
2,3,4,6-Tetra-O-acetyl-1-S-acetyl-1-thio-α-D-mannopyranose (28):[7c]
Following the general procedure, the reaction was carried out with per-O-
acetylated mannoside 27 (102 mg, 0.26 mmol) and potassium thioacetate
(2.0 equiv) in the presence of BF3·Et2O (6.0 equiv) in ethyl acetate (1.5
mL) at 75 ℃ for 16 h. The crude material was purified by flash column
chromatography (petroleum/EtOAc 2:1), afforded 28 as a colorless oil
(86.8 mg, 81% yield). 1H NMR (400 MHz, CDCl3): δ 5.92 (d, 1H, H-1), 5.31
(m, 1H, H-4), 5.29 (dd, 1H, H-2), 5.06 (dd, 1H, H-3), 4.26 (dd, 1H, H-6a),
4.04 (dd, 1H, H-6b), 3.90 (ddd, 1H, H-5), 2.40 (s, 3H, SCOCH3), 2.16, 2.06,
2.02, 1.97 (4 × s, 12H, COCH3). 13C NMR (151 MHz, CDCl3) δ 190.4, 170.6,
169.9, 169.8, 169.5, 80.2, 72.5, 71.0, 69.9, 65.7, 62.2, 31.3, 20.9, 20.7,
20.7, 20.6.
Bis(2,3,4,6-tetra-O-acetyl-1-thio-1-deoxy-β-D-glucopyranosy-l)-1,1′-
disulfide (2a):[12e] The reaction was carried out with per-O-acetylated
glucoside 1 (101 mg, 0.26 mmol). The crude material was purified by flash
column chromatography (petroleum/EtOAc 1:1), afforded 2a as a colorless
oil (85.5 mg, 91% yield). 1H NMR (400 MHz, CDCl3): δ 5.28−5.17 (m, 4H,
H-2, H-3), 5.09 (t, 2H, H-4), 4.65 (d, 2H, H-1), 4.33 (dd, 2H, H-6a), 4.22 (dd,
2H, H-6b), 3.78 (ddd, 2H, H-5), 2.13, 2.10, 2.02, 2.00 (4 ×s, 24H, COCH3).
13C NMR (151 MHz, CDCl3) δ 170.7, 170.1, 169.3, 169.2, 87.2, 76.2, 73.9,
69.7, 67.9, 61.6, 20.8, 20.7, 20.6.
3,4,6-Tri-O-acetyl-N-acetyl-S-acetyl-1-thio-β-D-glucosamine (30):[7c]
Following the general procedure, the reaction was carried out with per-O-
acetylated glucosamine 29 (103 mg, 0.26 mmol) and potassium
thioacetate (2.0 equiv) in the presence of BF3·Et2O (6.0 equiv) in ethyl
acetate (1.5 mL) at 75 ℃ for 16 h. The crude material was purified by flash
column chromatography (petroleum/EtOAc 1:6), afforded 30 as a white
solid (69.4 mg, 65% yield). 1H NMR (400 MHz, CDCl3): δ 5.61 (d, 1H, NH),
5.16-5.07 (m, 3H, H-1, H-3, H-4), 4.36 (m, 1H, H-2), 4.23 (dd, 1H, H-6a),
4.08 (dd, 1H, H-6b), 3.78(ddd, 1H, H-5), 2.37 (s, 3H, SCOCH3), 2.08, 2.04,
2.04, 1.92 (4 × s, 12H, COCH3). 13C NMR (151 MHz, CDCl3) δ 193.7, 171.3,
170.7, 170.0, 169.2, 81.7, 76.6, 74.0, 67.7, 61.8, 52.3, 30.8, 23.2, 20.8,
20.7, 20.6.
Bis-(2,3,4-tri-O-acetyl-1-thio-1-deoxy-β-D-xylopyranosyl)-1,1'-
disulfide (12a):[12e] The reaction was carried out with per-O-acetylated
xyloside 11 (106 mg, 0.33 mmol). The crude material was purified by flash
column chromatography (petroleum/EtOAc 2:1), afforded 12a as a
colorless oil (70 mg, 72% yield). 1H NMR (400 MHz, CDCl3): δ 5.18 (t, 2H,
H-2), 5.10 (t, 2H, H-3), 4.96-4.91 (m, 2H, H-4), 4.69 (d, 2H, H-1), 4.24 (dd,
2H, H-5a), 3.45 (dd, 2H, H-5b), 2.09, 2.06, 2.05 (3 ×s, 18H, COCH3). 13
C
NMR (151 MHz, CDCl3) δ 169.8, 169.7, 169.2, 88.2, 71.7, 69.2, 68.2, 65.3,
20.7, 20.7.
Bis-(2,3,4,6-tetra-O-acetyl-1-thio-1-deoxy-α-D-mannopyranosyl)-1,1'-
disulfide (28a): [12e] The reaction was carried out with per-O-acetylated
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100357
European Journal of Organic Chemistry
FULL PAPER
mannoside 27 (102 mg, 0.26 mmol). The crude material was purified by
flash column chromatography (petroleum/EtOAc 1:1), afforded 28a as a
colorless oil (70.3 mg, 74% yield). 1H NMR (400 MHz, CDCl3): δ 5.47-5.46
(m, 2H, H-3), 5.34-5.23 (m, 6H, H-1, H-2, H-4), 4.32 (dd, 2H, H-6a), 4.21
(ddd, 2H, H-5), 4.09 (dd, 2H, H-6b), 2.16, 2.10, 2.06, 2.00 (4 ×s, 24H,
COCH3). 13C NMR (151 MHz, CDCl3) δ 170.6, 169.8, 169.7, 169.6, 87.4,
70.9, 69.7, 68.9, 65.9, 62.0, 20.8, 20.7, 20.7, 20.6.
H-3, H-4), 4.37 - 4.34 (m, 1H, H-5), 4.30 (dd, 1H, H-6a), 4.12 (dd, 1H, H-
6b), 2.28 (d, 1H, SH), 2.17, 2.10, 2.06, 2.00 (4 × s, 12H, COCH3). 13C NMR
(101 MHz, CDCl3) δ 170.7, 169.9, 169.9, 169.7, 77.0, 71.9, 69.7, 68.5,
66.1, 62.2, 20.9, 20.8, 20.7, 20.6.
3,4,6-tri-O-acetyl-1-thio-2-acetamido-2-deoxy-β-D-glucopyranose
(30b):[7c] The reaction was carried out with per-O-acetylated glucosamine
29 (156 mg, 0.4 mmol). The crude material was purified by flash column
chromatography (petroleum/EtOAc 1:3), afforded 30b as a colorless oil (89
mg, 61% yield). 1H NMR (400 MHz, CDCl3): δ 5.70 (1H, d, NH), 5.14 - 5.05
(m, 2H, H-4, H-3), 4.57 (t, 1H, H-1), 4.23 (dd, 1H, H-6a), 4.16 - 4.09 (m, 2H,
H-6b, H-2), 3.68 (ddd, 1H, H-5), 2.57 (d, 1H, SH), 2.10, 2.04, 2.02, 1.98 (4
× s, 12H, COCH3). 13C NMR (101 MHz, CDCl3) δ 171.2, 170.8, 170.5,
169.2, 80.3, 76.3, 73.5, 68.1, 62.2, 56.8, 23.3, 20.8, 20.7, 20.6.
Bis-(3,4,6-tri-O-acetyl-2-N-acetyl-1-thio-1-deoxy-β-D-glucosamine)-
1,1'-disulfide (30a):[12e] Following the general procedure, the reaction was
carried out with per-O-acetylated glucosamine 29 (117 mg, 0.3 mmol). The
crude material was purified by flash column chromatography
(petroleum/EtOAc 1:5), afforded 30a as a colorless oil (65 mg, 60% yield).
1H NMR (400 MHz, CDCl3): δ 6.08 (d, 2H, NH), 5.40 (t, 2H, H-3), 5.00 (t,
2H, H-4), 4.88 (d, 2H, H-1), 4.44 (dd, 2H, H-6a), 4.07 (dd, 2H, H-6b), 3.99
(dd, 2H, H-2), 3.77 (ddd, 2H, H-5), 2.13, 2.02, 2.02, 2.01 (4 ×s, 24H,
COCH3). 13C NMR (101 MHz, CDCl3) δ 170.9, 170.6, 170.5, 169.5, 88.8,
76.1, 73.0, 68.5, 62.1, 53.4, 23.4, 20.9, 20.7, 20.6.
The synthesis of thioglucoside analogues of canagliflozin 37: In a 10
mL reactor, it was added tetraacetylated thioglucose 2b (150 mg, 0.41
mmol), 35 (167.5 mg, 0.41 mmol) and Xantphos Pd precatalyst 3rd
generation (15 mg, 4 mol%, 0.016 mmol). The reactor is flushed with
nitrogen 5 times and then THF is added (2 mL). Upon stirring the reaction
mixture, Et3N (56 μL, 0.41mmol) is added to the medium. After 1h, TLC
check indicates the total consumption of both starting material and the
formation of one product (petroleum/EtOAc 2:1). The reaction mixture was
concentrated in vacuo and purified by silica gel chromatography
General procedure for the application of this method to synthesize
per-O-acetylated glycosyl 1-thiols without intemediates purification:
Potassium thioacetate (2 – 3 equiv) was added into a solution of a per-O-
acetyl glycoside (100 mg) in ethyl acetate (1.5 mL), and stirred for 2
minutes. After the addition of BF3·Et2O (4 – 6 equiv) to the mixture, the
reaction was allowed to proceed at 50 – 75 ℃ for 4 – 20 h. When TLC
indicated full conversion of the starting material, the resulting mixture was
treated with TEA. After filtered to remove potassium salts, the reaction
mixture was concentrated in vacuo and the residue was disolved in DMF
(1 mL). N2H4·H 2O (1.3 – 1.5 equiv) was added into the solution and the
reaction was allowed to proceed at room temperature for 2 min. Then the
reaction mixture was neutrilized by acetic acid and extracted with CH2Cl2
and water. The combined organic phases were dried with MgSO4, and
concentrated in vacuo. The crude material was purified by silica gel
chromatography.
1
(petroleum/EtOAc 3:1) to provide 36 (90%, 238mg, 0.37 mmol). H NMR
(600 MHz, CDCl3): δ 7.50 – 7.48 (m, 2H), 7.34 (d, J = 2.0 Hz, 1H), 7.30
(dd, J = 7.8, 2.0 Hz, 1H), 7.26 (s, 1H), 7.12 (d, J = 7.9 Hz, 1H), 7.06 – 7.01
(m, 3H), 6.69 (dd, J = 2.9, 1.8 Hz, 1H), 5.20 (t, J = 9.4 Hz, 1H, H-3), 5.03
(t, J = 9.8 Hz, 1H, H-4), 4.94 (t, J = 9.7 Hz, 1H, H-2), 4.65 (d, J = 10.1 Hz,
1H, H-1), 4.18 (dd, J = 12.3, 4.9 Hz, 1H, H-6a), 4.11 – 4.09 (m, 3H, H-6b),
3.66 (ddd, J = 10.1, 4.9, 2.4 Hz, 1H, H-5), 2.32 (s, 3H), 2.06(4 × s, 12H).
13C NMR (101 MHz, CDCl3) δ 170.6, 170.2, 169.4, 169.2, 163.4, 160.9,
142.5, 141.8, 139.1, 137.1, 134.1, 131.9, 131.0, 130.7, 130.7, 128.7, 127.2,
127.1, 126.3, 122.8, 115.9, 115.7, 86.0, 75.8, 74.0, 69.9, 68.1, 62.1, 33.9,
20.78, 20.7, 20.6, 20.6, 19.3.
2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranose(2b):[7c] Following the
general procedure, the reaction was carried out with per-O-acetylated
glucoside 1 (196 mg, 0.5 mmol). The crude material was purified by flash
column chromatography (petroleum/EtOAc 2:1), afforded 2b as a colorless
In a 10 mL reactor, it was added 36 (130 mg, 0.20 mmol), NaOH (4 mg,
0.10 mmol) and MeOH (1 mL). The reaction mixture was stirred at room
temperature for 8 h under nitrogen protection and monitored with TLC.
Then the mixture was neutralized with Amberlite IR-120 (H+) ion exchange
resin and filtered. Purified by silica gel chromatography (EtOAc/MeOH
10:1) to provide thioglucoside analogues of canagliflozin 37 (97%, 93mg,
0.195mmol). M.p.156-157 °C; [α]D21=－21.7 (c = 0.23, MeOH); 1H NMR
(400 MHz, CD3OD): δ 7.55-7.47 (m, 3H), 7.36 (dd, J = 7.8, 2.0 Hz, 1H),
7.12-7.04 (m, 4H), 6.73 (d, J = 3.6 Hz, 1H), 4.53 (d, J = 9.8 Hz, 1H, H-1),
4.12 (s, 2H), 3.82 (dd, J = 12.0, 1.7 Hz, 1H, H-6a), 3.63 (dd, J = 12.1, 5.0
Hz, 1H, H-6b), 3.39-3.35 (m, 1H, H-3), 3.33-3.20 (m, 3H, H-4, H-5, H-2),
2.28 (s, 3H, CH3). 13C NMR (101 MHz, CD3OD) δ 163.3, 160.9, 143.2,
141.4, 139.1, 135.7, 132.7, 131.0, 130.7, 130.5, 130.4, 126.8, 126.0, 122.6,
115.4, 115.1, 88.1, 80.7, 78.3, 72.2, 69.9, 61.4, 33.3, 17.8. HRMS (ESI-
TOF) m/z: [M+Na] + calcd for: C24H25FNaO5S2 499.1020; Found 499.1024.
1
oil (165 mg, 90% yield). H NMR (400 MHz, CDCl3): δ 5.18 (t, 1H, H-3),
5.10 (t, 1H, H-4), 4.97 (t, 1H, H-2), 4.54 (t, 1H, H-1), 4.24 (dd, 1H, H-6a),
4.12 (dd, 1H, H-6b), 3.72 (ddd, 1H, H-5), 2.31 (d, 1H, SH), 2.09, 2.07, 2.02,
2.00 (4 × s, 12H, COCH3). 13C NMR (151 MHz, CDCl3) δ 170.7, 170.1,
169.6, 169.4, 78.7, 76.4, 73.6, 73.5, 68.1, 62.0, 20.8, 20.7, 20.6, 20.6.
Large-scale: following the general procedure, the reaction was carried out
with per-O-acetylated glucoside 1 (2.0 g, 5.12 mmol), afforded 2b as a
yellow oil (1.65 g, 88% yield).
2,3,4-tri-O-acetyl-1-thio-β-D-xylopyranose (12b): [7c] The reaction was
carried out with per-O-acetylated xyloside 11 (101 mg, 0.32 mmol). The
crude material was purified by flash column chromatography
(petroleum/EtOAc 3:1), afforded 12b as a colorless oil (68 mg, 73% yield).
1H NMR (400 MHz, CDCl3): δ 5.16 (t, 1H, H-3), 5.01 - 4.95 (m, 1H, H-4),
4.91 (t, 1H, H-2), 4.56 (dd, 1H, H-1), 4.20 (dd, 1H, H-5a), 3.38 (dd, 1H, H-
5b), 2.28 (d, 1H, SH), 2.08, 2.04, 2.04 (3 × s, 9H, COCH3). 13C NMR (101
MHz, CDCl3) δ 169.9, 169.7, 169.7, 78.9, 73.3, 72.4, 68.6, 66.2, 20.8, 20.7.
The synthesis of thioglucoside analogues of dapagliflozin 40: In a 10
mL reactor, it was added tetraacetylated thioglucose 2b (150 mg, 0.41
mmol), 38 (153.5 mg, 0.41 mmol) and Xantphos Pd precatalyst 3rd
generation (15 mg, 4 mol%, 0.016 mmol). The reactor is flushed with
nitrogen 5 times and then THF is added (2 mL). Upon stirring the reaction
mixture, Et3N (56 μL, 0.41mmol) is added to the medium. After 30
minutes2h, TLC check indicates the total consumption of both starting
material and the formation of one product (petroleum/EtOAc 2:1). The
reaction mixture was concentrated in vacuo and purified by silica gel
chromatography (petroleum/EtOAc 3:1) to provide 39 (93%, 233mg, 0.38
mmol). 1H NMR (400 MHz, CDCl3): δ 7.29 – 7.08 (m, 3H), 7.09 (d, J = 8.5
Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 5.19 (t, J = 9.3 Hz, 1H, H-3), 5.02 (t, J =
2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranose
(28b):[7c]
The
reaction was carried out with per-O-acetylated mannoside 27 (117 mg, 0.3
mmol). The crude material was purified by flash column chromatography
(petroleum/EtOAc 2:1), afforded 28b as a colorless oil (76 mg, 70% yield).
1H NMR (400 MHz, CDCl3): δ 5.56 (d, 1H, H-1), 5.36 - 5.28 (m, 3H, H-2,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100357
European Journal of Organic Chemistry
FULL PAPER
9.8 Hz, 1H, H-4), 4.92 (t, J = 9.6 Hz, 1H, H-2), 4.61 (d, J = 10.1 Hz, 1H, H-
1), 4.18 (dd, J = 12.4, 4.9 Hz, 1H, H-6a), 4.06 – 3.98 (m, 5H, H-6b), 3.61
(ddd, J = 10.2, 4.9, 2.3 Hz, 1H, H-5), 2.05, 2.04, 2.02, 1.99 (4 × s, 12H),
1.40 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 170.6, 170.2, 169.3,
169.2, 157.6, 140.1, 134.9, 134.6, 131.9, 130.6, 130.2, 130.0, 129.9, 114.6,
85.5, 75.9, 73.9, 69.7, 68.0, 63.4, 61.9, 38.3, 20.7, 20.6, 20.6, 14.9.
silica gel chromatography (petroleum/EtOAc 1:1) to afford auranofin (117
mg, 72%, calculated by KAuCl4) as a white solid. H NMR (400 MHz,
1
CDCl3): δ 5.16-5.07 (m, 3 H, H-1, H-3, H-4), 4.98 (m, 1 H, H-2), 4.23 (dd,
1 H, J = 4.8, 12.4 Hz, H-6a), 4.09 (dd, 1 H, J = 2.4, 12.4 Hz, H-6b), 3.72 (m,
1 H, H-5), 2.07, 2.05, 2.00, 1.97 (4×s, 12 H, COCH3), 1.84 (dq, 6 H, J =
7.6, 9.6 Hz, CH2CH3), 1.20 (dt, 9 H, J = 7.6, 18.4 Hz, CH2CH3). 31P NMR
(162 MHz, CDCl3) δ 37.1.
In a 10 mL reactor, it was added 39 (122 mg, 0.20 mmol), NaOH (4 mg,
0.10 mmol) and MeOH (1 mL). The reaction mixture was stirred at room
temperature for 8 h under nitrogen protection and monitored with TLC.
Then the mixture was neutralized with Amberlite IR-120 (H+) ion exchange
resin and filtered. Purified by silica gel chromatography (EtOAc/MeOH
10:1) to provide thioglucoside analogues of dapagliflozin 40 (98%, 87mg,
0.197mmol). M.p.123-124 °C; [α]D21=－56.7 (c = 0.15, MeOH); 1H NMR
(400 MHz, CD3OD): δ 7.39-7.29 (m, 3H), 7.10 (d, J = 8.6 Hz, 2H), 6.83 (d,
J = 8.6 Hz, 2H), 4.52 (d, J = 9.8 Hz, 1H, H-1), 4.02-3.97 (m, 4H), 3.77 (dd,
J = 12.1, 2.1 Hz, 1H, H-6a), 3.61 (dd, J = 12.1, 5.2 Hz, 1H, H-6b), 3.37-3.14
(m, 4H, H-3, H-4, H-5, H-2), 1.36 (t, J = 7.0 Hz, 1H). 13C NMR (101 MHz,
CD3OD): δ 157.6, 139.8, 133.3, 132.9, 132.7, 131.0, 130.3, 129.6, 129.3,
114.2, 87.6, 80.6, 78.3, 72.2, 69.8, 63.1, 61.3, 37.7, 13.8. HRMS (ESI-
TOF) m/z: [M+Na] + calcd for: C21H25ClNaO6S 463.0953; Found 463.0958.
HPLC analysis: All the reactions with enzyme were incubated in 50 mM
tris-hydrochloride buffer (pH = 7.3) at 37 °C in a total volume of 2.0 ml.
Briefly, to a solution of β-glucosidase (2.0 mg) in tris-hydrochloride buffer
(1.0 mL) was added 4-Nitrophenyl β-D-glucopyranoside (30.1 mg, 0.1
mmol), TDA (46.3 mg, 0.1 mmol), TCA (49.9 mg, 0.1 mmol), a mixture of
4-Nitrophenyl β-D-glucopyranoside (15.1 mg, 0.05 mmol) and TDA (23.1
mg, 0.05 mmol), and a mixture of 4-Nitrophenyl β-D-glucopyranoside (15.1
mg, 0.05 mmol) and TCA (25.0 mg, 0.05 mmol), respectively. After 1 – 15
days of reaction, 10 μL samples were taken for analysing by HPLC.
Acknowledgments
Application of this method to synthesize auranofin:[7b]
This study was supported by the National Nature Science
Foundation of China (Nos. 21772049). Hai Dong thanks his good
friend, Mr. Zhixin Zhang, for his personal financial support for the
scientific research of Dong’s group. The authors are also grateful
to the staffs in the Analytical and Test Centre of HUST for support
with the NMR instruments.
Method A: To a solution of glucosyl disulfide 2a (80.0 mg, 0.11 mmol) and
PEt3AuCl (78 mg, 0.22 mmol) in CH2Cl2 (0.8 mL), Et3P (18 μl, 0.13 mmol)
was added at 0 °C. After stirring for 5 min, a solution of potassium
carbonate (36 mg, 0.26 mmol) in water (0.4 mL) was added to the mixture.
The temperature was allowed to warm to room temperature and stirring
was continued for 2 h. The CH2Cl2 layer was separated and the aqueous
layer was extracted four times with CH2Cl2. The combined organic layers
were dried over MgSO4, filtered and concentrated in vacuo. The crude
material was purified by silica gel chromatography (petroleum/EtOAc 1:1)
to afford auranofin (130 mg, 87%) as a white solid.
Keywords: 1-glycosyl thioacetate • glycosyl 1-thiol •
thioglucoside gliflozin analogue • auranofin • SGLT2 inhibitor
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Method B: To a solution of KAuCl4 (100 mg, 0.26 mmol) in water (1.6 mL),
4,4'-dihydroxydiphenyl sulfide (114 mg, 0.52 mmol) was slowly added at
0 °C. After stirring for 10 min, a solution of Et3P (56 μl, 0.42 mmol) in
acetone (2 drops) was added to the mixture. After stirring for 3 h at 0 °C,
a solution of the glucosyl disulfide 2a (97.3 mg, 0.14 mmol, prepared by
this method) in CH2Cl2 (1.0 mL) and a solution of potassium carbonate
(43.1 mg, 0.31 mmol) in water (0.4 mL) were added to the reaction mixture.
The temperature was allowed to warm to room temperature and stirring
was continued for 2 h. The CH2Cl2 layer was separated and the aqueous
layer was extracted four times with CH2Cl2. The combined organic layers
were dried over MgSO4, filtered and concentrated in vacuo. The crude
material was purified by silica gel chromatography (petroleum/EtOAc 1:1)
to afford auranofin (126.2 mg, 70.3%, calculated by KAuCl4) as a white
solid.
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Method C: Following the general procedure to synthesize per-O-
acetylated glycosyl 1-thiols, the reaction was carried out with per-O-
acetylated glucoside 1 (100 mg, 0.26 mmol). The crude material 2b was
dissolved in CH2Cl2 (0.9 mL). To a solution of KAuCl4 (90.6 mg, 0.24 mmol)
in water (1.5 mL), 4,4'-dihydroxydiphenyl sulfide (105 mg, 0.48 mmol) was
slowly added at 0 °C. After stirring for 10 min, a solution of Et3P (32 μl,
0.24 mmol) in acetone (2 drops) was added to the mixture. After stirring
for 3 h at 0 °C, the solution of the crude glucosyl 1-thiol 2b in CH2Cl2 (0.9
mL) and a solution of potassium carbonate (40 mg, 0.29 mmol) in water
(0.4 mL) were added to the reaction mixture. The temperature was allowed
to warm to room temperature and stirring was continued for 2 h. The
CH2Cl2 layer was separated and the aqueous layer was extracted four
times with CH2Cl2. The combined organic layers were dried over MgSO4,
filtered and concentrated in vacuo. The crude material was purified by
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10.1002/ejoc.202100357
European Journal of Organic Chemistry
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10.1002/ejoc.202100357
European Journal of Organic Chemistry
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We reported relative green synthesis of 1-thioglycosides by straightforward reaction of per-O-acetylated glycoses with KSAc in
EtOAc. Furthermore, the highly efficient method to synthesize per-O-acetylated glycosyl disulfide and glycosyl 1-thiol were
developed. Based on this, the synthesis of auranofin was improved and two thioglucoside gliflozin analogues (possible SGLT
inhibitors) were efficiently synthesized in high yields.
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This article is protected by copyright. All rights reserved.