Kinetically Controlled Fischer Glycosidation under Flow Conditions: A New Method for Preparing Furanosides

Article abstract of DOI:10.1055/s-0037-1611643

Kinetically controlled Fischer glycosidation was achieved under flow conditions. β-Hydroxy-substituted sulfonic acid functionalized silica (HO-SAS) was used as an acid catalyst. This reaction directly converted aldohexoses into kinetically favored furanosides to enable the practical synthesis of furanosides. After optimization of the reaction temperature and residence time, glucofuranosides, galactofuranosides, and mannofuranosides were synthesized in good yields.

Full text of DOI:10.1055/s-0037-1611643

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Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
A
en
S. Masui et al.
Letter
Synlett
Kinetically Controlled Fischer Glycosidation under Flow
Conditions: A New Method for Preparing Furanosides
Seiji Masuia
Yoshiyuki Manabea,b
OH OH
O
O
O
Si
O
S O
Silica
Kohtaro Hirao
O
HO-SAS
Atsushi Shimoyamaa,b
Takahide Fukuyamac
Ilhyong Ryuc
OH
HO
HO
O
O
OMe
HO
Koichi Fukase*a,b
0
0
0
0-
0
0
0
1-8
8
4
4-0
7
1
0
OH
in MeOH
OH
flow conditions
67–86%
a Department of Chemistry, Graduate School of Science, Osaka
University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043,
Japan
Precise temperature
Precise residence time
Suppression of overreaction
kinetically favored
koichi@chem.sci.osaka-u.ac.jp
b Core for Medicine and Science Collaborative Research and Educa-
tion, Project Research Center for Fundamental Sciences, Osaka
University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043,
Japan
c Department of Chemistry, Graduate School of Science, Osaka
Prefecture University, Sakai, Osaka 599-8531, Japan
Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue
Received: 28.09.2018
Accepted after revision: 03.12.2018
Published online: 07.01.2019
The simple and efficient syntheses of furanosides re-
main an important issue3 even though various synthetic
methods have been reported, including the kinetically con-
trolled cyclization of dithioacetals in alcohol,4 perbenzoyla-
tion of arabinose and galactose at high temperatures,5 re-
duction of D-galactono-1,4-lactone with disiamylborane,6
acetylation of hexoses and pentoses in the presence of boric
acid,7 and the selective activation of the anomeric position
using 2,4,6-trichloro-1,3,5-triazine-activated DMSO.8
Here, we achieved a concise synthesis of furanosides via
kinetically controlled Fischer glycosidation. Fischer glycosi-
dation9 of aldoses or ketoses is generally carried out in alco-
hols using acid catalysts. In this reaction, thermodynami-
cally favored α-pyranosides are preferentially obtained
(Scheme 1), whereas Fisher glycosidation can provide fura-
nosides under kinetically controlled conditions.10 Chelation
by a specific metal can control which isomer is favored. Fu-
ranosides can be obtained as major products when FeCl3 is
used as a Lewis acid.11 Microwave irradiation conditions
were applied to this reaction, and the pyranosides/furano-
DOI: 10.1055/s-0037-1611643; Art ID: st-2018-b0619-l
License terms:
Abstract Kinetically controlled Fischer glycosidation was achieved un-
der flow conditions. β-Hydroxy-substituted sulfonic acid functionalized
silica (HO-SAS) was used as an acid catalyst. This reaction directly con-
verted aldohexoses into kinetically favored furanosides to enable the
practical synthesis of furanosides. After optimization of the reaction
temperature and residence time, glucofuranosides, galactofuranosides,
and mannofuranosides were synthesized in good yields.
Key words Fischer glycosidation, flow chemistry, furanosides, sup-
ported catalysis, carbohydrate, kinetically controlled reaction
Various furanosides occur naturally, such as those in
plants, bacteria, protozoa, archaebacteria, and fungi, al-
though furanosides only occur as nucleic acids in mam-
mals.1 The most common furanoside is sucrose, which con-
sists of glucopyranose and fructofuranose. L-Arabinofura-
nose and D-fructofuranose are main components of plant
cell walls. Because galactofuranosides are essential for the
growth of many pathogens, including Mycobacterium tuber-
culosis, Trypansoma cruzi, and Aspergillus fumigates, fura-
noside derivatives, which can inhibit the biosynthesis of fu-
ranose glycans, are expected to be drug candidates.1,2 In
particular, inhibitors of uridine diphosphate (UDP)-α-D-
pyranose mutase, which catalyzes the isomerization of
UDP-α-D-pyranose to UDP-α-D-furanose, are being enthusi-
astically developed.
HO
O
HO
OR
thermodynamically favored
HO
O
+
ROH
acid
HO
OH
OH
O
OR
HO
OH
kinetically favored
Scheme 1 Fischer glycosidation. Pyranosides are thermodynamically
favored, whereas furanosides are kinetically favored.
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

B
S. Masui et al.
Letter
Synlett
sides ratio and their α/β isomerization changed depending
on the Lewis acid used.12 The addition of CaCl2 also im-
proved the selectivity toward β-furanosides.13 However, the
generation of a certain amount of pyranosides is inevitable.
Because the stability of the furanoside chelates formed by
various metals depends on their structure, challenges re-
main with respect to versatility in the preparation of vari-
ous furanosides. In the present work, to overcome this
drawback, we used a continuous flow system.
Continuous flow synthesis provides an innovative reac-
tion control system that enables fast and efficient mixing,
rapid heating and cooling, strict temperature control, and
precise residence time control.14 Scalability is also an im-
portant advantage of flow reactions: scaled-up syntheses
can be achieved with a flow system under the same condi-
tions to realize the practical supply of target compounds.
These excellent features have been applied to glycosylation
reactions. Seeberger et al. first reported microflow glyco-
sylation.15 We previously achieved stereoselective and effi-
cient α-sialylation,16 β-mannosylation,17 and N-glycosyla-
tion18 using efficient mixing and precise reaction tempera-
ture control under microflow conditions.
here is shown in Figure 1. A solution of sugar in alcohol was
introduced into the column (φ 4.0 mm × 50 mm) packed
with HO-SAS (350 mg, 0.9–1.0 mmol/g loading of SO3H).
The outlet of the flow system was connected to a back-pres-
sure regulator (75 psi) to elevate the reaction temperature
above the boiling point of the solvent. In this system, be-
cause the products can be removed from the reaction sys-
tem, isomerization of furanosides to pyranosides can be
suppressed. The narrow channel reduces the diffusion of
the reaction mixture and enables flash heating, enabling
precise control of the reaction time and the temperature.
Therefore, this system is ideal for kinetic-controlled Fisher
glycosidations.
OH OH
O
O
O
Silica
Si
O
S O
O
HO-SAS
flow
back pressure
regulator
pump
heat by oil bath
OH
O
HO
HO
In this study, continuous flow synthesis was applied to
Fisher glycosidation to obtain kinetically favored furano-
sides. Overreaction, i.e., conversion of furanosides to pyra-
nosides, was suppressed through transfer of the products
from the reaction system immediately after completion of
the reaction.
O
OMe
HO
in MeOH
OH
OH
Figure 1 Flow setup for Fischer glycosidation under flow conditions
using HO-SAS
We previously reported the acid-catalyzed dehydration
reaction of alcohols under continuous flow conditions and
the application of this reaction to the commercial produc-
tion of pristane.19 Quantitative dehydration was achieved
using one equivalent of strong acid under flash heating con-
ditions. Immediate quenching completely suppressed the
decomposition of alkenes, e.g., cationic isomerization and
polymerization. In an acid-catalyzed dehydration reaction,
generated water deactivates the acid catalyst, and the used
acid must be neutralized during the workup. However, flow
dehydration using a supported acid catalyst can overcome
these issues. Generated water is washed out, and the acid
catalyst can be kept active. Neutralization is not necessary.
Sulfonic acid functionalized silica gel (SAS), which exhibits
strongly acidity, a large surface area, and high thermal sta-
bility,20 has been widely used for the dehydration of sug-
ars,21 glycerol,22 nitro alcohols,23 and chromanols.24 Dume-
sic et al. applied a flow dehydration process using SAS to
the production of 5-hydroxymethylfurfural from fruc-
tose.21h We also achieved the dehydration of alcohols under
flow conditions using β-hydroxy-substituted sulfonic acid
functionalized silica (HO-SAS)25 with strong acidity and
good stability and applied this process to the waste-free
synthesis of pristane.19b
Fischer glycosidation of glucose with methanol under
flow conditions was first investigated (Table 1).26 A 0.1 M
glucose solution in methanol was introduced at a flow rate
of 0.1 mL/min into the column packed with HO-SAS (resi-
dence time: 5 min). At room temperature, the reaction
hardly proceeded; only a trace amount of furanosides 2 was
observed (Table 1, entry 1). Elevating the reaction tempera-
ture increased the yield of 2 (28% yield at 60 °C and 71%
yield at 80 °C, respectively, Table 1, entries 2 and 3). By con-
trast, major products were changed to pyranosides 3 at 100
°C (Table 1, entry 4). At 140 °C, the products were decom-
posed and neither 2 nor 3 were recovered (Table 1, entry 5).
When the residence time was shortened to 1 min, furano-
sides 2 were obtained as the main products even at 100 °C
(Table 1, entry 6). In entries 7 and 8, HCl and TsOH were
used as the acid catalyst instead of HO-SAS under flow con-
ditions. HCl gave furanosides 2 with high selectivity but
with low conversion (Table 1, entry 7), whereas TsOH re-
sulted in higher conversion and lower selectivity (Table 1,
entry 8). These results indicate that the reactivity of HO-
SAS was higher than that of HCl and slightly lower than that
of TsOH.
The supported acid catalyst has several advantages over
liquid catalysts, such as easy separation, simple workup,
and reusability. The reaction using HO-SAS under batch
In the present study, we achieved kinetically controlled
Fischer glycosidations under flow conditions using HO-SAS
to obtain furanosides (Scheme 1). The flow system used
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

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S. Masui et al.
Letter
Synlett
Table 1 Fischer Glycosidation of Glucose (1) with Methanol under Flow
Conditions
OH
OH
O
OMe
HO
HO-SAS (350 mg)
HO
HO
HO
OH
O
2
+
HO
OH
HO
HO
HO
O
1
0.1 mol/L in MeOH
HO
OMe
3
Entry Flow /
Batch
Temp Time
Yield (%)a
(°C)
(min)
2 (α/β)
3 (α/β)
1 (recovery)
1
2
flow
r.t.
5
5
Trace
0
100
66
flow
flow
flow
flow
flow
flow
flow
batch
batch
60
80
28 (29:71)
71 (35:65)
28 (39:16)
decomp.
4 (50:50)
Scheme 2 Investigation of reusability of HO-SAS
3
5
13 (46:54)
61 (59:41)
decomp.
16
4
100
140
100
80
5
11
OH
OH
HO-SAS
HO
OH
5
5
decomp.
3
HO
HO
HO
O
O
OMe
OMe
HO
6
1
70 (43:57)
60 (58:42)
48 (40:60)
19 (42:58)
67 (36:64)
27 (52:48)
6 (50:50)
35 (49:51)
4 (25:75)
15 (47:53)
OH
7b
8c
9d
10e
5
32
4
100 °C,
5
67%
(α/β = 76:24)
Residence Time = 0.5 min
0.02 mol/L in MeOH
80
5
17
80
5
77
OH
O
OH
OH
HO-SAS
HO
80
60
17
O
HO
a Estimated by 1H NMR using benzene as an internal standard.
b HCl (1 equiv., 0.1 M) is used instead of HO-SAS.
c TsOH (1 equiv., 0.1 M) is used instead of HO-SAS.
d HO-SAS (350 mg), sealed tube.
HO
HO
OH
OH
60 °C,
6
7
Residence Time = 15 min
0.02 mol/L in MeOH
86%
(α/β = 26:74)
e HO-SAS (350 mg), sealed tube.
HO-SAS
HO
HO
HO
HO
O
O
HO
conditions proceeded much slowly to give 2 in 19% yield af-
ter 5 min and in 67% after 60 min (Table 1, entries 9 and 10).
The selectivity of 2 to 3 in the latter was slightly decreased
compared to flow conditions (Table 1, entry 10). These re-
sults indicate that flash heating and efficient contact to HO-
SAS surface under flow conditions increase the reaction
rate and furanosides selectivity.
HO
AcHN
AcHN
OH
OMe
Residence Time = 5 min
8
9
0.025 mol/L in MeOH
80 °C: quant (α/β = 36:64)
100 °C: quant (α/β = 79:21)
Scheme 3 Kinetically controlled Fischer glycosidation of mannose (4),
galactose (6), and N-acetylglucosamine (8). The yields and the α/β ratio
were estimated by NMR spectroscopy.
To confirm the reusability of HO-SAS, the reaction was
repeated six times without changing the HO-SAS (Scheme
2). The yields of glucofuranosides 2 were between 71% and
75% in all of the trials, and the average yield was 73%. To
demonstrate the scalability, the reaction was carried out
using 1.73 g (9.61 mmol) of glucose (1) to give furanosides
2 (1.33 g) in 71% yield. Considering 350 mg of HO-SAS (0.9–
1.0 mmol/g loading of SO3H) was packed in the column, the
acidity was not reduced after 25 catalytic cycles.
The kinetically controlled flow Fischer glycosidations
under flow conditions were then applied to other sugars
(Scheme 3). To maximize the yields of furanosides, the re-
action temperature and residence time were optimized. Al-
though isomerization of mannofuranosides 5 to mannopy-
ranosides was faster than the isomerization of glucose, a
high temperature (100 °C) and short residence time (0.5
min) gave a moderate yield of 5 (67%). In this case, lower
concentration gave better results (0.02 mol/L: 67%, 0.1
mol/L: 59%). On the other hand, galactofuranosides 7 were
readily produced: the reaction at 60 °C for 15 min gave 7 in
86% yield. In this reaction, low concentration (0.02 mol/L)
was required because of the low solubility of galactose (6)
in methanol.
In the case of N-acetyl-glucosamine, only pyranosides 9
were obtained, without the formation of furanosides. Inter-
estingly, elevating the reaction temperature from 80 °C to
100 °C changed the α/β ratio of 9 from 36:64 to 79:21.
These results suggest that the Fisher glycosidation of N-ace-
tyl-glucosamine (8) predominantly proceeded without a
ring-opening process because of the rapid dehydration as-
sisted by the acetamide group. The reaction-temperature
dependence of the α/β ratio can be explained by the fact
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

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S. Masui et al.
Letter
Synlett
that the β-isomer is kinetically favored because of neigh-
boring participation, whereas the α-isomer is thermody-
namically favored because of the anomeric effect.
In summary, we achieved Fisher glycosidation under
flow conditions using HO-SAS as a solid acid catalyst. In this
system, both kinetically favored furanosides and thermody-
namically favored pyranosides were obtained through con-
trol of the reaction temperature and the residence time. We
successfully demonstrated that flow Fischer glycosidation
can be a powerful and practical method to prepare furano-
sides.
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Funding Information
This work was financially supported in part by JSPS KAKENHI Grant
Number 15H05836 in Middle Molecular Strategy, JSPS KAKENHI
Grant Number 16H01885, JSPS KAKENHI Grant Number 16H05924,
and JSPS KAKENHI Grant Number 18H04620.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611643.
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References and Notes
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A flow reactor system consisting of syringe pump, column (φ
4.0 mm × 50 mm, filled with HO-SAS (350 mg, 0.9–1.0 mmol/g
loading of SO3H), backpressure regulator and tubes (inner diam-
eter φ = 50 μm, length L1 = 40 cm, L2 = 10 cm, L3 = 20 cm) was
used. A solution of glucose (1, 90 mg, 0.5 mmol) in methanol (5
mL, 0.10 M glucose solution) was filled in the syringe. The
syringe was pumped using the syringe pump at flow rates of 0.1
mL/min (residence time = 5 min), and the reaction solution was
passed through the column filled with HO-SAS. After the reac-
tion solution came out, the solution was send to the waste for 3
min (priming time = 3 min). Then, the solution was collected for
10 min. After concentration in vacuo, the crude mixture was
analyzed by NMR spectroscopy. New HO-SAS was packed each
experiments except for the experiments in Scheme 2.
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D