Microwave-assisted one-pot synthesis of 1,6-anhydrosugars and orthogonally protected thioglycosides

Article abstract of DOI:10.1021/ja504804v

Living organisms employ glycans as recognition elements because of their large structural information density. Well-defined sugar structures are needed to fully understand and take advantage of glycan functions, but sufficient quantities of these compounds cannot be readily obtained from natural sources and have to be synthesized. Among the bottlenecks in the chemical synthesis of complex glycans is the preparation of suitably protected monosaccharide building blocks. Thus, easy, rapid, and efficient methods for building-block acquisition are desirable. Herein, we describe routes directly starting from the free sugars toward notable monosaccharide derivatives through microwave-assisted one-pot synthesis. The procedure followed the in situ generation of per-O-trimethylsilylated monosaccharide intermediates, which provided 1,6-anhydrosugars or thioglycosides upon treatment with either trimethylsilyl trifluoromethanesulfonate or trimethyl(4-methylphenylthio)silane and ZnI₂, respectively, under microwave irradiation. We successfully extended the methodology to regioselective protecting group installation and manipulation toward a number of thioglucosides and the glycosylation of persilylated derivatives, all of which were conducted in a single vessel. These developed approaches open the possibility for generating arrays of suitably protected building blocks for oligosaccharide assembly in a short period with minimal number of purification stages.

Full text of DOI:10.1021/ja504804v

Article
pubs.acs.org/JACS
Microwave-Assisted One-Pot Synthesis of 1,6-Anhydrosugars and
Orthogonally Protected Thioglycosides
Yen-Chun Ko,†,⊥,○ Cheng-Fang Tsai,†,⊥,○ Cheng-Chung Wang,*,‡ Vijay M. Dhurandhare,‡,§,¶
Pu-Ling Hu,‡ Ting-Yang Su,‡,# Larry S. Lico,†,∇ Medel Manuel L. Zulueta,† and Shang-Cheng Hung*,†
‡
§
†Genomics Research Center, Institute of Chemistry, and Chemical Biology and Molecular Biophysics, Taiwan International
Graduate Program, Academia Sinica, 128, Section 2, Academia Road, Taipei 115, Taiwan
¶
⊥Department of Chemistry and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, 101, Section 2,
Kuang-Fu Road, Hsinchu 300, Taiwan
#Department of Chemistry and Biochemistry, National Chung Cheng University, Min-Hsiung, Chiayi 621, Taiwan
∇Institute of Chemistry, College of Science, University of the Philippines, Diliman, Quezon City 1101, Philippines
S
* Supporting Information
ABSTRACT: Living organisms employ glycans as recognition
elements because of their large structural information density.
Well-defined sugar structures are needed to fully understand and take
advantage of glycan functions, but sufficient quantities of these
compounds cannot be readily obtained from natural sources and
have to be synthesized. Among the bottlenecks in the chemical
synthesis of complex glycans is the preparation of suitably protected
monosaccharide building blocks. Thus, easy, rapid, and efficient
methods for building-block acquisition are desirable. Herein, we
describe routes directly starting from the free sugars toward notable
monosaccharide derivatives through microwave-assisted one-pot
synthesis. The procedure followed the in situ generation of per-O-
trimethylsilylated monosaccharide intermediates, which provided 1,6-anhydrosugars or thioglycosides upon treatment with either
trimethylsilyl trifluoromethanesulfonate or trimethyl(4-methylphenylthio)silane and ZnI2, respectively, under microwave
irradiation. We successfully extended the methodology to regioselective protecting group installation and manipulation toward a
number of thioglucosides and the glycosylation of persilylated derivatives, all of which were conducted in a single vessel. These
developed approaches open the possibility for generating arrays of suitably protected building blocks for oligosaccharide assembly
in a short period with minimal number of purification stages.
are available. Traditional synthesis as well as the promising
preactivation,3 programmable one-pot,4 and automated5
strategies supplied numerous well-defined complex oligosac-
charide sequences. These methods, however, rely on suitably
protected monosaccharide building blocks to achieve proper
chain assembly and the introduction of the necessary
functionalizations in the target compounds. The preparations
of glycosyl building blocks are often painstaking, laborious, and
time-consuming multistep processes involving regioselective
protection of hydroxy groups and functionalization at the
anomeric carbon.
Use of microwave (MW) as an unconventional heat source
was shown to provide fast, clean, and high-yielding reactions.6
Specialized MW devices enable the flash heating of reaction
solutions even at temperatures well above the boiling points of
commonly used organic solvents, rendering conditions that are
not feasible under typical means. Because MW-enhanced
INTRODUCTION
■
Biological systems display glycan scaffolds with enormous
diversity and complexity.1 While these biopolymers are built
from only a few types of monosaccharide units, the multiple
chiral centers available, the branching possibilities, the regio-
and stereochemical aspects of the glycosidic linkages, and the
potential for further enzymatic modifications supply extensive
structural information that prove vital in recognition, adhesion,
and signal transduction events. Insights on the character of the
interactions involving glycans could drive the development of
novel therapeutic and diagnostic agents. Nonetheless, sufficient
quantities of well-defined sugar constructs required by
structure−activity relationship studies could not be readily
acquired from nature, and chemical syntheses remain the most
common manner of access.2 Notably, the characteristics that
made sugars so complex are also the prevailing reasons for the
unfortunate hardships encountered in carbohydrate syntheses.
Despite various efforts to develop efficient strategies for the
synthesis of oligosaccharides and glycoconjugates, no standard
synthetic methods akin to protein and nucleic acid acquisitions
Received: May 14, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja504804v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
synthesis has yet to fully permeate the carbohydrate field,7 we
decided to explore MW in the preparation of monosaccharide
building blocks.
a
Scheme 2. MW-Assisted 1,6-Anhydroglucose Formation
One-pot protection strategies have gained traction in recent
years as an attractive method in reducing time, wastes, and
effort in carbohydrate synthesis.4,8 Our work on this topic
centered on the trimethylsilyl trifluoromethanesulfonate
(TMSOTf)-catalyzed regioselective transformations of various
per-O-trimethylsilylated starting materials into several fully and
partially protected building blocks in one pot.9 In this paper, we
examined the utility of MW irradiation in the transformation of
persilylated monosaccharide derivatives into anhydrosugars and
thioglycosides. Together with an efficient silylation method and
our collective experience in one-pot protection, we developed
an integrated MW-assisted one-pot procedure that starts from
the free sugars, leading to a diverse range of sugar derivatives
and presenting an opportunity for the rapid and practical
preparations of others.
a
Reagents and conditions: (a) HMDS, TMSOTf, CH2Cl2, rt, 30 min;
(b) TMSOTf, CH2Cl2, MW (100 °C), 5 min; 78% (two steps); (c)
HMDS, TMSOTf, CH2Cl2, rt, 1 h; TMSOTf, CH2Cl2, MW (100 °C),
5 min; HMDS, rt, 30 min; 72% (one pot).
1
(Figure 1a). The C4 conformation of the pyranosyl ring is
made obvious by the W-coupling between 1-H and 3-H (see
RESULTS AND DISCUSSION
■
One-Pot Preparation of Anhydrosugars. Per-O-trime-
thylsilylated monosaccharides are important gateways to a
wealth of sugar derivatives.9,10 The trimethylsilylation of
alcohols is traditionally carried out using chlorotrimethylsilane
(TMSCl), which require long reaction times (typically
overnight for sugars), large excesses of bases, and product
purification prior to any succeeding steps. We recently reported
a trimethylsilylation procedure using hexamethyldisilazane
(HMDS) under TMSOTf catalysis.10a As shown in Scheme
1, each activated HMDS can silylate two alcohol groups,
Scheme 1. Proposed Catalytic Cycle for the TMSOTf-
Mediated Alcohol Sialylation by HMDS
Figure 1. HMBC spectra identifying the backbone structure of the (a)
1,6-anhydroglucopyranose 3, (b) 1,6-anhydrogalactopyranose 11, and
(c) 1,6-anhydrogalactofuranose 12.
the Supporting Information). A sharp drop in yield was
observed when the MW temperature is set to 90 °C (32%).
When the same starting mixture was refluxed with CH2Cl2 for
30 min, only the partially desilylated compounds were
produced. Following this discovery, a one-pot approach to
synthesize 3 by adopting the fruitful MW condition was
pursued. Thus, the per-O-TMS 2, generated in situ by using
HMDS and TMSOTf, was mixed with 10 mol % of TMSOTf,
and the mixture was exposed to similar MW heating. While the
1,6-anhydroglucose formation is successful, MW irradiation
unfortunately cleaved some TMS groups. After another
treatment with HMDS in the same flask to reinstall the lost
TMS groups, compound 3 was attained in 72% yield.
followed by the liberation of ammonia gas, which also assists in
driving the cycle forward. Aside from HMDS being more
economical than TMSCl, the reaction is finished in a short
period in excellent yields without the need for high excesses of
HMDS. The essentially neutral final pH consequently permits
the potential integration with our previously developed one-pot
procedure.
The initial exposure of D-glucose (1) to 2.5 equiv of HMDS
and catalytic TMSOTf in CH2Cl2 produced the penta-O-TMS
intermediate 2 in almost quantitative yield (Scheme 2).10a We
found that the subsequent treatment with 10 mol % TMSOTf
under MW irradiation at 100 °C for 5 min resulted in the
generation of the 1,6-anhydroglucose 3 in 78% yield after
chromatographic purification. The 1,6-anhydropyranose back-
bone could be readily identified through the HMBC NMR
correlations between the anomeric proton and carbon and the
respective carbons and protons at the 5- and 6-positions
Anhydrosugars are useful intermediates in the synthesis of
natural products, biologically potent oligosaccharides and
glycoconjugates, and polymers.11 The rigid [3.2.1]-bicyclic
structure of 1,6-anhydropyranoses reorients the hydroxy groups
and, hence, forces a sometimes handy reversal of their reactivity
B
dx.doi.org/10.1021/ja504804v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Table 1. Microwave-Assisted One-Pot Synthesis of Different 1,6-Anhydrosugars
entry
starting material
catalyst
temp (°C)
time (min)
solvent
CH2Cl2
product
yield (%)
1
4
4
5
5
5
5
6
6
7
8
9
TMSOTf
TfOH
100
180
100
100
150
100
150
100
150
100
100
5
20
5
10
78
90
2
EtCN
10
a
3
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TfOH
CH2Cl2
ClCH2CH2Cl
CHCl3
11/12
11/12
11/12
12
46/46
a
4
5
59/23
a
5
10
5
11/61
6
MeNO2
CH2Cl2
MeCN
72
a
7
10
3
13/14
13
62/8
8
57
68
68
70
9
TMSOTf
TfOH
10
3
CH2Cl2
MeCN
15
10
11
16
TfOH
3
MeCN
17
a
Products were chromatographically isolated as mixtures of isomers, and the yields shown are estimates using the ratios of peaks corresponding to
1
the respective anomeric protons in H NMR: Cbz, benzyloxycarbonyl; Troc, 2,2,2-trichloroethoxycarbonyl; TCA, trichloroacetyl.
pattern. Furthermore, the opening of the 1,6-anhydrobridge for
further functionalization is a simple operation.12 With this in
mind, we applied our MW-assisted procedure to other
monosaccharides (Table 1). Application of the TMSOTf-
catalyzed condition on D-mannose (4) with MW irradiation
similar to that used for 1 produced the 1,6-anhydromannose 10
in good yield (entry 1). Alternatively, a better result was
obtained under a more drastic reaction condition (entry 2). For
D-galactose (5), treatment with TMSOTf under MW heating at
100 °C in CH2Cl2 resulted in a 1:1 mixture of the
anhydropyranose 11 and the anhydrofuranose 12 (entry 3).
The backbone connectivities of these isomers were recognized
through the relevant correlations in the HMBC spectra (Figure
1b,c). Different solvents apparently affect the product
preference. A solvent change to dichloroethane furnished the
pyranose 11 (59%) as the major product (entry 4). With
CHCl3, the product preference was somehow reversed, favoring
the formation of the anhydrofuranose 12 with 61% yield and
with compound 11 generated in 11% yield (entry 5).
Compound 12 was exclusively obtained in good yield when
the solvent is MeNO2 (entry 6).
We also applied the one-pot procedure to several D-
glucosamine derivatives. The azide 6 was transformed into
the anhydropyranose 13 in 62% yield with the minor furanoside
side product through treatment with TMSOTf in CH2Cl2
under MW heating to 150 °C (entry 7). When trifluorome-
thanesulfonic acid (TfOH) and MeCN were used under 100
°C (entry 8), the anhydropyranose 13 was exclusively obtained.
Entries 9−11 show the synthesis of several N-protected 1,6-
anhydrohexopyranoses 15−17 from their corresponding
starting materials in good yield. Interestingly, ultrasonication
in a bath kept at 25 °C for 50 min and plain heating in an oil
bath at 60 °C for 30 min, instead of MW irradiation in the one-
pot reaction sequence in entry 11, delivered the target product
17, albeit in much lower yields of 45% and 35%, respectively.
Use of CH2Cl2 in place of MeCN for these latter cases did not
generate the anhydrosugar.
The extension of the MW-assisted anhydrosugar formation
to glycosylation in one pot was next examined. We opted to
form the dimannose derivative 19, which holds the crucial α(1
→ 2) linkage found in important glycan structures such as
glycosylphosphatidylinositol anchors13 and bacterial cell-wall
phosphatidylinositol mannosides14 (Scheme 3). D-Mannose (4)
Scheme 3. One-Pot Synthesis of a α(1 → 2)-Linked
Mannose Disaccharide via the MW-Assisted Anhydrosugar
a
Formation
a
Reagents and conditions: (a) HMDS, TMSOTf, CH2Cl2, rt, 1 h;
TMSOTf, CH2Cl2, MW (100 °C), 5 min; 18 (1.0 equiv), BF3·Et2O,
−60 °C, 3 h; TBAF, rt, 1 h, 53% (one pot). Bn. benzyl; Bz. benzoyl;
TBAF. tetrabutylammonium fluoride.
was silylated with HMDS and then subjected to MW irradiation
to furnish the desired anhydro-intermediate 10. Here, the
equatorial orientation of O2 in derivative 10 makes it more
susceptible to glycosylation than the other positions. Thus, the
activation of the mannosyl donor 1815 with BF3·Et2O in the
same flask, followed by desilylation resulted to the disaccharide
19 in a 53% overall yield. Compound 19 can be easily
functionalized to act as a building block in glycan assembly.
One-Pot Preparation of Thioglycosides. Thioglyco-
sides16 are common and useful building blocks in carbohydrate
synthesis. Their stability in numerous protection and
deprotection steps as well as their ability to act as acceptors
in various glycosylation conditions offer immense synthetic
value. Furthermore, programmable one-pot glycosylation,
which relies on the relative reactivities of glycosyl donors, are
mainly carried out using thioglycosides.17 We have demon-
strated the utility of persilylated thioglycosides in regioselective
C
dx.doi.org/10.1021/ja504804v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
one-pot protection.9 However, the traditional preparation of
these silylated thioglycosides from unprotected starting
materials is laborious. This procedure usually involves a
number of separate steps, including per-acetylation, thioglyco-
sylation, deacetylation, and silylation.9a,18 In this regard, the
MW-assisted one-pot thioglycosylation was further explored
and then later expanded to provide a number of differentially
functionalized thioglycosides in a fast and convenient manner.
We found that the penta-O-TMS intermediate can be directly
transformed into a thioglycoside in the presence of trimethyl(4-
methylphenylthio)silane (TMSSTol) and ZnI2 under MW
irradiation (Scheme 4). Again using D-glucose (1) as the model
Table 2. One-Pot Synthesis of Per-O-silylated
Thioglycosides
a
entry
free sugar
product
yield (%)
α/β ratio
1
2
3
4
D-mannose (4)
D-galactose (5)
L-rhamnose (23)
21
22
24
26
71
62
71
66
4.5/1
4.5/1
1.7/1
2.5/1
a
Scheme 4. MW-Assisted One-Pot Thioglucoside Formation
L-fucose (25)
a
1
Determined by using H NMR.
persilylated thioglycosides could be useful as direct donors
and acceptors. Our activation of the tetra-O-TMS thioglucoside
20 with either N-iodosuccinimide/TMSOTf or p-toluenesul-
fenyl chloride/silver(I) trifluoromethanesulfonate (AgOTf)
promoter system in the presence of a 6-alcohol acceptor
(methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside20) unfortu-
nately did not generate the expected disaccharide (see Table
S1 in the Supporting Information). Instead, the anhydroglucose
3 was isolated as the main product together with the acceptor
(as a TMS derivative due to the resilylation step). Apparently,
the intramolecular attack of the C6 TMS ether on the
oxocarbenium ion occurs so much faster than the approach of a
separate primary alcohol nucleophile.
a
Reagents and conditions: (a) HMDS, TMSOTf, CH2Cl2, rt, 30 min;
(b) TMSSTol, ZnI2, CH2Cl2, MW (150 °C), 8 min, 83% (two steps,
α/β = 4.2/1); (c) HMDS, TMSOTf, CH2Cl2, rt, 1 h; TMSSTol, ZnI2,
CH2Cl2, MW (150 °C), 8 min; HMDS, rt, 1 h; 76% (one pot, α/β =
5/1). Tol, 4-tolyl.
system, MW-induced heating to 150 °C furnished the per-O-
TMS thioglucoside 20 in 83% yield. In contrast, no target
products were formed upon MW heating to 100 °C as well as
the plain CH2Cl2 reflux conditions. Interestingly, while the
conventional route using the D-glucose pentaacetate as starting
material and BF3·Et2O exclusively furnish the β-anomer,18 the
MW-assisted transformation above provided the α-anomer as
the major product (α/β = 4.2/1). In the absence of a
participating acyl moiety, such stereoselectivity probably came
as a result of the anomeric effect. Following the same sequence
of reactions, a one-pot approach was performed, supplying
compound 20 in 76% yield after chromatographic purification
with relatively similar stereoselectivity (α/β = 5/1). Like the
MW-assisted 1,6-anhydrosugar formation, MW irradiation also
resulted in the partial cleavage of the silyl groups, which were
reinstalled by another treatment with HMDS. This novel route
thus enabled access to the persilylated thioglucoside from the
unprotected sugar in just a few hours as opposed to several days
using the conventional procedure.
The feasibility of our MW-assisted one-pot thioglycosylation
procedure was further explored for other monosaccharides
(Table 2). Manipulation of D-mannose (4, entry 1) and D-
galactose (5, entry 2) provided the corresponding thioglyco-
sides 21 and 22 in excellent 71% and 62% yields, respectively.
Conversely, thioglycosylation of L-rhamnose (23, entry 3) and
L-fucose (25, entry 4) conveniently afforded compounds 24
and 26, in 71% and 66% yields, respectively. In all these cases,
the predominant stereochemical orientation of the thiotolyl
group is biased toward the thermodynamically favored axial
position.
The acceptor potential of the persilylated thioglycosides was
next evaluated under a one-pot setting starting from the free
sugars 1, 4, and 5 (Table 3). After persilylation and MW-
Table 3. Glycosylation of the in Situ Generated Persilylated
Thioglycosides
a
entry
free sugar
product
yield (%)
α/β ratio
1
2
3
D-glucose (1)
27
28
29
36
49
44
2/1
D-mannose (4)
4/1
D-galactose (5)
10/1
a
1
Determined by using H NMR.
induced thioglycosylation, the sugar derivatives were treated
with the imidate 18, which was selectively activated by AgOTf.
The addition of TBAF was then performed to remove all TMS
groups. Consequently, the α1 → 6 disaccharides 27−29 were
acquired in moderate yields with no other regioisomers found.
Moreover, about 20−30% of the thiomannoside 30 was isolated
from the reaction solution. This side-product was, however, not
recovered after separate condensations of 18 and the purified
thioglycosides 20−22, indicating that the thio group in 30 came
from the remaining TMSSTol reagent in the reaction flask. In
this latter single step procedure, disaccharides 27, 28, and 29
were acquired in 51%, 65%, and 71% yields, respectively.
Whether thioglycosides can be made to act as either donor or
acceptor in glycan assembly depends on their level of
protection. The formation of compound 19 displayed the
potential of persilylated derivatives as direct acceptors in
glycosylation. A related work by Gervay−Hague showed the
successful application of persilylated glycosyl iodide as glycosyl
donor.19 In these regards, we examined whether our
D
dx.doi.org/10.1021/ja504804v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
We then considered the merging and compatibility of the
MW-based approach and our established regioselective and
combinatorial one-pot protection strategy (Scheme 5). A
Table 4. Regioselective One-Pot Protection of Fully
Protected Thioglucosides
Scheme 5. One-Pot Synthesis of Thioglucoside Deviratives
a
via the MW-Assisted Thioglycosylation
yield (%)
a
a
entry
RX
product
α
β
1
2
3
4
2-NAPBr
PMBCl
p-BrBnBr
AllBr
37: R = 2-NAP
38: R = PMB
39: R = p-BrBn
40: R = All
38
37
38
42
7
8
5
10
a
Notation: 2-NAP, 2-naphthylmethyl; PMB, p-methoxybenzyl; All,
allyl.
groups under Williamson’s condition. While the introduction of
these groups at O2 is feasible under our acidic and reductive
procedure, a basic condition is utilized here to avoid the side
products that might be produced because of the presence of the
remaining benzaldehyde reagent in the reaction solution. The
fully protected thioglucosides 37−40 were obtained in good
one-pot yields, with the α-isomer as major product, after six
transformation stages and a single chromatographic purifica-
tion.
a
Reagents and conditions: (a) HMDS, TMSOTf, CH2Cl2, rt, 1 h;
TMSSTol, ZnI2, CH2Cl2, MW (150 °C), 8 min; PhCHO, TMSOTf, 0
°C, 2 h; (b) PhCHO, Et3SiH, TMSOTf, −78 °C, 5 h; (c) TBAF, rt, 30
min; (d) Ac2O, Et3N, rt, 16 h; (e) AcOH, Ac2O, Et3N, 0 °C, 16 h; (f)
Ac2O, TMSOTf, 0 °C, 16 h; (g) TfOH, Et3SiH, −78 °C, 30 min; (h)
BH3·THF, TMSOTf, 0 °C, 16 h. Ac, acetyl.
CONCLUSIONS
successful integration is expected to further alleviate building
block preparation. Accordingly, after the MW-assisted one-pot
thioglycosylation of D-glucose, the 4,6-O-benzylidene group was
introduced using benzaldehyde and TMSOTf to afford the
supposed intermediate 31. Subsequent treatment with
benzaldehyde, Et3SiH, and TMSOTf at −78 °C then
regioselectively introduced a benzyl group at the 3-O-position.
The inductive effect by the two oxygens attached to the
anomeric carbon contributes to the lower nucleophilicity of O2
and, therefore, the regioselective reductive 3-O-benzylation in
this acidic condition. By the same reason, the typical base-
assisted benzylation as well as acylation theoretically favors the
2-O-position. Further desilylation using TBAF and treatment
with Ac2O and Et3N in the same pot furnished the fully
protected thioglycoside 32 as a mixture of separable anomers in
a combined yield of 52%. The 2-alcohol 33 was synthesized in
five transformations using a similar procedure as that for
compound 32, except for acetylation.21 On the other hand, the
3-alcohol 34 can be obtained in a one-pot manner by first
converting D-glucose into the intermediate 31, followed by
desilylation and regioselective 2-O-acetylation under basic
condition.9c The preparations of the 4- and 6-alcohols were
carried out in the same flask by regioselective 4,6-O-
benzylidene ring-opening at O4 and O6, respectively, after
the TMSOTf-catalyzed 3-O-benzylation and 2-O-acetylation
stages. The addition of TfOH and Et3SiH furnished the 4-
glycosyl alcohol 35, whereas BH3·THF and TMSOTf afforded
the 6-alcohol 36.20
■
We have developed an efficient and rapid method for preparing
1,6-anhydrosugars and thioglycosides directly from unprotected
monosaccharides via the MW-assisted one-pot reaction. The
faster reaction times, minimal purification step, high preference
to α-thioglycosides, and the fact that the process starts from the
free sugars are among the attractive qualities of this approach.
In addition, the extension of the synthetic method to
glycosylation and the regioselective and combinatorial one-
pot protection protocol developed by us offer ready access to
numerous suitably protected thioglycoside building blocks for
the synthesis of essential glycans. Further applications of this
method to broader sugar systems are now under study.
EXPERIMENTAL SECTION
■
General Procedure for the MW-Assisted One-Pot Synthesis
of 1,6-Anhydrosugars. In a microwave tube, TMSOTf (0.2 equiv)
was added at room temperature (rt) under N2 atmosphere to a
suspension of the free sugar (1.0 equiv) and HMDS (2.5 equiv) in dry
CH2Cl2 (10 mL per gram of the free sugar). The reaction was stirred
for at least 30 min and monitored by thin layer chromatography. Once
the reaction was completed, the mixture was purged with dry N2 gas,
which eliminated the ammonia byproduct and also vaporized most of
the solvent. Then, the per-O-trimethylsilylated intermediate was
dissolved in CH2Cl2 (20 mL per gram of the free sugar) followed
by the addition of 10 mol % of TMSOTf or TfOH. The resulting
reaction mixture was subjected to MW irradiation in the respective
mode for the time interval described in Table 1. The reaction mixture
was further treated with HMDS (2 equiv) and stirred for 30 min at
room temperature. The crude reaction mixture was purified in a short
column using silica gel (ethyl acetate/hexanes = 1/25 to 1/15).
General Procedure for the MW-Assisted One-Pot Synthesis
of Thioglycosides. In a microwave tube, TMSOTf (0.2 equiv) was
added to a mixture of the free sugar (1.0 equiv) and HMDS (2.6
equiv) in CH2Cl2 (10 mL per gram of the free sugar) under N2
atmosphere. After stirring at room temperature for 30 min, the mixture
Aside from the participating acetyl group, nonparticipating
orthogonal protecting groups were also introduced at O2 using
the one-pot procedure to show the flexibility of the method in
providing a diverse set of fully protected thioglycosides. As
shown in Table 4, the O2 position was readily masked in a one-
pot setting with 2-NAP, PMB, p-BrBn, and allyl protecting
E
dx.doi.org/10.1021/ja504804v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
was purged with dry N2 gas, which eliminated the ammonia byproduct
and also vaporized most of the solvent. CH2Cl2 (20 mL per gram of
the free sugar), ZnI2 (0.2 equiv), and TMSSTol (1.1 equiv) were
consecutively added to the reaction mixture, and the resulting mixture
was heated to 150 °C by MW irradiation for 8 min. The reaction was
then cooled down to room temperature and HMDS (1.8 equiv) was
added to the mixture, which was further stirred for another hour. The
mixture was filtered through a pad of Celite and the filtrate was
concentrated under reduced pressure. Purification of the crude residue
was carried out by flash column chromatography in silica gel (ethyl
acetate/hexanes = 1/150).
General Procedure for the MW-Assisted One-Pot Synthesis
of Disaccharides Bearing a Thiotolyl Aglycone Function. In a
microwave tube, TMSOTf (0.2 equiv) was added to a mixture of the
free sugar (1.0 equiv) and HMDS (2.6 equiv) in CH2Cl2 (10 mL per
gram of the free sugar) under N2 atmosphere. After being stirred at
room temperature for 30 min, the mixture was purged with dry N2 gas,
which eliminated the ammonia byproduct and also vaporized most of
the solvent. CH2Cl2 (20 mL per gram of the free sugar), ZnI2 (0.2
equiv), and TMSSTol (1.05 equiv) were consecutively added to the
reaction mixture, and the resulting mixture was heated to 150 °C by
MW irradiation for 8 min. The reaction was cooled to room
temperature, and activated 3 Å molecular sieves (2 g per gram of the
free sugar) and compound 18 (1.1 equiv) were added to the reaction.
The mixture was further cooled down to −20 °C. AgOTf (3 equiv)
was then added, and the mixture was stirred for 3 h. Afterward, TBAF
(1 M solution in THF, 3 equiv) was added, and the resulting mixture
was stirred for 1 h at room temperature. The mixture was filtered
through a pad of Celite and concentrated under reduced pressure. The
products were separated and purified by flash column chromatography
(ethyl acetate/hexanes =1/1 to 1/3) in silica gel.
General Procedure for the MW-Assisted One-Pot Synthesis
of Fully Protected Thioglucosides with Various Ether-Type
Protection at O2. In a microwave tube, TMSOTf (0.2 equiv) was
added to a mixture of D-glucose (1) and HMDS (2.6 equiv) in CH2Cl2
(10 mL per gram of the free sugar) under a N2 atmosphere. After
stirring at room temperature for 30 min, the reaction was purged with
N2 gas, which eliminated the ammonia byproduct and also vaporized
most of the solvent. CH2Cl2 (20 mL per gram of sugar), ZnI2 (1.12
equiv), and TMSSTol (0.2 equiv) were added to the reaction flask,
and the mixture was heated in the microwave reactor at 150 °C for 8
min. The reaction was cooled to room temperature and activated 3 Å
molecular sieves (2.5 g per gram of the free sugar) was added. The
solution was further cooled down to 0 °C, and PhCHO (1.2 equiv)
and TMSOTf (0.2 equiv) were subsequently added to the solution.
After stirring for another 2 h, the reaction mixture was cooled to −78
°C and stirred for another 15 min. Et3SiH (1.12 equiv), PhCHO (1.12
equiv), and TMSOTf (0.2 equiv) were consecutively added to the
reaction mixture and stirred for another 5 h. TBAF (1 M solution in
THF, 1.0 equiv) was added to the solution and the reaction flask was
warmed up to room temperature and stirred for 1 h. Then, NaH (10
equiv) and the alkyl halide (5.0 equiv) were sequentially added to the
reaction mixture, and the resulting solution was stirred at room
temperature for another 16 h. The whole mixture was filtered through
a pad of Celite, the filtrate was diluted with H2O, and the crude
product was extracted with CH2Cl2. The organic layer was washed
with brine and concentrated under reduced pressure to furnish the
crude residue, which was purified by flash column chromatography in
silica gel (ethyl acetate/hexanes = 1/5).
wangcc@chem.sinica.edu.tw
Author Contributions
○Y.-C.K. and C.-F.T. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Ministry of Science and
Technology (MOST 100-2113-M-001-019-MY3, MOST 101-
427 2113-M-001-011-MY2, MOST 102-2628-M-001-001, and
MOST 103-2113-M-001-022) and Academia Sinica.
REFERENCES
■
(1) Schmaltz, R. M.; Hanson, S. R.; Wong, C.-H. Chem. Rev. 2011,
111, 4259−4307.
(2) (a) Boltje, T. J.; Buskas, T.; Boons, G.-J. Nat. Chem. 2009, 1,
611−622. (b) Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48,
1900−1934. (c) Wang, L.-X.; Davis, B. G. Chem. Sci. 2013, 4, 3381−
3394.
(3) Yang, L.; Qin, Q.; Ye, X.-S. Asian J. Org. Chem. 2013, 2, 30−49.
(4) Hsu, C.-H.; Hung, S.-C.; Wu, C.-Y.; Wong, C.-H. Angew. Chem.,
Int. Ed. 2011, 50, 11872−11923.
(5) Seeberger, P. H. Carbohydr. Res. 2008, 343, 1889−1896.
(6) (a) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250−6284.
(b) Caddick, S.; Fitzmaurice, R. Tetrahedron 2009, 65, 3325−3355.
(7) (a) Soderberg, E.; Westman, J.; Oscarson, S. J. Carbohydr. Chem.
̈
2001, 20, 397−410. (b) Corsaro, A.; Chiacchio, U.; Pistara, V.;
Romeo, G. Curr. Org. Chem. 2004, 8, 511−538. (c) Das, S. K. Synlett
2004, 915−932. (d) Cioffi, E. A. Curr. Top. Med. Chem. 2008, 8, 152−
158. (e) Richel, A.; Laurent, P.; Wathelet, B.; Wathelet, J.-P.; Paquot,
M. C. R. Chim. 2011, 14, 224−234.
(8) Wang, C.-C.; Zulueta, M. M. L.; Hung, S.-C. Chimia 2011, 65,
54−58.
(9) (a) Wang, C.-C.; Lee, J.-C.; Luo, S.-Y.; Kulkarni, S. S.; Huang, Y.-
W.; Lee, C.-C.; Chang, K.-L.; Hung, S.-C. Nature 2007, 446, 896−899.
(b) Wang, C.-C.; Kulkarni, S. S.; Lee, J.-C.; Luo, S.-Y.; Hung, S.-C.
Nat. Protoc. 2008, 3, 97−113. (c) Chang, K.-L.; Zulueta, M. M. L.; Lu,
X.-A.; Zhong, Y.-Q.; Hung, S.-C. J. Org. Chem. 2010, 75, 7424−7427.
(d) Huang, T.-Y.; Zulueta, M. M. L.; Hung, S.-C. Org. Lett. 2011, 13,
1506−1509. (e) Patil, P. S.; Lee, C.-C.; Huang, Y.-W.; Zulueta, M. M.
L.; Hung, S.-C. Org. Biomol. Chem. 2013, 11, 2605−2612. (f) Huang,
T.-Y.; Zulueta, M. M. L.; Hung, S.-C. Org. Biomol. Chem. 2014, 12,
376−382.
(10) (a) Joseph, A. A.; Verma, V. P.; Liu, X.-Y.; Wu, C.-H.;
Dhurandhare, V. M.; Wang, C.-C. Eur. J. Org. Chem. 2012, 744−753.
(b) Joseph, A. A.; Chang, C.-W.; Wang, C.-C. Chem. Commun. 2013,
49, 11497−11499. (c) Hsieh, H.-W.; Schombs, M. W.; Witschi, M. A.;
Gervay-Hague, J. J. Org. Chem. 2013, 78, 9677−9688.
(11) (a) Caron, S.; Stoermer, D.; Mapp, A. K.; Heathcock, C. H. J.
Org. Chem. 1996, 61, 9126−9134. (b) Noya, B.; Paredes, M. D.;
Ozores, L.; Alonso, R. J. Org. Chem. 2000, 65, 5960−5968. (c) Hung,
S.-C.; Thopate, S. R.; Chi, F.-C.; Chang, S.-W.; Lee, J.-C.; Wang, C.-C.;
Wen, Y.-S. J. Am. Chem. Soc. 2001, 123, 3153−3154. (d) Kusuno, A.;
Mori, M.; Satoh, T.; Miura, M.; Kaga, H.; Kakuchi, T. Chirality 2002,
14, 498−502. (e) Kulkarni, S. S.; Lee, J. C.; Hung, S. C. Curr. Org.
Chem. 2004, 8, 475−509. (f) Satoh, T.; Imai, T.; Ishihara, H.; Maeda,
T.; Kitajyo, Y.; Sakai, Y.; Kaga, H.; Kaneko, N.; Ishii, F.; Kakuchi, T.
Macromolecules 2005, 38, 4204−4212. (g) Shimawaki, K.; Fujisawa, Y.;
Sato, F.; Fujitani, N.; Kurogochi, M.; Hoshi, H.; Hinou, H.; Nishimura,
S.-I. Angew. Chem., Int. Ed. 2007, 46, 3074−3079. (h) Hattori, K.;
Yoshida, T. Macromolecules 2009, 42, 6044−6049. (i) Hoai, N. T.;
Sasaki, A.; Sasaki, M.; Kaga, H.; Kakuchi, T.; Satoh, T.
Biomacromolecules 2011, 12, 1891−1899.
ASSOCIATED CONTENT
* Supporting Information
■
S
Additional experimental procedures and characterization data
for relevant compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
schung@gate.sinica.edu.tw
■
(12) (a) Lee, J.-C.; Tai, C.-A.; Hung, S.-C. Tetrahedron Lett. 2002, 43,
851−855. (b) Hu, Y.-P.; Lin, S.-Y.; Huang, C.-Y.; Zulueta, M. M. L.;
Liu, J.-Y.; Chang, W.; Hung, S.-C. Nat. Chem. 2011, 3, 557−563.
F
dx.doi.org/10.1021/ja504804v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(c) Lepage, M. L.; Bodlenner, A.; Compain, P. Eur. J. Org. Chem. 2013,
1963−1972.
(13) Paulick, M. G.; Bertozzi, C. R. Biochemistry 2008, 47, 6991−
7000.
(14) Cao, B.; Williams, S. J. Nat. Prod. Rep. 2010, 27, 919−947.
(15) Tanaka, H.; Iwata, Y.; Takahashi, D.; Adachi, M.; Takahashi, T.
J. Am. Chem. Soc. 2005, 127, 1630−1631.
(16) Pachamuthu, K.; Schmidt, R. R. Chem. Rev. 2005, 106, 160−187.
(17) (a) Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov,
T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734−753. (b) Hsu, Y.;
Lu, X.-A.; Zulueta, M. M. L.; Tsai, C.-M.; Lin, K.-I.; Hung, S.-C.;
Wong, C.-H. J. Am. Chem. Soc. 2012, 134, 4549−4552.
(18) Tai, C.-A.; Kulkarni, S. S.; Hung, S.-C. J. Org. Chem. 2003, 68,
8719−8722.
(19) Kulkarni, S. S.; Gervay-Hague, J. Org. Lett. 2008, 10, 4739−
4732.
(20) Shie, C.-R.; Tzeng, Z.-H.; Kulkarni, S. S.; Uang, B.-J.; Hsu, C.-Y.;
Hung, S.-C. Angew. Chem., Int. Ed. 2005, 44, 1665−1668.
(21) Wang, C.-C.; Lee, J.-C.; Luo, S.-Y.; Fan, H.-F.; Pai, C.-L.; Yang,
W.-C.; Lu, L.-D.; Hung, S.-C. Angew. Chem., Int. Ed. 2002, 41, 2360−
2362.
G
dx.doi.org/10.1021/ja504804v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX