Palladium(ii)-assisted activation of thioglycosides

Article abstract of DOI:10.1039/d1ob00004g

Described herein is the first example of glycosidation of thioglycosides in the presence of palladium(ii) bromide. While the activation with PdBr₂alone was proven feasible, higher yields and cleaner reactions were achieved when these glycosylat

Full text of DOI:10.1039/d1ob00004g

Organic &
Biomolecular Chemistry
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Palladium(II)-assisted activation of thioglycosides†
Samira Escopy, Yashapal Singh * and Alexei V. Demchenko
*
Cite this: Org. Biomol. Chem., 2021,
19, 2044
Described herein is the first example of glycosidation of thioglycosides in the presence of palladium(II)
bromide. While the activation with PdBr2 alone was proven feasible, higher yields and cleaner reactions
were achieved when these glycosylations were performed in the presence of propargyl bromide as an
additive. Preliminary mechanistic studies suggest that propargyl bromide assists the reaction by creating
an ionizing complex, which accelerates the leaving group departure. A variety of thioglycoside donors in
reactions with different glycosyl acceptors were investigated to determine the initial scope of this new
reaction. Selective and chemoselective activation of thioglycosides over other leaving groups has also
been explored.
Received 1st January 2021,
Accepted 10th February 2021
DOI: 10.1039/d1ob00004g
rsc.li/obc
gained popularity due to their high affinity to non-toxic Au(I),
Introduction
Au(III)38,39 and other transition metal salts.40,41 However, these
Improved understanding of the roles of glycans in various bio- methods require specialized leaving groups that have been
logical processes earned this class of molecules a unique specifically purposed to be compatible with these activation
stature in contemporary research.1 To elucidate specific func- conditions. Activation of conventional thioglycosides through
tions of carbohydrates, the availability of analytically pure the direct coordination of a green post-transition metal salt
glycans is essential. However, practically all aspects of the syn- with the anomeric sulfur was first reported by Pohl et al. who
thesis and purification of complex carbohydrates remain employed a sub-stoichiometric amount of Ph3Bi(OTf)2.42,43
challenging.2,3 Numerous approaches have been developed for Subsequently, Sureshan et al.44 demonstrated the direct acti-
the installation of glycosidic linkages.4 Among known glycosyl vation of thioglycosides using a sub-stoichiometric amount of
donors, halides,5 imidates6 and thioglycosides7 are the most AuCl3 at ambient temperature. Zhu et al.45 also showed that
common. First reported by Fischer in 1916,8 thioglycosides are propargyl thioglycosides are activated through the direct
very stable compounds and many are already commercially coordination of Au(III) to the sulfur atom rather than the
available. However, thioglycosides can be readily activated remote pathway via the alkyne functionality. As a part of our
using thiophilic promoter systems, and are known to fit as efforts toward the development of novel methods for glycosyla-
building blocks into various strategies for glycan synthesis.9–11 tion, herein we report first activation of alkyl/aryl thioglyco-
A significant effort has been dedicated to the development of sides with palladium bromide (PdBr2).
activators for the glycosidation of thioglycosides12 including
metal salts,13–16 halogens,17–22 organosulfur reagents,23–28
alkylating reagents,29 photo-activators with or without heavy
metal additives,30–33 and single electron-transfer activators.34
Nevertheless, many of these approaches have pitfalls, and the
quest for better activators continues.
Transition metal catalysis is a relatively new trend in syn-
thesis to replace toxic chemicals and establish greener reaction
conditions. This approach has also found its application in
glycochemistry.35–38 Specifically, a new class of glycosyl donors
having alkyne-containing aglycones as leaving groups have
Results and discussion
Palladium(II) catalysis is among commonly used methods in
organic chemistry, and its application in glycochemistry is also
known.36,46–54 In our previous endeavors, we encountered Pd
(II) and Pt(IV) mediated reactions that served as the basis for
the development of the temporary deactivation approach,55,56
metal-complexation directed stereoselective glycosylations,57,58
and glycosyl donors with switchable stereoselectivity.59,60
However, the direct utility of these metal salts in activation of
thioglycosides did not occur to us, because every time the com-
plexation took place with the involvement of the anomeric
sulfur, those thioglycoside complexes appeared deactivated
rather than activated. For example, complexes A–C, in all of
which Pt/Pd atom was coordinated via the anomeric sulfur
Department of Chemistry and Biochemistry, University of Missouri – St. Louis, One
University Boulevard, St. Louis, MO 63121, USA. E-mail: demchenkoa@umsl.edu,
satpal04@gmail.com
†Electronic supplementary information (ESI) available: Additional experimental
details and NMR spectra for all new compounds. See DOI: 10.1039/d1ob00004g
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Table 1 PdBr2-mediated glycosidation of donor 1 with glycosyl accep-
tor 2
were stable and could not be activated for glycosylation using
traditional thioglycoside activators (Fig. 1). In contrast, com-
plexes D–G, in which Pt/Pd atom was coordinated away from
the anomeric sulfur, could be activated for glycosylation with
thioglycoside promoters.
Regardless of their structure, no complexes showed propen-
sity to be activated on their own, without added thioglycoside
activators. This is why we were greatly surprised when a reac-
tion between ethylthio galactoside donor 1 61 and glycosyl
acceptor 2 62 produced disaccharide 3 63 in the presence of
only 20 mol% of PdBr2 (see Table 1, entry 1). The yield of dis-
accharide 3 was rather modest (12%), and the reaction was
very sluggish (72 h), but an important precedent was set, and
this result has served as a proof that PdBr2 is capable of acti-
vating standard thioglycosides for glycosylation.
Entry
PdBr2 (equiv)
C3H3Br (equiv)
Conditions
Yield of 3
1
2
3
4
5
6
7
0.2
0.2
0.5
0.8
1.0
1.0
1.0
—
72 h, rt
24 h, rt
24 h, rt
24 h, rt
24 h, rt
48 h, rt
18 h, 60 °C
12%
31%
39%
60%
96%
76%
77%
1.0
1.0
1.0
1.0
—
Encouraged by this observation, albeit dissatisfied with the
rate and the yield of the reaction, we decided to investigate the
mode of interaction of PdBr2 with glycosyl donor 1 using
NMR. For this purpose, a solution of thiogalactoside 1 in
CDCl3 was placed into a standard NMR tube, PdBr2 (1.0 equiv.)
—
1
was added, and H NMR spectrum was recorded after 12 h. As
evident from Fig. 2, a new set of signals has appeared along
with signals of donor 1, which were still predominant in the
spectrum. This result suggested the formation of 1-PdBr2, a
complex between Pd(II) and thiogalactoside 1 via bidentate
coordination. Pd–Metal centre appeared to be coordinated
with the anomeric sulfur atom as evident from a downfield
shift and division of the S-methylene protons that appeared at
2.90 ppm (marked as Ha) and 3.19 ppm (Hb) in 1-PdBr2. The
second complexation site appeared to be the oxygen atom at
C-6, as evidenced by a prominent downfield shift of 6-O-
benzylic protons to 5.39 ppm (marked as Hc) and 5.80 ppm
(Hd) in 1-PdBr2.
Fig. 2 1H NMR study of PdBr2 complexation with thioglycoside 1 in
CDCl3.
Some other minor shifts were also been noted, and these
observations were fully consistent with the previously reported polydentate complexes of transition metals.56,57 However,
based on the NMR monitoring, nothing really implied that the
activation is taking place in this environment. Perhaps, the
process is different in the presence of a nucleophile, but it was
clear that other, more effective activation modes, need to be
engaged to enhance rates and yields of this glycosylation reac-
tion. Analogy with published work64–66 made us believe that
additives such as alkynes may be suitable for this purpose.
After preliminary screening, propargyl bromide was chosen as
the preferred additive. Glycosylation between donor 1 and
acceptor 2 in the presence of catalytic PdBr2 (0.20 equiv.) and
C3H3Br (1.0 equiv.) in CH2Cl2 at rt was more rapid than the
previous reaction with PdBr2 alone. When the reaction was
stopped after 24 h, disaccharide 3 was isolated in an improved
yield of 31% (Table 1, entry 2). Increasing the amount of PdBr2
to 0.50 and 0.80 equiv. showed an increase in yields of disac-
charide 3 to 39 and 60%, respectively, in 24 h (entries 3 and 4).
When a similar glycosylation reaction was conducted in the
presence of a stoichiometric amount of PdBr2, disaccharide 3
was obtained in an excellent yield of 96% (entry 5).
To confirm the active role of propargyl bromide in the latter
glycosylation reaction promoted with stoichiometric PdBr2, a
Fig. 1 Representative platinum group metal complexes synthesized in
our lab.
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similar reaction was conducted in the absence of propargyl ducing disaccharide 21 in 60% (entry 10). This result indicates
bromide. This reaction was notably slower and required 48 h that common STol donors can also be activated with PdBr2 in
to afford disaccharide 3 in 76% yield (entry 6). Setting up a the presence of propargyl bromide, just like their SEt
similar reaction at 60 °C helped to reduce the reaction time to counterparts.
18 h albeit the yield of disaccharide 3 remained practically the
With the acquired knowledge of a very slow activation of the
same (77%, entry 7). This preliminary reaction optimization disarmed donor 18 (see entry 8), we hypothesized that the
study suggested that the promoter and the additive both are established reaction conditions would allow for chemoselective
required in a stoichiometric amount to produce disaccharide 3 armed-disarmed activation of thioglycoside building blocks.
in an excellent yield and in a reasonable reaction time. We To verify the viability of this hypothesis we activated armed
have tried activation with several other palladium(II) salts thioglycoside 20 over disarmed thioglycoside acceptor 23.81
including PdI2, PdCl2 and Pd(OAc)2. However, these reactions Although, we investigated reactions with up to 2.0 equiv. of
were notably slower and lead to lower yields of the products.
PdBr2, this chemoselective reaction was slow, which translated
Having optimized the reaction conditions, we proceeded to into a poor yield of SEt disaccharide 24 91 (α/β = 2.0/1, entry
studying differently protected glycosyl donors and acceptors of 11). We then attempted to activate the armed S-tolyl donor 22
other sugar series. For the purity of comparison, all reactions over the disarmed glycosyl acceptor 25 82 bearing the same
were stopped after 24 h, but some yields could be improved if leaving group. Again, a slow reaction even with 2.0 equiv.
the reactions were kept longer. Glycosylation conducted PdBr2 was observed, and disaccharide 26 83 was produced in
between glycosyl donor 1 and 6-OH glycosyl acceptor 4 67 de- 35% yield (α/β = 2.5/1, entry 12). However, glycosidation of
activated by benzoyl ester groups afforded disaccharide 5 68 in armed SEt thioglycoside 20 with the disarmed S-tolyl acceptor
a good yield of 75% (Table 2, entry 1). Glycosidation of donor 25 was much more effective in the presence of 2.0 equiv.
1 with more hindered, secondary 3-OH glycosyl acceptor 6 62 PdBr2, and disaccharide 26 was obtained in a good yield of
and cholesterol 8 produced the corresponding products 7 63 73% (α/β = 2.5/1, entry 13). To expand the utility of this
and 9 in modest yields of 37–43% (entries 2 and 3). A notable approach, we activated the STol leaving group of the resulting
drop in the yield of glycosides produced from the secondary disarmed disaccharide 26 in the presence of a more powerful
hydroxyls compared to the primary ones suggests that the gly- promoter system NIS/TfOH to form trisaccharide 27 in 71%
cosylation rates also depend on the nucleophilicity of glycosyl (entry 14). This synthesis represents a conventional two-step
acceptors. All these reactions were completely β-stereoselective armed–disarmed sequence for streamlined oligosaccharide
due to the participatory effect of the 2-O-benzoyl group in synthesis.11 Glycosidation of thioglycoside 1 with allyl glyco-
donor 1.
side acceptor 28 was also attempted to investigate the applica-
Subsequently, we extended our glycosylation study to glyco- bility of this approach in selective activation strategies wherein
syl donors of other series. Glycosidation of per-benzylated one class of the leaving group is activated over another. This
galactosyl donor 10 19,69 with the primary glycosyl acceptor 2 reaction proceeded smoothly and disaccharide 29 was
was smooth and efficient. This reaction produced disaccharide obtained in a good yield of 78% (entry 15). It should be noted
11 70 in a high yield of 81% albeit with low stereoselectivity (α/ that the latter example represents selective activation, because
β = 1.5/1, entry 4). Glycosidation of mannosyl donor 12 71 and the allyl group in compound 29 can be activated for sub-
glucosyl donor 14 72 with 6-OH acceptor 2 produced very sequent chain elongation.84,85 In this context, this type of acti-
different results. Glycosidation of thiomannoside 12 was rela- vation reaction cannot be performed in the presence of other
tively slow, which was reflected in a modest yield of 50% for thioglycoside activators (except methyl triflate)86 due to their
disaccharide 13 73 (entry 5). However, glycosidation of thioglu- cross reactivity with olefins.
coside 14 was much swifter, and disaccharide 15 70 was pro-
While many further steps are still needed to fully under-
duced in a good yield of 80% (entry 6). The drop in the yields stand the main driving forces and the substrate scope of this
of disaccharides 13 and 15 compared to that of 3 (96%) could reaction, our current working hypothesis of the reaction
be due to the relative reactivity of different sugar series.74,75
mechanism87 is as follows. As depicted in Scheme 1, upon
It has also occurred to us that the reactivity of glycosyl complexation with PdBr2, thioglycoside donor will form
donors seems to be the key for success because unreactive complex H that is fairly stable. Complex H forms only partially
glucosamine donor 16 76 and per-benzoylated (disarmed) glu- and probably exists in equilibrium with the glycosyl donor. We
cosyl donor 18 77 were practically ineffective in glycosidations observed that it will revert to the starting material in the
with glycosyl acceptor 2 under these reaction conditions. As a absence of a nucleophile or upon work-up. This was proven by
result, disaccharides 17 and 19 78 were obtained in 23 and 10% performing a separate experiment in the absence of a glycosyl
yield, respectively, even after 48 h (entries 7 and 8). In contrast, acceptor. In the presence of a glycosyl acceptor (R′OH),
glycosidation of per-benzylated (armed) glucosyl donor 20 79 complex H will slowly produce the R′O-glycoside product. We
with acceptor 2 was much more effective. Disaccharide 21 70 hypothesize that in the presence of propargyl bromide addi-
was obtained in 61% yield albeit with low stereoselectivity due tive, complex H will undergo oxidative addition to form
to the lack of a participating group at C-2 (α/β = 2.0/1, entry 9). complex I (or similar). The latter is expected to be much more
A practically identical result was obtained in glycosylation reactive than H, and will fall apart with the formation of an
between S-tolyl (STol) donor 22 80 and glycosyl acceptor 2 pro- oxacarbenium (or acyloxonium if an ester group is present at
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Table 2 Broadening the scope of the PdBr2-assisted glycosylation with various donors and acceptors
Entry
1
Donor
Acceptor
Product, yield, α/β ratio
2
3
1
1
4
5
2
6
2
2
7a
8a
2
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Table 2 (Contd.)
Entry
9
Donor
Acceptor
Product, yield, α/β ratio
2
10
2
21, 60%, 2.0/1
11b
20
22
12b
13b
14c
20
26
25
4
26, 73%, 2.5/1
15
1
a Reaction time 48 h. b PdBr2 (2.0 equiv.). c Performed in the presence of NIS (2.0 equiv.)/TfOH (0.2 equiv.), 15 min.
C-2) intermediate J. In the presence of R′OH it will readily presence of allyl bromide, which supports the important role
produce the R′O-glycoside product, but in the absence of the of propargyl bromide in the activation process. Since no other
nucleophile, it may produce glycosyl bromide or other by-pro- side products have been isolated from these reactions, the
ducts. However, the formation of glycosyl bromide is not exact fate of the reagents is yet to be determined. By analogy
detected during regular glycosylations with the glycosyl accep- with published work and our own spectroscopic investigation,
tor present from the beginning.
we postulate that the departed leaving group precipitates as
Indeed, a test reaction of 1 with PdBr2 in the presence of Pd6(SEt)12 or a similar cluster;88 and allene produces oligo-
propargyl bromide monitored by NMR showed the formation meric brominated alkenes.89 These products are removed
of glycosyl bromide as the main product (see the ESI† for during the standard work-up procedure (see the ESI† for
details). In contrast, glycosyl bromide was not observed in the additional details).
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otherwise, 1H NMR spectra were recorded at 300 MHz, 13C
1
NMR spectra were recorded at 75 MHz. The H NMR chemical
shifts are referenced to tetramethylsilane (δH = 0 ppm) or
CHCl3 (δH = 7.26 ppm) for 1H NMR spectra for solutions in
CDCl3. The 13C NMR chemical shifts are referenced to the
central signal of CDCl3 (δC = 77.00 ppm) for solutions in
CDCl3. The HRMS analysis was performed using Agilent 6230
ESI TOF LC/MS mass spectrometer.
Synthesis of building blocks
Ethyl 2-O-benzoyl-3,4,6-tri-O-benzyl-1-thio-β-D-galactopyrano-
side (1) was synthesized as reported previously and its analyti-
cal data was in accordance with that previously described.61
Methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (2) was syn-
thesized as reported previously and its analytical data was in
accordance with that previously described.62
Methyl 2,3,4-tri-O-benzoyl-α-D-glucopyranoside (4) was syn-
thesized as reported previously and its analytical data was in
accordance with that previously described.67
Scheme 1 Anticipated PdBr2-promoted reaction pathway in the pres-
ence of propargyl bromide additive.
Methyl 2,4,6-tri-O-benzyl-α-D-glucopyranoside (6) was syn-
thesized as reported previously and its analytical data was in
accordance with that previously described.62
Conclusions
A new method for the activation of thioglycosides has been
developed. The activation with PdBr2 can be sluggish, but it
accelerates significantly in the presence of propargyl bromide
additive that forms a more reactive reaction intermediate, and
possibly acts as the leaving group scavenger. A preliminary
mechanistic analysis and studying the complexation modes
Ethyl
2,3,4,6-tetra-O-benzyl-1-thio-β-D-galactopyranoside
(10) was synthesized as reported previously and its analytical
data was in accordance with that previously described.19,69
Ethyl 2-O-benzoyl-3,4,6-tri-O-benzyl-1-thio-α-D-mannopyra-
noside (12) was synthesized as reported previously and its
analytical data was in accordance with that previously
described.71
1
relied on H NMR spectroscopy. Upon standardizing the basic
reaction conditions, further examination of various thioglyco-
sides has been performed. In most cases, our activation system
was effective at room temperature, but the reaction time and
the product yield were dependent on the reactivity of the
donor and acceptor. Chemoselective and selective activation
schemes have been investigated and successfully applied in a
two-step synthesis of a trisaccharide. Further optimization of
the reaction conditions and its application in automated syn-
thesis of glycans are currently underway in our laboratory.
Ethyl 2-O-benzoyl-3,4,6-tri-O-benzyl-1-thio-β-D-glucopyrano-
side (14) was synthesized as reported previously and its analyti-
cal data was in accordance with that previously described.72
Ethyl 4,6-di-O-benzyl-2-deoxy-3-O-fluorenylmethoxycarbo-
nyl-2-phthalimido-1-thio-β-D-glucopyranoside (16) was syn-
thesized as reported previously and its analytical data was in
accordance with that previously described.76
Ethyl 2,3,4,6-tetra-O-benzoyl-1-thio-β-D-glucopyranoside (18)
was synthesized as reported previously and its analytical data
was in accordance with that previously described.77
Ethyl 2,3,4,6-tetra-O-benzyl-1-thio-β-D-glucopyranoside (20)
was synthesized as reported previously and its analytical data
was in accordance with that previously described.79
Experimental
General
Tolyl 2,3,4,6-tetra-O-benzyl-1-thio-β-D-glucopyranoside (22)
All chemicals used were reagent grade and used as supplied. was synthesized as reported previously and its analytical data
The ACS grade solvents used for reactions were purified and was in accordance with that previously described.80
dried in accordance with standard procedures. Column chrom-
Ethyl 2,3,4-tri-O-benzoyl-1-thio-β-D-glucopyranoside (23)
atography was performed on silica gel 60 (70–230 mesh), reac- was synthesized as reported previously and its analytical data
tions were monitored by TLC on Kieselgel 60 F254. The com- was in accordance with that previously described.81
pounds were detected by examination under UV light and by
Tolyl 2,3,4-tri-O-benzoyl-1-thio-β-D-glucopyranoside (25) was
charring with 10% sulfuric acid in methanol. Solvents were synthesized as reported previously and its analytical data was
removed under reduced pressure at <40 °C. CH2Cl2 was dis- in accordance with that previously described.82
tilled from CaH2 directly prior to the application. Molecular
Allyl 2-azido-4-O-benzyl-2-deoxy-β-D-glucopyranoside (28). A
sieves (3 Å), used for reactions, were crushed and activated in mixture containing 3,6-di-O-acetyl-2-azido-4-O-benzyl-2-deoxy-
vacuo at 390 °C during 8 h in the first instance and then for α-D-glucopyranosyl bromide90 (1.77 g, 4.0 mmol), allyl alcohol
2–3 h at 390 °C directly prior to application. Optical rotations (0.50 mL, 6.0 mmol) and molecular sieves (4 Å, 2.0 g) in aceto-
were measured at ‘Jasco P-2000’ polarimeter. Unless noted nitrile (20 mL) under argon was cooled to −40 °C. Mercury(II)
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cyanide (1.01 g, 4.0 mmol) was added, the external cooling was
Methyl 6-O-(2-O-benzoyl-3,4,6-tri-O-benzyl-β-D-galactopyra-
removed, the resulting mixture was allowed to warm to rt, and nosyl)-2,3,4-tri-O-benzoyl-α-D-glucopyranoside (5) was obtained
stirred for additional 2.5 h at rt. After that, the solids were fil- from thioglycoside 1 and glycosyl acceptor 4 by the general gly-
tered off through a pad of Celite and washed successively with cosylation method in 75% yield as a white amorphous solid.
DCM. The combined filtrate (∼150 mL) was concentrated Analytical data for 5 was in accordance with that reported
under reduced pressure and dried in vacuo. The crude residue previously.68
was dissolved in MeOH (40 mL), a 1 M solution of NaOMe in
Methyl 3-O-(2-O-benzoyl-3,4,6-tri-O-benzyl-β-D-galactopyra-
MeOH was added dropwise to pH ∼ 9, and the resulting nosyl)-2,4,6-tri-O-benzyl-α-D-glucopyranoside (7) was obtained
mixture was stirred for 22 h at rt. After that, the reaction from thioglycoside 1 and glycosyl acceptor 6 by the general gly-
mixture was neutralized with Dowex (H+). The resin was fil- cosylation method in 43% yield as a clear film. Analytical data
tered off and rinsed successively with MeOH. The combined for 7 was in accordance with that reported previously.63
filtrate (∼80 mL) was concentrated under reduced pressure.
Cholesteryl 2-O-benzoyl-3,4,6-tri-O-benzyl-β-D-galactopyra-
The residue was purified by column chromatography on silica nosyl (9) was obtained from thioglycoside 1 and cholesterol 8
gel (ethyl acetate–hexanes gradient elution). Fractions contain- by the general glycosylation method in 37% yield as a white
ing β-28 were combined, concentrated under reduced pressure, amorphous solid. Analytical data for 9: Rf = 0.70 (ethyl acetate/
22
and the residue was recrystallized from ethyl acetate–hexanes hexane, 2/3, v/v); [α]D +0.6 (c = 1, CHCl3); 1H NMR (300 MHz,
to afford the title compound as white crystals in 55% yield CDCl3): δ, 0.64 (s, 3H), 0.84–0.90 (m, 14H), 0.96–1.10 (m, 8H),
(0.74 g, 2.2 mmol). Also eluted from the column was α-28 that 1.25 (s, 3H), 1.31–1.55 (m, 10H), 1.74–2.11 (m, 5H), 3.44 (m,
was obtained in 12% yield. Analytical data for β-28: Rf = 0.35 1H), 3.60–3.66 (m, 4H, H-3′, 5′, 6a′, 6b′), 3.99 (d, 1H, J4′,5′ = 2.2
(ethyl acetate/hexane, 2/3, v/v); [α]2D1 −15.7 (c = 1, CHCl3); Hz, H-4′), 4.47–4.50 (m, 3H, 3 × CHPh), 4.56 (d, 1H, J1′,2′ = 7.9
2
m.p. 121–122 °C (ethyl acetate–hexanes); 1H NMR (300 MHz, Hz, H-1′), 4.62–4.68 (m, 2H, 2 × CHPh), 4.98 (d, 1H, J = 11.7
CDCl3): δ 1.88 (m, 1H, 6-OH), 2.39 (s, 1H, 3-OH), 3.29–3.35 (m, Hz, CHPh), 5.19 (d, J = 5.0 Hz, 1H), 5.59 (dd, 1H, J2′,3′ = 8.0 Hz,
2H, H-2, 5), 3.47–3.53 (m, 2H, H-3, 4), 3.73–3.80 (m, 1H, H-6a), H-2′), 7.13–7.60 (m, 18H, aromatic), 8.01 (d, 2H, J = 7.8 Hz, aro-
3.87–3.93 (m, 1H, H-6b), 4.12 (dd, 1H, OCH2 CHv), 4.35–4.41 matic) ppm; 13C NMR (75 MHz, CDCl3): δ 11.9, 18.6, 19.2, 20.9,
a
(m, 2H, J1,2 = 8.1 Hz, H-1, OCH2bCHv), 4.71 (dd, 2H, CH2Ph), 22.5, 22.6, 22.8, 23.7, 24.2, 27.9, 28.2, 29.4, 29.7, 31.7, 31.8,
a
5.23 (dd, 1H, J = 10.7 Hz, CHvCH2 ), 5.32 (dd, 1H, J = 17.0 Hz, 35.7, 36.1, 36.6, 37.2, 38.7, 39.4, 39.7, 42.2, 50.0, 56.0, 56.6,
CHvCH2b), 5.90–5.99 (m, 1H, CHvCH2), 7.17–7.59 (m, 5H, 68.7, 71.5, 72.1, 73.5 (×2), 74.3, 76.5, 79.3, 79.9, 100.2, 121.5,
aromatic) ppm; 13C NMR (75 MHz, CDCl3): δ 61.7, 66.1 (×2), 127.5 (×2), 127.6, 127.8 (×2), 127.9 (×2), 128.1 (×2), 128.2 (×2),
70.6, 74.8, 75.1 (×2), 101.0, 118.0, 128.1 (×2), 128.2, 128.6 (×2), 128.4 (×4), 129.7, 130.0, 132.8, 137.6, 137.8, 138.2, 138.4, 140.7,
133.2, 137.8 ppm; HR-FAB MS [M
C16H21N3O5Na 358.1379, found 358.1401.
+
Na]+ calcd for 165.3 ppm; HR-FAB MS [M + Na]+ calcd for C61H78O7Na
945.5645, found 945.5662.
Methyl 6-O-(2,3,4,6-tetra-O-benzyl-α/β-D-galactopyranosyl)-
2,3,4-tri-O-benzyl-α-D-glucopyranoside (11) was obtained from
thioglycoside 10 and glycosyl acceptor 2 by the general glycosy-
Synthesis of O-glycosides
General procedure for PdBr2–C3H3Br assisted glycosidation lation method in 81% yield (α/β = 1.5/1) as a colorless syrup.
of thioglycosides. A mixture of thioglycoside precursor (30 mg, Analytical data for 11 was in accordance with that reported
0.05–0.04 mmol), glycosyl acceptor (0.04–0.03 mmol) and previously.70
freshly activated molecular sieves (3 Å, 90 mg) in dry CH2Cl2
Methyl 6-O-(2-O-benzoyl-3,4,6-tri-O-benzyl-α-D-mannopyra-
(1.0 mL) was stirred under argon for 1 h at rt. After that, pro- nosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (13) was obtained
pargyl bromide (C3H3Br, 0.05 mmol) followed by palladium from thioglycoside 12 and glycosyl acceptor 2 by the general
bromide (PdBr2, 0.05–0.01 mmol) were added and the reaction glycosylation method in 50% yield as a colorless syrup.
mixture was stirred for 24 h. The solids were filtered off Analytical data for 13 was in accordance with that reported
through a pad of Celite and rinsed successively with CH2Cl2. previously.73
The combined filtrate (∼20 mL) was washed with H2O (2 ×
Methyl 6-O-(2-O-benzoyl-3,4,6-tri-O-benzyl-β-D-glucopyrano-
5 mL). The organic phase was separated, dried with MgSO4, syl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (15) was obtained
and concentrated in vacuo. The residue was purified by from thioglycoside 14 and glycosyl acceptor 2 by the general
column chromatography on silica gel (ethyl acetate–hexanes glycosylation method in 80% yield as a clear film. Analytical
gradient elution) to afford a glycoside derivative in yields listed data for 15 was in accordance with that reported previously.70
in tables. Anomeric ratios (if applicable) were determined by
comparison of the integral intensities of relevant signals in 1H carbonyl-2-phthalimido-β-D-glucopyranosyl)-2,3,4-tri-O-benzyl-
NMR spectra. α-D-glucopyranoside (17) was obtained from thioglycoside 16
Methyl 6-O-(4,6-di-O-benzyl-2-deoxy-3-O-fluorenylmethoxy-
Methyl 6-O-(2-O-benzoyl-3,4,6-tri-O-benzyl-β-D-galactopyra- and glycosyl acceptor 2 by the general glycosylation method as
nosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (3) was obtained a clear film in 23% yield. Analytical data for 17: Rf = 0.50 (ethyl
from thioglycoside 1 and glycosyl acceptor 2 by the general gly- acetate/hexane, 2/3, v/v); [α]2D1 +10.0 (c = 1, CHCl3); 1H NMR
cosylation method in 96% yield as a clear film. Analytical data (300 MHz, CDCl3): δ 3.14 (s, 3H, OCH3), 3.26 (dd, 1H, J4,5 = 9.2
for 3 was in accordance with that reported previously.63
Hz, H-4), 3.36 (dd, 1H, J2,3 = 3.7 Hz, H-2), 3.63–3.67 (m, 2H,
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H-5, 6a), 3.74–3.91 (m, 6H, 3, 4′, 5′, 6a′, 6b′, OCOCH2CH), 3.99 H-3″, 4″, 5″, 6a, 6a′, 6a″, 6b′, 6b″), 4.01–4.09 (m, 3H, 5, 5′, 6b),
a
(dd, 1H, OCOCH2 ), 4.09–4.16 (m, 3H, 6b, OCOCH2b, CHPh), 4.33–4.69 (m, 7H, H-1″, 6 × CHPh), 4.78–4.85 (m, 2H, H-1,
4.34 (d, 1H, J1,2 = 3.4 Hz, H-1), 4.39 (d, 1H, 2J = 10.1 Hz, CHPh), CHPh), 4.88–5.00 (m, 3H, H-1′, 2, CHPh), 5.31 (dd, 1H, J4,5
=
4.45 (dd, 1H, J2′,3′ = 8.7 Hz, H-2′), 4.54–4.73 (m, 7H, 7 × CHPh), 9.0 Hz, H-4), 5.48–5.54 (m, 2H, H-2′, 4′), 5.83 (dd, 1H, J3′,4′ = 9.6
4.83 (d, 1H, 2J = 10.7 Hz, CHPh), 5.39 (d, 1H, J1′,2′ = 8.4 Hz, Hz, H-3′), 5.98 (dd, 1H, J3,4 = 9.7 Hz, H-3), 7.11–7.51 (m, 38H,
H-1′), 5.70 (dd, 1H, J3′,4′ = 8.8 Hz, H-3′), 7.01–7.70 (m, 37H, aro- aromatic), 7.74–7.98 (m, 12H, aromatic) ppm; 13C NMR
matic) ppm; 13C NMR (75 MHz, CDCl3): δ 46.3, 54.8 (×2), 68.6, (75 MHz, CDCl3): δ 54.1, 66.2, 67.1, 67.4, 67.5 (×2), 68.4, 68.8,
69.2, 70.2, 73.3, 73.4, 74.7, 74.9, 75.6 (×2), 79.6, 81.8, 97.8, 69.2, 70.9, 71.2, 71.9, 72.0, 72.4, 73.8, 74.5, 95.4, 96.4, 100.3,
98.1, 113.8, 119.8 (×2), 123.3 (×2), 124.9, 125.1, 127.1 (×2), 112.9, 126.5, 126.6 (×2), 126.7 (×6), 126.8 (×2), 126.9, 127.0
127.5 (×2), 127.6 (×5), 127.7 (×6), 127.8 (×2), 127.9 (×2), 128.0 (×6), 127.2 (×5), 127.3 (×3), 127.4, 127.8 (×2), 127.9, 128.0 (×2),
(×4), 128.2 (×5), 128.3 (×4), 128.4 (×2), 133.8 (×2), 137.6, 137.7, 128.1, 128.2 (×2), 128.5 (×2), 128.6 (×2), 128.8, 128.9 (×3),
138.0, 138.1, 138.6, 140.9, 141.0, 142.8, 143.2, 154.6, 167.2, 131.0, 132.0 (×2), 132.1(×4), 132.3 (×4), 132.4, 136.9, 137.0,
168.1 ppm; HR-FAB MS [M + Na]+ calcd for C71H67NO14Na 137.1, 137.2, 137.2, 137.5, 137.8, 138.0, 164.1, 164.2 (×2), 164.7
1180.4460, found 1180.4550.
(×2), 164.8 ppm; HR-FAB MS [M + Na]+ calcd for C89H82O22Na
Methyl
6-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)- 1525.5196, found 1525.5174.
2,3,4-tri-O-benzyl-α-D-glucopyranoside (19) was obtained from
Allyl 6-O-(2-O-benzoyl-3,4,6-tri-O-benzyl-β-D-galactopyrano-
thioglycoside 18 and glycosyl acceptor 2 by the general glycosy- syl)-2-azido-4-O-benzyl-2-deoxy-β-D-glucopyranoside (29) was
lation method in 10% yield as a clear film. Analytical data for obtained from thioglycoside 1 and glycosyl acceptor 28 by the
19 was in accordance with that reported previously.78
Methyl
general glycosylation method in 78% yield as a white amor-
6-O-(2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranosyl)- phous solid. Analytical data for 29: Rf = 0.55 (ethyl acetate/
2,3,4-tri-O-benzyl-α-D-glucopyranoside (21) was obtained from hexane, 2/3, v/v); [α]D21 +11.8 (c = 1, CHCl3); 1H NMR (300 MHz,
thioglycosides 20 or 22 and glycosyl acceptor 2 by the general CDCl3): δ 3.17–3.26 (m, 2H, H-2, 5), 3.36–3.42 (m, 2H, H-3, 4),
glycosylation method in 61 and 60% yield (α/β = 2.0/1) as a 3.57–3.66 (m, 5H, H-3′, 5′, 6a, 6a′, 6b′), 3.76 (dd, 1H,
colorless syrup. Analytical data for 21 was in accordance with OCH2 CHv), 3.98–4.03 (m, 2H, H-4′, OCH2bCHv), 4.12–4.18
a
that reported previously.70
(m, 2H, H-1, 6b), 4.39–4.70 (m, 7H, H-1′, 6 × CHPh), 4.96 (d,
2
a
Ethyl 6-O-(2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranosyl)-2,3,4- 1H, J = 11.6 Hz, CHPh), 5.09 (dd, 1H, J = 10.0 Hz, CHvCH2 ),
tri-O-benzoyl-1-thio-β-D-glucopyranoside (24) was obtained 5.16 (dd, 1H, J = 17.7 Hz, CHvCH2b), 5.61–5.74 (m, 2H, H-2′,
from thioglycoside 20 and glycosyl acceptor 23 by the general CHvCH2), 7.14–7.56 (m, 23H, aromatic), 7.96 (d, 2H, J = 7.7
glycosylation method in 26% yield (α/β = 2.0/1) as a colorless Hz, aromatic) ppm; 13C NMR (75 MHz, CDCl3): δ 65.9 (×2),
syrup. Analytical data for 24 was in accordance with that 67.4, 68.4, 69.5, 71.5, 71.6, 72.2, 73.5, 73.6, 74.4 (×2), 74.6,
reported previously.91
75.2, 79.8, 100.3, 101.3, 117.4, 118.5, 127.6 (×4), 128.1 (×4),
Tolyl 6-O-(2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranosyl)-2,3,4- 128.2 (×2), 128.3 (×5), 128.4 (×3), 129.8 (×3), 130.0, 130.2,
tri-O-benzoyl-1-thio-β-D-glucopyranoside (26) was obtained 132.9, 133.1, 134.0, 137.5, 137.7, 137.8, 138.3, 165.1 ppm;
from thioglycosides 20 or 22 and glycosyl acceptor 25 by the HR-FAB MS [M + Na]+ calcd for C50H53N3O11Na 894.3578,
general glycosylation method in 73 or 35% yield (α/β = 2.5/1) found 894.3587.
as a colorless syrup. Analytical data for 26 was in accordance
with that reported previously.83
Methyl
2,3,4-tri-O-benzoyl-β-D-glucopyranosyl-(1→6)-2,3,4-tri-O-benzoyl-
α-D-glucopyranoside (27). mixture of thioglycoside 26
2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranosyl-(1→6)- Conflicts of interest
There are no conflicts to declare.
A
(0.016 mmol), glycosyl acceptor 4 (0.015 mmol) and freshly
activated molecular sieves (3 Å, 52 mg) in dry CH2Cl2 (1.0 mL)
was stirred under argon for 1 h at rt. After that, NIS
(0.03 mmol) followed by TfOH (0.3 µL, 0.003 mmol) were
added, and the reaction mixture was stirred for 15 min at rt.
The solids were filtered off through a pad of Celite and rinsed
successively with CH2Cl2. The combined filtrate (∼20 mL) was
washed with sat. aq. Na2S2O3 (5 mL), sat. aq. NaHCO3 (5 mL)
and brine (2 × 5 mL). The organic phase was separated, dried
with MgSO4, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel
(ethyl acetate–hexanes gradient elution) to afford the title com-
pound in 71% yield (0.011 mmol) as a white amorphous solid.
Selected analytical data for α-27: Rf = 0.45 (ethyl acetate/
hexane, 2/3, v/v); 1H NMR (300 MHz, CDCl3): δ 3.03 (s, 3H,
OCH3), 3.39 (dd, 1H, J2″,3″ = 3.3 Hz, H-2″), 3.50–3.87 (m, 9H,
Acknowledgements
This work was supported by awards from the NIGMS
(GM111835) and the NSF (CHE-1800350). SE is indebted to the
SACM for providing her with the graduate fellowship.
Notes and references
1 A. Varki, Biological Roles of Glycans, Glycobiology, 2017, 27,
3–49.
2 P. H. Seeberger, The logic of automated glycan assembly,
Acc. Chem. Res., 2015, 48, 1450–1463.
3 M. Panza, S. G. Pistorio, K. J. Stine and A. V. Demchenko,
Automated Chemical Oligosaccharide Synthesis: Novel
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 2044–2054 | 2051

View Article Online
Paper
Organic & Biomolecular Chemistry
Approach to Traditional Challenges, Chem. Rev., 2018, 118, 19 J. O. Kihlberg, D. A. Leigh and D. R. Bundle, The in situ
8105–8150.
activation of thioglycosides with bromine: an improved gly-
cosylation method, J. Org. Chem., 1990, 55, 2860–2863.
20 K. P. M. Kartha, M. Aloui and R. A. Field, Iodine: a versatile
reagent in carbohydrate chemistry II. Efficient chemospeci-
fic activation of thiomethylglycosides, Tetrahedron Lett.,
1996, 37, 5175–5178.
21 M. D. Burkart, Z. Zhang, S.-C. Hung and C.-H. Wong, A
new method for the synthesis of fluoro-carbohydrates and
glycosides using selectfluor, J. Am. Chem. Soc., 1997, 119,
11743–11746.
4 X. Zhu and R. R. Schmidt, New principles for glycoside-bond
formation, Angew. Chem., Int. Ed., 2009, 48, 1900–1934.
5 S. S. Kulkarni and J. Gervay-Hague, Glycosyl chlorides, bro-
mides and iodides, in Handbook of Chemical Glycosylation,
ed. A. V. Demchenko, Wiley-VCH, Weinheim, Germany,
2008, pp. 59–93.
6 X. Zhu and R. R. Schmidt, Glycoside synthesis from
1-oxygen-substituted glycosyl imidates, in Handbook of
Chemical Glycosylation, ed. A. V. Demchenko, Wiley-VCH,
Weinheim, Germany, 2008, pp. 143–185.
22 T. Ercegovic, A. Meijer, G. Magnusson and U. Ellervik,
Iodine monochloride/silver trifluoromethanesulfonate (ICI/
AgOTf) as a convenient promoter system for O-glycoside
synthesis, Org. Lett., 2001, 3, 913–915.
7 W. Zhong and G.-J. Boons, Glycoside synthesis from
1-sulfur/selenium-substituted derivatives: thioglycosides in
oligosaccharide synthesis, in Handbook of Chemical
Glycosylation, ed. A. V. Demchenko, Wiley-VCH, Weinheim, 23 P. Fugedi and P. J. Garegg, A novel promoter for the
Germany, 2008, pp. 261–303.
8 E. Fischer and L. von Mechel, Synthesis of phenyl gluco-
sides, Ber. Dtsch. Chem. Ges., 1916, 49, 2813–2820.
efficient construction of 1,2-trans linkages in glycoside syn-
thesis, using thioglycosides as glycosyl donors, Carbohydr.
Res., 1986, 149, c9–c12.
9 J. T. Smoot and A. V. Demchenko, Oligosaccharide synthesis: 24 F. Dasgupta and P. J. Garegg, Use of sulfenyl halides in
from conventional methods to modern expeditious strat-
egies, Adv. Carbohydr. Chem. Biochem., 2009, 62, 161–250.
10 S. Kaeothip and A. V. Demchenko, Expeditious oligosac-
charide synthesis via selective and orthogonal activation,
Carbohydr. Res., 2011, 346, 1371–1388.
carbohydrate reactions. Part I. Alkyl sulfenyl triflate as acti-
vator in the thioglycoside-mediated formation of beta-gly-
cosidic linkages during oligosaccharide synthesis,
Carbohydr. Res., 1988, 177, C13–C17.
25 D. Crich and M. Smith, S-(4-Methoxyphenyl) benzenethio-
11 M. D. Bandara, J. P. Yasomanee and A. V. Demchenko,
Application of armed, disarmed, superarmed and superdi-
sarmed building blocks in stereocontrolled glycosylation
sulfinate(MPBT)/trifluoromethanesulfonic
(Tf2O): a convenient system for the generation of glycosyl
triflates from thioglycosides, Org. Lett., 2000, 2, 4067–4069.
anhydride
and expeditious oligosaccharide synthesis, in Selective 26 D. Crich and M. Smith, 1-Benzenesulfinyl piperidine/tri-
Glycosylations: Synthetic Methods and Catalysts, ed.
C. S. Bennett, Wiley, 2017, pp. 29–58.
12 G. Lian, X. Zhang and B. Yu, Thioglycosides in
Carbohydrate research, Carbohydr. Res., 2015, 403, 13–22.
13 R. J. Ferrier, R. W. Hay and N. Vethaviyasar, A potentially
fluoromethanesulfonic anhydride: a potent combination of
shelf-stable reagents for the low-temperature conversion of
thioglycosides to glycosyl triflates and for the formation of
diverse glycosidic linkages, J. Am. Chem. Soc., 2001, 123,
9015–9020.
versatile synthesis of glycosides, Carbohydr. Res., 1973, 27, 27 J. D. C. Codee, R. E. J. N. Litjens, R. Heeten,
55–61.
H. S. Overkleeft, J. H. van Boom and G. A. van der Marel,
Ph2SO/Tf2O: A powerful promotor system in chemoselective
glycosylations using thioglycosides, Org. Lett., 2003, 5,
1519–1522.
14 S. Sato, M. Mori, Y. Ito and T. Ogawa, An efficient approach
to O-glycosides through CuBr2-Bu4NBr mediated activation
of glycosides, Carbohydr. Res., 1986, 155, c6–c10.
15 M. J. Lear, F. Yoshimura and M. Hirama, A direct and 28 S. G. Duron, T. Polat and C. H. Wong, N-(Phenylthio)-ε-
efficient α-selective glycosylation protocol for the kedarci-
caprolactam: A new promoter for the activation of thiogly-
din sugar, L-mycarose: AgPF6 as a remarkable activator of
cosides, Org. Lett., 2004, 6, 839–841.
2-deoxythioglycosides, Angew. Chem., Int. Ed., 2001, 40, 29 H. Lonn, Synthesis of a tri- and a heptasaccharide which
946–949.
contain α-L-fucopyranosyl groups and are part of the
complex type of carbohydrate moiety of glycoproteins,
Carbohydr. Res., 1985, 139, 105–113.
16 L. Meng, P. Wu, J. Fang, Y. Xiao, X. Xiao, G. Tu, X. Ma,
S. Teng, J. Zeng and Q. Wan, Glycosylation Enabled by
Successive Rhodium(II) and Brønsted Acid Catalysis, J. Am. 30 R.-Z. Mao, F. Guo, D.-C. Xiong, Q. Li, J. Duan and X.-S. Ye,
Chem. Soc., 2019, 141, 11775–11780.
Photoinduced C-S Bond Cleavage of Thioglycosides and
17 G. H. Veeneman, S. H. van Leeuwen and J. H. van Boom,
Glycosylation, Org. Lett., 2015, 17, 5606–5609.
Iodonium ion promoted reactions at the anomeric centre. 31 W. J. Wever, M. A. Cinelli and A. A. Bowers, Visible Light
II. An efficient thioglycoside mediated approach toward the
formation of 1,2-trans linked glycosides and glycosidic
esters, Tetrahedron Lett., 1990, 31, 1331–1334.
Mediated Activation and O-Glycosylation of Thioglycosides,
Org. Lett., 2013, 15, 30–33.
32 M. L. Spell, K. Deveaux, C. G. Bresnahan, B. L. Bernard,
W. Sheffield, R. Kumar and J. R. Ragains, A Visible–Light–
Promoted O–Glycosylation with a Thioglycoside Donor,
Angew. Chem., Int. Ed., 2016, 55, 6515–6519.
18 K. C. Nicolaou, S. P. Seitz and D. P. Papahatjis, A mild and
general method for the synthesis of O-glycosides, J. Am.
Chem. Soc., 1983, 105, 2430–2434.
2052 | Org. Biomol. Chem., 2021, 19, 2044–2054
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Paper
33 R.-Z. Mao, D.-C. Xiong, F. Guo, Q. Li, J. Duan and X.-S. Ye,
Light-driven highly efficient glycosylation reactions, Org.
Chem. Front., 2016, 3, 737–743.
34 C. Amatore, A. Jutand, J. M. Mallet, G. Meyer and P. Sinay,
Electrochemical glycosylation using phenyl S-glycosides,
J. Chem. Soc., Chem. Commun., 1990, 718–719.
with N,S and S,S heterocyclic ligands, Inorg. Chim. Acta,
2006, 359, 4326–4334.
50 J. Yang, C. Cooper-Vanosdell, E. A. Mensah and
H. M. Nguyen, Cationic palladium(II)-catalyzed stereo-
selective glycosylation with glycosyl trichloroacetimidates,
J. Org. Chem., 2008, 73, 794–800.
35 M. J. McKay and H. M. Nguyen, Recent advances in tran- 51 E. A. Mensah, J. M. Azzarelli and H. M. Nguyen, Palladium-
sition metal-catalyzed glycosylation, ACS Catal., 2012, 2,
1563–1595.
36 X. Li and J. Zhu, Glycosylation via Transition-Metal
controlled β-selective glycosylation in the absence of the
C(2)-ester participatory group, J. Org. Chem., 2009, 74,
1650–1657.
Catalysis: Challenges and Opportunities, Eur. J. Org. Chem., 52 S. Xiang, J. He, Y. J. Tan and X.-W. Liu, Stereocontrolled
2016, 4724–4767.
O-Glycosylation with Palladium-Catalyzed Decarboxylative
37 M. M. Nielsen and C. M. Pedersen, Catalytic Glycosylations
Allylation, J. Org. Chem., 2014, 79, 11473–11482.
in Oligosaccharide Synthesis, Chem. Rev., 2018, 118, 8285– 53 S. Xiang, K. L. M. Hoang, J. He, Y. J. Tan and X. W. Liu,
8358.
Reversing the stereoselectivity of a palladium-catalyzed
O-glycosylation through an inner-sphere or outer-sphere
pathway, Angew. Chem., Int. Ed., 2015, 54, 604–607.
38 W. Li and B. Yu, Gold-catalyzed glycosylation in the syn-
thesis of complex carbohydrate-containing natural pro-
ducts, Chem. Soc. Rev., 2018, 47, 7954–7984.
39 S. Hotha and S. Kashyap, Propargyl glycosides as stable gly-
cosyl donors: anomeric activation and glycosyl syntheses,
J. Am. Chem. Soc., 2006, 128, 9620–9621.
54 A. Sau, R. Williams, C. Palo-Nieto, A. Franconetti,
S. Medina and M. C. Galan, Palladium–Catalyzed Direct
Stereoselective Synthesis of Deoxyglycosides from Glycals,
Angew. Chem., 2017, 129, 3694–3698.
40 G. Sun, Y. Wu, A. Liu, S. Qiu, W. Zhang, Z. Wang and 55 P. Pornsuriyasak, U. B. Gangadharmath, N. P. Rath and
J. Zhang, Substoichiometric FeCl3 Activation of Propargyl
Glycosides for the Synthesis of Disaccharides and
Glycoconjugates, Synlett, 2018, 668–672.
A. V. Demchenko, A novel strategy for oligosaccharide syn-
thesis via temporarily deactivated S-thiazolyl glycosides as
glycosyl acceptors, Org. Lett., 2004, 6, 4515–4518.
41 H. Imagawa, A. Kinoshita, T. Fukuyama, H. Yamamoto and 56 P. Pornsuriyasak, N. P. Rath and A. V. Demchenko, 4-
M. Nishizawa, Hg(OTf)2-catalyzed glycosylation using
alkynoate as the leaving group, Tetrahedron Lett., 2006, 47,
4729–4731.
(Pyridin-2-yl)thiazol-2-yl thioglycosides as bidentate ligands
for oligosaccharide synthesis via temporary deactivation,
Chem. Commun., 2008, 5633–5635.
42 M. Goswami, A. Ellern and N. L. Pohl, Bismuth(V)- 57 P. Pornsuriyasak, C. Vetter, S. Kaeothip, M. Kovermann,
mediated thioglycoside activation, Angew. Chem., Int. Ed.,
2013, 52, 8441–8445.
43 M. Goswami, D. C. Ashley, M. H. Baik and N. L. Pohl,
Mechanistic Studies of Bismuth(V)-Mediated Thioglycoside
J. Balbach, D. Steinborn and A. V. Demchenko,
Coordination chemistry approach to the long-standing
challenge of anomeric stereoselectivity, Chem. Commun.,
2009, 6379–6381.
Activation Reveal Differential Reactivity of Anomers, J. Org. 58 C. Vetter, P. Pornsuriyasak, J. Schmidt, N. P. Rath,
Chem., 2016, 81, 5949–5962.
T. Rüffer, A. V. Demchenko and D. Steinborn, Synthesis,
characterization and reactivity of carbohydrate platinum
(IV) complexes with thioglycoside ligands, Dalton Trans.,
2010, 39, 6327–6338.
44 A. M. Vibhute, A. Dhaka, V. Athiyarath and K. M. Sureshan,
A versatile glycosylation strategy via Au(III) catalyzed acti-
vation of thioglycoside donors, Chem. Sci., 2016, 7, 4259–
4263.
45 S. Adhikari, K. N. Baryal, D. Zhu, X. Li and J. Zhu, Gold-
catalyzed synthesis of 2-deoxy glycosides using S-but-3-ynyl
thioglycoside donors, ACS Catal., 2013, 3, 57–60.
59 A. K. Kayastha, X. G. Jia, J. P. Yasomanee and
A. V. Demchenko, 6-O-Picolinyl and 6-O-picoloyl building
blocks as glycosyl donors with switchable stereoselectivity,
Org. Lett., 2015, 17, 4448–4451.
46 D. Steinborn and H. Junicke, Carbohydrate complexes of 60 J. P. Yasomanee, A. R. Parameswar, P. Pornsuriyasak,
platinum-group metals, Chem. Rev., 2000, 100, 4283–4317.
47 A. C. Comely, R. Eelkema, A. J. Minnaard and B. L. Feringa,
De novo asymmetric bio- and chemocatalytic synthesis of
N. P. Rath and A. V. Demchenko, 2,3-Di-O-picolinyl build-
ing blocks as glycosyl donors with switchable stereo-
selectivity, Org. Biomol. Chem., 2016, 14, 3159–3169.
saccharides-stereoselective formal O-glycoside bond for- 61 M. Grube, B.-Y. Lee, M. Garg, D. Michel, I. Vilotijević,
mation using palladium catalysis, J. Am. Chem. Soc., 2003,
125, 8714–8715.
A. Malik, P. H. Seeberger and D. Varón Silva, Synthesis of
Galactosylated Glycosylphosphatidylinositol Derivatives
from Trypanosoma brucei, Chem. – Eur. J., 2018, 24, 3271–
3282.
48 R. S. Babu, M. Zhou and G. A. O’Doherty, De novo synthesis
of oligosaccharides using a palladium-catalyzed glycosyla-
tion reaction, J. Am. Chem. Soc., 2004, 126, 3428–3429.
49 C. Vetter, C. Wagner, J. Schmidt and D. Steinborn,
Synthesis and characterization of platinum(IV) complexes
62 S. C. Ranade, S. Kaeothip and A. V. Demchenko, Glycosyl
alkoxythioimidates as complementary building blocks for
chemical glycosylation, Org. Lett., 2010, 12, 5628–5631.
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 2044–2054 | 2053

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63 T. Mukaiyama, K. Takeuchi, H. Jona, H. Maeshima and 77 D. Sail and P. Kovac, Benzoylated ethyl 1-thioglycosides:
T. Saitoh, A catalytic and stereoselective glycosylation with
direct preparation from per-O-benzoylated sugars,
β-glycosyl fluorides, Helv. Chim. Acta, 2000, 83, 1901–1918.
Carbohydr. Res., 2012, 357, 47–52.
64 R. Hua, H. Takeda, S.-Y. Onozawa, Y. Abe and M. Tanaka, 78 B. A. Garcia and D. Y. Gin, Dehydrative glycosylation with
Nickel-catalyzed thioallylation of alkynes with allyl phenyl
sulfides, Org. Lett., 2007, 9, 263–266.
65 J. F. Hooper, A. B. Chaplin, C. González-Rodríguez,
activated diphenyl sulfonium reagents. Scope, mode of
C(1)-hemiacetal activation, and detection of reactive glyco-
syl intermediates, J. Am. Chem. Soc., 2000, 122, 4269–4279.
A. L. Thompson, A. S. Weller and M. C. Willis, Aryl methyl 79 F. Andersson, P. Fugedi, P. J. Garegg and M. Nashed,
sulfides as substrates for rhodium-catalyzed alkyne car-
bothiolation: arene functionalization with activating
group recycling, J. Am. Chem. Soc., 2012, 134, 2906–
2909.
Synthesis of 1,2-cis-linked glycosides using dimethyl(methyl-
thio)sulfonium triflate as promoter and thioglycosides as
glycosyl donors, Tetrahedron Lett., 1986, 27, 3919–3922.
80 S. K. Veleti, J. J. Lindenberger, S. Thanna, D. R. Ronning
and S. J. Sucheck, Synthesis of a Poly-hydroxypyrolidine-
Based inhibitor of Mycobacterium tuberculosis GlgE,
J. Org. Chem., 2014, 79, 9444–9450.
66 J. Wang, S. Zhang, C. Xu, L. Wojtas, N. G. Akhmedov,
H. Chen and X. Shi, Highly Efficient and Stereoselective
Thioallylation of Alkynes: Possible Gold Redox Catalysis
with No Need for a Strong Oxidant, Angew. Chem., 2018, 81 K. Agoston, L. Kroeger, G. Dekany and J. Thiem, On Resin
130, 6915–6920.
67 A. Stévenin, F.-D. Boyer and J.-M. Beau, Regioselective
Modification of Monosaccharides, J. Carbohydr. Chem.,
2007, 26, 513–525.
Control in the Oxidative Cleavage of 4,6-O-Benzylidene 82 X. Huang, L. Huang, H. Wang and X. S. Ye, Iterative one-
Acetals of Glycopyranosides by Dimethyldioxirane, J. Org.
Chem., 2010, 75, 1783–1786.
pot synthesis of oligosaccharides, Angew. Chem., Int. Ed.,
2004, 43, 5221–5224.
68 S. Escopy, Y. Singh, K. J. Stine and A. V. Demchenko, A 83 H. D. Premathilake and A. V. Demchenko, 2-Allylphenyl gly-
Streamlined regenerative glycosylation reaction: direct,
acid-free activation of thioglycosides, Chem. – Eur. J., 2021,
27, 354–361.
cosides as complementary building blocks for oligosac-
charide and glycoconjugate synthesis, Beilstein J. Org.
Chem., 2012, 8, 597–605.
69 S. Chatterjee, S. Moon, F. Hentschel, K. Gilmore and 84 P. Wang, P. Haldar, Y. Wang and H. Hu, Simple glycosyla-
P. H. Seeberger, An Empirical Understanding of the
Glycosylation Reaction, J. Am. Chem. Soc., 2018, 140,
11942–11953.
tion reaction of allyl glycosides, J. Org. Chem., 2007, 72,
5870–5873.
85 Y. Wang, X. Liang and P. Wang, Concise synthesis of
Bacillus anthracis exosporium tetrasaccharide via two stage
activation of allyl glycosyl donor strategy, Tetrahedron Lett.,
2011, 52, 3912–3915.
70 H. M. Nguyen, Y. N. Chen, S. G. Duron and D. Y. Gin,
Sulfide-mediated dehydrative glycosylation, J. Am. Chem.
Soc., 2001, 123, 8766–8772.
71 C. Elie, R. Verduyn, C. Dreef, D. Brounts, G. van der Marel 86 A. V. Demchenko and C. De Meo, semi-Orthogonality of
and J. van Boom, Synthesis of 6-0-(α-D-mannopyranosyl)-D-
myo-inositol: a fragment from mycobacteria phospholipids,
Tetrahedron, 1990, 46, 8243–8254.
O-pentenyl and, S-ethyl glycosides: application for the oligo-
saccharide synthesis, Tetrahedron Lett., 2002, 43, 8819–8822.
87 D. Crich, En Route to the Transformation of Glycoscience: A
Chemist’s Perspective on Internal and External Crossroads
in Glycochemistry, J. Am. Chem. Soc., 2021, 143, 17–34.
88 I. P. Romm, A. A. Malkov, S. A. Lebedev, V. V. Levashova
and T. M. Buslaeva, The Electronic Spectra and Structure of
Palladium(II) Molecular Complexes and Clusters,
Russ. J. Phys. Chem. A, 2011, 85, 248–253.
89 L. S. Hegedus, N. Kambe, Y. Ishii and A. Mori, Palladium-
Catalyzed Dimerization of Alienes to 2.3-Bis(chloromethyl)
butadienes. Synthesis of Conjugate Exocyclic Dienes, J. Org.
Chem., 1985, 50, 2240–2243.
72 K. Ekelof and S. Oscarson, Synthesis of oligosaccharide
structures from the lipopolysaccharide of Moraxella catar-
rhalis, J. Org. Chem., 1996, 61, 7711–7718.
73 F. Mathew, K. Jayaprakash, B. Fraser-Reid, J. Mathew and
J. Scicinski, Microwave-assisted saccharide coupling with
n-pentenyl glycosyl donors, Tetrahedron Lett., 2003, 44,
9051–9054.
74 N. L. Douglas, S. V. Ley, U. Lucking and S. L. Warriner,
Tuning glycoside reactivity: new tool for efficient oligosac-
charides synthesis, J. Chem. Soc., Perkin Trans. 1, 1998, 51–
65.
75 Z. Zhang, I. R. Ollmann, X. S. Ye, R. Wischnat, T. Baasov
and C. H. Wong, Programmable one-pot oligosaccharide
synthesis, J. Am. Chem. Soc., 1999, 121, 734–753.
90 H. Paulsen, A. Richter, V. Sinnwell and W. Stenzel,
Darstellung selektiv blockierter 2-azido-2-desoxy-D-gluco-
und -D-galactopyranosylhalogenide: reaktivität und
13C-NMR-spektren, Carbohydr. Res., 1978, 64, 339–362.
76 M. D. Bandara, K. J. Stine and A. V. Demchenko, The 91 H. Jona, H. Mandai, W. Chavasiri, K. Takeuchi and
chemical synthesis of human milk oligosaccharides: lacto-
N-tetraose (Galβ1-3GlcNAcβ1-3Galβ1-4Glc), Carbohydr. Res.,
2019, 486, 107824.
T. Mukaiyama, Protic acid catalyzed stereoselective glycosy-
lation using glycosyl fluorides, Bull. Chem. Soc. Jpn., 2002,
75, 291–309.
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