How do Various Reaction Parameters Influence Anomeric Selectivity in Chemical Glycosylation with Thioglycosides and NIS/TfOH Activation?

Article abstract of DOI:10.1002/ejoc.202100260

The reaction of glycosyl donor phenyl 2,3,4,6-tetra-O-benzyl-1-thio-β-D-glucopyranoside with NIS/TfOH(cat.) was systematically studied under various reaction conditions. Neither the molecular sieve pore size nor amount of NIS activator was found to have a

Full text of DOI:10.1002/ejoc.202100260

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: How do various reaction parameters influence anomeric
selectivity in chemical glycosylation with thioglycosides and NIS/
TfOH activation?
Authors: Helle H. Trinderup, Sofie M. Andersen, Mads Heuckendorff,
and Henrik Helligsoe Jensen
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100260
Link to VoR: https://doi.org/10.1002/ejoc.202100260
01/2020

10.1002/ejoc.202100260
European Journal of Organic Chemistry
How do various reaction parameters influence anomeric
selectivity in chemical glycosylation with thioglycosides and
NIS/TfOH activation?
Helle H. Trinderup, Sofie M. Andersen, Mads Heuckendorff, Henrik H. Jensen*
Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark
hhj@chem.au.dk
Abstract:
The reaction of glycosyl donor phenyl 2,3,4,6-tetra-O-benzyl-1-thio--D-glucopyranoside with
NIS/TfOH(cat.) was systematically studied under various reaction conditions. Neither the
molecular sieve pore size nor amount of NIS activator was found to have an effect on the -ratio
in reaction with L-menthol as glycosyl acceptor. Increasing concentration and the amount of triflic
acid catalyst, however was found to increase the -selectivity in certain cases. Also, lowering
temperature was found to have a strong effect on the glycosylation outcome.
Keywords: Glycosylation, stereoselectivity, reaction parameters
Introduction:
The chemical glycosylation reaction involving an electrophilic glycosyl donor, a nucleophilic
glycosyl acceptor and a suitable promoter is the tool used almost exclusively to prepare the
glycosidic bond interlinking the monosaccharide units of oligosaccharides.1–3 Given the
importance of these molecules in Nature there is a good reason for attempting to understand the
underlying mechanism of this reaction and improving current methodology. One of the challenges
inherent to the chemical glycosylation reaction is the diastereoselectivity of the glycosylation
reaction itself. Since this involves the stereochemistry of the anomeric center it is typically referred
1
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10.1002/ejoc.202100260
European Journal of Organic Chemistry
to as anomeric selectivity. This issue has plagued4 chemists for a long time and therefore remains
to have the attention of specialists in the carbohydrate chemistry field. Different donor types
(thioglycoside, trichloroacetimidate, glycosyl halide, etc.) and glycosylation conditions may be
sensitive in varying degrees to perturbations of external parameters. Only a limited number of
publications describe how glycosylation selectivity’s change across a series of conditions for a
given donor-type and results are typically only presented as one number and not as an average
over multiple determinations making the level of sensitivity unclear.
Ishiwata and Ito invented a high through-put screening method for glycosylation optimization and
1
demonstrated vast solvent screening using H-NMR and MS with Bn-d7 protected deuterated
substrates with a SMe functionalized donor and MeOTf-activation.5
In a recent paper by Seeberger and co-workers in the Journal of the American Chemical Society,
the authors eloquently describe how different permanent and environmental conditions can
influence the anomeric selectivity of a glycosylation reaction.6 Their main focus was on the
temperature sensitivity, which could be controlled very precisely in their automated flow reactor.
Donors of three types (trichloroacetimidate, n-butyl phosphate and thioethyl) were studied as they
reacted with various electron-rich nucleophiles like EtOH or iPrOH and electron-poor nucleophiles
like difluoroethanol or trifluoroethanol.7
In another recent attempt to systematically investigate the intricate nature of the glycosylation
reaction, Codée and co-workers have elegantly obtained much insightful data that correlate the
nucleophilicity of glycosyl acceptors like EtOH and hexafluoroisopropanol to the anomeric
selectivity in glycosylation with e.g. 4,6-benzylidene protected glucosyl- and mannosyl donors.4
Also carbohydrate-based acceptors were investigated in this study, which throughout employed
SPh-functionalized donors and activation by the Ph2SO/Tf2O/TTBP promoter system.8
Much of the current insight into the glycosylation mechanism builds on and originates from highly
detailed studies by Crich and co-workers.9,10 Throughout the past two decades they have been
immensely productive with the study of especially 4,6-benzylidene directed β-mannosylation, but
also many other glycosylations. In general, restricting conformational flexibility can have a drastic
influence on the stereochemical glycosylation outcome as also recently reviewed by Galan and co-
workers.11
2
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European Journal of Organic Chemistry
Despite the latest results and level of understanding, it is our impression that much still needs to
be uncovered with regards to the fundamental reaction most chemist use to connect saccharide
building blocks. There still seems to be a great deal of speculation with respect to how different
reaction parameters influence anomeric selectivity and what causes the observed effects. It
occurred to us that it is not always trivial to obtain reaction outcomes with sufficient reproducibility
that can substantiate detailed speculation. The aim of the present study has been to learn if there
are any trends that can be exploited so a higher yield of a desired isomer can be obtained and the
overall synthetic efficiency increased as a result. We undertook this project well aware that a
general in-depth mechanistic understanding and stereochemical control may never be obtained
across all donor-types and acceptors, but additional studies could still bring previously covered
effects to the surface and allow for their exploitation once revealed.
This paper describes our efforts to further illuminate how D-glucosylations in batch reactions are
affected by all influential factors and this cannot necessarily be extrapolated to e.g. D-
galactosylations and D-mannosylations. These are activator/catalyst concentration, substrate
concentration, the presence of molecular sieves, solvent, and acceptor.
Our contribution is not meant to be a solution to the /-selectivity problem as we offer no new
insight on this topic, but rather to point out which parameters have an influence on anomeric
selectivity and with which magnitude the selectivity can change upon perturbations in reaction
conditions.
Results and discussion
We decided to study a specific glycosylation reaction more thoroughly and selected N-
iodosuccinimide (NIS) activation of phenyl thio-glucopyranoside 1 with TfOH (cat.).12 For the
early stages of the project, we chose L-menthol as a model acceptor nucleophile as it is a non-
hygroscopic, cheap, secondary alcohol and could be compared to previous studied done by our
group (Scheme 1).13–15 Although it is not carbohydrate-like the results may not be directly
applicable to e.g. disaccharide synthesis, but the goal of the project is to search for trends in
glycosylation selectivity rather than absolute values and later confirm trends with more relevant
acceptors. Compared to some other activation methods of thioglycosides, NIS/TfOH is
3
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10.1002/ejoc.202100260
European Journal of Organic Chemistry
operationally very simple and a typical mode of activation of one of the most employed glycosyl
donor types. It can be viewed as a catalytic mode of activation similar to that of e.g.
trichloroacetimidates that remains equi-acidic throughout the course of reaction. This is in contrast
to e.g. thioglycoside activation by e.g. BSP/Tf2O16 or Ph2SO/Tf2O8 promoted activation, where all
donor is converted into glycosyl triflate or other highly reactive electrophiles before the acceptor
nucleophile is added. The reaction is believed to go through an oxacarbenium ion intermediate
with some degree of participation of the triflate counterion either through covalent attachment or
as solvent separated/contact ion pairs.9 Although the temperature with which a glycosylation is
conducted is known to influence the anomeric selectivity, cryostats or microreactors6 are not
available to all research groups. From a practical point-of-view, it was therefore initially decided
to conduct the experiments in an insulated cold bath and let the reaction temperature climb from -
78 ⁰C (dry ice/acetone bath) to 0 ⁰C. This was found to reproducibly take 3.5 hours with the cold
bath constructed and used for this entire project (see supporting information). Later in the project,
also isothermally conducted experiments were performed.
Scheme 1. General glucosylation of L-menthol or other alcohols.
The first goal was to achieve comparable results over a triplicate of -selectivity determinations.
This issue was important in order to both build confidence to our results, but also allow us to see
whether the observed variations are 1) outliers, 2) part of a trend, or 3) whether they are just the
result of typical experimental uncertainty. Obtaining sufficient reproducibility with respect to both
1
yield (as determined by H-NMR using an internal standard) and especially -ratios (as
determined by 13C-NMR of the crude reaction mixture) initially proved quite challenging. We took
4
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10.1002/ejoc.202100260
European Journal of Organic Chemistry
this as an early indication of there being some parameters that had a significant effect on the
glycosylation selectivity under the used conditions.
After some practice and especially increasing the scale to ca. 300 mg of donor (ca. 0.5 mmol) we
started observing both reproducible yields and selectivity. We ascribe this to the fact that the
amount of neat TfOH (10 mol%) could be added more accurately at this scale. It is not an option
to make a stock solution of TfOH in CH2Cl2 as these are not fully miscible. The additional benefit
of performing the reaction on this scale is, that there is sufficient crude product material to easily
obtain a 13C-NMR spectrum with excellent signal-to-noise ratio, which was used for determining
the anomeric selectivity (Figure 1).17
The reactions were, as mentioned, performed in triplicates and conducted independently a number
of times by two chemists. The results are shown in Table 1 and demonstrate a high degree of
reproducibility. With respect to yield determination we estimate an uncertainty of ±5%-points. The
observed -selectivity is in accordance with a previous study, where we have reported a 1:3 -
ratio.13
-ratioa
1:2.4
1:2.0
1:2.4
1:2.4
1:2.6
1:2.6
1:2.3
1:2.5
1:2.4
1:2.5
1:2.4
1:2.5
Average -ratio
Entry Acceptor
Yieldb
91%
102%
99%
102%
101%
94%
97%
94%
85%
94%
89%
86%
1
2
3
4
5
1:2.4
6
7
8
9
10
11
12
Table 1. Results from glucosylation of L-menthol (1.5 equiv.) according to Scheme 1 in CH2Cl2 with NIS (1.1 equiv.) and TfOH (10 mol%) with
respect to the donor from -78 ⁰C to 0 ⁰C over 3.5 hours. aDetermined by 13C-NMR. bDetermined by 1H-NMR using benzyl benzoate as internal
standard.
5
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European Journal of Organic Chemistry
Figure 1. 13C-NMR spectrum of crude glycosylation mixture showing the signals from the anomeric carbon atoms (: 101.3 ppm,
: 99.2 ppm) in CD3CN of 4/.
Entry Acceptor
Yieldb
97%
94%
78%
-ratioa
8.1:1
Average -ratio
1
2
3
8.0:1
8.1:1
8.1:1
Table 2. Results from glucosylation of trifluoroethanol according to Scheme 1 in CH2Cl2 with NIS (1.1 equiv.) and TfOH (10 mol%) with respect
to the donor from -78 ⁰C to 0 ⁰C over 3.5 hours. aDetermined by 13C-NMR. bDetermined by 1H-NMR using benzyl benzoate as internal standard.
As an additional control experiment, we also included 2,2,2-trifluoroethanol as an acceptor as it is
both achiral and known to induce a high level of -selectivity in glycosylation reactions. Codée
and co-workers have reported  3:1 under Ph2SO/Tf2O/TTBP pre-activation conditions from
donor 1.18
After having established a satisfactory test system that returned high glycosylation yields and
reproducible anomeric selectivity values as seen in Table 1, we had enough confidence to continue
the project and look for trends that arise upon changes in conditions.
First, the influence of molecular sieves was investigated. Until this point all experiments had been
carried out in the presence of powdered molecular sieves (3 Å) as a drying agent. As Table 3 shows,
we were able to demonstrate there being no influence on anomeric selectivity as a function of
desiccant pore size or its presence.
6
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European Journal of Organic Chemistry
Entry
Mol. sieves
Yieldb
83%
-ratioa

Average 
1:2.4
1
2
3
4
5
6
7
none
3 Å
99%

1:2.4c
1:2.2
1:2.3
1:2.5
1:2.4
96%
86%
102%
95%
4 Å
1:2.3
5 Å
1:2.5
Table 3. Results from glucosylation of L-menthol according to Scheme 1 in CH2Cl2 with NIS (1.1 equiv.) with a varying nature of the drying
agent. Reactions were performed from -78 ⁰C to 0 ⁰C over 3.5 hours. aDetermined by 13C-NMR. bDetermined by 1H-NMR using benzyl benzoate
as internal standard. cFrom Table 1.
Next, the effect of concentration on anomeric selectivity was investigated in the present system.
Others have previously studied the concentration effect on anomeric selectivity in sialylations19
and mannosylations.20–22
Reactions had been conducted with a donor concentration of 50 mM. Slightly lower and higher
selectivities were found at more dilute (25 mM) and increased (100 mM) concentrations,
respectively. There seems to be a clear, although mild trend, which would be somewhat more
uncertain to call if fewer experiments had been performed (Table 4).
Entry
Concentrationa
Yieldc
100%
100%
99%
-ratiob
1:1.9
Average 
1
2
3
4
25 mM
1:1.9
1:1.9
1:2.0
50 mM
1:2.4d
1:3.5
5
6
7
1:3.6
1:3.5
1:3.5
99%
96%
98%
100 mM
7
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European Journal of Organic Chemistry
Table 4. Results from glucosylation of L-menthol according to Scheme 1 in CH2Cl2 with NIS (1.1 equiv.) at varying concentration of the donora
from -78 ⁰C to 0 ⁰C over 3.5 hours. bDetermined by 13C-NMR. cDetermined by 1H-NMR using benzyl benzoate as internal standard. dFrom Table
1.
Dichloromethane is recognized as a non-participating solvent for glycosylation, whereas ethers
like Et2O, THF or dioxane are known to induce a higher degree of axial glycoside product in
opposition to acetonitrile, which is known to induce formation of the equatorial product.23 As we
believe we here have established a reproducible protocol we were interested in testing to which
extent acetonitrile affected the stereochemical outcome. The glycosylation reaction was conducted
as previously shown in Table 1 with the adjustment of solvent medium to contain either 25 vol%
or 50 vol% acetonitrile. As reported many times, a higher degree of -selectivity was observed in
both cases. The level of -selectivity was furthermore found to increase with increasing
concentration of acetonitrile (Table 5). This was an expected trend and constitutes a non-
controversial observation, but shows in the case of this specific system the size of the effect in
going from neat CH2Cl2 (/: 29/71), to 25% CH3CN in CH2Cl2 (/: 13/87) and 50% CH3CN in
CH2Cl2 (/: 6/94). Had the experiments been carried out in a less precise and confident fashion
it might be reasonable to round of the selectivity values to /: 10/90 making 25% and 50%
CH3CN-values indistinguishable.
Entry
Solvent
Only CH2Cl2
Yieldb
-ratioa

Average 
1:2.4c
1
2
3
4
5
6
7
1:7.2
93%
98%
92%
99%
94%
97%
CH2Cl2/CH3CN
(3:1)
1:6.7
1:7.0
1:7.2
1:14.0
1:14.5
1:16.1
CH2Cl2/CH3CN
(1:1)
1:14.9
Table 5. Results from glucosylation of L-menthol according to Scheme 1 in various solvents with NIS (1.1 equiv.) and TfOH (10 mol%).
Reactions were performed from -78 ⁰C to 0 ⁰C over 3.5 hours. aDetermined by 13C-NMR. bDetermined by 1H-NMR using benzyl benzoate as
internal standard. cFrom Table 1.
8
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10.1002/ejoc.202100260
European Journal of Organic Chemistry
Next, the effect of the amount of NIS was investigated. We had noticed that this parameter often
varies between 1.1 equiv. to more than 2.5 equiv. in literature protocols. This could originate from
the necessity to obtain full conversion of donor and possibly be ascribed to the quality of the
iodonium-ion reagent. The NIS (98%+) used for this entire project, was obtained from a specific
supplier and known by us in previous projects to induce full conversion with just 1.1 equiv. as also
shown in Table 1.24 It was stored at 5 °C and used without further purification.
As indicated by the result shown in Table 6 there seems to be no influence on neither the yield nor
the anomeric selectivity upon increasing the excess of NIS. This could possibly be explained by it
being protonated NIS (or I+ -OTf) that is the real activator and not NIS itself, which depends on
the amount of TfOH instead.
Entry
NIS (equiv.)
1.1
Yieldb
-ratioa

Average 
1
2
3
4
5
6
7
1:2.4c
98%
100%
88%
95%
104%
94%

1:2.6
1:2.5
1:2.3
1:2.6
1:2.4
3.0
5.0
1:2.4
1:2.4
Table 6. Results from glucosylation of L-menthol according to Scheme 1 in CH2Cl2 with varying NIS and TfOH (10 mol%) with respect to the
donor from -78 ⁰C to 0 ⁰C over 3.5 hours. aDetermined by 13C-NMR. bDetermined by 1H-NMR using benzyl benzoate as internal standard. cFrom
Table 1.
Next, the influence of the amount of TfOH on the anomeric ratio was investigated. The results are
listed in Table 7 and indicate a significant increase in -selectivity as a function of increasing the
amount of TfOH using both L-menthol (from 10% to 30%) and galactose diacetone (2) (from 10%
to 20%). For acceptor 3 (4-OH) no effect was observed, which may be linked to the nearly
unselective glycosylation at 10% TfOH.
9
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-ratioa

Average 
Entry
1
Acceptor
TfOH
10 mol%
Yieldb
1:2.4d
2
102%
98%

1:4.0
1:3.3
1:5.2
1:5.2
1:5.6




1:4.3
1:4.3
1:4.2
1:4.2
1:4.4
1:1.5
1:1.5
1:1.5
1:1.3
1:1.1
1:1.1
1:1.6
1:1.4
1:1.4
20 mol%
30 mol%
10 mol%
1:3.7
1:5.3
1:3.3
3
4
95%
5
101%
98%
6
7
101%
97%
8
9
91%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
100%
109%
95%
20 mol%
30 mol%
10 mol%
20 mol%
30 mol%
1:4.2
1:4.3
1:1.5
1:1.2
1:1.5
94%
96%
97%
101%
80%c
84% c
87% c
76% c
73% c
54% c
88%c
102%c
75%c
OBn
O
HO
BnO
BnO
OMe
3
Table 7. Results from glucosylations of L-menthol and acceptors 2-3 according to Scheme 1 in CH2Cl2 with NIS (1.1 equiv.) and varying amount
of TfOH with respect to the donor from -78 ⁰C to 0 ⁰C over 3.5 hours. aDetermined by 13C-NMR. bDetermined by 1H-NMR using benzyl benzoate
as internal standard. cIsolated yields. dFrom Table 1.
10
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One explanation of the significant increase in -selectivity in the case of L-menthol and galactose
diacetone (2) could originate from the more forcing conditions and the fact that the experiments
were conducted under gradient warming. Reactions performed with e.g. 30 mol% TfOH were
found to initiate at a lower temperature as indicated by the development of colour due to the
formation of iodine, than those conducted with 10 mol% catalyst. This observation also correlates
with the higher level of -selectivity observed at higher concentrations (Table 4).
We have previously observed how the more reactive per-O-benzylether protected glucosyl donor
(1) gave an improved -selectivity over the less reactive per-O-p-chlorobenzyl protected analogue
under gradient warming. This was then also speculated to be a result of different activation
temperatures, which was supported by result from glycosylations carried out under isothermal
conditions (-10 °C), which were found to give the same level of selectivity.13
Under the assumption, that the -selectivity is a direct result of an SN2-type displacement of an
anomerically bound triflate an additional explanation could be given. Both the rate of
interconversion between - and -triflate and the position of equilibrium will be expected to be
altered by temperature.25 A higher reaction temperature would favour more of the -triflate in
equilibrium according to the principle of Le Châtelier and a faster equilibrium, which would result
in more -glycoside and an eroded selectivity in the present case, which is in accordance with the
findings. This effect would additionally be strengthened by the common ion effect, which would
increase the amount of covalently attached triflate over the SN1 path going through an
oxacarbenium ion/triflate ion pair.
It appears clear from the results of Table 7 that the effect of increasing the amount of TfOH does
not generally provide an improved selectivity. The reason for results of galactose diacetone (2)
being unaffected in going from 20 mol% to 30 mol% could be a result of the smaller percentage
increase (50%) than going from 10 mol% to 20 mol% (100%). One may also expect there to be a
maximum selectivity that can be reached with a given acceptor nucleophile, and that this was
obtained at around 1:4.2. The selectivity in glycosylation of 3 appears to be unaffected by changes
in the amount of TfOH. Again, this may be a result of the maximum level of selectivity, which, at
the limit (100 mol% TfOH) will be comparable to the result obtained through BSP/Tf2O or
11
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Ph2SO/Tf2O. In actual fact, Kim and Seeberger have reported an unselective reaction (α/β 1:1)
with BSP/Tf2O/TTBP activation.26
Until this point, all reactions had been performed using the same cooling bath with acetone/dry ice
starting at -78 °C. Once all reagents had been added, a set of tweezers were used to remove the
remaining lumps of dry ice and let the reaction mixture slowly warm until 0 °C over 3.5 hours.
This way, the reaction initiates once the cooling bath temperature reaches a certain point. This
modus operandi is frequently used in oligosaccharide synthesis to secure the lowest possible
reaction temperature, which could result in the best possible selectivity for the reaction in question.
It additionally makes it unnecessary to know a specific reaction temperature and to use a
potentially expensive cryostat capable of holding a fixed temperature. It is our firm impression
that the warming in our case occurs reproducibly as also indicated by the small degree of variation
across different experiments. The drawback with the procedure could be, however, that different
reaction parameters may change the temperature at which a certain reaction occurs, and that this
in turn may influence the stereochemical outcome.
The glycosylation reaction with varying amounts of TfOH was next tested under isothermal
conditions using a cryostat at -50 °C in order to separate the effect of the reaction temperature and
the amount of TfOH. This temperature was chosen since the development of colour from the
formation of iodine was observed at around this temperature with a TfOH load of 10 mol%, which
indicates that reaction is occurring. The results of Table 8 still show an increased selectivity for
the kinetic -product as a function of catalyst, albeit to a lesser extent than the data collected under
gradient warming conditions.
12
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Entry
TfOH
Yieldb
100%
97%
-ratioa



1:5.6
Average 
1
2
3
4
5
6
7
8
9
1:5.2
(1:2.4)c
10 mol%
101%
100%
100%
104%
103%
102%
105%
20 mol%
30 mol%
1:5.7
1:5.6
(1:3.7)c
1:5.6
1:6.1
1:6.3
1:6.3
(1:5.3)c
1:6.5
Table 8. Results from glucosylation of L-menthol according to Scheme 1 in CH2Cl2 with NIS (1.1 equiv.) and varying amount of TfOH with
respect to the donor at -50 ⁰C over 5 hours. aDetermined by 13C-NMR. bDetermined by 1H-NMR using benzyl benzoate as internal standard.
cConducted at -78 ⁰C to 0 ⁰C over 3.5 hours for comparison (Table 7).
To investigate the influence on glycosylation selectivity of performing the reaction at various
constant temperatures (isothermal) was next investigated (Table 9).
Entry
Temperature
-50 °C
Yieldb
-ratioa
Average 
1
2
3
4
5
6
7
8
9

1:5.2c
(1:2.4)d
98%
100%
92%
98%
99%
98%






-40 °C
-10 °C
1:3.1
1:1.3
Table 9. Results from glucosylation of L-menthol according to Scheme 1 in CH2Cl2 with NIS (1.1 equiv.) and TfOH (10 mol%) with respect to
the donor. aDetermined by 13C-NMR. bDetermined by 1H-NMR using benzyl benzoate as internal standard. cFrom Table 8. dConducted at -78 ⁰C
to 0 ⁰C over 3.5 hours for comparison (Table 1).
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The glycosylation selectivity with L-menthol as acceptor was found to depend strongly on the
temperature and much more so than on the amount of TfOH catalyst. Temperature being a major
parameter in influencing anomeric outcome is in accordance with observations by Seeberger and
co-workers.6 Although gradient warming is convenient this shows that a vastly improved
selectivity can be obtained through temperature control.
We have previously investigated whether pure menthyl -glucopyranoside 4 anomerizes under
the reaction conditions (NIS, 1.1 equiv; TfOH 10 mol%) by conducting a glycosylation with donor
1 and acceptor 2 under the standard conditions in its presence.13 For this project, a similar
experiment with 30 mol% TfOH was conducted with a similar result (Scheme 2). Since menthyl
-glucopyranoside (4) was not affected we conclude that all reported selectivity values are the
result of the glycosylation outcome and not influenced by post-glycosylation anomerization
towards the thermodynamic -product.
Scheme 2. Investigation of degree of product anomerization (see ref. 13).
We were next curious to investigate whether simultaneously changing two different reaction
parameters that each induce better -selectivity would further improve the selectivity for the
equatorial isomer. As shown in Table 10 both increasing the amount of TfOH from 10 mol% to
30 mol% and using CH2Cl2/acetonitrile 1:1 as reaction medium indeed afforded an even better
level of -selectivity although there is only a small actual difference between 1:14.9 and 1:19.7. A
careful optimisation with regards to reaction temperature may increase the selectivity even further,
but this was not investigated.
14
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European Journal of Organic Chemistry
Entry
1
Solvent (TfOH)
Yieldb
-ratioa
Average 
Only CH2Cl2
(10 mol%)
CH2Cl2/CH3CN
(1:1)
1:2.4c

2
3
1:14.9d
1:5.3e
[10 mol%]
Only CH2Cl2
[30 mol%]
CH2Cl2/CH3CN
(1:1)
4
5
6
1:18.1
1:18.2
1:22.8
93%
91%
91%
1:19.7
[30 mol%]
Table 10. Results from glucosylation of L-menthol according to Scheme 1 in various solvents with NIS (1.1 equiv.) and TfOH (10 mol%).
Reactions were performed from -78 ⁰C to 0 ⁰C over 3.5 hours. aDetermined by 13C-NMR. bDetermined by 1H-NMR using benzyl benzoate as
internal standard. cFrom Table 1. dFrom Table 10. eFrom Table 8.
Conclusion
Chemical glycosylation will remain a reaction with great practical importance as it can supply
glycobiologists with homogeneous samples for biological evaluation. Its synthetic efficiency is
intimately linked to the control of the stereochemical outcome of the glycoside forming reaction
and it is widely accepted that each glycosylation reaction is a new challenge.27 We have
systematically investigated one of the most typical glycosyl donor types and their activation with
the NIS/TfOH promoter system and learned that obtaining reproducible selectivity results is not
trivial, which should be kept in mind in cases where detailed speculation is given.
The amount of NIS or the molecular sieve pore size were found not to influence glycosylation
selectivity with L-menthol whereas concentration was found to have some degree of influence.
Our selectivity determinations, however, clearly show how various nucleophiles (glycosyl
acceptors) have different degrees of sensitivity to temperature and TfOH loading. This sensitivity
was found to be highest for galactose diacetone (2) and especially L-menthol, while secondary
alcohol 3 was insensitive.
15
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10.1002/ejoc.202100260
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With our setup and triplicate measurements, we furthermore were able to establish to which degree
accurate temperature control can increase selectively compared to reactions conducted under
gradient warming conditions.
From a practical point-of-view we believe the NIS/TfOH (cat.)-method has a lot to offer, even
with the more convenient gradient warming approach used here. In this paper we showed how the
-selectivity can be pushed from 1:2.4 to 1:19.7 by combining the effects of a higher catalyst load
and the presence of acetonitrile as co-solvent.
Despite the influence of intrinsic parameters such as glycosyl acceptor structure, using the ideas
and thoroughness presented here a lot can be learned about how external parameters can be
manipulated in order to increase anomeric selectivity. Although the task may seem immense since
other donors varying in both protecting group pattern and stereochemistry undoubtedly will behave
differently, valuable insight can certainly be gained.
Experimentals
General Remarks. All reagents were used as purchased without further purification. High purity
NIS was bought from Chempur (004499, N-iodosuccinimide/98%+). TfOH was bought from
Sigma-Aldrich (158534, reagent grade/98%+). Dry solvents were taken from a solvent purification
system. Glassware used for water-free reactions were dried for 12 h at 120 °C or flame dried before
use. Molecular sieves were bought from Fluka (3Å, 95664, powder) and activated. Columns were
packed with silica gel 60 (230−400 mesh) as the stationary phase. TLC plates were visualized by
cerium (IV) sulphate/ammonium molybdate in 10% aq. sulphuric acid and heating until spots
1
13
appeared. H NMR and C NMR spectra were recorded on the same 400 MHz spectrometer.
Chemical shifts (δ) are reported in ppm relative to the residual solvent signal (CDCl3 or CD3CN).
High-resolution mass spectral (HRMS) data were obtained on an electrospray (ES) mass
spectrometer analyzing time-of-flight. NMR assignments were based on DEPT-135, COSY and
HSQC NMR experiments.
Phenyl 2,3,4,5-tetra-O-acetyl-1-thio-β-D-glucopyranoside (S1)
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β-D-Glucose pentaacetate (19.865 g, 0.051 mol) was dissolved in anhydrous CH2Cl2 (100 mL)
and cooled to 0 °C. Thiophenol (10.5 mL, 0.102 mol, 2 eq.) and BF3ꞏOEt2 (19.0 mL, 0.154 mol, 3
eq.) was added and the reaction mixture was stirred at rt for 22 h. Sat. aq. NaHCO3 was added and
the water phase was extracted with CH2Cl2. The combined organic phases were washed with brine,
dried over MgSO4, filtered and concentrated in vacuo. Upon addition of Et2O product precipitated
immediately as a white solid. The crude product was used without further purification.
Rf (EtOAc/Pentane 2:1) 0.57, HRMS (ES) calcd. for C21H30NO8S+ m/z 458.1479, found m/z
458.1498.
Phenyl 2,3,4,5-O-benzyl-1-thio-β-D-glucopyranoside (1)
Crude S1 was dissolved in MeOH (500 mL). Sodium methoxide was added until pH 10. The
reaction mixture was stirred overnight at rt, neutralized with amberlite IR120, filtered and
concentrated in vacuo. The crude mixture was dissolved in anhydrous DMF (150 mL) under a N2
atmosphere and cooled to 0 °C. Benzylbromide (36.3 mL, 0.305 mol, 6 eq.) was added followed
by sodium hydroxide (60 % in mineral oil) (16.31 g, 0.408 mol, 8 eq.). The reaction mixture was
stirred at rt overnight and quenched with MeOH and H2O. The aqueous phase was extracted with
EtOAc. The combined organic phases were washed with H2O. The crude product was partly
purified by flash column chromatography (EtOAc/Pentane 1:10  EtOAc/Pentane 1:1).
Impurities were crystallized from Et2Oand filtered off. 1 was crystallized from CH2Cl2/Pentane as
white needles (28.828 g, 0.046 mol, 90% over 3 steps).
Rf (EtOAc/Pentane 1:10) 0.31, [α]D298K + 1.8 (c 1.0, CHCl3) lit. + 328, Mp (uncorr.) 92.0-93.4 °C
(CH2Cl2/Pentane) lit. 91-92 °C.1
1H-NMR (400 MHz, CDCl3) δH 7.64-7.58 (m, 2H, ArH), 7.45-7.20 (m, 23H, ArH), 4.96-4.83 (m,
2H, CHHPh), 4.76 (d, 1H, J 12 Hz, CHHPh), 4,70 (d, 1H, J 8 Hz, H1), 4.67-4.54 (m, 3H, CHHPh),
3.85-3.64 (m, 4H, H6, H4, H3), 3.58-3.50 (m, 2H, H2, H5). 13C-NMR (101 MHz, CDCl3) δC 138.5,
138.4, 138.1, 133.9 (Ar), 132.1-127.6 (ArH), 87.6 (C1), 86.9 (C3), 80.9 (C2), 79.2 (C5), 77.9 (C4),
76.0 (CH2Ph), 75.6 (CH2Ph), 75.2 (CH2Ph), 73.5 (CH2Ph), 69.1 (C6). HRMS (ESI) calcd. for
C41H46NO4S+ m/z 650.2953, found m/z 650.2956. Spectral values were in accordance with
literature.13
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Methyl 2,3-di-O-benzyl-4,6-O-benzylidene-α-D-glucopyranoside (S2)
Methyl α-D-glucopyranoside (19.982 g, 0.103 mol) was dissolved in dry DMF (120 mL) under a
N2 atmosphere. Benzaldehyde dimethylacetal (27 mL, 0.185 mol, 1.8 eq.) and (+)-10-camphor
sulfonic acid (2.401 g, 0.103 mol, 0.1 eq.) was added to the solution and the reaction was stirred
at 50 °C for 3.5 h. The reaction mixture was cooled to rt and anhydrous DMF (350 mL) was added.
Benzyl bromide (36.8 mL, 0.309 mol, 3 eq.) and sodium hydride (60 % in mineral oil) (14.832 g,
0.618 mol, 6 eq.) was added to the reaction mixture and stirred at rt overnight. The reaction was
diluted with EtOAc and quenched with MeOH and H2O. The water phase was extracted with
EtOAc. The combined organic phases were washed with water and brine, dried over MgSO4,
filtered and concentrated. The product was partly purified by flash column chromatography
(EtOAc/Pentane 1:9  1:6) to give S2 as white crystals (24.023 g, 45.61 mmol, 51%). The impure
fractions were recrystallized from CH2Cl2/pentane to give an overall yield of 59% (28.006 g, 53.18
mmol).
298K
Rf (Pentane/EtOAc 9:1) 0.30, [α]D
-27.8 (c 1.0, CHCl3) lit. -31.529, Mp 82.9-84.3 °C
(CH2Cl2/Pentane), lit. 93 °C.29
1H-NMR (400 MHz, CDCl3) δH 7.45-7.33 (m, 2H, ArH), 7.32-7.10 (m, 14H, ArH), 5.44 (s, 1H,
OCHO), 4.81 (d, Jgem 11.4 Hz, 1H, CHHPh), 4.75 (d, Jgem 12.2 Hz, 1H, CHHPh), 4.73 (d, Jgem
11.4 Hz, 1H, CHHPh), 4.59 (d, Jgem 12.2 Hz, 1H, CHHPh), 4.48 (d, J1,2 3.6 Hz, 1H, H1), 4.16 (dd,
J6a,6b 10.4 Hz, J6a,5 4.8 Hz, 1H, H6a) 3.94 (t, J3,2/4 9.2 Hz, 1H, H3), 3.72 (td, J5,4/6b 10.0 Hz, 1H,
H5), 3.60 ( app. t, 1H, H6) 3.49 (t, 1H, H4), 3.45 (dd, 1H, H2), 3.29 (s, 3H, OCH3). 13C-NMR (101
MHz, CDCl3) δC 138.8, 138.2, 137.5 (CAr), 129.0-126.1 (CHAr), 101.3 (OCHO), 99.3 (C1), 82.2
(C4), 79.2 (C2), 78.7 (C3), 75.5 (CH2Ph), 73.9 (CH2Ph) 69.1 (C6), 62.4 (C5), 55.5 (CH3). HRMS
(ESI) calcd. for C28H30O6H+ m/z 463.2115, found m/z 463.2133. Spectral values were in
accordance with literature.29
Methyl 2,3,6-tri-O-benzyl-α-D-glucopyranoside (3)
S2 (12.641 g, 27.3 mmol) was dissolved in dry CH2Cl2 under a N2 atmosphere. Triethylsilane (22.0
mL, 0.138 mol, 5 eq.) was added and the reaction mixture was cooled to 0 °C. Trifluoroacetic acid
(10.5 mL, 0.138 mol, 5 eq.) was added. The reaction mixture was stirred at rt for 16 h.
Triethylsilane (4.4 mL, 27.5 mmol, 1 eq.) and trifluoroacetic acid (2.1 mL, 27.4 mmol, 1 eq.) was
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10.1002/ejoc.202100260
European Journal of Organic Chemistry
added and the reaction mixture was stirred for 0.5 h. NaHCO3 was added and the reaction mixture
was diluted with CH2Cl2. The organic phase was washed with NaHCO3 and brine, dried over
MgSO4, filtered and concentrated. The product was purified by flash column chromatography
(Pentane/EtOAc, 4:1  3:1) to give 3 as a colorless oil (8.552 g, 18.411 mmol, 67 %).
Rf (Pentane/EtOAc, 3:1) 0.26, [α]D298K +16.2 (c 1.0, CHCl3) lit. 12.5.29
1H-NMR (400 MHz, CDCl3) δH 7.56-7.22 (m, 15H, ArH), 5.05 (d, Jgem 11.6 Hz, 1H, CHHPh),
4.81 (d, Jgem 12.0 Hz, 1H, CHHPh), 4.78 (d, Jgem11.6 Hz, 1H, CHHPh), 4.74-4.66 (2x d, Jgem
12.0 Hz, J1,2 3.6 Hz, 2H, CHHPh, H1), 4.63 (d, Jgem 12.2 Hz, 1H, CHHPh), 4.58 (d, Jgem 12.2 Hz,
1H, CHHPh), 3.83 (t, J3,2/4 8.8 Hz, 1H, H3), 3.78-3.61 (m, 4H, H4, H5, H6b, H6a), 3.58 (dd, J2,3
9.6 Hz, 2H, H2), 3.43 (s, 3H, OCH3). 13C-NMR (101 MHz, CDCl3) δC 138.9, 138.1, 138.1 (CAr),
128.7-127.7 (CHAr), 98.3 (C1), 81.5 (C3), 79.6 (C2), 75.5 (CH2Ph), 73.6 (CH2Ph), 73.2 (CH2Ph),
+
70.7 (C4/C5), 69.9 (C4/C5), 69.5 (C6), 55.3 (CH3). HRMS (ESI) calcd. for C28H32O6NH4 m/z
482.2537, found m/z 482.2558. Spectral values were in accordance with literature.29
Standard glycosylation protocol:
Donor (1 eq. (ca. 300 mg, 0.5 mmol)), acceptor (1.5 equiv.), benzylbenzoate (0.5 equiv.) and
freshly activated molecular sieves (3 Å, 50 mg/mL solvent) was added to a special designed screw-
top vial and dissolved in anhydrous CH2Cl2 (donor conc. 0.05 M) under an Ar atmosphere. The
reaction mixture was stirred for 1 h at rt and then cooled to -78 °C for 15 min in a dry ice/acetone
bath. NIS (1.1 equiv.) and TfOH (0.10 equiv.) were added at -78 °C. TfOH was added using 10
µL Hamilton syringe by inserting the tip of the syringe into the solution to ensure full addition of
the acid. The reaction was allowed to heat to 0 °C at which Et3N was added (ca. 0.1 mL) until a
color change to orange was observed. The mixture was filtered, washed with 10% aq. Na2S2O3,
dried over MgSO4, filtered and concentrated in vacuo. The crude reaction product was analyzed
by 13C-NMR and 1H-NMR.
L-menthyl 2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranoside (4α/β)
4α: Appearance: Colorless oil. Rf (Pentane/EtOAc 10:1) 0.43. [α]D300K +33.2 (c 1.0, CHCl3), lit.
+31 (c 1.0, CHCl3)13. 1H-NMR (400 MHz, CDCl3) δH 7.44-7.02 (m, 20H, CHAr), 5.02 (d, J1,2 3,6
Hz, 1H, H1), 4.98 (d, Jgem 10.8 Hz, 1H, CHHPh), 4.83 (2x d, Jgem 10.8 Hz, Jgem 10.8 Hz, 2H,
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CHHPh, CHHPh), 4.75-4.58 (m, 3H, CHHPh, CHHPh, CHHPh), 4.46 (2x d, Jgem 12.4 Hz, Jgem
10.8 Hz, 2H, CHHPh, CHHPh), 4.07-3.91 (m, 2H, H3, H5), 3.75 (dd, J6a,6b 10.8 Hz, J6a,5 4.0 Hz,
1H, H6a), 3.69-3.59 (m, 2H, H6b, H4), 3.55 (dd, J2,3 9.6 Hz, 1H, H2), 3.45-3.30 (m, 1H, OCH-
menthyl), 2.49-2.34 (m, 1H), 2.12 (m, 1H), 1.67-1.60 (m, 2H), 1.46-1.22 (m, 3H), 1.13-0.77 (m,
13H), 0.70 (d, J 6.8 Hz, 3H). 13C-NMR (101 MHz, CDCl3): δC 138.9-127.5 (CAr), 98.6 (C1), 82.0,
80.9, 80.5, 78.1, 77.2, 75.5, 75.1, 73.5, 73.2, 70.3, 68.6, 48.8, 43.1, 34.3, 31.8, 24.6, 22.9, 22.3,
+
21.1, 16.1. HRMS (ESI) calcd. for C44H54O6NH4 m/z 696.4259, found m/z 696.4286. Spectral
were in accordance with previously found values.13
4β: Appearance: White solid. Rf (Pentane/EtOAc 10:1) 0.57. [α]D300K -17.4 (c 1.0, CHCl3), lit. -16
(c 1.0, CHCl3)13. Mp (uncorr.) 79.0-80.5 °C, lit.76.5-78.8 °C.13 1H-NMR (400 MHz, CDCl3): δH
7.38 – 7.22 (m, 19H, CHAr), 7.22 – 7.16 (m, 1H, CHAr), 4.94 (2xd, Jgem 10.7 Hz, 2H, CHHPh,
CHHPh), 4.80 (2x d, Jgem 10.8 Hz, 2H, CHHPh, CHHPh), 4.68 (d, Jgem 10.8 Hz, 1H, CHHPh),
4.64 – 4.50 (m, 3H, CHHPh, CH2Ph), 4.47 (d, J1,2 7.8 Hz, 1H, 1H), 3.69 (d, J 3.2 Hz, 2H, H6ab),
3.67-3.55 (m, 2H, H3, H4), 3.50 (td, Jvic 10.6 Hz, Jvic 4.2 Hz, 1H, OCH-menthyl), 3.45–3.36 (m,
2H, H2, H5), 2.42-2.27 (m, 1H), 2.19 – 2.07 (m, 1H), 1.66 (m, 2H), 1.42-1.20 (m, 2H), 1.08 – 0.86
(m, 9H), 0.82 (d, J 6.8 Hz, 3H). 13C-NMR (101 MHz, CDCl3): δC 138.9-127.7 (CAr), 100.9 (C1),
85.1, 82.3, 78.1, 77.9, 75.8, 75.2, 75.0, 74.9, 73.8, 69.4, 48.2, 41.1, 34.6, 31.6, 31.1, 25.4, 23.3,
+
22.4, 21.2, 16.1. HRMS (ESI) calcd. for C44H54O6NH4 m/z 696.4259, found m/z 696.4287.
Spectral values were in accordance with previously found values.13
2,2,2,-Trifluoroethyl 2,3,4,6-tetra-O-benzyl-/-D-glucopyranoside (5α/β)
α/β: 8:1. 1H NMR (400 MHz, CDCl3) δH 7.37-7.15 (m, 152H, CHAr), 7.14-7.04 (m, 18H, CHAr),
4.94 (d, Jgem 10.8 Hz, 8H, CHHPhα), 4.90 (d, Jgem 11.0 Hz, 1H, CHHPhβ), 4.89 (d, Jgem 10.7 Hz,
1H, CHHPhβ), 4.82-4.71 (m, 32H), 4.64 (d, Jgem 10.8 Hz, 1H, CHHPhβ), 4.61-4.37 (m, 28H),
4.23-4.11 (m, 1H), 3.95 (t, J 9.3 Hz, 8H, α), 3.89-3.77 (m, 15H), 3.75-3.51 (m, 42H), 3.50-3.38
13
(m, 2H). C NMR (101 MHz, CDCl3) δC 138.8-134.6 (CAr), 129.9-119.7 (CHAr), 103.7 (C1β),
97.9 (C1α), 84.4, 81.8, 81.7, 79.7, 77.3, 75.9, 75.3, 75.2, 75.1, 73.6, 71.0, 68.6, 68.2, 66.3, 66.0,
+
64.8 (q, 1C, 2JC,F 35 Hz, CH2CF3α). HRMS (ESI) calcd. for C36H37F3O6NH4 m/z 640.2880, found
m/z 640.2910. Spectral values were in accordance with previously found values.30
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2,3,4,6-Tetra-O-benzyl-α/β-D-glucopyranosyl-(16)-[1,2:3,4]-di-O-isopropylidene-α-D-
galactopyranose (6α/β)
α/β: 1.1:1. 1H NMR (500 MHz, CDCl3) δH 7.42-7.39 (m, 2H, CHAr), 7.36-7.21 (m, 34H, CHAr),
7.14-7.10 (m, 4H, CHAr), 5.55 (d, J1,2 5.0 Hz, 1H, H1β), 5.50 (d, J1,2 5.0 Hz, 1H, H1α), 5.04 (d,
Jgem 11.2 Hz, 1H, CHHPhβ), 4.98 (d, J1’,2’ 3.6 Hz, 1H, H1’α), 4.96 (d, Jgem 11.0 Hz, 1H, CHHPhα),
4.94 (d, Jgem 11.1 Hz, 1H, CHHPhβ), 4.82-4.65 (m, 8H, 2x CH2Phα, CHHPhβ, 2x CHHPhβ), 4.62-
4.56 (m, 4H, CHHPhα, CHHPhβ, H4α, H4β), 4.51 (d, Jgem 12.5 Hz, 1H, CHHPhβ), 4.49 (d, Jgem
11.2 Hz, 1H, CHHPhβ), 4.47 (d, Jgem 10.9 Hz, 1H, CHHPhα), 4.45 (d, Jgem 12.2 Hz, 1H, CHHPhα),
4.44 (d, J1’,2’ 7.8 Hz, 1H, H1’β), 4.34 (dd, J3,2 7.9 Hz, J3,4 2.0 Hz, 1H, H3α), 4.31-4.28 (m, 2H,
H2α, H2β), 4.23 (dd, J3,2 7.9 Hz, J3,4 1.9 Hz, 1H, H3β), 4.15 (dd, J6a,6b 10.7 Hz, J6a,5 3.7 Hz, 1H,
H6aβ), 4.08 (ddd, J5’,4’ 7.3 Hz, J5’,6a’ 3.5 Hz, J5’,6b’ 1.7 Hz, 1H, H5’β), 4.05-4.00 (m, 1H, H5’α),
3.97 (t, J3’,4’/2’ 9.4 Hz, 1H, H3’α), 3.83-3.54 (m, 12H, H2’α, H3’β, H4’α, H5α, H5β, H6α, H6’α,
H6bβ, H6’β), 3.48-3.40 (m, 2H, H2’β, H4’β), 1.52 (s, 3H, CH3α), 1.49 (s, 3H, CH3β), 1.44 (s, 6H,
CH3α, CH3β), 1.32-1.28 (4x s, 12H, 2x CH3α, 2x CH3β). 13C NMR (101 MHz, CDCl3) δC 138.8-
138.1 (CAr), 128.8-127.6 (CHAr), 109.5 (β-OCO-), 109.3 (α-OCO-), 108.7 (α-OCO-), 108.7 (β-
OCO-), 104.5 (C1’β), 97.2 (C1’α), 96.5 (C1β), 96.4 (C1α), 84.7 (H3’β), 82.1 (H3’α), 81.8 (H2’β),
79.9 (H2’α), 77.9 (H5β), 77.7, 75.8, 75.8, 75.1, 74.9 (C4’β), 74.5, 73.6, 73.6, 72.5, 71.6, 70.9,
70.9, 70.8, 70.8, 70.6, 70.4, 69.8 (C6β), 68.9 (C6’β), 68.5 (C6α/C6’α), 67.5 (C5’β), 66.3
(C6α/C6’α), 65.8 (H5’α), 26.3 (CH3α), 26.2 (CH3α), 26.2 (CH3β), 26.1 (CH3β), 25.2 (CH3β), 25.1
(CH3α), 24.8 (CH3α), 24.6 (CH3β). HRMS (ESI) calcd. for C46H54O11Na+ m/z 805.3558, found
m/z 805.3558. Spectral values were in accordance with previously found values.13
Methyl
2,3,6-tri-O-benzyl-4-O-(2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranosyl)-α-D-
glucopyranoside (7/)
1
α/β 1:1.4. H NMR (400 MHz, CDCl3) δH 7.53-7.02 (m, 93H, CHAr), 5.73 (d, J1’,2’ 3.6 Hz, 1H,
H1’α), 5.12 (d, Jgem 11.2 Hz, 1H), 5.07 (d, J 11.6 Hz, 1H), 4.94-4.86 (m, 3H), 4.86-4.70 (m, 12H),
4.66-4.50 (m, 13H), 4.50-4.38 (m, 6H), 4.29 (d, J 12.4 Hz, 1H), 4.17-4.04 (m, 3H), 4.03-3.81 (m,
13
8H), 3.79-3.45 (m, 17H), 3.45-3.29 (m, 10H, 2x CH3). C NMR (101 MHz, CDCl3) δC 139.6-
134.5 (CAr), 129.8-126.8 (CHAr), 102.6 (C1’β), 98.5 (C1β), 97.8 (C1α), 96.7 (C1’α), 84.9, 82.9,
21
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European Journal of Organic Chemistry
82.1, 80.5, 80.2, 79.5, 78.8, 77.7, 77.4, 76.7, 75.7, 75.6, 75.5, 75.2, 75.0, 75.0, 74.9, 74.5, 73.7,
73.5, 73.4, 73.3, 73.2, 72.2, 71.0, 70.0, 69.5, 69.0, 68.1, 67.9, 55.4, 55.2, 53.5, 29.8. Spectral
values were in accordance with previously found values.13
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Table of Content:
Achieving the highest possible selectivity in a glycosylation where both the - and -anomer are
potential isomeric products is a central challenge in oligosaccharide synthesis. Our practically
angled manuscript describes which parameters have (and don’t have) an influence on the anomeric
outcome and with which magnitude the selectivity varies as a function of changing reaction
parameters.
24
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