Synthesis of β-Glucosides with 3-O-Picoloyl-Protected Glycosyl Donors in the Presence of Excess Triflic Acid: Defining the Scope

Article abstract of DOI:10.1002/chem.201905278

Excellent β-stereoselectivity for the glycosylation with glucosyl donors equipped with the 3-O-picoloyl (Pico) group, without the use of participating group, was achieved in the presence of NIS/excess TfOH promoter system. A complete investigation of the scope of this reaction was performed, revealing all important attributes of successful glycosylation. While altering the halogen source was tolerated, substitution of the triflate anion resulted in complete loss of stereoselectivity. Protonation of the Pico group was determined to be crucial in this reaction. The stability or extent of the protonated pyridine ring was also found to be another important key factor in obtaining high stereoselectivity. The nucleophilicity of the acceptor was found to be proportional to the stereoselectivity obtained, suggesting an S_N2-like mechanism.

Full text of DOI:10.1002/chem.201905278

A Journal of
Accepted Article
Title: Synthesis of β-glucosides with 3-O-picoloyl-protected glycosyl
donors in the presence of excess triflic acid: defining the scope
Authors: Michael Mannino and Alexei V. Demchenko
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: Chem. Eur. J. 10.1002/chem.201905278
Link to VoR: http://dx.doi.org/10.1002/chem.201905278
Supported by

10.1002/chem.201905278
Chemistry - A European Journal
Synthesis of β-glucosides with 3-O-picoloyl-protected glycosyl donors in the presence of
excess triflic acid: defining the scope
Michael P. Mannino and Alexei V. Demchenko*
Department of Chemistry and Biochemistry, University of Missouri – St. Louis
One University Boulevard, St. Louis, Missouri 63121, USA
e-mail: demchenkoa@umsl.edu
Abstract: Excellent β-stereoselectivity for the glycosylation with 3-Pico glucosyl donors, without
the use of participating group, was achieved in the presence of NIS/ excess TfOH promoter system.
A complete investigation of the scope of this reaction was performed, revealing all important
attributes of successful glycosylation. While altering the halogen source was tolerated, substitution
of the triflate anion resulted in complete loss of stereoselectivity. Protonation of the Pico group
was determined to be crucial in this reaction. The stability or extent of the protonated pyridine ring
was also found to be another important key factor in obtaining high stereoselectivity. The
nucleophilicity of the acceptor was found to be proportional to the stereoselectivity obtained,
suggesting an SN2-like mechanism.
Keywords: glycosylation, synthesis, oligosaccharides, stereoselectivity, mechanism
1
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
Introduction
Chemical O-glycosylation is arguably the most important and challenging reaction in
glycochemistry.[1] This reaction connects the hydroxyl group of the glycosyl acceptor to the
anomeric carbon of the glycosyl donor through the formation of a glycosidic bond. One of the
biggest difficulties this reaction faces is controlling the stereoselectivity of this new bond
formation. Many glycosylation reactions have been developed, among which methods and
strategies that provide reliable stereocontrol are highly desirable, and have been the focus of many
research efforts in the field.[2] One such method is the Hydrogen-bond-mediated Aglycone
Delivery (HAD) reaction was introduced by our lab.[3] In accordance with this reaction, the
glycosyl donor is functionalized with a hydrogen bond accepting protecting group such as picoloyl
ester (Pico) at a remote position of the sugar (C-3, 4 or 6). The Pico group forms a hydrogen bond
with the free hydroxyl of the glycosyl acceptor, resulting in the formation of a hydrogen-bonded
complex. The orientation of this complex determines the stereoselectivity afforded as the acceptor
is “delivered” to the anomeric carbon in a syn-fashion with respect to the Pico group. In a majority
of applications, the HAD reaction provided excellent stereocontrol and yields.[3]
In the previous article in this issue, we reported excellent β-stereoselectivity obtained
without the assistance of a neighboring participating group. Instead, those glycosylations were
performed with 3-O-picoloyl (Pico) functionalized glucosyl donor. Although the β-
stereoselectivity would be expected via the HAD pathway, the reaction conditions that we have
developed made us doubt whether the excellent stereoselectivity achieved was actually due to the
HAD pathway. In this method, the donors are activated using the N-iodosuccinimide (NIS) and
triflic acid (TfOH) promoter system. Although typically employed in catalytic amounts, we
developed reaction conditions wherein TfOH was used in excess to NIS. The presence of the
2
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
excess protic acid suggests that the HAD pathway, by which Pico-protected donors are known to
perform,[4] is not active in the presence of excess electrophilic species, as was demonstrated by
several labs.[3, 5] A preliminary mechanistic investigation of this reaction by NMR spectroscopy
revealed that the 3-Pico group is protonated in the presence of equimolar TfOH, as indicated by a
downfield shift in the aromatic Pico protons.[6] This was deemed to be a crucial step in this reaction.
Further NMR experiments performed with the entire promoter system consisting of both NIS and
TfOH showed the presence of an intermediate derived from the donor substrate with an anomeric
signal resonating at 6.9 ppm. The identity of this new species was hypothesized to be the glucosyl
triflate, which was the key intermediate en route to glycoside products.[6] With the general goal of
determining the scope of this new reaction and gaining further mechanistic insights, presented
herein is screening of various reaction conditions, studying other promoter systems, protecting
groups, and investigating the glycosyl donor and acceptor scope.
Results and Discussion
Through our investigation reported in the previous article in this issue,[6] it was discovered
that the stereoselective outcome of glycosylations is directly proportional to the amount of TfOH
added. Improvements were observed when TfOH was specifically used in excess to NIS. Taking
these reaction conditions as the benchmark, herein we present further investigation of this reaction.
Typical HAD reaction conditions applied to the glycosidation of donor 1[6] to acceptor 2[7] in 1,2-
DCE produced disaccharide 3 in an excellent yield of 90% albeit fairy low stereoselectivity α/β =
1/2.6 (Table 1, entry 1). The same glycosylation reaction performed in the presence of NIS (1.2
equiv) and TfOH (2.5 equiv), novel reaction conditions introduced in our previous article,[6]
produced disaccharide 3 in a similar yield of 85% but drastically improved stereoselectivity α/β =
3
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
1/23 (entry 2). Our previous mechanistic study employed 3-Pico donor 4 in which all remaining
positions were methylated.[6] Glycosidation of donor 4 was performed using the same promoter
system, but for the purpose of monitoring by NMR, the reaction was conducted at -50 oC. These
conditions were found to be very favorable for glycosylation of acceptor 2 as well, producing the
corresponding disaccharide 5 in 90% yield and complete β-stereoselectivity (entry 3). To be able
to perform the reaction at -50 oC we used DCM as the reaction solvent because 1,2-DCE is known
to freeze at -35 oC. With these preliminary observations, we decided to investigate the solvent and
the temperature effects on glycosidation of benzylated 3-Pico donor 1. Over the course of this
study, a steady drop in stereoselectivity was observed when the reaction temperature was increased
from -50 oC (α/β = 1/23) to room temperature (α/β = 1/3.5, entries 4-9). This result was consistent
with the proposed reaction pathway taking place via the intermediacy of glycosyl triflate, which is
expected to be more stable at low temperatures.[8] It should be noted that the yield has also
o
decreased following the reaction temperature increase from -50 C (85%) to room temperature
(59%, entries 4-9). We explained this by the occurrence of the competing hydrolysis reaction,
judged by the formation of significant quantities of the hemiacetal side product, which is
accelerated at higher temperatures.
Table 1. Optimization of the reaction solvent and temperature for glycosidation of 1
Promoter (equiv)
conditions, time
Product, yield,
Entry Donor (50 mM)
α/β ratio
DMTST (2)
4Å MS, 1,2-DCE
-30 oC  rt, 3 h
1
3, 90%, 1/2.6
1 (5 mM)
4
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
NIS(1.2)/TfOH(2.5)
4Å MS, 1,2-DCE
-30 oC, 30 min
2
3
3, 85%, 1/23
1
NIS(1.2)/TfOH(2.5)
4Å MS, DCM
5, 90%, < 1/25
-50 oC, 30 min
4
1
NIS(1.2)/TfOH(2.5)
4Å MS, DCM
4
5
6
7
8
9
3, 85%, 1/23
3, 85%, < 1/25
3, 70%, 1/11.5
3, 66%, 1/8.3
3, 70%, 1/5.6
3, 59%, 1/3.5
-50 oC, 30 min
NIS(1.2)/TfOH(2.5)
4Å MS, DCM
1
1
1
1
1
-30 oC, 30 min
NIS(1.2)/TfOH(2.5)
4Å MS, DCM
-10 oC, 30 min
NIS(1.2)/TfOH(2.5)
4Å MS, DCM
0 oC, 30 min
NIS(1.2)/TfOH(2.5)
4Å MS, DCM
10 oC, 30 min
NIS(1.2)/TfOH(2.5)
4Å MS, DCM
rt, 30 min
NIS(1.2)/TfOH(2.5)
4Å MS, DCM
10
3, 41%, 1/20
1
-50 oC, 30 min
Preactivation
To gain further insight into the mechanism responsible for the excellent stereoselectivity
observed, we performed glycosylation by preactivation of the donor with the promoter followed
by the addition of the acceptor. Previously, it has been demonstrated that preactivation causes a
complete loss of stereoselectivity in the HAD reactions.[3] This was attributed to the necessity to
form the hydrogen-bonded donor-acceptor pair for the HAD effect to take place. The reaction
performed via preactivation of glycosyl donor 1 in the presence of excess TfOH provided
comparably high stereoselectivity, albeit reduced yield (41%, entry 10). This lower yield was due
to competing hydrolysis side reaction that resulted in the formation of the corresponding
5
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
hemiacetal derivative. This result further reinforces the idea that this reaction that does not follow
the HAD pathway under these promoter conditions.
We then investigated the effect of the promoter on the outcome of glycosylation. The
promoter systems of NIS/TfOH and NBS/TfOH were previously examined and both were found
to produce the glucosyl triflate intermediate by NMR.[6] The application of these promoter systems
in glycosylation are surveyed in entries 1 and 2 of Table 2. In most cases, the optimized conditions
(excess of electrophilic reagent) resulted in fast reactions that produced disaccharide 3 in high
yields. Other reactions that employed standard catalytic amounts of electrophilic promoter were
allowed to warm up to room temperature as was done with the HAD reactions. All sluggish
reactions were stopped after 24 h. In the case of NIS or NBS, both sets of experiments showed a
remarkable increase in stereoselectivity as we moved from the conventional ratio to excess TfOH
(entries 1 and 2).
We then wondered whether the availability of the proton provided by TfOH is essential for
these reactions. First, we replaced TfOH with trimethylsilyl triflate (TMSOTf) which has been
reported to coordinate to the Pico group.[9] NIS/TMSOTf-promoted reactions showed the identical
outcome (entry 3) to that achieved with NIS/TfOH (entry 1). On the other hand, NIS/AgOTf
promoted reactions afforded only a modest improvement over HAD reactions upon increase from
the catalytic amount (α/β = 1/2.3) to excess of AgOTf (α/β = 1/7.0, entry 4). We believe that the
modest increase in stereoselectivity can be attributed to the slow release of TfOH over the course
of this reaction. As a result of this study, we concluded that a sufficiently available Pico
coordinating source, excess TfOH or TMSOTf, is required to achieve excellent stereoselectivity.
6
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
Table 2. Investigation of promoters for glycosidation of donor 1 with acceptor 2
Entry
Promoter (equiv), time
Yield of 3, α/β ratio
NIS(2)/TfOH(0.2), 24 h
NIS(1.2)/TfOH(2.5), 30 min
NBS(2)/TfOH(0.2), 24 h
89%, 1/3.0
85%, 1/23
1
2
3
4
5
6
7
12%,a 1/3.1
79%, < 1/25
79%, 1/2.6
86%, < 1/25
69%, 1/2.3
92%, 1/7.0
22%, 1/1.0
37%, 1.6/1
No reactionb
56%, 1/1.3
62%, 1/1.0
94%, 1/1.0
No reaction
83%, 1/7.2
82%, 1/13.3
NBS(1.2)/TfOH(2.5), 3 h
NIS(2)/TMSOTf(0.2), 24 h
NIS(1.2)/TMSOTf(2.5), 30 min
NIS(2)/AgOTf(0.2), 24 h
NIS(1.2)/AgOTf(2.5), 30 min
NIS(2)/AgOTs(0.2), 24 h
NIS(1.2)/AgOTs(2.5), 24 h
NIS(2)/MsOH(0.2), 24 h
NIS(1.2)/MsOH(2.5), 24 h
NIS(2)/HN(Tf)2(0.2), 24 h
NIS(1.2)/HN(Tf)2(2.5), 30 min
IDCH(2)/TfOH(0.2), 24 h
IDCH(1.2)/TfOH(2.5), 30 min
IDCH(1.2)/TfOH(3.2), 30 min
8
a - Glycosyl bromide was formed as the major by-product;
b – 6-O-Mesylated acceptor was obtained along with unreacted starting materials
Subsequently, we endeavored to identify the role of the counter-ion in the reaction. For this
purpose, we selected several co-promoters as replacements for TfOH. Alternative sulfonates,
methanesulfonic acid (MsOH) and silver p-toluenesulfonate (AgOTs), were chosen along with
trifluormethanesulfonamide (HN(Tf)2). AgOTs was selected over p-toluenesulfonic acid because
the latter exists as a monohydrate, which could be problematic in water sensitive glycosylation
reactions. HN(Tf)2 was investigated because it has a similar pKa to TfOH, -12.3 and -11.4,
7
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
respectively,[10] but it is unable to produce the anomeric triflate intermediate. As a result of this
study summarized in entries 5-7 (Table 2), these additives were practically ineffective in enhancing
the stereoselectivity of glycosylations. This result reinforces the importance of the triflate counter-
anion. . However, we cannot exclude other factors that could be of relevance to the excellent
stereoselectivity observed
We then turned our attention to studying possible effect of succinimide as a side-product
or as a counter ion on the outcome of this glycosylation reaction. For this purpose, we changed the
iodonium source from NIS to iodonium(di-γ-collidine)hexafluorophosphate (IDCH).[11] IDCH
was chosen as an alternative source of iodonium ion instead of the more common IDCP
(perchlorate) because of the presence of the nucleophilic perchlorate counter ion has been known
to influence the stereoselectivity of glycosylation reactions.[8, 12] Over the course of the study
summarized in entry 8, we observed a modest stereoselectivity improvement using the optimized
reaction conditions. Interestingly, further improvement in stereoselectivity was achieved when the
amount of TfOH was tripled in respect to IDCH. To rationalize this result, we hypothesized that
excess acid is required to quench the conjugate base of the iodonium source, two equivalents of
collidine in case of IDCH, and still have a full equivalent to be able to interact with the Pico group
of the glycosyl donor. From these experiments we were able to determine that NIS is not directly
involved in the reaction pathway further reinforcing our hypothesis that the reaction proceeds via
the intermediacy of glycosyl triflate.
We next sought to expand the acceptor scope for these reaction conditions. As listed in
Table 3, glycosyl donor 1 was glycosidated with various secondary acceptors 6, 8, 10 and
electronically deactivated primary acceptors 12, 14, and 16 using the optimized conditions. Both
yields and stereoselectivities for the formation of disaccharides 7, 9, and 11 derived from the
8
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
standard secondary acceptors were poor, demonstrating only improved reaction time (entries 1-3).
This result was expected because secondary acceptors have been known to perform poorly in SN2-
like reactions in general, and as substrates for glycosyl triflates in particular.[13] Albeit
insignificant, we note a reversal of the stereoselectivity in glycosylations to produce disaccharides
7 and 9 under standard versus novel reaction conditions (entries 1 and 2). Alternatively, the
optimized conditions exhibited moderate to high stereoselectivities for glycosylation of relatively
deactivated primary acceptors to from the respective disaccharides 13, 15, and 17 with
stereoselectivities ranging from α/β = 1/7.7 to α/β >1/25 (entries 4-6). Interestingly, the
nucleophilicity of the acceptor seemed to be directly proportional to the observed stereoselectivity.
This trend could be followed by varying the number of deactivating benzoyl substituents in
glycosyl acceptors 12, 14, and 16. This is to be expected from an SN2-like reaction pathway, and
has shown to be a factor in the stereoselectivities obtained from glycosyl triflates.[14]
To further expand the scope of this reaction, we investigated the glycosidation of other
picoloylated donors of the D-galacto and D-manno series. These results are summarized in Table
4. Galactosyl donor 18 afforded a lower improvement in stereoselectivity compared to the drastic
improvement achieved with glucosyl donor 1 (Table 4, entries 2 vs. 1). Nevertheless, the reaction
still seemed to follow a similar trend and the corresponding disaccharide 19 was obtained in a good
yield and the stereoselectivity improved from α/β = 1/2.5, achieved under standard conditions, to
α/β = 1/9.0 under the new conditions (entry 2). The same cannot be said of the mannosyl donor
20, which exhibited a complete reversal in stereoselectivity (entry 3).
9
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
Table 3. Glycosidation of donor 1 with different glycosyl acceptors
Entry
1
Acceptor
Time, yield, α/β ratioa
Product
24 h, 57%, 2.1/1
1.5 h, 78%, 1/1.5
6
8
7
9
24 h, 68%, 1/1.7
1.5 h, 53%, 3.0/1
2
3
24 h, 40%, 1/2.0
1.5 h, 44%, 1/1.7
10
12
14
16
11
13
15
17
3 h, 67%, 1/2.4
30 min, 92%, 1/7.7
4
5
6
3 h, 87%, 1/3.0
30 min, 80%, 1/16.7
3 h, 86%, 1/2.6
30 min, 79%, >1/25
a – first set of data is for reaction under standard conditions NIS(2)/TfOH(0.2)
and the second set of data is for the new conditions NIS(1.2)/TfOH(2.5)
10
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
It is important to note that, similar to glucosyl donor 1, the stereoselectivities obtained with
donors 18 and 20 were found to be proportional to the ratios of NIS/TfOH employed, suggesting
that the TfOH might have a similar effect on the reaction pathway involving these substrates (see
the Supporting Information Table 1S for further details). We next investigated whether the new
reaction conditions can be applied to glycosyl donors bearing the Pico group at other remote
positions. Interestingly, glucosyl donors functionalized with 4- or 6-Pico group showed practically
no change in stereoselectivity (entries 4 and 5). These results demonstrate that the newly optimized
conditions provide dramatic stereoselectivity enhancement only when the Pico group is at the C-3
position of the glycosyl donor. This is believed to be due to the increased proximity of the electron
withdrawing group at C-3 to the anomeric center. The stabilizing effect electron withdrawing
groups have on glycosyl triflate intermediates has been shown to be dependent on the functional
group location and it is optimal from the C-3 position.[15] Considering that the HAD glycosylation
method is optimal with donors functionalized with 4- or 6-Pico groups,[4a, 16] these results also
reinforce a different reaction pathway by which 3-Pico protected glycosyl donors may react.
The HAD method has previously been shown to suffer by the presence of excess protic
acid and/or preactivation of the glycosyl donor, both of which are well tolerated in this new
reaction pathway. In addition, switching from the donor equipped with the Pico group to its
regioisomers, 3-O-nicotinoyl (Nico) protected donor 26 and 3-O-iso-nicotinoyl (iNico) protected
donor 28, led to the complete loss of stereoselectivity in the HAD reaction.[3] In the presence of
excess TfOH, protonation of the Pico group is expected to be optimal due to the stabilizing effects
of the resulting five-member ring between the nitrogen and carbonyl oxygen. However, the Nico
i
and Nico protecting groups are still expected to be protonated and may exhibit a similar affect
under these conditions.
11
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
Table 4. Investigation of various glycosyl donor under new reaction conditions
Entry
Donor
Product, reaction time, yield, α/β ratioa
3, 24 h, 89%, 1/3.0
3, 30 min, 92%, 1/23
1
2
1
19, 24 h, 89%, 1/2.5
19, 30 min, 76%, 1/9.0
18
21, 24 h, 82%, 1/3.8
21, 30 min, 79%, 5.4/1
3
4
5
20
22
24
23, 24 h, 86%, 1.2/1
23, 30 min, 89%, 1/1.8
25, 2 h, 89%, 1/10
25, 30 min, 75%, 2.6/1
27, 24 h, 62%, 1/1.3
27, 30 min, 66%, 1/6.0
6
7
26
29, 24 h, 70%, 1/1.3
29, 30 min, 82%, 1/4.0
28
a – first set of data is for reaction under standard conditions NIS(2)/TfOH(0.2)
and the second set of data is for the new conditions NIS(1.2)/TfOH(2.5)
i
Predictably, we observed a reduction in stereoselectivity with the Nico and Nico donors,
26 and 28 (entries 6 and 7), compared to the Pico donor 1. However, these substrates still exhibit
12
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
improved β-stereoselectivity using the optimized reaction conditions compared to no
stereoselectivity obtained with catalytic TfOH (HAD conditions). These results further suggest
that reactions under the newly optimized conditions do not proceed through the HAD pathway.
Comparing the results in Table 4 for Pico, Nico and iNico protecting groups; it appears that
the same mechanistic pathway is occurring with each donor but to different degrees. These
variations are believed to arise from different stabilities of the protonated protecting groups,
altering the stereoselectivity. In an attempt to identify changes correlating to the protonation that
varies among the donors in a similar manner to stereoselectivity we turned spectroscopic studies.
1H NMR analysis of each donor in the presence of TfOH (1.0 equiv) was performed to determine
possible chemical shift changes indicative of protonation. As reported in the preceding article,[6]
chemical shift changes are not observed for the 3-O-benzoylated or per-O-benzylated
thioglycoside donors.
Figure 1. Chemical shifts comparison of 3-Pico, 3-Nico, and 3-iNico donors 1,
26 and 28 in the presence of TfOH
13
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
These spectroscopic studies revealed that in the presence of TfOH, several proton signals
experience chemical shift changes. Among these was the upfield shift of the δ H-3 proton.
Previously this chemical shift change was postulated and qualitatively proven to be a result of π-π
or cation-π interactions with the neighboring benzyl substituents and the electronically deficient
protonated pyridine ring.[6] Since each donor substrate contains the same number and location of
benzyl groups, the TfOH induced chemical shift changes for each sample should be a function of
the electronic nature of the substituent at C-3. To this extent the change in δ H-3 for each sample
was found to follow the same trend as the stereoselectivities obtained in their glycosidations (1,
∆δ H-3 = 0.32 ppm; 26, ∆δ H-3 = 0.17 ppm; 28, ∆δ H-3 = 0.10 ppm, Figure 1). These results
indicate that the Pico group experiences a stronger electronic effect compared to that of the Nico
i
and Nico substituents, suggesting a correlation between the C-3 electronics and the observed
stereoselectivity.
In conclusion, excellent β-stereoselectivity for the glycosylation with 3-Pico glucosyl
donors, without the use of participating group, was expanded upon. This method utilizes the
optimized NIS/TfOH promoter conditions previously reported.[6] Protonation of the Pico group
was determined to be crucial in this reaction. Further investigation using IDCH as the iodonium
source confirmed the necessity to have sufficient amount of TfOH to quench the conjugate base
and protonate the donor. Furthermore, the stability or extent of the protonated pyridine ring was
also found to be a key factor in obtaining high stereoselectivity. The stability of the five-membered
ring formed between the nitrogen and neighboring carbonyl oxygen of the protonated Pico group
affords dramatically improved stereoselectivity compared to the Nico and iNico counterparts. The
identity of the glycosyl donor and acceptor was also shown to be a determining factor in this
reaction. The nucleophilicity of the acceptor was found to be proportional to the stereoselectivity
14
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
obtained, suggesting an SN2-like mechanism. Changing the donor substrate led to a variety of
results. Moving the Pico group to other remote positions was not well tolerated. Galactosyl donors
functionalized with 3-Pico showed good stereoselectivity while mannosyl donors showed a
preference for the α-product. Since these stereoselectivities follow a similar trend with the
NIS/TfOH ratio as the glucosyl donor, it is suspected that the reaction pathway is somewhat similar
in the case of D-galacto series but differs drastically in the case of the D-manno series. The
mechanistic pathway was thoroughly investigated and, in our estimation, we have provided
significant evidence for the formation and importance of the protonated Pico-dependent glycosyl
triflate intermediate.
Experimental
General. Column chromatography was performed on silica gel 60 (70-230 mesh), reactions were
monitored by TLC on Kieselgel 60 F254. The compounds were detected by examination under
UV light and by charring with 10% sulfuric acid in methanol. Solvents were removed under
reduced pressure at <40 °C. CH2Cl2 and ClCH2CH2Cl (1,2-DCE) were distilled from CaH2 directly
prior to application. Molecular sieves (3 or 4 Å) used for reactions were crushed and activated in
vacuo at 390 °C for an initial 8 h and then for 2-3 h at 390 °C directly prior to application. Optical
1
rotation was measured at ‘Jasco P-2000’ polarimeter. Unless noted otherwise, H NMR spectra
were recorded in CDCl3 at 300 or 600 MHz, 13C NMR spectra were recorded in CDCl3 at 75 MHz.
High resolution mass spectrometry (HRMS) was carried out on ESI-TOF mass spectrometer.
15
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
Synthesis of glycosyl donors
Ethyl 2,4,6-tri-O-benzyl-3-O-picoloyl-1-thio-β-D-glucopyranoside (1) was synthesized
according to the reported procedure and its analytical data was essentially the same as reported
previously.[6]
Ethyl 2,4,6-tri-O-methyl-3-O-picoloyl-1-thio-β-D-glucopyranoside (4) was synthesized
according to the reported procedure and its analytical data was essentially the same as reported
previously.[6]
Ethyl 2,4,6-tri-O-benzyl-3-O-picoloyl-1-thio-β-D-galactopyranoside (18). Picolinic acid (0.10
g, 0.80 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.155 g, 0.80 mmol), and 4-
dimethylaminopyridine (0.01 g, 0.08 mmol) were added to a solution of ethyl 2,4,6-tri-O-benzyl-
1-thio-β-D-galactopyranoside[17] (0.20 g, 0.40 mmol) in and the resulting mixture was stirred under
argon for 30 min at rt. The reaction mixture was diluted with CH2Cl2 (~100 mL) and washed with
sat. aq. NaHCO3 (30 mL) and water (3 x 10 mL). The organic phase was separated, dried with
magnesium sulfate, and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate – toluene gradient elution) to give the title compound
as a white amorphous solid in 93% yield. The analytical data for 18: Rf = 0.60 (ethyl
21
1
acetate/toluene, 2/3, v/v); [α]D 40.5 (c 1.0, CHCl3); H NMR: δ, 1.37 (t, 3H, J = 7.4 Hz,
SCH2CH3), 2.83 (m, 2H, SCH2CH3), 3.63-3.73 (m, 2H, H-6a, 6b), 3.85 (m, 1H, H-5), 4.08 (dd,
1H, J2,3 = 9.6 Hz, H-2), 4.23 (dd, 1H, J4,5 = 3.0 Hz, H-4), 4.47 (d, 1H, J = 11.9 Hz, CHPh), 4.55
2
(d, 1H, J = 11.0 Hz, CHPh), 4.77 (m, 2H, J1,2 = 8.4 Hz, H-1, CHPh), 4.74 (d, 1H, J = 11.7 Hz,
CHPh), 4.75 (d, 1H, J = 10.7 Hz, CHPh), 4.93 (d, 1H, J = 10.7 Hz, CHPh), 5.31 (dd, 1H, J3,4 = 3.0
Hz, H-3), 7.18-7.37 (m, 15H, aromatic), 7.53 (m, 1H, Pico-H), 7.83 (m, 1H, Pico-H), 7.93 (d, 1H,
13
J = 7.8 Hz, Pico-H), 8.83 (d, 1H, J = 4.7 Hz, Pico-H) ppm; C NMR: δ, 15.1, 25.1, 68.4, 73.5,
16
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
74.4, 74.9, 75.6, 76.9, 78.3, 85.4, 125.3, 127.0, 127.6, 127.7, 127.8, 127.9 (ⅹ2) 128.2 (ⅹ9), 128.5
(ⅹ2), 136.9, 137.8, 137.9, 138.1, 147.6, 150.2, 164.3 ppm; ESI-TOF [M+Na]+ calcd for
C35H37NNaO6S 622.2239, found 622.2236.
Ethyl 2,4,6-tri-O-benzyl-3-O-picoloyl-1-thio-β-D-mannopyranoside (20) was synthesized
according to the reported procedure and its analytical data was essentially the same as reported
previously.[4b]
Ethyl 2,3,6-tri-O-benzyl-4-O-picoloyl-1-thio-β-D-glucopyranoside (22) was synthesized
according to the reported procedure and its analytical data was essentially the same as reported
previously.[3]
Ethyl 2,3,4-tri-O-benzyl-6-O-picoloyl-1-thio-β-D-glucopyranoside (24) was synthesized
according to the reported procedure and its analytical data was essentially the same as reported
previously.[3]
Ethyl 2,4,6-tri-O-benzyl-3-O-nicotinoyl-1-thio-β-D-glucopyranoside (26). Nicotinic acid (0.10
g, 0.80 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.155 g, 0.80 mmol), and 4-
dimethylaminopyridine (0.01 g, 0.08 mmol) were added to a solution of ethyl 2,4,6-tri-O-benzyl-
1-thio-β-D-glucopyranoside[18] (0.20 g, 0.80 mmol) in CH2Cl2 (10 mL), and the resulting mixture
was stirred under argon for 30 min at rt. The reaction mixture was diluted with CH2Cl2 (~ 100 mL)
and washed with sat. aq. NaHCO3 (30 mL) and water (3 x 10 mL). The organic phase was
separated, dried with magnesium sulfate, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (ethyl acetate – toluene gradient elution) to give the title
compound as a white amorphous solid in 90% yield. The analytical data for 26: Rf = 0.40 (ethyl
21
1
acetate/toluene, 2/3, v/v); [α]D -27.0 (c 0.8, CHCl3); H NMR: δ, 1.37 (t, 3H, J = 7.4 Hz,
SCH2CH3), 2.83 (m, 2H, SCH2CH3), 3.68 (m, 2H, H-6a, 6b), 3.85 (m, 1H, J5,6a = 6.6 Hz, H-5),
17
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
4.08 (dd, 1H, J2,3 = 9.6 Hz, H-2), 4.23 (dd, 1H, J4,5 = 3.0 Hz, H-4), 4.46-4.76 (m, 5H, H-1, 4 ×
CHPh), 4.75 (d, 1H, 2J = 10.6 Hz, CHPh), 4.94 (d, 1H, 2J = 10.7 Hz, CHPh), 5.33 (dd, 1H, J3,4 =
9.6 Hz, H-3), 7.18-7.35 (m, 15H, aromatic), 7.53 (m, 1H, Pico-H), 7.81 (m, 1H, Pico-H), 7.93 (d,
1H, J = 7.8 Hz, Pico-H), 8.84 (d, 1H, J = 4.6 Hz, Pico-H) ppm; 13C NMR: δ, 15.1, 25.2, 68.5, 73.6,
74.4, 74.9, 75.8, 78.1, 78.9, 79.2, 85.2, 123.1, 125.8, 127.7 (ⅹ3), 127.9 (ⅹ2), 128.0 (ⅹ2), 128.2
(ⅹ4), 128.3 (ⅹ2), 128.4, 137.1, 137.3, 137.4, 137.9, 150.8, 153.3, 164.1 ppm; ESI-TOF [M+Na]+
calcd for C35H37NNaO6S 622.2239, found 622.2232.
Ethyl 2,4,6-tri-O-benzyl-3-O-iso-nicotinoyl-1-thio-β-D-glucopyranoside (28). Iso-Nicotinic
acid (0.10 g, 0.80 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.155 g, 0.80 mmol),
and 4-dimethylaminopyridine (0.01 g, 0.08 mmol) were added to a solution of ethyl 2,4,6-tri-O-
benzyl-1-thio-β-D-glucopyranoside[18] (0.20 g, 0.80 mmol) in CH2Cl2 (10 mL), and the resulting
mixture was stirred under argon for 30 min at rt. The reaction mixture was diluted with CH2Cl2 (~
100 mL) and washed with sat. aq. NaHCO3 (30 mL) and water (3 x 10 mL). The organic phase
was separated, dried with magnesium sulfate, and concentrated in vacuo. The residue was purified
by column chromatography on silica gel (ethyl acetate – toluene gradient elution) to give the title
compound as a white amorphous solid in 89% yield. The analytical data for 28: Rf = 0.45 (ethyl
21
1
acetate/toluene, 2/3, v/v); [α]D -37.0 (c 0.9, CHCl3); H NMR: δ, 1.42 (t, 3H, J = 7.4 Hz,
SCH2CH3), 2.86 (m, 2H, SCH2CH3), 3.61 (dd, 1H, J2,3 = 9.5 Hz, H-2) 3.64 (m, 1H, H-5), 3.85 (m,
2H, H-6a, 6b), 3.88 (dd, 1H, J4,5 = 9.6 Hz, H-4), 4.46 (d, 1H, 2J = 11.2 Hz, CHPh), 4.54-4.65 (m,
4H, H-1, 3 × CHPh), 4.75 (d, 1H, 2J = 12.1 Hz, CHPh), 4.88 (d, 1H, 2J = 11.2 Hz, CHPh), 5.56
(dd, 1H, J3,4 = 9.3 Hz, H-3), 7.04-7.44 (m, 16H, aromatic), 8.13 (m, 1H, Nico-H), 8.82 (d, 1H, J =
4.8 Hz, Nico-H), 9.04 (s, 1H, Nico-H) ppm; 13C NMR: δ, 15.2, 25.4, 68.5, 73.6, 74.4, 74.9, 75.8,
78.5, 78.9, 79.2, 85.3, 122.9 (ⅹ2), 127.9 (ⅹ2), 128.0 (ⅹ4), 128.3 (ⅹ7), 128.5 (ⅹ2), 137.0, 137.3,
18
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
137.4, 137.9, 150.5 (ⅹ2), 164.1 ppm; ESI-TOF [M+Na]+ calcd for C35H37NNaO6S 622.2239,
found 622.2241.
Synthesis of disaccharides
General procedure for glycosylation. Glycosyl donor (0.05 mmol) and glycosyl acceptor (0.038
mmol) were dried in vacuo for 1 h at rt. Molecular sieves (4 Å, 60 mg or 150 mg for 50 mM or 5
mM reaction, respectively) and freshly distilled 1,2-dichloroethane or dichloromethane (1.0 mL
for 50 mM reaction or 10.0 mL for 5 mM) were added and the resulting mixture was stirred under
argon for 1 h at rt. The mixture was cooled (-30 °C or -50°C) and the promoter was added. The
external cooling was removed, and the reaction mixture was allowed to warm gradually to rt for
reactions longer than 2 h. Upon completion (see the time listed in Tables), the solid was filtered
off through a pad of Celite and rinsed successively with dichloromethane. The combined filtrate
(~ 30 mL) was washed with either sat. aq. NaHCO3 (10 mL) or 10% NaS2O3 (10 mL, for NIS-
promoted reactions) and water (2 x 10 mL). The organic phase was separated, dried with
magnesium sulfate, and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate – hexanes gradient elution) to afford the corresponding
disaccharide. Diastereomeric ratios were determined by comparison of the integral intensities of
relevant signals in 1H NMR spectra.
Methyl O-(2,4,6-tri-O-benzyl-3-O-picoloyl-β-D-glucopyranosyl)-(16)-2,3,4-tri-O-benzyl-α-
D-glucopyranoside (3) was obtained as a white amorphous solid from glycosyl donor 1 and
acceptor 2 in 85% (α/β = 1/23). Analytical data for 3 was in accordance with that reported
previously.[6]
19
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
Methyl O-(2,4,6-tri-O-methyl-3-O-picoloyl-β-D-glucopyranosyl)-(16)-2,3,4-tri-O-benzyl-
α-D-glucopyranoside (5) was obtained as a white amorphous solid from glycosyl donor 4 and
acceptor 2 in 90% (α/β > 1/25). Analytical data for 5 was in accordance with that reported
previously.[6]
Methyl O-(2,4,6-tri-O-benzyl-3-O-picoloyl-α/β-D-glucopyransyl)-(12)-3,4,6-tri-O-benzyl-
α-D-glucopyranoside (7) was obtained as a clear syrup from glycosyl donor 1 and glycosyl
acceptor 6 in 78% yield (α/β = 1/1.5). Selected analytical data for α-7: Rf = 0.55 (ethyl
acetate/toluene, 2/3, v/v); 1H NMR: δ, 5.06 (d, 1H, J1’,2’ = 3.5 Hz, H-1’), 6.04 (dd, 1H, J3’,4’ = 9.4
Hz, H-3’), 8.09 (d, 1H, J = 7.7 Hz, Pico-H), 8.80 (d, 1H, J = 3.9 Hz, Pico-H) ppm; 13C NMR: δ,
1
94.2, 96.5 ppm. Selected analytical data for β-7: Rf = 0.55 (ethyl acetate/toluene, 2/3, v/v); H
NMR: δ, 5.57 (dd, 1H, J3’,4’ = 9.4 Hz, H-3’), 7.90 (d, 1H, J = 7.8 Hz, Pico-H), 8.76 (d, 1H, J = 4.7
13
Hz, Pico-H) ppm; C NMR: δ, 99.8, 104.0 ppm; ESI-TOF [M+Na]+ calcd for C61H63NNaO12
1024.4248, found 1024.4262.
Methyl O-(2,4,6-tri-O-benzyl-3-O-picoloyl-α/β-D-glucopyranosyl)-(13)-2,4,6-tri-O-benzyl-
α-D-glucopyranoside (9) was obtained as a clear syrup from glycosyl donor 1 and glycosyl
acceptor 8 in 68% yield (α/β = 1/1.7). Selected analytical data for α-9: Rf = 0.60 (ethyl
acetate/toluene, 2/3, v/v); 1H NMR: δ, 4.02 (dd, 1H, J4’,5’ = 9.6 Hz, H-4’), 5.71 (d, 1H, J1’,2’ = 3.4
Hz, H-1’), 8.04 (d, 1H, J = 7.7 Hz, Pico-H) ppm; 13C NMR: δ, 97.2, 97.5 ppm. Selected analytical
1
2
data for β-9: Rf = 0.60 (ethyl acetate/toluene, 2/3, v/v); H NMR: δ, 5.15 (d, 1H, J = 10.7 Hz,
CHPh), 5.28 (d, 1H, J1’,2’ = 7.8 Hz, H-1’), 5.68 (dd, 1H, J3’,4’ = 9.5 Hz, H-3’), 8.11 (d, 1H, J = 7.8
Hz, Pico-H) ppm; ESI-TOF [M+Na]+ calcd for C61H63NNaO12 1024.4248, found 1024.4254.
Methyl O-(2,4,6-tri-O-benzyl-3-O-picoloyl-α/β-D-glucopyranosyl)-(14)-2,3,6-tri-O-benzyl-
α-D-glucopyranoside (11) was obtained as a clear syrup from glycosyl donor 1 and glycosyl
20
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
acceptor 10 in 44% yield (α/β = 1/2.0). Selected analytical data for α-11: Rf = 0.55 (ethyl
acetate/toluene, 2/3, v/v); 1H NMR: δ, 5.03 (d, 1H, 2J = 11.7 Hz, CHPh), 5.76 (d, 1H, J1’,2’ = 3.5
Hz, H-1’), 5.82 (dd, 1H, J3’,4’ = 9.8 Hz, H-3’) ppm; 13C NMR: δ, 96.5, 97.8 ppm; Selected analytical
1
2
data for β-11: Rf = 0.55 (ethyl acetate/toluene, 2/3, v/v); H NMR: δ, 5.12 (d, 1H, J = 11.3 Hz,
CHPh), 5.44 (dd, 1H, J3’,4’ = 9.4 Hz, H-3’) ppm; 13C NMR: δ, 98.5, 102.6 ppm; ESI-TOF [M+Na]+
calcd for C61H63NNaO12 1024.4248, found 1024.4260.
Methyl
O-(2,4,6-tri-O-benzyl-3-O-picoloyl-α/β-D-glucopyranosyl)-(16)-2,3,4-tri-O-
benzoyl-α-D-glucopyranoside (13) was obtained as a clear syrup from glycosyl donor 1 and
methyl 2,3,4-tri-O-benzoyl-α-D-glucopyranoside 12[19] in 92% yield (α/β = 1/7.7). Analytical data
for β-13: Rf = 0.60 (ethyl acetate/ toluene, 2/3, v/v); 1H NMR: δ, 3.46 (s, 3H, OCH3), 3.57 (m, 1H,
H-5’), 3.66 (dd, 1H, J2’,3’ = 9.6 Hz, H-2’), 3.77 (m, 2H, H-6a’, 6b’), 3.92 (dd, 1H, J6a,6b = 11.0 Hz,
H-6a), 4.00 (dd, 1H, J4’,5’ = 9.6 Hz, H-4’), 4.17 (dd, 1H, H-6b), 4.45 (m, 1H, J5,6a = 6.3 Hz, H-5),
4.46-4.70 (m, 5H, 5 x CHPh), 4.67 (d, 1H, J1’,2’ = 6.8 Hz, H-1’), 4.96 (d, 1H, 2J = 12.0 Hz, CHPh),
5.27-5.34 (m, 2H, H-1, 2), 5.53 (dd, 1H, J4,5 = 9.7 Hz, H-4), 5.62 (dd, 1H, J3’,4’ = 9.5 Hz, H-3’),
6.24 (dd, 1H, J3,4 = 9.7 Hz, H-3), 7.05-8.02 (m, 33H, aromatic), 8.81 (d, 1H, J = 6.4 Hz, Pico-H)
ppm; 13C NMR: δ, 55.6, 68.2, 69.1, 69.8, 70.5, 72.2, 73.5, 74.1, 74.5, 74.8, 75.8, 77.3, 79.2, 96.9,
104.0, 125.5, 126.8, 127.3, 127.6 (ⅹ2), 127.8 (ⅹ2), 127.9 (ⅹ2), 128.0 (ⅹ4), 128.2 (ⅹ2), 128.3
(ⅹ4), 128.4 (ⅹ4), 128.9, 129.1, 129.2, 129.7 (ⅹ2), 130.0 (ⅹ4), 133.1, 133.3, 133.5, 136.8, 137.6,
138.0, 138.2, 147.9, 149.7, 164.3, 165.5, 165.8 (ⅹ2) ppm; ESI-TOF [M+Na]+ calcd for
C61H57NNaO15 1066.3626, found 1066.3625.
Methyl O-(2,4,6-tri-O-benzyl-3-O-picoloyl-α/β-D-glucopyranosyl)-(16)-2,3-di-O-benzoyl-
4-O-benzyl-α-D-glucopyranoside (15) was obtained as a clear syrup from glycosyl donor 1 and
methyl 2,3-di-O-benzoyl-4-O-benzyl-α-D-glucopyranoside 14[20] in 80% (α/β = 1/16.7) yield.
21
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
1
Analytical data for β-15: Rf = 0.60 (ethyl acetate/toluene, 2/3, v/v), H NMR: δ, 3.43 (s, 3H,
OCH3), 3.57 (m, 1H, J5’,6a’ = 2.8 Hz, H-5’), 3.74 (dd, 1H, J2’,3’ = 9.6 Hz, H-2’), 3.83-3.90 (m, 3H,
H-6a, 6a’, 6b’), 3.93 (dd, 1H, J4,5 = 9.3 Hz, H-4), 4.01 (dd, 1H, J4’,5’ = 9.6 Hz, H-4’), 4.10 (m, 1H,
J5,6a = 2.0 Hz, H-5), 4.30 (dd, 1H, H-6b), 4.52 (d, 1H, J1’,2’ = 7.8 Hz, H-1’), 4.54-4.78 (m, 7H, 7 ⅹ
CHPh), 5.00 (d, 1H, 2J = 11.6 Hz, CHPh), 5.17-5.22 (m, 2H, H-1, 2), 5.66 (dd, 1H, J2’,4’ = 9.5 Hz,
H-3’), 6.10 (dd, 1H, J3,4 = 9.3 Hz, H-3), 7.09-8.08 (m, 33H, aromatics), 8.82 (d, 1H, J = 4.4 Hz,
13
Pico-H) ppm; C NMR: δ, 55.3, 68.4, 68.6, 69.9, 70.6, 72.3, 72.7, 73.5, 74.5, 74.6, 74.8, 75.0,
79.0, 77.2, 79.3, 96.9, 104.0, 125.5, 126.9, 127.4, 127.6 (ⅹ2), 127.7 (ⅹ2), 127.8 (ⅹ4), 128.0 (ⅹ2),
128.2 (ⅹ4), 128.4 (ⅹ8), 129.1, 129.6 (ⅹ2), 129.9 (ⅹ2), 133.1, 133.3 (ⅹ2), 136.9, 137.5, 137.6,
138.0, 138.1, 147.7, 149.8, 164.4, 165.6, 166.0 ppm; ESI-TOF [M+Na]+ calcd for C61H59NNaO14
1052.3833, found 1052.3816.
Methyl O-(2,4,6-tri-O-benzyl-3-O-picoloyl-α/β-D-glucopyranosyl)-(16)-2-O-benzoyl-3,4-
di-O-benzyl-α-D-glucopyranoside (17) was obtained as a clear oil from glycosyl donor 1 and
methyl 2-O-benzoyl-3,4-di-O-benzyl-α-D-glucopyranoside 16 in 79% yield (α/β >1/25).
1
Analytical data for β-17: Rf = 0.60 (ethyl acetate/toluene, 2/3, v/v); H NMR: δ, 3.33 (s, 3H,
OCH3), 3.55 (m, 1H, H-5’), 3.62-6.68 (m, 2H, H-2’, 4), 3.73-3.77 (m, 3H, H-6a, 6a’, 6b’), 3.92
(dd, J4’,5’ = 9.5 Hz, H-4’), 3.92-3.96 (m, 1H, H-5), 4.16-4.26 (m, 2H, H-3, 6b), 4.46-4.58 (m, 5H,
H-1’, 4 ⅹCHPh), 4.63 (dd 1H, 2J = 11.7 Hz, CHPh), 4.67 (d, 1H, 2J = 12.1 Hz, CHPh), 4.73 (d,
1H, 2J = 11.3 Hz, CHPh), 4.78-4.79 (m, 2H, 2 ⅹCHPh), 4.86 (d, 1H, 2J = 11.5 Hz, CHPh), 5.05
(d, 1H, J1,2 = 3.6 Hz, H-1), 5.11 (dd, 1H, J2,3 = 9.8 Hz, H-2), 5.57 (dd, 1H, J3,4 = 9.4 Hz, H-3’),
6.99-7.49 (m, 28H, aromatic), 7.58 (m, 1H, Pico-H), 7.81 (m, 1H, Pico-H), 7.97 (d, 1H, J = 7.8
13
Hz, Pico-H), 8.05 (m, 2H, aromatic), 8.75 (d, 1H, J = 4.7 Hz, Pico-H) ppm; C NMR: δ, 55.1,
68.6, 70.1, 73.5, 74.0, 74.5, 74.9, 75.0, 75.5, 76.0, 77.2, 78.1, 79.1, 80.1, 97.0, 103.8, 125.5, 126.8,
22
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
127.3, 127.6 (ⅹ2), 127.8 (ⅹ3), 127.9 (ⅹ6), 128.0 (ⅹ2), 128.1 (ⅹ2), 128.2 (ⅹ2), 128.3 (ⅹ2), 128.4
(ⅹ2), 128.4 (ⅹ3), 129.7, 129.8 (ⅹ2), 133.3, 136.9, 137.6, 137.8, 138.1 (ⅹ3), 147.7, 149.7, 164.3,
166.0 ppm; ESI-TOF [M+Na]+ calcd for C61H61NNaO13 1038.4041, found 1038.4049.
Methyl
O-(2,4,6-tri-O-benzyl-3-O-picoloyl-α/β-D-galactopyranosyl)-(16)-2,3,4-tri-O-
benzyl-α-D-glucopyranoside (19) was obtained as a clear oil from glycosyl donor 18 and glycosyl
acceptor 2 in 76% yield (α/β = 1/9). Analytical data for β-19: Rf = 0.70 (ethyl acetate/toluene, 2/3,
v/v); 1H NMR: δ, 3.37 (s, 3H, OCH3), 3.51 (dd, 1H, J4,5 = 9.9 Hz, H-4), 3.55-3.59 (m, 1H, H-2),
3.67-3.81 (m, 4H, H-5’, 6a, 6a’, 6b), 3.90 (m, 1H, H-5), 4.02-4.09 (m, 2H, H-2’, 3), 4.17-4.24 (m,
2H, H-4’, 6b’), 4.50 (d, 1H, J1’,2’ = 7.8 Hz, H-1’), 4.52-4.87 (m, 10H, 10 × CHPh), 4.65 (d, 1H, J1,2
= 3.5 Hz, H-1), 4.94 (d, 1H, 2J = 11.4 Hz, CHPh), 5.03 (d, 1H, 2J = 10.8 Hz, CHPh), 5.28 (dd, 1H,
13
J3’,4’ = 10.1 Hz, H-3’), 7.08-7.84 (m, 33H, aromatic), 8.84 (d, 1H, J = 4.6 Hz, Pico-H) ppm; C
NMR: δ, 55.2, 67.8, 68.3, 70.0, 73.0, 73.3, 73.4, 74.4, 74.7, 74.9, 75.8, 76.5, 77.2, 78.2, 79.7, 82.0,
97.9, 104.1, 125.2, 126.9, 127.4, 127.5, 127.6 (ⅹ2), 127.7 (ⅹ4), 127.9 (ⅹ6), 128.1 (ⅹ6), 128.2,
128.4 (ⅹ4), 128.5 (ⅹ2), 137.0, 137.8, 138.1 (ⅹ2), 138.2, 138.8, 147.4, 150.0, 164.1 ppm; ESI-
TOF [M+Na]+ calcd for C61H63NNaO12 1024.4248, found 1024.4243.
Methyl
O-(2,4,6-tri-O-benzyl-3-O-picoloyl-α/β-D-mannopyranosyl)-(16)-2,3,4-tri-O-
benzyl-α-D-glucopyranoside (21) was obtained as a white amorphous solid from glycosyl donor
20 and acceptor 2 in 82% yield (α/β = 1/3.8). Analytical data for 21 was in accordance with that
reported previously.[4b]
Methyl O-(2,3,6-tri-O-benzyl-4-O-picoloyl-α/β-D-glucopyranosyl)-(16)-2,3,4-tri-O-benzyl-
α-D-glucopyranoside (23) was obtained as a white amorphous solid from glycosyl donor 22 and
acceptor 2 in 86% yield (α/β = 1.2/1). Analytical data for 23 was in accordance with that reported
previously.[3]
23
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
Methyl O-(2,3,4-tri-O-benzyl-6-O-picoloyl-α/β-D-glucopyranosyl)-(16)-2,3,4-tri-O-benzyl-
α-D-glucopyranoside (25) was obtained as a white amorphous solid from glycosyl donor 24 and
acceptor 2 in 89% yield (α/β = 1/10). Analytical data for 25 was in accordance with that reported
previously.[3]
Methyl
O-(2,4,6-tri-O-benzyl-3-O-nicotinoyl-α/β-D-glucopyranosyl)-(16)-2,3,4-tri-O-
benzyl-α-D-glucopyranoside (27) was obtained as a clear syrup from glycosyl donor 26 and
glycosyl acceptor 2 in 66% yield (α/β = 1/6). Selected analytical data for α-27: Rf = 0.60 (ethyl
acetate/toluene, 2/3, v/v); 1H NMR: δ, 5.11 (d, 1H, J1’,2’ = 3.5 Hz, H-1’), 5.80 (dd, 1H, J3’,4’ = 9.0
1
Hz, H-3’) ppm. Selected analytical data for β-27: Rf = 0.60 (ethyl acetate/toluene, 2/3, v/v); H
NMR: δ, 3.92 (m, 1H, H-5’), 4.07 (dd, 1H, J4,5 = 9.3 Hz, H-4), 4.26 (dd, 1H, H-6b), 5.04 (d, 1H,
2J = 10.7 Hz, CHPh), 5.48 (dd, 1H, J3’,4’ = 9.4 Hz, H-3’) ppm; 13C NMR: δ, 98.0, 103.8 ppm; ESI-
TOF [M+Na]+ calcd for C61H63NNaO12 1024.4248, found 1024.4252.
Methyl O-(2,4,6-tri-O-benzyl-3-O-iso-nicotinoyl-α/β-D-glucopyranosyl)-(16)-2,3,4-tri-O-
benzyl-α-D-glucopyranoside (29) was obtained as a clear syrup from glycosyl donor 28 and
glycosyl acceptor 2 in 82% yield (α/β = 1/4). Selected analytical data for α-29: Rf = 0.50 (ethyl
acetate/toluene, 2/3, v/v); 1H NMR: δ, 5.12 (d, 1H, J1’,2’ = 3.5 Hz, H-1’), 5.78 (dd, 1H, J3’,4’ = 9.7
1
Hz, H-3’) ppm. Selected analytical data for β-29: Rf = 0.50 (ethyl acetate/toluene, 2/3, v/v); H
NMR: δ, 4.07 (dd, 1H, J4,5 = 9.3 Hz, H-4), 4.23 (dd, 1H, H-6b), 5.04 (dd, 1H, 2J = 10.7 Hz, CHPh),
5.45 (dd, 1H, J3’,4’ = 9.5 Hz, H-3’) ppm; 13C NMR: δ, 98.1, 103.9 ppm; ESI-TOF [M+Na]+ calcd
for C61H63NNaO12 1024.4248, found 1024.4245.
24
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
ASSOCIATED CONTENT
Supporting Information
Additional experimental data and NMR spectra for all new compounds. This material is available
free of charge via the Internet at
AUTHOR INFORMATION
Corresponding Author
* Department of Chemistry and Biochemistry, University of Missouri – St. Louis, One University
Boulevard, St. Louis, Missouri 63121, USA; demchenkoa@umsl.edu
Author Contributions
The manuscript was written through contributions of all authors. / All authors have given approval
to the final version of the manuscript.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the National Science Foundation (CHE-1800350).
25
This article is protected by copyright. All rights reserved.

10.1002/chem.201905278
Chemistry - A European Journal
REFERENCES
[1] A. V. Demchenko in General aspects of the glycosidic bond formation, Vol. (Ed. A. V.
Demchenko), Wiley-VCH, Weinheim, Germany, 2008, pp. 1-27.
[2] a) S. S. Nigudkar and A. V. Demchenko, Chem. Sci. 2015, 6, 2687–2704; b) R. Das and B.
Mukhopadhyay, ChemOpen 2016, 5, 401-433; c) K. Toshima and K. Tatsuta, Chem. Rev. 1993,
93, 1503-1531.
[3] J. P. Yasomanee and A. V. Demchenko, J. Am. Chem. Soc. 2012, 134, 20097-20102.
[4] a) M. P. Mannino, J. P. Yasomanee and A. V. Demchenko, Carbohydr. Res. 2018, 470, 1-7;
b) S. G. Pistorio, J. P. Yasomanee and A. V. Demchenko, Org. Lett. 2014, 16, 716-719; c) A.
Behera, D. Rai, D. Kushwaha and S. S. Kulkarni, Org. Lett. 2018, 20, 5956-5959.
[5] a) J.-H. Ruei, P. Venukumar, A. B. Ingle and K.-K. T. Mong, Chem. Commun. 2015, 51,
5394-5397; b) K. L. M. Hoang and X.-W. Liu, Nat. Commun. 2014, 5, 5051.
[6] M. P. Mannino and A. V. Demchenko, 2019, submitted.
[7] a) J. M. Kuester and I. Dyong, Justus Liebigs Ann. Chem. 1975, 2179-2189; b) S. C. Ranade,
S. Kaeothip and A. V. Demchenko, Org. Lett. 2010, 12, 5628-5631.
[8] T. G. Frihed, M. Bols and C. M. Pedersen, Chem. Rev. 2015, 115, 4963-5013.
[9] Y. L. Lu, B. Ghosh and K. T. Mong, Chem. Eur. J. 2017, 23, 6905-6918.
[10] E. Raamat, K. Kaupmees, G. Ovsjannikov, A. Trummal, A. Kütt, J. Saame, I. Koppel, I.
Kaljurand, L. Lipping, T. Rodima, V. Pihl, I. A. Koppel and I. Leito, J. Phys. Org. Chem. 2013,
26, 162-170.
[11] Y. Brunel and G. Rousseau, J. Org. Chem. 1996, 61, 5793-5800.
[12] S. J. Hasty, S. C. Ranade and A. V. Demchenko, Reports Org. Chem. 2014, 4, 1-10.
[13] a) D. Crich and P. Jayalath, J. Org. Chem. 2005, 70, 7252-7259; b) D. Crich, V.
Subramanian and T. K. Hutton, Tetrahedron 2007, 63, 5042-5049; c) P. Wei and R. J. Kerns, J.
Org. Chem. 2005, 70, 4195-4198.
[14] D. Crich, T. K. Hutton, A. Banerjee, P. Jayalath and J. Picione, Tetrahedron: Asymmetry
2005, 16, 105-119.
[15] J. Y. Baek, B. Y. Lee, M. G. Jo and K. S. Kim, J. Am. Chem. Soc. 2009, 131, 17705-17713.
[16] J. P. Yasomanee and A. V. Demchenko, Chem. Eur. J. 2015, 21, 6572-6581.
[17] S. Chatterjee, S. Moon, F. Hentschel, K. Gilmore and P. H. Seeberger, J. Am. Chem. Soc.
2018, 140, 11942-11953.
[18] K. M. Sureshan, A. M. Riley, M. P. Thomas, S. C. Tovey, C. W. Taylor and B. V. L. Potter,
J. Med. Chem. 2012, 55, 1706-1720.
[19] a) F. Zhang, W. Zhang, Y. Zhang, D. P. Curran and G. Liu, J. Org. Chem. 2009, 74, 2594-
2597; b) H. Fujii, N. Shimada, M. Ohtawa, F. Karaki, M. Koshizuka, K. Hayashida, M.
Kamimura, K. Makino, T. Nagamitsu and H. Nagase, Tetrahedron 2017, 73, 5425-5429.
[20] M. Tatina, S. K. Yousuf, S. Aravinda, B. Singh and D. Mukherjee, Carbohydr. Res. 2013,
381, 142-145.
26
This article is protected by copyright. All rights reserved.