Self-promoted and stereospecific formation of N-glycosides

Article abstract of DOI:10.1039/c9sc00857h

A stereoselective and self-promoted glycosylation for the synthesis of various N-glycosides and glycosyl sulfonamides from trichloroacetimidates is presented. No additional catalysts or promoters are needed in what is essentially a two-component reaction. When α-glucosyl trichloroacetimidates are employed, the reaction resulted in the stereospecific formation of the corresponding β-N-glucosides in high yields at ambient conditions. On the other hand, when equatorial glucosyl donors were used, the stereospecificity decreased and resulted in a mixture of anomers. By NMR-studies, it was concluded that this decrease in stereospecificity was due to an, until now, unpresented anomerization of the trichloroacetimidate under the very mildly acidic conditions. The mechanism and kinetics of the glycosylations have been studied by NMR-experiments, which gave an insight into the activation of trichloroacetimidates, suggesting an S_Ni-like mechanism involving ion pairs. The scope of glycosyl donors and sulfonamides was found to be very broad including popular N-protective groups and common glycosyl donors of various reactivity. Peracetylated GlcNAc trichloroacetimidate could be used without the need for any promotors or additives and a tyrosine side chain was glycosylated as an N-glycosyl carbamate. The N-carbamates and the N-sulfonyl groups functioned as orthogonal protective groups of the N-glycoside and hence allowed further N-functionalization without risking mutarotation of the N-glycoside. The N-glycosylation was also performed on a gram scale, without a drop in stereoselectivity nor yield.

Full text of DOI:10.1039/c9sc00857h

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ARTICLE
Self-promoted and stereospecific formation of N-
glycosides
Received 00th January 20xx,
Accepted 00th January 20xx
Michael Martin Nielsen,a Patrycja Mała, Eirikur Þórir Baldursson,a and Christian Marcus
a,b
Pedersena*
DOI: 10.1039/x0xx00000x
A stereoselective and self-promoted glycosylation for the synthesis of various N-glycosides and glycosyl sulfonamides from
trichloroacetimidates is presented. No additional catalysts or promoters are needed in what is essentially a two-component
reaction. When α-glucosyl trichloroacetimidates are employed, the reaction resulted in the stereospecific formation of the
corresponding β-N-glucosides in high yields at ambient conditions. On the other hand when equatorial glucosyl donors were
used, the stereospecificity decreased and resulted in a mixture of anomers. By NMR-studies, it was concluded that this
decrease in stereospecificity was due to an, until now, unpresented anomerization of the trichloroacetimidate under the
very mildly acidic conditions. The mechanism and kinetics of the glycosylations have been studied by NMR-experiments,
which gave an insight into the activation of trichloroacetimidates, suggesting an SNi-like mechanism involving ion pairs. The
scope of glycosyl donors and sulfonamides was found to be very broad including popular N-protective groups and common
glycosyl donors of various reactivity. Peracetylated GlcNAc trichloroacetimidate could be used without the need for any
promotors or additives and a tyrosine side chain was glycosylated as an N-glycosyl carbamate. The N-carbamates and the N-
sulfonyl groups functioned as orthogonal protective groups of the N-glycoside and hence allowed further N-functionalization
without risking mutarotation of the N-glycoside. The N-glycosylation was also performed on a gram scale, without a drop in
stereoselectivity nor yield.
interest in this concept that has since led to substantial advances,
which has recently been reviewed in detail.9,12
Introduction
Trichloroacetimidates (TCAs) remain one of the most
popular glycosyl donors in catalytic glycosylations.1 Since the
introduction of TCA donors by Schmidt,2 numerous Lewis- and
Brønsted acids have been shown to catalyze their activation.2–4
In common for many of the methods is the formation of an
oxocarbenium ion intermediate or similar, i.e. with no memory
of the stereochemistry of the donor.5 The TCAs are synthesized
from reacting the hemiacetal with trichloroacetonitrile under
basic conditions and depending on the conditions, mainly the α-
or the β-anomer can be synthesized.6–8 Since it is possible to
access the TCAs stereoselectively, several researchers have been
interested in utilizing this particular glycosyl donor in
stereospecific glycosylations.9
Stereospecific glycosylations have previously been
performed via pre-complexation in O-glycoside synthesis by
using additives such as chloral,3 boron fluorides10 or silanes11 to
complex the acceptor alcohol making it more acidic and hence
able to activate the trichloroacetimidate. This method was
however initially limited to a few glycosyl donor types and
simple glycosyl acceptors. Still, the early results sparked a wide
Schmidt, 1982
BnO
O
BnO
BnO
HO
O
O
BnO
O
OH
BnO
+
+
P
BnO
P
BnO
HO OH
BnO HO
O
O
NH
CCl3
Miller, 2013
BnO
O
BnO
BnO
BnO
O
O
O
BnO
R
BnO
R
OH
BnO
BnO
O
NH
CCl3
O
Undesired byproduct
This work
-stereoselective
Up to 95% isolated yield
Obtained in one step
PGO
PGO
PGO
O
O
PGO
No additives
SO2Ar
ArO2S
+
O
PGO
PGO
N
H
OR
N
OR
CH2Cl2
PGO
O
NH
CCl3
PGO
O
Scheme 1 Self-promoted O- and N-glycosylations.
In the early eighties, the Schmidt group reported that certain
carboxylic acids and phosphorous acid derivatives could activate
the α-trichloroacetimidates and substitute these with inversion of
stereochemistry (Scheme 1).13 The inversion of stereochemistry
was explained by pre-complexation of the TCA donor and acid,
leading to a pseudo six-membered transition state3 and a
a. Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100
Copenhagen O, Denmark
b. Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61614
Poznań, Poland
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Journal Name
concerted mechanism, without the formation of an 6 exemplifies unreactive, but synthetically interesting glycosyl
View Article Online
DOI: 10.1039/C9SC00857H
oxocarbenium intermediate.
donors.
D-Gluco
BnO
BnO
BnO
Likewise, the Miller group have shown more recently14 that
a wide range of carboxylic acids can act as catalytic activators of
TCA donors, concluding that the catalytic efficiency of these
catalysts was inversely proportional to their pKa-value;
carboxylic acids with higher pKa-values simply resulted in self-
condensation of the catalyst and TCA donor, thus yielding
undesired glycosyl esters. It is important to note that these
glycosyl ester by-products were produced with inverted
stereochemistry compared to the TCA donors (Scheme 1). There
have been numerous reports of the in situ formation of several
different intermediates,15 but the concept of self-condensation of
the glycosyl donor and an acidic reactant in the context of
glycoside synthesis has only received little attention. However,
it seems quite clear that this reaction could have interesting
applications considering the apparent stereospecific formation of
the undesired by-products.
BnO
BnO
BnO
O
O
O
NH
CCl3
2-deoxy-2-azido-D-gluco
AcO
AcO
AcO
N3
2-deoxy-D-Gluco
BnO
BnO
BnO
BnO
O
NH
O
1
1
O
CCl3
D-Galacto
BnO
BnO
O
NH
O
NH
CCl3
5
OBn
O
OBn
O
4
BnO
BnO
CCl3
O
NH
CCl3
BnO
D-GlcNAc
BnO
BnO
2
BnO
BnO
BnO
AcO
AcO
AcO
O
NH
CCl3
O
O
O
NH
CCl3
2
AcNH
O
NH
4
D-Manno
BnO
6
CCl3
BnO
BnO
BnO
O
O
NH
CCl3
3
Low
Relative reactivity
High
Chart 1 Glycosyl donors used in this study.
As part of our ongoing interest in stereospecific catalytic
glycosylations, we have studied acidic N-H groups as potential
self-promoters in glycosylation (Scheme 1).
The scope of glycosyl acceptors consisted of various
functional groups (Chart 2), namely tosylcarbamates 7-11, 16
and 17 and nosylcarbamates 12-15. These carbamates are
selected for various reasons; 7-15 represent a wide pKa-range,
which could give an indication of the limits of the self-promoted
glycosylation procedure, but also vary significantly in size,
allowing an investigation of how steric bulk influences this
particular glycosylation reaction. Also, it was found that both the
tosyl- and nosyl groups can be selectively removed after the
glycosylation using two different procedures, further widening
the scope of post-glycosylational N-functionalization (vide
infra).
An amino acid-derived glycosyl acceptor was also
investigated in this study, namely tyrosine-derivative, 16. Also
carbamate 17 was found as an interesting O-functionalized
carbamate for the self-promoted glycosylations. Compounds 7-
11, 13-15, 16 and 17 were all obtained in a single step from
commercially available starting materials (Scheme 2).
Glycosyl sulfonamides are an important group of compounds
that have been shown to be carbonic anhydrase inhibitors16–20
and more recently, the antitumor activity of this class of
compounds has been recognized.17,21,22 Their synthesis has
mainly been from reduction of the corresponding β-glycosyl
azide,23–27 reductive amination of the lactol,28 from 1,2 diols
using Burgess reagent,29 from glycals16,19,21,30–36 or via anomeric
substitution under strongly acidic conditions.17,37,38 Thus, it
would be of interest to get access to this class of compounds via
a milder, higher-yielding route.
The Miller group have reported that sulfonamides are
sufficiently acidic to act as catalytic activators of TCA glycosyl
donors, enabling the synthesis of O-glycosides in good yields,
albeit with low stereoselectivty.39 This inspired us to develop a
glycosylation procedure in which a glycosyl TCA donor is
condensed with a sulfonamide, leading to the stereoselective
formation of the desired N-glycosides. This reaction takes place
in common organic solvents without the addition of any
additives and is, to the best of our knowledge, the first example
of a self-promoted N-glycosylation. This has resulted in the
stereoselective formation of various glycosyl sulfonamides in
high yields on a gram scale, including the synthesis of an amino
acid-functionalized N-glycoside. We believe that this method
serves as the simplest possible method for selective N-
glycosylations and seek to further broaden its scope and
possibilities in future studies.
Tosylcarbamates
O
H
H
H
H
O
Ts
N
N
N
N
O
N
H
Boc
Ts
Alloc
Ts
Troc
Ts
, pKa = 3.8
Cbz
Ts
7
8
, pKa = 6.0
, pKa = 4.8
9
10
11
, pKa = 5.0
, pKa = 4.8
Nosylcarbamates
O
H
N
H
H
N
O
Ns
N
N
O
Boc
Ns Alloc
Ns Troc
15
Ns
H
12
13
14
, pKa = 4.2
, pKa = 3.7
, pKa = 3.9
, pKa = 3.5
Synthesis of N-glycosides
Amino acid-derived tosylcarbamates
Sugar-derived tosylcarbamate
O
Initial glycosylation reactions
O
O
H
Ts
O
HN
OMe
NHBoc
Glycosyl donors 1-6 (Chart 1) were investigated in a series of
self-promoted N-glycosylations to investigate the effect of
various protecting group patterns, donor reactivities and
configurations; 1-3 represents the three most common glycosyl
donors employed in carbohydrate synthesis, deoxysugar 4
represents a highly reactive glycosyl donor whereas donors 5 and
O
Ts
O
N
O
O
O
H
Tyr-side chain
O
17
, pKa = 4.0
16
, pKa = n.d
Chart 2 Glycosyl acceptors employed for self-promoted N-glycosylations
2 | J. Name., 2012, 00, 1-3
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Table 1 Overview of initial glycosylations employing α-TCA donors 1-6.
View Article Online
DOI: 10.1039/C9SC00857H
O
O
No additive
R1
R2
PGO
PGO
N
+
R1
CH2Cl2 (0.04 - 0.2 M)
rt
H
N
O
NH
CCl3
1.5-2.0 equiv.
R2
Preparation of tosyl- and nosylcarbamates
1-6
7-15
O
O
O
Ts
C
+
Ts
Ns
R-OH
N
RO
N
H
CH2Cl2
rt
Entry
Donor
Acceptor
t (h)
c
Yield
α/βc
(M)a
0.15
0.1
0.2
0.2
0.2
0.08
0.2
0.04
0.08
0.2
0.2
0.2
0.05
0.2
0.2
0.2
0.04
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
(%)b
92
80
90
95
93
67
62
85
95
78
35d
33d
79d
63
61
79
90
90
78
64
74
72
79
66
70
44
45
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24e
25f
26f
27f
1α
1α
1α
1α
1α
1α
1α
1α
1α
1α
1α
1α
1α
2α
2α
2α
2α
2α
3α
3α
3α
3α
3α
3α
5
7
9
9
o.n.
16
16
o.n.
o.n.
o.n.
4.5
1
1
0.75
24
4
o.n.
18
16
2.5
3
5
24
20
o.n.
24
6.5
o.n.
3.25
1.5
1.5
0:100
0:100
0:100
0:100
0:100
1:99
6:94
0:100
6:94
O
NH2
+
Ns
Cl
OR
RO
N
H
CH2Cl2
rt
10
11
12
14
15
15
15
8
13
13
9
11
14
15
15
7
Cheap, commercially
available
Scheme
2 General reaction scheme for the preparation of tosylcarbamates and
nosylcarbamates.
6:94
0:100d
n.d.d
Certain trends were clear from the initial series of
glycosylations carried out from the α-glycosyl donors (Table 1).
Glycosylations with 1α (Entries 1-10) were essentially β-
stereospecific, resulting in yields of 78-95% at various
concentrations. Even notoriously unreactive glycosyl donors
such as 5 and 6 (Entries 25-27) served as suitable glycosyl
donors in this glycosylation procedure, both resulting in
formation of the corresponding β-glycosides in good yields,
albeit at elevated temperatures. No formation of the common
oxazoline by-product40,41 was observed during the glycosylation
with donor 6.
Boc-derivatives 8 and 13 (Table 1, entries 11-13) were
unsuitable for this type of reaction and led to the formation of
by-products which made both purification and determination of
stereoselectivity troublesome. This indicated a certain limit for
the size of the N-substituents for this particular reaction to
proceed successfully. Despite this, the desired N-glycosides were
obtained, although in relatively lowered yields.
Glycosylations involving donor 2α (Entries 14-18)
proceeded in high yields of 61-90%, with a clear preference for
the formation of the desired β-glycoside. Glycosylations with
mannopyranosyl TCA donor 3α were α-selective, indicating that
the formation of 1,2-cis glycosidic linkages were likely
disfavored by the steric factors due to the bulkiness of the
acceptors. This was also the case when the same glycosylation
was carried out at lowered temperature (Entry 24). The steric
bulk of the acceptors was also apparent when analyzing the 1H-
NMR spectra of the α-glycosides since these were found to adopt
a skew boat conformation, whereas all the β-glycosides all
adopted a 4C1-like conformation (Figure 1).
0:100d
29:71
34:66
25:75
26:74
33:67
100:0
100:0
100:0
100:0
100:0
100:0
0:100
19:81
5:95
9
10
11
14
14
15
14
15
6
6
aConcentration of glycosyl donor. bIsolated yield. cDetermined from crude 1H-NMR.
dThe Boc-derivatives 8 and 13 were found to give rise to various by-products,
making it challenging to precisely determine yield and selectivity. eReaction was
stirred at -78 °C for 3 h and then allowed to reach 0 °C. fReaction carried out in 1,2-
dichloroethane at 80 °C.
3J1,2 = 8 Hz
3J1,2 = 9 Hz
SO2Ar
SO2Ar
H
H
OBn
O
N
SO2Ar
N
BnO
BnO
BnO
BnO
BnO
BnO
R
R
BnO
BnO
H
N
R
O
O
OBn
OBn
OBn
H
-N-glucoside
skew boat
-N-glucoside
chair
-N-mannoside



skew boat
Figure 1 Observed conformations of N-glycosides determined from 1H-NMR
coupling constants.
Next, it was investigated whether a glycosylation with β-
TCA glycosyl donors would produce the corresponding α-
It was investigated whether altering the reaction
concentration would have an effect on the yield and selectivity
(Table 1). This gave rise to alternating variations in yield
depending on which acceptor was used, but the stereoselectivity
seemingly remained unaffected by the change in concentration.
In practice, this glycosylation method was incredibly easy as it
only required mixing two compounds in CH2Cl2. Furthermore,
the excess of acceptor could be removed by an extraction with
1M aq. NaOH.42 The excess of acceptor could alternatively be
recovered by flash column chromatography.
glycosides with
a
similar stereospecific inversion of
stereochemistry as was found in the initial glycosylations with
α-TCA donors. These results are summarized in Table 2.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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O
O
Table 2 Overview of glycosylations employing β-TCA donors 1 and 2.
View Article Online
Ts
OMe
HN
OMe
DOI: 10.1039/C9SC00857H
O
NHBoc
NHBoc
Ts
C
CH2Cl2
82%
OBn
OBn
O
+
HO
O
O
N
BnO
BnO
BnO
BnO
R1
R2
+
O
16
N
O
NH
CCl3
CH2Cl2 (0.04 - 0.2 M)
rt
H
R2
N
BnO
or 2
1.5-2.0 equiv.
7-14
BnO
O
O
O
R1
1


O
H
H
O
O
O
O
O
O
+
Ts
C
Ts
CH2Cl2
85%
O
Entry
Donor
1β
1β
1β
1β
1β
1β
2β
2β
Acceptor
t (h)
4 d
16
o.n.
o.n.
24
4.5
o.n.
2.5
c (M)a
0.15
0.2
0.2
0.2
0.04
0.2
0.2
Yield (%)b
α/βc
N
H
N
HO
O
O
17
1
2
3
4
5
6
7
8
7
9
96
73
80
82
45
78
71
67
66:34
43:57
50:50
45:55
76:24
52:48
77:23
80:20
Scheme 4 Synthesis of carbamates 18 and 19.
10
11
12
14
7
conditions for synthesizing the carbamate acceptors (Scheme 2)
were also suitable for the synthesis of two amino acid- or
carbohydrate-derived carbamates, 16 and 17 from cheap,
commercially available starting materials (Scheme 4).
Glycosyl acceptors 16 and 17 were found to perform
convincingly in glycosylations, following similar conditions as
previously described for the glycosylations in Table 1 and Table
2, underlining that even in these more complex systems, there
was still no need for further additives. The glycosylations with
TCA donor 1α (Scheme 5) proceeded with complete β-
stereoselectivity and in high yields, whereas the glycosylation
starting from 1β was reacting slower and resulted a mixture of
anomers.
14
0.2
aConcentration of glycosyl donor. bIsolated yield. cDetermined from crude 1H-NMR.
Generally, the glycosylations proceeded in high yields of 67-
82% and with a higher degree of α-selectivity. It was clear that
although a significantly higher selectivity for the desired α-
glycosides was achieved, the stereospecificity was lower than in
the previous glycosylations summarized in Table 1, indicative of
unfavorable configuration of 1,2-cis-glycosides with bulky
glycosyl acceptors. It is also noteworthy that the galactosylations
(Entries 7 and 8) proceeded with a higher degree of
stereospecificity than the corresponding glucosylations (Entries
1-6).
In an attempt to rule out whether it was a sterically repulsive
effect from the C2-substituents that was inhibiting the formation
of 1,2-cis glycosidic linkages, 2-deoxyglucosyl TCA donors 4α
and 4β were synthesized (Scheme 3). It was however found that
both glycosylations gave rise to essentially identical
stereoselectivity independent on the configuration of the
glycosyl donor, which strongly suggests the formation a
common intermediate, which reacts with a reaction rate near the
diffusion limit, seemingly negating the stereochemical
information from the glycosyl donors.
NHBoc
MeO
O
O
BnO
BnO
BnO
O
Ts
O
HN
OMe
NHBoc
Ts
N
BnO
BnO
BnO
+
BnO
O
O
NH
CCl3
CH2Cl2
4.75 h
67%
O
O
1
16
BnO
18
O
Only 
O
O
O
O
BnO
BnO
BnO
H
O
H
O
O
O
Ts
BnO
BnO
BnO
+
Ts
O
O
N
H
BnO
O
N
CH2Cl2
o.n.
64%
O
NH
CCl3
O
O
1
O
17
BnO
19
Only 
O
O
O
O
H
O
O
O
O
BnO
BnO
BnO
H
O
O
O
O
O
O
O
NH
BnO
BnO
BnO
+
Ts
O
N
H
BnO
Glycosylations with functionalized carbamates
CH2Cl2
3 days
34%
CCl3
O
O
N
1
O
17
BnO
19
/ 56:44
Ts
With a well-established glycosylation procedure in hand, it was
investigated whether this glycosylation strategy could be
employed to make biologically relevant model-compounds
derived from carbohydrates. It was found that the general
Scheme 5 Glycosylations of carbamates 18 and 19 with donors 1α and 1β.
Orthogonal deprotections of N-glycosides
With access to the fully protected or selectively functionalized
N-glycosides, the orthogonality of the protective groups was
evaluated. Initially, the deprotection of the tosylderivatives was
investigated (Scheme 6). Using Zemplén conditions on 20
(K2CO3 in MeOH) under reflux resulted in the deprotected N-
glycoside as a 1:1 mixture of anomers. The same results and ratio
was achieved when using an anomeric mixture of 20. The in situ
anomerization was confirmed by applying the same conditions
on the pure β-anomer of the desired glycosyl sulfonamide, which
again gave the same anomeric ratio. The anomeric ratio was
eventually 1:0.6 after five days of heating (see SI).
OBn
OBn
O
O
O
O
BnO
BnO
BnO
BnO
+
7
N
CH2Cl2
rt, 74 %
O
Ts
O
NH
CCl3
4
 69:31
OBn
O
OBn
O
O
O
BnO
BnO
BnO
BnO
O
NH
CCl3
+
7
N
Ts
CH2Cl2
rt, 87 %
O
 1:5
4
 67:33
Scheme 3 Glycosylations employing 2-deoxy-glycosyl TCA donors 4α and 4β.
4 | J. Name., 2012, 00, 1-3
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OBn
Ns
OBn
O
1: R = -Allyl: 87%
The orthogonal N-deprotections were then studied using
different carbamates, which are more commonly used as
protective groups. The Troc protective group in 21 was
deprotected using Zn in AcOH at 70°C giving the glycosyl
sulfonamide in 82% yield albeit still with some anomerization
(α/β 28:72). The Boc protective group in 22 was deprotected
under acidic conditions, TFA in CH2Cl2, and gave the glycosyl
sulfonamide in 84% as a mixture of anomers. The problems with
anomerization under acidic or basic conditions could be
overcome by using the Alloc protective group (23), as it was
deprotected under milder conditions using palladium catalysis in
combination with a mild acid or nucleophile.29 The removal of
the Alloc protective group was performed on a variety of
substrates, with different stereochemistry, and both the Ts or Ns
group. No anomerization was observed under these conditions
and the glycosyl sulfonamides could be isolated in high yields
(89 and 87% respectively, Schemes 6 and 7). With the protocols
for carbamate deprotections in place, the attention was turned to
the desulfonylation to give the corresponding N-glycosyl
carbamates.
The Ts-group has a somewhat bad reputation as an N-
protective group and the first attempts to remove it were indeed
not very successful. As an example, deprotection using lithium
naphthalide only gave 22% of the desired product. Instead,
employing the protocol by Nyasse et al.43 turned out to be the
solution (Scheme 6). Magnesium turnings were used as the
reductant in anhydrous MeOH at rt and under these mild
conditions, the desired carbamate-protected N-glycosides could
be obtained in high yields. The major byproduct was found to be
the glycosyl sulfonamides, i.e. carbamate deprotection, which
increased if water was present. The reductive removal of the Ts-
group worked well on the various N-glycosides with different
carbamate protective groups. Removal of the Ns-group (Scheme
7) was more straightforward using thiophenolate in DMF,
employing either K2CO3 or KOH as the base. This reaction was
generally fast and clean giving isolated yields in the range of 58-
96% depending on the conditions. Caution should however be
taken not to leave the reaction at prolonged reaction times, as
anomerization eventually takes place.
View Article Online
2: R = -CH2CCl3: n.r. a
O
BnO
BnO
BnO
BnO
N
O
1, 2 or 3
R
DOI: 10.1039/C9SC00857H
Ns
3: R = -tBu: 70% b
N
BnO
BnO
O
H
25: R = -CH2CH2OCH2
26: R = -CH2CCl3
27: R = -tBu
PhSH
K2CO3 or KOH
R = -CH2CH2OCH3: 86%c
R = -Allyl: 76%c
R = -CH2CCl3: 58%c
R = -CH2CCl3: 63%d
R = -tBu: 96%d
OBn
O
H
DMF
BnO
BnO
N
OR
28: R = Allyl
BnO
O
Scheme 7 Orthogonal Deprotection of Nosyl-Protected N-Glycosides. Reaction
conditions 1) Sodium p-toluenesulfinate (1.1 equiv.), Pd(PPh3)4 (0.1 equiv.),
0.012M in MeOH/THF 1:2, rt, 1.5 h. 2) Zn (20 equiv.), 0.025M in AcOH, rt, 0.5 h. 3)
TFA (20 equiv.), 0.4m in CH2Cl2, rt, o.n. aResulted in reduction of the Ns nitro group
to the corresponding amine. bGlycosylation and deprotection carried out in a
single step, 70% overall yield. cK2CO3 used as base. dKOH used as base.
The carbamate-deprotection of nosyl-protected N-glycosides
25-28 (Scheme 7) proved to be somewhat more challenging
compared to the tosyl-derivatives, since the Ns-group is
generally more sensitive towards various reaction conditions.
Thus it was reduced to the amine with Zn in AcOH when trying
to remove the Troc group in 26. The deprotection of the Alloc-
and Boc-groups (27 and 28 respectively) was however efficient,
resulting in yields of 70-77%. Thus it seemed that for both tosyl-
and nosyl-protected N-glycosides, the ideal combination with
both was the Alloc protective group.
Scale-up and N-Functionalization
With optimized deprotection-procedures in hand, a significant
upscaling of the reaction was carried out (Scheme 8). It was
found that N-deprotected glycosides 29 and 30 could be obtained
in
82%
and
76%
yields
accordingly
in
a
glycosylation/deprotection procedure following optimized
reaction conditions from Scheme 6. Furthermore, the two
products, 29 and 30, are crystalline which simplifies purification
and isolation on a large scale, yielding two ideal starting
materials for further N-funtionalization.
Worth mentioning is the formation of a minor byproduct
during the Alloc-deprotection to give 29, namely allyl p-tolyl
sulfone,44 via a sulfonate-sulfone rearrangement that has
previously been shown to take place under similar
conditions.45,46
OBn
H
O
BnO
BnO
N
Ns
BnO
29
OBn
BnO
BnO
BnO
Ts
N
1: R = -CH2CH2OCH3: 65%
2: R = -CH2Cl3: 82%
3: R = -tBu: 84%
Conditions
1, 2, 3 or 4
O
O
OR
BnO
BnO
>10 g
Alloc-Cl
Et3N
DMAP
-anomer is crystalline
Ts
O
O
Purified by crystallization
OBn
-Tol-SO Na
Pd(PPh3)4
MeOH/THF 1:2
N
p
BnO
2
O
H
S
4: R = Allyl: 89%
82%
Ns
Alloc
20: R = -CH2CH2OCH2
21: R = -CH2CCl3
22: R = -tBu
NH2
OBn
O
N
H
Mg, MeOH
Sonication
CH2Cl2
71%
H
R = -CH2CH2OCH3: 80%
R = -Allyl: 84%
R = -Bn: 66%
O2N
OBn
O
BnO
BnO
N
OR
Alloc
2 g scale
OBn
23: R = Allyl
BnO
BnO
BnO
N
O
Ns
CH2Cl2
88%
24: R = Bn
O
BnO
BnO
OBn
O
Cl3CCN
NaH
CH2Cl2
BnO
11:89

76%
PhSH
K2CO3
DMF
BnO
BnO
BnO
O
NH
CCl3
Scheme 6 Orthogonal deprotection of tosyl-protected N-glycosides. Reaction
conditions: 1) K2CO3 (2 equiv.), 0.02m in MeOH, reflux, 4 h. 2) Zn (8 equiv.), 0.12m
in AcOH, 70 °C, 2 h. 3) TFA (20 equiv.), 0.03m in CH2Cl2, rt, 8 h. 4) PhSiH3 (4 equiv.),
Pd(PPh3)4 (0.05 equiv.), 0.75m in CH2Cl2, rt, overnight.
OH
BnO
1,
92:8

75%
OBn
H
O
BnO
BnO
N
Alloc
BnO
30,
10:90

-anomer is crystalline
Scheme 8 Gram-scale synthesis of 1-amino-1-deoxy-glycosides.
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Table 3 Comparison of relative rate constants and pKa-values of glycosyl acceptors.
View Article Online
DOI: 10.1039/C9SC00857H
a
Acceptor
pKa
3.9
5.0
3.8
4.8
4.2
3.7
3.5
krel
R2 b
OBn
O
NHBoc
O
HO
O
7
0.019
0.014
0.53
0.99
0.99
0.99
0.95
1.00
1.00
O
O
OBn
O
DIC
DMAP
H
Bn
BnO
BnO
9
BnO
BnO
N
+
O
Ns
CH2Cl2
82%
N
NHBoc
31
BnO
29
BnO
Ns
10
11
13
14
15
32
BnO
0.15
Scheme 9 Synthesis of glycopeptide model 32.
0.0053
1.00
With the deprotected N-glycoside 29 in hand, it was
investigated whether this would be a suitable starting material
for synthesis of glycopeptides. Several methods were
investigated, but it was found that the NH of 29 could undergo a
DIC coupling with a commercially available aspartic acid
building block 31, facilitating the synthesis of 32 in an 82% yield
with no anomerization taking place. This underlines the
efficiency of the self-promoted glycosylations, since relatively
complex compounds such as 32 can be achieved in very few
simple and high-yielding steps.
~25 c
‒
c
aRelative rate. krel for consumption of 1α under reaction with acceptor 14 set to
1.00. Determined from 1H-NMR in CD2Cl2 at 300 K using mesitylene as internal
standard. Donor concentration was 0.032 mM and 1.5 equiv. of acceptor was used
in all cases. bLinear fit to ln[1α] vs. time. CStarting material was already consumed
when two 1H-NMR spectrums had been acquired.
To determine the overall reaction order, a series of glycosylation
reactions with varying concentrations were carried out and followed
by 1H-NMR-spectroscopy. Acceptor 10 was chosen as the model
compound for this experiment as it expressed mid-range reactivity
according to Table 3. When doubling the concentration of either 1α
or 10, the estimated initial rate of product formation was
approximately doubled, hence suggesting a second order reaction
mechanism. Graph S1 and S2 (see SI) clearly demonstrates the
dependence of initial rates on changing concentrations of 1α and 10.
Mechanistic studies
Reaction kinetics
Having established a solid understanding of the scope of the
reaction, the reaction mechanism was scrutinized via NMR-
experiments and kinetic studies. Since the glycosyl acceptors all
have different pKa-values ranging from 3.5-6.0, a series of
glycosylations were followed by 1H-NMR to clarify whether the
pKa-values corresponded to the observed rate of reaction. All
reactions follow a first-order kinetic profile in the glycosyl
donors (See SI) and the relative rate constants are summarized in
Table 3.
From Table 3 it is clear that there is no clear correlation between
the acidity of the glycosyl acceptors and the relative rate of
glycosylation, which underlines that steric parameters may be
similarly important. It is however noteworthy that all the nosyl-
derivatives 14-15 react considerably faster than the tosyl-
derivatives 7-11.
Table 4 Overview of estimated initial rates at various concentrations.
c(1α)(mM)
29
c(10)(mM)
58
v(initial)(mM hr-1)a
15
25
58
58
117
234
58
58
58
29
58
157
15
58
58
117
234
55
162
aDetermined from 1H-NMR in CD2Cl2 at 300 K using mesitylene as internal standard.
NMR-studies
1
Next, the reaction mechanism was investigated by H-NMR. It
was decided to use carbamate 7 as a model acceptor since this
particular acceptor reacted somewhat slowly, thus being suitable
1
for the H-NMR time scale. Furthermore, the progress of the
reaction could also easily be determined due to the –OCH3
group, which is distinguished from other signals in the crude
spectra. The glycosylation of glycosyl donors 1α and 1β were
1
followed by H-NMR at room temperature to identify possible
intermediates or by-products formed during the reaction. The
glycosylation of 1α proceeded as expected (Scheme 10), yielding
only the desired product 20β. However, during the glycosylation
of 1β, it was found that the β-TCA donor partly anomerized in
situ to the corresponding α-TCA donor as a competing reaction,
which was then glycosylated, yielding the β-N-glycoside (Figure
6 | J. Name., 2012, 00, 1-3
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2A and 2B). This in situ anomerization is unprecedented in equatorial TCA donors gave lower selectivity, which could be
View Article Online
organic solvents and has only previously been reported by Poletti because of certain steric requirements DfOoIr: 10a.10d3o9n/Cor9-SaCc0c0e8p5t7oHr
when performing glycosylations in ionic liquids.47,48 Thus, it complex. Therefore, it was investigated whether a complex
seems that the β-TCA donor reacts via two competing reaction between donor 1α and acceptor 7 was initially formed during the
1
pathways: Either it reacts in a glycosylation, apparently yielding glycosylations (Scheme 11). However, no change in the H-
primarily the α-N-glycoside, but the competing reaction yields NMR spectrum of either 1α or 7 was observed when titrating the
the α-TCA donor that is then converted exclusively into the β-N- donor with acceptor (0.2-1.0 equiv., See SI), ruling out the
glycoside, thus giving rise to anomeric mixtures of 20α and 20β. formation of a stable donor-acceptor complex.
The kinetics are of first order for both glycosyl donor and
acceptor. The selectivity observed, with inversion of
stereochemistry, suggests an SN2-like reaction, which could be
OBn
OBn
O
O
on the protonated acetimidate, i.e. involving associated ion-pair
and therefore an SNi-type of mechanism as recently suggested by
Tanaka et al. for a glycosylation reaction.54 When the solvent
polarity is increased, e.g. by using acetonitrile (Scheme 12), 33
is formed. This indicates the formation of a glycosyl cation, and
competition from the solvent when the ion-pair is more
Ts
N
O
O
BnO
BnO
O
Ts
O
BnO
BnO
O
+
O
7
N
H
BnO
O
NH
CCl3
BnO
O
1

20
-specific
OBn
O
O
OBn
O
BnO
BnO
O
NH
O
Ts
O
+
O
N
BnO
BnO
H
BnO
dissociated.
It should be emphasized that the reaction
CCl3
Anomerization
N
BnO
O
7
1

Ts
20
Mixture of anomers
mechanism can change and these conditions cannot be directly
transferred to reactions in CH2Cl2.
OBn
O
Glycosylation
7
BnO
BnO
BnO
O
NH
1

CCl3
Observed by 1H-NMR
O
O
O
O
O
BnO
BnO
OBn
O
OBn
O
Ts
H
N
O
Ts
N
BnO
BnO
BnO
BnO
BnO
O
Scheme 10 Observed difference in the glycosylation behavior of glycosyl donors
1α and 1β. Conditions: T=300K 0.075m in dry, neutralized CDCl3 (passed through
basic Al2O3) using 3 equiv. of acceptor 7.
7
+
BnO
BnO
O
NH
CCl3
BnO
O
N
H
1
CCl3
Not observed by 1H-NMR
1
1
20
20
A
B
70
60
50
40
30
20
10
0
70
60
50
40
1
1
Scheme 11 Proposed complex favoring an SN2-like reaction mechanism.
c
c
(mM) 30
(mM)
20
10
0
OBn
OBn
O
O
-10
O
BnO
BnO
0
2
4
6
8
10
0
10
20
30
40
50
60
BnO
BnO
7
+
Ts
N
t (hr)
t (hr)
MeCN
rt
BnO
33
O
NH
CCl3
BnO
or 1
N
O
1


33% from 1
86% from 1
O
Figure 2 A) Graphical illustration of the anomerization of 1β to 1α under the
reaction conditions shown in scheme 10. B) Graphical illustration of the formation
of either 20α or 20β during the anomerization of 1β. Mesitylene was used as an
internal standard for concentration determination.
Scheme 12 Trapping of glycosyl cation by using acetonitrile as the solvent.
Two simplified mechanistic scenarios for both the α- and β-
anomer are shown in Scheme 13. Two different conformers (A
and D) have been proposed for the α-TCA donors of which A
has previously been found to be energetically favorable.3 Upon
activation of A, the associated ion pair, B, will be formed. In this
ion pair, the amide ion is in close proximity to the glycosyl cation
intermediate, and should thus react to form C much more readily
than its counterpart E in which the nucleophilic attack is
sterically hindered by the C-2 substituent, blocking the required
trajectory leading to F.
Also, the back reaction to form the TCA donor D could be a
competing reaction (orange dotted arrow). This can explain why
such a high preference for the formation of 1,2-trans-glycosides
was found for both the gluco and galacto α-TCA donors. The
manno donors (not shown) also yielded 1,2-trans-glycosides, as
the associated ion pair B would be obscured by the axial C-2
The mechanistic details of the glycosylation reaction have been
discussed thoroughly for more than half a century.49,50,51
Recently, the interest in mechanistic studies in glycosylation
chemistry received renewed interest with the appearance of new
methods for selective glycosylations, suggesting SN2-like
mechanisms.5,52 Also, the conformation of the oxocarbenium ion
has been found to influence the stereochemical outcome of
glycosylations.53
From the results of the mechanistic investigation, it is clear
that the glycosylation of the α- and the β-TCA donors do not
necessarily pass through the same intermediate and hence can
follow different reaction paths. In many cases, the reaction gave
inversion of stereochemistry, which was most pronounced using
the axial TCA in 1,2-cis glycosyl donors. On the other hand, the
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1
substituent, instead making the dissociated ion pair E the more by H-NMR) will be a competing reaction. Thus,ViietwseAretimclesOtnhlinaet
DOI: 10.1039/C9SC00857H
both reaction pathways leading to products I and L will have
favorable intermediate leading to F.
For the β-TCA donors (Scheme 13, right side), two different certain drawbacks, possibly explaining the lowered
conformers (G and J) are also presented. Here, however, the stereoselectivity observed during glycosylations with β-TCA
associated ion pair H will not be as favorable as its counterpart donors. The lowered stereoselectivity is also a natural
B since the C-2 substituent of H will block the trajectory of the consequence of the observed formation of the α-TCA as this will
incoming nucleophile, impeding the formation of I. On the other result in a loss of stereochemical information from the glycosyl
hand, the dissociated ion pair, K, should have less hindered donor.
trajectory for the nucleophilic attack, leading to L, but since the
nucleophile will be further away from the glycosyl cation, and
possibly hydrogen-bonded to the leaving group, the
anomerization to the corresponding α-TCA donor (as observed
-TCA
D
-TCA
J


R'
H
R
R'
O
N
R
O
N
H
O
A
G
O
O
X
O
CCl3
NH
O
CCl3
X
O
O
NH
NH
CCl3
X
X
O
NH
CCl3
NH
R'
X
CCl3
Anomerization to -TCA
R'
H
H
N
N
R
R
Dissociated ion pair
Dissociated ion pair
Associated ion pair
Associated ion pair
R
R'
O
N
R
O
CCl3
NH2
E
O
N
O
X
R'
B
H
K
CCl3
NH2
H2N
O
O
X
O
X
NH2
O
X
CCl3
R
N
CCl3
N
R'
R
R'
Favorable
trajectory
Unfavorable
trajectory
Unfavorable
trajectory
Unfavorable
trajectory
R
R
C
F
I
L
O
O
O
X
O
N
N
R'
R'
X
X
N
N
X
R
R'
R
R'
Major product
Scheme 13 Proposed intermediates during an SNi-like glycosylation with both α- and β-TCA glycosyl donors.
enabling easily accessible 1-amino-1-deoxy glycosides for
further functionalization.
The selectivity and reaction mechanism has been
investigated on basis and NMR-experiments and an SNi-like
mechanism has been proposed.
The self-promoted glycosylation was shown to allow
acceptors with a wide range of pKa-values (3.5-6.0) and very
different steric bulk. It was also shown that the procedure was
easily scaled up to a column-free procedure on multiple grams
without observing a drop in selectivity and yield, which
underlines that this glycosylation protocol represents a way of
simplifying N-glycosylations, whilst still achieving high yield
and selectivity.
Conclusions
In conclusion, we have developed
a self-promoted N-
glycosylation using TCA donors and easily obtainable N-
sulfonyl carbamates. It has been shown that tosylcarbamates,
easily obtained from amino acids or carbohydrates, are capable
of reacting in this self-promoted glycosylation, which could be
of great interest in the glycosylation of e.g. peptide side chains
or other biomolecules. The obtained N-glycosides are stable and
hence could be a useful linker for biomolecules in general as they
can be used for classic coupling reactions with carboxylic acids,
giving glycosyl amides in high yields.
Besides the very mild reaction conditions, it was found that
the reaction often was stereospecific, especially when
substituting an axial TCA, even in the absence of neighboring
group participation. In addition, this glycosylation method
allows for the orthogonal deprotection of the N-glycosides,
It is our belief that this method could prove very valuable in
the synthesis of various biomolecules and a further investigation
into the scope of this method for the functionalization of proteins
and other relevant biomolecules is currently on-going in our
laboratory.
8 | J. Name., 2012, 00, 1-3
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(20)
(21)
(22)
Winum, J.-Y.; Colinas, P. A.; Supuran, C. T. Bioorg. Med.
Conflicts of interest
There are no conflicts to declare.
View Article Online
DOI: 10.1039/C9SC00857H
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Crespo, R.; de Bravo, M. G.; Colinas, P. A.; Bravo, R. D.
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Acknowledgements
We thank Christian Tortzen for his help with NMR-experiments.
Professor Richard R. Schmidt is acknowledged for fruitful
discussions. PM acknowledge grant no. POWR.03.02.00-00-
I026/16 co-financed by the European Union through the
European Social Fund under the Operational Program
Knowledge Education Development, for support. We also thank
the anonymous reviewers for their comments and valuable
input for the discussion of the mechanistic studies.
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