Glycosyl alkoxythioimidates as building blocks for glycosylation: A reactivity study

Article abstract of DOI:10.1016/j.carres.2014.06.025

Structural modifications of the leaving group of S-glycosyl O-methyl phenylcarbamothioates (SNea) involving change of substituents that express different electronic effects led to a better understanding of how the reactivity of these glycosyl donors can b

Full text of DOI:10.1016/j.carres.2014.06.025

Carbohydrate Research xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Glycosyl alkoxythioimidates as building blocks for glycosylation:
a reactivity study
⇑
Sneha C. Ranade, Alexei V. Demchenko
Department of Chemistry and Biochemistry, University of Missouri – St. Louis, St. Louis, MO 63121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Structural modifications of the leaving group of S-glycosyl O-methyl phenylcarbamothioates (SNea)
involving change of substituents that express different electronic effects led to a better understanding
of how the reactivity of these glycosyl donors can be modified by changing the structure of their leaving
groups. Mechanistic studies involving the isolation of departed aglycones were indicative of the direct
activation of both p-methoxy-SNea and p-nitro-SNea leaving groups via the anomeric sulfur rather than
the remote nitrogen atom. The presence of an electron donating substituent (p-methoxy) has a strong
effect on the nucleophilicity of the sulfur atom that becomes more susceptible toward the attack of
thiophilic reagents, in particular. This key observation allowed to differentiate the reactivity levels of
p-methoxy-SNea versus p-nitro-SNea and even unmodified SNea leaving groups. The reactivity difference
observed in the series of SNea leaving groups is sufficient to be exploited in expeditious oligosaccharide
synthesis via selective activation strategies.
Received 29 April 2014
Received in revised form 16 June 2014
Accepted 22 June 2014
Available online xxxx
Keywords:
Glycosylation
Thioimidates
Carbohydrates
Oligosaccharides
Ó 2014 Published by Elsevier Ltd.
1. Introduction
strategy for oligosaccharide synthesis.6 The armed–disarmed strat-
egy has been exploited in a number of ways, and a variety of chemo-
Structural complexity of carbohydrates makes these natural
compounds attractive and challenging targets for many synthetic
chemists. In spite of the abundance of complex carbohydrates in
nature, their isolation and purification are cumbersome. Chemical
and enzymatic syntheses are also challenging, and many past and
ongoing research efforts have been directed to improve synthetic
capabilities to obtain oligosaccharides with high efficiency and
yields. The outcome of chemical glycosylation reactions is largely
dependent on a variety of factors that include the structure of gly-
cosyl donor, glycosyl acceptor, activator, solvent, temperature,
etc.1–4 Among these, different aspects and components of the
glycosyl donor, such as the structure and the mode of activation
of the leaving group, the nature of protecting groups, conforma-
tion, configuration, etc. all may have a profound effect on stability
and reactivity of glycosyl donors and often affect the outcome of
glycosylation.
selective approaches, many of which are based on the previously
underappreciated effect of remote protecting groups, have emerged
as its extension. These more recent adjustments of the classic
armed–disarmed strategy include torsional deactivation,7–9 tunable
reactivity,10 programmable synthesis,11 deactivation by a single
remote moiety,12,13 inverse armed–disarmed,14,15 conformationally
superarmed,16–19 electronically superarmed/superdisarmed,20–23
and other approaches.24
While the electronic effect of both neighboring and remote pro-
tecting groups on the reactivity of glycosyl donors has been inves-
tigated in a variety of ways,25–27 the electronic effects originated
from the leaving group are much less explored beyond a series of
glycosyl halides.28,29 Roy and co-workers were among the first to
observe the differential reactivity of electronically activated p-(N-
acetamido)phenyl thioglycoside versus electronically deactivated
p-nitrophenyl counterpart. This discovery led to the development
of a practical and efficient strategy for oligosaccharide synthesis
termed active-latent strategy.30 The active-latent concept was fur-
ther extended by Fraser-Reid,31 Boons,32 Kim,33,34 and others,35–37
but, to the best of our knowledge, only Roy’s original approach
relies on the reactivity differentiation by electronic properties of
the leaving group.
The effect of neighboring protecting groups on reactivity of
glycosyl donors and stereoselectivity of their glycosidation has been
noticed long time ago.5 A dedicated study by Fraser-Reid and co-
workers generalized the accumulated knowledge and served as
the basis for the development of a so-called ‘armed–disarmed’
Along similar lines, Kahne et al. demonstrated the difference in
reactivity depending on the nature of the substituent at the para-
position of phenyl sulfoxides.38 In this study, the reactivity was
⇑
Corresponding author. Tel.: +1 3145167995.
E-mail address: demchenkoa@umsl.edu (A.V. Demchenko).
http://dx.doi.org/10.1016/j.carres.2014.06.025
0008-6215/Ó 2014 Published by Elsevier Ltd.
Please cite this article in press as: Ranade, S. C.; Demchenko, A. V. Carbohydr. Res. (2014), http://dx.doi.org/10.1016/j.carres.2014.06.025

2
S. C. Ranade, A. V. Demchenko / Carbohydrate Research xxx (2014) xxx–xxx
observed to decrease in the following order: OMe > H > NO2. The
difference in the reactivity was utilized for the synthesis of Cicla-
mycin 0 trisaccharide via selective two-step activation in one
pot. Similar observations of electronic effect originated from vari-
ous substituents on the leaving group have been reported by van
Boom and co-workers,39 Hanessian et al.,40 and our group.41
As a part of the ongoing research effort to develop new glycosyl
thioimidates as versatile building blocks for chemical35,36 and
enzymatic42 glycosylation,43,44 previously we introduced glycosyl
alkoxythioimidate donor (SNea, Fig. 1).45 This leaving group was
specifically designed as the bridging intermediate leaving group
between glycosyl thiocyanates46,47 and S-benzoxazolyl (SBox)
thioimidates.48,49 Our anticipation was that the activation profile
of the SNea leaving group would be similar to that of both thiocy-
anates and SBox leaving groups. We were intrigued, however, by a
significant discrepancy of results obtained with the SNea donor
and the structurally similar SBox donor. The activation profile
seemed so drastically different that this even allowed us to develop
an orthogonal-like activation50 of building blocks equipped with
SNea (rapidly activated with copper(II) triflate) and SBox (rapidly
activated with methyl triflate) leaving groups.45
On the other hand, comparative studies between glycosyl thio-
cyanate and glycosyl SNea donors showed that the activation con-
ditions for these two glycosyl donors are similar.45 Earlier
mechanistic investigations indicated that the SBox leaving group
tends to be activated via the anomeric sulfur51 (direct activation
pathway similar to that of alkyl/aryl thioglycosides)52 regardless
of the activation condition chosen. Relying on the similarity of
reactivity of SNea and SCN leaving groups we hypothesized that
glycosyl SNea donors may follow the remote activation pathway
as seen in case of glycosyl thiocyanates (Fig. 1).46,47 Reported
herein is a dedicated study involving a series of building blocks
modified with electron-withdrawing and electron-donating sub-
stituents at the phenyl group of SNea leaving group that was
designed to test this hypothesis. We postulated that the presence
of these substituents would have a significant effect on the
nucleophilicity of the nitrogen atom. Hence, if the activation of
the SNea moiety was indeed taking place via the remote
nitrogen, such modifications would significantly impact the
reactivity of the respective alkoxythioimidoyl leaving group. We
also thought that the effect of such modification on the
nucleophilicity of the anomeric sulfur atom (direct activation)
would be somewhat weaker due to the remoteness of these two
centers.
nitrogen atom, we obtained a series of glycosyl donors: standard
SNea donor (1),45 p-methoxy-SNea donor (2), and p-nitro-SNea
donor (3, Table 1) using earlier established protocols.45 In order
to test the relative reactivity of a new series of glycosyl donors in
glycosylation we chose a range of metal triflates that showed
excellent results with glycosyl thioimidates and SNea donors in
our previous studies.44 Herein, we tested copper(II) trifluorometh-
anesulfonate (Cu(OTf)2), bismuth(III) trifluoromethanesulfonate
(Bi(OTf)3), and silver(I) trifluoromethanesulfonate (AgOTf). Glycos-
idation reactions of donor 1 with acceptor 453 in the presence of
Cu(OTf)2 or Bi(OTf)3 as promoters were very smooth and com-
pleted within 1 h. As a result, disaccharide 554 was isolated in
91% and 95% yields, respectively (entries 1 and 2, Table 1).
AgOTf-promoted glycosylation reaction was even faster (30 min)
and disaccharide 5 was obtained in 95% yield (entry 3, Table 1).
Encouraged by this strong performance of SNea donor 1, we
turned our attention to investigating the modified donors. When
p-methoxy-SNea donor 2 was reacted with glycosyl acceptor 4 in
the presence of Cu(OTf)2, a similar result to that obtained with stan-
dard SNea donor 1 was achieved. The glycosidation required a
slightly longer time (2 h for 2 vs 1 h for 1) and afforded disaccharide
5 in 86% yield (entry 4, Table 1). In case of Bi(OTf)3, the reaction was
much faster and completed within 10 min (1 h for 1) to give disac-
charide 5 in 93% yield (entry 5, Table 1). AgOTf-promoted reaction
gave 97% of disaccharide 5 in 30 min, which was practically the
same reaction time as that recorded for SNea donor 1. Resultantly,
disaccharide 5 was isolated in 97% yield (entry 6, Table 1). As a
whole, these comparative glycosylations showed that both SNea 1
and p-methoxy-SNea 2 thiocarbamates are excellent glycosyl
donors for chemical glycosylation. p-Methoxy-SNea derivative 2
showed slightly decreased reactivity in the presence of Cu(OTf)2
and was significantly more reactive in the presence of Bi(OTf)3.
In case of the reaction of p-nitro-SNea donor 3 with glycosyl
acceptor 4 in the presence of Cu(OTf)2 disaccharide 5 was formed
in 90% yield showing somewhat insignificant deviation in reactiv-
ity (entry 7, Table 1). The reaction of p-nitro-SNea donor 3 with
acceptor 4 in the presence of Bi(OTf)3 gave disaccharide 5 in 71%
yield (entry 8) in 1 h, similar to that of glycosidation of the stan-
dard SNea donor 1. Interestingly, donor 3 reacted very slowly in
the presence of AgOTf, and even after 24 h only trace amount of
disaccharide 5 was obtained (entry 9).
Since the results of activations of different leaving groups with
metal triflates were somewhat inconclusive, we decided to deepen
this study by looking into other activation strategies. In addition, in
order to gain the direct proof of the mode of activation, it would be
desirable to isolate and establish the structure of the departed
aglycones.55 Although we had had some prior success,56 elucida-
tion of exact mode of activation using metal-based promoters
can be difficult. This is because upon departure, thioimidoyl
2. Results and discussion
With these considerations in mind, and to test the hypothesis of
the anticipated remote activation of the SNea leaving group via the
Examples of Remote Activation
E
?
H
S
S
N
O
O
E
S
S
N
N
O
O
thiocyanates
OMe
EW
SNea
H
N
???
ED
Examples of Direct Activation
E
E
O
O
S
N
S
OBz
OBz
O
S-alkyl/aryl
SBox
Figure 1. Direct versus remote activation of leaving groups and possible electronic effects.
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S. C. Ranade, A. V. Demchenko / Carbohydrate Research xxx (2014) xxx–xxx
3
Table 1
Comparative glycosidations of glycosyl donors 1–3 with glycosyl acceptor 4 in the presence of various metal-based promoters
OBz
O
OBz
O
OH
O
Promoter
BzO
BzO
BzO
BzO
BnO
BnO
O
S
N
MS 3Å/4Å
DCE
BzO
O
BnO
OBz
BnO
O
BnO
OMe
R
BnO
4
OMe
5
1: R = H
2: R = OMe
: R = NO2
3
Entry
1
Glycosyl donor
OBz
Promoter (3 equiv)
Cu(OTf)2
Time
Yield (%) of 5
O
BzO
S
N
BzO
1 h
1 h
91
OBz
O
1
1
1
2
3
Bi(OTf)3
AgOTf
95
95
30 min
OBz
O
BzO
S
N
BzO
4
Cu(OTf)2
2 h
86
OBz
O
O
2
2
2
5
6
Bi(OTf)3
AgOTf
10 min
30 min
93
97
OBz
O
BzO
S
N
BzO
7
Cu(OTf)2
2 h
90
OBz
O
NO2
3
3
3
8
9
Bi(OTf)3
AgOTf
2 h
24 h
71
<10
leaving groups often result in the formation of metal inclusion
polymers (AMASAC@NA)n, which are very cumbersome to char-
acterize.56 Having these considerations in mind, while turning
our attention toward studying alternative activation pathways
we were particularly interested in those pathways that would
allow for gaining a reliable insight into the activation mode of
alkoxythioimidates. Hence, promoters used for this extended study
included methyl trifluoromethanesulfonate (MeOTf), N-iodosuc-
cinimide/trifluoromethanesulfonic acid (NIS/TfOH), and trimethyl-
silyl trifluoromethanesulfonate (TMSOTf). These reaction
conditions were proven successful for determining activation
pathways of SBox (MeOTf),56 STaz (MeOTf, BnBr),57 SBiz (BnBr),41
SEt (MeOTf),52 and ortho-allylphenyl (TMSOTf and NIS/TfOH)58
leaving groups. We also included molecular iodine (I2) into the list
of promoters to be tested due to our fruitful experience with differ-
entiating armed versus super armed levels of reactivity of various
thioglycosides and thioimidates using these reaction conditions.23
With this new set of promoters, we were bound to improve our
understanding of the activation modes and relative reactivities of
glycosyl donors 1–3. The progress of all side-by-side experiments
was monitored by TLC, and the reactions were quenched as soon
as the acceptor has been consumed. To maintain standard compar-
ison between different glycosyl donors, the incomplete reactions,
as judged by TLC, were stopped after 24 h. Previously, we have
shown that glycosyl SNea donor 1 reacts quite sluggishly in the
presence of 3 equiv of MeOTf.45 Indeed, reaction of donor 1 with
glycosyl acceptor 4 was practically ineffective, and even after
24 h afforded disaccharide 5 in only 12% yield (entry 1, Table 2).
The activation of SNea donor 1 was also ineffective in the presence
of iodine, wherein no traces of the anticipated product 5 were
detected (entry 2). SNea donor 1 was much more reactive in the
presence of NIS/TfOH or TMSOTf; these reactions completed in
3–3.5 h. However, disaccharide 5 was formed in modest yields of
45% and 65%, respectively, due to high rates of competing hydroly-
sis, as judged by accumulation of the corresponding hemiacetal
derivative (entries 3 and 4, Table 2). Thus, none of these non-
metallic electrophilic promoters offered
a reliable activation
pathway for glycosidation of SNea donor 1 at the ambient temper-
ature. Lowering the reaction temperature allowed to control the
competing hydrolysis and afforded disaccharide 5 in a higher yield.
This result, however, cannot be compared with all other experi-
ments performed at room temperature and, hence, is not listed.
Encouragingly, p-methoxy-SNea donor 2 was significantly more
reactive than its non-substituted SNea counterpart 1. Both MeOTf
and molecular iodine, which were practically ineffective with
donor 1, promoted glycosidations of glycosyl donor 2 with accep-
tor 4. These reactions were still rather slow and incomplete even
after 24 h, but disaccharide 5 was obtained in 62% and 43% yields,
respectively (entries 5 and 6). NIS/TfOH promoted glycosidation of
2 was completed in 30 min, but again yielded disaccharide 5 in a
modest yield of 48% due to the competing hydrolysis (entry 7).
Similar reaction time was recorded for glycosidation of donor 2
with acceptor 4 in the presence of TMSOTf, but this reaction was
much cleaner and afforded disaccharide 5 in 90% yield (entry 8).
Similar to our earlier observations made with metal triflates, p-
methoxy donor 2 showed over-all higher reactivity in comparison
to that of its unmodified SNea counterpart 1 in the presence of
non-metallic promoters. While in a series of metal triflates, only
Bi(OTf)3 showed a significant level of differentiation between the
reactivities of donors 1 and 2, practically every non-metallic elec-
trophilic promoter was much more effective with p-methoxy-SNea
donor 2, as surveyed in Table 2.
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4
S. C. Ranade, A. V. Demchenko / Carbohydrate Research xxx (2014) xxx–xxx
Table 2
Comparative glycosidations of donors 1–3 with acceptor 4 in the presence of various electrophilic and thiophilic promoters
Entry
Donor
Promotera
Time
24 h
Yield (%) of 5
OBz
O
BzO
BzO
S
N
1
MeOTf
12
OBz
O
1
1
1
1
2
3
4
I2
24 h
3.5 h
3 h
NRb
45
65
NIS/TfOH
TMSOTf
OBz
O
BzO
BzO
S
N
5
MeOTf
24 h
62
OBz
O
O
2
2
2
2
6
7
8
I2
24 h
30 min
30 min
43
48
95
NIS/TfOH
TMSOTf
OBz
O
BzO
BzO
S
N
9
MeOTf
24 h
10
OBz
O
NO2
3
3
3
3
10
11
12
I2
24 h
15 min
1 h
<10
85
85
NIS/TfOH
TMSOTf
a
2 equiv of TMSOTf and 3 equiv of all other promoters have been used.
NR: no reaction.
b
Having completed the comparison of donors 1 and 2, we turned
methylation is irreversible as it was determined over the course of
our earlier study by performing reaction monitoring by HPLC.57
Hence, the methylation site should be indicative of the mode of
activation of the leaving group.
our attention to studying p-nitro-SNea donor 3. When donor 3
reacted with acceptor 4 in the presence of MeOTf, the reaction
was found to be very sluggish, similar to that observed with SNea
donor 1. As a result, disaccharide 5 was isolated in a very modest
yield of 10% (entry 9, Table 2). A similar observation was made
in case of molecular iodine; the reaction was very slow and gave
only traces of disaccharide 5, even after 24 h (entry 10, Table 2).
However, in case of NIS/TfOH, the reaction proceeded rather fast
and completed in 15 min affording disaccharide 5 in 85% yield
(entry 11, Table 2). A similar result was obtained in the TMSOTf-
promoted glycosylation that required 1 h to afford disaccharide 5
in 85% yield (entry 12, Table 2).
From results obtained during the comparative study it is clear
that a notable difference in reactivity can be achieved upon mod-
ification of the structure of the leaving group. Next, we were
bound to extend results obtained in glycosylations promoted with
MeOTf to investigating the mechanistic profile of this reaction. A
range of experiments were performed to isolate the departed agly-
cones, the structure of which would help to determine the activa-
tion mode of these leaving groups during the glycosylation
reaction. For this mechanistic study we obtained acetylated p-
methoxy-SNea (6) and p-nitro-SNea (7) donors, which were set
to react with isopropanol as the glycosyl acceptor in the presence
of MeOTf (Scheme 1). These reactions were monitored by TLC and
upon disappearance of the glycosyl donor, the reaction mixture
was concentrated in vacuo. After that, all components of the reac-
tion have been isolated by column chromatography. Glycosidation
of p-methoxy-SNea donor 6 afforded isopropyl glycoside 8;59,60
also isolated was the departed aglycone that was found to be
methylated at sulfur, O,S-dimethyl (4-methoxyphenyl)carbonimi-
dothioate (9). Glycosidation of p-nitro-SNea donor 7 afforded
isopropyl glycoside 8. Also isolated was the departed aglycone that
was found to be also methylated at sulfur, S-methyl
(4-nitrophenyl)carbamothioate (10). The identity of compounds
9 and 10 was proven by spectral methods. It should be noted that
As aforementioned, it was initially hypothesized that the activa-
tion of the SNea leaving group takes place via the remote activation
pathway. If this was the case, the presence of electron-donating or
electron-withdrawing p-phenyl substituents would have a very
strong effect on the nucleophilicity of the nitrogen atom and hence
affect the overall reactivity of the leaving group. However, our
mechanistic study showed that both p-methoxy-SNea and
p-nitro-SNea leaving groups seem to undergo the direct activation
pathway. Since some difference in reactivity was still observed,
this result indicates that the presence of an electron-donating or
electron-withdrawing substituent at the remote p-position of the
N-phenyl ring can also affect the nucleophilicity of the anomeric
sulfur. Consequently, due to the presence of the distant electron
donating substituent, p-methoxy-SNea leaving group is activated
more efficiently in comparison with its SNea and p-nitro-SNea
counterparts. To test the viability of this key observation and gain
a more reliable evidence of differential reactivity of glycosyl donors
2 and 3, a competitive glycosylation reaction depicted in Scheme 2
was planned.
In this experiment, glycosyl donors 2 and 3 were set to compete
against each other for a limited amount of glycosyl acceptor 4, a
protocol that became standard in our laboratory to perform direct
comparison of reactivity levels of different building blocks.21,45,58
Since the greatest degree of differentiation was achieved with
AgOTf as the promoter (Table 1), we chose to apply these reaction
conditions. Upon addition of AgOTf, the reaction between glycosyl
donors 2 and 3 and acceptor 4 proceeded smoothly to give
disaccharide 5 in 86% yield (Scheme 2). Also recovered was the
unreacted glycosyl donor 3, which was isolated in 83% yield. These
results confirm that the p-methoxy-SNea donor 2 is indeed
significantly more reactive in the presence of AgOTf than its
p-nitro-SNea counterpart 3.
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S. C. Ranade, A. V. Demchenko / Carbohydrate Research xxx (2014) xxx–xxx
5
S
N
O
O
9
OAc
O
6 R = OMe
OAc
O
AcO
AcO
MeOTf
S
N
OH
AcO
AcO
O
OAc
MS 3Å
1,2-DCE
O
OAc
R
7 R = NO2
8
H
N
S
O
10
NO2
Scheme 1. Mechanism of activation of alkoxythioimidates 6 and 7 with MeOTf.
was dried by refluxing with magnesium methoxide, distilled, and
stored under argon. Pyridine and acetonitrile were dried by reflux-
ing with CaH2, distilled, and stored over molecular sieves (3 Å).
Molecular sieves (3 Å and 4 Å) used for reactions were crushed
and activated in vacuo at 390 °C during 8 h at first and then for
2–3 h at 390 °C prior to application. AgOTf was co-evaporated with
toluene (3 Â 10 mL) and dried in vacuo for 2–3 h prior to using in
reactions. Optical rotations were measured using ‘Jasco P-1020’
polarimeter. 1H NMR spectra were recorded in CDCl3 at 300 MHz;
13C NMR spectra were recorded in CDCl3 at 75 MHz (Bruker
Avance), unless noted otherwise. HRMS determinations were made
with the use of JOEL MStation (JMS-700) Mass spectrometer, matrix
m-nitrobenzyl alcohol, and with NaI as necessary.
OBz
O
BzO
BzO
S
N
OBz
O
OMe
2
OBz
O
BzO
BzO
OH
O
O
BnO
AgOTf
BzO
O
BnO
BnO
BnO
BnO
MS 3Å
1,2-DCE
OMe
BnO
4
5
OMe
86%
OBz
O
BzO
83% recovery
S
N
BzO
OBz
O
NO2
3
4.2. O-Methyl (4-methoxyphenyl)carbamothioate
Scheme 2. Competitive glycosylation involving two glycosyl donors with different
reactivities 2 and 3.
A 1 M solution of NaOMe in methanol (9.1 mL) was added to the
flask containing p-methoxyphenyl isothiocyanate (0.8 mL,
6.05 mmol) and the resulting mixture was stirred for 15 min at
rt. Then, concd aq. HCl (ꢀ5 mL) was added till the pH reaches
ꢀ4–5. The resulting precipitate was filtered off and rinsed
successively with methanol. The combined filtrate (ꢀ100 mL)
was concentrated in vacuo. The residue containing the title com-
pound was used directly in subsequent transformations. Analytical
data for the title compound: Rf = 0.57 (ethyl acetate/hexanes, 3:7,
v/v); 1H NMR: d, 3.81 (s, 1H, OCH3), 4.12 (s, 1H, OCH3), 6.87 (dd,
2H, aromatic), 7.16 (dd, 2H, aromatic), 7.41 (br. s, 1H, NH) ppm;
13C NMR: d, 55.7, 58.9, 114.4 (Â2), 124.2, 126.2, 130.0, 157.6,
189.7 ppm; HR-FAB MS [M]+ calcd for C9H11NO2S+ 197.0510, found
197.0510.
3. Conclusions
Structural modifications of SNea leaving group involving change
of substituents that express different electronic effects led to a bet-
ter understanding of how the reactivity of glycosyl donors can be
modified by changing the structure of their leaving groups.
Mechanistic studies involving the isolation of departed aglycones
were indicative of the direct activation of both p-methoxy-SNea
and p-nitro-SNea leaving groups via the anomeric sulfur. The
presence of an electron donating substituent (p-methoxy) has a
noticeable effect on the nucleophilicity of the distant sulfur atom
that becomes more susceptible toward the attack of thiophilic
reagents. This key observation allowed to differentiate the reactiv-
ity levels of p-methoxy-SNea versus p-nitro-SNea and even
unmodified SNea leaving groups. The reactivity difference
observed in the series of SNea leaving groups is sufficient to be
exploited in expeditious oligosaccharide synthesis via selective
activation strategies.50
4.3. O-Methyl (4-nitrophenyl)carbamothioate
A 1 M solution of NaOMe in methanol (16.5 mL) was added to the
flask containing p-nitrophenyl isothiocyanate (2.0 g, 11.1 mmol)
and the resulting mixture was stirred for 15 min at rt. Then, concd
aq. HCl (ꢀ5 mL) was added till the pH reaches ꢀ4–5. The resulting
precipitate was filtered off and rinsed successively with methanol.
The combined filtrate (ꢀ100 mL) was concentrated in vacuo. The
residue containing the title compound was used directly in subse-
quent transformations. The analytical data of the title compound
were essentially the same as described previously.61
4. Experimental section
4.1. General remarks
The reactions were monitored by TLC on Kieselgel 60 F254 (EM
Science). Detection of compounds was achieved using UV light
and by charring with 10% sulfuric acid in methanol. Purification
by column chromatography was performed on silica gel 60 (EM Sci-
ence, 70–230 mesh). Removal of solvents was achieved in vacuo at
<40 °C using rotary evaporators. CH2Cl2 and ClCH2CH2Cl were dis-
tilled from CaH2 directly before using for the reactions. Methanol
4.4. S-(2,3,4,6-Tetra-O-benzoyl-b-
D-glucopyranosyl) O-methyl
(4-methoxyphenyl)carbonimidothioate (2)
O-Methyl
(4-methoxyphenyl)carbamothioate
(1.1 g,
5.69 mmol) and KOH (212 mg, 3.79 mmol) were added to a
Please cite this article in press as: Ranade, S. C.; Demchenko, A. V. Carbohydr. Res. (2014), http://dx.doi.org/10.1016/j.carres.2014.06.025

6
S. C. Ranade, A. V. Demchenko / Carbohydrate Research xxx (2014) xxx–xxx
solution of 2,3,4,6-tetra-O-benzoyl-
a-D
-glucopyranosyl bromide62
3.78 (s, 3H, OCH3), 3.99 (s, 3H, OCH3), 4.13 (dd, 1H, J6a,6b = 12.4 Hz,
(2.5 g, 3.79 mmol) in dry acetonitrile (30 mL) and the resulting
mixture was stirred for 2.5 h at rt. After that, the solid was filtered
off and rinsed successively with CH2Cl2. The combined filtrate
(ꢀ100 mL) was washed with satd aq. NaHCO3 (15 mL) and water
(3 Â 15 mL). The organic phase was separated, dried with MgSO4,
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate–toluene gradient elu-
tion) to afford the title compound in 22% yield (650 mg) as a
H-6a), 4.25 (dd, 1H, H-6b), 4.99 (dd, 1H, J2,3 = 9.1 Hz, H-2), 5.03 (dd,
1H, J4,5 = 9.8 Hz, H-4), 5.20–5.27 (m, 2H, H-3, H-1), 6.74–6.84 (m,
4H, aromatic) ppm; 13C NMR: d, 20.8 (Â3), 20.9, 55.6, 56.8, 62.1,
68.2, 69.9, 74.1, 76.2, 81.4, 114.5 (Â2), 122.5 (Â2), 139.4, 154.6,
156.6, 169.3, 169.5, 170.3, 170.8 ppm; HR-FAB MS [M+Na]+ calcd
for C23H29NO11SNa+ 550.1359, found 550.1371.
4.7. S-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl) O-methyl (4-
nitrophenyl)carbonimidothioate (7)
white foam. Analytical data for 2: Rf = 0.6 (ethyl acetate/toluene,
30
1:9, v/v); [
a]
D
À7.4 (c 1, CHCl3); 1H NMR: d, 3.76 (s, 3H,
OCH3), 3.89 (s, 3H, OCH3), 4.25 (m, 1H, J5,6a = 2.9 Hz,
J5,6b = 5.7 Hz, H-5), 4.48 (dd, 1H, J6a,6b = 12.2 Hz, H-6a), 4.64 (dd,
1H, H-6b), 5.53 (dd, 1H, J2,3 = 9.9 Hz, H-2), 5.61 (d, 1H,
J1,2 = 10.2 Hz, H-1), 5.64 (dd, 1H, J4,5 = 9.8 Hz, H-4), 5.94 (dd, 1H,
J3,4 = 9.3 Hz, H-3), 6.64–7.91 (m, 24H, aromatic) ppm; 13C NMR:
d, 55.4, 56.6, 63.2, 69.4, 70.5, 74.1, 77.2, 81.7, 144.3 (Â2), 122.3
(Â2), 128.3 (Â2), 128.4 (Â6), 128.5 (Â2), 128.7, 128.9, 129.6,
129.8 (Â3), 129.9 (Â3), 133.2, 133.3, 133.4, 133.5, 139.3, 154.4,
156.4, 164.9, 165.1, 165.7, 166.1 ppm; HR-FAB MS [M+Na]+ calcd
for C43H37NO11SNa+ 798.1985, found 798.1977.
O-Methyl (4-nitrophenyl)carbamothioate (1.2 g, 5.84 mmol)
and NaOH (194 mg, 4.87 mmol) were added to a stirring solution
of 2,3,4,6-tetra-O-acetyl-a-D
-glucopyranosyl bromide63 (2.0 g,
4.87 mmol) in dry acetonitrile (30 mL) and the resulting reaction
mixture was stirred overnight (16 h) at rt. After that, the solid
was filtered off and rinsed successively with CH2Cl2. The combined
filtrate (ꢀ100 mL) was washed with satd aq. NaHCO3 (25 mL) and
water (3 Â 25 mL). The organic phase was separated, dried with
MgSO4, and concentrated in vacuo. The residue was purified by col-
umn chromatography on silica gel (ethyl acetate–toluene gradient
elution) to afford the title compound in 61% yield (1.6 g) as a pale-
4.5. S-(2,3,4,6-Tetra-O-benzoyl-b-D-glucopyranosyl) O-methyl
(4-nitrophenyl)carbonimidothioate (3)
yellow foam. Analytical data for 7: Rf = 0.61 (ethyl acetate/hexanes,
30
2:3, v/v) [
a
]
D
11.8 (c 1, CHCl3), 1H NMR: d, 2.00, 2.02, 2.03, 2.10
(4s, 12H, 4Â COCH3), 3.78 (m, J5,6a = 2.3 Hz, J5,6b = 5.4 Hz, H-5),
4.03 (s, 3H, OCH3), 4.14 (dd, 1H, J6a,6b = 12.3 Hz, H-6a), 4.25 (dd,
1H, H-6b), 5.01 (dd, 1H, J2,3 = 9.2 Hz, H-2), 5.05 (dd, 1H,
J4,5 = 9.8 Hz, H-4), 5.25 (dd, 1H, J3,4 = 9.3 Hz, H-3), 5.25 (d, 1H,
J1,2 = 10.3 Hz, H-1), 6.91–6.96 (m, 2H, aromatic), 8.14–8.18 (m,
2H, aromatic) ppm; 13C NMR: d, 20.8 (Â3), 20.9, 57.3, 68.1, 69.6,
73.9, 76.4, 81.5, 122.1 (Â2), 125.3 (Â2), 144.5, 152.6, 155.7,
169.3, 169.5, 170.3, 170.8 ppm; HR-FAB MS [M+Na]+ calcd for C22-
H26N2O12SNa+ 565.1104, found 565.1106.
Sodium salt of O-methyl (4-nitrophenyl)carbamothioate
(0.426 g, 1.82 mmol) and 15-crown-5 (30.4
lL, 0.15 mmol) were
added to a solution of 2,3,4,6-tetra-O-benzoyl-
a
-D
-glucopyranosyl
bromide62 (1.0 g, 1.52 mmol) in dry acetonitrile (10.0 mL) and the
resulting reaction mixture was stirred for 45 min at rt. After that,
the solid was filtered off and rinsed successively with CH2Cl2. The
combined filtrate (ꢀ50 mL) was washed with satd aq. NaHCO3
(10 mL) and water (3 Â 10 mL). The organic phase was separated,
dried with MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (ethyl acetate–
toluene gradient elution) to afford the title compound in 47%
5. General glycosylation procedures
yield (560 mg) as a white foam. Analytical data for 3: Rf = 0.63
5.1. Method A—activation with Cu(OTf)2
À18.2 (c 1, CHCl3); 1H
30
(ethyl acetate/toluene, 1:9, v/v); [
a]
D
NMR: d, 3.94 (s, 3H, OCH3), 4.31 (m, 1H, J5,6a = 2.8 Hz,
J5,6b = 5.6 Hz, H-5), 4.54 (dd, 1H, J6a,6b = 12.2 Hz, H-6a), 4.69 (dd,
1H, H-6b), 5.56–5.63 (m, 2H, H-1, H-2), 5.70 (dd, 1H,
J4,5 = 9.8 Hz, H-4), 6.01 (dd, 1H, J3,4 = 9.1 Hz, H-3), 6.83–8.10 (m,
24H, aromatic) ppm; 13C NMR: d, 57.2, 63.2, 69.4, 70.5, 74.0,
76.9, 82.0, 122.1 (Â2), 125.2 (Â2), 128.5 (Â2), 128.6 (Â3), 128.7
(x 5), 128.8 (Â2), 129.7, 129.9 (Â3), 130.1 (Â3), 133.5, 133.6,
133.8, 133.9, 144.4, 152.6, 155.8, 165.1, 165.3, 165.9,
166.2 ppm; HR-FAB MS [M+Na]+ calcd for C42H34N2O12SNa+
813.1730, found 813.1724.
A mixture of the glycosyl donor (0.038 mmol), glycosyl acceptor
(0.03 mmol), and freshly activated molecular sieves (4 Å, 90 mg) in
ClCH2CH2Cl (0.5 mL) was stirred under argon for 1.5 h at rt.
Cu(OTf)2 (41.3 mg, 0.114 mmol) was added and the resulting mix-
ture was stirred for 1–2 h (see Table 1) at rt. After that, the reaction
mixture was diluted with CH2Cl2, the solid was filtered-off, and
rinsed successively with CH2Cl2. The combined filtrate (ꢀ25 mL)
was washed with satd aq. NaHCO3 (5 mL) and water (3 Â 5 mL).
The organic phase was separated, dried with MgSO4, and concen-
trated in vacuo. The residue was purified by column chromatogra-
phy on silica gel (ethyl acetate–toluene gradient elution) to afford
disaccharide 5.
4.6. S-(2,3,4,6-Tetra-O-acetyl-b-
D-glucopyranosyl) O-methyl (4-
methoxyphenyl)carbonimidothioate (6)
5.2. Method B—activation with Bi(OTf)3
O-Methyl
5.84 mmol) and NaOH (194 mg, 4.87 mmol) were added to a solu-
tion of 2,3,4,6-tetra-O-acetyl-
-glucopyranosyl bromide63 (2.0 g,
(4-methoxyphenyl)carbamothioate
(1.2 g,
A mixture containing glycosyl donor (0.038 mmol), glycosyl
acceptor (0.03 mmol), and freshly activated molecular sieves (3 Å,
90 mg) in ClCH2CH2Cl (0.5 mL) was stirred under argon for 1.5 h
at rt. Bi(OTf)3 (74.8 mg, 0.114 mmol) was added and the reaction
mixture was stirred for 10 min—2 h (see Table 1) at rt. After that,
the reaction mixture was diluted with CH2Cl2, the solid was fil-
tered-off, and rinsed successively with CH2Cl2. The combined fil-
trate (ꢀ25 mL) was washed with satd aq. NaHCO3 (5 mL) and
water (3 Â 5 mL). The organic phase was separated, dried with
MgSO4, and concentrated in vacuo. The residue was purified by col-
umn chromatography on silica gel (ethyl acetate/toluene gradient
elution) to afford the disaccharide 5.
a-D
4.87 mmol) in dry acetonitrile (30 mL) and the resulting reaction
mixture was stirred for 1.5 h at rt. After that, the solid was filtered
off and rinsed successively with CH2Cl2. The combined filtrate
(ꢀ100 mL) was washed with satd aq. NaHCO3 (25 mL) and water
(3 Â 25 mL). The organic phase was separated, dried with MgSO4,
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate–toluene gradient elu-
tion) to afford the title compound in 35% yield (897 mg) as a white
foam. Analytical data for 6: Rf = 0.48 (ethyl acetate/hexanes, 2:3, v/
30
v), [
a]
D
À2.3 (c 1, CHCl3), 1H NMR: d, 1.99, 2.01, 2.02, 2.09 (4 s,
12H, 4ÂCOCH3), 3.75 (m, 1H, J5,6a = 2.4 Hz, J5,6b = 4.8 Hz, H-5),
Please cite this article in press as: Ranade, S. C.; Demchenko, A. V. Carbohydr. Res. (2014), http://dx.doi.org/10.1016/j.carres.2014.06.025

S. C. Ranade, A. V. Demchenko / Carbohydrate Research xxx (2014) xxx–xxx
7
5.3. Method C—activation with AgOTf
the reaction mixture was diluted with CH2Cl2, the solid was fil-
tered-off, and then rinsed successively with CH2Cl2. The combined
filtrate (ꢀ25 mL) was washed with satd aq. NaHCO3 (5 mL) and
water (3 Â 5 mL). The organic phase was separated, dried with
MgSO4, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (ethyl acetate/toluene
gradient elution) to afford the disaccharide 5.
A mixture containing glycosyl donor (0.038 mmol), glycosyl
acceptor (0.03 mmol), and freshly activated molecular sieves (3 Å,
90 mg) in ClCH2CH2Cl (0.5 mL) was stirred under argon for 1.5 h
at rt. Freshly activated AgOTf (29.3 mg, 0.114 mmol) was added
and the reaction mixture was stirred for 30 min—24 h (see Table 1)
at rt. After that, the reaction mixture was diluted with CH2Cl2, the
solid was filtered-off, and rinsed successively with CH2Cl2. The
filtrate (ꢀ25 mL) was washed with satd aq. NaHCO3 (5 mL) and
water (3 Â 5 mL). The organic phase was separated, dried with
MgSO4, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (ethyl acetate/toluene gradi-
ent elution) to afford the disaccharide 5.
5.7.1. Methyl 6-O-(2,3,4,6-tetra-O-benzoyl-b-
2,3,4-tri-O-benzyl- -glucopyranoside (5)
The title compound was synthesized as described in Tables 1
and 2. For example, the synthesis from glycosyl donor
D-glucopyranosyl)-
a-D
2
(0.038 mmol) and glycosyl acceptor 4 (0.03 mmol) using Method
A allowed the title compound in 91% yield. Analytical data for 5
were essentially the same as reported previously.54
5.4. Method D—activation with MeOTf
5.8. Aglycone isolation
A mixture containing glycosyl donor (0.038 mmol), glycosyl
acceptor (0.03 mmol), and freshly activated molecular sieves (3 Å,
90 mg) in ClCH2CH2Cl (0.5 mL) was stirred under argon for 1.5 h
5.8.1. O,S-Dimethyl (4-methoxyphenyl)carbonimidothioate (9)
The title compound was isolated by column chromatography
from the reaction mixture resulted from MeOTf-promoted glyco-
sylation between 6 and isopropanol. Also isolated was isopropyl
at rt. MeOTf (14.2 lL, 0.114 mmol) was added and the reaction mix-
ture was stirred for 24 h (see Table 1) at rt. After that, the reaction
mixture was diluted with CH2Cl2, the solid was filtered-off, and
rinsed successively with CH2Cl2. The combined filtrate was washed
with satd aq. NaHCO3 (5 mL) and water (3 Â 5 mL). The organic
layer was separated, dried with MgSO4, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel
(ethyl acetate/toluene gradient elution) to afford the disaccharide 5.
2,3,4,6-tetra-O-acetyl-b-D
-glucopyranoside (8).59,60 Analytical data
for 9: Rf = 0.62 (ethyl acetate/toluene, 0.5:9.5, v/v), 1H NMR: d, 2.34
(s, 3H, SCH3), 3.79 (s, 3H, OCH3), 3.97 (s, 3H, OCH3), 6.82–6.86 (m,
4H, aromatic) ppm; 13C NMR: d, 13.7, 55.6, 56.3, 114.5 (Â2), 122.7
(Â2), 140.8, 156.3, 159.4 ppm; HR-FAB MS [M+Na]+ calcd for C10-
H13NO2S 211.0667, found 211.0663.
5.5. Method E—activation with molecular I2
5.8.2. S-Methyl (4-nitrophenyl)carbamothioate (10)
The title compound was isolated by column chromatography
from the reaction mixture resulted from glycosylation between 7
and isopropanol as white solid. Also isolated was compound 8.
Complete analytical data for 10 were reported previously.64 1H
NMR: d, 2.27 (s, 3H, SCH3), 7.59–7.62 (m, 2H, aromatic), 8.06–
8.09 (m, 2H, aromatic) 13C NMR: d, 12.4, 119.6 (Â2), 126.1 (Â2),
144.3, 146.4, 169.1 ppm.
A mixture containing glycosyl donor (0.025 mmol), glycosyl
acceptor (0.02 mmol), and freshly activated molecular sieves (3 Å,
60 mg) in ClCH2CH2Cl (0.4 mL) was stirred under argon for 1.5 h
at rt. Iodine (19.3 mg, 0.076 mmol) was added and the reaction
mixture was stirred for 24 h (see Table 1) at rt. After that, the reac-
tion mixture was diluted with CH2Cl2, the solid was filtered-off,
and rinsed successively with CH2Cl2. The combined filtrate
(ꢀ25 mL) was washed with 10% Na2S2O3 (5 mL) and water
(3 Â 5 mL). The organic phase was separated, dried with MgSO4,
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate/toluene gradient elu-
tion) to afford the disaccharide 5.
5.8.3. Competitive glycosylation between glycosyl donor 2 and 3
A mixture of glycosyl donor 2 (40 mg, 0.05 mmol), glycosyl
donor
3 (41 mg, 0.05 mmol), glycosyl acceptor 4 (19.5 mg,
0.04 mmol), and freshly activated molecular sieves (3 Å, 120 mg)
in 1,2-dichloroethane (0.8 mL) was stirred under argon for 1 h at
rt. AgOTf (40 mg, 0.16 mmol) was added and the resulting mixture
was stirred for 1.5 at rt. At this time point, glycosyl acceptor 4 had
been completely consumed as indicated by TLC (ethyl acetate/
toluene, 1:9, v/v). The solid was filtered off and rinsed successively
with CH2Cl2. The combined filtrate (ꢀ50 mL) was washed with satd
aq. NaHCO3 (5 mL) and water (3 Â 5 mL). The organic phase was
separated, dried with MgSO4, and concentrated in vacuo. The resi-
due was purified by column chromatography on silica gel (ethyl
acetate–toluene gradient elution) to afford disaccharide 5 in 86%
yield. Also isolated was unreacted glycosyl donor 3 (83% yield).
5.6. Method F—activation with NIS/TfOH
A mixture containing glycosyl donor (0.025 mmol), glycosyl
acceptor (0.02 mmol), and freshly activated molecular sieves (4 Å,
60 mg) in ClCH2CH2Cl (0.4 mL) was stirred under argon for 1.5 h
at rt. NIS (17.1 mg, 0.076 mmol) and TfOH (0.7 lL, 0.007 mmol)
were added and the reaction mixture was stirred for 15 min—
3.5 h (see Table 1) at rt. After that, the reaction mixture was diluted
with CH2Cl2 (25 mL), the solid was filtered-off, and rinsed with
CH2Cl2. The filtrate was washed with 10% Na2S2O3 (5 mL) and
water (3 Â 5 mL). The organic phase was separated, dried with
MgSO4, and concentrated in vacuo. The residue was purified by col-
umn chromatography on silica gel (ethyl acetate/toluene gradient
elution) to afford the disaccharide 5.
Acknowledgements
The authors thank the National Science Foundation (Award
CHE-1058112) and National Institute of General Medical Studies
(Award GM077170) for providing generous financial support.
5.7. Method G—activation with TMSOTf
Supplementary data
A mixture containing glycosyl donor (0.025 mmol), glycosyl
acceptor (0.02 mmol), and freshly activated molecular sieves (4 Å,
60 mg) in ClCH2CH2Cl (0.4 mL) was stirred under argon for 1.5 h
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.carres.2014.06.
025.
at rt. TMSOTf (9.0
lL, 0.05 mmol) was added and the reaction
mixture was stirred for 30 min—3 h (see Table 1) at rt. After that,
Please cite this article in press as: Ranade, S. C.; Demchenko, A. V. Carbohydr. Res. (2014), http://dx.doi.org/10.1016/j.carres.2014.06.025

8
S. C. Ranade, A. V. Demchenko / Carbohydrate Research xxx (2014) xxx–xxx
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Please cite this article in press as: Ranade, S. C.; Demchenko, A. V. Carbohydr. Res. (2014), http://dx.doi.org/10.1016/j.carres.2014.06.025