S-Benzimidazolyl (SBiz) Imidates as a Platform for Oligosaccharide Synthesis via Active-Latent, Armed-Disarmed, Selective, and Orthogonal Activations

Article abstract of DOI:10.1021/acs.joc.6b02478

This article describes the development of S-benzimidazolyl (SBiz) imidates as versatile building blocks for oligosaccharide synthesis. The SBiz imidates have been originally developed as a new platform for active-latent glycosylations. This article expands upon the utility of these compounds. The application to practically all common concepts for the expeditious oligosaccharide synthesis including selective, chemoselective, and orthogonal strategies is demonstrated. The strategy development was made possible thanks to our enhanced understanding of the reaction mechanism and the modes by which SBiz imidates interact with various promoters of glycosylation.

Full text of DOI:10.1021/acs.joc.6b02478

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Article
S-Benzimidazolyl (SBiz) imidates as a platform for oligosaccharide synthesis
via active-latent, armed-disarmed, selective and orthogonal activations
Scott J. Hasty, Mithila D. Bandara, Nigam P. Rath, and Alexei V. Demchenko
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02478 • Publication Date (Web): 30 Jan 2017
Downloaded from http://pubs.acs.org on January 30, 2017
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S-Benzimidazolyl (SBiz) imidates as a platform for oligosaccharide synthesis via active-
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latent, armed-disarmed, selective and orthogonal activations
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Scott J. Hasty, Mithila D. Bandara, Nigam P. Rath, and Alexei V. Demchenko*
Department of Chemistry and Biochemistry, University of Missouri – St. Louis, One University
Boulevard, St. Louis, Missouri 63121, USA
This article describes the development of S-benzimidazolyl (SBiz) imidates as versatile building
blocks for oligosaccharide synthesis. The SBiz imidates have been originally developed as a new
platform for active-latent glycosylations. This article expands upon the utility of these com-
pounds. The application to practically all common concepts for the expeditious oligosaccharide
synthesis including selective, chemoselective, and orthogonal strategies is demonstrated. The
strategy development was made possible thanks to our enhanced understanding of the reaction
mechanism and the modes by which SBiz imidates interact with various promoters of glycosyla-
tion.
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Introduction
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Chemical synthesis of oligosaccharides remains challenging and the development of ex-
peditious strategies for the oligosaccharide and glycoconjugate synthesis stands out as timely and
demanding area of research in chemical, biological and medical sciences.1,2 As a part of the on-
going research effort, our laboratory has been investigating glycosyl thioimidates, glycosyl do-
nors equipped with the SCR1=NR2 leaving group.3 Among a variety of leaving groups studied by
us and others,4,5 we determined that S-benzimidazolyl (SBiz) imidates are potent glycosyl do-
nors.6 We also demonstrated that the SBiz leaving group offers an effective new platform for an
active-latent strategy pioneered by Roy,7 Fraser-Reid,8 Boons9 and more recently studied by
Kim10,11 and others.12-16 Thus, we showed that MeI can activate glycosyl donor 1 equipped with
unprotected SBiz (SBiz-H) leaving group, whereas N-anisoylated SBiz (SBiz-An) donor 2 re-
mained completely intact and could be recovered nearly quantitatively (98%, Scheme 1).6
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Scheme 1. Competition experiment between SBiz donor 1 (active) and its N-
anisoylated counterpart 2 (latent) in the presence of MeI.
OBn
O
OH
O
BnO
BnO
H
BnO
BnO
S
N
BnO
N
BnO
OMe
1
3
OBn
O
Anisoyl chloride
pyridine
BnO
BnO
MeI
BnO
O
OBn
O
O
N
O
BnO
BnO
OMe
BnO
BnO
S
BnO
OMe
BnO
N
4
(98% recovery)
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Subsequent selective activations clearly demonstrated the viability of the SBiz-based ac-
tive-latent concept. Thus, MeI-promoted glycosylation between building blocks 1 and 5 pro-
duced disaccharide 6 bearing the SBiz-An anomeric moiety in 75% yield (Scheme 2). After that,
the N-anisoyl group was removed by the treatment with one of the following reagents: tetrabu-
tylammonium fluoride (TBAF), NaOMe or guanidine.6 The resulting disaccharide 7 bearing the
SBiz-H moiety was subsequently activated with MeI to afford trisaccharide 8 in 71% yield. This
two-step SBiz activation sequence with the intermediate deprotection step (1  6  7  8)
mimics the traditional active-latent pathway for oligosaccharide synthesis.7 We also demonstrat-
ed that the intermediate disaccharide 6 can be directly activated for the reaction with acceptor 3
in the presence of a stronger promoter, silver(I) triflate (AgOTf).6
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Scheme 2. Synthesis of disaccharide 8 via the active-latent (1  6  7  8)
and the armed-disarmed (1  6  8) fashion.
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The preliminary mechanistic study made us believe that the deactivation effect of the N-
anisoyl moiety is electronic, and the latter pathway (1  6  8) resembles an armed-disarmed-
like activation. While the typical disarming effect in glycosylation refers to the neighboring acyl
substituents in the sugar moiety17 the disarming effect observed with the SBiz imidates is
achieved by acylation of the leaving group.
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Results and Discussion
Building upon our previous findings that the application of the SBiz moiety allows for
executing a rapid oligosaccharide assembly via active/latent and leaving group-based
armed/disarmed concepts, we continued looking into other possible applications of this new plat-
form. Other conditions applied for the activation of perbenzylated SBiz-H donor 1 and SBiz-An
donor 2 for glycosylation with glycosyl acceptor 318,19 included silver tetrafluoroborate (AgBF4)
that is a potent activator for thioimidates20 and common promoters for thioglycoside activation:
methyl triflate (MeOTf), N-iodosuccinimide (NIS)/ triflic acid (TfOH), iodonium dicollidine
perchlorate (IDCP), and dimethyl(thiomethyl) sulfonium triflate (DMTST).21 Both glycosyl do-
nors 1 and 2 could readily be activated with AgBF4, MeOTf, NIS/TfOH, and IDCP producing
disaccharide 4 in 15 min to 12 h in 81-96% yield (see the SI for details). To our surprise, only
the SBiz-An donor 2 could be activated in the presence of DMTST, whereas SBiz-H donor 1
seemed unreactive. This unexpected result was verified by the direct competition experiment be-
tween glycosyl donors 1 and 2 shown in Scheme 3. Opposite the previous competition experi-
ment wherein SBiz-An donor 2 remained unreactive in the presence of MeI (Scheme 1), in the
presence of DMTST, SBiz-H donor 1 remained practically intact and could be recovered nearly
quantitatively (96%).
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Scheme 3. Unexpected reactivity of glycosyl donors in the presence of DMTST: do-
nor 1 remains latent and 2 is now active.
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In our opinion, the set of the competition experiments presented in Schemes 1 and 3 is
clearly indicative of the completely orthogonal character of the SBiz-H and SBiz-An leaving
groups. Selective activation, wherein one leaving group is activated over another with no protect-
ing group manipulations in between, offers a streamlined access to oligosaccharides.22 However,
aligning multiple leaving groups is not always feasible and syntheses involving sequential activa-
tions of three or more different leaving groups are still rare.23 In this respect, the orthogonal
strategy that relies on only two leaving groups that can be orthogonally activated one over anoth-
er offers a significant advantage. Such activation pathway also requires a pair of orthogonal acti-
vators that would activate one, but not the other leaving group. Conceptually, this approach is
one of the most effective strategies for expeditious oligosaccharide synthesis.24-27 Yet this strate-
gy remains somewhat underdeveloped with too few known examples to become universally ap-
plicable. Only the following examples are known to date: the original S-phenyl vs. fluoride in-
troduced by Kanie et al.,24,25,28 thioimidate-based approaches developed in our lab,19,29-31 Hotha’s
O-pentenyl vs. O-propargyl,32 and O-allylphenyl-based approach also introduced by our group.33
Likewise, we reported a related, albeit less flexible, semi-orthogonal approach using S-ethyl vs.
O-pentenyl,34 which was extended to fluoride vs. O-pentenyl by Fraser-Reid and Lopez.35
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Hence, the subsequent study of this unusual reactivity of SBiz glycosyl donors and their
substituted analogues has focused on MeI and DMTST, promoters that showed the greatest dif-
ference in the activation profile. The preliminary results with per-benzylated (armed)17 donors 1
and 2 are summarized in Table 1 (entries 1-4). Thus, while donor 1 was practically unreactive in
the presence of DMTST (entry 1), it was readily activated in the presence of MeI. In the latter
case, disaccharide 4 was obtained in 89% yield (entry 2). Conversely, donor 2 readily produced
disaccharide 4 in the presence of DMTST in 86% yield (entry 3). In the presence of MeI, donor 2
remained unreactive (entry 4).
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To determine the relative reactivity of differentially protected SBiz imidates toward gly-
cosidation in the presence of DMTST or MeI we also incorporated 2,3,4,6-O-benzoylated (dis-
armed)17 SBiz-H donor 9 and its SBiz-An counterpart 106 in our comparative study. When at-
tempting to glycosidate SBiz-H donor 9 with acceptor 3 in the presence of DMTST, no formation
of the respective disaccharide 11 was expected based on our observation with the armed ben-
zylated SBiz-H donor 1 that gave no reaction (entry 1). Strikingly, benzoylated SBiz-H donor 9
“disappeared“ within 2 h (entry 5)! An in depth study showed that no disaccharide 11 was pro-
duced; instead, donor 9 was entirely converted into its N-thiomethylated derivative 15 (see Table
1 footnote). When per-benzoylated SBiz-H donor 9 was subjected to MeI-promoted activation,
no reaction took place (entry 6). Since per-benzylated SBiz-H donor 1 smoothly reacted within
12 h (entry 2), we attribute this result to the electron-withdrawing nature of benzoyl substituents
in donor 9 (Fraser-Reid’s armed-disarmed concept).17 The viability of this rationalization was
confirmed by the direct chemoselective activation experiment (vide infra).
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Table 1. Glycosidation of differentially protected SBiz and N-anisoyl SBiz
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glycosyl donors.
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entry
1
donor
1
promotera
DMTST
MeI
time, h
120
12
product (yield, α/β ratio)
no reaction
2
1
4 (89%, 4.8/1)6
4 (86%, 3.3/1)
no reaction6
3
2
DMTST
MeI
12
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120
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DMTST
MeI
no disaccharide b
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120
24
no reaction
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12
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DMTST
MeI
11 (88%, β only)
no reaction
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120
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DMTST
MeI
14 (94%, β only)
14 (88%, β only)
14 (92%, β only)
no reaction
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11
12
15
DMTST
0.75
MeI
120
a performed in 1,2-dichloroethane in the presence of molecular sieves 3 Å at 35 °C (MeI)
or rt (DMTST)
b The following compound was produced as the only product
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Results obtained with SBiz-An donor 10 were more predictable. DMTST-promoted acti-
vation was completed within 24 h and afforded disaccharide 11 in 88% yield and complete β-
stereoselectivity due to the participation of the 2-O-benzoyl substituent. For comparison, the
armed SBiz-An donor 2 reacted faster (12 h, entry 3), which is also indicative of the armed-
disarmed-like activation. No glycosidation of SBiz-An donor 10 took place in the presence of
MeI, even after 120 h (entry 8).
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We then began investigating glycosyl donors of the superarmed series equipped with 2-
O-benzoyl-3,4,6-tri-O-benzyl protecting group pattern. The superarming in glycosyl donors of
this series is based on the combination of electronic and anchimeric effects rationalized by the
existence of the O2/O5 cooperative effect in glycosylation.36-38 Glycosidation of the SBiz-H do-
nor 12 resulted in another interesting outcome: both DMTST and MeI were effective, and the
corresponding disaccharide 14 was obtained in high yields in 8 and 15 h, respectively (entries 9
and 10). Again, complete β-stereoselectivity observed in this reaction shall be attributed to the
participation of the 2-O-benzoyl group. SBiz-An donor 13 was rapidly activated with DMTST
and disaccharide 14 was produced in 92% in 45 min (entry 11). Still, no reaction took place with
MeI (entry 12).
To investigate these somewhat mixed results obtained with SBiz-H donors 1, 9 and 12 in
the presence of DMTST, we first set out to determine how the O-protecting groups influence the
outcome: no reaction (with 1), the formation of a stable by-product/intermediate 15 (from 9), and
smooth glycosylation (with 12). Since the disarmed donor 9 produced intermediate 15 (Table 1
and Scheme 4), we attempted to search for similar intermediates in glycosidation with other se-
ries of SBiz-H donors. Upon a more detailed investigation by NMR, we determined that a small
amount of unstable compound 16 was indeed present in the reaction mixture originated from do-
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nor 1 (Scheme 4). This intermediate cannot be glycosidated since no disaccharide 4 was pro-
duced (entry 1, Table 1), but it instead rapidly equilibrated into the starting material 1. There-
fore, the reaction outcome is overall indicative of DMTST being deactivated by the interaction
with donor 1. In case of the superarmed glycosyl donor 12, the reaction intermediate 17 is high-
ly reactive. It is possible that it equilibrates back to the starting material 12, but it can also be
glycosidated to form disaccharide 14. In our opinion, the relatively slow reaction time of 8 h is
indicative of the high rate of the competitive reverse reaction. For comparison, the anisoylated
superarmed donor 13 was smoothly glycosidated in the presence of DMTST in 45 min (compare
entries 9 and 11).
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Scheme 4. Activation of differently protected SBiz-H donors 1, 9 and 12 with
DMTST.
Having uncovered the reaction pathway by which unprotected SBiz leaving group may
interact with DMTST, we began studying the activation of substituted SBiz donors. The
DMTST-mediated activation of SBiz-An donor 2 smoothly produced disaccharide 4 in 12 h (Ta-
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ble 1, entry 3). To further investigate possible effects of the N-substitution, we obtained armed
and disarmed N-methylated (SBiz-Me) donors 18 and 19, respectively (Figure 1). When these
donors were subjected to glycosidation with acceptor 3 in the presence of DMTST, the reactions
smoothly produced the corresponding disaccharides 4 and 11 in 9 h (79%) and 72 h (87%), re-
spectively (see the SI for details). This result indicates that the N-protection of SBiz leaving
group is needed to permit the activation of armed and disarmed SBiz imidates with DMTST.
The nature of the substituent is somewhat less important for these activation conditions because
both electron-withdrawing N-anisoyl and electron-donating N-methyl protection produced simi-
lar results.
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Figure 1. N-Methylated SBiz-Me donors 18 and 19
We then began studying the activation pathways for the series of the armed glycosyl do-
nors equipped with the differentially N-substituted SBiz-H, SBiz-An, and SBiz-Me leaving
groups (1, 2, and 18, respectively) in the presence of MeI. Previously, we reported that benzyl
bromide-mediated glycosidation of SBiz-H donor 1 produced 2-benzylsulfanyl-1H-
benzimidazole39,40 indicating the direct activation of the leaving group via the anomeric sulfur
atom.6 Similarly, when SBiz-H donor 1 was glycosidated in the presence of MeI, disaccharide 4
was obtained along with 2-methylsulfanyl-1H-benzimidazole 20 (Scheme 5). This result indi-
cates that the MeI-mediated reaction also follows the direct activation pathway rather than the
remote activation via the nitrogen atom that could have been another viable activation pathway
for the leaving group of this class.41 When a similar experiment was conducted with SBiz-An
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donor 2, neither disaccharide 4 nor products derived from the departed aglycone were detected in
the reaction mixture. However, when SBiz-Me donor 18 was subjected to glycosidation with
MeI, disaccharide 4 was smoothly produced (15 h, 79%). The departed aglycone was also iso-
lated and determined to be 1-methyl-2-methylsulfanyl-1H-benzimidazole 21 by spectral methods
and X-ray crystallography.
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Scheme 5. Activation of SBiz-H, SBiz-An, and SBiz-Me donors with MeI.
Overall, these mechanistic studies have ultimately proven the activation pathways of the
differentially N- and O-substituted SBiz imidates. We also discovered that the N-methylated
SBiz leaving group can be smoothly activated independently on the type of the activation condi-
tions used. The extended study of the N-methylated SBiz donors as well as their N-allyl and N-
benzyl counterparts will be reported elsewhere.
This mechanistic study that allowed us to understand the driving forces for the unusual
orthogonal reactivity profile of the SBiz-H and SBiz-An leaving groups has then evolved into
studying various synthetic pathways for the expeditions oligosaccharide assembly. First, the two-
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way orthogonal synthesis of trisaccharide 8 was explored (Scheme 6). On the one hand, SBiz-H
donor 1 was activated over SBiz-An acceptor 5 in the presence of MeI. The resulting disaccha-
ride 6 isolated in 75% yield was then glycosidated with acceptor 3 in the presence of DMTST to
afford trisaccharide 8 in 84% yield. On the other hand, the activation of the SBizAn leaving
group of glycosyl donor 2 over the SBiz leaving group of acceptor 22 was effected in the pres-
ence of DMTST. The resulting disaccharide 7 isolated in 66% yield was then glycosidated with
acceptor 3 in the presence of MeI to afford trisaccharide 8 in 82% yield.
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Scheme 6. Orthogonal activation of SBiz-H and SBiz-An imidates for the synthesis
of trisaccharide 8.
Subsequently, we decided to expand upon our previous finding of differential reactivity
of armed, disarmed and superarmed SBiz-H donors 1, 9 and 12. Direct chemoselective activation
of the superarmed glycosyl donor 12 over benzoylated (disarmed) glycosyl acceptor 2342 was
conducted in the presence of AgOTf or MeI (not shown). As a result, disaccharide 24 was pro-
duced in 10 min in 67% yield ultimately confirming the electronic (arming-disarming) effects of
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O-protecting groups on the reactivity of differentially protected SBiz-H imidates (Scheme 7). It
should be mentioned that AgOTf-mediated activation of thioimidates in general and SBiz in par-
ticular also offers a convenient and reliable entry into oligosaccharide synthesis via selective ac-
tivation over alkyl/aryl thioglycosides.22 To illustrate the viability of this statement, we conduct-
ed a AgOTf-mediated activation of SBiz donor 1 over S-ethyl acceptor 25.43 This selective acti-
vation led to the formation of disaccharide 26 in 92% yield. Apparently, both disaccharides 24
and 26 can be used in subsequent chain elongations without the need for the interim protecting or
leaving group manipulations.
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Scheme 7. Chemoselective and selective activations using SBiz-H donors 1 and 12.
Conclusions
We have uncovered various activations pathways that S-benzimidazolyl leaving group platform
offers. Efficient activations for the multistep oligosaccharide synthesis via a variety of conceptu-
al approaches were possible due to the mechanistic study that enhanced our understanding of
how O- and N-substituents influence the reactivity of benzimidazole-based thioimidate leaving
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groups. We have demonstrated further reactivity exploitations of S-benzimidazolyl imidates in-
volving DMTST-mediated activation complementing our previous study employing MeI.
Through our investigation it was determined that the nitrogen protection, utilizing whether an
alkyl or an acyl group, is a requirement to achieve glycosylations using DMTST with all but the
superarmed SBiz imidates. Also reported is an orthogonal strategy in which essentially the same
class of building blocks can be used, but the promoter selection as well as the N-protection is
critical. Our further investigation of this promising platform in application to the synthesis of lin-
ear and branched oligosaccharide sequences using conventional solution or automated solid-
phase synthesis is underway in our laboratory.
10
11
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Experimental
General remarks.
The reactions were performed using commercial reagents and the ACS grade solvents used for
reactions were purified and dried in accordance with standard procedures. Column chromatog-
raphy was performed on silica gel 60 (70-230 mesh), reactions were monitored by TLC on Kie-
selgel 60 F254. The compounds were detected by examination under UV light and by charring
o
with 10% sulfuric acid in methanol. Solvents were removed under reduced pressure at < 40 C.
CH2Cl2 and ClCH2CH2Cl were distilled from CaH2 directly prior to application. Anhydrous
DMF was used as is. Methanol was dried by refluxing with magnesium methoxide, distilled and
stored under argon. Pyridine and acetonitrile were dried by refluxing with CaH2 and then dis-
tilled and stored over molecular sieves (3 Å). Molecular sieves (3 Å or 4 Å), used for reactions,
were crushed and activated in vacuo at 390 °C during 8 h in the first instance and then for 2-3 h
+
at 390 °C directly prior to application. DOWEX MONOSPHERE 650C (H ) was washed three
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times with MeOH and stored under MeOH. Optical rotations were measured using a polarimeter.
1H NMR spectra were recorded at 300 or 600 MHz, 13C NMR spectra were recorded at 75 or 150
MHz. The 1H NMR chemical shifts are referenced to the signal of the residual CHCl3 (δH = 7.27
ppm) for solutions in CDCl3. The 13C NMR chemical shifts are referenced to the central signal of
CDCl3 (δC = 77.23 ppm) for solutions in CDCl3. HRMS determinations were made with the use
of a mass spectrometer with FAB ionization and ion-trap detection.
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Synthesis of glycosyl donors
Benzimidazol-2-yl 2,3,4,6-tetra-O-benzyl-1-thio-β-D-glucopyranoside (1). The title com-
pound was obtained from ethyl 2,3,4,6-tetra-O-benzyl-1-thio-β-D-glucopyranoside44 and 2-
benzimidazolethione, potassium salt (KSBiz) as previously reported.6 Analytical data for 1 were
the same as those reported previously.6
(N-Anisoyl)benzimidazol-2-yl 2,3,4,6-tetra-O-benzyl-1-thio-β-D-glucopyranoside (2). The
title compound was obtained from 1 and anisoyl chloride as previously reported.6 Analytical da-
ta for 2 were the same as those reported previously.6
Benzimidazol-2-yl 2,3,4,6-tetra-O-benzoyl-1-thio-β-D-glucopyranoside (9). The title com-
pound was obtained from 2,3,4,6-tetra-O-benzoyl-α-D-glucopyranosyl bromide45 and KSBiz as
previously reported.6 Analytical data for 9 were the same as those reported previously.6
(N-Anisoyl)benzimidazol-2-yl 2,3,4,6-tetra-O-benzoyl-1-thio-β-D-glucopyranoside (10). The
title compound was obtained from 9 and anisoyl chloride as previously reported.6 Analytical da-
ta for 10 were the same as those reported previously.6
Benzimidazol-2-yl 2-O-benzoyl-3,4,6-tri-O-benzyl-1-thio-β-D-glucopyranoside (12). The
title compound was obtained from 3,4,6-tri-O-benzyl-1,2-O-methoxybenzylidene-α-D-
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glucopyranose46 and 2-mercaptobenzimidazole as previously reported.6 Analytical data for 12
were the same as those reported previously.6
7
8
9
(N-Anisoyl)benzimidazol-2-yl 2-O-benzoyl-3,4,6-tri-O-benzyl-1-thio-β-D-glucopyranoside
(13). Anisoyl chloride (0.58 mL, 4.29 mmol) was added dropwise to a stirring solution of 12
(1.0 g, 1.4 mmol) in pyridine (10 mL). The resulting reaction mixture was stirred under argon
for 15 min at rt. After that, the volatiles were removed in vacuo and the residue was co-
evaporated with toluene (3 x 10 mL). The residue was diluted with CH2Cl2 (200 mL), and
washed with water (20 mL), 1N aq. HCl (20 mL), water (20 mL), sat. aq. NaHCO3 (2 x 20 mL),
and water (3 x 10 mL). The organic phase was separated, dried over Na2SO4, and concentrated
in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate – tol-
uene gradient elution) to afford the title compound (1.05 g, 91%) as an off-white foam. Analyti-
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24
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1
cal data for 13: Rf = 0.52 (ethyl acetate/toluene, 1/9, v/v); [α]D +119.5 (c = 1.0, CHCl3); H-
n.m.r.: δ, 3.89-4.08 (m, 7H, H-4, 5, 6a, 6b, OCH3), 4.11 (dd, 1H, J3,4 = 8.7 Hz, H-3) 4.68 (dd,
2
2
2
2H, J = 12.0 Hz, CH2Ph), 4.85 (dd, 2H, J = 10.9 Hz, CH2Ph), 4.85 (dd, 2H, J = 11.1 Hz,
CH2Ph), 5.63 (dd, 1H, J2,3 = 9.8 Hz, H-2), 6.27 (d, 1H, J1,2 = 10.4 Hz, H-1), 6.93-7.67 (m, 28H,
aromatic) ppm; 13C-n.m.r.: δ, 55.7, 68.7, 72.8, 73.5, 75.1, 75.4, 77.8, 80.1, 83.6, 84.3, 113.3,
114.2, 118.9, 123.3, 124.1, 124.4, 127.7, 127.8, 127.9, 128.0 (x6), 128.2 (x2), 128.4 (x3), 128.5
(x2), 129.6 (x2), 130.0 (x3), 132.6 (x2), 132.9, 133.3, 134.6, 137.8, 138.1, 143.6, 151.6, 164.4,
165.2, 167.1 ppm; HR-FAB MS [M+Na]+ calcd for C49H44N2O8SNa+ 843.2716, found 843.2699.
(N-Methyl)benzimidazol-2-yl 2,3,4,6-tetra-O-benzyl-1-thio-β-D-glucopyranoside (18). Me-
thyl iodide (0.14 mL, 2.2 mmol) was added to a stirring solution of benzimidazol-2-yl 2,3,4,6-
tetra-O-benzoyl-1-thio-β-D-glucopyranoside (0.25 g, 0.37 mmol) and KOH (0.10 g, 1.9 mmol)
in tetrahydrofuran (5 mL) and the resulting mixture was stirred under argon for 30 min at rt. Up-
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on completion (TLC), the reaction mixture was diluted with CH2Cl2 (~100 mL) and washed with
water (20 mL), sat. aq. NaHCO3 (20 mL), and water (3 x 20 mL). The organic phase was sepa-
rated, dried over NaSO4, and concentrated in vacuo. The residue was purified by column chro-
matography on silica gel (ethyl acetate – hexane gradient elution) to afford the title compound
(0.229 g, 90% yield) as a colorless syrup. Analytical data for 18: Rf 0.55 (ethyl acetate/hexane
3/7, v/v); [α]D18 +3.7 (c 1.0, CHCl3); 1H-n.m.r.: δ 3.51-3.79 (m, 6H, H-2, 3, 4, 5, 6a, 6b), 3.74 (s,
10
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2
2
3H, NCH3), 4.44 (dd, 2H, J = 11.9 Hz, CH2Ph), 4.66 (dd, 2H, J = 10.9 Hz, CH2Ph), 4.87 (dd,
2H, 2J = 10.9 Hz, CH2Ph), 5.02 (dd, 2H, 2J = 10.7 Hz, CH2Ph), 5.68 (d, 1H, J1,2 = 9.0 Hz, H-1),
7.14-7.78 (m, 24H, aromatic) ppm; 13C-n.m.r.: δ 31.0, 68.9, 73.5, 75.1, 75.5, 75.9, 79.2, 81.0,
86.2, 86.7, 109.5, 119.6, 122.4, 122.9, 127.8, 127.9 (x2), 128.0 (x3), 128.2 (x2), 128.4, 128.5
(x5), 128.6 (x6), 129.1, 136.8, 138.1, 138.2, 138.3, 138.5, 143.4, 147.2 ppm; HRMS–MS (m/z):
[M + Na]+ calcd for C42H42N2O5SNa+, 709.2712; found, 709.2719
(N-Methyl)benzimidazol-2-yl 2,3,4,6-tetra-O-benzoyl-1-thio-β-D-glucopyranoside (19). The
titled compound was obtained from 9 as described for the synthesis of 18 in 90% yield as a white
amorphous solid. Analytical data for 18: Rf = 0.55 (ethyl acetate/hexane, 3/7, v/v); [α]D21 +68.0
1
(c 1.0, CHCl3); H-n.m.r.: δ, 3.66 (s, 3H, OCH3), 4.34 (m, 1H, J5,6a = 5.9, J5,6b = 2.1 Hz, H-5),
4.45 (dd, 1H, J6a,6b = 11.9 Hz, H-6a), 4.60 (dd, 1H, H-6b), 5.77 (dd, 1H, J4,5 = 9.6 Hz, H-4), 5.80
(dd, 1H, J2,3 = 10.2 Hz, H-2), 6.11 (dd, 1H, J3,4 = 9.5 Hz, H-3), 6.21 (dd, 1H, J1,2 = 10.3 Hz, H-
1), 7.13-7.97 (m, 24H, aromatic) ppm; 13C-n.m.r.: δ, 30.6, 63.2, 69.4, 71.1, 74.1, 85.1, 109.4,
119.0, 122.6, 122.9, 128.5 (x7), 128.6 (x2), 128.7 (x2), 128.9, 129.5, 129.8 (x2), 129.9 (x2),
130.0 (x2), 130.1 (x2), 130.3, 133.2, 133.5, 133.7, 136.7, 143.2, 147.4, 165.3, 165.6, 165.8,
166.2 ppm; HR-FAB MS [M+H]+ calcd for C42H35N2O9S+ 743.2063, found 743.2062.
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Synthesis of glycosyl acceptors.
5
6
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8
Methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (3). Analytical data for the title compound
was the same as previously described.18,19
9
10
11
12
13
14
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18
19
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(N-Anisoyl)benzimidazol-2-yl 2,3,4-tri-O-benzyl-1-thio-β-D-glucopyranoside (5). The title
compound was obtained from 23 and anisoyl chloride via temporary TMS-protection of the pri-
mary hydroxyl as previously reported.6 Analytical data for 5 were the same as those reported
previously.6
Benzimidazol-2-yl 2,3,4-tri-O-benzyl-1-thio-β-D-glucopyranoside (22). The title compound
was obtained from 2,3,4-tri-O-benzoyl-6-O-tert-butyldimethylsilyl-β-D-glucopyranosyl bro-
mide47 and 2-benzimidazolethione, potassium salt (KSBiz) followed by desilylation as previous-
ly reported.6 Analytical data for 23 were the same as those reported previously.6
Benzimidazol-2-yl 2,3,4-tri-O-benzoyl-1-thio-β-D-glucopyranoside (23). The title compound
was
obtained
from
ethyl
2,3,4-tri-O-benzoyl-6-O-tert-butyldimethylsilyl-1-thio-β-D-
glucopyranoside48 and 2-benzimidazolethione, potassium salt (KSBiz) followed by desilylation
as previously reported.42 Analytical data for 24 were the same as those reported previously.42
Ethyl 2,3,4-tri-O-benzyl-1-thio-β-D-glucopyranoside (25). Analytical data for the title com-
pound was the same as previously described.43
Synthesis of glycosides
Typical DMTST-promoted glycosylation procedure. A mixture of glycosyl donor (0.036 mmol),
glycosyl acceptor (0.030 mmol), and freshly activated molecular sieves (4Å, 100 mg) in 1,2-
dichloroethane (1.0 mL) was stirred under argon for 1 h at rt. DMTST (0.072 mmol) was added
and the reaction mixture was monitored by TLC. Upon completion (see Table), Et3N (0.3 mL)
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was added and the resulting mixture was stirred for 30 min. The mixture was then diluted with
CH2Cl2 (~15 mL), the solid was filtered off and washed successively with CH2Cl2. The com-
bined filtrate (~40 mL) was washed with sat. aq. NaHCO3 (10 mL) and water (3 x 10 mL). The
organic phase was separated, dried with Na2SO4, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (ethyl acetate - toluene gradient elution).
Anomeric ratios (if applicable) were determined by comparison of the integral intensities of rele-
vant signals in 1H NMR spectra.
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Typical methyl iodide-promoted glycosylation procedure. A mixture of glycosyl donor (0.036
mmol), glycosyl acceptor (0.030 mmol), and freshly activated molecular sieves (4Å, 100 mg) in
1,2-dichloroethane (1.0 mL) was stirred under argon for 1 h at rt. Methyl iodide (0.216 mmol)
was added and the reaction mixture was monitored by TLC. Upon completion (see Tables) the
mixture was then diluted with CH2Cl2 (~15 mL), the solid was filtered off and washed succes-
sively with CH2Cl2. The combined filtrate (~40 mL) was washed with 20% aq Na2S2O3 (5 mL)
and water (3 x 5 mL). The organic phase was separated, dried with Na2SO4, and concentrated in
vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate - toluene
gradient elution). Anomeric ratios (if applicable) were determined by comparison of the integral
intensities of relevant signals in 1H NMR spectra.
Typical AgOTf-promoted glycosylation procedure. A mixture of glycosyl donor (0.036 mmol),
glycosyl acceptor (0.030 mmol), and freshly activated molecular sieves (3Å, 100 mg) in 1,2-
dichloroethane (1.0 mL) was stirred under argon for 1 h. AgOTf (0.072 mmol) was added and
the reaction mixture was monitored by TLC. Upon completion (see Tables), the reaction mixture
was then diluted with CH2Cl2 (~15 mL), the solid was filtered off and washed successively with
CH2Cl2. The combined filtrate (~40 mL) was washed with sat. aq. NaHCO3 (10 mL) and water
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(3 x 10 mL). The organic phase was separated, dried with Na2SO4, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel (ethyl acetate - toluene gradi-
ent elution). Anomeric ratios (if applicable) were determined by comparison of the integral in-
tensities of relevant signals in 1H NMR spectra.
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11
12
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Methyl
6-O-(2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranosyl)-2,3,4-tri-O-benzyl-α-D-
glucopyranoside (4). The title compound was prepared from donor 1 or 2 and acceptor 3 as de-
scribed in Tables. Analytical data for 4 was the same as previously described.49 50
(N-Anisoyl)benzimidazol-2-yl 6-O-(2,3,4,6-tri-O-benzyl-α/β-D-glucopyranosyl)-2,3,4-tri-O-
benzyl-β-D-glucopyranoside (6). The title compound was prepared from donor 1 and acceptor 5
in 75% yield in accordance with the general glycosylation procedure in the presence of MeI. The
analytical data for 6 were in a good agreement with those reported previously.6
2-Benzimidazolyl 6-O-(2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranosyl)-2,3,4-tri-O-benzyl-β-
D-glucopyranoside (7). The title compound was prepared from donor 2 and acceptor 22 in 66%
yield in accordance with the general glycosylation procedure in the presence of DMTST. The
analytical data for 7 were in a good agreement with those reported previously.6
Methyl O-(2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranosyl)-(16)-O-(2,3,4-tri-O-benzyl-α/β-
D-glucopyranosyl)-(16)-2,3,4-tri-O-benzyl-β-D-glucopyranoside (8). The title compound
was prepared from donor 6 and acceptor 3 in 84% yield in accordance with the general glycosyl-
ation procedure in the presence of DMTST. The title compound was also prepared from donor 7
and acceptor 3 in 82% yield in accordance with the general glycosylation procedure in the pres-
ence of MeI. The analytical data for 7 were in a good agreement with those reported previously.31
Methyl
6-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-2,3,4-tri-O-benzyl-α-D-
glucopyranoside (11). The title compound was prepared from donor 9 or 10 and acceptor 3 as
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described in Tables in accordance with the general glycosylation procedure in the presence of
DMTST. Analytical data for 11 was the same as previously described.49
7
8
9
Methyl 6-O-(2-O-benzoyl-3,4,6-tri-O-benzyl-β-D-glucopyranosyl)-2,3,4-tri-O-benzyl-α-D-
glucopyranoside (14). The title compound was prepared from donor 12 or 13 and acceptor 3 as
described in Tables. Analytical data for 14 was the same as previously described.50
10
11
12
13
14
15
16
17
18
19
20
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22
23
24
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Benzimidazol-2-yl 6-O-(2-O-benzoyl-3,4,6-tri-O-benzyl-α/β-D-glucopyranosyl)-2,3,4-tri-O-
benzoyl-1-thio-β-D-glucopyranoside (24). The title compound was prepared from donor 12
and acceptor 23 in 67% yield in accordance with the general glycosylation procedure in the pres-
ence of AgOTf. Analytical data for 24: Rf = 0.70 (ethyl acetate/toluene, 3/7, v/v); [α]D22 +56.8 (c
= 1.0, CHCl3); 1H-n.m.r. (600 MHz, CDCl3): δ, 3.31 (dd, 1H, J6a’,6b’ = 10.5 Hz, H-6aʹ), 3.50-3.58
(m, 3H, J5’,6a’ = 4.3 Hz, H-4ʹ, 5ʹ, 6bʹ), 3.87 (dd, 1H, J3’,4’ = 8.7 Hz, H-3ʹ), 3.92 (dd, 1H, J6a,6b
=
11.5 Hz, H-6a), 3.96 (dd, 1H, H-6b), 4.14 (m, 1H, J5,6a = 3.8 Hz, J5,6b = 7.6 Hz, H-5), 4.37 (dd,
2H, 2J = 12.2 Hz, CH2Ph), 4.60 (dd, 2H, 2J = 10.9 Hz, CH2Ph), 4.65 (d, 1H, J1’,2’ = 8.0 Hz, H-1ʹ),
2
4.75 (dd, 2H, J = 11.3 Hz, CH2Ph), 5.21 (d, 1H, J1,2 = 10.1 Hz, H-1), 5.37 (dd, 1H, J4,5 = 10.0
Hz, H-4), 5.38 (dd, 1H, J2’,3’ = 8.7 Hz, H-2ʹ), 5.51 (dd, 1H, J2,3 = 9.7 Hz, H-2), 5.86 (dd, 1H, J3,4
= 9.4 Hz, H-3), 7.20-7.95 (m, 39H, aromatic), 10.53 (br. s, 1H, NH) ppm; 13C-n.m.r. (150 MHz,
CDCl3): δ, 68.6, 68.7, 69.6, 70.7, 73.5, 73.8, 73.8, 75.3, 75.4 (×2), 77.0, 77.97, 82.6, 84.4, 101.6,
127.9 (×3), 128.1 (×7), 128.4 (×2), 128.5 (×5), 128.6 (×11), 128.7, 128.8 (×2), 129.6, 129.8 (×2),
130.0 (×4), 130.1 (×2), 133.4, 133.5, 133.6, 133.7, 137.8 (×3), 144.8, 165.4 (×2), 165.7, 165.9
ppm; HR-FAB MS [M+Na]+ calcd for C68H60N2O14SNa+ 1183.3663, found 1183.3634.
Ethyl
6-O-(2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranosyl)-2,3,4-tri-O-benzyl-1-thio-β-D-
glucopyranoside (26). The title compound was prepared from donor 1 and acceptor 25 in 92%
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yield (α/β = 1/1.4) in accordance with the general glycosylation procedure in the presence of
AgOTf. Analytical data for the title compound was the same as previously described.20
7
8
9
Procedure for competitive glycosylation
10
11
12
13
14
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23
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Methyl
6-O-(2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranosyl)-2,3,4-tri-O-benzyl-α-D-
glucopyranoside (4). A mixture of glycosyl donor 1 (0.045 mmol), glycosyl donor 2 (0.045
mmol), glycosyl acceptor 3 (0.041 mmol), and freshly activated molecular sieves (3Å, 130 mg),
in 1,2-dichloroethane (1.5 mL) was stirred under argon for 1 h. After that, DMTST (0.135 mmol)
was added, and the reaction mixture was monitored by TLC. Upon disappearance of the glycosyl
acceptor, the solid was filtered off and the filtrate was diluted with CH2Cl2 (30 mL), washed with
sat. aq. NaHCO3 (10 mL) and water (3 x 10 mL). The organic layer was separated, dried with
MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography
on silica gel.
Mechanistic studies, intermediate/aglycone isolation/ characterization
(N-Thiomethyl)benzimidazol-2-yl 2,3,4,6-tetra-O-benzoyl-1-thio-β-D-glucopyranoside (15).
Dimethyl(thiomethyl)sulfonium triflate (0.024 g, 0.094 mmol) was added to a stirred solution of
benzimidazol-2-yl 2,3,4,6-tetra-O-benzoyl-1-thio-β-D-glucopyranoside (0.035 g, 0.047 mmol) in
1,21-dichloroethane (1.0 mL). The resulting reaction mixture was allowed to stir for 2 h. Then
triethylamine (~0.25 mL) was added. The resulting mixture was then diluted with CH2Cl2 (100
mL) and subsequently washed water (10 mL). The organic phase was separated, dried with
Na2SO4 and concentrated in vacuo. The crude residue was then used to obtain 1H-n.m.r. and 13C-
n.m.r. Selected analytical data for 15: Rf = 0.66 (ethyl acetate/toluene, 1/5, v/v); 1H-n.m.r.: δ,
2.44 (s,3H, SCH3), 4.50 (m, 2H, J5,6b = 4.9 Hz, J6a,6b = 14.3 Hz, H-5, 6a), 4.62 (dd, 1H, H-6b),
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5.76 (dd, 1H, J4,5 = 9.5 Hz, H-4), 5.84 (dd, 1H, J2,3 = 9.4 Hz, H-2), 6.15 (dd, 1H, J3,4 = 9.4 Hz,
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H-3), 6.36 (d, 1H, J1,2 = 10.4 Hz, H-1), 7.18-7.88 (m, 24H, aromatic) ppm; C-n.m.r.: δ, 23.0,
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63.3, 69.6, 70.9, 74.3, 83.9, 110.2, 119.0, 123.2, 128.4 (x2), 128.5 (x4), 128.6 (x3), 128.8 (x2),
128.9, 129.7, 129.8 (x3), 129.9 (x2), 130.0 (x2), 130.1 (x2), 133.1, 133.5, 133.6, 133.7, 138.7,
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+
143.9, 155.3, 165.4 (x2), 165.6, 165.8 ppm; HR-FAB MS [M+H]+ calcd for C42H35N2O9S2
775.1784, found 775.1773.
2-Methylsulfanyl-1H-benzimidazole (20). The title compound was isolated from a reaction be-
tween donor 1 and acceptor 3 in the presence of MeI. The identity of 20 was confirmed by com-
parison with the authentic commercial sample.
1-Methyl-2-methylthio-1H-benzimidazole (21). The title compound was isolated as colorless
crystals from a reaction between donor 18 and acceptor 3 in the presence of MeI. Selected ana-
lytical data for 21: Rf = 0.43 (ethyl acetate/hexane, 1/1, v/v); m.p. 121-124 °C (dichloro-
1
methane/toluene, 1/1, v/v); H-n.m.r.: δ, 2.80 (s, 3H, SCH3), 3.67 (s, 3H, NCH3), 7.15-7.71 (m,
13
4H, aromatic) ppm; C-n.m.r.: δ, 14.8, 30.1, 108.5, 118.2, 121.9 (x2), 137.1, 143.6, 153.4 ppm;
HR-FAB MS [M+H]+ calcd for C9H11N2S+ 179.0643, found 179.0645.
X-ray Structure Determination of Compound 21
Crystals of appropriate dimension were obtained by slow evaporation of a mixture of dichloro-
methane and toluene (1/1, v/v). A crystal of approximate dimensions of 0.576 x 0.119 x 0.041
3
mm was mounted on MiTeGen cryoloops in a random orientation. Preliminary examination and
data collection were performed using a X8 Kappa Apex II Charge Coupled Device (CCD) Detec-
tor system single crystal X-Ray diffractometer equipped with an Cryostream LT device. All data
were collected using graphite monochromated Mo K radiation (= 0.71073 Å) from a fine fo-
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cus sealed tube X-Ray source. Preliminary unit cell constants were determined with a set of 36
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narrow frame scans. Typical data sets consist of combinations of  and  scan frames with typi-
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cal scan width of 0.5 and counting time of 15 seconds/frame at a crystal to detector distance of
4.0 cm. The collected frames were integrated using an orientation matrix determined from the
narrow frame scans. Apex II and SAINT software packages were used for data collection and
data integration. Analysis of the integrated data did not show any decay. Final cell constants
were determined by global refinement of reflections harvested from the complete data set. Col-
lected data were corrected for systematic errors using TWINABS based on the Laue symmetry
using equivalent reflections.
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Crystal data and intensity data collection parameters are listed in Table 3S of the support-
ing information (SI). Structure solution and refinement were carried out using the SHELXTL-
PLUS software package.51 The structure was solved by direct methods and refined successfully
in the space group P1. Data from one of the two twin components were used for structure re-
finement (data from the minor component were ignored, HKLF 4 data used). Full matrix least-
2
2 2
squares refinements were carried out by minimizing w(F -F ) . The non-hydrogen atoms
o
c
were refined anisotropically to convergence. The NH H atom was located and refined freely. All
other hydrogen atoms were treated using appropriate riding model (AFIX m3). The final residu-
al values and structure refinement parameters are listed in Table 3S (see SI). The I- anion was
disordered in this structure. The disorder was modeled with partial occupancy atoms (99:1%) and
displacement parameter constraint, EADP.
Complete listings of positional and isotropic displacement coefficients for hydrogen at-
oms, anisotropic displacement coefficients for the non-hydrogen atoms are included as the sup-
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plementary material (Tables 4S, 6S and 7S). Table of calculated and observed structure factors
are available in electronic format.
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Supporting Information
1H and 13C NMR spectra for all new compounds, comparative glycosylation data and X-ray crys-
tallography data for compound 21. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* Department of Chemistry and Biochemistry, University of Missouri – St. Louis, One Universi-
ty Boulevard, St. Louis, Missouri 63121, USA; demchenkoa@umsl.edu
Author Contributions
The manuscript was written through contributions of all authors. / All authors have given ap-
proval to the final version of the manuscript.
ACKNOWLEDGMENT
This work was supported by awards from the NIGMS (GM077170 and GM111835). We thank
funding from the NSF-MRI (CHE-0420497) for the purchase of the Apex-II diffractometer. We
also thank Dr. Rensheng Luo (UM – St. Louis) for acquiring spectral data using 600 MHz NMR
spectrometer that was purchased thanks to the NSF (award CHE-0959360). Dr. Winter and Mr.
Kramer (UM – St. Louis) are thanked for HRMS determinations.
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