Regio- and stereoselective glycosylation of 2-(o-dihydroxyborylbenzyl) thioglucoside and unprotected methyl glycosides

Article abstract of DOI:10.1002/jccs.201900475

A highly regio- and stereoselective glycosylation of a boronic acid-containing thioglucoside and unprotected methyl glycosides is described. A boronic acid moiety was installed at the ortho-position of the 2-O-benzyl group of a thioglucosyl donor. This provides transient partial protection for the unprotected glycosyl acceptor upon condensation and concomitantly prearranged the acceptor with respect to the donor for the ensuing intramolecular glycosylation.

Full text of DOI:10.1002/jccs.201900475

Received: 6 November 2019
DOI: 10.1002/jccs.201900475
Revised: 10 February 2020
Accepted: 11 February 2020
S P E C I A L I S S U E P A P E R
Regio- and stereoselective glycosylation of 2-(o-
dihydroxyborylbenzyl) thioglucoside and unprotected
methyl glycosides
1
1,2
1
Sarah Lam | Mei-Yuan Hsu
| Cheng-Chung Wang
1
Institute of Chemistry, Academia Sinica, Taipei, Taiwan
2
Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program (TIGP), Academia Sinica, Taipei, Taiwan
Correspondence
Cheng-Chung Wang, Institute of
Chemistry, Academia Sinica,
Abstract
A highly regio- and stereoselective glycosylation of a boronic acid-containing
thioglucoside and unprotected methyl glycosides is described. A boronic acid
moiety was installed at the ortho-position of the 2-O-benzyl group of a thioglucosyl
donor. This provides transient partial protection for the unprotected glycosyl
acceptor upon condensation and concomitantly prearranged the acceptor with
respect to the donor for the ensuing intramolecular glycosylation.
1
1
28, Section 2, Academia Road, Taipei
15, Taiwan.
Email: wangcc@chem.sinica.edu.tw
Funding information
Academia Sinica, Grant/Award Numbers:
AS-SUMMIT-108, MOST 108-3114-Y-
001-002; Ministry of Science and
Technology, Taiwan, Grant/Award
Numbers: 106-2113-M-001-009-MY2,
MOST 108-2133-M-001-019-Dedicated to
Professor Chien-Hong Cheng on the
Occasion of His 70th Birthday.
K E Y W O R D S
boronic acid, glycosylation, regioselectivity, stereoselectivity
In carbohydrate chemistry, the ability to control regio- and
stereoselectivity when constructing glycosidic bonds is vital
for efficient synthesis of structurally well-defined oligomers.
The traditional way to achieve the desired regioselectivity is
by protecting all the hydroxyl groups not involving in glyco-
sylation in the glycosyl acceptor prior to glycosylation. The
tedious protecting group manipulation involved in this
approach was not desirable and numerous efforts have been
devoted to directly use fully unprotected or partially protec-
soluble in low-polarity solvents. When these arylboronic
acid-sugar complexes were used as glycosyl acceptors,
most of the hydroxyl groups were masked and only one
or two free hydroxyl groups were available for glycosyla-
tion. Moderate to excellent regioselectivities of these
[
8–12]
intermolecular glycosylation have been achieved.
Similarly, a boronic acid moiety was incorporated in a
polymeric support for regioselective solid phase glyco-
[
13,14]
sylations of partially protected glycosides.
In these
[1,2]
ted substrate for glycosylation.
The insolubility of the
intermolecular glycosylation, the stereochemistry of
newly formed glycosidic bond was not controlled except
when 2-O-aryl substituted glycosyl donor was used. Alt-
eratively, the boronic acid-sugar adduct could be acti-
vated by coordination of the boron center to oxygen or
highly polar unprotected sugars in organic solvents, which
are the usual glycosylation media, posed an additional chal-
lenge for their direct glycosylation. One way to tackle these
problems in the literature was to use arylboronic acid,
which is known to form cyclic boronic ester with
nitrogen-based Lewis base so that one of bounded alk-
[
3–7]
[15–19]
1
,3-diol or cis-1,2-diol on the unprotected sugar,
to
oxy groups underwent glycosylation.
An elegant
provide transient protection. This also reduced the over-
all substrate polarity and rendered the resulting adduct
work by Toshima has demonstrated that the coordina-
tion of the epoxy oxygen atom of 1,2-anhydro glycosyl
©
2020 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J Chin Chem Soc. 2020;1–5.
http://www.jccs.wiley-vch.de
1

2
LAM ET AL.
donors to the boron atom of the boronic acid-bounded
glycosyl acceptors activated both entities for an intramo-
lecular aglycol delivery that resulted in an overall highly
using thin layer chrmotagraphy by tracking the disap-
pearance of thioglucoside 2. Upon completion of glyco-
sylation, the reaction was quenched with trimethylamine
and a few drops of saturated sodium thiosulfate. To
ensure an accurate determination of glycosylation yields,
all boronates were converted back to boronic acid by
treating the crude mixture with acetic anhydride and pyr-
[
20–22]
regio- and 1,2-cis-stereoselective glycosylation.
Recently, a boronic acid moiety was introduced into the
leaving group of thioglycosyl donors with the aim to
selectively deliver the glycosyl acceptor intramolecularly
from one face, though the stereoselectivities obtained
[
25]
idine overnight.
This concomitantly protected all the
[
12,23]
were only moderate.
hydroxyl groups, which facilitated isolation and charac-
terization of any glycosylation product formed.
We envisioned that by incorporating a boronic acid
moiety in the 2-O-benzyl protecting group in a per-O-
benzylated thioglucoside, an unprotected glycosyl accep-
tor would anchor as a transient cyclic boronate. This pre-
organized donor and acceptor prior to glycosylation and
would potentially bring one of the unmasked hydroxyl
groups closer to and potentially from one face of the
anomeric center of the glycosyl donor, thereby leading
to a regio- and stereoselective glycosylation (Scheme 1).
To verify this hypothesis, 2-(o-dihydroxyboryl)benzyl
thioglucoside 2 was synthesized from 2-(o-bromobenzyl)
The reaction was first examined with unprotected
methyl glucoside 4, which was known to preferentially
form a 4,6-boronate with an arylboronic acid. Following
the general procedure with the use of N-iodosaccinimide
ꢀ
(NIS)/triflic acid (TfOH) as the promotor at −40 C,
β-(1!3)-linked disaccharide 5 was afforded as the sole
product in 35% yield (entry 1). The regio- and stereo-
chemistry of disaccharide 5 was unambiguously deter-
mined by nuclear magnetic resonance (NMR)
spectroscopy (Data S1). The reaction conditions were var-
ied to improve the glycosylation yield. It was found that
the cyclic boronic ester could alternatively be generated
by refluxing thioglucosyl donor 2 and unprotected accep-
tor 4 in toluene overnight. However, this method required
a solvent switch prior to glycosylation. The additional
manipulation and the difficulty in excluding water in this
process, which led to a lower glycosylation yield in gen-
eral, were not desirable. When the reaction was repeated
with other commonly employed glycosylation promoter
system for activation of thioglycosyl donor, such as
NIS/TMSOTf, NBS/TfOH, Ph SO/Tf O/TTBP, and p-
[24]
thioglucoside 1
by lithium-bromine exchange using n-
butyllithium followed by quenching with trimethyl
borate and hydrolysis upon acidic workup (Scheme 2).
With the boronic acid-containing thioglucoside 2 in
hand, we set out to test its reaction with unprotected glyco-
syl acceptors. The proposed reaction involved a formation of
a condensed donor-acceptor boronate complex prior to addi-
tion of activator for an intramolecular glycosylation to pro-
ceed. In practice, the boronic acid-containing thioglucoside
2
was first treated with an equimolar unprotected methyl
glycoside in dichloromethane overnight and activated
molecular sieve was added to scavenger the water generated
in the condensation of boronic acid and diol. The mixture
was then directly subjected to glycosylation. As the cyclic
boronate was readily hydrolyzed in the presence of mois-
ture, the progress of glycosylation could easily be monitored
2
2
TolSCl/AgOTf, either a low disaccharide yield or a compli-
cated mixture without any identifiable product was
obtained. Therefore, this glycosylation was optimized
based on the initial conditions using the NIS/TfOH pro-
moter system. The use of a larger excess of NIS failed to
SCHEME 1 Envisioned boronic acid
functionality on glycosyl donor to direct regio-
and stereoselective of glycosylation with
unprotected glycosyl acceptor
SCHEME 2 Preparation of boronic acid-
containing glycosyl donor 2

LAM ET AL.
3
improve the glycosylation. Instead, there was more severe
decomposition and as a result, a reduced amount of disac-
charide 5 was isolated (entry 2). The reaction concentra-
tion effect was studied (entry 1, 3–4). A more dilute
condition was advantageous for this intramolecular glyco-
sylation. A slightly diminished glycosylation yield was
obtained when the glycosylation was carried out at a
higher (entry 5) or lower temperature (entry 6). The addi-
tion of 2,6-di-tert-butyl-4-methylpyridine (DTBMP) to
reduce the acidity in the reaction mixture during glycosyl-
ation only attenuate the donor reactivity and the reaction
FIGURE 1 Plausible reaction intermediate responsible for the
regio- and stereoselectivity observed in the reaction with
unprotected methyl glucoside 4
TABLE 1 Glycosylation of thioglucoside 2 and unprotected methyl glucoside 4
ꢀ
a
Entry
Concentration
0.05 M
n
T ( C)
Yield
35%
19%
36%
45%
30%
37%
39%
21%
1
2
3
4
5
6
1.05
1.20
1.05
1.05
1.05
1.05
1.05
1.05
−40
−40
−40
−40
−20
−60
−40
−40
0.05 M
0.02 M
0.01 M
0.01 M
0.01 M
b
7
0.01 M
c
8
0.01 M
a
Isolated yield.
b
Addition of 0.2 equiv DTBMP in step 2.
.5 equiv of thioglucoside 2 was used.
c
1
SCHEME 3 Reaction of boronic
acid-containing thioglucoside 2 and
unprotected methyl galactoside 6

4
LAM ET AL.
outcome was not affected, though a longer reaction time
was required for complete consumption of the thioglucosyl
donor (entry 7). To our surprise, when an excess amount
of the boronic acid-containing donor 2 was employed
aiming to ensure a more complete formation of cyclic
boronate with the unprotected acceptor 4, the disaccharide
yield dropped dramatically (entry 8). In all cases, disaccha-
ride 5 was the only isolatable glycosylation product.
The regio- and stereoselectivity observed was rational-
ized by the plausible reaction intermediate depicted in
Figure 1. The unprotected methyl glucoside 4 preferen-
tially form a 4,6-cyclic boronate with the boronic acid
moiety in thioglucoside 2 and this brought the 3-hydroxyl
group close in proximity to the top face of anomeric cen-
ter after activation using NIS/TfOH (Table 1).
Having identified the optimal conditions for the reac-
tion between glucosides, the reactions with other unpro-
tected glycosides were studied. It was found that the
reaction was substrate dependent and different reaction
outcomes were obtained when using different glycosyl
acceptors. When the same reaction conditions were
employed in the reaction with unprotected galactoside 6, a
macrocyclic β-(1!3)-linked disaccharide dimer 7 was
afforded as the only product (Scheme 3). Using NBS in
place of NIS slightly improved the yield to 48%. The forma-
tion of the disaccharide dimer was confirmed by mass
spectroscopy, while the regio- and stereochemistry of the
dimer was determined by NMR spectroscopy. The unusual
upfield shift of proton signal of the 2-acetyl group in H
1
NMR spectrum indicated that the acetyl group was
shielded by the macrocycle. It was postulated that a six-
membered 4,6-boronate was preferentially formed over
a five-membered cis-3,4-boronate after condensation
between the boronic acid moiety of thioglucoside 2 and
galactoside 6 under thermodynamic conditions, leaving
the 2- and 3-hydroxyl group on the galactoside available
for glycosylation. However, unlike the boronate formed
with the glucoside acceptor, this condensed species had
two free hydroxyl groups oriented further away from the
reactive anomeric center and this prevented any intra-
molecular reaction from proceeding (Figure 2). Instead,
intermolecular reaction was geometrically favorable,
leading to the formation of the macrocyclic dimer 7 of
β-(1!3)-linked disaccharide.
When unprotected methyl mannoside 8 was used as
the glycosyl acceptor, no disaccharide was formed under
any glycosylation conditions attempted (Scheme 4).
Thioglucoside 2 decomposed while mannoside 8 was
acetylated. Presumably, the availability of two orthogonal
sites for the formation of cyclic cis-2,3- and 4,6-boronate
on the unprotected methyl mannoside 8 was responsible
for this reaction outcome. The initially insoluble unpro-
tected mannoside 8 became soluble after the formation
of the first cyclic boronate and this promoted the rapid
formation of the second boronate, leaving no free
hydroxyl group available for glycosylation. As there was
only one equivalent of boronic acid in the mixture, the
other half equivalent of mannoside remained unco-
ndensed. The insolublity of the unprotected mannoside
in dichloromethane prevented it from undergoing any
glycosylation.
To conclude, we have demonstrated that a boronic
acid moiety installed at the ortho-position of the 2-benzyl
group of thioglucoside was able to act as a transient
protecting group for the unprotected methyl glucosyl and
galactosyl acceptors to partially shield the hydroxyl
groups and as a molecular clamp to bring the acceptor
into a specific orientation with respect to donor. The
reaction outcome was highly substrate dependent. In
other words, the success of glycosylation was governed
FIGURE 2 Plausible reaction intermediates responsible for
the regio- and stereoselectivity observed in the reaction with
unptorected methyl galactoside 7
SCHEME 4 Attempts in reaction
of boronic acid-containing thioglucoside
2
and unprotected methyl mannoside 8

LAM ET AL.
5
by the ability to selectively form a condensed boronate
intermediate that possess one or more free hydroxyl
groups, in which one of them is in a closer proximity to
the reactive anomeric center where glycosylation took
place possibly also from one face. This was the case for
the glucoside acceptor and a β-(1!3)-linked disaccharide
was afforded as the sole product. For galactoside accep-
tor, although intramolecular glycosylation of the con-
densed 4,6-boronate was not favorable, an intermolecular
glycosylation proceeded with high regio- and stereo-
selectivity, resulting in a formation of a β-(1!3)-linked
disaccharide dimer. The inability of mannoside acceptor
to form a condensed boronate with any free hydroxyl
groups was postulated to be the reason for the failure of gly-
cosylation. In general, excellent regio- and stereoselective
glycosylations of unprotected glycosides were achieved
when glycosylation of the condensed boronate complex was
possible. The highly specific formation of glycosidic bond
using unprotected glycosyl acceptor is desirable in
complex oligosaccharides synthesis. Thus, the idea of
placing a boronic acid moiety at the other positions of
per-O-benzylated glycoside donors may possibly lead to
formation of disaccharides with a different glycosyl
linkage and merit further investigation.
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ACKNOWLEDGEMENTS
This work was supported by the Ministry of Science and
Technology, Taiwan (MOST 108-2133-M-001-019-;
[
[
[
1
1
06-2113-M-001-009-MY2) and Academia Sinica (MOST
08-3114-Y-001-002; AS-SUMMIT-108). S.L. thanks Aca-
demia Sinica for a postdoctoral fellowship.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
ORCID
Cheng-Chung Wang https://orcid.org/0000-0002-2562-
0
658
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How to cite this article: Lam S, Hsu M-Y,
Wang C-C. Regio- and stereoselective glycosylation
of 2-(o-dihydroxyborylbenzyl) thioglucoside and
unprotected methyl glycosides. J Chin Chem Soc.
2020;1–5. https://doi.org/10.1002/jccs.201900475
2
002, 1325.