Thermodynamically controlled regioselective glycosylation of fully unprotected sugars through Bis(boronate) intermediates

Article abstract of DOI:10.1002/ejoc.201402255

Fully unprotected D-glucose, D-mannose, and D-fructose were regioselectively glycosylated with several phenylthioglycosides to afford glycosyl-β(1→6)-α/β-D-glucopyranose, glycosyl- β(1→1)-α-D-mannofuranoside, and glycosyl-β(1→1)- β-D-fructopyranose in goo

Full text of DOI:10.1002/ejoc.201402255

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402255
Thermodynamically Controlled Regioselective Glycosylation of Fully
Unprotected Sugars through Bis(boronate) Intermediates
Eisuke Kaji,*[a] Daisuke Yamamoto,[a] Yuko Shirai,[a] Koji Ishige,[a] Yoshika Arai,[a]
Tatsuya Shirahata,[a] Kazuishi Makino,[a] and Takashi Nishino[a]
Keywords: Oligosaccharides / Glycosylation / Regioselectivity / Boronates
Fully unprotected
were regioselectively glycosylated with several phenylthio-
glycosides to afford glycosyl-β(1Ǟ6)-α/β- -glucopyranose,
glycosyl-β(1Ǟ1)-α- -mannofuranoside, and glycosyl-
β(1Ǟ1)-β- -fructopyranose in good yields. The regioselectiv-
D
-glucose,
D
-mannose, and
D
-fructose
ity might have arisen from a thermodynamically controlled
bis(phenylboronate) intermediate, which leaves only one
free hydroxy group to be glycosylated in complete regio-
selectivity.
D
D
D
ample, methyl α/β-d-glucopyranoside, methyl α/β-d-galac-
topyranoside, methyl α/β-d-rhamnopyranoside, and so on,
and the yields and regioselectivity were not always high.
Therefore, it is of special interest to develop a novel regiose-
lective glycosylation method applicable to fully unprotected
1-OH free hexoses. To realize our goal, we noted the bis-
(arylboronate)s of hexoses, which leave only one free hy-
droxy group feasible for perfect regioselective glycosylation
(cf. Scheme 1). Regioselectivity might be expected owing to
the bis(phenylboronate) structures, which are capable of
masking four hydroxy groups of the hexoses in the most
stable thermodynamic forms. Thus, d-glucose, d-galactose,
and d-mannose as aldohexoses as well as d-fructose as a
ketohexose were employed as glycosyl acceptors. Several O-
acylated thioglycosides were used as glycosyl donors for
glycosylation of these acceptors under the conditions em-
ployed in our “transient masking” method, which was used
for the regioselective glycosylation of several alkyl glycos-
ides.[6]
Introduction
Carbohydrates are considered to be target molecules of
great importance owing to their biological functions.[1]
Their elucidation requires the chemical synthesis of oligo-
saccharides, which are indispensable for providing diverse
substances in pure form in enough quantity, especially if
isolation from natural sources is limited. An extensive arse-
nal of methods for oligosaccharide synthesis is currently
available.[2] Conventional methods based on a protection–
deprotection processes typically involve several synthetic
steps, expensive reagents, and extensive manipulation of the
protecting group. To minimize these drawbacks, several
methods for the regioselective protection of carbohydrates
have been developed and are used for oligosaccharide syn-
thesis, which thereby reduces the number of reaction steps
for the preparation of partially protected sugars.[3] However,
more straightforward methodology is required for the re-
gioselective glycosylation of fully unprotected sugars with-
out the need for the preparation of the protected sugars.
In this context, very few precedents have been reported;
however, stannylene-mediated regioselective glycosylation
of unprotected hexopyranosides is reported to produce a
one-pot assembly of some oligosaccharides.[4] In addition,
boronate-mediated regioselective glycosylation has also
been reported.[5] Recently, we developed a novel method for
the regioselective glycosylation of fully unprotected methyl
hexopyranosides by means of “transient masking” of the
hydroxy groups with arylboronic acids.[6] All previous
methods were limited to alkyl glycoside acceptors, for ex-
Scheme 1. Regioselective glycosylation of fully unprotected hexoses
by transient masking method; Bz = benzoyl.
[a] School of Pharmacy, Kitasato University,
5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan
E-mail: kajie@pharm.kitasato-u.ac.jp
Results and Discussion
First, we tested our method by using d-glucose as a fully
unprotected acceptor. Molecular recognition between gluc-
http://www.kitasato-u.ac.jp/pharm/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402255.
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Regioselective Glycosylation of Fully Unprotected Sugars
ose and arylboronic acid in aqueous media has been widely
Because of the complexity of the NMR spectra of disac-
investigated in the detection of glucose for biological pur- charide 4 obtained from the all-hydroxy-free d-glucose ac-
poses.[7] In non-aqueous media, however, the structures of ceptor, acetylation of the crude product was performed to
the boronate complexes of glucose are poorly understood furnish an anomeric mixture of 2,3,4,6-tetra-O-benzoyl-β-
in most cases. Eggert et al. reported a furanose-type com- d-glucopyranosyl-(1Ǟ6)-1,2,3,4-tetra-O-acetyl-α,β-d-gluco-
plex of 1,2:3,5-bis(boronate) 2 of glucose (Table 1) prepared pyranose (5),[10] namely a gentiobiose derivative. Alterna-
in DMF, the structure of which was elucidated on the basis tively, to avoid formation of anomeric isomers of 5, we tried
of NMR spectroscopy.[8] We screened various non-aqueous to lead 4 into bis(boronate) derivative 6 by treatment of 4
solvents that might be suitable for our purpose. Among the with phenylboronic acid (2 equiv.), which afforded a single
low-boiling solvents tested, acetone was found to be a good isomer of 6 in pure form (Figure 1). The structure of 6 was
solvent for generating the bis(arylboronate)s complex of d- reasonably elucidated by the HMBC spectra designated in
glucose. The structure was identified as bis(boronate) com- Figure 1. Previous access to gentiobiose by the conventional
plex 2.
protection–deprotection method required six steps from d-
glucose to give a combined yield of less than 25%.[11]
Table 1. Regioselective glycosylation of d-glucose.[a]
Entry Donor [equiv.]
T [°C]
–30
–30
–30
–10
0
Time [h]
Yield[b] [%]
Figure 1. Acetyl and bis(boronate) derivatives of disaccharide 4.
DMAP = 4-(N,N-dimethylamino)pyridine.
1
2
3
4
5
6
2.0
3.0
4.0
2.0
2.0
2.0
10
5
6
1.5
0.3
0.2
79
90
94
79
86
79
As the disaccharide (a gentiobiose derivative) was ob-
tained from d-glucose as expected, we attempted our
method on glycosyl donors 7 and 8. A one-pot reaction
of d-glucose with phenylboronic acid (2 equiv.) followed by
glycosylation with phenylthiogalactoside 7 and mannoside
8 under the reaction conditions employed in entry 5 of
Table 1, except for the reaction time (20 h), readily gave de-
sired disaccharides 9 and 10 in good yields as the sole prod-
ucts (Scheme 2). The structures of the disaccharides were
unambiguously elucidated on the basis of O-acetylated de-
rivatives 11 and 12, as described for 4.[12] The anomeric
configuration of the nonreducing end of 9 and 10 was de-
duced to be β and α, respectively, as expected by anchimeric
assistance of the 2Ј-O-benzoyl group.
r.t.
[a] NIS = N-iodosuccinimide, TMSOTf = trimethylsilyl trifluoro-
methanesulfonate, MS = molecular sieves. [b] Yield of isolated
product.
Although boronate is not stable enough to store at ambi-
ent temperatures,[9] it is acceptable for the “transient mask-
ing” of hydroxy groups. Accordingly, bis(boronate) 2
seemed to be an appropriate intermediate for the glycosyl-
(1Ǟ6)-linked glucose structure, and the glycosylation con-
ditions required for 2 were investigated after evaporation of
acetone with glycosyl donor 3 in 1,2-dichloroethane (DCE,
cf. Table 1).
Under the reaction conditions employed (Table 1), glyc-
osylation of 2 with tetra-O-benzoyl-1-thio-β-d-glucopyr-
anoside (3) provided disaccharide 4 in 79% yield. The yield
of disaccharide 4 was increased to 94% if the number of
equivalents of donor 3 (2–4 equiv.) was also increased
(Table 1, entries 1–3).
The effects of the reaction temperature were also exam-
ined with the aim of obtaining sizeable improvements in the
yield as well as improved reaction times (Table 1, entries 1,
4–6). Among those examined, entry 5 could be recom-
mended owing to a good yield (86%), short reaction time
(20 min), and lower number of equivalents of the donor
(2 equiv.).
Scheme 2. Regioselective glycosylation of fully unprotected glucose
with galactosyl and mannosyl donors.
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3537

E. Kaji et al.
SHORT COMMUNICATION
Next, we applied our method to other acceptors, d-ga-
lactose and d-mannose, as aldohexoses other than d-gluc-
ose. We observed that the bis(boronate)s of d-galactose that
were formed in acetone at 50 °C gave a complex mixture
of isomers of boronates, the structures of which were not
elucidated at this stage on the basis of NMR spectroscopy.
Subsequently, we tested the bis(boronate) formation of
d-mannose, which was reported to form an α-d-mannofur-
anose cyclic 2,3:5,6-bis(n-butylboronate).[8b] As expected,
hydroxy-free d-mannose 13 reacted with phenylboronic acid
(2 equiv.) in acetone to generate 2,3:5,6-bis(phenylboronate)
complex 14 of the furanose form possessing a free hemiace-
tal function at the anomeric center.
Glycosylation readily occurred with glucosyl donor 3 un-
der the conditions described above to afford β-d-glucopyr-
anosyl-(1Ǟ1)-α-d-mannofuranoside 15 in 83% yield
(Scheme 3). Structural identification was performed by
analysis of bis(boronate) derivative 16 by NMR spec-
troscopy, as depicted in Figure 2. The newly formed 1Ǟ1-
linked intersaccharide linkage of 16 was identified by
HMBC spectroscopy, which clearly showed cross signals be-
tween H-1Ј and C-1, H-1Ј and C-5Ј, H-1 and C-1Ј, as well
as H-1 and C-4. From the anomeric configurations, the β-d-
glucopyranosyl form was demonstrated from the coupling
constant of JH1Ј,H2Ј = 8.0 Hz, whereas the NOE between
H-1 and H-1Ј suggested an α-configuration of the manno-
furanosyl moiety (Figure 2).
Figure 2. HMBC and NOE spectra of β-d-glucopyranosyl-(1Ǟ1)-
α-d-mannofuranoside 2,3:5,6-bis(phenylboronate) 16.
showed a cross signal between H-1 and H-3. The β-d-fruc-
topyranosyl structure should be estimated from the above
data as well as intermediary 2,3:4,5-bis(boronate) structure
18, with which glycosyl donor 3 attacks a free 1-OH func-
tion of 18 at the glycosylation stage.
Scheme 4. Glycosylation of d-fructose (17) with glucosyl donor 3.
Conclusions
In summary, straightforward and novel regioselective
glycosylation of fully unprotected hexoses was developed
for the following. 1) Hexose structure-dependent bis(boron-
ate)s were formed in situ and glycosylated with several glyc-
osyl donors to afford disaccharides with complete regiose-
lectivity. 2) Among the aldohexoses employed, d-glucose
was glycosylated to 6-OH of the acceptors to provide 1Ǟ6-
linked disaccharides, whereas d-mannose was glycosylated
to 1-OH to afford a 1Ǟ1-linked disaccharide comprising a
mannofuranoside. 3) A ketohexose, d-fructose, was glyc-
osylated to give 1Ǟ1-linked disaccharide comprising a fruc-
topyranose. Our method might significantly improve the
synthesis of disaccharides included in the above categories
with regard to the reaction steps and manipulations re-
quired.
Scheme 3. Glycosylation of d-mannose 13 with glucosyl donor 3.
Finally, we applied our method to d-fructose (17), a
ketohexose. Although the bis(boronate) of d-fructose has
been reported,[13] we tried to obtain it by using our own
method to yield β-d-fructopyranose cyclic 2,3:4,5-bis(phen-
ylboronate) (18, Scheme 4). Glycosylation of 18 in situ with
glucosyl donor 3 readily gave β-d-glucopyranosyl-(1Ǟ1)-β-
d-fructopyranose 19 in 97% yield. The regio- and stereose-
lectivity of the newly formed intersaccharide linkages were
unambiguously determined on the basis of their NMR
spectra (HMBC and ROESY). An anomeric configuration
of the β-d-glucopyranosyl portion was identified by the
JH1Ј,H2Ј coupling constant (8.0 Hz, 5.04 ppm). However, the
second-order HMBC spectrum showed cross signals be-
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data for all new
tween H-1Ј and C-1 and between H-1 and C-5, and ROESY compounds associated with this article.
3538 Eur. J. Org. Chem. 2014, 3536–3539
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Regioselective Glycosylation of Fully Unprotected Sugars
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Acknowledgments
This work was supported by the Japan Society for the Promotion
of Science (Grants-in-Aid for Scientific Research, to T. N.) and by
Kitasato University (Research Grant for Young Researchers, to
D. Y.). We also thank Dr. Kenichiro Nagai, Mses. Noriko Sato,
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Received: March 12, 2014
Published Online: April 30, 2014
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