Regioselective glycosylation of fully unprotected methyl hexopyranosides by means of transient masking of hydroxy groups with arylboronic acids

Article abstract of DOI:10.1016/j.tetlet.2010.01.048

Facile, one-pot synthesis was developed for several β(1→2)-, β(1→3)- or β(1→4)-linked disaccharides from fully unprotected methyl hexopyranosides according to the molecular recognition by arylboronic acids. The methodology was successfully applied to faci

Full text of DOI:10.1016/j.tetlet.2010.01.048

Tetrahedron Letters 51 (2010) 1570–1573
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective glycosylation of fully unprotected methyl hexopyranosides
by means of transient masking of hydroxy groups with arylboronic acids
*
Eisuke Kaji , Takashi Nishino, Koji Ishige, Yohei Ohya, Yuko Shirai
School of Pharmacy, Kitasato University, Shirokane 5-9-1, Minato-ku, Tokyo 108-8641, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Facile, one-pot synthesis was developed for several b(1?2)-, b(1?3)- or b(1?4)-linked disaccharides
from fully unprotected methyl hexopyranosides according to the molecular recognition by arylboronic
acids. The methodology was successfully applied to facile, short step assembly of the trisaccharide frag-
ment of type II arabinogalactan.
Received 4 December 2009
Revised 13 January 2010
Accepted 15 January 2010
Available online 20 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Oligosaccharide
Glycosylation
Regioselectivity
Masking
Arylboronate
Practical chemical synthesis of oligosaccaharide usually re-
quires an adequate stereoselectivity and regioselectivity for glyco-
sylation reaction, by which diversely designed oligosaccharides are
provided on a preparatory scale.1 At present, stereoselectivity of
the anomeric centers has been nearly overcome by utilizing the
anomeric effect and anchimeric assistance.2 With regard to regio-
selective glycosylation, most of the present methods are based
on the protection–deprotection method, which requires a stepwise
protection of undesired hydroxy groups. In this method, after gly-
cosylation of the desired hydroxy group, the protective groups
have to be removed, and accordingly the overall synthetic scheme
becomes lengthy and impractical.3 Additional drawbacks to the
protection–deprotection method seem to waste excess reagents
used for protection in terms of atomic efficiency as well as time
and energy for multi-step manipulation.
Recently, Hung and co-workers reported regioselective
protection of sugar hydroxy groups, which has been applied to
the one-pot synthesis of influenza virus-binding trisaccharide
library.4 Further novel approach for regioselective protection of
hydroxy groups were provided by nonenzymatic regioselective
acylation5 as well as catalytic regioselective functionalization of
1,2-diols involving carbohydrates.6 However, few methods have
been reported for regioselective glycosylation of fully unprotected
sugars without any protection on glycosyl acceptors.
tion7–10 or activated boronate formation.11 These methods pro-
vided early success for regioselectivity, however, they are limited
to b(1?6)-linked disaccharides only in the case of glycosylation
of methyl hexopyranosides possessing both primary and secondary
hydroxy groups in the same molecule. The only exception pre-
sented to our previous method was by means of ion-pair interme-
diates based on the stannylated methyl b-D-galactopyranoside,
providing b(1?3)-linked disaccharides as the major product albeit
in low yields.10 The activating method has drawbacks limited to
the primary rather than the secondary hydroxy group. Alkyl stann-
ylene compounds also seem to be responsible for environmental
preservation.
We focused on an alternative procedure without activation but
with deactivation (masking) of hydroxy groups. As such, we se-
lected boronate intermediates, since boronates are susceptible to
hydrolysis for use in the protective group of diols.12 However, they
must be utilized as promising mediators for molecular recognition
of carbohydrates,13 such that boronic acids easily form sterically
demanding cyclic boronates, which function as a transient masking
rather than as protection for hydroxy groups.
In general (cf. Scheme 1), sugar hydroxy groups might be recog-
nized by the boronic acids at 1,2-cis-diol as well as 4,6-diols of hex-
oses.13 Accordingly, a glycosyl donor can conceivably attack a free
hydroxy group other than masked hydroxy groups giving rise to
regioselective glycosylation. After glycosylation, boronic acid
should be removed easily from the reaction mixture in situ by
exposure to aqueous sodium perborate.14
The former approach of regioselective glycosylation was
achieved by activation of the target hydroxy group using stannyla-
This procedure would provide a widely applicable, simple, one-
pot glycosylation reaction such that the reaction would enable us
* Corresponding author. Tel.: +81 3 3444 6161; fax: +81 3 3444 4741.
E-mail address: kajie@pharm.kitasato-u.ac.jp (E. Kaji).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.048

E. Kaji et al. / Tetrahedron Letters 51 (2010) 1570–1573
1571
1) Stannylene activation method
OH
OH
stannylation
O
O
O
glycosylation
OH
HO
O
O
OR
OR
Bu2SnO
OH
O
O
OR'
OR
Sn
Bu
O
OH
Bu
X
OR'
2) Boronate masking method
OH
O
O
OH
O
Ar-B(OH)2
O
glycosylation
HO
O
OR
O
OR'
OR
OH
O
B
O
HO
OR
Ar
OH
X
OR'
Scheme 1. General scheme for regioselective glycosylation of fully unprotected sugars.
to glycosylate any hydroxy group which has not been accessible by
the previous methods.7–11
moters affording the disaccharides regioselectively as depicted in
Scheme 2 and Table 1. This set of reactions resulted in glycosyl-
b(1?3)-galactosides in predominantly higher yields compared to
the corresponding b(1?2)-linked disaccharides. The b(1?6)-
galactosides were not detected from the reaction products. Accord-
ingly, this method is applicable to the secondary hydroxy groups
rather than the primary hydroxy groups. This selectivity should
be rationalized by the expected masking of 4,6-hydroxy groups
with arylboronic acid generating 4,6-boronate as the
intermediate.15
First, in order to achieve elucidation of structure–regioselective
relationships, we set up model experimental conditions using
readily available glycosyl donors and acceptors. Glycosyl bromides
(1–2) functioning as reactive donors and phenyl thioglycosides (3–
5) as stable, versatile donors were employed for glycosylation of
several acceptors, for example, methyl hexopyranosides (6–12) in
the presence of arylboronic acids (13–15) as shown in Figure 1.
The results are summarized in Table 1, where optimum reaction
conditions were examined for glycosylation of methyl b-
D
-galacto-
Comparing with the previous method10 providing 42% yield at
best for glycosyl-b(1?3)-galactosides, the experiments described
at entries 1 and 3 provide good yields with high regioselectivity.
With regard to the anomeric isomers of the glycosidic linkage,
b-isomers were obtained, except for entry 5, where the mannosyl
pyranoside (7). In both cases using bromide and phenylthio glyco-
side, the donor, the acceptor, and arylboronic acid were mixed in
the appropriate solvent in a reaction flask to form boronic ester
at room temperature for 16 h, then treated with glycosylation pro-
R1
R2
PivO
OPiv
R1
R2
BzO
OBz
OBz
O
BzO
BzO
BzO
O
O
SPh
PivO
BzO
Br
SPh
1 : R1 = H, R2 = OPiv
2 : R1 = OPiv, R2 = H
3 : R1 = H, R2 = OBz
4 : R1 = OBz, R2 = H
5
HO
OH
OH
O
OH
O
HO
HO
O
HO
R1
R1
HO
HO
HO
HO
R2
HO
R2
OMe
6 : R1 = H, R2 = OMe
7 : R1 = OMe, R2 = H
8 : R1 = H, R2 = OMe
9 : R1 = OMe, R2 = H
10
R1
OMe
OMe
O
O
R2
OH
HO
HO
OH
OH
HO
B
HO OH
11
12
13 : R1 = H, R2 = H
14 : R1 = OMe, R2 = H
15 : R1 = H, R2 = Ac
Figure 1. Glycosyl donors, acceptors, and arylboronic acids employed for regioselective glycosylation.

1572
E. Kaji et al. / Tetrahedron Letters 51 (2010) 1570–1573
Table 1
Glycosylation of methyl b-D-galactopyranoside (7) with several glycosyl donorsa,b
Entry
Donor
Boronic acid
Solventc
Promoterd
Temp (°C)
Time (h)
Product
Yield (%)
Compd no.
1?3:1?2e (ratio)
1
2
3
4
5
6f
1
2
3
4
5
3
13
14
14
14
14
—
DCE
DCE
DCE–AN
DCE–AN
DCE–AN
DCE–AN
A
A
B
B
B
B
0
0
À30
À30
À30
À30
24
24
2
2
5
bGlc–bGal
bGal–bGal
bGlc–bGal
bGal–bGal
78
66
71
76
73
—
22 + 23
24 + 25
16 + 17
18 + 19
20 + 21
92:8
94:6
93:7
91:9
81:19
—
aMan–bGal
5
bGlc–bGal
a
b
c
The reactions were performed in the presence of 1.0 equiv of arylboronic acid.
Two equivalent donors were employed.
DCE (1,2-dichloroethane):AN (acetonitrile) = 1:1.
d
A: Ag(I) silica–alumina16 (900 mg to 0.50 mmol of glycosyl bromide employed); B: N-iodosuccinimide–trimethylsilyl trifluoromethanesulfonate (NIS-TMSOTf).17 NIS
(0.28 mmol) and TMSOTf (0.02 mmol) were employed to 0.20 mmol of the 1-thio-glycosides.
e
f
The ratio of b(1?3)-disaccharide: b(1?2)-disaccharide for entries 1–4. The ratio of
a
(1?3)-disaccharide:
a
(1?2)-disaccharide for entry 5.
The reaction was carried out without boronic acid.
OMe
HO
OH
O
BzO
R1
R2
BzO
R1
B
OBz
O
HO
HO
R1
R2
BzO
OH
O
HO
OBz
O
OH
O
HO
OH
HO
O
OMe
R2
14
O
SPh
OMe
O
OMe
BzO
1)1,2-DCE:MeCN
rt, 16 h
2) NIS / TMSOTf
–30°C
OBz
OH
OBz
OH
OBz
3 : R1 = H, R2 = OBz
4 : R1 = OBz, R2= H
7
16 : R1= H, R2 = OBz
18 : R1 = OBz, R2 = H
17 : R1 = H, R2 = OBz
19 : R1 = OBz, R2 = H
BzO
BzO
BzO
BzO
BzO
BzO
OBz
O
OBz
O
BzO
OBz
HO
HO
OH
O
OH
HO
OH
O
O
14
HO
BzO
OMe
BzO
O
O
OMe
O
O
Me
OH
OH
1), 2) as above
SPh
OH
7
5
20
21
Scheme 2. Regioselective glycosylation of fully unprotected methyl b-D-galactopyranoside.
donor (5) provided only the
a
-anomer as generally anticipated. For
Glycosylation of various glycosyl acceptors with such glycosyl
glycosylation with bromide (1), 1,2-dichloroethane (DCE) is the
favored solvent, while with the thioglycoside, the mixed solvent
system using DCE/MeCN (1:1) provided better yields, probably
due to good solubility of the thioglycosides, acceptors, and promot-
ers in the mixed solvent employed in the glycosylation. Glycosyla-
tion of the galactoside 7 without boronic acid resulted in product
mixture hardly isolable as a pure product (cf. Table 1, entry 6).
Structures of the disaccharides obtained were unambiguously
elucidated on the basis of their MS, 1H and 13C NMR spectra.18
The intersaccharide linkages were defined by the deshielding effect
of the 13C NMR chemical shift, where the O-glycosylated carbon
atom sizably shifted to a lower magnetic field.10 Further, HMBC
and NOESY data supported the above statement by the corre-
sponding crossed signals of the second order analyses. As for the
donors as bromide (1 and 2) and phenylthio glycoside (3) are sum-
marized in Table 2. Glycosylation of a-galactoside (6) with 1 pro-
vided b(1?3)-disaccharide predominantly with less selectivity
compared with the b-galactoside probably due to steric relief
around the C-2 hydroxyl group (entry 1). In contrast, glycosylation
of
preference to b(1?3)-disaccharides in the ratio of ca. 7:1 (entries 2
and 3). In the case of -glucopyranoside (8) as the acceptor, the
a-D-glucopyranoside (8) afforded b(1?2)-linked disaccharide in
a-D
donor attacks the 2-hydroxy group easier than the 3-hydroxyl
group according to the steric surroundings, affording b(1?2)-
disaccharide predominantly. The b-
D-glucopyranoside acceptor
(9) is found to have less selectivity comparing the
a-anomer (8)
affording the b(1?2)-: b(1?3)-disaccharides in the ratio of ca.
7:3 (entries 4 and 5). The relatively low yields (35–44%) were ob-
served at the entries 2, 3, and 5, whereas the starting materials as
well as other products were not isolable from the reaction mixture.
For 6-deoxyhexopyranosides (11 and 12), masking of the cis-diol
leaves only one hydroxy group free, which causes the entire regi-
glycosylation of methyl b-D-galactopyranoside (7), b(1?3)-linked
disaccharides (16 and 18) have been obtained predominantly. This
selectivity would be rationalized by the generation of the 4,6-bor-
onate intermediate,15 which could be glycosylated in situ to give
the b(1?3)- and b(1?2)-linked disaccharides. The b(1?3)-selec-
tivity is probably due to the steric effect, where the electrophiles
seem to attack the 3-hydroxy group in preference to the 2-hydroxy
group. In the galactopyranoside there would be more enough space
around the 3-hydroxy group because of the neighboring axial hy-
droxy group at position 4. This assumption might be supported
oselectivity affording b(1?2)-disaccharide for
(entry 6) as well as b(1?4)-disaccharide for
side (entry 7) in good yields.
a
-
L
-fucopyranoside
a
-L-rhamnopyrano-
Furthermore, utility of our method was evaluated by a facile
assembly of the trisaccharide fragment (37) [Galp-b1?3 (Galp-
b1?6)-Galp-b1?Me] of type II arabinogalactan (a Chinese
medicine, Ohgi).19–21 For construction of the trisaccharide (37)
we employed the disaccharide 18 obtained by regioselective glyco-
sylation at a 69% yield (cf. entry 4 in Table 1). Although the disac-
charide 18 has three free hydroxy groups, the C-6 hydroxy group
was selectively glycosylated with 4 to afford the desired trisaccha-
by further experiments using methyl anomeric D-glucopyranosides
(8 and 9) as the acceptors, where glucose acceptors having no such
space around the 3-OH group result in reversed regioselectivity
affording b(1?2)-linked disaccharides in the glycosylation (cf. Ta-
ble 2, entries 2 and 3).

E. Kaji et al. / Tetrahedron Letters 51 (2010) 1570–1573
1573
Table 2
Glycosylation of various acceptors with the glycosyl donors 1–3a
Entry
Donor/acceptor
Boronic acid
Solventb
Promoterc
Temp (°C)
Time (h)
Productsd
Yield (%)
Compd no.
b1?3:b1?2e (ratio)
1
2
3
4
5
6
7
1/6
1/8
3/8
3/9
3/9
3/11
3/12
14
14
15
13
15
14
14
DCE
DCE
DCE–AN
DCE
DCE
A
A
B
B
B
B
B
0
rt
24
24
1
0.3
0.2
0.5
0.3
bGlc–
bGlc–
bGlc–
bGlc–bGlc
bGlc–bGlc
a
a
a
Gal
Glc
Glc
58
43
44
63
35
74
89
26 + 27
28 + 29
30 + 31
32 + 33
32 + 33
34
86:14
14:86
12:88
30:70
28:72
0:100f
100:0g
À10
À10
À10
À30
À30
DCE
DCE
bGlc–
bGlc–
a
a
Fuc
Rha
35
a
b
c
Two equivalent donors were employed.
DCE (1,2-dichloroethane):AN (acetonitrile) = 1:1.
A: Ag(I) silica-alumina; B: N-iodosuccinimide–trimethylsilyl trifluoromethanesulfonate (NIS-TMSOTf). Quantities of the promoters employed were same as described in
Table 1.
d
e
f
The disaccharide obtained by the combination of the donor and the acceptor employed for regioselective glycosylation.
The ratio of b(1?3)-disaccharide: b(1?2)-disaccharide.
Only the b(1?2)-disaccharide was obtained.
g
Only the b(1?4)-disaccharide was obtained.
OR
BzO
BzO
OBz
O
RO
RO
O
O
SPh
OR
BzO
BzO
HO
O
OBz
O
OH
O
RO
RO
HO
O
OR
O
OBz
4
O
OMe
OMe
1)1,2-DCE:MeCN
rt, 16 h
OBz
OH
OR
OH
18
2) NIS / TMSOTf
–30°C
36 : R = Bz
37 : R = H
Scheme 3. Synthesis of the trisaccharide fragment of type II arabinogalactan.
Weinheim, 2008; (b) Seeberger, P. H.; Werz, D. B. Nature 2007, 446, 1046; (c)
Tanaka, H.; Yamada, H.; Takahashi, T. Trends Glycosci. Glycotechnol. 2007, 19,
183.
ride 36 in 70% yield, which was easily deprotected to give the tar-
get trisaccharide 37 in 85% yield. Accordingly, the trisaccharide 37
has been obtained in only three steps from methyl b-
D-galactopy-
2. (a) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155; (b) Schmidt, R. R.
Angew. Chem., Int. Ed. Engl. 1986, 25, 212; (c) Kunz, H. Angew. Chem., Int. Ed. Engl.
1987, 26, 294; (d) Sinaÿ, P. Pure Appl. Chem. 1991, 63, 519; (e) Suzuki, K.;
Nagasawa, T. J. Synth. Org. Chem. Jpn. 1992, 50, 378; (f) Toshima, K.; Tatsuta, K.
Chem. Rev. 1993, 93, 1503; (g) Ernst, B.; Hart, G. W.; Sinaÿ, P. Carbohydrate in
Chemistry and Biochemistry; Wiley-VCH: Weinheim, 2000. Part 1; (h) Crich, D.;
Smith, M. J. Am. Chem. Soc. 2001, 123, 9015.
3. Bartolozzi, A.; Seeberger, P. H. Curr. Opin. Struct. Biol. 2001, 11, 587.
4. Wang, C.-C.; Lee, J.-C.; Luo, S.-Y.; Kulkarni, S. S.; Huang, Y.-W.; Lee, C.-C.; Chang,
K.-L.; Hung, S.-C. Nature 2007, 446, 896.
ranoside (7) (Scheme 3).
In summary, a simple, one-pot, regioselective glycosylation has
been developed for fully unprotected methyl hexopyranosides
with several glycosyl donors (glycosyl bromides and phenylthio
glycosides) in the presence of arylboronic acids: (1) Various
b(1?2)-linked disaccharides for methyl
sides, and b(1?3)-linked disaccharides for methyl
a
- and b-
D
-glucopyrano-
- and b-
a
D-
5. Kawabata, T.; Furuta, T. Chem. Lett. 2009, 38, 640.
galactopyranosides were obtained regioselectively even in the
presence of the primary hydroxy group. (2) Glycosylation of
methyl a-L-fuco- and a-L-rhamnopyranoside resulted in complete
regioselection affording b(1?2)-linked disaccharide and b(1?4)-
linked disaccharide, respectively. (3) It only took three steps using
our method for facile assembly of the trisaccharide fragment of the
arabinogalactan. Research into further applications of our method
to facile one-pot assembly of complex oligosaccharides is still in
progress.
6. (a) Demizu, Y.; Kubo, Y.; Miyoshi, H.; Maki, T.; Matsumura, Y.; Moriyama, N.;
Onomura, O. Org. Lett. 2008, 10, 5075; (b) Maki, T.; Ushijima, N.; Matsumura, Y.;
Onomura, O. Tetrahedron Lett. 2009, 50, 1466.
7. Garegg, P. J.; Maloisel, J.; Oscarson, S. Synthesis 1995, 409.
8. Kartha, R. K. P.; Kiso, M.; Hasegawa, A.; Jennings, H. L. J. Chem. Soc., Perkin Trans.
1 1995, 3023.
9. Kaji, E.; Harita, N. Tetrahedron Lett. 2000, 41, 53.
10. Kaji, E.; Shibayama, K.; In, K. Tetrahedron Lett. 2003, 44, 4881.
11. (a) Oshima, K.; Aoyama, Y. J. Am. Chem. Soc. 1999, 121, 2315; (b) Oshima, K.;
Yamauchi, T.; Shimomura, M.; Aoyama, Y. Bull. Chem. Soc. Jpn. 2002, 75, 1319.
12. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.;
Wiley: New York, 1999.
13. (a) Ferrier, R. J. J. Chem. Soc. 1961, 2325; (b) Ferrier, R. J.; Hannaford, A. J.;
Oerend, W. G.; Smith, B. C. Carbohydr. Res. 1965, 1, 38; (c) Oshima, K.; Kitazono,
E.; Aoyama, Y. Tetrahedron Lett. 1997, 38, 5001; (d) Brimacombe, J. S.; Hunedy,
F.; Husain, A. Carbohydr. Res. 1969, 10, 141; (e) Shiomi, Y.; Saisho, M.;
Tsukagoshi, K.; Shinkai, S. J. Chem. Soc., Perkin Trans. 1 1993, 2111.
14. Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. J. Org. Chem. 1989, 54, 5930.
15. Formation of the 4,6-boronate of the acceptor 7 could be observed on the basis
of the NMR spectra, which are shown in the Supplementary data.
16. Van Boeckel, C. A. A.; Beetz, T.; Kock- van Dalen, A. C.; van Bekkum, H. Recl.
Trav. Chim. Pays-Bas 1987, 106, 596.
17. Konradsson, P.; Udodong, U. E.; Fraser-Reid, B. Tetrahedron Lett. 1990, 31, 4313.
18. Spectral data of the isolated compounds are shown in the Supplementary data.
19. Yu, K.-W.; Kiyohara, H.; Matsumoto, T.; Yang, H.-C.; Yamada, H. Planta Med.
1998, 64, 714.
20. Clarke, A. E.; Anderson, R. L.; Stone, B. A. Phytochemistry 1979, 18, 521.
21. Taguchi, I.; Kiyohara, H.; Matsumoto, T.; Yamada, H. Carbohydr. Res. 2004, 339,
763.
Acknowledgments
This work was supported by Grants-in-Aid for Scientific Re-
search from the JSPS (Nos. 12672059 and 19590010). We also
thank Dr. K. Nagai, Mses. M. Sato, and A. Nakagawa, and Y. Kawau-
chi at Kitasato University for instrumental analyses.
Supplementary data
Supplementary data (experimental procedures and compound
characterization) associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2010.01.048.
References and notes
1. (a)For reviews, see: Handbook of Chemical Glycosylation: Advances in
Stereoselectivity and Therapeutic Relevance; Demchenko, A. V., Ed.; Wiley-VCH: