6-Nitro-2-benzothiazolyl α-Glucoside and α-Mannoside in β-Selective Glycosylations

Article abstract of DOI:10.1246/bcsj.77.169

Highly β-selective glucosylations of glycosyl acceptors having α primary hydroxy group with a 6-nitro-2-benzothia-zolyl α-glucoside donor 3α proceeded smoothly in the presence of a catalytic amount of trifluoromethanesulfonic acid (TfOH) in CH ₂Cl₂ at -78 °C to afford the corresponding glycosides in high yields. With the use of 3α, β-saccharides could be obtained more dominantly than other α-glucosyl donors such as thioform- and trichloroacet-imidates or fluoride in the glucosylation under the same conditions. Similarly, highly β-selective mannosylations of glycosyl acceptors with a 6-nitro-2-benzothiazolyl α-mannoside donor 18α were carried out smoothly in the presence of a catalytic amount of tetrakis(pentafluorophenyl)boric acid H[B(C₆F₅) ₄] to afford the corresponding disaccharides in good to high yields; 18α apparently behaved as a potent donor here for the construction of β-mannoside linkage. Interestingly, in situ anomerization from 18β to 18α was observed when β-mannosyl donor 18β was treated with a catalytic amount of H[B(C₆F₅)₄] in CH ₂Cl₂.

Full text of DOI:10.1246/bcsj.77.169

ꢀ 2004 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 77, 169–178 (2004)
169
6-Nitro-2-benzothiazolyl ꢀ-Glucoside and ꢀ-Mannoside
in ꢁ-Selective Glycosylations
ꢀ;1;2
Takashi Hashihayata,1 Hiroki Mandai,1 and Teruaki Mukaiyama
1Center for Basic Research, The Kitasato Institute (TCI), 6-15-5 Toshima, Kita-ku, Tokyo 114-0003
2The Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
Received June 20, 2003; E-mail: mukaiyam@abeam.ocn.ne.jp
Highly ꢀ-selective glucosylations of glycosyl acceptors having a primary hydroxy group with a 6-nitro-2-benzothia-
zolyl ꢁ-glucoside donor 3ꢀ proceeded smoothly in the presence of a catalytic amount of trifluoromethanesulfonic acid
ꢂ
(TfOH) in CH2Cl2 at ꢁ78 C to afford the corresponding glycosides in high yields. With the use of 3ꢀ, ꢀ-saccharides
could be obtained more dominantly than other ꢁ-glucosyl donors such as thioform- and trichloroacet-imidates or fluoride
in the glucosylation under the same conditions. Similarly, highly ꢀ-selective mannosylations of glycosyl acceptors with a
6-nitro-2-benzothiazolyl ꢁ-mannoside donor 18ꢀ were carried out smoothly in the presence of a catalytic amount of tet-
rakis(pentafluorophenyl)boric acid H[B(C6F5)4] to afford the corresponding disaccharides in good to high yields; 18ꢀ ap-
parently behaved as a potent donor here for the construction of ꢀ-mannoside linkage. Interestingly, in situ anomerization
from 18ꢁ to 18ꢀ was observed when ꢀ-mannosyl donor 18ꢁ was treated with a catalytic amount of H[B(C6F5)4] in
CH2Cl2.
To develop stereoselective glycosylation reactions is one of
CF
3
the most fundamental and important topics in carbohydrate
chemistry.1 Concerning syntheses of glycosides, Koenigs–
Knorr reaction2 has long been employed commonly as one of
the most useful tools; however, there are several problems.
For example, one must use a stoichiometric amount of heavy-
metal salt and its reaction conditions are drastic. In order to im-
prove these weak points, many excellent glycosyl donors have
been developed1 during these two decades: e.g., thioglycosides,
selenoglycosides, glycosyl sulfoxides, glycosyl trichloroaceti-
midates, glycosyl acetate, 1-hydroxy sugar, glycals, pentenyl
glycoside, and donors having phosphorus-containing leaving
groups. These were employed in combination with suitable ac-
tivators in the syntheses of various saccharide chains. In 1981,
it was reported from our laboratory3 that ꢁ-glucosides could be
obtained with good stereoselectivities when glucosyl fluoride
was treated with various glycosyl acceptors by using a combi-
nation of tin(II) chloride (SnCl2) and silver perchlorate
(AgClO4) as a promoter in diethyl ether (Et2O) (Scheme 1). Af-
ter the above-mentioned combined-catalyst system was intro-
duced, the fluoride became one of the most popular glycosyl
donors. Thus, many preparation methods of glycosides using
glycosyl fluorides in combination with suitable activators have
BnO
BnO
BnO
O
BnO
BnO
BnO
O
BnO
O
N
BnO
F C
3
O
N
S
S
R
Fig. 1.
been established.4
Very recently, prominent characteristics were found in a
newly devised donor glucosyl p-trifluoromethylbenzylthio-N-
p-trifluoromethylphenylformimidate: that is, it was easily pre-
pared in stable crystalline form and in good yield; catalytic and
highly ꢁ- or ꢀ- and chemo-selective glucosylations of several
glycosyl acceptors with ꢁ-glucosyl thioformimidate were suc-
cessfully performed in the co-existence of 0.05 molar amounts
of trifluoromethanesulfonic acid (TfOH) and molecular sieve
5A (MS 5A) in an ether or nitrile solvent, respectively.5 Thus,
further development of a newer donor, 6-nitro-2-benzothiazolyl
glycoside, that possesses a structurally-similar leaving group
was planned (Fig. 1). Since a moiety [–O–C(=NR1)–SR2] ac-
tivated easily by Lewis or protic acids was involved in a read-
ily-available benzothiazolyl glycoside, it was expected to be as
useful and characteristic a donor as glycosyl thioformimidate in
the glycosylation. In this paper, we would like to describe effi-
cient ꢀ-stereoselective glycosylations with glucosyl and man-
nosyl donors.6
OBn
O
BnO
BnO
OBn
O
F
SnCl2 – AgClO4
MS 4A
BnO
BnO
BnO
O
BnO
BnO
O
Results and Discussion
OH
O
Et2O, –15 °C, 24 h
BnO
BnO
ꢁ-Selective Glucosylation Using 6-Nitro-2-benzothiazolyl
ꢀ-Glucoside. 6-Nitro-2-benzothiazolyl 2,3,4,6-tetra-O-ben-
zyl-D-glucopyranoside (3) was easily prepared by a direct con-
densation reaction between anomeric hydroxy group of 2,3,4,6-
BnO
OMe
BnO
84%
= 84/16
BnO
OMe
α/β
Scheme 1.
Published on the web January 13, 2004; DOI 10.1246/bcsj.77.169

170 Bull. Chem. Soc. Jpn., 77, No. 1 (2004)
6-Nitro-2-benzothiazolyl Glycoside
Table 1. Preparation of 6-Nitro-2-benzothiazolyl ꢁ-Gluco-
side
Table 2. Glucosylation Using Various Donors by TfOH Cat-
alyst
BnO
BnO
O
O
BnO
BnO
Base (1.2 mol. amt.)
2-Chloro-6-nitrobenzo-
thiazole (2) (1.2 mol. amt.)
BnO
BnO
BnO
BnO
BnO
BnO
O
N
BnO
BnO
O
TfOH (0.05 mol. amt.)
MS 5A (3 g/mmol)
R
O
BnO
BnO
Donor (1.1 mol. amt.)
S
BnO
O
O
BnO
OH
HO
Solvent, Temp., Time
CH2Cl2
1.0 h
3
O
1
BnO
BnO
BnO
BnO
+
NO
2
BnO
BnO
OMe
OMe
5
Temp. Time Yield/%
Acceptor 4 (1.0 mol. amt.)
Entry
Base
Solvent
/ꢂC
/h
15 86 (29/71)
96 (34/66)
21 82 (85/15)
24 71 (83/17)
48 74 (76/24)
(ꢁ=ꢀ)a)
a)
Entry
Donor (R)
Temp./°C
Yield/% (α β
)
/
1
2
3
4
5
6
7
8
9
KH
NaH
LiH
THF
THF
THF
THF
0
rt
rt
rt
0
rt
rt
rt
0
N
O
97 (31/69)
91 (4/96)
3
1
2
0
S
NO
2
3
α
−78
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
THF
NH
99 (56/44)
98 (8/92)
3
4
0
O
Et2O
CH2Cl2
DMF
24
24
trace
trace
CCl
3
6
−78
24 19 (86/14)
48 92 (88/12)
5b)
6b)
NC H -pCF
3
LiN(SiMe3)2 THF–DMFb)
6
4
98 (66/34)
97 (43/57)
0
O
a) The ꢁ=ꢀ ratios were determined by 1H NMR measurements.
b) THF–DMF (9:1).
SCH C H -pCF
3
2
6
4
−78
7
8
96 (57/43 )
7
8
0
F
tetra-O-benzyl-D-glucopyranose7 (1) and 2-chloro-6-nitroben-
zothiazole8 (2) (Table 1). The reaction smoothly proceeded in
THF in the presence of a base and afforded the corresponding
6-nitro-2-benzothiazolyl glucoside 3 in high yield. Interesting-
ly, both of the stereoisomers were prepared selectively depend-
ing on the nature of the bases (Entries 1, 3). Though the ob-
served ꢁ-selectivity in DMF was high, the chemical yield de-
creased because of the partial decomposition of the donor dur-
ing the coupling reaction (Entry 8). The ꢁ-selective
condensation reaction using lithium bis(trimethylsilyl)amide
[LiN(SiMe3)2] proceeded smoothly in a mixed solvent (THF–
DMF, 9/1, v/v) to give a mixture of 6-nitro-2-benzothiazolyl
glucosides 3 in 92% chemical yield (Entry 9, ꢁ=ꢀ ¼ 88=12).
Each isomer of 3ꢀ or 3ꢁ was separated and purified by silica
gel chromatography. The former was obtained in 77% and
the latter in 7% yields, respectively, based on 1. It was noted
that glucosyl donors having non-substituted benzothiazole were
so labile that the product was partly hydrolyzed during the
work-up procedure. This result indicated that the introduction
of a nitro group at 6-position of benzothiazole ring contributed
to the stabilization of the glucosyl donor.
−78
Not detected
a) The ꢁ=ꢀ ratios were determined by HPLC analysis. b) These
results were previously reported in Ref. 5b.
ꢀ-selective manner than the ꢁ-glucosyl trichloroacetimidate12
(6) did at 0 C (Entries 1, 3). The ꢁ-glucosyl fluoride13 (8), a
ꢂ
less reactive donor compared with the above glucosyl imidates,
reacted with acceptor 4 to afford the glucosides with moderate
ꢁ-selectivity (Entry 7). These results showed that the glucosy-
lation reaction of 3ꢀ under the above-mentioned conditions
gave ꢀ-saccharide more predominantly than the cases using
6, 7, and 8. Finally, the highest ꢀ-selectivity (ꢁ=ꢀ ¼ 4=96)
was obtained when the donor 3ꢀ was allowed to react at ꢁ78
ꢂC (Entry 2).
Next, in order to extend the scope of this reaction, ꢀ-selec-
tive glucosylation of various glycosyl acceptors such as methyl
glycoside 914 that contained a hindered secondary hydroxy
group, thioglycoside 10,15 11,11c and glycosyl fluoride 125d with
3ꢀ was examined without utilizing the neighboring effect of 2-
O-acyl protecting group (Table 3). In those cases that used gly-
cosyl acceptors having primary hydroxy groups, the desired
disaccharides were obtained all in high yields with high ꢀ-se-
lectivities, while a moderate ꢀ-selectivity was observed
(ꢁ=ꢀ ¼ 27=73) in the case of using 9 (Entry 1), which was
the only exception. The donor 3ꢀ gave the ꢀ-saccharide more
dominantly than ꢁ-glucosyl trichloroacetimidate 6 even when
the hindered acceptor 9 was used (56%, ꢁ=ꢀ ¼ 50=50). Fur-
thermore, the chemoselective glucosylations using acceptors
such as ethyl 2,3,4-tri-O-benzoyl-1-thio-ꢀ-D-glucopyranoside
(10), ethyl 3-O-acetyl-4-O-benzyl-2-deoxy-2-phthalimido-1-
thio-ꢀ-D-glucopyranoside (11), or 2,3,4-tri-O-benzyl-ꢀ-D-glu-
copyranosyl fluoride (12) gave good results without giving
any damage to a thio-group and to a fluorine-atom linked at
their anomeric positions (Entries 2, 3, and 4). These results
showed that none of the frequently-employed glycosyl donors
such as thioglycoside and glycosyl fluoride were activated un-
In general, reactivities and stereoselectivies of glucosyla-
tions that use conventional donors were influenced considera-
bly by the properties of donors, catalysts, and solvents. Initially,
glucosylation9 of a glycosyl acceptor 410 with 3ꢀ in the pres-
ence of 0.05 molar amounts of TfOH in CH2Cl2, a nonpolar sol-
vent, was tried under the conditions previously reported5b
ꢂ
(Table 2). The reaction proceeded smoothly at 0 C to afford
the corresponding disaccharides 511 in high yield with moderate
ꢀ-selectivity (Entry 1, ꢁ=ꢀ ¼ 31=69). Interestingly, ꢀ-selec-
tivity of this glucosylation was higher than that using donor
7,5d which afforded the disaccharide with moderate ꢁ-selectiv-
ity (ꢁ=ꢀ ¼ 66=34) under the same conditions as shown in our
previous report (Entry 5).5b Although the above two donors, 3ꢀ
and 7, possessed similar moieties [–O–C(=NR1)–SR2], stereo-
selectivities of the disaccharides afforded were reversed (En-
tries 1, 5). The donor 3ꢀ also gave the disaccharides in a higher

T. Hashihayata et al.
Bull. Chem. Soc. Jpn., 77, No. 1 (2004)
171
Table 3. Glucosylation of Various Acceptors
ꢀ-mannopyranoside is considered rather difficult in chemical
synthesis because of the following three reasons: i) ꢁ-manno-
pyranoside formation is favored by its anomeric effect; ii) steric
repulsion of hydroxy group at C-2 position; and iii) opposite
participation of its neighboring group. However, some useful
methods have been developed to date to overcome these prob-
lems and to allow the synthesis of ꢀ-mannoside; namely, 1) ef-
fective epimerization of ꢀ-glucoside or galactoside at C-2 po-
sition;18 2) intramolecular aglycon delivery mannosylation;19
3) direct intermolecular mannosylation. Of the methods report-
ed, the catalytic or stoichiometric direct mannosylation20–27
turned out to be most effective for the convenient construction
of ꢀ-mannopyranoside. Reactions using mannosyl donors such
as mannosyl phosphinothioate,20 phosphate,21 halide,22,23 or
sulfoxide23 in combination with suitable activators, and a donor
having 1,2-stannylene acetal24 were thus reported. The best re-
sults were obtained when donors having an electron-withdraw-
ing protecting group at O-2 position25 or a cyclic acetal protect-
ing group at O-4,6 position26 were activated by trimethyl-
silyl triflate, benzenesulfenyl triflate/2,6-di-t-butyl-4-methyl-
pyridine (DTBMP), or trifluoromethanesulfonic anhydride/
DTBMP. In spite of those reports of success, development of
a new and convenient method for the stereoselective synthesis
of ꢀ-mannopyranosides still remains as one of the most impor-
tant and challenging topics in carbohydrate chemistry. In the
above section, it was pointed out that the benzothiazolyl glyco-
side had a potent and characteristic feature for the formation of
ꢀ-saccharide. In this section, the application of the above con-
cept to a direct ꢀ-selective mannosylation of several glycosyl
acceptors using a newly devised donor, 6-nitro-2-benzothiazol-
yl ꢁ-mannoside is described.
TfOH (0.05 mol. amt)
MS 5A (3 g/mmol)
BnO
BnO
BnO
Donor 3
α
(1.1 mol. amt.)
+
O
BnO
OR
CH2Cl2
Acceptor (1.0 mol. amt.)
ROH
Disaccharide
−78 °C, 1.0 h
a)
Acceptor
Entry
1
Yield/% (α/β)
Product
BnO
HO
O
80 (27/73)b,c)
98 (9/91)
13
BnO
BnO
OMe
9
HO
BzO
O
2
3
4
SEt
14
15
BzO
BzO
10
HO
BnO
O
90 (9/91)
SEt
AcO
d)
NPhth
11
HO
BnO
O
89 (7/93)e)
16
F
BnO
BnO
12
a) The ꢁ=ꢀ ratios were determined by HPLC analysis. b) The re-
action time was 4 h. c) 13 was obtained in 56% yield
(ꢁ=ꢀ ¼ 50=50) when 6 was used instead of 3ꢀ. d) NPhth: phtha-
limido. e) The ꢁ=ꢀ ratio was determined by isolated yields of both
isomers.
BnO
BnO
BnO
BnO
O
O
O
BnO
O
BnO
O
BnO
BnO
O
BzO
BnO
BnO
BnO
SEt
OMe
BzO
BzO
13
14
BnO
BnO
BnO
BnO
BnO
BnO
O
O
O
O
O
O
BnO
BnO
BnO
BnO
SEt
F
AcO
BnO
6-Nitro-2-benzothiazolyl 2,3,4,6-tetra-O-benzyl-D-manno-
pyranoside (18) was also prepared easily according to a manner
similar to that used for glucosyl donor 3; both stereoisomers
were selectively prepared by choosing suitable bases (Table 4,
Entries 2, 3). Interestingly, the induction of stereoselectivity de-
pended on the kinds of counter cation of the bases; for example,
stereoselective preparation of 18ꢀ was performed by using po-
tassium bis(trimethylsilyl)amide [KN(SiMe3)2] while 3ꢀ was
NPhth
BnO
15
16
der these conditions. Therefore, this glucosylation may have
broader applicability to the chemoselective synthesis16 of oli-
go- and poly-saccharides.
In the presence of a catalytic amount of TfOH, the glucosy-
lation using 3ꢀ enabled higher ꢀ-selectivity in CH2Cl2 than
those using donors 6, 7, or 8. These results imply that benzothia-
zolyl glycoside has a potent feature to construct ꢀ-glycosidic
linkage without even utilizing the neighboring effect of the 2-
O-acyl protecting group. This glycosylation with benzothiazol-
yl glycoside exhibited further possible applications to the trou-
blesome ꢀ-mannosylation.
ꢁ-Selective Mannosylation Using 6-Nitro-2-benzothiazol-
yl ꢀ-Mannoside. ꢀ-Mannopyranosyl units are the essential
constituents of naturally-occurring biologically-active oligo-
saccharides and glycoconjugates (Scheme 2).1,17 Formation of
Table 4. Preparation of 6-Nitro-2-benzothiazolyl ꢁ-Manno-
side
BnO
BnO
O
BnO
Base (1.2 mol.amt.)
BnO
BnO
BnO
O
N
2-Chloro-6-nitrobenzo-
thiazole (2) (1.2 mol. amt.)
O
BnO
BnO
S
OH
Solvent, Temp., Time
18
17
NO
2
Temp. Time Yield/%
(ꢁ=ꢀ)a)
Entry
Base
Solvent
/ꢂC
/h
1
2
3
4
5
6
LiN(SiMe3)2
NaN(SiMe3)2
KN(SiMe3)2
THF
THF
THF
rt
rt
rt
45 27 (40/60)
0.5 92 (34/66)
0.5 90 (73/27)
O
HO
β
-Mannnoside Linkage
O
HO
HO
OH
O
HO
KN(SiMe3)2 THF–DMFb) ꢁ20
3
77 (63/37)
O
NHAc
H
N
O
HO
HO
O
Peptides
O
O
KH
DBUc)
THF
CH2Cl2
ꢁ20
0.5 68 (63/37)
12 64 (48/52)
HO
O
O
O
NHAc
O
rt
OH
HO
a) The ꢁ=ꢀ ratios were determined by isolations of both stereo-
isomers. b) THF–DMF (9:1). c) DBU: 1,8-diazabicyclo-
[5.4.0]undec-7-ene.
OH
HO
Scheme 2.

172 Bull. Chem. Soc. Jpn., 77, No. 1 (2004)
6-Nitro-2-benzothiazolyl Glycoside
Table 6. Effects of Solvent and Reaction Temperature
stereoselectively prepared by using LiN(SiMe3)2 (Table 1 vs
Table 4). It was thought then that the stereoselections were
strongly influenced by steric repulsion and chelating effect of
the hydroxy group at C-2 position of mannose when condensa-
tion reactions were carried out in the presence of bases such as
KN(SiMe3)2. The ꢁ-selective condensation reaction between
the anomeric hydroxy group of 2,3,4,6-tetra-O-benzyl-D-man-
nopyranose28 (17) and 2-chloro-6-nitrobenzothiazole (2) pro-
ceeded smoothly to give ꢁ-isomer 18ꢀ and ꢀ-isomer 18ꢁ in
66% and 24% yields, respectively, under the above conditions
(Entry 3).
In the first place, the effect of various activators on the man-
nosylation of methyl 2,3,4-tri-O-benzyl-ꢁ-D-glucopyranoside
(4) with 18ꢀ in CH2Cl2 was examined (Table 5). In most cases,
the reactions smoothly proceeded at ꢁ78 ꢂC to give the corre-
sponding disaccharides 1911a in high yields. It was interesting to
note that the activators having anions such as sulfonate
(RSO3ꢁ) or tetrakis(pentafluorophenyl)borate [ꢁB(C6F5)4]
gave disaccharides with high ꢀ-selectivities (Entries 2, 3, 8–
10). The highest ꢀ-selectivity was achieved when tetrakis(pen-
tafluorophenyl)boric acid29 H[B(C6F5)4] was employed (Entry
BnO
BnO
BnO
BnO
Donor 18
α
(1.2 mol. amt.)
+
O
O
H[B(C6F5)4] (0.20 mol. amt.)
MS 5A (3 g/mmol)
HO
BnO
BnO
O
O
BnO
BnO
0.5 h
BnO
4 (1.0 mol. amt.)OMe
BnO
OMe
19
Entry
Solvent
Temp./ꢂC
Yield/% (ꢁ=ꢀ)a)
1
2
3
4
5
6
7
8
EtCN
Et2O
ꢁ78
ꢁ78
ꢁ78
ꢁ78
ꢁ94
ꢁ60
ꢁ30
0
49b) (73/27)
89 (38/62)
91 (14/86)
96 (16/84)
92 (28/72)
98 (22/78)
quant. (45/55)
quant. (59/41)
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
a) The ꢁ=ꢀ ratios were determined by isolations of both stereo-
isomers. b) The reaction time was 1 h.
Table 7. Effect of Catalyst Amount
10, ꢁ=ꢀ ¼ 16=84), while weaker acids such as Et2O BF3 and
BnO
BnO
ꢃ
Donor 18
α
(1.2 mol. amt.)
O
BnO
H[BF4] induced ꢁ-selectivities conversely (Entries 1 and 4).
The mechanisms by which the above sulfonates and tetrakis-
(pentafluorophenyl)borates achieve high ꢀ-selectivities are not
yet clearly explained. The H[B(C6F5)4]-catalyzed-mannosyla-
tion in the absence of MS 5A did not proceed as smoothly
(29%, ꢁ=ꢀ ¼ 41=59) as other glycosylation reactions that used
glycosyl fluoride11c or thioformimidate5d as a donor.
O
+
HO
O
BnO
H[B(C6F5)4]
MS 5A (3 g/mmol)
BnO
O
BnO
BnO
BnO
CH2Cl2, −78 °C, 0.5 h
BnO
4 (1.0 mol. amt.)OMe
BnO
OMe
19
Entry
Catalyst amount/mol. amt.
Yield/% (ꢁ=ꢀ)a)
1
2
3
4
5
0.30
0.20
0.10
0.05
0.01
97 (17/83)
96 (16/84)
quant (17/83)
99 (24/76)
91b) (30/70)
Table 5. Mannosylation Using Various Activators
HO
O
BnO
O
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
O
O
BnO
BnO
OMe
a) The ꢁ=ꢀ ratios were determined by isolations of both stereo-
isomers. b) The reaction time was 2 h.
4 (1.0 mol. amt.)
O
N
Activator
O
BnO
BnO
S
MS 5A (3 g/mmol)
CH2Cl2, −78 °C, 0.5 h
BnO
OMe
Next, reaction conditions were examined by taking the reac-
tion of 4 with 18ꢀ in the presence of 0.20 molar amounts of
H[B(C6F5)4] as a model. High ꢀ-selectivity was observed when
the mannosylation was carried out in toluene or CH2Cl2, a non-
polar solvent (Table 6, Entries 3, 4) and the highest yield for ꢀ-
mannosylation was obtained when the reaction was carried out
in CH2Cl2 (Entry 4). On the other hand, the same mannosyla-
tion afforded disaccharide with ꢁ-selectivity in a nitrile solvent
(Entry 1) that was frequently employed for the effective con-
struction of ꢁ-mannoside.21,23 Further, this mannosylation us-
ing 18ꢀ proceeded even at ꢁ94 ꢂC (Entry 5) and the ꢀ-selectiv-
ities were observed at the temperatures ranging from ꢁ60 ꢂC to
18
α
(1.2 mol. amt.)
19
NO2
Activator
(mol. amt. based on acceptor)
Entry
Yield/% (ꢁ=ꢀ)b)
1
2
3
4
5
6
7
8
9
10
Et2O BF3 (1.2)
70 (78/22)
95 (25/75)
97c) (34/66)
57d) (72/28)
89 (45/55)
92 (43/57)
90 (44/56)
99 (29/71)
99 (27/73)
96 (16/84)
ꢃ
TMSOTf (1.2)
Tr[B(C6F5)4] (1.2)
H[BF4] (0.20)
H[ClO4] (0.20)e)
H[NTf2] (0.20)f)
H[SbF6] (0.20)f)
FSO3H (0.20)
ꢂ
ꢁ94 C (Entries 4, 5, and 6), whereas no ꢀ-selectivties were
TfOH (0.20)
H[B(C6F5)4] (0.20)g)
ꢂ
recognized at higher temperatures, ꢁ30 ꢂC to 0 C (Entries 7,
8). This was probably because the undesirable SN1-type proc-
ess took place competitively under these conditions and thus
gave ꢁ-mannoside. Concerning the amount of catalyst, only
0.01 molar amounts of H[B(C6F5)4] was enough to carry out
the mannosylation at ꢁ78 ꢂC. (Table 7, Entry 5). They also pro-
ceeded successfully by using at least 0.10 molar amounts of
H[B(C6F5)4] to give disaccharide with highest ꢀ-selectivities
(Entries 1, 2, and 3).
a) In the case of using Ag[B(C6F5)4]4c or CH3ꢂSO3H as an ac-
tivator, almost no reaction took place at ꢁ78 C. b) The ꢁ=ꢀ
ratios were determined by isolations of both stereoisomers. c)
The reaction time was 1 h. d) The reaction time was 3 h. e)
Protic acid was generated from silver salt and tBuCl in toluene,
and the supernatant was used. f) Protic acid was generated from
silver salt and tBuBr in toluene, and the supernatant was used.
g) Protic acid was generated from silver salt and tBuBr in tol-
uene–diethyl ether (1:1), and the supernatant was used.
In order to extend the scope of this reaction, ꢀ-selective

T. Hashihayata et al.
Bull. Chem. Soc. Jpn., 77, No. 1 (2004)
173
Table 8. Mannosylation of Several Acceptors
Table 9. Effects of 6-Nitro-2(3H)-benzothiazolone 26 and
Donor
Donor 18
α
(1.2 mol. amt.)
+
BnO
O
BnO
H[B(C6F5)4] (0.20 mol. amt.)
H
BnO
Donor (1.2 mol. amt.)
BnO
O
N
BnO
BnO
BnO
BnO
MS 5A (3 g/mmol)
CH2Cl2, −78 °C, 0.5 h
Acceptor (1.0 mol. amt.)
ROH
26
O
OR
+
Disaccharide
S
NO
2
HO
O
O
a)
H[B(C6F5)4] (0.20 mol. amt.)
α β
/
Yield/% ( )
O
Entry Acceptor (ROH)
Product
BnO
BnO
BnO
BnO
BnO
MS 5A (3 g/mmol)
HO
OMe
BnO
OMe
O
BnO
BnO
CH2Cl2, −78 °C, 0.5 h
19
96 (16/84)
83 (10/90)
82 (11/89)
77 (25/75)
89 (30/70)
4 (1.0 mol. amt.)
1
2
3
19
BnO
OMe
4
Entry
Donor
Additive 26/mol. amt.
Yield/% (ꢁ=ꢀ)a)
HO
1
2
3
4
18ꢀ
18ꢀ
25
0
2.4
0
96 (16/84)
85 (19/81)
67 (36/64)
71 (35/65)
O
BnO
21
22
23
24
SEt
AcO
11PhthN
25
1.2
HO
O
BnO
BnO
F
a) The ꢁ=ꢀ ratios were determined by isolations of both stereo-
isomers.
BnO
12
BnO
HO
BnO
O
BnO
O
BnO
BnO
BnO
BnO
BnO
BnO
O
BnO
4
5
BnO
OMe
O
9
N
O
NH
CCl
O
S
18
α
25
3
OBn
O
NO
2
OH
N
3
20
a) The ꢁ=ꢀ ratios were determined by isolations of both stereo-
isomers.
er with the desired mannoside, its influences on ꢀ-selectivity
and on yield were considered. In order to study the induction
of ꢀ-selectivity, mannosylation of 4 with 18ꢀ or the corre-
sponding ꢁ-mannosyl trichloroacetimidate donor 2512 was
tried in the presence of 26; neither ꢀ-selectivity nor yield
was influenced (Table 9). This may be due to the extreme in-
solubility of 6-nitro-2(3H)-benzothiazolone 26 in CH2Cl2.
Thus, high ꢀ-selectivity is entirely dependent on the character-
istic property of 18ꢀ.
BnO
BnO
BnO
BnO
BnO
BnO
BnO
O
O
O
O
BnO
O
O
BnO
BnO
BnO
SEt
F
21
AcO
22
NPhth
BnO
O
OBn
BnO
BnO
BnO
BnO
O
BnO
BnO
O
BnO
BnO
BnO
O
O
BnO
O
O
N
3
Next, mannosylation of 4 with ꢀ-isomer of donor 18ꢁ was
tried under the above mentioned conditions (Scheme 3). Inter-
estingly, ꢀ-selective mannosylation also proceeded smoothly
to give disaccharide in high yield similar to the case of using
ꢁ-donor 18ꢀ. In order to study its mechanism, a reaction using
18ꢁ was tried in the absence of glycosyl acceptor 4 under the
same conditions. After stirring for only 5 minutes, the reaction
mixture was swiftly quenched with a proton scavenger, 2,6-di-
t-butylpyridine. It was interesting to note that the ꢁ-isomer 18ꢀ
was obtained in 47% yield while ꢀ-isomer 18ꢁ was not detect-
ed. This result may indicate that in situ anomerization takes
place rapidly. As far as we know, this is the first report on
the in situ anomerization in which the imidate-type glycosyl
donor was treated with acids. As shown in Table 9, 6-nitro-2-
benzothiazolyl mannoside donor enabled the mannosylation
to achieve higher ꢀ-stereoselectivity than mannosyl trichloro-
acetimidate. It may be considered that the mannosylation reac-
tion using ꢀ-donor 18ꢁ proceeded via in situ anomerization to
18ꢀ before forming disaccharide with glycosyl acceptor 4 and
that the mannosylation consequently took place via a SN2-like
concerted process between ꢁ-isomer 18ꢀ and a glycosyl ac-
ceptor more dominantly (Scheme 4). Additionally, it was found
that the ꢀ-selective mannosylation could be performed by using
a mixture of ꢁ- and ꢀ-donor 18 (ꢁ=ꢀ ¼ 73=27: obtained by the
condensation reaction shown in Table 4, Entry 3) as shown in
Scheme 5. This result may extend the utility of 6-nitro-2-benzo-
BnO
OMe
23
24
mannosylation of several glycosyl acceptors such as thioglyco-
side 11, glycosyl fluoride 12, methyl glycoside 9, and glucosa-
mine derivative 2030 with 18ꢀ were tried at ꢁ78 ꢂC (Table 8).
All glycosyl acceptors having primary hydroxy groups reacted
smoothly to afford the desired disaccharides with high ꢀ-selec-
tivities (Entries 1–3). Furthermore, moderate ꢀ-stereoselectiv-
ities were observed in the similar mannosylations using 9 and
20 (Entries 4, 5). To the best of our knowledge, these are the
highest yields of ꢀ-disaccharides, 19, 23, and 24, by direct
mannosylations with 2,3,4,6-tetra-O-benzyl-mannosyl donor.
It should also be noted that the chemoselective mannosylations
using glycosyl acceptors such as ethyl 3-O-acetyl-4-O-benzyl-
2-deoxy-2-phthalimido-1-thio-ꢀ-D-glucopyranoside (11) and
2,3,4-tri-O-benzyl-ꢀ-D-glucopyranosyl fluoride (12) gave good
results as well without giving any damage to a thio-group or to
a fluorine-atom linked at their anomeric positions (Entries 2, 3).
Thus, the donor 18ꢀ is noted to have a potent and character-
istic feature for the construction of ꢀ-mannoside. This feature
enabled us to achieve the mannosylation with high ꢀ-selectiv-
ity at ꢁ78 ꢂC in CH2Cl2. The ꢀ-selectivity was influenced by
the nature of acid catalyst; the highest ꢀ-selectivities were ob-
served when H[B(C6F5)4] was used.
Since 6-nitro-2(3H)-benzothiazolone 26 was formed togeth-

174 Bull. Chem. Soc. Jpn., 77, No. 1 (2004)
6-Nitro-2-benzothiazolyl Glycoside
HO
BnO
O
BnO
BnO
BnO
BnO
BnO
BnO
OMe
BnO
BnO
O
O
4 (1.0 mol. amt.)
O
BnO
O
N
BnO
H[B(C6F5)4] (0.20 mol. amt.)
O
S
BnO
BnO
MS 5A (3 g/mmol)
BnO
CH2Cl2, −78 °C, 0.5 h
OMe
NO
2
18β (1.2 mol. amt.)
19 94% (
α
/β
= 19/81)
BnO
O
BnO
"Without acceptor"
BnO
BnO
H[B(C6F5)4] (0.20 mol. amt.)
O
N
S
18
β
MS 5A (3 g/mmol)
CH2Cl2, −78 °C, 5 min
Then, 2,6-di-t-butylpyridine
NO
2
18
α 47%
(18
β ; Not Detected)
Scheme 3.
H+
BnO
BnO
BnO
BnO
O
O
N
O
BnO
O
BnO
BnO
BnO
HO
S
18
β
BnO
O
NO
BnO
BnO
BnO
2
O
O
H+
N
O
In Situ
Anomerization
S
Very Fast
β
-Isomer (Major)
NO
2
SN2-like Concerted Process
BnO
O
BnO
BnO
BnO
H+
H
N
H+
+
O
N
O
S
NO
2
26
S
BnO
O
O
BnO
BnO
BnO
NO
18
α
2
BnO
O
HO
BnO
BnO
BnO
O
O
Oxocarbenium Intermediate
α-Isomer (Minor)
Scheme 4.
HO
O
BnO
BnO
BnO
BnO
BnO
BnO
BnO
O
BnO
BnO
BnO
BnO
OMe
4 (1.0 mol. amt.)
O
O
O
N
H[B(C6F5)4] (0.20 mol. amt.)
S
O
BnO
BnO
MS 5A (3 g/mmol)
BnO
OMe
CH2Cl2, −78 °C, 0.5 h
NO
2
18 (1.2 mol. amt.,
α
/β
= 73/27)
19 97% (α/β = 18/82)
Scheme 5.
thiazolyl mannoside donor because a separation procedure of
the two isomers, 18ꢀ and 18ꢁ, is not needed.
All stereochemistries of novel mannosides were confirmed
by geminal 13C–1H coupling constants of anomeric positions.31
sugar with 2-chloro-6-nitrobenzothiazole in the presence of a
base, 2) the glucosyl donor 3ꢀ enabled the glucosylation to
achieve higher ꢀ-stereoselectivities than the donors 6, 7, or 8
when a catalytic amount of TfOH was used in CH2Cl2, 3) the
donor 1ꢂ8 enabled the mannosylation with high ꢀ-selectivities
at ꢁ78 C in CH2Cl2, and 4) the ꢀ-selectivity was influenced
by the nature of acid catalyst. The highest ꢀ-selectivity was ob-
served when H[B(C6F5)4] was used. Thus, benzothiazolyl glu-
Conclusion
It is noted that 1) 6-nitro-2-benzothiazolyl glucoside 3ꢀ was
easily prepared by a direct condensation reaction of 1-hydroxy

T. Hashihayata et al.
Bull. Chem. Soc. Jpn., 77, No. 1 (2004)
175
by preparative TLC (silica gel) to afford the mixture of 3ꢀ and 3ꢁ
(61.5 mg, 92%, ꢁ=ꢀ ¼ 88=12). The ratios of 3 were determined by
1H NMR measurements. Both anomers were also isolated by prep-
arative TLC (silica gel) to give 3ꢀ (51.5 mg, 77%) and 3ꢁ (5.0
mg, 7%).
coside and mannoside were found to behave as efficient glyco-
syl donors and to have a potent feature for the construction of
stereoselective ꢀ-saccharide linkage.
Experimental
3ꢀ: colorless oil; Rf 0.36 (hexane/CHCl3/Et2O, 6/6/1, v/v/v);
20
1
General. All melting points were measured on a Yanaco MP-
S3 micro melting point apparatus. Infrared spectra were recorded
½ꢁꢅD þ122:1ꢂ (c 1.00, CHCl3); H NMR (270 MHz, CDCl3) ꢂ
3.65 (1H, d, J ¼ 10:8 Hz), 3.73–3.88 (3H, m), 3.97 (1H, d, J ¼
9:7 Hz), 4.12 (1H, t, J ¼ 9:2 Hz), 4.44 (1H, d, J ¼ 12:2 Hz),
4.52 (1H, d, J ¼ 10:8 Hz), 4.58 (1H, d, J ¼ 12:2 Hz), 4.74 (1H,
d, J ¼ 11:9 Hz), 4.79 (1H, d, J ¼ 11:9 Hz), 4.87 (1H, d, J ¼
10:8 Hz), 4.89 (1H, d, J ¼ 10:8 Hz), 5.01 (1H, d, J ¼ 10:8 Hz),
6.61 (1H, d, J ¼ 3:2 Hz, H-1), 7.13–7.38 (20H, m, Ar-H), 7.76
(1H, d, J ¼ 8:9 Hz), 8.26 (1H, dd, J ¼ 2:2, 8.9 Hz), 8.59 (1H, d,
J ¼ 2:2 Hz); 13C NMR (67.8 MHz, CDCl3) ꢂ 67.71, 73.19,
73.38, 73.56, 75.27, 75.77, 79.09, 98.37 (C-1), (127.68–128.39,
137.32, 137.54, 137.78, 138.37) (C-Ar), (117.78, 121.18, 121.84,
132.33, 143.82, 153.65, 174.93) (Benzothiazole); IR (neat) 702,
740, 1119, 1342, 1527, 2931 cmꢁ1; HRMS m=z calcd for
1
on a Horiba FT-300 infrared spectrometer. H NMR spectra were
recorded on a JEOL JNM-EX270 (270 MHz), JNM-EX300 (300
MHz), JNM-LA400 (400 MHz), or JEOL JNM-LA500 (500
MHz) spectrometer; chemical shifts (ꢂ) are reported in parts per
million relative to teteramethylsilane. Splitting patterns are desig-
nated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br,
broad. 13C NMR spectra were recorded on a JEOL JNM-EX270L
(68 MHz), a JEOL JNM-LA400 (100 MHz), or a JEOL JNM-
LA500 (125 MHz) spectrometer with complete proton decoupling.
Chemical shifts are reported in parts per million relative to tetra-
methylsilane with the solvent resonance as the internal standard
(CDCl3; ꢂ 77.0). High-resolution mass spectra were recorded on
a Micromass Q-TOF2 instrument [ESI positive, 0.01 M (1 M =
1 mol dmꢁ3) AcONH4 in H2O/MeCN]. High-performance liquid
chromatography (HPLC) was carried out using a Hitachi LC-Or-
ganizer, L-4000 UV Detector, L-6200 Intelligent Pump, and D-
2500 Chromato-Integrator with Shodex SIL-5B (normal phase:
C41H38N2O8 NH4 [M + NH4]þ 736.2693, found 736.2712.
ꢃ
3ꢁ: colorless oil; Rf 0.29 (hexane/CHCl3/Et2O, 6/6/1, v/v/v);
21
½ꢁꢅD þ6:3ꢂ (c 1.02, CHCl3); 1H NMR (270 MHz, CDCl3) ꢂ
3.77–3.83 (6H, m), 4.48 (1H, d, J ¼ 12:2 Hz), 4.58 (2H, t, J ¼
10:8 Hz), 4.83 (2H, brs), 4.84 (1H, d, J ¼ 12:2 Hz), 4.86 (1H, d,
J ¼ 11:1 Hz), 4.93 (1H, d, J ¼ 11:1 Hz), 6.03 (1H, d, J ¼ 7:3
Hz, H-1), 7.13–7.80 (20H, m, Ar-H), 7.78 (1H, d, J ¼ 8:9 Hz),
8.27 (1H, dd, J ¼ 2:2, 8.9 Hz), 8.59 (1H, d, J ¼ 2:2 Hz); 13C NMR
(67.8 MHz, CDCl3) ꢂ 67.98, 73.42, 75.01, 75.68, 76.52, 80.92,
84.35, 101.08 (C-1), (127.68–128.40, 137.49, 137.66, 137.49,
138.09) (C-Ar), (117.80, 121.40, 121.90, 132.45, 143.93, 153.49,
174.72) (Benzothiazole); IR (neat) 702, 748, 1080, 1257, 1342,
ꢀ
120 A, 5 mm, ꢃ4:6 ꢄ 250 mm) and YMC J’sphere M80 (reverse
ꢀ
phase: 80 A, 4 mm, ꢃ4:6 ꢄ 250 mm). Optical rotations were re-
corded on a Jasco-P-1020 polarimeter. Analytical TLC was done
on precoated (0.25 mm) silica gel 60 F254 plates (E. Merck).
Thin-layer chromatography was performed on Wakogel B-5F. Col-
umn chromatography was performed on Silica gel 60 (Merck).
All reactions were carried out under argon atmosphere in dried
glassware, unless otherwise noted. All reagents were purchased
from Tokyo Kasei Kogyo, Kanto Chemical, or Aldrich and used
without further purification, unless otherwise noted. TfOH (donat-
ed by Central Glass Co. Ltd.) was simply distilled and used for gly-
cosylation. H[ClO4], H[NTf2], H[SbF6], and H[B(C6F5)4] were
generated according to the published procedures.11c CH2Cl2 was
distilled from P2O5 and then from CaH2 and was stored over mo-
lecular sieves 4A. Toluene was distilled from P2O5 and was stored
over molecular sieves 4A. Dry THF and Et2O were purchased from
Kanto Chemical. Powdered and pre-dried (at 260 ꢂC/133 Pa, 6 h)
molecular sieves 5A (MS 5A) were used in glycosylation reactions.
2-Chloro-6-nitrobenzothiazole8 (2). This compound was pre-
pared from 2-chlorobenzothiazole according to a published proce-
dure. Colorless solid; Rf 0.42 (hexane/ethyl acetate, 3/1, v/v); Mp
1450, 1520, 2870 cmꢁ1; HRMS m=z calcd for C41H38N2O8 NH4
ꢃ
[M + NH4]þ 736.2693, found 736.2686.
Glucosylation Using TfOH as Catalyst (The General
Procedure). To a stirred suspension of MS 5A (150 mg), glucosyl
donor (0.055 mmol), and glucosyl acceptor (0.050 mmol) in
CH2Cl2 (1.25 mL) was successivelꢂy added TfOH (0.750 mg in tol-
uene, 0.10 mL, 2.5 mmol) at ꢁ78 C. After the completion of the
glucosylation reaction by monitoring TLC, the reaction was
quenched by adding sat. aq. NaHCO3. Then the mixture was fil-
tered through Celite and the aqueous layer was extracted with
CH2Cl2. The combined organic layer was washed with brine and
dried over Na2SO4. After filtration and evaporation, the resulting
residue was purified by preparative TLC (silica gel) until afforded
the corresponding disaccharide. The ꢁ to ꢀ ratios for 5,11c 13,11c
14,11c and 1511c were determined by HPLC analysis and the ratios
for 165d were determined by isolation of both isomers according to
the published conditions.
ꢂ
1
193–195 C; H NMR (270 MHz, CDCl3) ꢂ 8.08 (1H, d, J ¼ 8:9
Hz), 8.39 (1H, dd, J ¼ 2:2, 8.9 Hz), 8.76 (1H, d, J ¼ 2:2 Hz);
13C NMR (67.8 MHz, CDCl3) ꢂ 117.60, 122.15, 123.22, 136.29,
145.20, 154.55, 158.64; IR (KBr) 748, 1026, 1057, 1334, 1512,
3062 cmꢁ1; HRMS m=z calcd for C7H3ClN2O2S [M]þ 213.9604,
found 213.9606.
Methyl 2,3,4-Tri-O-benzyl-6-O-(20,30,40,60-tetra-O-benzyl-D-
glucopyranosyl)-ꢀ-D-glucopyranoside (5): The ratios were de-
termined by HPLC analysis11c (hexane/ethyl acetate = 4/1; flow
rate, 1.0 mL/min; 12.4 min, ꢀ-isomer; 14.6 min, ꢁ-isomer).
Methyl 2,3,6-Tri-O-benzyl-4-O-(20,30,40,60-tetra-O-benzyl-D-
glucopyranosyl)-ꢀ-D-glucopyranoside (13): The ratios were de-
termined by HPLC analysis11c (MeOH/H2O = 20/1; flow rate, 1.0
mL/min; 14.4 min, ꢁ-isomer; 15.9 min, ꢀ-isomer).
6-Nitro-2-benzothiazolyl
2,3,4,6-Tetra-O-benzyl-D-gluco-
pyranoside (3). To a solution of 2,3,4,6-tetra-O-benzyl-D-gluco-
pyranose7 1 (50.3 mg, 93.0 mmol) in THF–DMF (1.0 mL, 9/1, v/v)
was added lithium bis(trimethylsilyl)amide (0.50 M in THF, 0.22
mL, 0.11 mmol) at 0 ꢂC. After stirring for 0.5 h at the same temper-
ature, 2 (23.8 mg, 0.11 mmol) was added to the reaction mixture.
After additional stirring for 48 h at the same temperature, the mix-
ture was quenched by adding sat. aq. NaHCO3. The aqueous layer
was extracted with EtOAc, washed with brine, and dried over
Na2SO4. After filtration and evaporation, the residue was purified
Ethyl 2,3,4-Tri-O-benzoyl-6-O-(20,30,40,60-tetra-O-benzyl-D-
glucopyranosyl)-1-thio-ꢁ-D-glucopyranoside (14): The ratios
were determined by HPLC analysis11c (hexane/ethyl acetate =
4/1; flow rate, 1.0 mL/min; 10.4 min, ꢀ-isomer; 12.1 min, ꢁ-iso-
mer).
Ethyl 3-O-Acetyl-4-O-benzyl-2-deoxy-6-O-(20,30,40,60-tetra-

176 Bull. Chem. Soc. Jpn., 77, No. 1 (2004)
6-Nitro-2-benzothiazolyl Glycoside
O-benzyl-D-glucopyranosyl)-2-phthalimido-1-thio-ꢁ-D-gluco-
pyranoside (15): The ratios were determined by HPLC analy-
sis11c (hexane/ethyl acetate = 4/1; flow rate, 1.0 mL/min; 20.8
min, ꢀ-isomer; 23.7 min, ꢁ-isomer).
pyranoside (21): This compound was synthesized from mannosyl
donor 18ꢀ and glycosyl acceptor 11.11c
21ꢀ: colorless oil; Rf 0.41 (hexane/ethyl acetate, 2/1, v/v);
21
½ꢁꢅD þ30:2ꢂ (c 1.00, CHCl3); 1H NMR (500 MHz, CDCl3) ꢂ
6-Nitro-2-benzothiazolyl 2,3,4,6-Tetra-O-benzyl-D-manno-
pyranoside (18). To a solution of 2,3,4,6-tetra-O-benzyl-D-man-
nopyranose28 17 (50.0 mg, 92.5 mmol) in THF (1.0 mL) was added
potassium bis(trimethylsilyl)amide (0.50 M in toluene, 0.22 mL,
0.11 mmol) at 0 ꢂC. After stirring for 0.5 h at the same temperature,
2 (23.8 mg, 0.11 mmol) was added to the reaction mixture. Then
the reaction mixture was stirring for 0.5 h at room temperature.
The reaction was quenched by adding sat. aq. NaHCO3. The aque-
ous layer was extracted with EtOAc, and the combined organic lay-
er was washed with brine and dried over Na2SO4. After filtration
and evaporation, the residue was purified by preparative TLC (sili-
ca gel) to afford 18ꢀ (44.0 mg, 66%) and 18ꢁ (16.1 mg, 24%).
18ꢀ: colorless oil; Rf 0.54 (hexane/ethyl acetate, 7/3, v/v);
1.14 (3H, t, J ¼ 7:0 Hz), 1.79 (3H, s), 2.57–2.65 (2H, m), 3.59
(1H, t, J ¼ 9:5 Hz), 3.63–3.68 (2H, m), 3.73–3.80 (3H, m), 3.84
(1H, s), 3.89–3.92 (2H, m), 4.02 (1H, t, J ¼ 9:5 Hz), 4.24 (1H, t,
J ¼ 9:5 Hz), 4.50 (1H, d, J ¼ 12:5 Hz), 4.53 (1H, d, J ¼ 11:0
Hz), 4.54 (2H, s), 4.66 (1H, d, J ¼ 12:5 Hz), 4.67 (2H, s), 4.76
(2H, s), 4.92 (1H, d, J ¼ 11:0 Hz), 5.07 (1H, s, H-10), 5.48 (1H,
d, J ¼ 9:5 Hz, H-1), 5.81 (1H, t, J ¼ 9:5 Hz), 7.19–7.37 (23H,
m, Ar-H), 7.43 (2H, d, J ¼ 7:0 Hz, Ar-H), 7.71–7.74 (2H, m,
Ar-H), 7.83–7.88 (2H, m, Ar-H); 13C NMR (125 MHz, CDCl3) ꢂ
14.90, 20.43, 24.33, 54.31, 65.63, 69.17, 71.92, 71.95, 72.35,
73.16, 74.06, 74.54, 74.85, 74.89, 76.53, 78.50, 79.36, 80.77 (C-
1), 98.31 (C-10, JC{H ¼ 170 Hz), (123.40, 123.52, 131.20,
131.72, 134.04, 134.20, 167.40, 167.59) (C-Phth), (127.27–
128.31, 137.68, 138.26, 138.39, 138.41, 138.47) (C-Ar), 169.85;
IR (neat) 702, 748, 1103, 1381, 1712, 2353, 3016 cmꢁ1; HRMS
23
½ꢁꢅD þ63:2ꢂ (c 1.00, CHCl3); 1H NMR (270 MHz, CDCl3) ꢂ
3.74 (1H, dd, J ¼ 1:6, 10.8 Hz), 3.82 (1H, dd, J ¼ 4:6, 10.8 Hz),
3.95–4.02 (2H, m), 4.08 (1H, t, J ¼ 1:9 Hz), 4.17 (1H, t, J ¼ 9:5
Hz), 4.52 (1H, d, J ¼ 11:9 Hz), 4.55 (1H, d, J ¼ 10:5 Hz), 4.60
(1H, d, J ¼ 11:3 Hz), 4.65 (1H, d, J ¼ 11:9 Hz), 4.66 (1H, d, J ¼
11:3 Hz), 4.83 (2H, s), 4.91 (1H, d, J ¼ 10:5 Hz), 6.48 (1H, d, J ¼
1:9 Hz, H-1), 7.16–7.46 (20H, m, Ar-H), 7.74 (1H, d, J ¼ 8:9 Hz),
8.25 (1H, dd, J ¼ 2:2, 8.9 Hz), 8.55 (1H, d, J ¼ 2:2 Hz); 13C NMR
(67.8 MHz, CDCl3) ꢂ 68.52, 72.34, 72.76, 72.97, 73.28, 73.86,
74.69, 75.16, 78.86, 98.68 (C-1, JC{H ¼ 178 Hz), (127.48–
128.35, 137.54, 137.86, 137.93, 137.96) (C-Ar), (117.76, 121.18,
121.87, 132.25, 143.84, 153.50, 173.74) (Benzothiazole); IR (neat)
748, 895, 1119, 1342, 1520, 2916 cmꢁ1; HRMS m=z calcd for
C41H38N2O8 NH4 [M + NH4]þ 736.2693, found 736.2682.
m=z calcd for C59H61NO12S NH4 [M + NH4]þ 1025.4258, found
ꢃ
1025.4266.
21ꢁ: colorless amorphous material; Rf 0.34 (hexane/ethyl ace-
22
tate, 2/1, v/v); ½ꢁꢅD ꢁ15:8ꢂ (c 1.00, CHCl3); 1H NMR (500
MHz, CDCl3) ꢂ 1.13 (3H, t, J ¼ 7:0 Hz), 1.81 (3H, s), 2.52–2.65
(2H, m), 3.43–3.46 (1H, m), 3.48 (1H, dd, J ¼ 2:5, 9.0 Hz),
3.59–3.65 (2H, m), 3.76–3.82 (3H, m), 3.87 (1H, d, J ¼ 2:5 Hz),
3.93 (1H, t, J ¼ 9:0 Hz), 4.28–4.32 (2H, m), 4.34 (1H, s, H-10),
4.51–4.68 (7H, m), 4.90 (1H, d, J ¼ 12:0 Hz), 4.91 (1H, d, J ¼
11:0 Hz), 4.99 (1H, d, J ¼ 11:0 Hz), 5.48 (1H, d, J ¼ 10:5 Hz,
H-1), 5.85 (1H, t, J ¼ 9:5 Hz), 7.19–7.37 (23H, m, Ar-H), 7.50
(2H, d, J ¼ 7:0 Hz, Ar-H), 7.72–7.73 (2H, m, Ar-H), 7.85–7.88
(2H, m, Ar-H); 13C NMR (125 MHz, CDCl3) ꢂ 14.86, 20.40,
24.02, 54.27, 68.86, 69.52, 71.51, 73.39, 73.69, 73.75, 74.07,
74.29, 74.87, 75.00, 75.96, 77.15, 78.86, 80.63 (C-1), 82.18,
102.05 (C-10, JC{H ¼ 156 Hz), (123.39, 123.46, 131.21, 131.74,
133.92, 134.18, 167.40, 167.59) (C-Phth), (127.30–128.32,
137.61, 138.12, 138.31, 138.42, 138.68) (C-Ar), 169.80; IR (neat)
748, 1103, 1227, 1381, 1713, 2931 cmꢁ1; HRMS m=z calcd for
ꢃ
18ꢁ: colorlꢂess solid; Rf 0.42 (hexane/ethyl acetate, 7/3, v/v);
Mp 109–110 C; ½ꢁꢅD ꢁ25:6ꢂ (c 1.00, CHCl3); H NMR (270
MHz, CDCl3) ꢂ 3.72–3.86 (4H, m), 4.05 (1H, t, J ¼ 8:6 Hz),
4.24 (1H, d, J ¼ 1:6 Hz), 4.51 (1H, d, J ¼ 12:2 Hz), 4.57 (1H,
d, J ¼ 10:8 Hz), 4.61 (1H, d, J ¼ 12:2 Hz), 4.64 (1H, d, J ¼
11:6 Hz), 4.70 (1H, d, J ¼ 11:6 Hz), 4.88 (1H, d, J ¼ 10:8 Hz),
4.88 (2H, s), 6.00 (1H, brs, H-1), 7.16–7.72 (20H, m, Ar-H),
7.70 (1H, d, J ¼ 9:2 Hz), 8.25 (1H, dd, J ¼ 2:2, 9.2 Hz), 8.56
(1H, d, J ¼ 2:2 Hz); 13C NMR (67.8 MHz, CDCl3) ꢂ 68.89,
72.31, 72.86, 73.37, 74.04, 74.12, 74.84, 76.46, 81.06, 99.52 (C-
1, JC{H ¼ 162 Hz), (127.53–128.44, 137.77, 137.80, 137.91,
137.96) (C-Ar), (117.79, 121.15, 121.83, 132.41, 143.89, 153.39,
174.30) (Benzothiazole); IR (KBr) 702, 748, 1103, 1342, 1520,
23
1
C59H61NO12S NH4 [M + NH4]þ 1025.4258, found 1025.4260.
ꢃ
2,3,4-Tri-O-benzyl-6-O-(20,30,40,60-tetra-O-benzyl-D-manno-
pyranosyl)-ꢁ-D-glucopyranosyl Fluoride (22): This compound
was synthesized from mannosyl donor 18ꢀ and glycosyl acceptor
12.5d
22ꢀ: colorless oil; Rf 0.50 (hexane/ethyl acetate, 2/1, v/v);
21
2916 cmꢁ1; HRMS m=z calcd for C41H38N2O8 NH4 [M + NH4]þ
736.2693, found 736.2704.
½ꢁꢅD þ36:4ꢂ (c 1.12, CHCl3); 1H NMR (500 MHz, CDCl3) ꢂ
ꢃ
3.53–3.60 (3H, m), 3.63–3.76 (5H, m), 3.84 (1H, s), 3.87–3.90
(2H, m), 4.01 (1H, t, J ¼ 9:0 Hz), 4.47–4.53 (3H, m), 4.60–4.65
(3H, m), 4.71–4.81 (5H, m), 4.85–4.91 (3H, m), 5.03 (1H, s, H-
10), 5.26 (1H, dd, J ¼ 6:0, 53.0 Hz, H-1), 7.16–7.42 (35H, m,
Ar-H); 13C NMR (125 MHz, CDCl3) ꢂ 65.67, 69.18, 71.85,
72.10, 72.35, 73.19, 74.09 (d, J ¼ 1:9 Hz), 74.38 (d, J ¼ 3:6
Hz), 74.50, 74.77, 74.82, 74.87, 75.16, 76.52, 79.35, 81.24 (d, J ¼
22:9 Hz), 83.38 (d, J ¼ 10:1 Hz), 98.61 (C-10, JC{H ¼ 170 Hz),
109.48 (d, J ¼ 216 Hz, C-1), (127.25–128.37, 137.58, 138.10,
138.33, 138.42, 138.60) (C-Ar); IR (neat) 694, 741, 1095, 1458,
1496, 1604, 1737, 1959, 2931 cmꢁ1; HRMS m=z calcd for
Mannosylation Using H[B(C6F5)4] as Catalyst (The General
Procedure). To a stirred suspension of MS 5A (150 mg), manno-
syl donor (0.06 mmol) and glycosyl acceptor (0.050 mmol) in
CH2Cl2 (1.25 mL) was successively added H[B(C6F5)4] (0.050
M toluene–Et2O (1:1), 0.20 mL, 0.01 mmol) at ꢁ78 ꢂC. After
the completion of the mannosylation reaction was verified by mon-
itoring TLC, the reaction was quenched by addition of sat. aq.
NaHCO3. Then, the mixture was filtered through Celite and the
aqueous layer was extracted with CH2Cl2. The combined organic
layer was washed with brine and dried over Na2SO4. After filtra-
tion and evaporation, the resulting residue was purified by prepara-
tive TLC (silica gel) and afforded the corresponding disaccharide.
The ꢁ to ꢀ ratios for 19,11a 21, 22, 23, and 24 were determined by
isolations of both isomers.
C61H63O10F NH4 [M + NH4]þ 992.4749, found 992.4764.
ꢃ
22ꢁ: colorless solid; Rf 0.43 (hexane/ethyl acetate, 2/1, v/v);
22
Mp 129–130 ꢂC; ½ꢁꢅD ꢁ5:0ꢂ (c 0.85, CHCl3); 1H NMR (500
MHz, CDCl3) ꢂ 3.43–3.46 (2H, m), 3.53–3.62 (3H, m), 3.70–
3.82 (4H, m), 3.87 (1H, d, J ¼ 3:0 Hz), 3.91 (1H, t, J ¼ 9:5 Hz),
4.26 (1H, d, J ¼ 10:5 Hz), 4.29 (1H, s, H-10), 4.50–4.66 (7H,
Ethyl 3-O-Acetyl-4-O-benzyl-2-deoxy-6-O-(20,30,40,60-tetra-
O-benzyl-D-mannopyranosyl)-2-phthalimido-1-thio-ꢁ-D-gluco-

T. Hashihayata et al.
Bull. Chem. Soc. Jpn., 77, No. 1 (2004)
177
m), 4.73 (1H, d, J ¼ 11:0 Hz), 4.81 (2H, d, J ¼ 11:0 Hz), 4.87–
5.00 (4H, m), 5.30 (1H, dd, J ¼ 6:5, 52.5 Hz, H-1), 7.19–7.50
(35H, m, Ar-H); 13C NMR (125 MHz, CDCl3) ꢂ 68.40, 69.58,
71.45, 73.37, 73.48, 73.65, 74.15 (d, J ¼ 1:9 Hz), 74.64 (d, J ¼
4:6 Hz), 74.85, 74.96, 75.15, 75.95, 76.95, 81.37 (d, J ¼ 22:0
Hz), 83.45 (d, J ¼ 10:1 Hz), 101.73 (C-10, JC{H ¼ 155 Hz),
109.60 (d, J ¼ 216 Hz, C-1), (127.24–128.32, 137.61, 137.79,
138.12, 138.16, 138.33, 138.41, 138.66) (C-Ar); IR (KBr) 694,
741, 1111, 1358, 1458, 1496, 2908 cmꢁ1; HRMS m=z calcd for
d, J ¼ 10:8 Hz), 5.52 (1H, s, H-1), 7.16–7.40 (25H, m, Ar-H);
13C NMR (100 MHz, CDCl3) ꢂ 59.01, 65.12, 69.38, 72.01,
72.13, 72.38, 72.90, 73.17, 73.58, 74.68, 74.72, 74.82, 75.10,
75.71, 79.69, 97.97 (C-10, JC{H ¼ 167 Hz), 100.42 (C-1),
(127.40–128.45, 136.93, 137.96, 138.08, 138.15, 138.31) (C-Ar);
IR (neat) 702, 748, 1034, 1365, 1458, 1604, 2098, 2924 cmꢁ1
;
HRMS m=z calcd for C47H49N3O9 NH4 [M + NH4]þ 817.3813,
found 817.3813.
ꢃ
24ꢁ: colorless oil; Rf 0.21 (hexane/ethyl acetate, 2/1, v/v);
23
C61H63O10F NH4 [M + NH4]þ 992.4749, found 992.4737.
½ꢁꢅD ꢁ28:2ꢂ (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) ꢂ
ꢃ
Methyl 2,3,6-Tri-O-benzyl-4-O-(20,30,40,60-tetra-O-benzyl-D-
mannopyranosyl)-ꢀ-D-glucopyranoside (23): This compound
was synthesized from mannosyl donor 18ꢀ and glycosyl acceptor
9.14
3.27 (1H, s), 3.48–3.52 (1H, m), 3.56 (1H, dd, J ¼ 2:8, 9.2 Hz),
3.73–3.81 (3H, m), 3.82 (1H, brs), 3.91 (1H, t, J ¼ 9:2 Hz), 3.99
(1H, s), 4.05 (1H, d, J ¼ 2:8 Hz), 4.14 (1H, d, J ¼ 7:6 Hz), 4.48
(1H, d, J ¼ 12:0 Hz), 4.52 (1H, d, J ¼ 12:0 Hz), 4.57 (1H, d, J ¼
10:8 Hz), 4.57 (1H, d, J ¼ 11:6 Hz), 4.57 (1H, d, J ¼ 12:0 Hz),
4.59 (1H, d, J ¼ 12:0 Hz), 4.65 (1H, d, J ¼ 11:6 Hz), 4.69 (1H,
d, J ¼ 7:2 Hz), 4.70 (1H, s, H-10), 4.91 (1H, d, J ¼ 12:0 Hz),
4.94 (1H, d, J ¼ 10:8 Hz), 5.03 (1H, d, J ¼ 12:0 Hz), 5.54 (1H,
s, H-1), 7.15–7.48 (25H, m, Ar-H); 13C NMR (100 MHz, CDCl3)
ꢂ 59.27, 64.74, 69.52, 71.19, 72.04, 72.18, 72.58, 73.24, 73.90,
74.05, 74.58, 75.07, 75.94, 77.51, 82.00, 98.52 (C-10, JC{H ¼ 154
Hz), 100.44 (C-1), (127.18–128.32, 137.34, 137.88, 138.06,
138.75) (C-Ar); IR (neat) 702, 741, 1103, 1627, 2098, 2360,
23ꢀ: colorless oil; Rf 0.44 (hexane/ethyl acetate, 2/1, v/v);
24
½ꢁꢅD þ18:1ꢂ (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) ꢂ
3.41 (3H, s), 3.56 (1H, dd, J ¼ 3:6, 9.6 Hz), 3.59 (1H, dd,
J ¼ 1:6, 10.4 Hz), 3.68 (1H, dd, J ¼ 4:4, 10.4 Hz), 3.73–3.75
(5H, m), 3.79–3.85 (2H, m), 3.88 (1H, dd, J ¼ 2:8, 9.2 Hz), 3.99
(1H, t, J ¼ 9:2 Hz), 4.23 (1H, d, J ¼ 12:4 Hz), 4.33 (1H, d, J ¼
12:4 Hz), 4.44 (1H, d, J ¼ 12:4 Hz), 4.45 (1H, d, J ¼ 12:0 Hz),
4.51 (1H, d, J ¼ 10:8 Hz), 4.53–4.63 (6H, m), 4.63 (1H, d, J ¼
3:6 Hz, H-1), 4.69 (1H, d, J ¼ 12:4 Hz), 4.86 (1H, d, J ¼ 10:8
Hz), 5.11 (1H, d, J ¼ 11:6 Hz), 5.32 (1H, d, J ¼ 2:0 Hz, H-10),
7.12–7.32 (35H, m, Ar-H); 13C NMR (100 MHz, CDCl3) ꢂ
55.12, 69:22 ꢄ 2, 69.65, 71.90, 72.11, 72.83, 73.02, 73.11, 73.21,
74.78, 74.84, 74.87, 76.13, 77.61, 79.60, 79.83, 81.41, 97.54 (C-
1), 100.36 (C-10, JC{H ¼ 169 Hz), (126.56–128.31, 137.72,
138.21, 138.28, 138.42, 138.43, 138.52, 138.68) (C-Ar); IR (neat)
694, 741, 1049, 1103, 1635, 2353, 2931 cmꢁ1; HRMS m=z calcd
2962 cmꢁ1; HRMS m=z calcd for C47H49N3O9 NH4 [M + NH4]þ
ꢃ
817.3813, found 817.3809.
In Situ Anomerization Reaction with 18ꢁ Using H[B(C6F5)4]
as Catalyst. To a stirred suspension of MS 5A (113 mg) and 18ꢁ
(0.045 mmol) in CH2Cl2 (0.94 mL) was successively added
H[B(C6F5)4] (0.050 M toluene–Et2O (1:1), 0.15 mL, 7.50 mmol)
at ꢁ78 ꢂC. After stirring for 5 min, the reaction was quenched
by addition of 2,6-di-t-butylpyridine (20.2 mL, 0.090 mmol). To
the mixture was then added sat. aq. NaHCO3; the mixture was fil-
tered through Celite and the aqueous layer was extracted with
CH2Cl2. The combined organic layer was washed with brine and
dried over Na2SO4. After filtration and evaporation, the resulting
residue was purified by preparative TLC (silica gel) to afford
18ꢀ (15.3 mg, 47%) as a single isomer.
for C62H66O11 NH4 [M + NH4]þ 1004.4949, found 1004.4955.
ꢃ
23ꢁ: colorless oil; Rf 0.37 (hexane/ethyl acetate, 2/1, v/v);
24
½ꢁꢅD ꢁ16:0ꢂ (c 0.67, CHCl3); 1H NMR (400 MHz, CDCl3) ꢂ
3.29 (1H, dd, J ¼ 2:8, 9.6 Hz), 3.27–3.30 (1H, m), 3.39 (3H, s),
3.46–3.58 (4H, m), 3.67–3.75 (2H, m), 3.71 (1H, d, J ¼ 2:8 Hz),
3.88 (1H, t, J ¼ 9:6 Hz), 3.90–3.94 (2H, m), 4.37 (1H, d, J ¼
11:2 Hz), 4.38 (1H, d, J ¼ 12:0 Hz), 4.43 (1H, s, H-10), 4.45
(1H, d, J ¼ 11:6 Hz), 4.45 (1H, d, J ¼ 12:0 Hz), 4.50 (1H, d, J ¼
11:6 Hz), 4.54 (1H, d, J ¼ 10:8 Hz), 4.58 (1H, d, J ¼ 11:2 Hz),
4.59 (1H, d, J ¼ 3:6 Hz, H-1), 4.61 (1H, d, J ¼ 12:0 Hz), 4.76
(1H, d, J ¼ 11:2 Hz), 4.78 (1H, d, J ¼ 12:0 Hz), 4.84 (2H, brs),
4.86 (1H, d, J ¼ 10:8 Hz), 5.16 (1H, d, J ¼ 11:2 Hz), 7.15–7.41
(35H, m, Ar-H); 13C NMR (100 MHz, CDCl3) ꢂ 55.15, 68.57,
69.41, 69.56, 71.52, 73.33, 73.42, 73.50, 73.95, 74.68, 74.88,
74.91, 75.09, 76.05, 77.01, 78.99, 80.21, 82.46, 98.25 (C-1),
100.73 (C-10, JC{H ¼ 154 Hz), (126.86–128.37, 137.58, 138.18,
138.21, 138.39, 138.69, 138.76, 139.50) (C-Ar); IR (neat) 702,
741, 1049, 1103, 1458, 1720, 2353, 2839 cmꢁ1; HRMS m=z calcd
This study was supported in part by a Grant of the 21st Cen-
tury COE Program from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT). We thank Asahi
Glass Engineering Co. Ltd. for providing Tr[B(C6F5)4], and
Central Glass Co. Ltd. for providing TfOH. We thank Mr.
Hirokazu Ohsawa and Dr. Shigeru Nakajima, Banyu Pharma-
ceutical Company, for their kind help concerning High Resolu-
tion Mass Spectrometry analyses and NMR spectral analyses.
for C62H66O11 NH4 [M + NH4]þ 1004.4949, found 1004.4979.
References
ꢃ
1,6-Anhydro-2-azido-3-O-benzyl-2-deoxy-4-O-(20,30,40,60-
tetra-O-benzyl-D-mannopyranosyl)-ꢁ-D-glucopyranose (24):
This compound was synthesized from mannosyl donor 18ꢀ and
glycosyl acceptor 20.30
1
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(1H, d, J ¼ 12:0 Hz), 4.87 (1H, d, J ¼ 1:6 Hz, H-10), 4.91 (1H,
2
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