Single-step multisyntheses of glycosyl acceptors: Benzylation of n-1 hydroxyl groups of phenylthio glycosides of xylose, mannose, glucose, galactose, 2-azido-2-deoxy-glucose, and 2-azido-2-deoxy-galactose

Article abstract of DOI:10.1081/CAR-200053712

An array of synthons is required to access an oligosaccharide library; however, multistep and thus time-consuming synthesis is inevitable. To rapidly access such synthetic units, multiple benzylation reactions of monosaccharides under phase-transfer condi

Full text of DOI:10.1081/CAR-200053712

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Single‐Step Multisyntheses of Glycosyl
Acceptors: Benzylation of n‐1 Hydroxyl
Groups of Phenylthio Glycosides of
Xylose, Mannose, Glucose, Galactose,
2‐Azido‐2‐deoxy‐glucose, and
2‐Azido‐2‐deoxy‐galactose
Kaori Suzuki a , Isao Ohtsuka a , Takuya Kanemitsu a , Takuro Ako a
Osamu Kanie a
&
a Mitsubishi Kagaku Institute of Life Sciences (MITILS), Tokyo, Japan
Version of record first published: 16 Aug 2006.
To cite this article: Kaori Suzuki, Isao Ohtsuka, Takuya Kanemitsu, Takuro Ako & Osamu Kanie
(2005): Single‐Step Multisyntheses of Glycosyl Acceptors: Benzylation of n‐1 Hydroxyl Groups
of Phenylthio Glycosides of Xylose, Mannose, Glucose, Galactose, 2‐Azido‐2‐deoxy‐glucose, and
2‐Azido‐2‐deoxy‐galactose, Journal of Carbohydrate Chemistry, 24:3, 219-236
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Journal of Carbohydrate Chemistry, 24:219–236, 2005
Copyright # Taylor & Francis, Inc.
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1081/CAR-200053712
Single-Step Multisyntheses
of Glycosyl Acceptors:
Benzylation of n-1 Hydroxyl
Groups of Phenylthio
Glycosides of Xylose,
Mannose, Glucose,
Galactose, 2-Azido-2-deoxy-
glucose, and 2-Azido-2-
deoxy-galactose
Kaori Suzuki, Isao Ohtsuka, Takuya Kanemitsu, Takuro Ako, and
Osamu Kanie
Mitsubishi Kagaku Institute of Life Sciences (MITILS), Tokyo, Japan
An array of synthons is required to access an oligosaccharide library; however, multistep
and thus time-consuming synthesis is inevitable. To rapidly access such synthetic units,
multiple benzylation reactions of monosaccharides under phase-transfer conditions
were examined. Multiple benzyl groups were successfully incorporated in one step,
especially in the cases of reactions with triol systems.
Keywords Phase transfer, Benzylation, Random reactions, Thioglycosides, Glycosyl
acceptors
Received November 10, 2004; accepted January 7, 2005.
Address correspondence to Osamu Kanie, Mitsubishi Kagaku Institute of Life Sciences
(MITILS), Minamiooya 11, Machida-shi, Tokyo 194-8511, Japan. E-mail: kokanee@
libra.ls.m-kagaku.co.jp
219

K. Suzuki et al.
220
INTRODUCTION
Oligosaccharides displayed on the cell surface as a part of glycoproteins or gly-
colipids play important roles in cellular recognition processes. Such processes
include the differentiation and development of cells,[1] immune response,[2]
and fertilization[3] in the animal kingdom. Other functions are the role of recep-
tors as ligands present on the surfaces of bacteria[4] and viruses[5] that cause
infectious diseases.
To access the functions and mechanisms involved in such interactions, syn-
thetic oligosaccharides can be used as molecular probes. Satisfying the increas-
ing need to produce such molecules relies largely on the availability of
synthetic monosaccharide units. In most cases, it is relatively easy to syn-
thesize the units, but they usually require three to five steps for just protecting
group manipulations and thus are time consuming and expensive. In the
course of our study to synthesize an oligosaccharide library, it was necessary
to prepare a series of suitably protected monosaccharide synthetic units. Con-
sidering the large number of monosaccharides required, we came to the con-
clusion that the stereochemistry is not strictly controlled by neighboring
group participation, but rather mildly controlled by a solvent effect[6] and
anomeric effect.[7] This decision would reduce the number of required
synthons.[8] Despite the potential complexity of the formation of an a- and
b-anomeric mixture, it is considered that this may be advantageous for the
following reasons: 1) the formation of orthoester and related byproducts can
be prevented and 2) another anomer, which may be biologically important, is
obtained at the same time. It should also be stressed that most of the current
“stereoselective” glycosylation methods inevitably yield an unwanted anomer
because the glycosylation mechanism involves SN1 character. Individual
synthesis of protected monosaccharides, however, still requires multistep
operations. To overcome this problem, we considered a method to introduce
n-1 protecting groups into monosaccharides having n hydroxyl groups in a
random fashion to yield a set of monosaccharides, which can directly be used
as acceptors in glycosylation reactions (Fig. 1).
Here we report the results of benzylation of phenylthio glycosides of the
monosaccharides xylose, mannose, glucose, galactose, 2-azido-2-deoxy-
glucose, and 2-azido-2-deoxy-galactose under phase-transfer conditions to
directly access glycosyl acceptors.
RESULTS AND DISCUSSION
Prior to initiating the program, we decided to prepare monosaccharides as
phenylthio glycosides because of their important roles in oligosaccharide
synthesis,[9–15] especially in conjunction with the orthogonal glycosylation
strategy.[16–18] In an effort to introduce n-1 benzyl groups into

Single-Step Multisyntheses of Glycosyl Acceptors
221
Figure 1: Concept of direct conversion of nonprotected monosaccharide into a glycosyl
acceptor.
monosaccharides, we decided to use phase-transfer conditions after examining
various possible conditions. Unlike usual methods,[19,20] our objective was to
obtain multiple products in the least number of steps possible (Sch. 1).[21]
For this, we have examined the conditions to “optimize” the randomness of
the introduction of n-1 benzyl groups. The criteria for this are that (1) n-1
hydroxyl groups are succsessfully benzylated and (2) the expected abundance
of individual products is equal. 1.25–1.5 Equivalents of benzyl bromide
(BnBr) for each hydroxyl group, tetra-n-butyl ammonium hydrogensulfate
(Bu4NHSO4) as a catalyst, and sodium hydroxide were used in a dichloro-
methane water-solvent system under gentle reflux conditions at a bath tempe-
rature of 508C. It was found that the desired compounds, which have one
Scheme 1: Comparison of the step-by-step preparation of the glycosyl accepters and the
random alkylation protocol.

K. Suzuki et al.
222
hydroxyl group and other hydroxyl groups that were benzylated, were
produced in relatively scattered ratios.
Randomized Dibenzylation Reactions of Phenylthio-
Glycosides of Monosaccharides Carrying Three
Hydroxyl Groups (2/3 Benzylation Reactions)
Under the above-mentioned phase-transfer conditions, the reaction
of phenyl 2-azido-2-deoxy-1-thio-b-D-galactopyranoside (GalN) yielded
GalN3, GalN4, and GalN6 in yields of 17%, 36%, and 13%, respectively
(Fig. 2, Table 1). A starting material having three hydroxyl groups has a
greater partition coefficient to the aqueous phase, and therefore, a greater
chance exists for an alkoxide to be involved in the reaction. The dominant
factor in this step should be basically the basisity of each alkoxide. In this
case, the anomeric position and C-2 are substituted by electron withdrawing
groups (e.g. phenylthio- and azido-groups). Thus, the most basic and nucleophi-
lic alkoxide will be O-4. This was consistent with the analysis of the isolated
mono-benzyl compound that was found to be exclusively O-4 benzyl
compound. However, this evidence does not mean that the first generation
reaction went through the benzylation at 4-OH because the major product of
the dibenzylation was a 4-OH compound. This inconsistent result suggests
Figure 2: Generations of benzylation reaction.

Table 1: Isolated yields of dibenzylated monosaccharides with three OHs.
GalN
GlcN
Yields (%)a
Xyl
Yields (%)a
Number
of OHs
Position
of OH
Yields (%)a
Ratiob
Ratiob
Ratiob
1 (di Bn)
2
3
4
6
—
—
—
17
36
13
—
—
—
—
1.4
3.6
1.0
—
—
13
17
37
—
—
—
—
1.0
1.5
2.8
—
11
34
25
—
—
—
1.0
3.0
2.0
—
—
—
70
66
93
67
98
88
—
9.2
8.3
0 (tri Bn)
2 (mono Bn)
13
14
17
14
—
—
aIsolated yields after silica gel chromatography.
bRatio obtained by HPLC analysis (see experimental section for retention time for each compound).

K. Suzuki et al.
224
that the first-generation reaction would preferentially occur at 3- and 6-OH.
The second generation would be largely affected by steric factors; thus, the
3-OBn compound preferentially produces a 3,6-di-Bn compound (GalN4), for
example. The situation would be the same in the case of 6-OBn compound.
The 4-OBn compound, however, would resist the second reaction due to the
steric inpediment of the first benzyl group. Yields of dibenzylation indicate
that the order of observed nucleophilicity (reactivity) is O-6 ꢀ O-3 . O-4
(Table 2). This result was further confirmed by additional experiments where
the initial reaction rate was examined using one equivalent of benzyl
1
bromide, and the reaction course was followed by H NMR (data not shown).
Furthermore, the reaction rate constant should be reduced for the second-
generation reaction because of the lower partition coefficient in the aqueous
phase, and the reaction is influenced by steric factor as well.
In the case of the glucosamine precursor GlcN, however, the order of the
product ratio obtained was different from that of GalN (Table 1). An important
observation was that the orders of reactivity of 3- and 4-OH were the same
(Table 2). The observed different reactivity for 6-OHs in GalN and GlcN
might be affected by the orientation of 6-OH (rotamers). Neverthless, the
observed reactivity was found to be O-3 . O-4 . O-6. Isolation of each
compound could not be accomplished by silica gel column chromatography in
this case, which yielded GlcN3 and a mixture of GlcN4 and GlcN6. Thus,
the latter mixture was subjected to silylation conditions using t-butyldimethyl-
silyl chloride (TBDMSCl), triethylamine (TEA), and 4-N,N-dimethylaminopyri-
dine (DMAP) in N,N-dimethylformamide (DMF). As a result, only compound
GlcN6 having a primary hydroxyl group was silylated, and thus GlcN6-
TBDMS and GlcN4 were separated by silica gel chromatography. Finally,
the TBDMS group was removed by means of tetra-n-butylammonium
fluoride (TBAF).
As for phenylthio-xyloside, the hydroxyl groups are all in a transequatorial
arrangement, and thus comparison of the reactivities must be more simple.
The result indicated that the order of basisity of alcholate is O-2 . O-4 . O-3
(Table 2). Isolation of each compound was done by silica gel column
chromatography.
Table 2: Ratio of benzylation.a
Position
of OH
GalN
GlcN
Xyl
Gal
Glc
Man
2
3
4
6
—
—
1.8
1.0
1.5
—
1.7
1.0
1.2
1.7
1.7
1.0
1.6
1.2
1.4
1.1
1.0
1.1
1.9
1.0
2.1
1.7
1.5
1.0
aRatio of sum of yields where target OH groups were benzylated.

Single-Step Multisyntheses of Glycosyl Acceptors
225
Overall, total yields for the dibenzylation reactions were within 66% and
70% yields. Individual compounds could be isolated by simple column chro-
matography. Therefore, the procedure may be effectively used to prepare a
set of glycosyl acceptors.
Randomized Tribenzylation Reactions of
Phenylthioglycosides of Monosaccharides Carrying
Four Hydroxyl Groups (3/4 Benzylation Reactions)
The tribenzylation reactions of monosaccharides carrying four hydroxyl
groups such as phenylthiogalactoside (Gal), phenylthioglucoside (Glc), and
phenylthiomannoside (Man) were found to be less efficient compared to the
dibenzylation of triols (Table 3). The distributions of mono-, di-, tri-, and tetra-
benzylated compounds were 4%, 20%, 35%, and 16%, respectively, for Gal.
Attempts to push the reaction further resulted in the accumulation of perben-
zylation product, which suggested that the partition coefficients for compounds
having more than two benzyl groups were similar. The same tendency was
observed for Glc as well. Attempts to isolate individual tribenzylated com-
pounds by chromatography yielded a mixture of Gal2, Gal3, and Gla4 (30%)
and isolated Gal6 (4.5%), and the mixture could not be resolved. HPLC,
however, could resolve all four regioisomers. Although it was not practical to
isolate tribenzylated phenylthio-glucoside, four isomers could be isolated by
means of HPLC. In the case of Man, tribenzylated compounds, namely
Man2, Man3, Man4, and Man6, were isolated on silica gel column chromato-
graphy. The reactivity of each hydroxyl group under the condition is in the
order of O-2 ꢀ O-6 . O-4 ꢀ O-3 (Gal), O-2 ꢀ O-4 . O-6 . O-3 (Glc), and
O-2 . O-3 ꢀ O-6 ꢀ O-4 (Man) (Table 2). In the case of Gal, it was found that
the reactivities of alcholates at O-3 and O-4 were similar, which was different
from those of alcohols for the glycosylation reactions.[22]
Conclusion
Through this investigation, it was revealed that there is a tendency for the
reactivity of alcoxide at O-2 to be greater than others in general. Comparison of
Gal versus GalN and Glc versus GlcN suggest that azide functionality
enhances the reactivity of O-3 alcholate despite its electron withdrawing char-
acter (Table 2). There exists a review article describing the reactivities of
hydroxyl goups of various carbohydrates, but the results were inconsistent
with ours.[23] Reasons for this are considered to be different reaction conditions
and the anomeric protecting groups utilized.
In summary, a random benzylation method of phenylthioglycosides of a
series of monosaccharides was examined in order to rapidly access a set of

Table 3: Isolated yields of tribenzylated monosaccharides with four OHs.
Gal
Glc
Yields (%)a
Man
Yields (%)a
Number of
OHs
Position
of OH
Yields (%)a
35
Ratiob
Ratiob
Ratioc
1 (tri Bn)
2
3
4
1.2
6.2
5.1
1.0
—
1.0
4.8
1.1
3.6
—
1.1
20
0.3
1.0
1.3
1.1
—
48
65
23
21
—
—
—
6
75
87
93
0 (tetra Bn)
2 (di Bn)
3 (mono Bn)
—
—
—
16
20
4.0
20
19
—
8.6
9.6
10
—
—
—
—
—
—
aYields after silica gel chromatography.
bRatio obtained by HPLC analysis (see experimental section for retention time for each compound).
cRatio estimated by 1H NMR.

Single-Step Multisyntheses of Glycosyl Acceptors
227
glycosyl acceptors. It was found that all phenylthio-glycosides can be converted
into glycosyl acceptors having one hydroxyl group in single phase-transfer
reactions. GalN, Xyl, and Man derivatives in particular could easily be
isolated by silica gel column chromatography. HPLC can be used when
simple purification is not possible. Despite some drawbacks in the purification
process, the method drastically reduces the synthetic steps and thus the overall
yields for most of the individual compounds are superior compared to tra-
ditional one-by-one and step-by-step methods.
EXPERIMENTAL
General Methods
Analytical thin layer chromatography (TLC) was performed on Merck Art
5715, Kieselgel 60 F254/0.25 mm thickness plates. Visualization was accom-
plished with UV light and phosphomolybdic acid and/or sulfuric acid
solution followed by heating. Column chromatography was performed with
1
Merck Art 7734 Silicagel 60 70–230 mesh. H NMR (500 MHz) spectra were
recorded with an AVANCE 500 spectrometer (Bruker Biospin Inc.) in deuter-
ated solvents using tetramethylsilane as an internal standard. 13C NMR
chemical shifts were obtained and assigned by HSQC experiments. Optical
rotations were measured in a 1.0 dm tube with a Horiba SEPA-200 polarimeter
at 26 + 18C.
1H NMR Assignments
To obtain unambiguous results regarding the structures of individual com-
pounds, all compounds were synthesized prior to this investigation. Assigned
chemical shifts and coupling constants of compounds are partially listed in
Tables 4 and 5, respectively.
Estimation of Compounds’ Ratio
Estimation of the ratio of each compound formed in a phase-transfer alkyl-
1
ation reaction was carried out based on H NMR integrals.
GalN: Although those of one of the H-6 protons of GalN3 and GalN4
were isolated in a spectrum of a mixture, there is no isolated signal for
GalN6. Therefore, the ratio of each compound was estimated as
follows: [GalN6] ¼ f[GalN3] þ [GalN4] þ [GalN6]g 2 f[GalN3] þ [GalN4]g,
where [GalN3] ¼ integral at d 3.70 (H-6a of GalN3) ¼ 0.39 and [GalN4] ¼
integral at d 3.77 (H-6a of GalN4) ¼ 1.00. f[GalN3] þ [GalN4] þ [GalN6]g ¼

Table 4: Chemical shifts of n-1 benzylated compounds.
Position of
Sugar
OH
H-1
H-2
3.55
3.64
3.85
3.28
3.31
3.33
3.72
3.33
3.73
4.01
3.70–3.66
H-3
3.67
3.38
3.42
3.59
3.36
3.54
3.63
3.73
3.64
3.48
3.70–3.66
H-4
3.90
4.05
3.84–3.80
3.51
3.62
3.52
3.57
3.51
H-5
3.52
3.55
3.41
3.45
3.45
3.38
4.29 3.52
4.04 3.21
4.42 3.53
3.66
H-6
Benzyl methylenes
GalN
3
4
6
3
4
6
2
3
4
2
3
4.42
4.37
4.40
4.44
4.43
4.46
4.92
4.63
5.20
4.53
4.62
3.70 3.70
3.77 3.77
3.48–3.80 3.54
3.80 3.76
3.78 3.74
3.87 3.71
—
4.72, 4.67, 4.54, 4.49
4.69, 4.65, 4.58, 4.55
4.89, 4.74, 4.71, 4.55
4.70, 4.65a, 4.57
4.89, 4.81, 4.59, 4.55
4.88, 4.85, 4.83, 4.64
4.83, 4.74, 4.64b
4.92, 4.75, 4.70, 4.63
4.78, 4.76, 4.61, 4.61
4.89, 4.74, 4.67, 4.57, 4.50,
4.89, 4.74, 464, 4.65, 4.52,
GlcN
Xyl
—
—
3.69
3.98
3.91
Gal
3.66 3.66
3.70–3.66
3.70–3.66
3.81 3.77
3.83 3.51
3.79 3.74
3.80 3.73
3.79 3.75
3.88 3.70
3.70–3.66
4
6
2
3
4
6
2
3
4
6
4.64
4.65
4.50
4.65
4.69
4.72
5.61
5.69
5.62
5.51
3.75
3.95
3.49
3.38
3.48
3.49
4.26
4.00
4.01
3.99
3.57
3.60
3.59
3.76
3.53
3.73
3.88
3.98
3.68
3.89
4.10
3.85
3.59
3.54
3.65
3.58
3.94
3.80
4.13
4.03
3.60
3.43
3.53
3.49
3.47
3.39
4.30
4.29
4.29
4.12
4.83, 4.75, 4.72, 4.68, 4.57b
4.97, 4.82, 4.75a, 4.63
Glc
4.90, 4.84, 4.82, 4.61, 4.57,
4.96, 4.78, 4.67, 4.62, 4.61,
4.91a, 4.78, 4.74, 4.58, 4.55
4.92, 4.91, 4.87, 4.86, 4.77,
4.84, 4.72b, 4.62, 4.53, 4.46
4.88, 4.78, 4.66, 4.55, 4.52,
4.70, 4.62, 4.58, 4.54, 4.54,
4.96, 4.69b, 4.66, 4.65, 4.61
Man
3.8
3.68
3.85 3.75
3.84 3.80
3.82 3.80
aSignal ovarlapped with other methylene protons.
bSignal appeared as a singlet.

Table 5: Chemical shifts and coupling constants of n-1 benzylated compounds.
Benzyl
Position
methylenes
Sugar
of OH
J1,2
J2,3
J3,4
J4,5
J5,5
J5,6
2.1
5.7 5.7
4.2 8.7
2.0 4.0
4.4 4.9
2.6 6.1
J6,6
(Jgem)
a
GalN
3
4
6
3
4
6
2
3
4
2
3
4
6
2
3
4
6
2
3
4
6
9.6
10.2
10.1
10.1
9.7
10.2
5.9
9.5
4.3
9.6
9.5
9.8
9.6
9.8
9.9
9.6
9.3
9.1
6.0
9.0
4.7
2.2
3.1
2.8
8.9
8.5
9.0
6.2
8.8
5.2
—
—
3
7.5
10.0
11.4
11.0
10.4
11.7, 11.7
11.5, 12.3
11.6, 11.7
11.3, 11.9
11.1, 11.8
10.5, 11.1
11.6, —c
10.9, 11.8
11.6, 12.1
11.5, 11.7, 11.9
10.8, 11.6, 11.7
10.3, 11.8, —c
10.2, 11.7, —a
11.2, 10.6, 12.0
11.0, 11.2, 11.9
11.4, 10.3, 11.9
10.2, 10.9, 10.9
10.8, 12.0, —c
11.0, 11.6, 11.9
12.3, 11.9, 11.7
10.9, 11.6, —c
2.7
a
GlcN
Xyl
9.6
9.6
9.2
6.5 3.1
6.1b
11.8
11.5
11.9
10.0 5.1
5.0 2.8
a
a
a
a
a
a
Gal
9.4
2.7
—
—
—
—
—
—
—
a
a
a
a
a
a
—
—
—
—
—
9.3
9.4
7.7
9.0
8.7
9.1
3.1
3.6
2.7
2.8
3.2
2.7
8.1
8.9
8.7
9.0
9.1
9.2
9.5
9.2
5.8 5.8
5.1 7.1
1.7 4.4
4.4 5.3
4.0 5.2
2.7 4.8
1.8 4.6
1.7 4.9
3.4 5.5
2.9 4.5
10.0
11.3
10.9
10.9
10.4
11.7
10.9
10.9
10.7
9.7
9.6
9.9
9.5
Glc
8.5
9.6
9.2
9.5
9.5
9.4
9.5
9.8
Man
1.0
a
—
0.7
1.2
10.0
5.9b
aCoupling constants were not determined due to the signal ovarlap.
bCoupling constants were affected by broadening of the signal due to hydroxyl proton.
cSignal appeared as a singlet.

K. Suzuki et al.
230
integral at d 4.42–4.40 (GalN3 þ GalN4 þ GalN6, H-1s) ¼ 1.66. Thus,
[GalN6] ¼ 1.66–1.39 ¼ 0.27.
GlcN: In a spectrum of a mixture, one of benzylidene methylene proton of
GlcN3 and H-6a of GlcN6 were separated, but none of the protons belonging
to GlcN4 was separated. The ratio of each compound was estimated as
follows:
[GlcN4] ¼ f[GlcN3] þ [GlcN4] þ [GlcN6]g 2 f[GlcN3] þ [GlcN6]g,
where [GlcN3] ¼ integral at d 4.70 (one of the benzylmethylene protons,
GlcN3) ¼ 0.37 and [GlcN6] ¼ integral at d 3.87 (H-6a, GlcN6) ¼ 1.00.
f[GlcN3] þ [GlcN4] þ [GlcN6]g ¼ integral at 4.46–4.43 (H-1s of three
compounds) ¼ 1.89. Thus, [GlcN4] ¼ 1.89–1.37 ¼ 0.52.
Xyl: Integrals of H-5 signals were used to obtain [Xyl2]:[Xyl3]:
[Xyl4] ¼ 1:3:2. Man: Integrals of H-1 signals were used to obtain
[Man2]:[Man3]:[Man4]:[Man6] ¼ 0.3:1:1.3:1.1.
Procedures
Phenyl 2-Azido-4,6-di-O-benzyl-2-deoxy-1-thio-b-D-galactopyrano-
side (GalN3), phenyl 2-azido-3,6-di-O-benzyl-2-deoxy-1-thio-b-D-galac-
topyranoside (GalN4), and phenyl 2-azido-3,4-di-O-benzyl-2-deoxy-1-
thio-b-D-galactopyranoside (GalN6). To a solution of phenyl 2-azido-2-
deoxy-1-thio-b-D-galactopyranoside (0.22 g, 0.75 mmol) dissolved in CH2Cl2
(50 mL) was added Bu4NHSO4 (0.051 g, 0.2 equiv.), 5% NaOH (3.0 mL,
5 equiv.), and BnBr (0.27 mL, 3 equiv.), and the resultant mixture was stirred
under gentle reflux (508C) overnight (18 hr). At that time, TLC indicated
approximately 70% conversion. The organic layer was washed with water,
dried with Na2SO4, and concentrated to dryness under vaccum. The residue
was subjected to a preparative TLC (6:1 toluene-EtOAc) to obtain dibenzylated
compounds, of which 1H NMR and COSYanalyses revealed the ratio of GalN3/
GalN4/GalN6 to be 1.4/3.6/1. Purification of the reaction mixture on silica gel
column chromatography using toluene-EtOAc (30:1) afforded tribenzyl
compound (50 mg, 13%), dibenzylated compounds, GalN3 (56 mg, 17%),
GalN4 (120 mg, 36%), and GalN6 (43 mg, 13%), and a mixture of monobenzy-
lated compounds (37 mg, 14%).
GalN3: m.p. 54.5–55.58C; [a]Dþ17.28C (c ¼ 1.02, CHCl3); 13C NMR
(CDCl3) d 138.0–127.6 (aromatic C), 86.5 (C-1), 77.4 (C-3), 75.2 (C-4), 75.1
(PhCH2), 74.2 (C-5), 73.6 (PhCH2), 68.1 (C-6), and 63.4 (C-2).
Anal. Calcd for C26H27N3O4S (477.58): C, 65.39; H, 5.70; N, 8.80. Found: C,
65.42; H, 5.76; N, 8.72.
GalN4: m.p. 77–788C; [a]D 230.58C (c ¼ 0.96, CHCl3); 13C NMR (CDCl3) d
137.7–127.7 (aromatic carbons), 86.2 (C-1), 81.0 (C-3), 77.0 (C-5), 73.6 and 71.9
(PhCH2 ꢁ 2), 69.3 (C-6), 65.5 (C-4), and 60.8 (C-2).
Anal. Calcd for C26H27N3O4S (477.58): C, 65.39; H, 5.70; N, 8.80. Found: C,
65.32; H, 5.80; N, 8.56.

Single-Step Multisyntheses of Glycosyl Acceptors
231
GalN6: m.p. 80.5–828C; [a]D 221.58C (c ¼ 1.03, CHCl3); 13C NMR (CDCl3)
d 138.0–127.8 (aromatic carbons), 86.4 (C-1), 82.6 (C-3), 78.9 (C-5), 74.1, and
72.7 (PhCH2 ꢁ 2), 71.8 (C-4), 62.1 (C-6), and 61.6 (C-2).
Anal. Calcd for C26H27N3O4S (477.58): C, 65.39; H, 5.70; N, 8.80. Found: C,
65.53; H, 5.84; N, 8.62.
Phenyl
2-Azido-4,6-di-O-benzyl-2-deoxy-1-thio-b-D-glucopyranoside
(GlcN3), phenyl 2-azido-3,6-di-O-benzyl-2-deoxy-1-thio-b-D-glucopyra-
noside (GlcN4), and phenyl 2-azido-3,4-di-O-benzyl-2-deoxy-1-thio-b-
D-glucopyranoside (GlcN6). To a solution of phenyl 2-azido-2-deoxy-1-thio-
b-D-glucopyranoside (1.1 g, 3.8 mmol) dissolved in CH2Cl2 (50 mL) was added
Bu4NHSO4 (0.26 g, 0.2 equiv.), 5% NaOH (15 mL, 5 equiv.), and BnBr (1.3 mL,
3 equiv.), and the resultant mixture was stirred under gentle reflux (508C) over-
night (15 hr). At that time, TLC indicated approximately 70% conversion. The
organic layer was washed with water, dried with Na2SO4, and concentrated to
dryness under vaccum. The residue was subjected to a preparative TLC (6:1
toluene-EtOAc) to obtain dibenzylated compounds, of which 1H NMR and
COSY analyses revealed the ratio of GlcN3/GlcN4/GlcN6 to be 1/1.5/2.8.
Purification of the reaction mixture on silica gel column chromatography
using toluene-EtOAc (30:1) afforded tribenzyl compound (17%), GlcN3 (13%),
a mixture of GlcN4 and GlcN6 (54%), and a mixture of monobenzylated com-
pounds (14%). A mixture of GlcN4 and GlcN6 (0.98 g, 2.1 mmol) was then dis-
solved in DMF (20 mL). To this solution, TBDMS-Cl (464 mg, 1.5 equiv.),
triethyamine (0.87 mL, 3 equiv.), and DMAP (0.12 mg, 0.5 equiv.) were added
and the resultant mixture was stirred for 30 min at rt. The mixture was
diluted with EtOAc and the organic layer was washed with water, dried over
Na2SO4, and concentrated to dryness under vacuum. The resultant residue
was subjected to silica gel column chromatography and eluted with toluene-
EtOAc (30:1) to afford GlcN4[24] (17%) and TBDMS-derivative of GlcN6. The
latter dissolved in THF (14 mL) was added to tetra-n-butylammonium
fluoride (TBAF, 1 mL, 2.5 equiv.) and the mixture was stirred at rt for 1 hr.
After evaporation of the solvent, purification of the residue on silica gel chrom-
atography using toluene-EtOAc (20:1) afforded GlcN6[25] (37%).
GlcN3: [a]D 231.48C (c ¼ 1.01, CHCl3); 13C NMR (CDCl3) d 138.2–127.7
(aromatic carbons), 86.1 (C-1), 79.1 (C-5), 77.3 (C-3), 77.3 (C-4), 74.8 and 73.5
(PhCH2 ꢁ 2), 68.8 (C-6), and 65.0 (C-2).
Anal. Calcd for C26H27N3O4S (477.58): C, 65.39; H, 5.70; N, 8.80. Found: C,
65.33; H, 5.71; N, 8.70.
Phenyl 3,4-di-O-benzyl-1-thio-b-D-xylopyranoside (Xyl2), phenyl 2,4-di-
O-benzyl-1-thio-b-D-xylopyranoside (Xyl3), and phenyl 2,3-di-O-
benzyl-1-thio-b-D-xylopyranoside (Xyl4). To a solution of phenyl 1-thio-b-
D-xylopyranoside (0.20 g, 0.83 mmol) dissolved in CH2Cl2 (10 mL) was added
Bu4NHSO4 (0.056 g, 0.2 equiv.), 5% NaOH (3.0 mL, 4.5 equiv.), and BnBr

K. Suzuki et al.
232
(0.23 mL, 2.3 equiv.), and the resultant mixture was stirred under gentle reflux
(508C) overnight (18 hr). At that time, TLC indicated approximately 70%
conversion. The organic layer was washed with water, dried with Na2SO4,
and concentrated to dryness under vaccum. The residue was subjected to a pre-
parative TLC (6:1 toluene-EtOAc) to obtain dibenzylated compounds, of which
1H NMR and COSYanalyses revealed the ratio of Xyl2/Xyl3/Xyl4 to be 1/3/2.
Purification of the reaction mixture on silica gel column chromatography using
toluene-EtOAc (30:1) afforded tribenzyl compound (9.2%), dibenzylated
compounds, Xyl2 (11%), Xyl3 (34%), and Xyl4 (25%), and a mixture of mono-
benzylated compounds (8.3%).
Xyl2: m.p. 73–748C; [a]D 21278C (c ¼ 0.99, CHCl3); 13C NMR (CDCl3) d
131.9–127.6 (aromatic carbons), 88.9 (C-1), 79.2 (C-3), 75.9 (C-4), 73.9 and
72.4 (PhCH2 ꢁ 2), 70.8 (C-2), and 63.4 (C-5).
Anal. Calcd for C25H26O4S (422.54): C, 71.06; H, 6.20. Found: C, 71.26; H,
6.28.
Xyl3: m.p. 80.5–81.58C; [a]D 215.38C (c ¼ 1.00, CHCl3); 13C NMR (CDCl3)
d 138.1–127.7 (aromatic carbons), 88.1 (C-1), 80.5 (C-2), 77.9 (C-3), 77.2 (C-4),
75.2 and 73.1 (PhCH2 ꢁ 2), and 67.5 (C-5).
Anal. Calcd for C25H26O4S (422.54): C, 71.06; H, 6.20. Found: C, 71.16;
H, 6.03.
Xyl4: m.p. 81.5–828C; [a]D 276.28C (c ¼ 1.02, CHCl3); 13C NMR (CDCl3) d
131.1–127.2 (aromatic carbons), 86.7 (C-1), 77.8 (C-3), 77.7 (C-2), 73.7 and 73.4
(PhCH2 ꢁ 2), 68.0 (C-4), and 64.6 (C-5).
Anal. Calcd for C25H26O4S (422.54): C, 71.06; H, 6.20. Found: C, 71.06;
H, 6.26.
Phenyl 3,4,6-Tri-O-benzyl-1-thio-b-D-galactopyranoside (Gal2), phenyl
2,4,6-tri-O-benzyl-1-thio-b-D-galactopyranoside (Gal3), phenyl 2,3,6-
tri-O-benzyl-1-thio-b-D-galactopyranoside (Gal4), and phenyl 2,3,4-
tri-O-benzyl-1-thio-b-D-galactopyranoside (Gal6). To
a solution of
phenyl 1-thio-b-D-galactopyranoside (0.20 g, 0.74 mmol) dissolved in CH2Cl2
(10 mL) was added Bu4NHSO4 (51 mg, 0.2 equiv.), 5% NaOH (4.1 mL,
7 equiv.), and BnBr (0.44 mL, 5 equiv.), and the resultant mixture was stirred
under gentle reflux (508C) overnight (16 hr). More BnBr (1 equiv.) was added
and stirred overnight. Further addition of 5% NaOH and BnBr (each
1 equiv. ꢁ 2) every 24 hr resulted in about 40% formation of tribenzylated
compounds. The organic layer was washed with water, dried with Na2SO4,
and concentrated to dryness under vaccum. The residue was subjected to a pre-
parative TLC (6:1 toluene-EtOAc) to obtain tribenzylated compounds, of which
1H NMR and COSYanalyses revealed the ratio of Gal2/Gal3/Gal4/Gal6 to be
1.2/6.2/5.1/1. Purification of the reaction mixture on silica gel column chrom-
atography using toluene-EtOAc (30:1) afforded tetrabenzyl compound (16%), a
mixture of Gal2, Gal3 and Gal4 (30%), Gal6 (4.5%), a mixture of dibenzylated

Single-Step Multisyntheses of Glycosyl Acceptors
233
compounds (20%), and a mixture of monobenzylated compounds (4%).
A mixture of tribenzyl compounds was separated by HPLC (Column: Inert
SIL C8-3, 5 mm [4.6 ꢁ 150 mm; GL Sciences Inc.]; Flow: 1.0 mL/min; Elution:
Gradient from hexane-EtOH (99:1) to hexane-EtOH (50:50) during 60 min;
Detection: 250 nm). Retension time for each compound was as follows:
Gal2[26] (6.0 min), Gal3[17] (6.4 min), Gal4[27] (6.5 min), and Gal6[28] (10 min).
Phenyl 3,4,6-Tri-O-benzyl-1-thio-b-D-glucopyranoside (Glc2), phenyl
2,4,6-tri-O-benzyl-1-thio-b-D-glucopyranoside (Glc3), phenyl 2,3,6-tri-
O-benzyl-1-thio-b-D-glucopyranoside (Glc4), and phenyl 2,3,4-tri-O-
benzyl-1-thio-b-D-glucopyranoside (Glc6). To a solution of phenyl 1-thio-
b-D-glucopyranoside (0.20 g, 0.74 mmol) dissolved in CH2Cl2 (10 mL) was
added Bu4NHSO4 (51 mg, 0.2 equiv.), 5% NaOH (4.1 mL, 7 equiv.), and BnBr
(0.44 mL, 5 equiv.), and the resultant mixture was stirred under gentle reflux
(508C) overnight (16 hr). More BnBr (1 equiv.) was added and stirred overnight.
Further addition of 5% NaOH and BnBr (each 1 equiv. ꢁ 2) every 24 hr resulted
in about 40% formation of tribenzylated compounds. The organic layer was
washed with water, dried with Na2SO4, and concentrated to dryness under
vaccum. The residue was subjected to a preparative TLC (6:1 toluene-EtOAc)
to obtain tribenzylated compounds, of which 1H NMR and COSY analyses
revealed the ratio of Glc2/Glc3/Glc4/Glc6 to be 1/4.8/1.1/3.6. Purification
of the reaction mixture on silica gel column chromatography using toluene-
EtOAc (30:1) afforded tetrabenzyl compound (20%), a mixture of Glc2 and
Glc3 (27%), a mixture of Glc4 and Glc6 (21%), and a mixture of dibenzylated
compounds (19%). A mixture of tribenzyl compounds was separated by HPLC
(Column: Inert SIL C8-3, 5 mm [4.6 ꢁ 150 mm; GL Sciences Inc.]; Flow:
1.0 mL/min; Elution: Hexane-EtOH (99:1); Detection: 250 nm). Retension
times for each compound were as follows; Glc2[29] (5.0 min), Glc3 (4.8 min),
Glc4[30] (7.8 min), and Glc6[31] (6.8 min).
Glc3: m.p. 89.5–908C; [a]D 26.568C (c ¼ 1.02, CHCl3); 13C NMR (CDCl3) d
138.2–127.5 (aromatic carbons), 87.1 (C-1), 80.6 (C-2), 78.8 (C-5), 78.7 (C-3),
77.4 (C-4), 75.2, 74.7 and 73.5 (PhCH2 ꢁ 3), and 69.1 (C-6).
Anal. Calcd for C33H34O5S (542.69): C, 73.04; H, 6.31. Found: C, 73.27; H,
6.16.
Phenyl 3,4,6-Tri-O-benzyl-1-thio-a-D-mannopyranoside (Man2), phenyl
2,4,6-tri-O-benzyl-1-thio-a-D-mannopyranoside (Man3), phenyl 2,3,6-
tri-O-benzyl-1-thio-a-D-mannopyranoside (Man4), and phenyl 2,3,4-tri-
O-benzyl-1-thio-a-D-mannopyranoside (Man6). To a solution of phenyl
1-thio-a-D-mannopyranoside (0.20 g, 0.74 mmol) dissolved in CH2Cl2 (10 mL)
was added Bu4NHSO4 (0.051g, 0.2 equiv.), 5% NaOH (4.1mL, 7 equiv.), and
BnBr (0.44 mL, 5 equiv.), and the resulted mixture was stirred under gentle
reflux (508C) overnight (16 hr). More BnBr (1equiv.) was added and stirred over-
night. Further addition of 5% NaOH and BnBr (each 1 equiv. ꢁ 2) every 24 hr

K. Suzuki et al.
234
resulted in about 40% formation of tribenzylated compounds. The organic layer
was washed with water, dried with Na2SO4, and concentrated to dryness under
vaccum. The residue was subjected to a preparative TLC (6:1 toluene-EtOAc) to
obtain tribenzylated compounds, of which 1H NMR and COSYanalyses revealed
the ratio of Man2/Man3/Man4/Man6 to be 0.3/1/1.3/1.1. Purification of the
reaction mixture on silica gel column chromatography using toluene-EtOAc
(30:1) afforded tetrabenzyl compound (8.6%), Man2[32] (1.1%), Man3[33] (20%),
Man4[34] (23%), Man6[35] (21%), a mixture of dibenzylated compounds (9.6%),
and a mixture of monobenzylated compounds (10%).
ACKNOWLEDGMENTS
We thank Dr. Y. Kanie for her critical disscussions on separation of a series of
product mixture by HPLC. This work was supported in part by Key Technology
Research Promotion Program, The New Energy and Industrial Development
Organization (NEDO), Ministry of Economy, Trade and Industry (METI) of
Japan.
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