Sequential one-pot glycosylation with glycosyl N-trichloroacetylcarbamate and trichloroacetate including dehydrative approach using 1-hydroxy sugars

Article abstract of DOI:10.1016/j.tet.2011.06.006

An efficient sequential one-pot glycosylation has been developed with glycosyl trichlorocarbamate and trichloroacetate activated by the same Lewis acid and enabled by a change in reaction temperature. The αα- selective glycosylation was achieved using glucose, galactose, and mannose substrates after investigation into the reactivities of the two types of glycosyl donors. Sequential one-pot dehydrative glycosylation, including in situ preparation of glycosyl donors followed by generation of two glycosyl bonds, provided three types of trisaccharide.

Full text of DOI:10.1016/j.tet.2011.06.006

Tetrahedron 67 (2011) 6482e6496
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Sequential one-pot glycosylation with glycosyl N-trichloroacetylcarbamate and
trichloroacetate including dehydrative approach using 1-hydroxy sugars
,
Tatsuya Shirahata a, Asami Kojima a, Satoko Teruya b, Jun-ichi Matsuo c y, Masaki Yokoyama a,
a
b
a
a
b,
*
ꢀ
Shogo Unagiike , Toshiaki Sunazuka , Kazuishi Makino , Eisuke Kaji , Satoshi Omura
,
Yoshinori Kobayashi a
,
*
a School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
b Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
c Center for Basic Research, The Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 April 2011
Received in revised form 31 May 2011
Accepted 2 June 2011
Available online 13 June 2011
An efficient sequential one-pot glycosylation has been developed with glycosyl trichlorocarbamate and
trichloroacetate activated by the same Lewis acid and enabled by a change in reaction temperature. The
aa-selective glycosylation was achieved using glucose, galactose, and mannose substrates after in-
vestigation into the reactivities of the two types of glycosyl donors. Sequential one-pot dehydrative
glycosylation, including in situ preparation of glycosyl donors followed by generation of two glycosyl
bonds, provided three types of trisaccharide.
Keywords:
Glycosylation
Ó 2011 Published by Elsevier Ltd.
Sequential one-pot glycosylation
Dehydrative approach
1. Introduction
are exploited to act either as a leaving group or as a protective
group at the anomeric position, resulting in formations of various
Over the past decades the importance of carbohydrates in the life
sciences has increased along with advances in glycochemistry and
glycobiology. For example, oligosaccharides have been found to play
fundamental roles in a series of life processes, such as recognition,
growth, function, and the survival of living cells. Carbohydrates re-
main a relatively undeveloped source of new drugs offering exciting
new therapeutic opportunities. Therefore, there is a need for sup-
plying oligosaccharides in sufficient quantities for biological studies.
The difficulty in obtaining pure oligosaccharides from natural sources
has created the need for new methods in the chemical synthesis of
carbohydrates.1,2 For example, a variety of efficient methods and
technologies have been developed for the synthesis of glycosides for
application in medicinal tools, such as adjuvants and vaccines.3,4 In
this regard, powerful glycosylation methods and innovative tech-
nologies have been disclosed,5 such as one-pot glycosylation.
types of sugars, such as blanched trisaccharides.6
Another approach is provided by the chemoselective strategy,
which takes advantage of the character of the protective groups of
glycosyl donors having the same type of leaving group at the
anomeric position. This concept has been achieved by exploiting
electron-donating protective groups (armed) and electron-with-
drawing protective groups (disarmed).7
Furthermore, another operation presented is a preactivation
strategy, which utilizes activation of a glycosyl donor in the absence
of the glycosyl acceptor to give a highly glycosylating species, which
is immediately treated with a second building block that is po-
tentially a glycosyl donor to provide a coupling saccharide, which
can be preactivated in situ for further glycosylation.8
These methods have some drawbacks in that activation of the
donors requires stoichiometric amounts of a promoter and per-
forming the experiments is not always convenient.
One efficient method utilized in glycochemistry is the orthog-
onal strategy, which is based on selective activation of one leaving
group over another. The two chemically different leaving groups
Recently, Iadonisi and co-workers reported on a new approach
inspired by the recognition of the well-differentiated activation
conditions of similarly protected glycosyl-trichloroacetylimidate
and (N-phenyl) trifluoroacetylimidate with various Lewis acids
as activators. This method allows to give oligosaccharides with
similar protective groups by simply changing the reaction tem-
perature and adding a Lewis acid at the start of the second step
efficiently.9
* Corresponding authors. E-mail addresses: omuras@insti.kitasato-u.ac.jp
ꢀ
(S. Omura), kobayashiy@pharm.kitasato-u.ac.jp (Y. Kobayashi).
y
Present address: Division of Pharmaceutical Sciences, Graduate School of Nat-
ural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa
920-1192, Japan.
0040-4020/$ e see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tet.2011.06.006

T. Shirahata et al. / Tetrahedron 67 (2011) 6482e6496
6483
We have described an efficient and straightforward procedure
for one-pot dehydrative glycosylation with glycosyl N-tri-
chloroacetylcarbamates prepared from the corresponding 1-
hydroxy sugars10 (Scheme 1).
2.1.2. Glycosylation of perbenzyloxy glycosyl trichloroacetyl donor.
With glycosyl donor 2 in hand, we next sought suitable conditions
for the sequential one-pot glycosylation by screening the activation
conditions for glycosylation of methyl 2,3,4-tri-O-benzoyl-D-glu-
copyranoside (3)14 (1.0 equiv) with 2 in CH2Cl2 over 5 A molecular
ꢁ
ꢁ
sieves (MS 5 A). Soft Lewis acids, such as Zn(OTf)2, AgOTf, Cu(OTf)2,
and Sc(OTf)3, were not able to activate donor 2 (Table 1, entries
1e4). However, the glycosylation proceeded moderately using
stoichiometric and catalytic amounts of SnCl4 (entries 5 and 6).
Decomposition of the glycosyl donor 2 with TfOH in the reaction
medium at room temperature, or even at ꢀ20 ꢁC, using a catalytic
amount of TfOH provided good result (entries 7e9). The use of
a stoichiometric amount of TMSOTf also achieved the glycosylation
at 0 ꢁC to afford a glucosyl 6,10-linked disaccharide 415 in good yield
Scheme 1. Stereoselective glycosylation with glycosyl trichloroacetylcarbamate.
In the next stage, we considered whether our convenient
methodology would allow sequential one-pot glycosylation, in-
cluding a dehydrative approach. Isodoli’s strategy is particularly
desirable in that glycosylation is afforded by a simple and conve-
nient procedure.9 In order to enhance the method using a glycosyl
carbamate donor, a glycosyl donor having weaker reactivity than
the carbamate donor in the reaction medium should be developed.
In this paper, we describe (i) the development of a partly pro-
tected glycosyl donor as a suitable coupling partner to glycosyl
carbamate to synthesize oligosaccharides, (ii) the establishment of
sequential one-pot glycosylation, and (iii) the achievement of se-
quential one-pot dehydrative glycosylation.
as a mixture of anomers (
a/b
¼68/32, anomeric ratio determined by
1H NMR in CDCl3) (entry 10). Employing a catalytic amount of
TMSOTf (0.2 equiv) similarly promoted the glycosylation (83% yield,
a/
b¼68/32, entry 11).
Table 1
Glycosylation with glycosyl trichloroacetate promoted by various Lewis acids
2. Results and discussion
2.1. Development of suitable glycosyl donor for sequential
one-pot glycosylation
2.1.1. Design and preparation of glycosyl N-trichloroacetate. A key
factor in establishing a successful sequential one-pot glycosylation
lies in the development of a suitable glycosyl donor as a coupling
partner to the glycosyl trichlorocarbamate donor. This coupling
partner must have less reactivity in the glycosylation to extend sac-
charide chain. The carbamate donor reacts with a hard Lewis acid due
to the electron-withdrawing nitrogen on the trichloroacetylcar-
bamate. In this regard, removal of the amide moiety including the
nitrogen on the trichloroacetylcarbamate leads to a trichloroacetyl
group.11 Having this functional group as a leaving group in the gly-
cosylation would be attractive for our purposes because of the facile
preparation and stability of the glycosyl donor as well as its reduced
reactivity in comparison to the glycosyl trichloroacetylcarbamate
donor possessing a similar protective group. To the best of our
knowledge, although glycosyl trichloroacetate donors protected with
acetyl and benzyl groups have been reported,12 perbenzylated donors
have not been investigated in terms of their reactivity and spectral
data.
Entry
Activator (equiv)
Temp
Time
Yielda
Ratiob
(a/b)
1
2
3
4
5
6
7
8
AgOTf
Cu(OTf)2
Zn(OTf)2
Sc(OTf)3
SnCl4
SnCl4
TfOH
TfOH
TfOH
(1.2)
rt
rt
rt
rt
rt
rt
2 h
2 h
2 h
2 h
4 h
4 h
30 min
1 h
1 h
NRc
NRc
NRc
NRc
52%
60%
48%
27%
83%
81%
83%
d
(1.2)
(1.2)
(1.2)
(1.2)
(0.2)
(1.2)
(1.2)
(0.2)
(1.2)
(0.2)
d
d
d
63/37
76/24
87/13
55/45
69/31
68/32
60/40
0
ꢁC
ꢀ20 ꢁC
9
10
11
0
0
0
ꢁC
ꢁC
ꢁC
TMSOTf
TMSOTf
20 min
30 min
a
Isolated yields.
b
c
Determined by 1H NMR (300 MHz) spectroscopy.
NR: no reaction.
Next, we explored the solvent effect for a-selective glycosyl-
ation16 of 3 with 2. Surprisingly the reaction did not proceed
when a stoichiometric amount of TMSOTf was employed at 0 ꢁC
in Et2O (Table 2, entry 1). On the other hand, good reactivity and
The preparation of glycosyl trichloroacetate donor 2 (
a
/b
¼83/17,
anomeric ratio determined by 1H NMR in CDCl3) was accomplished
by the reaction of 2,3,4,6-tetra-O-benzyl- -glucopyranose (1) (a/
D
¼86/14, anomeric ratio determined by 1H NMR in C6D6) with
a
-selectivity (
a
/
b
¼86/14) were observed for the glycosylation at
b
trichloroacetyl chloride13 in dry CH2Cl2 and pyridine at room
temperature (Scheme 2). The glycosyl donor 2 is stable for a couple
of months in a freezer.
room temperature in Et2O (entry 2). Furthermore, reducing the
amount of Lewis acid (0.2 equiv) gave similar results while
maintaining
a
-selectivity (
a
/
b
¼87/13, entry 3). To test the sta-
bility in a higher temperature medium, the glycosyl donor 2 was
applied to glycosylation at 40 ꢁC, resulting in good yield and
selectivity (84%,
amount of TMSClO4 was employed, the
slightly improved (
a
/
b
¼88/12, entry 4). When a stoichiometric
17
a
-selectivity ratio was
a
/
b
¼92/8, entry 5). Even a catalytic amount of
TMSClO4 catalyzed the glycosylation efficiently (entries 6 and 7).
However, the usage of TMSClO4 was not dramatically changed
their yields and ratios comparing with the using TMSOTf.
Meanwhile,
(entry 8).
b
-selective glycosylation18 in MeCN did not proceed
Scheme 2. Preparation of glycosyl trichloroacetate.

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T. Shirahata et al. / Tetrahedron 67 (2011) 6482e6496
Table 2
Glycosylation with glycosyl trichloroacetate (solvent effect)
Scheme 4. Synthetic plan for trisaccharide using glycosyl N-trichloroacetylcarbamate
5 and trichloroacetate 6.
Entry Activator (equiv)
Solvent Temp Time Yielda
Ratiob
(a/b)
2.2.2. Preparation of 6-OH glycosyl donor. Execution of the above
strategy required preparation of 6-OH glycosyl trichloroacetyl
glycosyl donor 6. Few reports describe the synthesis of 6-OH
glycosyl donors because it is difficult to find a protective
group that allows regioselective reaction between the more
reactive C6-OH and the anomeric hydroxy group. In addition,
liberation of the free 6-OH from the protected form might prove
difficult due to the presence of the sensitive leaving group at the
anomeric position.
One of the few reports on a 6-OH imidate donor was presented by
Fraser-Reid19, in which desilylation of 6-OTBDPS glycosyl imidate
with HF/pyridine provides conversion to the 6-OH glycosyl imidate
donor. We applied this method to the 6-OTBDPS glycosyl tri-
chloroacetate donor but obtained non-reproducible results, even
when using TBAF as a reagent for the deprotection, which suggests
that the trichloroacetyl donor is not stable in either acidic or basic
conditions. To allow deprotection in neutral conditions, the PMB
group was chosen as a suitable protective group at 6-OH (Scheme 5).
1
2
3
4
5
6
7
8
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSClO4
TMSClO4
TMSClO4
TMSOTf
(1.2)
(1.2)
(0.2)
(1.2)
(1.2)
(0.5)
(0.2)
(1.2)
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
MeCN
0
rt
rt
ꢁC
2 h
2 h
24 h 90%
84%
24 h 76%
24 h 87%
24 h 64%
NRc
85%
d
86/14
87/13
88/12
92/8
95/5
85/15
d
40 ꢁC 4 h
rt
rt
rt
rt
2 h
Decomposed
a
b
c
Isolated yields.
Determined by 1H NMR (300 MHz) spectroscopy.
NR: no reaction.
2.2. Development of sequential one-pot glycosylation
2.2.1. Synthetic plan for sequential one-pot glycosylation. Previous
research on the glycosyl carbamate 510 and the glycosyl tri-
chloroacetate 2 indicated a difference in reactivity of the glycosyl
donors when glycosylation was carried out in Et2O. For example,
the glycosyl carbamate 5 reacts at 0 ꢁC in Et2O, whereas the less
reactive glycosyl trichloroacetate donor only underwent glycosyl-
ation at room temperature (Scheme 3).
Scheme 5. Synthesis of 6-OH glycosyl donor 6.
The precursor 9, derived from penta-O-acetyl-b-D-glucopyrano-
side in seven steps according to previous reports,20 was treated with
trichloroacetyl chloride in the presence of pyridine to afford 2,3,4-tri-
Scheme 3. Difference in reactivity of two types of glycosyl donor 5.
Based on the distinct reactivities of the two glycosyl donors,
it was considered that a similar type of sequential one-pot
glycosylation to that reported by Iadonisi9 might be possible. As
illustrated in Scheme 4, we envisioned that the first step of
glycosylation would be carried out utilizing the glycosyl carba-
mate 5 and 6-OH glycosyl trichloroacetate 6 in the presence of
TMSOTf at 0 ꢁC to provide disaccharyl trichloroacetate 7. Sub-
sequently, addition of acceptor 3 and an increase in reaction
temperature to room temperature as the forcing condition
would initiate the second step and ideally provide trisaccharide
8 in a one-pot manner.
O-benzyl-6-O-p-methoxybenzyl-D-glucopyranosyl trichloroacetate
(10). Subsequently, the 6-OPMB group was deprotected with DDQ to
provide the desired 6-OH trichloroacetate donor 6 in good yield. In
this case, decomposition of sensitive 1-trichloroacetyl compounds
was not observed in the reaction medium. The reproducibility of this
reaction allowed for a reliable supply on the gram scale.
2.2.3. Attempt at sequential one-pot glycosylation. With 6-OH gly-
cosyl trichloroacetate 6 in hand, we attempted the sequential
one-pot glycosylation. This was performed by stirring with gly-
cosyl trichloroacetylcarbamate 5 (1.2 equiv) and 6 (1.0 equiv) in

T. Shirahata et al. / Tetrahedron 67 (2011) 6482e6496
6485
the presence of a stoichiometric amount of TMSOTf at 0 ꢁC until 6
was not detected by TLC, at which point the reaction medium
was warmed to ambient temperature and the acceptor 3 added.
The desired trisaccharide 8aa was slightly obtained; however,
the undesired disaccharide 9 was also yielded due to coupling
between 5 and 3. To prevent the side reaction, the reactivity of
glycosyl carbamate 5 was additively verified in the second-step
glycosylation. The structure of 8aa was determined by HMBC
experiments (cross peaks between C6-H and C-10, and between
C60-H and C-100), and from the coupling constants matching those
3
-glycoside (3JH1 ,H2 ¼3.8 Hz, JH1 ,H2 ¼3.5 Hz)
0
0
00
00
expected for an
(Scheme 6).
a
Scheme 7. Application of suitable conditions identified in Table 3 to the sequential
one-pot glycosylation. aAnomeric ratio was determined by HPLC [Senshu Pak PEGASIL
Silica 60e5 (4.6øꢂ250 mm), hexane/AcOEt¼3/2, UV at 254 nm, flow rate; 0.2 mL/min,
0
ꢁC].
A new side product 10 was identified from the crude product in
the previous reaction, explaining why the desired trisaccharide 8
was only obtained in moderated yields. These results suggested
that 10aa was produced by addition of 6-OH acceptor 6 instead of
addition of acceptor 3 to the intermediate 7
a as illustrated in
Scheme 8.
Scheme 6. First attempt at sequential one-pot glycosylation.
The key feature in our solution to the previous problem of the
undesired side reaction is to consume the glycosyl carbamate donor
in the first-step reaction. To explore conditions in which an excess
of the glycosyl acceptor is used in glycosylation with glycosyl car-
bamate, we re-examined the balance in amounts of glycosyl donor
5, glycosyl acceptor 3, and Lewis acid in the glycosylation (Table 3).
Changing the amount of the glycosyl acceptor 3 (entries 1e3)
revealed that 1.5 equiv of 3 was acceptable (entry 3). TLC analysis
showed that the reaction went to completion, providing 94% yield,
when an excess (1.5 equiv) of TMSOTf was used (entry 5).
Scheme 8. Mechanism for the generation of byproduct 10aa
.
To limit generation of 10 by the side reaction in the second gly-
cosylation, we used an excess of acceptor 3 in order to increase the
likelihoodofreactionbythedesiredpathwayandimprovetheyieldof
trisaccharide 8. Against our expectations, varying the amount of ac-
ceptor 3 gave similar results to that observed for 2.0 equiv (Table 4).
Table 3
Reaction conditions of glycosylation of 3 with glycosyl carbamate 5
Table 4
Sequential one-pot glycosylation (varying the amount of acceptor 3)
Entry Acceptor 2 (equiv) TMSOTf (equiv) Time (h) Yielda (%) Ratiob
(a/b)
1
2
3
4
5
1.0
1.2
1.5
1.5
1.5
1.0
1.0
1.0
1.2
1.5
20
5
4
5
4
85
86
85
82
94
91/9
88/12
88/12
84/16
86/14
Entry
Acceptor 3 (equiv)
Yielda (two steps) (%)
Ratiob
(aa/ab/ba/bb)
1
2
3
2.0
2.5
3.0
44
43
39
76/8/11/5
76/10/8/6
77/11/6/6
a
Isolated yields.
b
Determined by 1H NMR (300 MHz) spectroscopy.
a
Isolated yields.
b
Determined by HPLC [Senshu Pak PEGASIL Silica 60e5 (4.6øꢂ250 mm), hexane/
In practice, applying the conditions identified as suitable in
AcOEt¼3/2, UV at 254 nm, flow rate; 0.2 mL/min, 0 ꢁC].
Table 3 to the sequential one-pot glycosylation, that is, using
1.5 equiv of the acceptor and TMSOTf, reduced the generation of
undesired disaccharide 9, providing the trisaccharide 8 in moderate
yield (Scheme 7).
It is considered that the poor reactivity of acceptor 3 results in the
low observed yield of the desired trisaccharide 8 in sequential one-

6486
T. Shirahata et al. / Tetrahedron 67 (2011) 6482e6496
pot glycosylation. We expected that the desired glycosylation would
be accelerated in warmer reaction conditions at the second step.
Performing glycosylation at 30 ꢁC in the second step provided
trisaccharide 8 in improved yield (Table 5, entry 2, 50%). Furthermore,
the reaction smoothly proceeded under reflux conditions, providing
trisaccharide 8 in 72% yield with reasonable selectivity (entry 3).
perbenzylated galactosyl trichloroacetate 15, prepared from
2,3,4,6-tetra-O-benzyl- -galactopyranose (11), did not undergo
D
glycosylation with the galactosyl acceptor 13 at ꢀ20 ꢁC (entry 3). On
the other hand, the desired galactosyl disaccharide 14 could be
obtained by glycosylation at 0 ꢁC, providing 21% yield (entry 4). The
yield of 14 was further increased to 74% at ambient temperature
(entry 5). The significant differences identified in the reactivity
between the two types of donors, the galactosyl carbamate 12 and
the galactosyl trichloroacetate 15, indicated their suitability for
sequential one-pot glycosylation.
Table 5
Sequential one-pot glycosylation with glucose (changing the reaction temperature
in the second step)
2.3.2. Synthesis of 6-OH galactosyl donor. 2,3,4-Tri-O-benzyl-6-O-
p-methoxybenzyl-
in Scheme 9. A known thioglycoside 16
galactose in six steps according to previous reports.22 The 6-OH of
16 was masked with PMB group to derive the thioglycoside 17
Then the anomeric phenylthionyl moiety of 17 was oxidized to 18
D
-galactopyranose (18) was prepared as shown
b
was derived from (þ)-
D-
b
b.
b
having a 1-hydroxy group, followed by conversion into 6-OPMB 1-
trichloroacetate 19 as an anomeric mixture, which was separated
Entry
Temp
Time (h)
Yielda (two steps) (%)
Ratiob
(aa/ab/ba/bb)
by silica gel column chromatography to provide the stable
19 . Deprotection of the 6-OPMB group in 19 with DDQ according
to a similar protocol to that used in the glucose case gave the de-
sired 6-OH galactosyl donor 20a 23
a-isomer
1
2
3
rt
30 ꢁC
40 ꢁC
48
24
24
44
50
72
76/8/11/5
77/8/10/5
75/10/9/6
a
a
.
a
Isolated yields.
b
Determined by HPLC [Senshu Pak PEGASIL Silica 60e5 (4.6øꢂ250 mm), hexane/
AcOEt¼3/2, UV at 254 nm, flow rate; 0.2 mL/min, 0 ꢁC].
2.3. Sequential one-pot glycosylation with galactose
2.3.1. Investigating the reactivity for one-pot glycosylation of galac-
tosyl trichloroacetylcarbamate and galactosyl trichloroacetate. The
scope and limitations of the sequential one-pot glycosylation with
glycosyl N-trichloroacetylcarbamate and trichloroacetate were in-
vestigated by employing existing galactosyl and mannosyl building
blocks. Before attempting the sequential one-pot glycosylation, it is
necessary to first identify whether the glycosyl trichlorocarbamate
has a different reactivity from the trichloroacetate. Although the
preparation and glycosylation of galactosyl carbamate donor 12 has
already been described,10 we did not investigate the effect of re-
action temperature. The galactosyl donor 12 underwent glycosyl-
ation at ꢀ20 ꢁC in reaction with a known perbenzoylated galactosyl
acceptor 1321 in moderate yield (Table 6, entry 1). In contrast, the
Scheme 9. Synthesis of 6-OH galactosyl donor 20a.
2.3.3. Sequential one-pot galactosylation. With the three galactosyl
building blocks in hand, we attempted the sequential one-pot
galactosylation (Table 7). On the basis of the results of our in-
vestigations into the galactosyl carbamate 12 and the galactosyl
Table 7
Table 6
Sequential one-pot galactosylation
Reaction conditions of galactosyl carbamate 12 and trichloroacetate 15
Entry
Donor
Temp
Time (h)
Yielda
Ratiob
(a/b)
1
2
3
4
5
12
12
15
15
15
ꢀ20 ꢁC
2
2
9
2
14
56%
37%
NRc
21%
74%
68/32
70/30
d
Entry
Temp
Acceptor 13 (equiv)
Yielda (%)
Ratiob
(aa/ab/ba/bb)
0 ꢁ
C
ꢀ20 ꢁC
1
2
3
ꢀ20 ꢁC
2.0
2.0
3.0
68
56
53
44/23/22/11
45/22/22/11
43/23/22/12
0
ꢁC
73/27
73/27
0
0
ꢁC
ꢁC
rt
a
a
Isolated yields.
Isolated yields.
b
c
b
Determined by 1H NMR (400 MHz) spectroscopy.
NR: no reaction.
Determined by HPLC [Senshu Pak PEGASIL silica SP 100 (4.6øꢂ250 mm), hex-
ane/AcOEt¼4/1, UV at 254 nm, flow rate; 1.0 mL/min, rt].

T. Shirahata et al. / Tetrahedron 67 (2011) 6482e6496
6487
trichloroacetate 15, we envisaged performing the first-step glyco-
sylation at ꢀ20 ꢁC and completing the second-step glycosylation at
ambient temperature.
ꢀ20 ꢁC proceeded in moderate yield even after a long reaction
time (entry 5); no glycosylated product was observed by TLC after
4 h. Glycosylation could be completed in a shorter reaction time by
further increasing the reaction temperature to 0 ꢁC, with a similar
yield as the former reaction (entry 6). The mannosylation with 27
was completed at room temperature within 1 h to give a mannosyl
Glycosylation of the galactosyl trichloroacetate 20
a with the
galactosyl carbamate 15 was carried out at ꢀ20 ꢁC in the presence
ꢁ
of MS 5 A and a stoichiometric amount of TMSOTf for the first
coupling. Subsequently, addition of the galactosyl acceptor 13, and
warming to ambient temperature provided the desired galactosyl
disaccharide 26 in good yield and
a
selectivity (91%,
a
/
b
¼91/9,
entry 7). These results indicate that the difference in reactivity
between the two types of donors, the carbamate 24 and the tri-
chloroacetate 27, is sufficient, as shown by completion of the first-
step reaction in 4 h at ꢀ20 ꢁC.
trisaccharide 22 in 68% yield with reasonable anomeric ratios (aa
ab ba
bb¼44/23/22/11, Table 7, entry 1).
Because it was expected that the galactosyl carbamate 15 would
/
/
/
have better reactivity at 0 ꢁC than ꢀ20 ꢁC, the first coupling was
performed at 0 ꢁC, providing trisaccharide 22 in reduced yield (56%,
entry 2). In order to increase the reactivity in the second step,
3.0 equiv of the acceptor 13 was used, although a similar result to
entry 2 was obtained (53%, entry 3).
2.4.2. Synthesis of 6-OH mannosyl donor. Preparation of 2,3,
4-tri-O-benzyl-6-O-p-methoxybenzyl-
chloroacetate (32) is illustrated in Scheme 10. A partly protected
thiomannoside 28, the precursor of a 6-OH mannosyl donor 32 was
D
-mannnopyranosyl
tri-
Having higher reactivity than the glucose equivalent, the ga-
lactosyl carbamate 15 proved suitable for reaction at a lower tem-
perature in the first step. The structure of 22aa was determined by
HMBC experiments (cross peaks between C6-H and C-10, and be-
prepared in six steps from
ports.25 The 6-hydroxy group of 28
to provide 29 , followed by oxidative conversion of the phenylthio
group to give the anomeric OH group in 30 . A 1-trichloroacetyl
group was introduced using trichloroacetyl chloride to give the
fully protected sugar 31. After removal of the PMB group, the de-
sired 6-OH mannosyl donor 32 was identified by TLC analysis in the
reaction medium, but isolation of the product 32 failed. Because the
mannosyl 6-OH donor 32 is sensitive to many factors (e.g., acid,
base, and water), a non-aqueous work-up was accomplished by
quenching with anhydrous Na2SO4 followed by quick filtration
through silica gel and a Celite pad to remove any excess reagents
and the hydrated Na2SO4.
D
-mannose according to previous re-
a
was masked with a PMB group
a
a
tween C60-H and C-100), and from the coupling constants
3
(3JH1 ,H2 w3.5 Hz, JH1 ,H2 w3.5 Hz) matching those expected for an
0
0
00
00
a
-glycoside.
2.4. Sequential one-pot glycosylation with mannose
2.4.1. Investigating the reactivity for one-pot glycosylation of mannosyl
trichloroacetylcarbamate and mannosyl trichloroacetate. The man-
nosyl trichlorocarbamate and trichloroacetate were investigated
for their suitability in sequential one-pot glycosylation as in the
galactose study. The mannosyl carbamate 2410 reacted slightly
with the acceptor 2524 at ꢀ40 ꢁC to obtain 26 (Table 8, entry 1),
and was successfully glycosylated at higher temperatures (ꢀ20 ꢁC
and 0 ꢁC) with improved yield and anomeric ratio (entries 2 and
3). The mannosyl trichloroacetate 27 was derived from 2,3,4,6-
tetra-O-benzyl- -mannopyranose (23) by the usual procedure
D
and glycosylation was performed at the same temperature
(ꢀ40 ꢁC) at which mannosyl carbamate 24 was activated. How-
ever, in this case no product was obtained (entry 4). Reaction at
Scheme 10. Synthesis of 6-OH mannosyl donor 32.
Table 8
Reaction conditions for mannosyl carbamate 24 and trichloroacetate 27
2.4.3. Sequential one-pot mannosylation. With the mannosyl
building blocks in hand, one-pot mannosylation was investigated
based on the results on the reactivities of the two types of
mannosyl donors. The 6-OH mannosyl trichloroacetate 32 was
glycosylated with mannosyl carbamate 24 at ꢀ20 ꢁC in the
presence of a stoichiometric amount of Lewis acid followed by
addition of perbenzoylated mannosyl acceptor 25 to furnish the
desired trisaccharide 34 in moderate yield with good aa selec-
tivity (Table 9, entry 1). A warmer temperature at the first-step
glycosylation reduced the yield of 34 and produced the un-
desirable tetrasaccharide 35 due to over-glycosylation of di-
saccharide 33 with 32 at 0 ꢁC, followed by the addition of
acceptor 25 (entry 2).
Entry
Donor
Temp
Time (h)
Yielda
Ratiob
(a/b)
On the other hand, glycosylation with a catalytic amount of
Lewis acid was able to be performed, and although the yield was
moderate, it was comparable to that obtained with a stoichiometric
amount of the activator (entry 3).
1
2
3
4
5
6
7
24
24
24
27
27
27
27
ꢀ40 ꢁC
5
2
2
3
18
4
14%
70%
75%
NRc
45%
52%
91%
58/42
69/31
75/25
d
ꢀ20 ꢁC
0
ꢁC
ꢀ40 ꢁC
ꢀ20 ꢁC
75/25
76/24
91/9
The structure of mannose trisaccharide 34 was confirmed as
0
ꢁC
a
-configuration by HMBC experiments based on connections be-
rt
1
tween C6-H and C-10, and between C60-H and C-100, as well as GATE-
a
Isolated yields.
I [1JC,H¼168.7 Hz (99.24 ppm, d) for C10 and JC,H¼168.4 Hz
1
b
c
Determined by 1H NMR (400 MHz) spectroscopy.
NR: no reaction.
(99.15 ppm, d) for C100].

6488
T. Shirahata et al. / Tetrahedron 67 (2011) 6482e6496
Table 9
Sequential one-pot mannosylation
Scheme 11. Sequential one-pot dehydrative glycosylation. aAnomeric ratio was de-
termined by HPLC [Senshu Pak PEGASIL Silica 60e5 (4.6øꢂ250 mm), hexane/AcOEt¼3/
2, UV at 254 nm, flow rate; 0.2 mL/min, 0 ꢁC].
Entry
Temp (ꢁC)
TMSOTf (equiv)
Yielda (%)
Ratiob
(aa/ab/ba/bb)
1
2
3
ꢀ20
0
ꢀ20
1.0
1.0
0.2
52
37
53
71/14/13/2
75/10/9/6
70/12/12/6
a
Isolated yields.
b
Determined by HPLC [Senshu Pak PEGASIL silica SP 100 (4.6øꢂ250 mm), hex-
ane/AcOEt¼4/1, UV at 254 nm, flow rate; 0.5 mL/min, rt].
2.5. Sequential one-pot dehydrative glycosylation
Sequential one-pot glycosylations have usually been performed
after preparation of the individual glycosides as donors and ac-
ceptors. It would be advantageous to derive the glycosyl carbamate
from the corresponding 1-hydroxy glycose in situ, followed by ac-
tivation, as in so-called dehydrative glycosylation reported by
Gin.26 From this perspective, one-pot glycosylation using glycosyl
carbamates could offer a convenient new technology in which the
glycosyl donor is prepared and activated in situ to allow synthesis
of various trisaccharides in the same flask.
Scheme 12. Sequential one-pot dehydrative galactosylation. aAnomeric ratio was de-
termined by HPLC [Senshu Pak PEGASIL silica SP 100 (4.6øꢂ250 mm), hexane/
AcOEt¼4/1, UV at 254 nm, flow rate; 1.0 mL/min, rt].
In this sequential one-pot dehydrative glycosylation starting
from 1, a very slightly excess of trichloroacetyl isocyanate was
used in pre-glycosylation to prepare the carbamate 5 in situ, fol-
lowed by the addition of 6, a Lewis acid, and 3, resulting in tri-
saccharide 10 (Scheme 11). Our glycosylation procedure involving
preparation of the glycosyl donor in a one-pot procedure was
therefore successful.
Furthermore, galactosyl trisaccharide 22 was obtained in 71%
yield from 1-hydroxy galactose derivative 11 by a one-pot dehy-
drative technique, which is a better yield than that obtained with
the usual one-pot procedure employing the galactosyl carbamate
15 (Scheme 12).
Similarly, the mannosyl trisaccharide 34 was also synthesized in
71% yield from 1-hydroxy mannose 23 in 3 steps by one-pot
dehydrative glycosylation (Scheme 13).
We believe that, in the galactose and mannose cases, a higher
yield was obtained for the dehydrative reaction as compared to the
reaction starting from the corresponding carbamate because less
decomposition of the unstable glycosyl carbamates occurred dur-
ing the reactions.
Scheme 13. Sequential one-pot dehydrative mannosylation. aAnomeric ratio was de-
termined by HPLC [Senshu Pak PEGASIL silica SP 100 (4.6øꢂ250 mm), hexane/
AcOEt¼4/1, UV at 254 nm, flow rate; 0.5 mL/min, rt].
situ from the corresponding 1-hydroxy sugars enabled the se-
quential one-pot dehydrative glycosylation, produce various tri-
saccharides. The efficient implementation of the present
glycosylation approach, in particular for the sequential one-pot
dehydrative glycosylation, would be useful in the synthesis of
a variety of oligosaccharides.
3. Conclusion
In conclusion, we have demonstrated sequential one-pot gly-
cosylation using glycosyl donors with different reactivities (i.e.,
glycosyl carbamate and trichloroacetate) and enabled by a change
in reaction temperature. Derivation of the glycosyl carbamate in

T. Shirahata et al. / Tetrahedron 67 (2011) 6482e6496
6489
4. Experimental
4.1. General
128.16, 128.04, 127.97, 127.93, 127.91, 127.85, 127.81, 127.70, 95.68
(C-1), 89.78 (eCCl3), 81.04 (C-3), 78.84 (C-2), 76.40 (C-4), 75.69
(eCH2Ph), 75.40 (eCH2Ph), 73.85 (C-5), 73.51 (eCH2Ph), 73.46
(eCH2Ph), 67.68 (C-6); IR (NaCl) cmꢀ1
n: 3030.6, 2923.6, 3867.6,
All reactions were carried out under argon atmosphere in dried
glassware, unless otherwise noted. All reagents were purchased
from Tokyo Kasei Kogyo, Kanto Chemical, Fluka or Aldrich compa-
nies and used without further purification, unless otherwise noted.
Dry THF, toluene, and CH2Cl2 were purchased from Kanto Chemical
Co. Diethyl ether was freshly distilled from sodium and benzophe-
none. Precoated silica gel plates with a fluorescent indicator (Merck
60 F254) were used for analytical and preparative thin layer chro-
matography. Flash column chromatography was carried out with
Kanto Chemical silica gel (Kanto Chemical, silica gel 60N, spherical
neutral, 0.040e0.050 mm, Cat.-No. 37 563-84). Powdered and pre-
1771.3, 1496.5, 1454.1, 1361.5, 1241.0, 1072.2; HR-MS (FAB-pos, NBA
matrix) m/z 709.1323 [M]þ, calcd for C36H35O7Cl3: 709.1325 [M].
4.2.2. Typical procedure for glycosylation of 2,3,4,6-tetra-O-benzyl-
glucopyranosyl N-trichloroacetylcarbamate to obtain disaccharide;
methyl 2,3,4-tri-O-benzoyl-6-O-(2,3,4,6-tetra-O-benzyl- -gluco-
pyranosyl)- -glucopyranoside (4 and 4 ) (Table 1, entry 11). To
D-
a,b-D
a
-
D
a
b
ꢁ
ꢁ
a stirred suspension of MS 5 A (101.3 mg, MS 5 A/acceptor¼3 g/
1 mmol), 2 (30.7 mg, 0.0403 mmol), and acceptor 3 (17.4 mg,
0.0336 mmol) in dry CH2Cl2 (1.5 mL) was added TMSOTf (2.0 mL,
0.0067 mmol) at 0 ꢁC. After the reaction mixture was stirred at 0 ꢁC
for 30 min, the reaction was quenched by adding satd NaHCO3
solution and the mixture was filtered though Celite pad. The filtrate
was extracted with AcOEt, and the combined organic extracts were
washed with H2O and brine, dried over anhydrous Na2SO4, and
concentrated. The crude product was purified by preparative TLC
(silica gel, 10/1 benzene/AcOEt) to afford known disaccharide 4
1
ꢁ
ꢁ
dried molecular sieves 4 A, and 5 A were used in glycosylation. H
NMR spectra were recorded at 300, 400, and 600 MHz and 13C NMR
spectra were recorded at 75 or 100, 150 MHz on Varian VXR-300
(300 MHz), Varian XL-400 (400 MHz), Varian UNITY-400
(400 MHz), or Varian INOVA (600 MHz) spectrometers. The chem-
ical shifts are expressed in parts per million downfield from the
internal solvent peaks for CHCl3 (7.26 ppm, 1H NMR), CH3OH (3.31,
(31.1 mg, 0.0302 mmol, 83%,
a
/
b
¼60/40) as colorless oil. The
4.84 ppm, 1H NMR), C6H6 (7.27 ppm, 1H NMR), CDCl3 (77.0 ppm, 13
C
anomeric ratio was determined by 1H NMR (300 MHz).
NMR), CD3OD (49.0 ppm, 13C NMR), or C6D6 (128.0 ppm, 13C NMR)
and J values are given in Hertz. The coupling patterns are denoted s
(singlet), d (doublet), dd (double doublet), ddd (double double
doublet), t (triplet), dt (double triplet), q (quartet), m (multiplet), or
br (broad). High-performance liquid chromatography (HPLC) was
carried out using a Senshu UVevis Detector (SSC-5410) and Senshu
HPLC-pump (SSC-3461, UV; 254 nm) with Senshu Pak PEGASIL Silica
60e5 (normal phase: 4.6øꢂ250 mm) and Senshu Pak PEGASIL Silica
SP 100 (normal phase: 4.6øꢂ250 mm). All infrared spectra were
measured on a JASCO FT/IR-460 spectrometer. High- and low-
resolution mass spectra were measured on a JEOL JMS-T100 LP and
JEOL JMS-AX505 HA spectrometer. Optical rotations were measured
by using JASCO DIP-370 polarimeter. A 0.1 M solution of TMSClO4 in
Et2O was prepared as below; to a solution of AgClO4 (38.4 mg,
Compound
4a
:
Rf¼0.44 (hexane/AcOEt¼4/1ꢂ4); 1H NMR
(300 MHz, CDCl3)
d
: 7.99e7.93 (m, 4H, PheH), 7.88e7.84 (m, 2H,
PheH), 7.54e7.11 (m, 29H, PheH), 6.14 (t, J¼9.7 Hz, 1H, 3-H), 5.52
(dd, J¼10.4, 9.7 Hz, 1H, 4-H), 5.24e5.19 (m, 2H, 1-H, 2-H), 4.91 (d,
J¼11.0 Hz, 1H, eCH2Ph), 4.82 (d, J¼11.0 Hz, 1H, eCH2Ph), 4.77 (d,
J¼11.0 Hz, 1H, eCH2Ph), 4.76 (d, J¼12.3 Hz, 1H, eCH2Ph), 4.74 (d,
J¼3.5 Hz, 1H, 10-H), 4.62 (d, J¼12.3 Hz, 1H, eCH2Ph), 4.54 (d,
J¼12.0 Hz, 1H, eCH2Ph), 4.45 (d, J¼11.0 Hz, 1H, eCH2Ph), 4.37 (d,
J¼12.0 Hz, 1H, eCH2Ph), 4.32 (ddd, J¼10.4, 6.7, 2.1 Hz, 1H, 5-H), 3.96
(t, J¼9.2 Hz, 1H, 3-H), 3.88e3.83 (m, 2H, 6-H), 3.66e3.61 (m, 2H, 40-
H, 50-H), 3.58 (dd, J¼11.0, 2.5 Hz, 1H, 60-H), 3.53 (dd, J¼9.7, 3.5 Hz,
1H, 20-H), 3.50 (dd, J¼11.0, 2.1 Hz, 1H, 60-H), 3.43 (s, 3H, eOCH3).
Compound
(300 MHz, CDCl3),
4
b
:
d
Rf¼0.53 (hexane/AcOEt¼4/1ꢂ4); 1H NMR
: 7.99e7.91 (m, 4H, PheH), 7.86e7.83 (m, 2H,
185
189
m
m
mol) in Et2O (1.85 mL) at 0 ꢁC was added TMSCl (20.5 mg,
mol) and this mixture was stirred. After the mixture was left
PheH), 7.54e7.12 (m, 29H, PheH), 6.17 (t, J¼9.7 Hz, 1H, 3-H), 5.47 (t,
J¼9.7 Hz, 1H, 4-H), 5.25 (dd, J¼9.7, 3.5 Hz, 1H, 2-H), 5.20 (d,
J¼3.5 Hz, 1H, 1-H), 5.06 (d, J¼10.8 Hz, 1H, eCH2Ph), 4.91 (d,
J¼11.0 Hz, 1H, eCH2Ph), 4.80 (d, J¼11.0 Hz, 1H, eCH2Ph), 4.76 (d,
J¼11.0 Hz, 1H, eCH2Ph), 4.68 (d, J¼10.8 Hz, 1H, eCH2Ph), 4.53 (d,
J¼12.3 Hz, 1H, eCH2Ph), 4.51 (d, J¼11.0 Hz, 1H, eCH2Ph), 4.47 (d,
J¼7.8 Hz, 1H, 10-H), 4.43 (d, J¼12.3 Hz, 1H, eCH2Ph), 4.41e4.34 (m,
1H, 50-H), 4.12 (dd, J¼11.0, 2.1 Hz, 6-H), 3.81 (dd, J¼11.0, 7.5 Hz, 6-H),
3.67e3.56 (m, 4H, 20-H, 30-H, 40-H, 50-H), 3.48e3.43 (m, 2H, 60-H),
3.37 (s, 3H, eOCH3).
standing for 10 min without stirring, the supernatant was used for
glycosylation as a catalyst.
4.2. Development of suitable glycosyl donor for the
sequential one-pot glycosylation
4.2.1. 2,3,4,6-Tetra-O-benzyl-
and 2 ). To a stirred solution of 2,3,4,6-tetra-O-benzyl-
pyranose (1) (48.3 mg, 0.089 mmol) in dry CH2Cl2 (1.0 mL) were
added trichloroacetyl chloride (21.9 L, 0.200 mmol) and pyridine
(23.3 L, 0.300 mmol). After reaction mixture was stirred at room
D
-glucopyranosyl trichloroacetate (2
a
b
D-guluco-
m
4.3. Development of sequential one-pot glycosylation
m
temperature for 2 h, the solvent was evaporated in vacuo with
toluene as an azeotropic solvent. The crude product was purified by
flash column chromatography (hexane/AcOEt¼10/1) to afford 2
4.3.1. 2,3,4-Tri-O-benzyl-6-O-p-methoxybenzyl-
trichloroacetate (10 and 10 ). To a stirred solution of 2,3,4,6-tetra-
O-benzyl- -gulucopyranose (9) (50.0 mg, 0.088 mmol) in dry
CH2Cl2 were added trichloroacetyl chloride (19.1 L, 0.175 mmol)
and pyridine (21.2 L, 0.263 mmol). After reaction mixture was
a,b-D-glucopyranosyl
a
b
a,b-D
(57.2 mg, 0.096 mmol, 96%,
a/b
¼83/17) as yellow syrup. The
m
anomeric ratio was determined by 1H NMR (400 MHz).
a
: Rf¼0.56
m
(hexane/AcOEt¼2/1);
[
a 23
]
þ58.4 (c 1.01, CHCl3); 1H NMR
stirred at room temperature for 3 h, the solvent was evaporated in
vacuo with toluene as an azeotropic solvent. The crude product was
purified by flash column chromatography (hexane/AcOEt¼10/1) to
D
(400 MHz, CDCl3)
d
: 7.34e7.25 (m, 18H, PheH), 7.17e7.13 (m, 2H,
PheH), 6.37 (d, J¼3.5 Hz, 1H, 1-H), 4.92 (d, J¼11.0 Hz, 1H, eCH2Ph),
4.85 (d, J¼10.8 Hz, 1H, eCH2Ph), 4.82 (d, J¼10.8 Hz, 1H, eCH2Ph),
4.72 (d, J¼11.5 Hz, 1H, eCH2Ph), 4.68 (d, J¼11.5 Hz, 1H, eCH2Ph),
4.60 (d, J¼11.9 Hz, 1H, eCH2Ph), 4.52 (d, J¼11.0 Hz, 1H, eCH2Ph),
4.48 (d, J¼11.9 Hz, 1H, eCH2Ph), 3.96 (t, J¼9.4 Hz, 1H, 3-H), 3.95
(ddd, J¼10.0, 2.5, 2.0 Hz, 1H, 5-H), 3.78 (dd, J¼10.0, 9.4 Hz, 1H, 4-H),
3.77 (dd, J¼11.0, 2.5 Hz, 1H, 6-H), 3.76 (dd, J¼9.4, 3.5 Hz, 1H, 2-H),
afford 10 (57.9 mg, 0.081 mmol, 92%,
a
/
b
¼71/29) as yellow syrup.
The anomeric ratio was determined by 1H NMR (400 MHz).
Compound 10
a
: Rf¼0.67 (hexane/AcOEt¼3/1); [a 31
þ46.0 (c
]
D
1.03, CHCl3); 1H NMR (400 MHz, CDCl3)
d: 7.28e7.17 (m, 15H,
PheH), 7.11e7.05 (m, 2H, PheH), 6.82e6.77 (m, 2H, PheH), 6.32 (d,
J¼3.4 Hz, 1H, 1-H), 4.87 (d, J¼10.9 Hz, 1H, eCH2Ph), 4.78 (d,
J¼10.4 Hz, 1H, eCH2Ph), 4.77 (d, J¼10.9 Hz, 1H, eCH2Ph), 4.67 (d,
J¼11.6 Hz, 1H, eCH2Ph), 4.63 (d, J¼11.6 Hz, 1H, eCH2Ph), 4.51 (d,
3.66 (dd, J¼11.0, 2.0 Hz, 1H, 6-H); 13C NMR (100 MHz, CDCl3)
d:
160.34, 138.29, 137.79, 137.59, 137.37, 128.43, 128.42, 128.37, 128.28,

6490
T. Shirahata et al. / Tetrahedron 67 (2011) 6482e6496
J¼11.6 Hz, 1H, eCH2Ph), 4.43 (d, J¼10.4 Hz, 1H, eCH2Ph), 4.35 (d,
J¼11.6 Hz, 1H, eCH2Ph), 3.91 (t, J¼9.5 Hz, 1H, 3-H), 3.49 (ddd,
J¼10.0, 2.7, 1.8 Hz, 1H, 5-H), 3.72 (dd, J¼10.0, 9.5 Hz, 1H, 4-H), 3.72
(s, 3H, eOCH3), 3.71 (dd, J¼9.5, 3.4 Hz, 1H, 2-H), 3.69 (dd, J¼11.1,
2.7 Hz, 1H, 6-H), 3.69 (dd, J¼11.1, 1.8 Hz, 1H, 6-H).; 13C NMR
J¼10.0 Hz, 1H, 3-H), 6.23 (t, J¼10.0 Hz, 1H, 4-H), 5.60 (dd, J¼10.0,
3.8 Hz,1H, 2-H), 5.43 (d, J¼3.8 Hz,1H,1-H), 5.28 (d, J¼3.5 Hz,1H,100-
H), 5.26 (d, J¼11.0 Hz, 1H, eCH2Ph), 5.20 (d, J¼11.0 Hz, 1H, eCH2Ph),
5.16 (d, J¼11.0 Hz,1H, eCH2Ph), 5.11 (d, J¼11.0 Hz,1H, eCH2Ph), 5.02
(d, J¼11.0 Hz, 1H, eCH2Ph), 5.00 (d, J¼11.0 Hz, 1H, eCH2Ph), 4.99 (d,
J¼11.0 Hz, 1H, eCH2Ph), 4.95 (d, J¼3.8 Hz, 1H, 10-H), 4.78 (d,
J¼11.0 Hz, 1H, eCH2Ph), 4.70 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.65 (d,
J¼12.0 Hz, 1H, eCH2Ph), 4.60 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.57 (d,
J¼12.0 Hz, 1H, eCH2Ph), 4.55 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.50e4.37
(m, 2H, 30-H, 5-H), 4.48 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.41 (t,
J¼10.0 Hz, 1H, 300-H), 4.16e4.08 (m, 4H, 40-H, 50-H, 60-H, 500-H), 4.05
(dd, J¼11.0, 5.0 Hz, 1H, 6-H), 3.96 (dd, J¼10.0, 8.0 Hz, 1H, 400-H),
3.90e3.86 (m, 1H, 60-H), 3.84 (dd, J¼11.0 Hz, 4.0 Hz, 1H, 600-H), 3.73
(dd, J¼11.0, 2.0 Hz, 1H, 600-H), 3.70 (dd, J¼11.0, 1.0 Hz, 1H, 6-H), 3.69
(dd, J¼10.0, 3.5 Hz, 1H, 200-H), 3.64 (dd, J¼10.0, 3.8 Hz, 1H, 20-H),
(100 MHz, CDCl3) d: 160.34, 159.35, 138.33, 137.82, 137.39, 129.70,
129.61, 128.46, 128.41, 128.38, 128.37, 128.02, 127.98, 127.97, 127.94,
127.93, 127.89, 127.70, 113.82, 95.72 (C-1), 89.79 (eCCl3), 81.06 (C-
3), 78.81 (C-2), 76.40 (C-4), 75.68 (eCH2Ph), 75.38 (eCH2Ph), 73.83
(C-5), 73.46 (eCH2Ph), 73.12 (eCH2Ph), 67.17 (C-6), 55.20 (eOCH3);
IR (NaCl) cmꢀ1
n: 3030.6, 2909.1, 1770.3, 1512.9, 1245.8, 1072.2; HR-
MS (FAB-pos, NBA matrix) m/z 739.1419[M]þ, calcd for C37H37O8Cl3:
739.1431 [M].
4.3.2. 2,3,4-Tri-O-benzyl-
a solution of 10 (50.0 mg, 0.065 mmol) in CH2Cl2 (616
(34 L) at ambient temperature was added DDQ (22.1 mg,
a,b-D-glucopyranosyl trichloroacetate (6). To
mL) and H2O
3.23 (s, 3H, eOCH3); 13C NMR (100 MHz, C6D6)
d: 166.7 (eCOPh),
m
166.3 (eCOPh), 165.8 (eCOPh), 140.3, 140.2, 139.9, 139.7, 139.7,
139.5, 133.6, 133.3, 130.6, 130.6, 130.4, 130.2, 130.1, 129.1, 129.0,
129.0, 128.9, 128.9, 128.9, 128.8, 128.8, 128.5, 128.3, 128.1, 128.0,
128.0, 127.9, 127.9, 127.8, 98.1 (C-10), 97.9 (C-1), 97.8 (C-100), 82.6 (C-
30), 82.5 (C-300), 81.6 (C-20), 81.6 (C-200), 78.8 (C-400), 78.5 (C-40), 76.0
(eCH2Ph), 75.9 (eCH2Ph), 75.6 (eCH2Ph), 75.5 (eCH2Ph), 73.9
(eCH2Ph), 73.3 (eCH2Ph), 73.2 (C-2), 72.9 (eCH2Ph), 71.9 (C-50),
71.8 (C-3), 71.6 (C-500), 70.3 (C-4), 69.9 (C-600), 69.8 (C-5), 66.9 (C-6),
66.1 (C-60), 55.7 (eOCH3); HR-MS (FAB, NBA matrix) m/z 1483.5774
[M]þ, calcd for C89H88O19Na: 1483.5818 [M].
0.098 mmol) in one portion. The reaction mixture was stirred at
ambient temperature for 3 h. After this mixture was diluted with
CH2Cl2 (1 mL), the resultant mixture was filtered through Celite pad,
rinsed with CH2Cl2 (10 mL). The resultant mixture was washed with
satd aq NaHCO3 (20 mL). This satd aq NaHCO3 layer was extracted
with CH2Cl2 (20 mL). The combined organic layer was dried with
sodium sulfate, filtered, and concentrated under reduced pressure.
Flash column chromatography (hexane/AcOEt¼3/1/1/1) afforded 6
(39.3 mg, 0.060 mmol, 93%,
a
/
b
¼53/47) as a colorless oil.
Compound 6
a
: Rf¼0.33 (hexane/AcOEt¼2/1); [a 26
]
þ61.5 (c 1.03,
Compound 8ab: Rf¼0.29 (hexane/AcOEt¼2/1), 0.44 (toluene/
D
CHCl3); 1H NMR (400 MHz, CDCl3)
d: 7.38e7.25 (m, 15H, PheH),
AcOEt¼10/1ꢂ4); [a 27
]
þ26.1 (c 1.10, CHCl3); 1H NMR (400 MHz,
6.29 (d, J¼3.5 Hz, 1H, 1-H), 4.94 (d, J¼11.0 Hz, 1H, eCH2Ph), 4.90 (d,
J¼11.0 Hz, 1H, eCH2Ph), 4.85 (d, J¼11.0 Hz, 1H, eCH2Ph), 4.71e4.66
(m, 3H, eCH2Ph), 3.99 (t, J¼9.4 Hz, 1H, 3-H), 3.85 (dt, J¼10.0, 2.9 Hz,
1H, 5-H), 3.81 (dd, J¼12.5z, 2.9 Hz,1H, 6-H), 3.74 (dd, J¼12.5, 2.9 Hz,
1H, 6-H), 3.71 (dd, J¼9.4, 3.5 Hz, 1H, 2-H), 3.67 (dd, J¼10.0, 9.4 Hz,
C6D6)
d
: 8.29e8.26D(m, 2H, PheH), 8.16e8.10 (m, 4H, PheH),
7.67e7.64 (m, 1H, PheH), 7.60e7.58 (m, 1H, PheH), 7.49e6.90 (m,
42H, PheH), 6.81 (t, J¼10.0 Hz, 1H, 3-H), 6.06 (t, J¼10.0 Hz, 1H, 4-H),
5.69 (dd, J¼10.0, 3.8 Hz,1H, 2-H), 5.44 (d, J¼3.8 Hz,1H each, 1-H,100-
H), 5.24 (d, J¼11.0 Hz, 1H, eCH2Ph), 5.22 (d, J¼11.0 Hz, 1H, eCH2Ph),
5.12 (d, J¼11.0 Hz,1H, eCH2Ph), 5.11 (d, J¼11.0 Hz, 1H, eCH2Ph), 5.10
(d, J¼12.0 Hz, 1H, eCH2Ph), 4.99 (d, J¼11.0 Hz, 1H, eCH2Ph), 4.94 (d,
J¼12.0 Hz, 1H, eCH2Ph), 4.93 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.92 (d,
J¼11.0 Hz, 1H, eCH2Ph), 4.80 (d, J¼11.0 Hz, 1H, eCH2Ph), 4.76 (d,
J¼11.0 Hz, 1H, eCH2Ph), 4.70 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.61 (d,
J¼7.5 Hz, 1H, 10-H), 4.53 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.48 (ddd,
J¼10.0, 6.0, 2.0 Hz,1H, 5-H), 4.44 (d, J¼12.0 Hz,1H, eCH2Ph), 4.39 (t,
J¼9.0 Hz, 1H, 300-H), 4.30 (dd, J¼11.0, 2.0 Hz, 6-H), 4.18 (ddd, J¼10.0,
4.0, 2.0 Hz, 1H, 6-H), 4.10e4.05 (m, 2H, 40-H, 60-H), 4.00 (dd, J¼12.0,
1.5 Hz, 1H, 60-H), 3.95 (dd, J¼11.0, 6.0 Hz, 1H, 6-H), 3.90 (dd, J¼10.0,
9.0 Hz, 1H, 4000-H), 3.86 (dd, J¼10.0, 4.0 Hz, 1H, 600-H), 3.79 (dd, J¼9.0,
6.0 Hz, 1H, 3 -H), 3.77 (dd, J¼10.0, 2.0 Hz, 1H, 600-H), 3.71 (dd, J¼9.0,
3.8 Hz, 1H, 200-H), 3.60 (dd, J¼9.0, 7.5 Hz, 1H, 20-H), 3.40 (ddd, J¼9.0,
3.0, 1.5 Hz, 1H, 50-H), 3.22 (s, 1H, eOCH3); 13C NMR (100 MHz, C6D6)
1H, 4-H); 13C NMR (100 MHz, CDCl3)
d:160.44,138.19,137.65,137.31,
128.54, 128.47, 128.37, 128.19, 128.08, 128.01, 127.97, 127.88, 127.73,
95.39 (C-1), 89.68 (eCCl3), 80.89 (C-3), 78.88 (C-2), 78.91 (C-4),
75.68 (eCH2Ph), 75.34 (eCH2Ph), 74.54 (C-5), 73.52 (eCH2Ph),
61.06 (C-6); IR (NaCl) cmꢀ1
n: 3448.1, 2924.5, 1771.3, 1240.0, 1072.2;
HR-MS (FAB-pos, NBA matrix) m/z 617.0861 [M]þ, calcd for
C29H29O7Cl3: 617.0877 [M].
4.3.3. Methyl 2,3,4,6-tetra-O-benzyl-
tri-O-benzyl- -glucopyranosyl-(1/6)-2,3,4-tri-O-benzoyl-
glucopyranoside (8aa) (Table 5, entry 3). To a stirred suspension of
a-D-glucopyranosyl-(1/6)-2,3,4-
a
-
D
a-D-
ꢁ
ꢁ
MS 5 A (103.6 mg, MS 5 A/acceptor¼3 g/1 mmol), 5 (30.6 mg,
0.0412 mmol), and acceptor 6 (41.4 mg, 0.0618 mmol) in dry Et2O
(1.5 mL) was added TMSOTf (12 m
L, 0.0618 mmol) at 0 ꢁC. The re-
action mixture was stirred at 0 ꢁC for 4 h. A solution of acceptor 3
(42.3 mg, 0.0824 mmol) in Et2O was added, and then reaction
temperature was allowed to raise up to ambient temperature. The
reaction mixture was stirred at that temperature and warmed up to
40 ꢁC, and stirred for 24 h. The reaction mixture was quenched by
adding satd NaHCO3 solution, and filtered through Celite pad. The
filtrate was extracted with AcOEt, and the combined organic ex-
tracts were washed with H2O and brine, dried over anhydrous
Na2SO4, and concentrated. The crude product was purified by
preparative TLC (hexane/AcOEt¼2/1), (toluene/AcOEt¼10/1ꢂ4) to
d: 166.6 (eCOPh), 166.4 (eCOPh), 166.0 (eCOPh), 140.2, 140.0, 139.9,
139.7, 139.7, 139.4, 130.6,130.5, 130.4, 130.1,130.0, 130.0, 129.1,129.1,
128.9, 128.9, 128.9, 128.8, 128.8, 128.7, 128.6, 128.3, 128.3, 128.0,
128.0, 127.9, 127.8, 104.6 (C-10), 98.0 (C-100), 97.9 (C-1), 85.3 (C-600),
83.3 (C-20), 82.5 (C-300), 81.6 (C-200), 78.8 (C-400), 78.0 (C-40), 76.1 (C-
50), 75.9 (eCH2Ph), 75.9 (eCH2Ph), 75.5 (eCH2Ph), 75.4 (eCH2Ph),
75.3 (eCH2Ph), 73.9 (eCH2Ph), 73.0 (C-2), 72.7 (eCH2Ph), 71.7 (C-3),
71.6 (C-500), 70.7 (C-4), 70.2 (C-5), 70.0 (C-30), 68.7 (C-60), 66.2 (C-6),
55.8 (eOCH3). HR-MS (FAB, NBA matrix) m/z 1483.5787 [M]þ, calcd
for C89H88O19Na: 1483.5818 [M].
afford trisaccharide 8 (43.6 mg, 0.0298 mmol, 72%, aa
/ab
/ba
/
Compound 8bb: Rf¼0.35 (hexane/AcOEt¼2/1), 0.32 (toluene/
bb¼75/10/9/6, two steps) as colorless oil. The anomeric ratio was
determined by HPLC analysis [Senshu Pak PEGASIL Silica 60e5
(4.6øꢂ250 mm), hexane/AcOEt¼3/2, UV at 254 nm, flow rate;
0.2 mL/min, 0 ꢁC].
AcOEt¼10/1ꢂ4); [a 26
]
þ21.0 (c 0.85, CHCl3); 1H NMR (400 MHz,
C6D6)
d
: 8.28e8.25D(m, 2H, PheH), 8.14e8.10 (m, 4H, PheH),
7.62e7.58 (m, 4H, PheH), 7.53e7.50 (m, 2H, PheH), 7.46e7.40 (m,
4H, PheH), 7.36e6.86 (m, 34H, PheH), 6.79 (t, J¼10.0 Hz, 1H, 3-H),
5.95 (t, J¼10.0 Hz,1H, 4-H), 5.66 (dd, J¼10.0, 3.8 Hz,1H, 2-H), 5.39 (d,
J¼3.8 Hz,1H,1-H), 5.30 (d, J¼11.5 Hz,1H, eCH2Ph), 5.26 (d, J¼11.5 Hz,
1H, eCH2Ph), 5.25 (d, J¼11.5 Hz, 1H, eCH2Ph), 5.10 (d, J¼11.5 Hz, 1H,
eCH2Ph), 5.08 (d, J¼11.5 Hz, 1H, eCH2Ph), 5.02 (d, J¼11.5 Hz, 1H,
Compound 8aa: Rf¼0.29 (hexane/AcOEt¼2/1), 0.47 (toluene/
AcOEt¼10/1ꢂ4); [a 25
]
þ31.5 (c 1.10, CHCl3); 1H NMR (400 MHz,
C6D6)
d
: 8.29e8.25D(m, 2H, PheH), 8.19e8.16 (m, 2H, PheH),
8.14e8.11 (m, 2H, PheH), 7.52e6.87 (m, 44H, PheH), 6.78 (t,

T. Shirahata et al. / Tetrahedron 67 (2011) 6482e6496
6491
eCH2Ph), 4.95 (d, J¼11.5 Hz, 1H, eCH2Ph), 4.91 (d, J¼12.0 Hz, 1H,
eCH2Ph), 4.88 (d, J¼11.5 Hz, 1H, eCH2Ph), 4.87 (d, J¼11.5 Hz, 1H,
eCH2Ph), 4.74 (d, J¼8.0 Hz,1H,10-H), 4.71 (d, J¼11.5 Hz,1H, eCH2Ph),
4.68 (d, J¼7.8 Hz, 1H, 100-H), 4.63 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.61 (d,
J¼12.0 Hz, 1H, eCH2Ph), 4.55 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.54 (ddd,
J¼10.0, 6.0, 3.0 Hz, 1H, 5-H), 4.41 (dd, J¼11.5, 3.0 Hz, 1H, 6-H), 4.39
(dd, J¼11.0, 2.0 Hz,1H, 600-H), 3.99(dd, J¼11.5, 6.0 Hz,1H, 6-H), 3.94(t,
J¼9.0 Hz,1H, 30-H), 3.93 (dd, J¼11.0, 6.0 Hz,1H, 600-H), 3.90e3.83 (m,
3H, 40-H), 3.80 (t, J¼9.0 Hz, 1H, 300-H), 3.73 (dd, J¼9.0, 8.0 Hz, 1H, 20-
H), 3.70e3.67 (m,1H, 500-H), 3.68 (dd, J¼9.0, 7.8 Hz,1H, 200-H), 3.61 (t,
J¼9.0 Hz,1H, 400-H), 3.61e3.57 (m,1H, 50-H), 3.20 (s, 3H, eOCH3); 13C
J¼11.9 Hz, 1H, eCH2Ph), 4.69 (d, J¼11.9 Hz, 1H, eCH2Ph), 4.60 (d,
J¼11.7 Hz, 1H, eCH2Ph), 4.50 (br dd, J¼8.2, 3.5 Hz, 1H, 5-H), 4.40 (d,
J¼11.7 Hz, 1H, eCH2Ph), 4.37 (d, J¼7.8 Hz, 1H, 10-H), 4.35 (d,
J¼11.7 Hz, 1H, eCH2Ph), 4.04 (dd, J¼10.7, 3.5 Hz, 1H, 60-Ha), 3.89 (br
d, J¼2.9 Hz, 1H, 40-H), 3.83 (dd, J¼9.8, 7.8 Hz, 1H, 20-H), 3.77 (dd,
J¼10.7, 8.2 Hz, 1H, 60-Hb), 3.57e3.48 (m, 3H, 5-H, 6-H), 3.49 (dd,
J¼9.8, 2.9 Hz, 1H, 30-H), 3.38 (s, 3H, eOCH3); 13C NMR (100 MHz,
CDCl3) d: 166.1 (eOCOPh), 165.5 (eOCOPh), 165.4 (eOCOPh), 138.7,
138.6, 138.5, 137.8, 133.4, 133.3, 133.0, 129.9, 129.8, 129.7, 129.33,
129.27, 129.2, 128.6, 128.41, 128.39, 128.32, 128.25, 128.2, 128.1, 127.9,
127.8, 127.6, 127.52, 127.49, 104.2 (C-10), 97.4 (C-1), 81.9 (C-30), 79.6
(C-20), 75.2 (eCH2Ph), 74.5 (eCH2Ph), 73.5 (eCH2Ph), 73.3 (C-40), 73.4
(C-5), 72.9 (eCH2Ph), 69.9 (C-4), 69.6 (C-2), 68.9 (C-60), 68.7 (2C, C-3,
NMR (100 MHz, C6D6) d: 166.6 (eCOPh), 166.3 (eCOPh), 166.0
(eCOPh), 140.1, 139.9, 139.9, 139.8, 139.7, 139.5, 139.4, 133.6, 133.3,
130.6, 130.6, 130.3, 130.2, 130.0, 130.0, 129.0, 129.0, 128.9, 128.9,
128.8,128.8,128.7,128.4,128.3,128.2,128.1,128.0,128.0,127.9,127.9,
105.0 (C-10), 104.5 (C-100), 97.7 (C-1), 85.6 (C-30), 85.4 (C-300), 83.2 (C-
200), 83.1 (C-20), 79.0 (C-400), 78.8 (C-40), 76.0 (eCH2Ph, C-500), 75.9
(eCH2Ph), 75.7 (C-50), 75.4 (eCH2Ph), 75.3 (eCH2Ph), 75.2
(eCH2Ph), 75.1 (eCH2Ph), 74.0 (eCH2Ph), 73.0 (C-2), 71.7 (C-3), 71.2
(C-4), 70.0 (C-5), 69.9 (C-60), 69.4 (C-600), 69.1 (C-6), 55.8 (eOCH3);
HR-MS (FAB, NBA matrix) m/z 1483.5774 [MþNa]þ, calcd for
C89H88O19Na: 1483.5818 [M].
C-6), 68.3 (C-50), 55.6 (eOCH3); IR (NaCl) cmꢀ1
n: 2869.6, 1726.9,
1600.6, 1452.1, 1283.4, 1094.4. HR-MS (FAB-pos, NBA matrix) m/z
1051.3881 [MþNa]þ, calcd for C62H60O14Na: 1051.3870 [MþNa].
4.4.2. 2,3,4,6-Tetra-O-benzyl-
(15). To a stirred solution of 2,3,4,6-tetra-O-benzyl-
anose (11) (43.3 mg, 0.080 mmol) in dry CH2Cl2 were added tri-
chloroacetyl chloride (15.0 L, 0.138 mmol) and pyridine (15.0 L,
a,
b
-D-galactopyranosyl trichloroacetate
D-galactopyr-
m
m
0.184 mmol). After the reaction mixture was stirred at room tem-
perature for 1 h, the solvent was evaporated in vacuo with toluene
as an azeotropic solvent. The crude product was purified by column
chromatography (hexane/AcOEt¼5/1) to give 15 (52.9 mg,
4.4. Sequential one-pot glycosylation with galactose
4.4.1. Glycosylation with galactosyl carbamate 12: methyl 2,3,4-tri-
0.089 mmol, 97%,
a
/
b
¼67/33) as a yellow oil. The anomeric ratio
O-benzoyl-6-O-(2,3,4,6-tetra-O-benzyl-
a
,
b
-
D
-galactopyranosyl)-
a
-
D
-
was determined by 1H NMR (400 MHz).
galactopyranoside (14) (Table 6, entry 2). The glycosylation was
performed according to the typical procedure employing the car-
bamate donor 12 (30.7 mg, 0.0505 mmol), acceptor 13 (21.6 mg,
Compound 15
a
: Rf¼0.71 (hexane/AcOEt¼2/1); [a 26
þ53.5 (c
]
1.09, CHCl3); 1H NMR (400 MHz, CDCl3)
d
: 7.40e7.2D6 (m, 20H,
PheH), 6.42 (d, J¼3.3 Hz, 1H, 1-H), 4.99 (d, J¼11.3 Hz, 1H, eCH2Ph),
4.81 (d, J¼11.9 Hz, 1H, eCH2Ph), 4.75 (d, J¼11.9 Hz, 1H, eCH2Ph),
4.75 (br d, 2H, eCH2Ph), 4.60 (d, J¼11.3 Hz, 1H, eCH2Ph), 4.50 (d,
J¼11.7 Hz, 1H, eCH2Ph), 4.43 (d, J¼11.7 Hz, 1H, eCH2Ph), 4.25 (dd,
J¼9.8, 3.3 Hz, 1H, 2-H), 4.13 (ddd, J¼7.2, 5.9, 1.2 Hz, 1H, 5-H), 4.07
(dd, J¼2.7, 1.2 Hz, 1H, 4-H), 3.94 (dd, J¼9.8, 2.7 Hz, 1H, 3-H), 3.61
(dd, J¼9.4, 7.2 Hz, 1H, 6-Ha), 3.57 (dd, J¼9.4, 5.9 Hz, 1H, 6-Hb); 13C
0.0421 mmol), and TMSOTf (9
The anomeric mixture of the disaccharide 14 (30.3 mg,
m
L, 0.0505 mmol) at ꢀ20 ꢁC for 2 h.
0.0294 mmol, 56%,
a
/
b
¼68/32) was obtained as a colorless oil after
purification by preparative TLC (hexane/AcOEt¼2/1).
Compound 14
a
: Rf¼0.21 (hexane/AcOEt¼2/1); [a 30
ꢀ13.1 (c
]
D
1.06, CHCl3); 1H NMR (400 MHz, CDCl3)
d: 8.06e8.02 (m, 2H,
PheH), 8.00e7.96 (m, 2H, PheH), 7.80e7.76 (m, 2H, PheH),
7.60e7.55 (m, 1H, PheH), 7.53e7.47 (m, 1H, PheH), 7.46e7.19 (m,
27H, PheH), 5.97 (dd, J¼10.4, 3.5 Hz, 1H, 3-H), 5.93 (dd, J¼3.5,
1.0 Hz, 1H, 4-H), 5.62 (dd, J¼10.4, 3.5 Hz, 1H, 2-H), 5.23 (d, J¼3.5 Hz,
1H, 1-H), 4.92 (d, J¼11.6 Hz, 1H, eCH2Ph), 4.78 (d, J¼11.6 Hz, 1H,
eCH2Ph), 4.77 (d, J¼3.5 Hz, 1H, 10-H), 4.72 (d, J¼11.6 Hz, 1H,
eCH2Ph), 4.70 (d, J¼11.9 Hz, 1H, eCH2Ph), 4.66 (d, J¼11.9 Hz, 1H,
eCH2Ph), 4.56 (d, J¼11.6 Hz, 1H, eCH2Ph), 4.50 (d, J¼11.9 Hz, 1H,
eCH2Ph), 4.46 (ddd, J¼6.7, 5.7, 1.0 Hz, 1H, 5-H), 4.41 (d, J¼11.9 Hz,
1H, eCH2Ph), 4.04 (dt, J¼6.7, 1.0 Hz, 1H, 50-H), 4.01 (dd, J¼10.2,
3.5 Hz, 1H, 20-H), 3.95 (dd, J¼2.7, 1.0 Hz, 1H, 40-H), 3.90 (dd, J¼10.2,
2.7 Hz,1H, 30-H), 3.79 (dd, J¼10.7, 6.7 Hz,1H, 6-Ha), 3.69 (dd, J¼10.7,
5.7 Hz, 1H, 6-Hb), 3.51 (br d, J¼6.7 Hz, 2H, 60-H), 3.35 (s, 3H,
NMR (100 MHz, CDCl3) d: 160.3 (eOCOCCl3), 138.4, 138.1, 137.8,
137.6, 128.4, 128.34, 128.29, 128.2, 128.1, 128.0, 128.92, 127.88,
127.85, 127.80, 127.75, 127.72, 127.69, 127.62, 127.55, 127.5, 96.6 (C-
1), 89.9 (eOCOCCl3), 77.6 (C-3), 75.3 (C-2), 74.9 (eCH2Ph), 74.2 (C-
4), 73.52 (eCH2Ph), 73.48 (eCH2Ph), 73.0 (C-5), 72.9 (eCH2Ph), 68.1
(C-6); IR (NaCl) cmꢀ1
n: 3030.6, 2920.7, 2869.6, 1771.3, 1496.5,
1454.1, 1240.0, 1106.0; HR-MS (FAB-pos, NBA matrix) m/z 709.1325
[MþNa]þ, calcd for C36H35O735Cl237ClNa: 709.1323 [MþNa].
Compound 15
b
: Rf¼0.61 (hexane/AcOEt¼2/1); [a 30
þ16.8 (c
]
1.05, CHCl3); 1H NMR (400 MHz, CDCl3)
d
: 7.41e7.2D2 (m, 20H,
PheH), 5.62 (d, J¼8.0 Hz, 1H, 1-H), 4.94 (d, J¼11.3 Hz, 1H, eCH2Ph),
4.84e4.72 (m, 4H, eCH2Ph), 4.63 (d, J¼11.3 Hz, 1H, eCH2Ph),
4.50e4.39 (m, 1H, eCH2Ph), 4.08 (dd, J¼9.6, 8.0 Hz, 1H, 2-H), 4.00
(dd, J¼2.9, 1.0 Hz, 1H, 4-H), 3.76 (ddd, J¼7.2, 5.7, 1.0 Hz, 1H, 5-H),
3.67 (dd, J¼9.4, 7.2 Hz, 1H, 6-Ha), 3.64 (dd, J¼9.6, 2.9 Hz, 1H, 3-H),
eOCH3); 13C NMR (100 MHz, CDCl3)
d: 166.1 (eOCOPh), 165.6
(eOCOPh), 165.4 (eOCOPh), 138.8, 138.6, 138.5, 138.1, 133.4, 133.3,
133.0, 129.9, 139.8, 139.7, 139.4, 139.30, 129.25, 128.6, 128.4, 128.3,
128.2, 128.1, 127.8, 127.7, 127.6, 127.50, 127.45, 127.4, 98.2 (C-10), 97.4
(C-1), 78.6 (C-30), 76.3 (C-20), 75.1 (C-40), 74.7 (eCH2Ph), 73.34
(eCH2Ph), 73.31 (eCH2Ph), 72.9 (eCH2Ph), 69.63 (2C, C-50, C-4),
69.60 (C-2), 68.8 (C-60), 68.4 (C-3), 67.7 (C-5), 66.8 (C-6), 55.5
3.62 (dd, J¼9.4, 5.7 Hz, 1H, 6-Hb); 13C NMR (100 MHz, CDCl3)
d:
160.7 (eOCOCCl3), 138.3, 137.9, 137.8, 137.6, 128.43, 128.35, 128.3,
128.2, 128.1, 128.0, 127.94, 127.87, 127.80, 127.76, 127.7, 127.6, 98.6
(C-1), 89.4 (eOCOCCl3), 81.9 (C-3), 77.5 (C-2), 75.4 (eCH2Ph), 74.9
(eCH2Ph), 74.8 (C-5), 73.5 (eCH2Ph), 73.03 (C-4), 72.96 (eCH2Ph),
(eOCH3), IR (NaCl) cmꢀ1
n
: 2924.5, 1727.9, 1601.6, 1494.6, 1453.1,
67.8 (C-6). IR (NaCl) cmꢀ1
n: 3030.6, 2921.6, 2871.5, 1778.1, 1496.5,
1282.4, 1095.4; HR-MS (FAB-pos, NBA matrix) m/z 1051.3881
1454.1, 1230.4, 1102.1; HR-MS (FAB-pos, NBA matrix) m/z 709.1325
[MþNa]þ, calcd for C62H60O14Na: 1051.3871 [MþNa].
[MþNa]þ, calcd for C36H35O735Cl237ClNa: 709.1307 [MþNa].
Compound 14
b
: Rf¼0.20 (hexane/AcOEt¼2/1); [a 21
þ98.8 (c 0.45,
]
CHCl3); 1H NMR (400 MHz, CDCl3)
d
: 8.09e8.03 (Dm, 2H, PheH),
4.4.3. Glycosylation of galactosyl trichloroacetate 15: methyl 2,3,4-
8.00e7.95 (m, 2H, PheH), 7.80e7.76 (m, 2H, PheH), 7.64e7.57 (m,
1H, PheH), 7.54e7.18 (m, 28H, PheH), 5.95 (dd, J¼10.7, 3.5 Hz, 1H, 3-
H), 5.90 (dd, J¼3.5, 1.0 Hz, 1H, 4-H), 5.64 (dd, J¼10.7, 3.5 Hz, 1H, 2-H),
5.27 (d, J¼3.5 Hz, 1H, 1-H), 5.00 (d, J¼10.7 Hz, 1H, eCH2Ph), 4.93 (d,
J¼11.7 Hz, 1H, eCH2Ph), 4.74 (d, J¼10.7 Hz, 1H, eCH2Ph), 4.73 (d,
tri-O-benzoyl-6-O-(2,3,4,6-tetra-O-benzyl-
a,b-D-galactopyranosyl)-
a-D
-galactopyranoside (14) (Table 6, entry 5). The glycosylation was
performed according to the typical procedure employing tri-
chloroacetate donor 15 (20.2 mg, 0.034 mmol), acceptor 13
(14.2 mg, 0.028 mmol), and TMSOTf (6 mL, 0.034 mmol) at room

6492
T. Shirahata et al. / Tetrahedron 67 (2011) 6482e6496
temperature for 14 h. The anomeric mixture of the disaccharide 14
(25.8 mg, 0.0251 mmol, 74%,
oil after purification by preparative TLC (hexane/AcOEt¼2/1).
128.23, 128.20, 128.16, 128.14, 128.09, 127.9, 127.7, 127.53, 127.52,
a
/b
¼73/27) was obtained as a colorless
127.47, 127.4, 113.74, 113.71, 97.7 (C-1
80.7 (C-2 ), 78.7 (C-3 ), 76.5 (C-2 ), 75.0 (eCH2Ph), 74.7 (C-4
74.6 (eCH2Ph), 74.5 (eCH2Ph), 73.5 (C-4 ), 73.4 (C-5
(eCH2Ph), 73.1 (eCH2Ph), 73.0 (eCH2Ph), 72.8 (eCH2Ph, 2C), 69.4
(C-5 ), 68.6 (C-6 ), 68.5 (C-6
), 55.2 (eOCH3, 2C). IR (NaCl) cmꢀ1
b), 91.8 (C-1
a), 82.1 (C-3
b),
b
a
a
a),
b
b), 73.3
4.4.4. Phenyl 2,3,4-tri-O-benzyl-6-O-p-methoxybenzyl-1-thio-b-D-
galactopyranoside (17)22. To a solution of phenyl 2,3,4-tri-O-
a
a
b
n:
benzyl-1-thio-
b
-
D
-galactopyranoside (16) (5.87 g, 10.8 mmol) in
3417.2, 3029.6, 2911.0, 1612.2, 1512.9, 1454.1, 1098.3; HR-MS
(FAB-pos, NBA matrix) m/z 593.2526 [MþNa]þ, calcd for
C35H38O7Na: 593.2515 [MþNa].
DMF (100 mL) was added NaH (564 mg, 12.9 mmol, 55% disp.)
followed by PMBCl (1.61 mL, 11.9 mmol). The reaction mixture
was stirred at room temperature for 6 h, and quenched with
H2O. The resultant mixture was extracted with AcOEt. The
combined extracts were washed with H2O and brine, dried over
anhydrous Na2SO4, and concentrated. The crude product was
purified by flash column chromatography (hexane/AcOEt¼5/1),
followed by recrystallization from EtOH to give 17 (6.87 g,
10.6 mmol, 98%) as a white solid. The anomeric ratio was de-
termined by HPLC analysis; Rf¼0.68 (hexane/AcOEt¼3/2); 1H
4.4.6. 2,3,4-Tri-O-benzyl-6-O-p-methoxybenzyl-
anosyl trichloroacetate (19). To a stirred solution of 2,3,4-tri-O-
benzyl-6-O-p-methoxybenzyl- -galactopyranoside (18) (50.0 mg,
0.088 mmol) in dry CH2Cl2 (0.9 mL) were added trichloroacetyl
chloride (19.1 L, 0.175 mmol) and pyridine (21.2 L, 0.263 mmol).
a,b-D-galactopyr-
a,b-D
m
m
After the reaction mixture was stirred at room temperature for 4 h,
the solvent was evaporated in vacuo with toluene as an azeotropic
solvent. The crude product was purified by flash column chroma-
tography (hexane/AcOEt¼7/1) to afford 19 (62.7 mg, 0.088 mmol,
NMR (300 MHz, CDCl3) d: 7.60e7.52 (m, 2H, PheH), 7.41e7.15 (m,
20H, PheH), 6.88e6.82 (m, 2H, PheH), 4.96 (d, J¼11.4 Hz, 1H,
eCH2Ph), 4.78 (d, J¼10.3 Hz, 1H, eCH2Ph), 4.74 (d, J¼11.9 Hz, 1H,
eCH2Ph), 4.73 (d, J¼10.3 Hz, 1H, eCH2Ph), 4.69 (d, J¼11.9 Hz,
1H, eCH2Ph), 4.64 (d, J¼9.8 Hz, 1H, 1-H), 4.58 (d, J¼11.4 Hz, 1H,
eCH2Ph), 4.42 (d, J¼11.3 Hz, 1H, eCH2Ph), 4.35 (d, J¼11.3 Hz, 1H,
eCH2Ph), 3.98 (br d, J¼2.6 Hz, 1H, 4-H), 3.93 (t, J¼9.8 Hz, 1H, 2-
H), 3.79 (s, 3H, eOCH3), 3.66e3.55 (m, 4H, 3-H, 5-H, 6-H); 13C
quant,
a
/
b
¼89/11) as yellow syrup.
Compound 19
a
: Rf¼0.62 (hexane/AcOEt¼2/1); [a 24
þ41.9 (c
]
1.02, CHCl3); 1H NMR (400 MHz, CDCl3)
d
: 7.37e7.2D4 (m, 15H,
PheH), 7.22e7.16 (m, 2H, PheH), 6.88e6.82 (m, 2H, PheH), 6.38 (d,
J¼3.7 Hz, 1H, 1-H), 4.95 (d, J¼11.3 Hz, 1H, eCH2Ph), 4.81e4.68 (m,
4H, eCH2Ph), 4.56 (d, J¼11.3 Hz,1H, eCH2Ph), 4.41 (d, J¼11.3 Hz,1H,
eCH2Ph), 4.34 (d, J¼11.3 Hz, 1H, eCH2Ph), 4.22 (dd, J¼10.0, 3.7 Hz,
1H, 2e-H), 4.09 (ddd, J¼7.4, 5.7 Hz, 1.0 Hz, 1H, 5-H), 4.03 (dd, J¼2.7,
1.0 Hz, 1H, 4-H), 3.90 (dd, J¼10.0, 2.7 Hz, 1H, 3-H), 3.79 (s, 3H,
eOCH3), 3.56 (dd, J¼9.4, 7.4 Hz, 1H, 6-H), 3.52 (dd, J¼9.4, 5.7 Hz, 1H,
NMR (75 MHz, CDCl3) d: 159.1, 138.5, 138.1, 138.0, 133.9, 131.2,
129.7, 129.4, 128.5, 128.1, 128.1, 127.9, 127.5, 127.5, 127.4, 127.3,
127.2, 126.7, 113.6, 87.4 (C-1), 83.9 (C-3), 77.0 (C-5), 76.4 (C-2),
75.4 (eCH2Ph), 74.2 (eCH2Ph), 73.3 (C-4), 72.9 (eCH2Ph), 72.4
(eCH2Ph), 68.1 (C-6), 55.0 (eOCH3). HR-MS (FAB-pos, NBA ma-
trix) m/z 685.2607 [MþNa]þ, calcd for C41H42O6SNa: 685.2600
[MþNa].
6-H); 13C NMR (75 MHz, CDCl3)
d: 160.22, 159.32, 138.26, 138.10,
137.77, 129.62, 129.57, 129.54, 128.40, 128.38, 128.30, 128.25, 128.24,
128.18, 128.07, 127.79, 127.72, 127.67, 127.66, 127.62, 127.59, 127.55,
113.80, 96.62 (C-1), 89.92 (eCCl3), 77.52 (C-3), 75.29 (C-2), 74.93
(eCH2Ph), 74.15 (C-4), 73.44 (eCH2Ph), 73.14 (eCH2Ph), 72.96 (C-5),
4.4.5. 2,3,4-Tri-O-benzyl-6-O-p-methoxybenzyl-a,b-D-galactopyr-
anose (18). To a solution of 17 (4.85 g, 7.48 mmol) in acetone
(72 mL) and H2O (3 mL) was added NBS (2.00 g, 11.2 mmol) at
ꢀ15 ꢁC. The reaction mixture was stirred at ꢀ15 ꢁC for 20 min, and
diluted with AcOEt to stop the reaction. The resultant mixture was
extracted with AcOEt, washed with H2O, brine, dried over anhy-
drous Na2SO4, and concentrated. The crude product was purified by
preparative flash column chromatography (hexane/AcOEt¼5/1/1/
72.78 (eCH2Ph), 67.64 (C-6), 55.20 (eOCH3). IR (NaCl) cmꢀ1
n:
3030.5, 2922.5, 2869.5, 1770.3, 1612.2, 1512.9, 1454.1, 1246.8, 1102.1,
1029.8. HR-MS (FAB-pos, NBA matrix) m/z 739.1429[M]þ, calcd for
C37H37O8Cl3: 739.1431 [M].
Compound 19
b
: Rf¼0.53 (hexane/AcOEt¼2/1); [a 23
þ17.5 (c
]
0.97, CHCl3); 1H NMR (300 MHz, CDCl3)
d
: 7.36e7.2D6 (m, 15H,
PheH), 7.23e7.18 (m, 2H, PheH), 6.89e6.84 (m, 2H, PheH), 5.62 (d,
J¼8.0 Hz, 1H, 1-H), 4.94 (d, J¼11.4 Hz, 1H, eCH2Ph), 4.84e4.81 (m,
2H, eCH2Ph), 4.73e4.71 (m, 2H, eCH2Ph), 4.61 (d, J¼11.4 Hz, 1H,
eCH2Ph), 4.42 (d, J¼11.4 Hz, 1H, eCH2Ph), 4.37 (d, J¼11.3 Hz, 1H,
eCH2Ph), 4.07 (dd, J¼9.8, 8.0 Hz, 1H, 2-H), 4.00 (dd, J¼2.8, 0.9 Hz,
1H, 4-H), 3.80 (s, 3H, eOCH3), 3.77e3.71 (m, 1H, 5-H), 3.63 (dd,
J¼9.8, 2.8 Hz, 1H, 3-H), 3.69e3.55 (m, 2H, 6-H); 13C NMR (100 MHz,
1) to afford 18 (4.05 g, 7.10 mmol, 95%,
Anomeric ratio was determined by HPLC [Senshu Pak PEGASIL
a
/b
¼57/43) as a white solid.
Silica SP 100 (4.6øꢂ250 mm), hexane/AcOEt¼3/1, UV at 254 nm,
flow rate; 1.0 mL/min, rt]. Compound 18
a
: Rf¼0.50 (hexane/
AcOEt¼1/1); [a 31
]
þ9.99 (c 0.74, CHCl3); 1H NMR (400 MHz, CDCl3)
D
d: 7.42e7.23 (m, 15H, PheH), 7.23e7.17 (m, 2H, PheH), 6.89e6.82
(m, 2H, PheH), 5.28 (dd, J¼3.5, 2.2 Hz, 1H, 1-H), 4.92 (d, J¼11.5 Hz,
1H, eCH2Ph), 4.83 (d, J¼11.5 Hz, 1H, eCH2Ph), 4.79 (d, J¼11.7 Hz,1H,
eCH2Ph), 4.74 (d, J¼11.5 Hz, 1H, eCH2Ph), 4.71 (d, J¼11.7 Hz, 1H,
eCH2Ph), 4.57 (d, J¼11.5 Hz, 1H, eCH2Ph), 4.42 (d, J¼11.5 Hz, 1H,
eCH2Ph), 4.34 (d, J¼11.5 Hz, 1H, eCH2Ph), 4.15 (ddd, J¼6.8, 6.3,
1.0 Hz, 1H, 5-H), 4.03 (dd, J¼9.8, 3.5 Hz, 1H, 2-H), 3.96 (dd, J¼2.7,
1.0 Hz, 1H, 4-H), 3.91 (dd, J¼9.8, 2.7 Hz, 1H, 3-H), 3.80 (s, 3H,
eOCH3), 3.51 (dd, J¼9.2, 6.3 Hz, 1H, 6-H), 3.46 (dd, J¼9.2, 6.8 Hz, 1H,
6-H), 3.10 (br s, 1H, eOH).
CDCl3) d: 160.7, 159.3, 138.3, 137.9, 137.7,129.64,129.63,128.4, 128.3,
128.3, 128.2, 128.0, 127.8, 127.73, 127.71, 127.5, 113.8, 98.5 (C-1), 89.4
(eCCl3), 81.9 (C-3), 77.5 (C-2), 75.4 (eCH2Ph), 74.83 (eCH2Ph), 74.77
(C-5), 73.1 (eCH2Ph), 73.0 (C-4), 72.9 (eCH2Ph), 67.4 (C-6), 55.2
(eOCH3). IR (NaCl) cmꢀ1
n: 2870.5, 1777.1, 1612.2, 1512.9, 1454.1,
1246.8, 1100.2, 1027.0; HR-MS (FAB-pos, NBA matrix) m/z 739.1431
[MþNa]þ, calcd for C37H37O8Cl3Na: 739.1426 [MþNa].
4.4.7. 2,3,4-Tri-O-benzyl-
To a solution of 19 (128.5 mg, 0.180 mmol) in CH2Cl2 (1.8 mL) and
H2O (100 L) at ambient temperature was added DDQ (62.8 mg,
a-D-galactopyranosyl trichloroacetate (20a).
Compound 18
b
: 1H NMR (400 MHz, CDCl3)
d
: 7.39e7.25 (m, 15H,
a
PheH), 7.22e7.17 (m, 2H, PheH), 6.88e6.83 (m, 2H, PheH), 4.93 (d,
J¼11.5 Hz, 1H, eCH2Ph), 4.91 (d, J¼11.0 Hz, 1H, eCH2Ph), 4.81 (d,
J¼11.0 Hz, 1H, eCH2Ph), 4.74e4.71 (m, J¼2H, eCH2Ph), 4.66 (dd,
J¼7.2, 6.5 Hz, 1H, 1-H), 4.58 (d, J¼11.5 Hz, 1H, eCH2Ph), 4.41 (d,
J¼11.5 Hz, 1H, eCH2Ph), 4.34 (d, J¼11.5 Hz, 1H, eCH2Ph), 3.88 (br d,
J¼2.9 Hz, 1H, 4-H), 3.80 (s, 3H, eOCH3), 3.75 (dd, J¼9.8, 7.2 Hz, 1H,
2-H), 3.54 (dd, J¼9.8, 2.9 Hz, 1H, 3-H), 3.62e3.47 (m, 3H, 5-H, 6-H),
m
0.270 mmol) in one portion. The reaction mixture was stirred at
ambient temperature for 1 h. After this mixture was diluted with
CH2Cl2 (20 mL), the resultant mixture was filtered through Celite
pad, and rinsed with CH2Cl2. The resultant mixture was washed
with satd aq NaHCO3. This satd aq NaHCO3 layer was extracted with
CH2Cl2. The combined organic layer was dried with sodium sulfate,
filtered, and concentrated under reduced pressure. Flash column
3.06 (d, J¼6.5 Hz, 1H, eOH); 13C NMR (100 MHz, CDCl3)
d: 159.3,
159.2, 138.6, 138.5, 138.4, 138.3, 138.2, 129.61, 129.57, 128.31, 128.30,
chromatography (hexane/AcOEt¼5/1) afforded 20a (90.3 mg,

T. Shirahata et al. / Tetrahedron 67 (2011) 6482e6496
6493
0.152 mmol, 84%) as a colorless oil; Rf¼0.35 (hexane/AcOEt¼2/1);
(eCH2Ph), 75.59 (eCH2Ph), 74.06 (eCH2Ph), 73.96 (eCH2Ph), 73.64
(eCH2Ph), 73.37 (eCH2Ph), 73.36 (eCH2Ph), 70.75 (C-4), 70.73 (C-
2), 70.65 (C-50), 70.64 (C-500), 69.45 (C-600), 69.68 (C-3),ꢀ618.57 (C-5),
[
a 25
]
þ72.8 (c 1.01, CHCl3); 1H NMR (300 MHz, CDCl3)
d: 7.40e7.27
(mD, 15H, PheH), 6.41 (d, J¼3.4 Hz, 1H, 1-H), 5.00 (d, J¼11.6 Hz, 1H,
eCH2Ph), 4.85 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.77 (d, J¼12.0 Hz, 1H,
eCH2Ph), 4.76 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.73 (d, J¼12.0 Hz, 1H,
eCH2Ph), 4.67 (d, J¼11.6 Hz, 1H, eCH2Ph), 4.25 (dd, J¼9.8, 3.4 Hz,
1H, 2-H), 3.97 (dd, J¼2.8,1.3 Hz,1H, 4-H), 3.93 (dd, J¼9.8, 2.8 Hz,1H,
3-H), 3.98e3.88 (m, 1H, 5-H), 3.73 (dd, J¼11.4, 6.3 Hz, 1H, 6-H), 3.52
67.60 (C-6), 67.99 (C-60), 55.76 (eOCH3); IR (NaCl) cm
n: 3030.6,
2924.5, 1727.9, 1601.6, 1495.5, 1453.1, 1283.4, 1097.3, 1056.8; HR-MS
(FAB-pos, NBA matrix) m/z 1483.5828 [M]þ, calcd for C29H29O7Cl3:
1483.5818 [M].
(dd, J¼11.4, 5.4 Hz, 1H, 6-H); 13C NMR (75 MHz, CDCl3)
d
: 160.28,
4.5. Sequential one-pot glycosylation with mannose
138.05, 137.81, 137.73, 128.59, 128.58, 128.45, 128.37, 128.19, 127.80,
127.79, 127.75, 96.45 (C-1), 89.89 (eCCl3), 77.68 (C-3), 75.40 (C-2),
74.62 (eCH2Ph), 74.30 (C-5), 73.97 (C-4), 73.57 (eCH2Ph), 73.32
4.5.1. Glycosylation with mannosyl carbamate 24: methyl 2,3,4-tri-
O-benzoyl-6-O-(2,3,4,6-tetra-O-benzyl-a,b-D-mannopyranosyl)-a-D-
(eCH2Ph), 61.81 (C-6); IR (NaCl) cmꢀ1
n
: 3444.2, 3030.6, 2911.0,
mannopyranoside (26) (Table 8, entry 3). The glycosylation was
performed according to the typical procedure employing carba-
mate donor 24 (30.0 mg, 0.051 mmol), acceptor 25 (21.3 mg,
1759.4, 1496.5, 1454.1, 1241.0, 1132.0; HR-MS (FAB-pos, NBA matrix)
m/z 617.0861 [M]þ, calcd for C29H29O7Cl3: 617.0877 [M].
0.042 mmol), and TMSOTf (7
anomeric mixture of a disaccharide 26 (31.7 mg, 0.0316 mmol, 75%,
¼75/25) was obtained as a colorless oil after purification by
m
L, 0.050 mmol) at 0 ꢁC for 2 h. The
4.4.8. Methyl 2,3,4,6-tetra-O-benzyl-
2,3,4-tri-O-benzyl- -galactopyranosyl-(1/6)-2,3,4-tri-O-benzoyl-
-galactopyranoside (22aa (Table 7, entry 1). To stirred
suspension of MS 5 A (123.6 mg, MS 5 A/acceptor¼3 g/1 mmol), 15
(30.1 mg, 0.0412 mmol), and acceptor 20 (40.5 mg, 0.0618 mmol)
in dry Et2O (1.5 mL) was added TMSOTf (12 L, 0.0618 mmol) at
0 ꢁC. The reaction mixture was stirred at 0 ꢁC for 2 h. A solution of
the acceptor 13 (41.7 mg, 0.0824 mol) in Et2O was added, and then
a-D-galactopyranosyl-(1/6)-
a-
D
a/b
a-D
)
a
preparative TLC (hexane/AcOEt¼2/1).
Compound 26
a
; Rf¼0.40 (hexane/AcOEt¼2/1); [a 32
þ50.0 (c
]
ꢁ
ꢁ
a
1.03, CHCl3); 1H NMR (400 MHz, CDCl3)
d
: 8.10e8.06 (m,D2H, PheH),
m
7.94e7.90 (m, 2H, PheH), 7.85e7.81 (m, 2H, PheH), 7.56e7.50 (m,
1H, PheH), 7.48e7.38 (m, 4H, PheH), 7.36e7.21 (m, 22H, PheH),
7.18e7.13 (m, 2H, PheH), 5.92 (t, J¼9.9 Hz, 1H, 4-H), 5.86 (dd, J¼9.9,
3.2 Hz, 1H, 3-H), 5.63 (dd, J¼3.2, 1.6 Hz, 1H, 2-H), 4.97 (d, J¼1.6 Hz,
1H, 10-H), 4.94 (d, J¼1.6 Hz, 1H, 1-H), 4.85 (d, J¼10.8 Hz, 1H,
eCH2Ph), 4.65 (d, J¼12.4 Hz, 1H, eCH2Ph), 4.61 (d, J¼12.4 Hz, 1H,
eCH2Ph), 4.57 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.47 (d, J¼10.8 Hz, 1H,
eCH2Ph), 4.41 (d, J¼12.0 Hz, 2H, eCH2Ph), 4.36 (d, J¼12.0 Hz, 1H,
eCH2Ph), 4.21e4.15 (m, 1H, 5-H), 3.97 (t, J¼9.5 Hz, 1H, 40-H), 3.95
(br d, J¼10.8 Hz, 1H, 6-Ha), 3.85 (dd, J¼9.5, 3.2 Hz, 1H, 30-H), 3.72
(ddd, J¼10.8, 4.7, 1.4 Hz, 1H, 50-H), 3.71 (dd, J¼3.2, 1.6 Hz, 1H, 20-H),
3.70e3.68 (m, 1H, 6-Hb), 3.67 (dd, J¼10.8, 4.7 Hz, 1H, 60-Ha), 3.58
(dd, J¼10.8, 1.4 Hz, 1H, 60-Hb), 3.44 (s, 3H, eOCH3); 13C NMR
m
reaction temperature was allowed to raise up to ambient temper-
ature. The reaction mixture was stirred for 2 h at ambient tem-
perature and, quenched by adding satd NaHCO3 solution and,
filtered through Celite pad. The filtrate was extracted with AcOEt,
and the combined organic extracts were washed with H2O and
brine, dried over anhydrous Na2SO4, and concentrated. The crude
product was purified by preparative TLC (hexane/AcOEt¼2/1),
(toluene/AcOEt¼8/1) to afford trisaccharide 22 (40.9 mg, 68%, aa
/
ab/ba
/
bb¼44/22/23/11, two steps) as colorless oil. The anomeric
ratio was determined by HPLC analysis [Senshu Pak PEGASIL silica
SP 100 (4.6øꢂ250 mm), hexane/AcOEt¼4/1, UV at 254 nm, flow
rate; 1.0 mL/min, rt].
(100 MHz, CDCl3) d: 165.5 (eOCOPh), 165.44 (eOCOPh), 165.35
(eOCOPh), 138.6, 138.53, 138.46, 138.4, 133.5, 133.3, 133.1, 129.8,
129.7, 129.4, 129.2, 129.1, 128.6, 128.4, 128.3, 128.2, 128.2, 127.9,
127.7, 127.5, 127.42, 127.36, 98.5 (1JC,H¼172.0 Hz, C-1), 98.1
(1JC,H¼168.0 Hz, C-10), 80.1 (C-30), 75.0 (eCH2Ph), 74.74 (C-20), 74.70
(C-40), 73.2 (eCH2Ph), 72.5 (eCH2Ph), 71.9 (C-50), 71.8 (eCH2Ph),
70.6 (C-2), 69.9 (C-3), 69.1 (C-5), 69.0 (C-60), 67.9 (C-4), 66.7 (C-6),
Compound 22aa; Rf¼0.43 (hexane/AcOEt¼2/1); [a 31
þ52.7 (c
]
0.62, CHCl3); 1H NMR (600 MHz, C6D6)
d
: 8.30e8.26 (m, D2H, PheH),
8.26e8.22 (m, 2H, PheH), 8.10e8.07 (m, 2H, PheH), 7.54e7.37 (m,
15H, PheH), 7.36e7.17 (m, 21H, PheH), 7.16e7.12 (m, 2H, PheH),
7.07e7.02 (m, 2H, PheH), 6.99e6.94 (m, 2H, PheH), 6.88e6.83 (m,
2H, PheH), 6.48 (dd, J¼10.5, 3.5 Hz, 1H, 3-H), 6.37 (dd, J¼3.5, 1.0 Hz,
1H, 4-H), 6.28 (dd, J¼10.5, 3.5 Hz, 1H, 2-H), 5.58 (d, J¼3.5 Hz, 1H, 1-
H), 5.20 (d, J¼11.5 Hz, 1H, eCH2Ph), 5.19 (d, J¼11.5 Hz, 1H, eCH2Ph),
5.18 (d, J¼3.5 Hz, 1H, 100-H), 5.00 (d, J¼3.5 Hz, 1H, 10-H), 4.85 (d,
J¼11.5 Hz, 2H, eCH2Ph), 4.78 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.75 (d,
J¼12.0 Hz, 1H, eCH2Ph), 4.74 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.74 (d,
J¼11.5 Hz, 1H, eCH2Ph), 4.63 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.62 (d,
J¼12.0 Hz, 1H, eCH2Ph), 4.59 (d, J¼11.5 Hz, 1H, eCH2Ph), 4.55 (d,
J¼12.0 Hz, 1H, eCH2Ph), 4.54 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.44 (d,
J¼11.5 Hz, 1H, eCH2Ph), 4.44 (ddd, J¼7.0, 6.0, 1.0 Hz, 1H, 500-H), 4.43
(ddd, J¼7.0, 6.0, 1.0 Hz, 1H, 50-H), 4.39 (dd, J¼10.0, 3.5 Hz, 1H, 200-H),
4.38 (dt, J¼6.0, 1.0 Hz, 1H, 5-H), 4.33 (dd, J¼10.0, 3.5 Hz, 1H, 20-H),
4.32 (dd, J¼10.0, 3.5 Hz, 1H, 300-H), 4.31 (dd, J¼9.0, 6.0 Hz, 1H, 60-H),
4.22 (dd, J¼3.5, 1.0 Hz, 1H, 400-H), 4.21 (dd, J¼3.5, 1.0 Hz, 1H, 40-H),
4.16 (dd, J¼10.5, 6.0 Hz, 1H, 6-H), 4.13 (dd, J¼10.0, 3.5 Hz, 1H, 30-H),
4.03 (dd, J¼9.0, 7.0 Hz, 1H, 60-H), 4.00 (dd, J¼9.0, 7.0 Hz, 1H, 600-H),
3.88 (dd, J¼10.5, 6.0 Hz, 1H, 6-H), 3.87 (dd, J¼9.0, 6.0 Hz, 1H, 600-H),
55.4 (eOCH3); IR (NaCl) cmꢀ1
n: 2914.9, 1729.8, 1601.6, 1452.1,
1264.1, 1097.3; HR-MS (FAB-pos, NBA matrix) m/z 1051.3881
[MþNa]þ, calcd for C62H60O14Na: 1051.3884 [MþNa].
Compound 26
b
; Rf¼0.40 (hexane/AcOEt¼2/1); [a 30
ꢀ101.8 (c
]
0.28, CHCl3); 1H NMR (400 MHz, CDCl3)
d
: 8.07e8D.03 (m, 2H,
PheH), 7.95e7.90 (m, 2H, PheH), 7.85e7.81 (m, 2H, PheH),
7.57e7.21 (m, 27H, PheH), 7.18e7.13 (m, 2H, PheH), 5.89 (dd,
J¼10.0, 3.1 Hz, 1H, 3-H), 5.83 (dd, J¼10.0, 9.8 Hz, 1H, 4-H), 5.66 (dd,
J¼3.1, 1.8 Hz, 1H, 2-H), 5.01 (d, J¼12.3 Hz, 1H, eCH2Ph), 5.00 (d,
J¼1.8 Hz, 1H, 1-H), 4.87 (d, J¼11.0 Hz, 1H, eCH2Ph), 4.84 (d,
J¼12.3 Hz, 1H, eCH2Ph), 4.52 (d, J¼12.3 Hz, 1H, eCH2Ph), 4.49 (d,
J¼11.0 Hz, 1H, eCH2Ph), 4.46 (d, J¼12.3 Hz, 1H, eCH2Ph), 4.44 (d,
J¼12.1 Hz, 1H, eCH2Ph), 4.43 (br s, 1H, 10-H), 4.40 (d, J¼12.1 Hz, 1H,
eCH2Ph), 4.35 (ddd, J¼9.8, 7.2, 1.8 Hz, 1H, 5-H), 4.23 (dd, J¼11.0,
1.8 Hz, 1H, 6-Ha), 4.03 (br d, J¼2.9 Hz, 1H, 20-H), 3.85 (t, J¼9.6 Hz,
1H, 40-H), 3.74 (dd, J¼11.0, 7.2 Hz, 1H, 6-Hb), 3.70 (dd, J¼11.0, 2.0 Hz,
1H, 60-Ha), 3.66 (dd, J¼11.0, 5.5 Hz, 1H, 60-Hb), 3.48 (s, 3H, eOCH3),
3.47 (dd, J¼9.6, 2.9 Hz,1H, 30-H), 3.38 (ddd, J¼9.6, 5.5, 2.0 Hz,1H, 50-
3.22 (s, 3H, eOCH3); 13C NMR (150 MHz, C6D6)
d: 166.70 (eOCOPh),
166.31 (eOCOPh), 166.15 (eOCOPh), 140.13, 140.06, 139.93, 139.86,
139.78,139.36,133.59,133.33,130.63,130.55,130.50,130.35,130.20,
129.18,128.97,128.95,128.93,128.89,128.85,128.36,128.82,128.78,
128.70, 128.64, 128.56, 128.50, 128.48, 128.40, 128.34, 128.32,
128.24, 128.14, 128.12, 128.03, 128.01, 128.00, 127.99, 127.98, 127.93,
127.91, 99.16 (C-100), 99.13 (C-10), 98.45 (C-1), 80.15 (C-300), 79.34 (C-
30), 77.81 (C-20), 77.80 (C-200), 76.47 (C-400), 76.25 (C-40), 75.69
H); 13C NMR (100 MHz, CDCl3)
d: 165.7 (eOCOPh), 165.6 (eOCOPh),
165.4 (eOCOPh), 138.7, 138.3, 138.2, 138.1, 133.4, 133.1, 129.8, 129.6,
129.3, 129.1, 128.9, 128.5, 128.4, 128.28, 128.25, 128.1, 128.0, 127.8,
127.60, 127.55, 127.5, 127.4, 102.4 (1JC,H¼152.6 Hz, C-10), 98.4 (C-1),
81.9 (C-30), 76.0 (C-50), 75.1 (eCH2Ph), 74.6 (C-40), 74.2 (eCH2Ph),
74.0 (C-20), 73.4 (eCH2Ph), 71.2 (eCH2Ph), 70.6 (C-2), 70.0 (C-3),
69.9 (C-5), 69.4 (C-60), 69.0 (C-6), 67.2 (C-4), 55.3 (eOCH3); IR (NaCl)

6494
T. Shirahata et al. / Tetrahedron 67 (2011) 6482e6496
cmꢀ1
n
: 2865.7, 1729.8, 1601.6, 1452.1, 1278.6, 1262.2, 1107.9; HR-MS
0
ꢁC for 2 h, and quenched with H2O. The resultant mixture was
(FAB-pos, NBA matrix) m/z 1051.3881 [MþNa]þ, calcd for
C62H60O14Na: 1051.3877 [MþNa].
extracted with AcOEt. The combined extracts were washed with
H2O and brine, dried over anhydrous Na2SO4, and concentrated.
The crude product was purified by flash column chromatography
(hexane/AcOEt¼8/1/4/1/3/1), followed by recrystallization from
4.5.2. 2,3,4,6-Tetra-O-benzyl-
(27). To a stirred solution of 2,3,4,6-tetra-O-benzyl-
anose (23) (199.1 mg, 0.370 mmol) in dry CH2Cl2 (4 mL) were added
trichloroacetyl chloride (60.7 L, 0.555 mmol) and pyridine (59.5 L,
a,b-D-mannoopyranosyl trichloroacetate
D-mannopyr-
EtOH to give 29a (13.4 g, 20.7 mmol, 83%) as a yellow oil. The
anomeric ratio was determined by 1H NMR analysis.
m
m
Compound 29
a
: Rf¼0.49 (hexane/AcOEt¼2/1); [a 23
þ70.4 (c
]
0.740 mmol). After the reaction mixture was stirred at room tem-
perature for 1.5 h, the solvent was evaporated in vacuo with toluene
as an azeotropic solvent. The crude product was purified by column
chromatography (hexane/AcOEt¼7/1) to give 27 (227.0 mg,
1.01, CHCl3); 1H NMR (400 MHz, CDCl3)
d
: 7.47e7.42 (m,D2H, PheH),
7.38e7.21 (m, 18H, PheH), 7.21e7.16 (m, 2H, PheH), 6.86e6.79 (m,
2H, PheH), 5.61 (d, J¼1.7 Hz, 1H, 1-H), 4.89 (d, J¼10.7 Hz, 1H,
eCH2Ph), 4.74 (d, J¼12.4 Hz, 1H, eCH2Ph), 4.63 (d, J¼12.4 Hz, 1H,
eCH2Ph), 4.62 (d, J¼12.6 Hz, 1H, eCH2Ph), 4.60 (d, J¼11.4 Hz, 1H,
eCH2Ph), 4.58 (d, J¼12.6 Hz, 1H, eCH2Ph), 4.50 (d, J¼10.7 Hz, 1H,
eCH2Ph), 4.41 (d, J¼11.4 Hz, 1H, eCH2Ph), 4.26 (ddd, J¼9.8, 5.0,
1.7 Hz, 1H, 5-H), 4.06 (t, J¼9.8 Hz, 1H, 4-H), 3.99 (dd, J¼3.1, 1.7 Hz,
1H, 2-H), 3.85 (dd, J¼9.8, 3.1 Hz, 1H, 3-H), 3.82 (dd, J¼11.0, 5.0 Hz,
0.382 mmol, quant,
a/b¼76/24) as yellow oil. The anomeric ratio was
determined by 1H NMR(400 MHz).
Compound 27
a
; Rf¼0.67 (hexane/AcOEt¼3/1); [a 23
þ43.1 (c
]
1.00, CHCl3); 1H NMR (400 MHz, CDCl3)
d
: 7.46e7.1D7 (m, 20H,
PheH), 6.26 (d, J¼2.1 Hz, 1H, 1-H), 4.90 (d, J¼10.6 Hz, 1H, eCH2Ph),
4.81 (d, J¼12.2 Hz, 1H, eCH2Ph), 4.76 (d, J¼12.2 Hz, 1H, eCH2Ph),
4.69 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.68 (d, J¼12.0 Hz, 1H, eCH2Ph),
4.62 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.57 (d, J¼10.6 Hz, 1H, eCH2Ph),
4.54 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.18 (dd, J¼9.7, 9.4 Hz, 1H, 4-H),
3.92 (ddd, J¼9.7, 4.4, 1.6 Hz, 1H, 5-H), 3.89 (dd, J¼9.4, 3.2 Hz, 1H, 3-
H), 3.83 (dd, J¼11.3, 4.4 Hz, 1H, 6-Ha), 3.78 (dd, J¼3.2, 2.1 Hz, 1H, 2-
1H, 6-H), 3.77 (s, 3H, eOCH3), 3.70 (dd, J¼11.0, 1.7 Hz, 1H, 6-H); 13
C
NMR (400 MHz, CDCl3) d: 159.1, 138.4, 138.2, 137.88, 137.87, 131.6,
130.8, 130.4, 129.9, 129.5, 129.1, 129.0, 128.5, 128.39, 128.36, 128.3,
128.1, 128.0, 127.8, 127.7, 127.6, 127.3, 113.6, 85.7 (1JC,H¼166.8 Hz, C-
1), 80.2 (C-3), 76.2 (C-2), 75.2 (eCH2Ph), 74.9 (C-4), 72.9 (eCH2Ph),
72.7 (C-5), 72.1 (eCH2Ph), 71.9 (eCH2Ph), 68.7 (C-6), 55.2 (eOCH3);
H), 3.73 (dd, J¼10.8, 1.4 Hz, 1H, 6-Hb); 13C NMR (100 MHz, CDCl3)
d:
IR (NaCl) cmꢀ1
n: 3029.6, 2905.2, 2865.7, 1612.2, 1512.9, 1247.7,
159.9 (eOCOCCl3), 138.1, 138.0, 137.8, 137.4, 128.44, 128.39, 128.3,
128.2, 128.0, 127.92, 127.89, 127.82, 127.77, 127.6, 96.9
(1JC,H¼178.8 Hz, C-1), 89.5 (eOCOCCl3), 78.3 (C-3), 75.3 (2C, C-5,
eCH2Ph), 73.9 (C-4), 73.7 (C-2), 73.4 (eCH2Ph), 73.0 (eCH2Ph), 72.6
1098.3; HR-MS (FAB-pos, NBA matrix) m/z 685.2606 [MþNa]þ,
calcd for C41H42O6SNa: 685.2600 [MþNa].
4.5.5. 2,3,4-Tri-O-benzyl-6-O-p-methoxybenzyl-
(30 ). To a solution of 29 (13.3 g, 20.6 mmol) in acetone (96 mL)
a-D-mannopyranose
(eCH2Ph), 68.4 (C-6).; IR (NaCl) cmꢀ1
n
: 3030.6, 2904.3, 2867.6,
a
a
1773.2, 1496.5, 1454.1, 1361.5, 1235.2, 1099.2; HR-MS (FAB-pos, NBA
matrix) m/z 709.1325 [MþNa]þ, calcd for C36H35O735Cl237ClNa:
709.1323 [MþNa].
and H2O (4 mL) was added NBS (5.49 g, 30.8 mmol) at ꢀ15 ꢁC. The
reaction mixture was stirred at ꢀ15 ꢁC for 1 h 30 min, and diluted
with AcOEt to stop the reaction. The resultant mixture was
extracted with AcOEt, washed with H2O, brine, dried over anhy-
drous Na2SO4, and concentrated. The crude product was purified by
flash column chromatography (hexane/AcOEt¼3/1/1/1) to afford
Compound 27
b
; Rf¼0.56 (hexane/AcOEt¼3/1); [a 24
ꢀ8.26 (c
]
1.05, CHCl3); 1H NMR (400 MHz, CDCl3)
d
: 7.45e7.1D5 (m, 20H,
PheH), 5.85 (d, J¼1.6 Hz, 1H, 1-H), 4.92 (d, J¼11.9 Hz, 1H, eCH2Ph),
4.80 (d, J¼11.2 Hz, 1H, eCH2Ph), 4.79 (d, J¼11.9 Hz, 1H, eCH2Ph),
4.63 (d, J¼11.9 Hz, 1H, eCH2Ph), 4.61 (d, J¼12.1 Hz, 1H, eCH2Ph),
4.58 (d, J¼11.2 Hz, 1H, eCH2Ph), 4.57 (d, J¼11.9 Hz, 1H, eCH2Ph),
4.55 (d, J¼12.1 Hz, 1H, eCH2Ph), 4.08 (dd, J¼2.9, 1.6 Hz, 1H, 2-H),
4.03 (t, J¼7.8 Hz, 1H, 4-H), 3.88 (dd, J¼10.6, 2.7 Hz, 1H, 6-Ha), 3.79
(dd, J¼10.6, 5.1 Hz, 1H, 6-Hb), 3.77 (ddd, J¼7.8, 5.1, 2.7 Hz, 1H, 5-H),
30a
(9.95 g, 17.4 mmol, 85%,
a
only) as white solid; Rf¼0.24 (hex-
ane/AcOEt¼2/1); [a 31
]
þ15.7 (c 0.82, CHCl3); 1H NMR (400 MHz,
CDCl3)
d
: 7.40e7.22D(m, 15H, PheH), 7.18e7.13 (m, 2H, PheH),
6.86e6.80 (m, 2H, PheH), 5.25 (dd, J¼3.3, 2.0 Hz, 1H, 1-H), 4.88 (d,
J¼10.8 Hz, 1H, eCH2Ph), 4.75 (d, J¼12.5 Hz, 1H, eCH2Ph), 4.72 (d,
J¼12.5 Hz, 1H, eCH2Ph), 4.63e4.60 (m, 2H, eCH2Ph), 4.52 (d,
J¼11.9 Hz, 1H, eCH2Ph), 4.48 (d, J¼10.8 Hz, 1H, eCH2Ph), 4.46 (d,
J¼11.9 Hz, 1H, eCH2Ph), 4.02 (ddd, J¼9.6, 6.5, 2.2 Hz, 1H, 5-H), 3.96
(dd, J¼9.6, 3.1 Hz, 1H, 3-H), 3.84 (t, J¼9.6 Hz, 1H, 4-H), 3.80 (dd,
J¼3.1, 2.0 Hz, 1H, 2-H), 3.77 (s, 3H, eOCH3), 3.69 (dd, J¼10.4, 2.2 Hz,
1H, 6-H), 3.64 (dd, J¼10.4, 6.5 Hz,1H, 6-H), 3.48e3.27 (m,1H, eOH):
3.71 (dd, J¼7.8, 2.9 Hz, 1H, 3-H); 13C NMR (100 MHz, CDCl3)
d: 160.6
(eOCOCCl3), 138.0, 137.9, 137.83, 137.79, 128.5, 128.39, 128.39,
128.35, 128.32, 128.30, 128.04, 127.99, 127.95, 127.9, 127.83, 127.78,
127.75, 127.74, 127.65, 127.60, 127.56, 96.6 (1JC,H¼165.3 Hz, C-1),
89.5 (eOCOCCl3), 79.7 (C-3), 76.6 (C-5), 74.4 (eCH2Ph), 73.9 (C-4),
73.8 (eCH2Ph), 73.4 (eCH2Ph), 73.0 (C-2), 72.3 (eCH2Ph), 68.9 (C-
13C NMR (100 MHz, CDCl3)
d: 159.1,138.5, 138.3,129.9,129.7,128.30,
6); IR (NaCl) cmꢀ1
n: 3030.6, 2921.6, 2868.6, 1777.1, 1496.5, 1454.1,
128.28, 128.2, 127.9, 127.8, 127.6, 127.54, 127.48, 113.7, 92.6
(1JC,H¼169.0 Hz, C-1), 79.7 (C-3), 75.3 (C-4), 75.0 (eCH2Ph), 74.8 (C-
2), 72.8 (eCH2Ph), 74.6 (eCH2Ph), 72.1 (eCH2Ph), 71.3 (C-5), 69.1 (C-
1363.4, 1228.4, 1096.3; HR-MS (FAB-pos, NBA matrix) m/z 709.1325
[MþNa]þ, calcd for C36H35O735Cl237ClNa: 709.1327 [MþNa].
6), 55.1 (eOCH3); IR (NaCl) cmꢀ1
n: 3398.9, 2910.1, 1612.2, 1512.9,
4.5.3. Glycosylation with mannosyl trichloroacetate 27: methyl 2,3,4-
1454.1, 1247.7, 1096.3; HR-MS (FAB-pos, NBA matrix) m/z 593.2524
tri-O-benzoyl-6-O-(2,3,4,6-tetra-O-benzyl-
a,b-D-mannopyranosyl)-
[MþNa]þ, calcd for C35H38O7Na: 593.2515 [MþNa].
a-D
-mannopyranoside (26) (Table 8, entry 7). The glycosylation was
performed according to the typical procedure employing tri-
chloroacetate donor 27 (29.9 mg, 0.050 mmol), acceptor 25
4.5.6. 2,3,4-Tri-O-benzyl-6-O-p-methoxybenzyl-
anosyl trichloroacetate (31). To a stirred solution of 2,3,4-tri-O-
benzyl-6-O-p-methoxybenzyl- -mannopyranose (30 ) (50.0 mg,
0.088 mmol) in dry CH2Cl2 (0.9 mL) were added trichloroacetyl
chloride (19.1 L, 0.175 mmol) and pyridine (21.2 L, 0.263 mmol).
a,b-D-mannopyr-
(25.9 mg, 0.050 mmol), and TMSOTf (11
temperature t. for 1 h. The anomeric mixture of the disaccharide 26
(46.7 mg, 0.0453 mmol, 91%,
mL, 0.061 mmol) at room
a
-D
a
a
/
b
¼91/9) was obtained as a colorless
m
m
oil after purification by preparative TLC (hexane/AcOEt¼2/1).
After the reaction mixture was stirred at room temperature for 3 h,
the solvent was evaporated in vacuo with toluene as an azeotropic
solvent. The crude product was purified by flash column chroma-
tography (hexane/AcOEt¼7/1) to afford 31 (55.7 mg, 0.078 mmol,
4.5.4. Phenyl 2,3,4-tri-O-benzyl-6-O-p-methoxybenzyl-1-thio-a-D-
mannopyranoside (29a). To a solution of phenyl 2,3,4-tri-O-benzyl-
1-thio- -mannopyranoside (28) (13.6 g, 25.0 mmol) in DMF
a
-D
89%,
a
/
b
¼88/12) as a yellow syrup.
(85 mL) was added NaH (1.30 g, 30.0 mmol, 55% disp.) followed by
PMBCl (3.73 mL, 27.5 mmol). The reaction mixture was stirred at
Compound 31
a
: Rf¼0.59 (hexane/AcOEt¼2/1); [a 31
þ45.1 (c
]
0.62, CHCl3); 1H NMR (400 MHz, CDCl3)
d
: 7.38e7.33 (m,D2H, PheH),

T. Shirahata et al. / Tetrahedron 67 (2011) 6482e6496
6495
7.33e7.19 (m, 13H, PheH), 7.16e7.11 (m, 2H, PheH), 6.81e6.76 (m,
2H, PheH), 6.20 (d, J¼2.1 Hz, 1H, 1-H), 4.82 (d, J¼10.6 Hz, 1H,
eCH2Ph), 4.74 (d, J¼12.1 Hz, 1H, eCH2Ph), 4.70 (d, J¼12.1 Hz, 1H,
eCH2Ph), 4.62 (d, J¼11.8 Hz, 1H, eCH2Ph), 4.57 (d, J¼11.8 Hz, 1H,
eCH2Ph), 4.55 (d, J¼11.8 Hz, 1H, eCH2Ph), 4.48 (d, J¼10.6 Hz, 1H,
eCH2Ph), 4.40 (d, J¼11.8 Hz,1H, eCH2Ph), 4.10 (t, J¼9.5 Hz,1H, 4-H),
3.84 (ddd, J¼9.5, 4.2, 1.8 Hz, 1H, 5-H), 3.82 (dd, J¼9.5, 3.2 Hz, 1H, 3-
H), 3.74 (dd, J¼11.4, 4.2 Hz, 1H, 6-H), 3.73 (s, 3H, eOCH3), 3.71 (dd,
J¼3.2, 2.1 Hz, 1H, 2-H), 3.63 (dd, J¼11.4, 1.8 Hz, 1H, 6-H); 13C NMR
4H, PheH), 6.67 (t, J¼10.0 Hz,1H, 4-H), 6.42 (dd, J¼10.0, 3.0 Hz,1H, 3-
H), 6.18 (dd, J¼3.0, 1.5 Hz, 1H, 2-H), 5.33 (d, J¼1.5 Hz, 1H, 100-H), 5.18
(d, J¼11.5 Hz, 1H, eCH2Ph), 5.11 (d, J¼11.5 Hz, 1H, eCH2Ph), 5.09 (d,
J¼1.5 Hz,1H,10-H), 4.87 (d, J¼3.5 Hz,1H,1-H), 4.74 (d, J¼12.0 Hz,1H,
eCH2Ph), 4.72 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.70 (d, J¼12.0 Hz, 1H,
eCH2Ph), 4.72e4.68 (m, 2H, eCH2Ph), 4.69 (d, J¼11.5 Hz, 1H,
eCH2Ph), 4.64 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.64 (d, J¼12.0 Hz, 1H,
eCH2Ph), 4.63 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.60 (d, J¼11.5 Hz, 1H,
eCH2Ph), 4.55 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.52 (d, J¼12.0 Hz, 1H,
eCH2Ph), 4.46 (t, J¼9.5 Hz,1H, 400-H), 4.41 (t, J¼9.5 Hz,1H, 40-H), 4.36
(dd, J¼9.5, 3.0 Hz, 1H, 30-H), 4.35 (dt, J¼10.0, 3.0 Hz, 1H, 5-H), 4.26
(dd, J¼9.5, 3.0 Hz, 1H, 300-H), 4.13 (dd, J¼11.0, 3.0 Hz, 1H, 6-H), 4.12
(ddd, J¼9.5, 5.0, 1.5 Hz, 1H, 500-H), 4.11 (dd, J¼12.0, 4.0 Hz, 1H, 60-H),
4.05 (dd, J¼3.0, 1.5 Hz, 1H, 200-H), 4.00 (dd, J¼3.0, 1.5 Hz, 1H, 20-H),
3.99 (ddd, J¼9.5, 4.0,1.5 Hz,1H, 50-H), 3.92 (dd, J¼11.5, 5.0 Hz,1H, 600-
H), 3.78 (dd, J¼11.0, 3.0 Hz, 1H, 6-H), 3.77 (dd, J¼12.0, 1.5 Hz, 1H, 60-
H), 3.76 (dd, J¼11.5, 1.5 Hz, 1H, 600-H), 3.14 (s, 3H, eOCH3); 13C NMR
(100 MHz, CDCl3) d: 159.91, 159.16, 137.98, 137.83, 137.45, 130.10,
129.52, 128.45, 128.38, 128.12, 127.94, 127.87, 127.82, 127.54, 113.71,
96.95 (C-1), 89.49 (-CCl3), 78.36 (C-3), 75.35 (C-5), 75.32 (eCH2Ph),
73.87 (C-4), 73.70 (C-2), 73.05 (eCH2Ph), 73.05 (eCH2Ph), 72.58
(eCH2Ph), 67.92 (C-6), 55.20 (eOCH3); IR (NaCl) cmꢀ1
n: 3030.6,
2908.1, 2868.6, 1771.3, 1512.9, 1246.8, 1097.3; HR-MS (FAB-pos, NBA
matrix) m/z 737.1465[M]þ, calcd for C37H37O8Cl3: 737.1452 [M].
4.5.7. 2,3,4-Tri-O-benzyl-
(32). To a solution of 31 (29.5 mg, 0.038 mmol) in CH2Cl2 (722
and H2O (40 L) at ambient temperature was added DDQ (17.3 mg,
a,
b-
D-mannopyranosyl
trichloroacetate
(150 MHz, C6D6) d: 166.70 (eOCOPh), 166.31 (eOCOPh), 166.15
mL)
(eOCOPh), 140.14, 139.96, 139.95, 139.91, 139.67, 139.62, 139.46,
133.86, 133.70, 133.40, 130.55, 130.51, 130.36, 130.21, 130.18, 129.28,
129.02,129.01,128.92,128.84,128.83,128.80,128.72,128.69,128.56,
128.56, 128.40, 128.32, 128.31, 128.24, 128.20, 128.17, 128.13, 128.11,
128.04, 127.87, 127.76, 127.70, 99.50 (C-1), 99.25 (1JC,H¼168.7 Hz, C-
10), 99.17 (1JC,H¼168.7 Hz, C-100), 81.41 (C-30), 80.39 (C-300), 76.64 (C-
20), 76.34 (C-200), 75.86 (C-400), 75.65 (eCH2Ph), 75.51 (eCH2Ph),
75.45 (C-40), 3.85 (eCH2Ph), 73.59 (eCH2Ph), 73.36 (C-500), 73.25
(eCH2Ph), 73.03 (C-50), 72.72 (eCH2Ph), 71.88 (eCH2Ph), 71.58 (C-2),
71.23 (C-3), 70.30 (C-5), 70.28 (C-600), 68.23 (C-4), 67.07 (C-6), 66.63
m
0.076 mmol) in one portion. The reaction mixture was stirred at
ambient temperature for 1.5 h. To this mixture was added anhy-
drous Na2SO4 followed by filtration to remove hydrated Na2SO4, the
resultant mixture was filtered over Celite and silica gel pad rinsed
with AcOEt. The resultant filtrate was concentrated under reduced
pressure. Flash column chromatography (CHCl3/MeOH¼40/1)
afforded 32 (17.8 mg, 0.027 mmol, 71%,
a
/
b
¼94/6) as a colorless oil.
Compound 32
a
: Rf¼0.43 (hexane/AcOEt¼2/1); Rf¼0.35 (CHCl3/
MeOH¼20/1); [a 27
]
þ38.2 (c 1.03, CHCl3); 1H NMR (400 MHz, CDCl3)
(C-60), 55.46 (eOCH3); IR (NaCl) cmꢀ1
n: 3030.6, 2924.5, 1729.8,
D
d
: 7.43e7.27 (m, 15H, PheH), 6.15 (d, J¼2.1 Hz, 1H, 1-H), 4.94 (d,
1601.6, 1495.5, 1453.1, 1278.6, 1106.9; HR-MS (FAB-pos, NBA matrix)
J¼10.6 Hz, 1H, eCH2Ph), 4.80 (d, J¼12.0 Hz, 1H, eCH2Ph), 4.71 (d,
J¼12.0 Hz, 2H, eCH2Ph), 4.68 (d, J¼10.6 Hz, 1H, eCH2Ph), 4.63 (d,
J¼12.0 Hz,1H, eCH2Ph), 4.11 (dd, J¼9.2 Hz,1H, 4-H), 3.89 (dd, J¼9.2,
3.0 Hz,1H, 3-H), 3.84 (dd, J¼13.4, 4.2 Hz,1H, 6-H), 3.81e3.76 (m,1H,
5-H), 3.80e3.76 (m, 1H, 6-H), 3.75 (dd, J¼3.0, 2.1 Hz, 1H, 2-H); 13C
m/z 1483.5817 [M]þ, calcd for C29H29O7Cl3: 1483.5818 [M].
4.6. One-pot dehydrative sequential glycosylation
4.6.1. Glucose. To a stirred solution of 2,3,4,6-tetra-O-benzyl-
gulucopyranose (1) (20.3 mg, 0.0370 mmol) in dry CH2Cl2 (0.25 mL)
was added trichloroacetyl isocyanate (6.0 L, 0.0381 mmol) at room
temperature. The reaction mixture was stirred at room temperature
D-
NMR (75 MHz, CDCl3) d: 159.96, 137.86, 138.76, 137.38, 128.54,
128.51, 128.34, 128.24, 128.08, 128.02, 127.96, 127.91, 96.75 (C-1),
89.41 (-CCl3), 78.35 (C-3), 75.71 (C-5), 75.42 (eCH2Ph), 73.88 (C-2),
73.55 (C-4), 73.35 (eCH2Ph), 72.75 (eCH2Ph), 61.63 (C-6); IR (NaCl)
m
ꢁ
ꢁ
for 1 h. To the resultant mixture was added MS 5 A (111.2 mg, MS 5 A/
acceptor¼3 g/1 mmol) and a solution of 6 (37.4 mg, 0.0555 mmol) in
dry Et2O (1.3 mL), followed by cooling to 0 ꢁC. To the stirred sus-
cmꢀ1
n: 3398.9, 3030.6, 2928.4,1767.4,1454.1,1236.2,1093.4; HR-MS
(FAB-pos, NBA matrix), m/z 619.0848[M]þ, calcd for C29H29O7Cl3:
619.0853 [M].
pension was added TMSOTf (14 mL, 0.0555 mmol). The reaction
mixture was stirred at 0 ꢁC for 4 h. Acceptor 3 (38.0 mg,
0.0740 mmol) was added, and then reaction temperature was
allowed to raise up to ambient temperature. The reaction mixture
was stirred at that temperature and warmed up to 40 ꢁC, and stirred
for 24 h. The reaction mixture was quenched by adding satd NaHCO3
solution, and filtered through Celite pad. The filtrate was extracted
with AcOEt, and the combined organic extracts were washed with
H2O and brine, dried over anhydrous Na2SO4, and concentrated. The
crude product was purified by preparative TLC (hexane/AcOEt¼2/1),
(toluene/AcOEt¼10/1ꢂ4) to afford glucosyl trisaccharide 8 (29.7 mg,
4.5.8. Methyl 2,3,4,6-tetra-O-benzyl-
2,3,4-tri-O-benzyl- -mannopyranosyl-(1/6)-2,3,4-tri-O-benzoyl-
-mannopyranoside (34aa) (Table 9, entry 1). To a stirred sus-
a-D-mannopyranosyl-(1/6)-
a-D
a-D
ꢁ
ꢁ
pension of MS 5 A (127.5 mg, MS 5 A/acceptor¼3 g/1 mmol), 24
(31.3 mg, 0.0429 mmol), and acceptor 32 (37.4 mg, 0.0630 mmol) in
dry Et2O (1.5 mL) was added TMSOTf (8 m
L, 0.0412 mmol) at 0 ꢁC.
The reaction mixture was stirred at ꢀ20 ꢁC for 2 h. A solution of the
acceptor 25 (43.6 mg, 0.0860 mmol) in Et2O was added, and then
reaction temperature was allowed to raise up to ambient temper-
ature. The reaction mixture was stirred for 2 h at ambient tem-
perature and, quenched by adding satd NaHCO3 solution, and
filtered through Celite pad. The filtrate was extracted with AcOEt,
and the combined organic extracts were washed with H2O and
brine, dried over anhydrous Na2SO4, and concentrated. The crude
product was purified by preparative TLC (hexane/AcOEt¼2/1),
(toluene/AcOEt¼10/1ꢂ4) to afford mannosyl trisaccharide 34
0.0203 mmol, 55%, aa
/
ab
/
ba
/
bb¼71/14/13/2, three steps) as color-
less oil. The anomeric ratio was determined by HPLC analysis [Sen-
shu Pak PEGASIL Silica 60e5 (4.6øꢂ250 mm), hexane/AcOEt¼3/2,
UV at 254 nm, flow rate; 0.2 mL/min, 0 ꢁC].
4.6.2. Galactose. To a stirred solution of 2,3,4,6-tetra-O-benzyl-
galactopyranose (11) (20.1 mg, 0.0372 mmol) in dry CH2Cl2
(0.25 mL) was added trichloroacetyl isocyanate (4.5 L,
D-
(32.6 mg, 52%, aa
/
ab/ba
/
bb¼71/14/13/2, two steps) as colorless oil.
m
The anomeric ratio was determined by HPLC analysis [Senshu Pak
PEGASIL silica SP 100 (4.6øꢂ250 mm), hexane/AcOEt¼4/1, UV at
254 nm, flow rate; 0.5 mL/min, rt].
0.0553 mmol) at room temperature. The reaction mixture was
stirred at room temperature for 1 h. To the resultant mixture was
ꢁ
ꢁ
added MS 5 A (111.0 mg, MS 5 A/acceptor¼3 g/1 mmol) and a so-
Compound 34aa; Rf¼0.43 (hexane/AcOEt¼2/1); [a 30
]
ꢀ13.1 (c
lution of acceptor 20a (33.0 mg, 0.0555 mmol) in dry Et2O (1.3 mL),
D
1.06, CHCl3); 1H NMR (600 MHz, C6D6)
d
: 7.54e7.10 (m, 38H, PheH),
followed by cooling to ꢀ20 ꢁC. To the stirred suspension was added
7.08e7.02 (m, 2H, PheH), 6.99e6.90 (m, 6H, PheH), 6.86e6.80 (m,
TMSOTf (10 mL, 0.0555 mmol). The reaction mixture was stirred at

6496
T. Shirahata et al. / Tetrahedron 67 (2011) 6482e6496
ꢀ20 ꢁC for 2 h. Acceptor 13 (37.9 mg, 0.0740 mmol) was added, and
then reaction temperature was allowed to raise up to ambient
temperature. The reaction mixture was stirred at that temperature
for 2 h. The reaction mixture was quenched by adding satd NaHCO3
solution and, filtered through Celite pad. The filtrate was extracted
with AcOEt, and the combined organic extracts were washed with
H2O and brine, dried over anhydrous Na2SO4, and concentrated.
The crude product was purified by preparative TLC (hexane/
AcOEt¼2/1) to afford trisaccharide 22 (38.5 mg, 0.0243 mmol, 71%,
References and notes
1. Stallforth, P.; Lepenies, B.; Adibekian, A.; Seeberger, P. H. J. Med. Chem. 2009, 52,
5561e5577.
2. Ernst, B.; Magnani, J. L. Nat. Rev. Drug Discov. 2009, 8, 661e677.
3. Galonic, D. P.; Gin, D. Y. Nature 2007, 446, 1000e1007.
4. Seeberger, P. H.; Werz, D. B. Nature 2007, 446, 1046e1051.
5. (a) Demchenko, A. V. Handbook of Chemical Glycosylation; Wiley-VCH:
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1900e1934; (c) Boltje, T. J.; Buskas, T. Nat. Chem. 2009, 1, 611e622; (d)
Tanaka, H.; Yamada, H.; Takahashi, T. Trends Glycosci. Glycotechnol. 2007, 19,
183e193.
6. (a) Kanie, O.; Ito, Y.; Ogawa, T. J. Am. Chem. Soc. 1994, 116, 12073e12074; (b)
Yamada, Y.; Kato, T.; Takahashi, T. Tetrahedron Lett. 1999, 40, 4581e4584.
7. (a) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B. J. Am. Chem. Soc.
1988, 110, 5583e5584; (b) Fraser-Reid, B.; Wu, Z.; Udodong, U. E.; Ottosson, H. J.
Org. Chem. 1990, 55, 6068e6070.
aa/ab
/ba
/
bb¼43/24/21/12, three steps) as a colorless oil. The
anomeric ratio was determined by HPLC analysis [Senshu Pak
PEGASIL silica SP 100 (4.6øꢂ250 mm), hexane/AcOEt¼4/1, UV at
254 nm, flow rate; 1.0 mL/min, rt].
8. Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am.
4.6.3. Mannose. To a stirred solution of 2,3,4,6-tetra-O-benzyl-
mannnopyranose (23) (20.3 mg, 0.0375 mmol) in dry CH2Cl2
(0.25 mL) was added trichloroacetyl isocyanate (4.5 L, 0.0553 mmol)
D-
Chem. Soc. 1999, 121, 734e753.
9. (a) Adinolfi, M.; Iadonisi, A.; Ravida, A. Synlett 2006, 583e586; (b) Valerio, S.;
ꢂ
Pastore, A.; Adinolfi, M.; Iadonisi, A. J. Org. Chem. 2008, 73, 4496e4503.
m
ꢀ
10. (a) Matsuo, J.; Shirahata, T.; Omura, S. Tetrahedron Lett. 2006, 47, 267e271; (b)
at room temperature. The reaction mixture was stirred at room
Shirahata, T.; Matsuo, J.; Teruya, S.; Hirata, N.; Kurimoto, T.; Akimoto, N.; Su-
ꢁ
ꢀ
temperature for 2 h. To the resultant mixture was added MS 5 A
nazuka, T.; Kaji, E.; Omura, S. Carbohydr. Res. 2010, 345, 740e749.
ꢁ
11. (a) Li, Z.-J.; Huang, H.-Q.; Cai, M.-S. J. Carbohydr. Chem. 1996, 15, 501e506;
(b) Wakao, M.; Nakai, Y.; Fukase, K.; Kusumoto, S. Chem. Lett. 1999,
27e28; (c) Lu, Y.-P.; Li, H.; Cai, M.-S.; Li, Z.-J. Carbohydr. Res. 2001, 334,
289e294.
(112.5 mg, MS 5 A/acceptor¼3 g/1 mmol) and a solution of acceptor
32(20.3mg, 0.0375mmol) indry Et2O (1.3 mL), followed bycooling to
ꢀ20 ꢁC. To the stirred suspension was added TMSOTf (7
mL,
0.0370 mmol). The reaction mixture was stirred at ꢀ20 ꢁC for 2 h.
Acceptor 25 (38.0 mg, 0.0740 mmol) was added, and then reaction
temperature was allowed to raise up to ambient temperature. The
reaction mixture was stirred at that temperature for 2 h. The reaction
mixture was quenched by adding satd NaHCO3 solution and, filtered
through Celite pad. The filtrate was extracted with AcOEt, and the
combined organic extracts were washed with H2O and brine, dried
over anhydrous Na2SO4, and concentrated. The crude product was
purified by preparative TLC (hexane/AcOEt¼2/1) to afford tri-
12. Zhu, X.-X.; Ding, P. Y.; Cai, M.-S. Tetrahedron: Asymmetry 1996, 7, 2833e2838.
€
€
13. Bindl, M.; Jean, L.; Herrmann, J.; Muller, R.; Furstner, A. Chem.dEur. J. 2009, 15,
12310e12319.
14. Hashimoto, S.; Hayashi, M.; Noyori, R. Tetrahedron Lett. 1984, 25, 1379e1382 In
our experience,10 2,3,4-benzyloxy acceptor and 2,3,4-benzoyloxy acceptor have
similar reactivity as acceptors, in this reason, 2,3,4-benzoyloxy acceptor 3 was
used.
15. Nagai, H.; Sasaki, K.; Matsumura, S.; Toshima, K. Carbohydr. Res. 2005, 340,
337e353.
16. Wulff, G.; Rohle, G. Angew. Chem., Int. Ed. Engl. 1974, 13, 157e170.
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hedron 2002, 58, 10189e10196.
saccharide 34 (38.4 mg, 0.0243 mmol, 71%, aa
/ab/ba/
bb¼75/11/11/3,
three steps) as a colorless oil. The anomeric ratio was determined by
HPLC analysis [Senshu Pak PEGASIL silica SP 100 (4.6øꢂ250 mm),
hexane/AcOEt¼4/1, UV at 254 nm, flow rate; 0.5 mL/min, rt].
21. Esmurziev, A.; Sundby, E.; Hoff, B. H. Eur. J. Org. Chem. 2009, 1592e1597.
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Acknowledgements
A part of this work was supported by KAKENHI, Grant-in-Aid for
Young Scientists (B) (20790017) from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT), Japan, Kitasato
University Research Grant for Young Researchers, and Eisai Award
in Synthetic Organic Chemistry, Japan. We also thank Ms. N. Sato
and Dr. K. Nagai at Kitasato University for various instrumental
analyses. We alsothank Ms. T. Otake, Mr. R. Okamoto, Ms. Y. Kinoshita,
Ms. M. Kuribara, Ms. N. Kamiyoshikawa, and Ms. R. Takahashi for
technical assistance.
23. The b-isomer 18b is not stable due to incomprehensive reason, and prevent the
isolation of 19 after the deprotection of PMB group.
24. Kumar, G. D. K.; Baskaran, S. J. Org. Chem. 2005, 70, 4520e4523.
25. (a) Lemanski, G.; Ziegler, T. Tetrahedron 2000, 56, 563e579; (b) Ekholm, F. S.;
ꢃ
ꢃ
Polakova, M.; Paw1owicz, A. J.; Leino, R. Synthesis 2009, 4, 567e576.
26. Garcia, B. A.; Gin, D. Y. J. Am. Chem. Soc. 2000, 122, 4269e4279.