Solvent-induced anomeric diastereoselectivity switching using a single glycosyl donor

Article abstract of DOI:10.1016/j.carres.2011.06.026

Highly diastereoselective glycosylation reactions have been developed; however, not all glycosylation reactions are diastereoselective and these reactions have probably not been reported. For some fucosylation reactions, unusually low or abnormally opposi

Full text of DOI:10.1016/j.carres.2011.06.026

Carbohydrate Research 346 (2011) 2098–2103
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Solvent-induced anomeric diastereoselectivity switching using a single
glycosyl donor
⇑
Ryuta Fujiwara, Shigeomi Horito
Department of Biological Science & Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 May 2011
Received in revised form 17 June 2011
Accepted 21 June 2011
Available online 29 June 2011
Highly diastereoselective glycosylation reactions have been developed; however, not all glycosylation
reactions are diastereoselective and these reactions have probably not been reported. For some fucosyla-
tion reactions, unusually low or abnormally opposite selectivities have been demonstrated. In the present
study, the fucosylation reaction of long-chain hydrocarbon alcohols, ethyl 9-hydroxynonanoate and dec-
anol using a series of the 2-O-benzyl-protected fucopyranosyl donors were investigated. The resulting
products demonstrated the solvent-induced diastereoselectivity switching using diethyl ether (Et2O) or
Keywords:
Glycosylation
Molecular assembly
Diastereoselectivity switching
Fucosylation
dichloromethane (CH2Cl2). Practical a-selectivities were observed using ether solvents. In contrast, prac-
tical b-selectivities were observed using CH2Cl2. The anomeric diastereoselectivity switching was simi-
larly observed in the alcohol galactosylation reaction. The larger spin-lattice relaxation time constant
(T1) actually indicated that molecular motion of ethyl 9-hydroxynonanoate was more vigorous in Et2O
than in CH2Cl2, suggesting its dissociation in Et2O and association in CH2Cl2. The bulkiness of the associ-
ated alcohols is most likely responsible for the observed diastereoselectivity.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
and increases the activation of Notch by Delta.16,17 However, not
only the Notch receptor, but also the Notch ligands (Drosophila
The central synthetic focus of naturally occurring glycoconju-
gates is the diastereoselective glycosylation of an aglycon with a
suitably protected glycon donor.1–4 Glycon and aglycon protecting
groups may significantly influence the yield and diastereoselectiv-
Delta and Serrate, Human Jagged 1, and Rat Delta-like 1) are
fucosylated and elongated by Fringe.18 Consequently, antibodies
against O-
complex Notch signaling modulation mechanism. We attempted
to synthesize the -fucosyl lipid antigens.
In this paper, we studied the influence of solvents on the ano-
meric ratio of fucosylation reactions using 2-O-benzyl- -fucosyl
L-fucosyl saccharides were required to elucidate the
ity of glycosylation reactions.5 If a 1,2-cis glycopyranosidic
a
link-
a-L
age is required in a D-gluco-, D-galacto-, and L-fucopyranosyl series,
then the presence of a non-participating group (e.g., benzyl) at the
C-2 of a glycon donor is essential for their diastereoselectivity.
Thus, the formation of a 1,2-cis glycosidic bond can predominantly
be produced through the use of a promoter, which is able to gen-
L
thioglycosides as the glycosyl donors and N-iodosuccinimide
(NIS) and silver triflate (AgOTf) as the promoters. In addition, the
influence of substituent effects on the fucosylation of a simple
erate an
leaving group (i.e., a halide,6 perchlorate,7 or triflate7). The
sylation preferentially occurs because the b-form intermediate is
much reactive than the -form and is stabilized by the anomeric
effect. However, unexpected b-
-fucosylation,8 b-selective
-fucosylation,9 and b-selective -galactosylation10 that results
a
- and a b-form intermediate equilibrium with a good
long-chain alcohol, decanol, and the L-fucosylation of a D-galactose
a-glyco-
derivative was also investigated. We then hypothesized why two
solvents (Et2O and CH2Cl2) switched the anomeric selectivity of
the glycosylation reactions.
a
L
L
D
2. Results and discussion
from using 2-O-benzyl-glycosyl donors have been found in the
literature.
The diastereoselectivities of the iodonium-assisted coupling
reactions between ethyl 9-hydroxynonanoate19 (1) and the
L-fuco-
Whereas, a significant biological role for O-L-fucosylation of
epidermal growth factor repeats in the Notch receptor has been re-
vealed.11–15 The expression of Fringe, which is a b-1,3-N-acetylglu-
cosaminyltransferase, inhibits the activation of Notch by Serrate
syl donor 2 in the presence of NIS and AgOTf were investigated in
different solvents. Conclusions regarding the solvent-induced dia-
stereoselectivity switching are summarized in Table 1.
The coupling reaction in toluene afforded L-fucopyranoside 3
with a poor diastereoselectivity of 10% de (entry 1). The similar
coupling reaction in Et2O afforded unusual but interesting results.
⇑
Corresponding author. Tel.: +81 4 7124 1501; fax: +81 4 7125 1841.
E-mail address: shorito@rs.noda.tus.ac.jp (S. Horito).
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.06.026

R. Fujiwara, S. Horito / Carbohydrate Research 346 (2011) 2098–2103
2099
Table 1
H
I
Fucosylationa of ethyl 9-hydroxynonanoate (1) with fucosyl donor 2
O
A
: Iodosulfonium triflate
S
OTf
OBn
OR
R
RO
SEt
OBn
O(CH2)8COOEt
OBn
O
O
B
D
: Oxacarbenium triflate
: Iodooxonium triflate
C: Glycosyl triflate
HO(CH2)8COOEt
BzO
CF3
IO
OBz
OBz
BzO
1
2
3
S
β
OTf
O
O
Dissociated acceptor
can mainly react with
the highly hindered
triflate by an SN2.
α
Entry
Solvent
Temp (°C)
Yieldb (%)
a 3b
% dec
O
OBn
unstable
OBn
3
O
H
OR
RO
RO
1
2
3
4
5
6
7
8
9
10
11
12
13
PhCH3
Et2O
Et2O
Et2O
Et2O
Et2O
PME
PME
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
À40
À60
À40
À10
0
41
50
66
78
72
73
80
82
53
18
23
50
34
50
44
29
15
20
19
19
13
44
63
66
50
61
10
6
α
CF3
IO
S
OTf
OR
RO
δ
O
OTf
O
O
39
68
57
59
62
73
9
À56
À48
0
OTf
OBn
O
OBn
unstable
OR
OR
OR
a>b
RO
stable
β
rt
0
Associated acceptor can
mainly react with the most
unstable intermediate by
an I+-assisted SN2.
Sugar acceptor can mainly
react with the most flexible
intermediate in an SN1.
δ
OTf
O
À10
OBn
stable
0
RO
À60
À40
0
À40
Scheme 1. Possible pathways for anomeric diastereoselectivity under kinetic
control.
À28
a
b
c
All reactions were continued for 1–2 h.
Isolated yield based on the donor.
Diastereomeric excess (% de) = [ratio of
conditions.8 A simple alcohol (e.g., allyl alcohol and 3-bromopropanol)
can react with glycosyl triflate C via an SN2 mechanism to predom-
a
anomer (%)] À [ratio of b anomer (%)].
inantly form the a-linkage from the more reactive b-triflate due to
the anomeric effect. In contrast, long-chain alcohols (e.g., decanol
and ethyl 9-hydroxynonanoate), which may be slightly hindered
by an association such as partial micelles in CH2Cl2, do not react
with triflate C. The alcohols react with less sterically hindered
iodooxonium triflate ion-pair D in an I+-assisted SN2 mechanism.
Consequently, it is reasonable that the b-linkage is predominantly
Good
a-selectivities of L-fucopyranoside 3 were observed at high
reaction temperatures of À10 °C to rt (entries 4, 5, and 6). Addi-
tionally, the diastereoselectivity almost disappeared at a low reac-
tion temperature of À60 °C (entry 2). The temperature dependence
found would not be accounted for by the stabilities of the interme-
diates and suggested an influence of a phase conversion. The high-
formed from the more reactive
a-orientated iodooxonium triflate
est a-selectivity (73% de) was performed using cyclopentyl methyl
ion-pair D due to the inverse anomeric effect.22
ether, which was also investigated at a high temperature of À10 °C
(entry 8). However, in the case of using a cyclic ether solvent (i.e.,
THF), the selectivity was drastically decreased to 9% de (entry 9).
This solvent effect of the cyclic ether was completely different from
The carbon-13 T1 values of 1 in the solvents CDCl3, rather than
CH2Cl2, and Et2O-d10, were measured to demonstrate molecular
assembly because T1 is nearly equal to T2 in the molecular weight
range of 1. All T1 values in Et2O-d10 were larger than those in CDCl3.
These results indicate that the molecular motion of 1 was more
vigorous in Et2O than in CH2Cl2, suggesting the dissociation and
association of 1 in Et2O and CH2Cl2, respectively (Fig. 1).
In the coupling reaction using Et2O, the dissociation of the sol-
vated long-chain hydrocarbon and OH group activation may ac-
count for the adverse diastereoselectivity. Moreover, dissociation
and activation by Et2O are generally facilitated at higher tempera-
tures. Thus, a dissociated and activated long-chain alcohol can re-
act with glycosyl triflate C in an SN2 mechanism to predominantly
the reported a
-directional effect of dioxane,20,21 indicating that the
observed ether-induced selectivity was due to neither participa-
tion of the ether oxygen atom with a glycosyl oxacarbenium ion7
nor anomeric effect potentiation in low-polar ether solvents.22 In
contrast, the highest b-selectivity (À56% de) for fucopyranoside 3
was observed in CH2Cl2 at a low reaction temperature of À60 °C
(entry 10); b-selectivity disappeared at a high reaction tempera-
ture of 0 °C (entry 12).
Because it has been reported that FeCl3 readily anomerizes b-
glycopyranosides to their corresponding a-anomers in good yields
and selectivities,23 the isolated b-anomer of 3 was exposed to the
initial (NIS/AgOTf, 4 Å MS) or final (I2, MeSSMe, TfOH, 4 Å MS) reac-
tion conditions for three days, which indicated that the b-anomer
was completely stable under these conditions examined. There-
fore, it was confirmed that both anomers were formed under ki-
netic control.
yield the
a-linkage. The drastic diastereoselectivity decrease in
THF was probably due to its weak hydrophobic interaction ability
because of its narrow hydrophobic face.
The reaction pathways shown in Scheme 1 were formulated
from these results. A thioglycoside reacts with iodotriflate to pro-
duce the iodosulfonium triflate ion-pair A, which is converted to
resonance-stabilized oxacarbenium triflate ion-pair B. Intermedi-
ate B reacts with iodotriflate or triflate to generate resonance-sta-
bilized iodooxonium triflate ion-pair D or glycosyl triflate C,
respectively. The iodooxonium triflate ion-pair D can also be gen-
erated by iodonium activation of the glycosyl triflate C. The glyco-
syl triflate generation from an oxacarbenium cation and triflate
anion has been well identified.24
Although slight b-selectivity (À6% de) in the coupling reaction
with ethyl 3,4-di-O-acetyl-2-O-benzyl-1-thio-b-L-fucopyranoside
Figure 1. Carbon-13 T1 of ethyl 9-hydroxynonanoate in solvents CDCl3 and Et2O-
d10. All samples were measured at a concentration similar to that of glycosylation
reaction and 23 °C. Each value represented the average of three samples SD. The
and decanol in CH2Cl2 has been reported, the
a-selectivities (24%
de or 40% de) of fucosylations with the same donor and allyl alcohol
or 3-bromopropanol have also been reported using similar reaction
differences were significant between CDCl3 and Et2O-d10 (
⁄⁄⁄p <0.0005).

2100
R. Fujiwara, S. Horito / Carbohydrate Research 346 (2011) 2098–2103
OH
OBz
O
OBz
O
was even observed in Et2O, and the selectivity was higher than that
in CH2Cl2. It was considered that donor 11, only possessing
ether protecting groups, is an ether molecule type that associates
with long-chain hydrocarbons. Thus, the sterically hindered
decanol can react with iodooxonium triflate D in an I+-assisted
SN2-reaction to afford a b-linkage even in Et2O (entries 23 and 24).
For the second exception, the reaction of a bulky alcohol (sugar
acceptor 8) and 2 may proceed only via flat oxacarbenium triflate
HO
BzO
BnO
BzO
BnO
a
SPh
b
SPh
O
O(CH2)8COOEt
BnO
BnO
BnO
BnO
4
5
6
Scheme 2. Reagents and conditions: (a) BzCl, pyridine, 93%; (b) ethyl 9-hydrox-
ynonanoate, NIS, AgOTf, solvent, MS 4 Å.
Predictably, moderate b-selectivity (À28% de) was observed in
CH3CN. This observation may be exerted by the occurrence of the
nitrilium–nitrile intermediate, which has often been used to dis-
cuss anomeric selectivity (entry 13).25
ion-pair B in an SN1 mechanism so that the
dominantly obtained even in CH2Cl2 by means of the anomeric ef-
fect (entry 26). The -selectivity was extremely improved using
a-anomer of 16 is pre-
a
Et2O that contained 12 equivalents of CH2Cl2 (based on the donor)
because the anomeric effect has more of a critical influence in a
less polar solvent, such as Et2O (entry 25). This type of solvent ef-
fect may be similar to the one reported.20,21
We then focused on the application of different protecting
groups and other sugar series donors. Diastereoselectivity switch-
ing was investigated for the coupling reactions with donor (fuco-
syl: 2, 9, and 1026 or galactosyl: 5, which was derived from 4,27
Scheme 2) and acceptor (1 or 7) combinations. However, the
switching was not investigated for all combinations involving
per-benzylated fucosyl donor 1128 or sugar acceptor 8.29 These re-
sults are summarized in Table 2.
3. Experimental
3.1. General methods
The solvent-induced diastereoselectivity switching by Et2O (a)
The optical rotations were measured at 25 °C using a JASCO DIP-
370 polarimeter. The 1H NMR and 13C NMR spectra were recorded
using a Bruker DRX-600 spectrometer at 600 and 125 MHz, respec-
tively. The dH-value in CDCl3 is relative to internal Me4Si, and the
dC-value is referenced to the solvent [dC (CDCl3) 77.0]. Assignments
were aided by COSY, TOCSY, and 1H- and 13C correlation spectros-
copy. The inversion–recovery method was used to measure the T1
values with prior determination of the 180° pulse for some sam-
ples. The elemental analyses were performed on a Perkin–Elmer
2400 II elemental analyzer. All reactions were monitored using
TLC with aluminum sheets that were coated with Silica Gel
60F254 (0.2 mm thickness, E. Merck, Darmstadt, Germany). Column
and CH2Cl2 (b) occurred in the coupling reaction of acceptor 1 with
donors 9 (3-O-benzyl-4-O-benzoyl donor), 10 (3,4-O-isopropyli-
dene-donor), or 5 (galactosyl donor) to produce each anomer of
12, 13, and 6, respectively (entries 14–19). The reaction of 2 or 7
and a long-chain alcohol that does not contain an acyl group (dec-
anol) exerted similar selectivity as 1 in Et2O (a: 60% de) and CH2Cl2
(b: À55% de) to afford each anomer of 14 (entries 20 and 21). The
glycosylation b-selectivity was decreased in EtOAc similar to that
observed in CH3CN because of the large polarity influence (entry
13 and 22).
The first exception of the switching was demonstrated in the
coupling reaction of 7 and 11. The b-selective production of 15
Table 2
Glycosylationa of alcohols 1, 7, and 8 using glycosyl donor 2, 5, or 9–11
Ph
Ph
O
O
O
O
O
O
HO(CH2)9CH3
BnO
BnO
O
HO
7
OMe
O
8
OMe
O
OBn
SEt
OBn
OR1
OBn
O
OR1
OBz
BzO
16
OR2
R2O
R3O
9: R1 = Bn, R2 = Bz
10: R1, R2 = (CH3)2C=
11: R1 = R2 = Bn
: R1 = (CH2)8COOEt, R2 = Bn, R3 = Bz
12
13: R1 = (CH2)8COOEt, R2, R3 = (CH3)2C=
14: R1 = (CH2)9CH3, R2 = R3 = Bz
15: R1 = (CH2)9CH3, R2 = R3 = Bn
Entry
Alcohol
Donor
Solvent
Temp (°C)
Product
Yieldb (%)
% dec
a
b
14
15
16
17
18
19
20
21
22
23
24
25
26
1
1
1
1
1
1
7
7
7
7
7
8
8
9
9
10
10
5
5
2
2
2
Et2O
CH2Cl2
Et2O
CH2Cl2
Et2O
CH2Cl2
Et2O
CH2Cl2
EtOAc
Et2O
CH2Cl2
Et2O/ CH2Cl2
À10
À40
0
12
12
13
13
6
65
20
49
18
68
20
71
21
32
19
28
85
85
29
70
33
49
13
64
18
73
60
76
64
0
38
À56
20
À60
À10
À40
À10
À40
À60
À5
À46
68
6
À52
14
14
14
15
15
16
16
60
À55
À30
À60
À39
100
77
11
11
2
À60
À10
À40
d
2
CH2Cl2
11
a
b
c
All reactions were continued for 1–2 h.
Isolated yield based on the donor.
Diastereomeric excess (% de) = [ratio of
a
anomer (%)] À [ratio of b anomer (%)].
d
Et2O-containing CH2Cl2 (12 equiv based on the donor); 2 was not soluble in Et2O and partially dissolved by addition of CH2Cl2 to afford fucal in a 15% yield as a byproduct.

R. Fujiwara, S. Horito / Carbohydrate Research 346 (2011) 2098–2103
2101
Table 3
1H NMR data of L-fucopyranosides
Chemical shifts (d), multiplicities, and coupling constants (Hz)
H-1 (J1,2
)
H-2 (J2,3
)
H-3 (J3,4
)
H-4 (J4,5
)
H-5 (J5,6
)
H-6
Othersa
2
9
3
4.86d
(10.6)
3.92t (9.8)
5.44dd
(3.4)
3.73dd
(3.4)
5.73dd
(3.4)
5.37dd
(3.4)
3.90dd
(3.8)
3.67m
(3.0)
5.66dd
(0.8)
5.63dd
(0.8)
5.67dd
(0.8)
5.58dd
(0.8)
5.63dd
(1.1)
5.56dd
(0.8)
3.99dq
(6.4)
3.78dq
(6.4)
4.32dq
(6.4)
3.96dq
(6.4)
4.2–4.1
(6.8)
3.74dq
(6.4)
1.30d
4.67, 4.64 Bn, 2.9–2.8, 1.38 SEt
4.51d (9.4) 3.69t (9.4)
1.27d
1.18d
1.29d
1.17d
1.27d
4.84, 4.82, 4.77, 4.57 Bn, 2.9–2.8, 1.35 SEt
a
4.10d (3.4) 4.2–4.1
(7.2)
4.58d (7.6) 3.85dd
(10.2)
4.84d (3.8) 4.09dd
(10.2)
4.69, 4.63 Bn, 4.2–4.1, 1.26 OEt, 2.30 CH2CO, 3.72, 3.49 OCH2, 1.8–1.3 CH2
3b
4.87, 4.70 Bn,
4.12, 1.25 OEt, 2.28 CH2CO, 4.04, 3.60 OCH2, 1.8–1.3 CH2
4.82, 4.81, 4.66, 4.60 Bn,
4.2–4.1, 1.26 OEt, 2.29 CH2CO, 3.65, 3.49 OCH2, 1.7–1.3 CH2
4.91, 4.79, 4.75, 4.58 Bn,
12
a
12b 4.41d (7.8) 3.67m
4.12, 1.25 OEt, 2.27 CH2CO, 3.99, 3.54 OCH2, 1.7–1.2 CH2
13
a
4.72d (3.4) 3.50dd
(7.9)
4.32dd
(5.7)
4.04dd
(2.6)
4.10m
(6.4)
1.4–
1.3
4.79, 4.70 Bn, 1.40, 1.35 CH3, 4.12, 1.25 OEt, 2.28 CH2CO, 3.62, 3.37 OCH2, 1.7–1.3
CH2
13b 4.28d (7.9) 3.38t (7.9)
4.2–4.1
(5.3)
4.00dd
(1.9)
3.83dq
(6.4)
1.41d
4.87, 4.81 Bn, 1.39, 1.36 CH3, 4.2–4.1, 1.28 OEt, 2.30 CH2CO, 3.95, 3.49 OCH2, 1.7–
1.3 CH2
14
a
4.95d (3.4) 4.11dd
(10.6)
5.73dd
(3.4)
5.37dd
(3.4)
3.50dd
(2.6)
5.66dd
(1.3)
5.58dd
(0.8)
3.55dd
(0.8)
4.32dq
(6.4)
3.96dq
(6.0)
3.43dq
(6.4)
1.19d
1.29d
1.17d
4.69, 4.63 Bn, 0.89 CH3, 3.72, 3.50 OCH2, 1.7–1.2 CH2
14b 4.58d (7.3) 3.85dd
4.87, 4.70 Bn, 0.88 CH3, 4.05, 3.60 OCH2, 1.8–1.2 CH2
(10.6)
15b 4.31d (7.6) 3.80dd
(9.8)
4.98, 4.94, 4.79, 4.76, 4.72, 4.69 Bn, 3.93, 3.46 OCH2, 1.7–1.2 CH2, 0.87 CH3
a
Phenyl proton signals commonly appeared at d 7.1–8.2.
Table 4
13C NMR data of L-fucopyranosides
Chemical shifts (d)
C-1
85.0
85.3
97.6
104.0
97.8
103.8
97.0
102.9
97.5
104.0
103.9
C-2
C-3
C-4
C-5
C-6
Othersa
2
9
3
3b
12
12b
13
13b
14
14b
15b
77.6
76.2
73.6
76.1
76.5
78.9
76.4
79.5
73.4
76.1
79.5
81.2
75.1
70.8
73.2
75.2
79.3
75.9
79.2
72.5
73.2
82.6
70.5
71.8
72.6
71.7
71.6
70.4
76.3
76.5
70.7
71.7
76.3
73.3
73.3
64.8
69.3
64.8
69.3
63.0
68.7
64.7
69.3
70.2
16.9
16.7
16.3
16.4
16.3
16.6
16.3
16.6
16.1
16.4
16.9
75.8, 71.7 Bn, 24.8, 15.0 SEt
75.5 Bn, 25.2, 15.0 SEt
a
72.8 Bn, 68.8 C-9N, 29.6, 29.4, 29.3, 26.3, 25.1 CH2, 34.5 C-2N, 60.3, 14.4 OEt
74.5 Bn, 70.6 C-9N, 29.7, 29.3, 29.1, 26.1, 25.0 CH2, 34.4 C-2N, 60.2, 14.3 OEt
73.3, 71.9 Bn, 68.4 C-9N, 29.5, 29.3, 29.1, 26.2, 25.0 CH2, 34.4 C-2N, 60.2, 14.3 OEt
75.3, 71.9 Bn, 70.5 C-9N, 29.8, 29.3, 29.2, 29.1, 26.1, 25.0, CH2, 34.4 C-2N, 60.2, 14.3 OEt
72.2 Bn, 108.7, 28.2, 26.1 iPr, 68.3 C-9N, 29.4, 29.3, 29.2, 29.1, 26.4, 25.0 CH2, 34.4 C-2N, 60.2, 14.3 OEt
73.6 Bn, 109.6, 27.9, 26.1 iPr, 69.7 C-9N, 29.7, 29.3, 29.2, 29.1, 26.4, 25.0 CH2, 34.4 C-2N, 60.2, 14.3 OEt
72.7 Bn, 68.7 OCH2, 31.9, 29.7, 29.5, 29.5, 29.4, 26.2, 22.7 CH2, 14.2 CH3
74.5 Bn, 70.6 OCH2, 31.9, 29.8, 29.7, 29.6, 29.5, 29.4, 26.2, 22.7, CH2, 14.2 CH3
75.1, 74.5, 73.2 Bn, 69.9 OCH2, 31.9, 29.8, 29.6, 29.6, 29.5, 29.4, 26.2, 22.7 CH2, 14.2 CH3
a
a
a
a
Carbonyl- and phenyl carbon signals commonly appeared at d 175–165 and 140–125, respectively. ‘N’ designates signals belonging to the ethyl 9-hydroxynonanoate (1).
chromatography was conducted using Wako Gel C-300E (Wako).
The solvent extracts were dried with anhydrous MgSO4 unless
otherwise specified.
described for 2, which was then purified using flash column chro-
matography (1:8 EtOAc–hexane) to afford 5 (3.00 g, 93%) as a col-
orless amorphous product: [
a]
+2.3 (c 1.02, CHCl3); 1H NMR
D
(CDCl3): d 8.01–7.49 (m, 25H, 5Ph), 5.90 (dd, 1H, J4,5 0.8 Hz, H-4),
4.75–4.85 (m, 3H, CHHPh), 4.75 (d, 1H, J1,2 9.4 Hz, H-1), 4.56 (dd,
1H, H-6a), 4.55 (d, 1H, CHHPh), 4.43 (dd, 1H, H-6b), 4.08 (m, 1H,
J5,6a 7.4 Hz, J5,6b 5.5 Hz, H-5), 3.80 (dd, 1H, J3,4 3.0 Hz, H-3), 3.76
(q, 1H, J2,3 9.1 Hz, H-2); 13C NMR (CDCl3): d 166.2, 165.7, 133.4,
133.3, 132.9, 132.9, 130.1, 129.8, 129.6, 129.5, 128.9, 128.5,
128.4, 128.3, 128.2, 127.9, 127.8, 87.4 (C-1), 81.2 (C-3), 76.6 (C-
2), 75.8 (CH2Ph), 74.9 (C-5), 72.0 (CH2Ph), 67.4 (C-4), 63.1 (C-6).
Anal. Calcd for C40H36O7S (660.78): C, 72.71; H, 5.49; S, 4.85.
Found: C, 72.50; H, 5.63; S, 4.82.
3.2. Ethyl 3,4-di-O-benzoyl-2-O-benzyl-1-thio-
b-
L-fucopyranoside (2)
To a solution of ethyl 2-O-benzyl-1-thio-b-L
-fucopyranoside30
(54.9 g, 184 mmol) in pyridine (510 mL) was added BzCl (210 mL,
1.81 mol) at 0 °C. The mixture was stirred at rt for 3 h. The mixture
was then diluted with CH2Cl2 and washed with 2 M aq HCl, satd aq
NaHCO3, and NaCl, dried, concentrated in vacuo, and purified using
flash column chromatography (1:8 EtOAc–hexane) to afford 2
(87.0 g, 93%) as a colorless syrup: [
a
]
À152 (c 1.04, CHCl3). Anal.
D
Calcd for C29H30O6S (506.61): C, 68.75; H, 5.97; S, 6.33. Found: C,
68.99; H, 5.93; S, 6.25. For 1H and 13C NMR data see Tables 3 and
4, respectively.
3.4. Ethyl 4-O-benzoyl-2,3-di-O-benzyl-1-thio-
b-L
-fucopyranoside (9)
The benzoylation of ethyl 2,3-di-O-benzyl-1-thio-b-L-fucopyr-
3.3. Phenyl 4,6-di-O-benzoyl-2,3-di-O-benzyl-1-thio-
anoside31 (2.10 g, 5.40 mmol) with pyridine (21.0 mL) and BzCl
(3.10 mL, 26.7 mmol) was performed as described for 2, which
was then purified using flash column chromatography (1:8
b-
D-galactopyranoside (5)
The benzoylation of 427 (2.23 g, 4.92 mmol) with pyridine
EtOAc–hexane) to afford 9 (1.63 g, 61%) as a colorless syrup: [
a]
D
(21.8 mL) and BzCl (6.30 mL, 54.3 mmol) was performed as
–49.4 (c 1.02, CHCl3). Anal. Calcd for C29H32O5S (492.63): C,

2102
R. Fujiwara, S. Horito / Carbohydrate Research 346 (2011) 2098–2103
70.70; H, 6.55; S, 6.51. Found: C, 70.54; H, 6.67; S, 6.44. For 1H and
13C NMR data see Tables 3 and 4, respectively.
3.7.2. Analytical data and spectral data for 6b
D +16.6 (c 1.08, CHCl3); 1H NMR (CDCl3): d 8.14–7.21 (m, 20H,
[a]
4Ph), 5.84 (dd, 1H, J3,4 3.0 Hz, J4,5 1.1 Hz, H-4), 4.90 (d, 1H, CHHPh),
4.83 (d, 1H, CHHPh), 4.74 (d, 1H, CHHPh), 4.59 (dd, 1H, H-6a), 4.59
(d, 1H, CHHPh), 4.47 (d, 1H, J1,2 7.6 Hz, H-1), 4.36 (dd, 1H, H-6b),
4.12 (q, 2H, OCH2CH3), 4.00–3.96 (m, 2H, H-5, OCHHCH2), 3.74–
3.68 (m, 2H, H-2, H-3), 3.57 (m, 1H, OCHHCH2), 2.27 (t, 2H,
CH2CH2COO), 1.74–1.57 (m, 4H, OCH2CH2, CH2CH2COO), 1.45–
1.24 (m, 8H, 4CH2CH2CH2), 1.25 (t, 3H, CH2CH3); 13C NMR (CDCl3):
d 173.9, 166.2, 165.9, 138.5, 137.8, 133.3, 130.1, 129.8, 129.7,
128.5, 128.3, 128.1, 128.0, 127.6, 104.0 (C-1), 79.3 (C-3), 79.0 (C-
2), 75.4 (CH2Ph), 72.2 (CH2Ph), 71.0 (C-5), 70.6 (COCH2CH2), 67.4
(C-4), 62.6 (C-6), 60.2 (CH2CH3), 34.4 (CH2CH2COO), 29.7, 29.3,
29.1, 26.1, 25.0, 14.3 (OCH2CH3). Anal. Calcd for C45H52O10
(752.89): C, 71.79; H, 6.96. Found: C, 71.55; H, 6.93.
3.5. General glycosylation procedure
A mixture of donor (1.00 mmol) and alcohol (1.50 mmol) in dry
solvent (for dehydration, 5.0 mL) was dried by azeotropic dehydra-
tion under Ar for 2 h and was then concentrated. The mixture was
dissolved in dry solvent (reaction, 5.0 mL) and cooled to the pre-
sented temperature (Tables 1 and 2). Molecular sieves (4 Å,
0.50 g), NIS (2.70 mmol), and AgOTf (0.10 mmol) were added to
the mixture, and the reaction was stirred at the same temperature
for 1–2 h. The reaction was quenched with Et3N. The precipitate
was filtered through a pad of Celite. The filtrate and washings were
combined, and the solution was successively washed with satd aq
NaHCO3, 1 M Na2S2O3, and satd aq NaCl, dried and concentrated.
The residue was purified by flash column chromatography to yield
the products.
3.8. 8-Ethoxycarbonyloctyl 4-O-benzoyl-2,3-di-O-benzyl-
fucopyranoside (12 ) and 8-ethoxycarbonyloctyl 4-O-benzoyl-
2,3-di-O-benzyl-b- -fucopyranoside (12b)
a-L-
a
L
3.6. 8-Ethoxycarbonyloctyl 3,4-di-O-benzoyl-2-O-benzyl-
fucopyranoside (3 ) and 8-ethoxycarbonyloctyl 3,4-di-O-
benzoyl-2-O-benzyl-b- -fucopyranoside (3b)
a-L-
Compound 1 (186 mg, 0.92 mmol), 9 (302 mg, 0.61 mmol), NIS
(370 mg, 1.65 mmol), and AgOTf (16.0 mg, 61.5 mol) were re-
acted as described in Section 3.5. The anomers were then purified
a
l
L
using flash column chromatography (1:8 EtOAc–hexane) to afford
Compound 1 (322 mg, 1.59 mmol), 2 (532 mg, 1.06 mmol), NIS
(640 mg, 2.86 mmol), and AgOTf (27.0 mg, 0.110 mmol) were re-
acted as described in Section 3.5. The anomers were then purified
using flash column chromatography (1:8 EtOAc–hexane) to afford
12a (251 mg, 65%) and 12b (113 mg, 29%) as colorless syrups.
3.8.1. Analytical data for 12
a
[a]
D À77.0 (c 0.92, CHCl3). Anal. Calcd for C38H48O8 (632.78): C,
3a
(562 mg, 82%) and 3b (89.0 mg, 13%) as colorless syrups.
72.13; H, 7.65. Found: C, 72.18; H, 7.72. For 1H and 13C NMR data
see Tables 3 and 4, respectively.
3.6.1. Analytical data for 3
a
[
a
]
À143 (c 0.99, CHCl3). Anal. Calcd for C38H46O9 (646.77): C,
D
3.8.2. Analytical data for 12b
70.57; H, 7.17. Found: C, 70.77; H, 7.21. For 1H and 13C NMR data
see Tables 3 and 4, respectively.
[a]
D À60.9 (c 1.06, CHCl3). Anal. Calcd for C38H48O8 (632.78): C,
72.13; H, 7.65. Found: C, 72.02; H, 7.69. For 1H and 13C NMR data
see Tables 3 and 4, respectively.
3.6.2. Analytical data for 3b
[
a
]
À132 (c 1.04, CHCl3). Anal. Calcd for C38H46O9 (646.77): C,
D
3.9. 8-Ethoxycarbonyloctyl 2-O-benzyl-3,4-O-isopropylidene-
-fucopyranoside (13 ) and 8-ethoxycarbonyloctyl 2-O-benzyl-
3,4-O-isopropylidene-b- -fucopyranoside (13b)
a-
70.57; H, 7.17. Found: C, 70.52; H, 6.75. For 1H and 13C NMR data
see Tables 3 and 4, respectively.
L
a
L
Compound 1 (462 mg, 2.28 mmol), 1026 (378 mg, 1.52 mmol),
NIS (920 mg, 4.10 mmol), and AgOTf (39.0 mg, 0.150 mmol) were
reacted as described in Section 3.5. The anomers were then puri-
fied using flash column chromatography (1:8 EtOAc–hexane) to af-
3.7. 8-Ethoxycarbonyloctyl 4,6-di-O-benzoyl-2,3-di-O-benzyl-
-galactopyranoside (6 ) and 8-ethoxycarbonyloctyl 4,6-di-O-
benzoyl-2,3-di-O-benzyl-b- -galactopyranoside (6b)
a-
D
a
D
Compound 1 (462 mg, 2.28 mmol), 1026 (378 mg, 1.52 mmol),
NIS (920 mg, 4.10 mmol), and AgOTf (39.0 mg, 0.150 mmol) were
reacted as described in Section 3.5. The anomers were then purified
using flash column chromatography (1:8 EtOAc–hexane) to afford
ford 13a (356 mg, 49%) and 13b (240 mg, 33%) as colorless syrups.
3.9.1. Analytical data for 13
a
[a]
D À75.8 (c 1.00, CHCl3). Anal. Calcd for C27H42O7 (478.62): C,
67.76; H, 8.84. Found: C, 67.90; H, 8.79. For 1H and 13C NMR data
see Tables 3 and 4, respectively.
13a (356 mg, 49%) and 13b (240 mg, 33%) as colorless syrups.
3.7.1. Analytical and spectral data for 6
a
[a]
D +40.3 (c 1.04, CHCl3); 1H NMR (CDCl3): d 8.06–7.22 (m, 20H,
3.9.2. Analytical data for 13b
4Ph), 5.90 (dd, 1H, J3,4 3.4 Hz, J4,5 0.8 Hz, H-4), 4.90 (d, 1H, J1,2
3.4 Hz, H-1), 4.85 (d, 1H, CHHPh), 4.83 (d, 1H, CHHPh), 4.66 (d,
1H, CHHPh), 4.62(d, 1H, CHHPh), 4.46 (m, 1H, H-6a), 4.38–4.33
(m, 2H, H-5, H-6b), 4.12 (m, 3H, H-3, CH2CH3), 3.94 (dd, 1H, J2,3
10.2 Hz, H-2), 3.65 (m, 1H, OCHHCH2), 3.48 (m, 1H, OCHHCH2),
2.27 (t, 2H, CH2CH2COO), 1.66–1.56 (m, 4H, OCH2CH2,
CH2CH2COO), 1.32–1.21 (m, 8H, 4CH2CH2CH2), 1.25 (t, 3H,
OCH2CH3,); 13C NMR (CDCl3): d 173.9, 166.1, 165.8, 138.5, 138.1,
133.2, 133.2, 130.0, 129.8, 129.7, 128.5, 128.4, 128.3, 128.2,
128.1, 127.9, 127.7, 127.5, 97.8 (C-1), 76.4 (C-2), 75.2 (C-3), 73.5
(CH2Ph), 72.1 (CH2Ph), 68.8 (C-4), 68.6 (COCH2CH2), 67.1 (C-5),
63.3 (C-6), 60.2, 34.4 (CH2CH2COO), 29.4, 29.2, 29.1, 26.1, 25.0,
14.3 (OCH2CH3). Anal. Calcd for C45H52O10 (752.89): C, 71.79; H,
6.96. Found: C, 71.57; H, 6.97.
[a] –47.6 (c 1.03, CHCl3). Anal. Calcd for C27H42O7 (478.62): C,
D
67.76; H, 8.84. Found: C, 68.04; H, 8.71. For 1H and 13C NMR data
see Tables 3 and 4, respectively.
3.10. Decyl 3,4-di-O-benzoyl-2-O-benzyl-
(14 ) and decyl 3,4-di-O-benzoyl-2-O-benzyl-b-
fucopyranoside (14b)
a-L-fucopyranoside
a
L-
Compound 7 (147 mg, 0.93 mmol), 2 (298 mg, 0.59 mmol), NIS
(370 mg, 1.67 mmol), and AgOTf (15.0 mg, 58.4 mol) were re-
l
acted as described in Section 3.5. The anomers were then purified
using flash column chromatography (1:20 EtOAc–hexane) to afford
a (250 mg, 71%) as a colorless syrup and 14b (62 mg, 18%) as a
colorless syrup.
14

R. Fujiwara, S. Horito / Carbohydrate Research 346 (2011) 2098–2103
2103
3.10.1. Analytical data for 14
a
16b was not obtained and was only detected by 1H NMR
[
a
]
À157 (c 0.97, CHCl3). Anal. Calcd for C37H46O7 (602.76): C,
spectroscopy.
D
73.73; H, 7.69. Found: C, 73.78; H, 7.79. For 1H and 13C NMR data
see Tables 3 and 4, respectively.
Acknowledgment
3.10.2. Analytical data for 14b
This work was supported by the City Area Program, ‘Chiba/
Tokatsu Area (Basic Stage),’ which was sponsored by the Ministry
of Education, Culture, Sport, Science, and Technology of the Japa-
nese Government.
[
a]
D
À129 (c 0.99, CHCl3). Anal. Calcd for C37H46O7 (602.76): C,
73.73; H, 7.69. Found: C, 73.90; H, 7.44. For 1H and 13C NMR data
see Tables 3 and 4, respectively.
3.11. Decyl 2,3,4-tri-O-benzyl-b-L-fucopyranoside (15b)
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acted as described in Section 3.5. The product was then purified
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D
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3.12. Methyl 3,4-di-O-benzoyl-2-O-benzyl-a-L-fucopyranosyl-
(1?2)-3-O-benzyl-4,6-O-benylidene-
a-D-galactopyranoside
(16a)
Compound 828 (265 mg, 0.71 mmol), 2 (240 mg, 0.47 mmol),
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l
acted as described in Section 3.5. The product was then purified
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16a
(331 mg, 85%) as a colorless syrup. [
a
]D À64.0 (c 1.00, CHCl3);
1H NMR (CDCl3): d7.93–7.10 (m, 25H, 5Ph), 5.82 (dd, 1H, J3,4 3.4 Hz,
H-3II), 5.68 (dd, 1H, J4,5 1.1 Hz, H-4II), 5.52 (s, 1H, CHPh), 5.30 (d,
1H, J1,2 3.8 Hz, H-1II), 5.01 (d, 1H, J1,2 3.4 Hz, H-1I), 4.82 (d, 1H,
CHHPh), 4.79 (d, 1H, CHHPh), 4.62 (d, 1H, CHHPh), 4.53 (d, 1H,
CHHPh), 4.46 (dq, 1H, J5,6 6.4 Hz, H-5II), 4.25 (dd, 1H, H-6aI), 4.23
(dd, 1H, J2,3 10.2 Hz, H-2I), 4.17 (dd, 1H, J4,5 0.8 Hz, H-4I), 4.08
(dd, 1H, J2,3 10.6 Hz, H-2II), 4.03 (dd, 1H, H-6bI), 3.99 (dd, 1H, J3,4
3.4 Hz, H-3I), 3.61 (d, 1H, J5,6 6.4 Hz, H-5I), 3.43 (s, 3H, OCH3),
1.19 (d, 3H, H-6II); 13C NMR (CDCl3): d 166.0, 165.7, 139.1, 137.9,
133.2, 132.9, 129.9, 129.8, 129.7, 129.0, 128.5, 128.3, 128.2,
128.2, 127.9, 127.7, 127.5, 127.4, 126.5, 126.4, 101.3 (CHPh),
100.1 (C-1I), 99.8 (C-1II), 77.4 (C-2I), 75.3 (C-4I), 74.2 (C-3I), 72.8
(C-2II), 72.4 (C-4II), 71.8 (CH2Ph), 70.4 (C-3II), 69.4 (C-6I), 65.0 (C-
5II), 62.4 (C-5I), 55.3 (OCH3), 16.3 (C-6II). Anal. Calcd for
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