Synthesis of 1-C-alkyl-α-d-glucopyranosides by Lewis acid- or Br?nsted acid-catalyzed O-glycosidation

Article abstract of DOI:10.1016/j.tet.2006.08.059

We prepared several kinds of 1-C-alkyl-2,3,4,6-tetra-O-benzyl-α-d-glucopyranose derivatives containing methyl, ethyl, n-butyl, and benzyl groups as the alkyl groups at their anomeric positions. The Lewis acid- or Br?nsted acid-catalyzed O-glycosidations u

Full text of DOI:10.1016/j.tet.2006.08.059

Tetrahedron 62 (2006) 10383–10392
Synthesis of 1-C-alkyl-a-D-glucopyranosides by Lewis
acid- or Brønsted acid-catalyzed O-glycosidation
a
Takashi Yamanoi,a, Yoshiki Oda, Sho Matsuda,a,b Ippo Yamazaki,a Kazuhide Matsumura,a
*
Kaname Katsuraya,c Mikio Watanabeb and Toshiyuki Inazud
aThe Noguchi Institute, 1-8-1 Kaga, Itabashi-ku, Tokyo 173-0003, Japan
bDepartment of Chemistry, School of Science, Tokai University, Kitakaname 1117, Hiratsuka, Kanagawa 259-1292, Japan
cSchool of Home Economics, Wayo Women’s University, Chiba 272-8533, Japan
dDepartment of Applied Chemistry, School of Engineering, Institute of Glycotechnology, Tokai University,
Kitakaname 1117, Hiratsuka, Kanagawa 259-1292, Japan
Received 5 July 2006; revised 9 August 2006; accepted 21 August 2006
Available online 8 September 2006
Abstract—We prepared several kinds of 1-C-alkyl-2,3,4,6-tetra-O-benzyl-a-D-glucopyranose derivatives containing methyl, ethyl, n-butyl,
and benzyl groups as the alkyl groups at their anomeric positions. The Lewis acid- or Brønsted acid-catalyzed O-glycosidations using them as
the glycosyl donors to synthesize 1-C-alkyl-D-glucopyranosides were investigated. Using 10 mol % of triphenylmethyl perchlorate efficiently
catalyzed the glycosidation of 2,3,4,6-tetra-O-benzyl-1-C-methyl-a-D-glucopyranosyl dimethylphosphinothioate. The glycosidation using
the 1-C-alkyl-2,3,4,6-tetra-O-benzyl-a-D-glucopyranosyl acetates smoothly proceeded in the presence of only 5 mol % of scandium(III)
trifluoromethanesulfonate. The dehydration–condensation type glycosidation using the 1-C-alkyl-2,3,4,6-tetra-O-benzyl-a-D-glucopyranoses
was significantly promoted using 5 mol % of bis(trifluoromethane)sulfonimide. These glycosidations successfully afforded various 1-C-alkyl-
a-D-glucopyranosides in good yields with high a-stereoselectivities.
Ó 2006 Published by Elsevier Ltd.
1. Introduction
glycono-1,5-lactones with organometallic reagents such as
organolithium reagents or Grignard reagents.4 To the best
of our knowledge, however, only a few O-glycosidations
using 1-C-alkyl-hexopyranose derivatives as the glycosyl
donors have ever been reported.5
The 1-C-alkyl-sugars, which have alkyl groups at their
anomeric carbon centers, are considered to be a novel class
of artificial ketoses, which replace naturally occurring
aldoses. Their glycosylated compounds, i.e., 1-C-alkyl-
glycosides, are expected to show biological functions
different from those of natural compounds.1 Therefore, con-
siderable attention has been paid to developing glycosida-
tion methods for synthesizing the 1-C-alkyl-O-glycosides.2
We previously studied the glycosidations using 1-O-di-
methylphosphinothioyl sugars6 and 1-O-acetyl sugars7 as the
glycosyl donors. The former study showed that the glyco-
sidations using the dimethylphosphinothioyloxy function
as the leaving group were activated by a catalytic amount
of triphenylmethyl perchlorate (TrtClO4). In the latter study,
ytterbium(III) triflate (Yb(OTf)3) was found to be an effec-
tive activator for the glycosidations using the acetoxy func-
tion as the leaving group.
The reported methods for synthesizing the 1-C-alkyl-O-
hexopyranosides involve glycosidations using the exo-glycal
or 1-C-alkyl-sugar derivatives as the glycosyl donors.
Although a few exo-glycals are conveniently utilized as
the glycosyl donors in both enzymatic and chemical glyco-
sidations,3 there appears to be limitations in the use of the
exo-glycals due to their synthetic difficulty. On the other
hand, various kinds of 1-C-alkyl-sugar derivatives could
be readily prepared by the reactions of the corresponding
Our recent interest in the formation reaction of 1-C-alkyl-
hexopyranosidic linkages by the O-glycosidation prompted
us to start an investigation of the catalytic synthesis of
1-C-alkyl-hexopyranosides using our newly developed
glycosidation methods. Part of the study was reported in
a preliminary letter about the synthesis of 1-C-alkyl-gluco-
pyranosides by the glycosidation of the 1-C-alkyl-D-gluco-
pyranosyl donors having the acetoxy function as a leaving
group. The reaction was activated by a catalytic amount of
Keywords: 1-C-Alkyl-glycopyranose; Ketopyranoside; Glycosidation;
Lewis acid; Brønsted acid.
* Corresponding author. Tel./fax: +81 3 5944 3213; e-mail: tyama@
noguchi.or.jp
0040–4020/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tet.2006.08.059

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T. Yamanoi et al. / Tetrahedron 62 (2006) 10383–10392
scandium(III) triflate (Sc(OTf)3).8 The following letter
describes the Brønsted acid-catalyzed glycosidation used
to synthesize 1-C-alkyl-glucopyranosides. During the glyco-
sidation, the anomeric hydroxyl function of the glycosyl
donors, the 1-C-alkyl-D-glucopyranoses, was conveniently
utilized as the leaving group.9 In these letters were men-
tioned some of the interesting glycosidation properties based
on these 1-C-alkyl-D-glucopyranosyl donor’s reactivities.
However, we considered that the 1-C-alkyl-hexopyranosyl
donors would have some unknown reactivities and their elu-
cidation would be important for their utilization in synthetic
carbohydrate chemistry.
preparing the aldopyranosyl dimethylphosphinothioates.6
The reaction of 2a with dimethylphosphinothioyl (Mpt)
chloride (1.2 equiv) using BunLi (1.2 equiv) in THF at 0 ꢀC
produced
2,3,4,6-tetra-O-benzyl-1-C-methyl-a-D-gluco-
pyranosyl dimethylphosphinothioate (3a) in 55% yield
(Scheme 2). However, similar reaction conditions using 2b
and 2c gave the corresponding dimethylphosphinothioates
in very poor yields. It is possible that the steric hindrances
on the anomeric centers of 2b and 2c and the bulkiness of
Mpt-Cl prevented introduction of the Mpt group into 2b
and 2c. Compound 3a was not as stable as the aldopyranosyl
dimethylphosphinothioates that we had previously prepared.
Therefore, 3a was used in the glycosidation reaction immedi-
ately after the purification using thin-layer chromatography.
In order to develop efficient synthetic methods for producing
1-C-alkyl-hexopyranosides, in this full paper, we summarize
theglycosidations using theglycosyl donors of the 1-C-alkyl-
2,3,4,6-tetra-O-benzyl-D-glucopyranosyldimethylphosphino-
thioates, 1-C-alkyl-2,3,4,6-tetra-O-benzyl-D-glucopyranosyl
acetates, and 1-C-alkyl-2,3,4,6-tetra-O-benzyl-D-glucopyra-
noses in the presence of catalytic amounts of Lewis acids
or Brønsted acids as the activators.
OBn
O Me
S
n
Bu Li
THF, 0 °C
BnO
BnO
+
2a
Cl-PMe2
BnO
3a
O
P(S)Me2
Scheme 2.
2.1.3. Glycosidation of 2,3,4,6-tetra-O-benzyl-1-C-methyl-
a-D-glucopyranosyl dimethylphosphinothioate (3a).11 The
reactivity of 3a as a glycosyl donor was expected to be high
because the electron donating effect of the methyl group in
3a would stabilize the glycosyl cation intermediate generated
from 3a in spite of its tertiary anomeric carbon center’s steric
hindrance.
2. Results and discussion
2.1. Glycosidation of the 1-C-alkyl-D-glucopyranosyl
dimethylphosphinothioate derivatives
We describe the preparation of the 1-C-alkyl-2,3,4,6-tetra-
O-benzyl-D-glucopyranosyl dimethylphosphinothioates and
their catalytic O-glycosidation to synthesize the 1-C-alkyl-
D-glucopyranosides.
Since our former research showed that the trityl salts were
efficient activators for the highly reactive glycosyl donors
such as the 2-deoxy-glycopyranosyl dimethylphosphino-
thioates, we used the trityl salts as the activators of 3a in
this glycosidation study. When 3a was glycosylated with
3b-cholestanol (4) using 10 mol % of TrtClO4 in benzene
at room temperature (Scheme 3), the corresponding 1-C-
methyl-D-glucopyranoside derivative (5a) was successfully
obtained in high yield of 88% with an a-stereoselectivity.
Even the reaction using only 5 mol % of TrtClO4 could
afford 5a in 71% yield. When other trityl salts were used,
the reactions using 10 mol % of triphenylmethyl hexachloro-
antimonate (TrtSbCl6), triphenylmethyl tetrafluoroborate
(TrtBF4), and triphenylmethyl pentachlorotin (TrtSnCl5) af-
forded 5a in moderate yields from 34 to 43%. The maximum
yield was attained from the reaction using 10 mol % of
TrtClO4. Although the combined use of I2 and 10 mol %
of TrtClO4 was found to be an effective activating system
for the glycosidation of several aldopyranosyl dimethyl-
phosphinothioates, the reaction between 3a and 4 using
this activating system did not produce 5a at all, but gave
an unknown product.
2.1.1. Preparation of 1-C-alkyl-2,3,4,6-tetra-O-benzyl-
a-D-glucopyranoses. According to the reported method,
several 1-C-alkyl-2,3,4,6-tetra-O-benzyl-a-D-glucopyrano-
ses (R1¼alkyl; methyl: a, ethyl: b, n-butyl: c, benzyl: d)
were prepared in high yields by the addition of the RLi
or RMgX reagent to 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-
lactone (1)10 (Scheme 1; Table 1).
OBn
O R1
BnO
BnO
BnO
OH
2a-d
Scheme 1.
Table 1. 1-C-Alkyl-2,3,4,6-tetra-O-benzyl-a-D-glucopyranose
Entry
R1
1-C-Alkyl-D-glucopyranose derivatives
1
2
3
4
Me
Et
2a
2b
2c
2d
Bun
CH2Ph
OBn
trityl salt
PhH, rt.
Me
O
BnO
BnO
R2OH
+
4, 6, 7
3a
2
BnO
OR
5a, 8a, 9a
2.1.2. Preparation of the 1-C-alkyl-2,3,4,6-tetra-O-
benzyl-D-glucopyranosyl dimethylphosphinothioates.
We examined the preparation of the 1-C-alkyl-2,3,4,6-tetra-
O-benzyl-D-glucopyranosyl dimethylphosphinothioates from
2a–d, according to our previously reported method for
Scheme 3.
Next, the glycosidation of 3a with n-octanol (6) or 1,2:
3,4-di-O-isopropylidene-a-D-galactopyranose (7) as the

T. Yamanoi et al. / Tetrahedron 62 (2006) 10383–10392
10385
Table 2. The glycosidation of 3a with alcohols (4, 6, and 7) in the presence
of trityl saltsa
+
-
R2OH
ClO4
Me
TrtClO4
O Me
O Me
OR2
O
O
P(S)Me2
Entry
Trityl salt (mol %)
Alcohol
Product
Yield (%)
O=P(S-Trt)Me2
HClO4
1
2
3
4
5
6
7
8
TrtClO4 (10)
TrtClO4 (5)
TrtSbCl6 (10)
TrtBF4 (10)
TrtPF6 (10)
TrtSnCl5 (10)
TrtClO4 (10)
TrtClO4 (10)
4
4
4
4
4
4
6
7
5a
5a
5a
5a
5a
5a
8a
9a
88
71
43
34
TrtClO4
HOP(S)Me2
No reaction
43
82
Scheme 4.
82b
investigated the glycosidation of the 1-C-alkyl-D-glucopyra-
nosyl donors having an acetoxy function as a leaving group
using Lewis acids as activators. As the acetyl group was less
bulky than the Mpt group, the acetyl group was expected
to be smoothly introduced into 2a–d in order to prepare
the corresponding 1-C-alkyl-D-glucopyranosyl acetates.
We describe the preparation of the 1-C-alkyl-2,3,4,6-tetra-
O-benzyl-D-glucopyranosyl acetates and the synthesis of
various 1-C-alkyl-2,3,4,6-tetra-O-benzyl-D-glucopyrano-
sides by the Lewis acid-catalyzed O-glycosidation using
them as the glycosyl donors.
a
Reaction conditions: molar ratio, 3a:alcohol¼1:1; reaction time, 1 h;
reaction temperature, rt.
The a/b ratio of glycoside was 70/30.
b
glycosyl acceptor was performed under similar reaction
conditions using 10 mol % of TrtClO4 in benzene. The
corresponding n-octyl 2,3,4,6-tetra-O-benzyl-1-C-methyl-
a-D-glucopyranoside (8a) was obtained in 82% yield with
an a-stereoselectivity, and 6-O-(2,3,4,6-tetra-O-benzyl-
1-C-methyl-a-D-glucopyranosyl)-1,2:3,4-di-O-isopropyl-
idene-a-D-galactopyranose (9a) was also obtained in 82%
yield with an a/b ratio¼70/30. The b-form of 9a would
be partially formed by the SN2-like reaction mechanism.
Judging from the glycosidation yields, 3a expectedly
worked as a highly reactive glycosyl donor in spite of its
sterically hindered tertiary anomeric carbon center. These
results are summarized in Table 2 (Fig. 1). The expected
reaction mechanism is indicated in Scheme 4.
2.2.1. Preparation of the 1-C-alkyl-2,3,4,6-tetra-O-benzyl-
D-glucopyranosyl acetates. We investigated the preparation
of 2,3,4,6-tetra-O-benzyl-1-C-methyl-D-glucopyranosyl ace-
tate (10a)12 by the acetylation of 2a (Scheme 5). Although
the ordinary acetylation of 2a using Ac2O/pyridine could
not give 10a at all, the use of BunLi as a strong base in
lieu of pyridine was effective. Compound 10a was obtained
in 69% yield by the reaction of 2a with BunLi followed
by the addition of Ac2O in THF at ꢁ78 ꢀC. In the next
experiment, the reaction temperature was gradually raised
as follows. After the reaction of 2a with BunLi at ꢁ78 ꢀC,
Ac2O was added to the reaction mixture at ꢁ30 ꢀC, and the
reaction was quenched at 0 ꢀC. The yield of 10a increased
to 80%.13
We found that the glycosidation of 3a with several alcohols in
the presence of 10 mol % of TrtClO4 in benzene at room tem-
perature smoothly proceeded to afford the 1-C-methyl-D-glu-
copyarnosides in good yields with high a-stereoselectivities.
2.2. Glycosidation of the 1-C-alkyl-D-glucopyranosyl
acetate derivatives
In order to establish the method for producing the 1-C-alkyl-
D-glucopyranosides having various kinds of alkyl groups, we
As another convenient synthetic route, the one-pot synthesis
of 10a from 1 was examined (Scheme 5). When the reaction
OH
O
O
HO
O
OH
O
O
HO
6
11
4
7
OH
O
OBn
O
B(OPh)3
BnO
BnO
BnO
BnO
13
BnO
15
BnO
16
OMe
OH
OBn
O
OBn
R1
BnO
OBn
Me
O
Me
BnO
BnO
BnO
BnO
O
BnO
BnO
O
BnO
O
O
BnO
O
O
5a
8a
O
9a-d
O
O
OBn
OBn
OBn
O Me
OBn
O
BnO
BnO
CH2Ph
O R1
BnO
BnO
O
BnO
BnO
Me
BnO
BnO
BnO
BnO
O
BnO
BnO
BnO
O
O
14a
O
12a-d
O
OBn
OBn
OBn
BnO
O
BnO
17d
OMe
BnO
18a
Figure 1. The acceptors utilized in the glycosidations and glycosides synthesized.

10386
T. Yamanoi et al. / Tetrahedron 62 (2006) 10383–10392
OBn
O
10a. Even the reaction using only 1 mol % of Sc(OTf)3 could
BnO
BnO
afford 12a in the yield of 73%, and only this reaction
produced a small amount of the b-isomer (a/b¼81/19). The
effect of the solvents was also examined using CH2Cl2,
PhCH3, and CH3CN. The reaction using PhCH3 increased
the yield of 12a up to 89%, however, these solvents did not
influence the glycosidation stereoselectivities at all.
O
BnO
1
Method A
R1Li or R1MgX
Method B
i) R1Li or R1MgX (-78 -30 °C)
ii) Ac2O (-30 0 °C)
(R1= Me, Et)
(R1= Me, Bun, CH2Ph)
Step 1
THF
THF, -78 °C
i) BunLi
ii) Ac2O
OBn
O
Furthermore, we examined the glycosidation of the 1-C-
alkyl-D-glucopyranosyl acetates (10a–d) with 11 or 7 under
similar reaction conditions. The reactions of 10a–d with 11
or 7 in the presence of 5 mol % of Sc(OTf)3 in PhCH3 stereo-
selectively afforded the corresponding phenethyl 1-C-alkyl-
2,3,4,6-tetra-O-benzyl-a-D-glucopyranosides (12b–d) or
6-O-(1-C-alkyl-2,3,4,6-tetra-O-benzyl-a-D-glucopyranosyl)-
1,2:3,4-di-O-isopropylidene-a-D-galactopyranoses (9a–d)
in the yields from 73 to 89%, respectively.
2a-d
R1
BnO
BnO
THF, -30 0 °C
BnO
OAc
10a-d
Step 2
Scheme 5.
of 1 with MeLi was carried out at ꢁ78 ꢀC in THF and Ac2O
was added at ꢁ30 ꢀC, followed by quenching the reaction at
0 ꢀC, 10a was obtained in 73% yield.
Our recent study indicated that triaryloxyboranes worked as
the reactive glycosyl acceptors of glycosyl acetates in the
presence of a catalytic amount of Yb(OTf)3 to afford the
corresponding aryl O-glycosides.7c Therefore, the synthesis
of phenyl 2,3,4,6-tetra-O-benzyl-1-C-methyl-a-D-gluco-
pyranoside (14a) was attempted by the reaction of 10a
with triphenoxyborane (13) using 5 mol % of Yb(OTf)3 in
CH2Cl2 at ꢁ78 ꢀC. The desired 14a was obtained in 80%
yield with an a-stereoselectivity. These results are shown in
Table 4 (Fig. 1). The proposed reaction mechanism is shown
in Scheme 7.
Furthermore, we examined the preparation of the 2,3,4,6-
tetra-O-benzyl-1-C-ethyl-a-D-glucopyranosyl acetate (10b),
2,3,4,6-tetra-O-benzyl-1-C-n-butyl-a-D-glucopyranosyl
acetate (10c), and 1-C-benzyl-2,3,4,6-tetra-O-benzyl-a-D-
glucopyranosyl acetate (10d). The acetate 10b–d were
prepared in good yields with a-stereoselectivities by the
acetylation of 2c and 2d using BunLi and Ac2O or by
the one-pot synthesis from 1 using EtMgBr and Ac2O
(Scheme 5). These results are summarized in Table 3.
Table 4. Synthesis of various 1-C-alkyl-a-D-glucopyranosides by the glyco-
sidation of 10a–d with acceptors (7, 11, and 13)a
Table 3. Preparation of 10a–d
Entry Acetate Alcohol Activator Solvent Product Yield (%)b
Entry Starting sugar derivative Methoda Product Yield (%)
1
2
3
4
10a
10a
10a
10a
10a
10a
10a
10a
10b
10c
10d
10a
10a
10b
10c
10d
10a
11
11
11
11
11
11
11
11
11
11
11
7
7
7
7
7
13
Yb(OTf)3 CH2Cl2 12a
Sc(OTf)3 CH2Cl2 12a
TMSOTf CH2Cl2 12a
76
80
69
74
67
73d
89
63
86
75
77
82
87e
77
73
74
80
1
2
3
4
5
2a
1
1
2c
2d
A
B
B
A
A
10a
10a
10b
10c
10d
80 (69)b
73
86
88
81
TrtClO4
CH2Cl2 12a
5
BF3$OEt2 CH2Cl2 12a
Sc(OTf)3 CH2Cl2 12a
Sc(OTf)3 PhCH3 12a
Sc(OTf)3 CH3CN 12a
Sc(OTf)3 PhCH3 12b
Sc(OTf)3 PhCH3 12c
Sc(OTf)3 PhCH3 12d
6c
7
Method A: after the reaction of 2a (2c or 2d) with BunLi (1.1 equiv) was
carried out in THF at ꢁ78 ꢀC, Ac2O (6 equiv) was added to the reaction
mixture at ꢁ30 ꢀC and the reaction was quenched by satd NaHCO3 solu-
tion at 0 ꢀC; Method B: after the reaction of 1 with MeLi or EtMgBr
(1.2 equiv) was carried out in THF at ꢁ78 ꢀC, Ac2O (6 equiv) was added
to the reaction mixture at ꢁ30 ꢀC and the reaction was quenched by satd
NaHCO3 solution at 0 ꢀC.
a
8
9
10
11
12
13c
14
15
16
17f
Sc(OTf)3 PhCH3
Sc(OTf)3 PhCH3
Sc(OTf)3 PhCH3
Sc(OTf)3 PhCH3
Sc(OTf)3 PhCH3
9a
9a
9b
9c
9d
b
The reaction was performed at ꢁ78 ꢀC.
2.2.2. Glycosidation of the 1-C-alkyl-2,3,4,6-tetra-O-
benzyl-a-D-glucopyranosyl acetates (10a–d). We exam-
ined in detail the glycosidation of 10a with phenethyl alcohol
(11) in the presence of various Lewis acids (Scheme 6).
When 5 mol % of a Lewis acid such as Yb(OTf)3, Sc(OTf)3,
TMSOTf, TrtClO4, and BF3$OEt2 was used as the activator
in dichloromethane at 0 ꢀC, each Lewis acid could activate
the glycosidation to give the corresponding glycoside 12a
in 67–80% yields with an a-stereoselectivity. Yb(OTf)3
and Sc(OTf)3 were especially effective for the activation of
Yb(OTf)3 CH2Cl2 14a
a
Reaction conditions: molar ratio, 10a–d:11:activator¼1:1:0.05; 10a–d:7:
activator¼1.5:1:0.075; reaction time, 1–3 h; reaction temperature, 0 ꢀC.
Only the a-glycoside was obtained.
Sc(OTf)3 (1 mol %) was used.
The a/b ratio of glycoside was 81/19.
b
c
d
e
f
The a/b ratio of glycoside was 85/15.
Reaction conditions: molar ratio, 10a:13:activator¼1:0.5:0.05; reaction
time, 3 h; reaction temperature, ꢁ78 ꢀC.
+
TfO-
R1
R2OH
O R1
OAc
O R1
OR2
Sc(OTf)3
O
OBn
R1
Lewis acid
TfOH
AcOSc(OTf)2
Sc(OTf)3
O
BnO
BnO
R2OH
10a-d
+
Solvent
OR2
9a-d, 12a-d, 14a
BnO
7, 11, 13
AcOH
Scheme 7.
Scheme 6.

T. Yamanoi et al. / Tetrahedron 62 (2006) 10383–10392
10387
Inanaga et al. reported that lanthanide triflates could not ac-
tivate at all the glycosidation using 2,3,4,6-tetra-O-benzyl-D-
glucopyranosyl acetate as the glycosyl donor.14 This is quite
different from our observations that any glycosidation using
10a–d smoothly proceeded in the presence of only 5 mol %
of Sc(OTf)3. These results showed that 10a–d indicated
a much higher reactivity than the 2,3,4,6-tetra-O-benzyl-
D-glucopyranosyl acetate as the glycosyl donor and the exis-
tence of the alkyl groups on 10a–d remarkably increased
their glycosyl donor’s reactivities. Moreover, the species of
the alkyl groups at the anomeric carbon centers of 10a–d
had almost no influence on the reactivities and stereo-
selectivities of the glycosidation. The reactivities of 10a–d
were similar to those of 3a.
(C8F17SO3H) and bis(trifluoromethane)sulfonimide (Tf2NH)
as the Brønsted acid analogs of TfOH and tetrafluoroboric
acid (HBF4) were similarly effective for the glycosidation
of 2a under similar reaction conditions. Particularly,
Tf2NH gave 12a in the maximum yield of 77%. Although
10 mol % of Tf2NH hardly increased the yield of 12a, the re-
action even using 1 mol % of Tf2NH gave 12a in 56% yield.
We also investigated the glycosidation of 2b–d with 11 in
acetonitrile at 0 ꢀC using 5 mol % of Tf2NH in order to
investigate how the difference in the alkyl groups at the
anomeric carbon centers would influence the reactivity and
stereoselectivity of the glycosidation. The desired 12b–d
were then obtained in yields ranging from 56 to 64% with
high a-stereoselectivities. The difference in the alkyl groups
at the anomeric carbon centers of 2a–d had almost no influ-
ence on the glycosidation reactivity and stereoselectivity.
This is similar to the above-mentioned glycosidation proper-
ties using 10a–d.
The high a-stereoselectivity of the glycosidation could be
explained by the anomeric effect and the disadvantageous
formation of b-glycosides due to the 1,3-diaxial interaction.
It was also possible that the anomerization might occur and
1-C-alkyl-b-glucopyranosides might be converted to the
corresponding a-glucopyranosides in the reaction system.
In order to examine this point, the b-glycoside of 9a (Table
4, entry 13) was added to the reaction in the presence of
10 mol % of Sc(OTf)3 in toluene at room temperature over-
night. No anomerization was observed in the reaction.
Furthermore, we examined the glycosidation of 2a (or 2d)
with 6, 7, and methyl 2,3,4-tri-O-benzyl-a-D-glucopyrano-
side (15) in acetonitrile at 0 ꢀC using 5 mol % of Tf2NH
or TfOH. The desired 8a, 9a, and methyl 6-O-(1-C-benzyl-
2,3,4,6-tetra-O-benzyl-a-D-glucopyranosyl)-2,3,4-tri-O-
benzyl-a-D-glucopyranoside (17d) were stereoselectively
obtained in good yields of 78, 55, and 66%, respectively. In-
terestingly, even when the anomeric mixture of 16 was used
as the glycosyl acceptor, the trehalose analog (18a), the prod-
uct by the reaction of 2a with 16 was obtained as a single iso-
mer based on its NMR spectrum. In the 1H NMR spectrum
of 18a, the anomeric proton of the glucopyranosyl residue
was observed at 5.34 ppm with a doublet peak (J¼3.4 Hz),
and the value of the coupling constant indicated a. This
suggested that the glycosidation strictly recognized the
anomeric stereochemistry of the acceptor 16 and only
the a-isomer of 16 was utilized as the glycosyl acceptor.
These results are summarized in Table 5 (Fig. 1). The pro-
posed glycosidation mechanism is indicated in Scheme 9.
We found that 10a–d worked as good glycosyl donors in the
presence of only 5 mol % of Sc(OTf)3 in toluene at 0 ꢀC to
afford various 1-C-alkyl-D-glucopyranosides in good yields
with high a-stereoselectivities.
2.3. Glycosidation of the 1-C-alkyl-a-D-glucopyranose
derivatives
In order to develop a more convenient synthetic method for
producing 1-C-alkyl-D-glucopyranosides, the direct glyco-
sidation of the 1-C-alkyl-D-glucopyranoses 2a–d without
introducing any other leaving group was examined. We
describe the dehydration–condensation type glycosidation
of 2a–d with alcohols using a catalytic amount of Brønsted
acids as the activators.
We have successfully developed the direct dehydrative
glycosidation using 2a–d without introducing any other
leaving group into them, and found that the glycosidation
using 2a–d was efficiently catalyzed using only 5 mol %
of Tf2NH or TfOH as the activators to afford various 1-C-
alkyl-a-D-glucopyranosides in good yields.
2.3.1. Glycosidation of the 1-C-alkyl-2,3,4,6-tetra-O-
benzyl-a-D-glucopyranoses (2a–d). We investigated the
dehydration–condensation type glycosidation using 2a as
a glycosyl donor and 11 as a glycoyl acceptor (Scheme 8).
Brønsted acids were used as the activators for this glycosida-
tion because they were expected to be potentially resistant to
water. As the Brønsted acids, 5 mol % of camphorsulfonic
acid, trifluoroacetic acid (CF3CO2H), and TfOH were used
in dichloromethane at 0 ꢀC in the presence of a drying agent,
Drierite (anhydrous CaSO4). Only TfOH could effectively
activate the glycosidation to stereoselectively give the cor-
responding 12a in 59% yield. The use of acetonitrile as the
solvent slightly increased the yield of 12a up to 73% with
an a-stereoselectivity. Heptadecafluorooctanesulfonic acid
3. Determination of the anomeric configurations of
1-C-alkyl-2,3,4,6-tetra-O-benzyl-D-glucopyranosyl
donors and 1-C-alkyl-2,3,4,6-tetra-O-benzyl-
D-glucopyranosides
The anomeric configurations of all the 1-C-alkyl-D-gluco-
pyranosyl donors (2a–d, 3a, and 10a–d) and 1-C-alkyl-
D-glucopyranosides (5a, 8a, 9a–d, 12a–d, 14a, 17d, and
18a) were determined by their NMR spectra. The a-forms
of them were determined by the measurement of the NOE
interactions between H-2 and H-10 of the alkyl groups of the
1-C-alkyl-D-glucopyranosyl rings as shown in Figure 2. The
b-forms of 9a and 12a were determined by the measure-
ments of the NOE interactions between H-3 (or H-5)
and H-10 of the methyl groups. Furthermore, the anomeric
OBn
Brφnsted acid
Solvent, 0 °C
O
R1
BnO
BnO
R2OH
2a-d
+
OR2
BnO
6, 7, 11, 15, 16
8a, 9a, 12a-d, 17d, 18a
Scheme 8.

10388
T. Yamanoi et al. / Tetrahedron 62 (2006) 10383–10392
Table 5. The glycosidation of 2a–d with various alcohols (6, 7, 11, 15, and 16) in the presence of Brønsted acida
Entry
1-C-Alkyl-glucopyranose
Alcohol
Brønsted acid (mol %)
Solvent
Product
Yield (%)
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2a
2a
2d
2a
11
11
11
11
11
11
11
11
11
11
11
11
11
6
Camphorsulfonic acid (5)
CF3CO2H (5)
TfOH (5)
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
12a
12a
12a
12a
12a
12a
12a
12a
12a
12a
12b
12c
12d
8a
No reaction
No reaction
59
73
56
77
73
69
65
56
57
64
56
78
55
66
47
TfOH (5)
C8F17SO3H (5)
Tf2NH (5)
HBF4 (5)
Tf2NH (10)
Tf2NH (3)
Tf2NH (1)
Tf2NH (5)
Tf2NH (5)
Tf2NH (5)
Tf2NH (5)
9
10
11
12
13
14
15b
16b
17b
7
15
16
Tf2NH (5)
TfOH (5)
Tf2NH (5)
9a
17d
18a
a
Reaction conditions: molar ratio, 2a–d:alcohol (6 or 11):Brønsted acid¼1:1:0.05; reaction time, 2 h; reaction temperature, 0 ꢀC.
b
Reaction conditions: molar ratio, 2a,d:alcohol (7, 15 or 16):Brønsted acid¼1.5:1:0.075; reaction time, 3 h; reaction temperature, 0 ꢀC.
+
TMS (dH¼0.00). The 13C NMR chemical shifts are refer-
Tf2N-
R1
O R1
OH
R2OH
O R1
OR2
Tf2NH
O
enced to the solvent signal (dC¼77.0 for the central line of
CDCl3). The ESI-MS spectra were recorded on a Mariner
(Applied Biosystems) spectrometer. Optical rotations were
recorded using a JASCO DIP-360 digital polarimeter. All
reactions were monitored by thin-layer chromatography
(TLC) using Merck silica gel 60 F254 precoated plates
(0.25 mm).
Tf2NH
H2O
Scheme 9.
NOE
BnO
BnO
H
H
H
5.2. Preparation of 2,3,4,6-tetra-O-benzyl-1-C-methyl-
a-D-glucopyranosyl dimethylphosphinothioate (3a)
O
R''
5
3
1'
BnO
1
2
BnO
OR'
To a solution of 2a (300 mg, 0.54 mmol) in dry THF (3 mL)
at 0 ꢀC was added a hexane solution of BunLi (0.65 mmol) un-
der an Ar atmosphere and stirred for 30 min. Mpt-Cl (88 mg,
0.69 mmol) was added to the solution, and stirred for 1 h at
0 ꢀC. The reactionwas then quenched bythe additionofwater.
The reaction mixture was extracted with CH2Cl2, and the or-
ganic layer was washed with water and a satd NaCl solution.
After the organic layer was dried over Na2SO4, the solvent
was evaporated under reduced pressure. The crude product
was purified by preparative silica gel TLC (CH2Cl2/ethyl
acetate/hexane¼1/1/4) to give 3a as a colorless oil (191 mg,
55%). [a]2D3 +48.8 (c 1.01, CHCl3); 1H NMR (CDCl3):
d 1.87 (3H, d, JHCCOP¼0.6 Hz, CH3), 1.90 (3H, d,
JHCP¼6.2 Hz, PCH3), 1.92 (3H, d, JHCP¼6.2 Hz, PCH3),
3.19 (1H, dd, J¼9.6 Hz, JHCCOC¼4.1 Hz, H-20), 3.92–3.80
(2H, m, H-6), 3.74 (1H, t, J¼9.6 Hz, H-4), 3.85 (1H, t,
J¼9.6 Hz, H-3), 3.87–3.90 (1H, m, H-5); 13C NMR
(CDCl3): d 24.3 (JCCOP¼4.3 Hz), 25.5 (JCP¼73.7 Hz), 26.0
(JCP¼70.8 Hz), 68.3, 73.0, 73.5, 75.2, 75.5, 75.7, 78.8, 82.8,
84.3 (JCCOP¼5.8 Hz), 105.8 (JCOP¼10.1 Hz); HRMS (ESI)
m/z calcd for C37H43O6PS$Na+: 669.2410; found: 669.2443.
Figure 2. The determination of anomeric configurations of 3a, 10a–d, and
glycosides.
configuration of 12a could be determined by the NMR
spectrum of the three bond coupling constants between the
3
carbon of the 10-C-methyl and the H-2 ( JC1 ,H2¼2.5 Hz
0
3
0
was a; JC1 ,H2¼1.5 Hz was b), according to the observa-
tions of Schlesselmann et al.3e
4. Conclusions
We have successfully developed the catalytic synthesis of
various kinds of 1-C-alkyl-a-D-glucopyranosides carrying the
methyl, ethyl, n-butyl, and benzyl groups as the alkyl groups
at their anomeric positions by glycosidation using several
1-C-alkyl-D-glucopyranosyl donors with the dimethylphos-
phinothioyloxy, acetoxy, andhydroxylfunctionsastheleaving
groupsin the presence of TrtClO4, Sc(OTf)3, and Tf2NH as the
activators, respectively. We believe that this study can provide
novel methods to synthesize biologically important neoglyco-
conjugates having 1-C-alkyl-sugar units.
5.3. Preparation of 1-C-alkyl-2,3,4,6-tetra-O-benzyl-a-
D-glucopyranosyl acetates
5. Experimental
5.1. General
5.3.1. Typical preparation by the acetylation of 1-C-
alkyl-2,3,4,6-tetra-O-benzyl-a-D-glucopyranoses. To
a
solution of 2a (123 mg, 0.2 mmol) in dry THF (1 mL) at
ꢁ78 ꢀC was added a hexane solution of BunLi (0.24 mmol)
under an Ar atmosphere and the reaction temperature was
raised to ꢁ30 ꢀC for 1 h while stirring. Then, acetic
The NMR spectra were measured using an ECA-600 (JEOL)
spectrometer at 600 MHz (1H) and 150 MHz (13C). The 1H
NMR chemical shifts are referenced to the internal standard

T. Yamanoi et al. / Tetrahedron 62 (2006) 10383–10392
10389
anhydride (0.3 mL) was added to the solution and the reac-
tion temperature was gradually raised to 0 ꢀC for 1 h. The re-
action was then quenched by the addition of a satd NaHCO3
solution (5 mL). The reaction mixture was extracted with
CHCl3, and the organic layer was washed with water and
a satd NaCl solution. After the organic layer was dried
over Na2SO4, the solvent was evaporated under reduced
pressure. The crude product was purified by preparative
silica gel TLC (ethyl acetate/hexane¼1/4) to give 10a as
a colorless oil (111 mg, 85%).
5.3.6. 1-C-Benzyl-2,3,4,6-tetra-O-benzyl-a-D-glucopyra-
nosyl acetate (10d). Colorless oil; [a]2D3 +46.1 (c 1.37,
CHCl3); H NMR (CDCl3): d 2.14 (3H, s, CH3), 3.25 (1H,
1
d, J¼13.7 Hz, CCHaHbPh), 3.30 (1H, d, J¼8.9 Hz, H-2),
3.67–3.70 (1H, m, H-5), 3.73 (1H, t, J¼9.0 Hz, H-4), 3.80
(1H, dd, J¼2.0 Hz, J¼11.0 Hz, Ha-6), 3.87 (1H, dd, J¼
2.8 Hz, J¼11.0 Hz, Hb-6), 4.03 (1H, t, J¼8.9 Hz, H-3),
4.20 (1H, d, J¼13.8 Hz, CCHaHbPh); 13C NMR (CDCl3):
d 22.4, 39.9, 68.5, 73.3, 73.6, 74.5, 75.2, 75.5, 77.6,
79.5, 83.3, 106.8, 168.9; HRMS (ESI) m/z calcd for
C43H44O7$Na+: 695.2985; found: 695.2944.
5.3.2. Typical preparation from 2,3,4,6-tetra-O-benzyl-
D-glucono-1,5-lactone. To a solution of 1 (288.8 mg,
0.54 mmol) in dry THF (3 mL) at ꢁ78 ꢀC was added a di-
ethyl ether solution of MeLi (0.64 mmol) under an Ar atmo-
sphere and the reaction temperature was raised to ꢁ30 ꢀC for
1 h while stirring. Acetic anhydride (0.6 mL) was then added
to the solution, and the reaction temperature was gradually
raised to 0 ꢀC for 1 h. The reaction was then quenched by
the addition of a satd NaHCO3 solution (5 mL). The reaction
mixture was extracted with CHCl3, and the organic layer was
washed with water and a satd NaCl solution. After the
organic layer was dried over Na2SO4, the solvent was evap-
orated under reduced pressure. The crude product was puri-
fied by preparative silica gel TLC (ethyl acetate/hexane¼
1/4) to give 10a as a colorless oil (233.7 mg, 73%).
5.4. Glycosidation
5.4.1. Typical glycosidation procedure using 3a as the
glycosyl donor. To a stirred solution of TrtClO4 (4 mg,
0.015 mmol) and 3b-cholestanol (58 mg, 0.15 mmol) in
benzene (2 mL) at room temperature was added 3a
˚
(96 mg, 0.15 mmol) in the presence of powdered 4 A molec-
ular sieves (ca. 100 mg). The resulting mixture was stirred
for 1 h. The reaction was then quenched by the addition of
a satd NaHCO3 solution (5 mL), and the reaction mixture
was filtered. The reaction mixture was extracted with ethyl
acetate, and the organic layer was washed with water and
a satd NaCl solution. After the organic layer was dried
over Na2SO4, the solvent was evaporated under reduced
pressure. The crude product was purified by preparative
silica gel TLC (ethyl acetate/hexane¼1/4) to give 5a as
a white solid (112 mg, 80%).
5.3.3. 2,3,4,6-Tetra-O-benzyl-1-C-methyl-a-D-glucopyra-
nosyl acetate (10a). [a]2D3 +45.2 (c 1.97, CHCl3); 1H NMR
(CDCl3): d 1.76 (3H, s, CH3), 2.07 (3H, s, C(O)CH3), 3.29
(1H, d, J¼9.5 Hz, H-2), 3.55–3.58 (1H, m, H-5), 3.67 (1H,
dd, J¼3.2 Hz, J¼11.1 Hz, Ha-6), 3.80 (1H, dd, J¼3.2 Hz,
J¼11.1 Hz, Hb-6), 3.82 (1H, t, J¼10.0 Hz, H-4), 4.02 (1H,
t, J¼9.3 Hz, H-3); 13C NMR (CDCl3): d 22.1, 22.3, 68.1,
73.2, 73.5, 75.2, 75.5, 75.9, 77.6, 82.8, 84.0, 104.3, 168.7;
HRMS (ESI) m/z calcd for C37H40O7$Na+: 619.2672; found:
619.2602.
5.4.2. Typical glycosidation procedure using 10a–d as the
glycosyl donors. To a stirred solution of Sc(OTf)3 (4.4 mg,
0.0089 mmol) and phenethyl alcohol (20.7 mg, 0.17 mmol)
in toluene was added 10a (101.2 mg, 0.17 mmol) at 0 ꢀC in
the presence of Drierite (ca. 100 mg). The resulting mixture
was stirred for 1 h. The reaction was then quenched by the
addition of a satd NaHCO3 solution (5 mL). The reaction
mixture was extracted with ethyl acetate, and the organic
layer was washed with water and a satd NaCl solution. After
the organic layer was dried over Na2SO4, the solvent was
evaporated under reduced pressure. The crude product was
purified by preparative silica gel TLC (ethyl acetate/
hexane¼1/4) to give 12a as a colorless oil (99.2 mg, 89%).
5.3.4. 2,3,4,6-Tetra-O-benzyl-1-C-ethyl-a-D-glucopyra-
nosyl acetate (10b). Colorless oil; [a]2D3 +47.7 (c 2.45,
CHCl3); 1H NMR (CDCl3): d 0.88 (3H, t, J¼1.6 Hz,
CH2CH3), 2.05 (1H, m, CHaHbCH3), 2.08 (3H, s, C(O)CH3),
2.58 (1H, m, CHaHbCH3), 3.52 (1H, d, J¼8.9 Hz, H-2), 3.65
(1H, m, H-5), 3.70 (1H, dd, J¼1.4 Hz, J¼10.0 Hz, Ha-6),
3.80 (2H, m, H-4, Hb-6), 4.00 (1H, t, J¼8.9 Hz, H-3); 13C
NMR (CDCl3): d 8.1, 22.3, 26.6, 68.4, 73.4, 73.5, 75.2, 75.3,
75.5, 77.8, 80.0, 83.1, 107.0, 168.7; HRMS (ESI) m/z calcd
for C38H42O7$Na+: 633.2823; found 633.2786.
5.4.3. Typical glycosidation procedure using 2a–d as the
glycosyl donors. To a stirred solution of Tf2NH (2.8 mg,
0.01 mmol) and 11 (24 mg, 0.2 mmol) in acetonitrile was
added 2a (111 mg, 0.2 mmol) at 0 ꢀC in the presence of
Drierite (ca. 100 mg). The resulting mixture was stirred for
2 h. The reaction was then quenched by the addition of a
satd NaHCO3 solution (5 mL). The reaction mixture was ex-
tracted with ethyl acetate, and the organic layer was washed
with water and a satd NaCl solution. After the organic layer
was dried over Na2SO4, the solvent was evaporated under
reduced pressure. The crude product was purified by prepar-
ative silica gel TLC (ethyl acetate/hexane¼1/4) to give 12a
as a colorless oil (102 mg, 77%).
5.3.5. 2,3,4,6-Tetra-O-benzyl-1-C-n-butyl-a-D-glucopyra-
nosyl acetate (10c). Colorless oil; [a]2D3 +35.1 (c 7.16,
CHCl3); 1H NMR (CDCl3): d 0.83 (3H, t, J¼7.6 Hz,
CH2CH2CH2CH3), 1.15 (1H, m, CH2CHaHbCH2CH3),
1.17 (1H, m, CH2CH2CHaHbCH3), 1.25 (1H, m,
CH2CH2CHaHbCH3), 1.47 (1H, m, CH2CHaHbCH2CH3),
2.02 (1H, m, CHaHbCH2CH2CH3), 2.07 (3H, s, C(O)CH3),
2.51 (1H, m, CHaHbCH2CH2CH3), 3.51 (1H, d, J¼8.9 Hz,
H-2), 3.58 (1H, m, H-5), 3.68 (1H, dd, J¼1.4 Hz, J¼
11.0 Hz, Ha-6), 3.77–3.82 (2H, m, H-4, Hb-6), 4.00 (1H,
t, J¼9.0 Hz, H-3); 13C NMR (CDCl3): d 14.0, 22.3,
22.8, 25.9, 33.4, 68.4, 73.4, 73.4, 75.2, 75.3, 75.5, 77.8,
80.3, 83.2, 106.7, 168.7; HRMS (ESI) m/z calcd for
C40H46O7$Na+: 661.3136; found 661.3157.
5.4.4. 3b-Cholestanyl 2,3,4,6-tetra-O-benzyl-1-C-methyl-
a-D-glucopyranoside (5a). [a]D23 +39.0 (c 2.6, CHCl3);
mp: 159–159.5 ꢀC; H NMR (CDCl3): d 0.89–1.97 (47H,
m, 3b-cholestanyl), 1.34 (3H, s, CH3), 3.27 (1H, d,
J¼9.7 Hz, H-2), 3.58 (1H, t, J¼9.5 Hz, H-4), 3.63–3.73
1

10390
T. Yamanoi et al. / Tetrahedron 62 (2006) 10383–10392
(2H, m, H-6), 3.92–3.93 (1H, m, H-5), 4.06 (1H, t, J¼9.2 Hz,
H-3); 13C NMR (CDCl3): d 12.1, 12.4, 18.7, 21.2, 22.6, 22.9,
23.9, 24.3, 28.1, 28.3, 28.8, 30.3, 32.1, 35.5, 35.5, 35.8, 36.2,
36.4, 37.3, 39.5, 40.1, 42.6, 45.4, 54.4, 56.3, 56.5, 69.0, 71.2,
71.5, 75.4, 75.4, 73.3, 78.9, 83.1, 84.8, 100.8; Anal. Calcd for
C62H84O6: C, 80.48; H, 9.15. Found: C, 80.38; H, 9.39.
HRMS (ESI) m/z calcd for C48H58O11$Na+: 833.3877;
found: 833.3872.
5.4.8. 6-O-(2,3,4,6-Tetra-O-benzyl-1-C-n-butyl-a-D-
glucopyranosyl)-1,2:3,4-di-O-isopropylidene-a-D-
galactopyranose (9c). Colorless oil; [a]2D3 ꢁ4.6 (c 6.65,
CHCl3); 1H NMR (CDCl3): d 0.80 (3H, t, J¼7.6 Hz,
CH2CH2CH2CH3), 1.05 (1H, m, CH2CHaHbCH2CH3),
1.13 (1H, m, CH2CH2CHaHbCH3), 1.21–1.26 (2H, m,
CH2CHaHbCHaHbCH3), 1.32 (3H, s, C(CH3)2), 1.33 (3H,
s, C(CH3)2), 1.43 (3H, s, C(CH3)2), 1.52 (3H, s, C(CH3)2),
1.73–1.80 (2H, m, CH2CH2CH2CH3), 3.51 (1H, d,
J¼8.9 Hz, H-20), 3.61–3.66 (3H, m, H-40, Ha-60, Ha-6),
3.75–3.78 (2H, m, Hb-60, Hb-6), 3.96 (1H, dd, J¼2.1 Hz,
J¼9.6 Hz, H-5), 4.02 (1H, t, J¼5.5 Hz, H-50), 4.14 (1H, t,
J¼9.6 Hz, H-30), 4.27 (1H, dd, J¼2.1 Hz, J¼4.9 Hz, H-2),
4.31 (1H, dd, J¼2.1 Hz, J¼7.6 Hz, H-4), 4.58 (1H, dd,
J¼2.0 Hz, J¼7.5 Hz, H-3), 5.51 (1H, d, J¼4.9 Hz, H-1):
13C NMR (CDCl3): d 14.0, 23.0, 24.3, 25.0, 25.9, 26.0,
26.2, 32.6, 60.0, 67.5, 68.9, 70.7, 70.8, 71.2, 71.5, 73.0,
74.2, 74.5, 75.2, 78.7, 80.3, 83.1, 96.2, 102.0, 108.5,
109.1; HRMS (ESI) m/z calcd for C50H62O11$Na+:
861.4184; found: 861.4200.
5.4.5. n-Octyl 2,3,4,6-tetra-O-benzyl-1-C-methyl-a-D-
glucopyranoside (8a). Colorless oil; [a]2D3 +26.8 (c 1.65,
CHCl3); 1H NMR (CDCl3): d 0.87 (3H, t, J¼6.9 Hz,
CH2(CH2)6CH3), 1.27–1.30 (13H, m, CH3, CH2CH2(CH2)5CH3),
1.55–1.63 (2H, m, CH2CH2(CH2)5CH3), 3.32 (1H, d,
J¼9.6 Hz, H-2), 3.41 (2H, dd, J¼6.9 Hz, J¼7.6 Hz,
CH2(CH2)6CH3), 3.62 (1H, dd, J¼8.6 Hz, J¼9.6 Hz, H-4),
3.63–3.72 (3H, m, H-5, H-6), 4.08 (1H, dd, J¼8.9 Hz,
J¼9.6 Hz, H-3); 13C NMR (CDCl3): d 14.1, 21.0, 22.7, 26.3,
29.3, 29.4, 29.7, 31.8, 60.8, 68.9, 71.4, 78.8, 83.2, 84.1,
100.2; HRMS (ESI) m/z calcd for C43H54O6$Na+: 689.3813;
found: 689.3828.
5.4.6. 6-O-(2,3,4,6-Tetra-O-benzyl-1-C-methyl-a-D-glu-
copyranosyl)-1,2:3,4-di-O-isopropylidene-a-D-galacto-
pyranose (9a). Colorless oil; [a]2D3 ꢁ10.4 (c 3.35, CHCl3);
1H NMR (CDCl3): d 1.31 (3H, s, C(CH3)2), 1.32 (3H, s,
C(CH3)2), 1.37 (3H, s, CH3), 1.42 (3H, s, C(CH3)2), 1.51
(3H, s, C(CH3)2), 3.34 (1H, d, J¼9.6 Hz, H-20), 3.60–3.75
(4H, m, H-60, H-6), 3.68 (1H, t, J¼9.0 Hz, H-40), 3.94 (1H,
m, H-50), 4.01 (1H, t, J¼5.5 Hz, H-5), 4.08 (1H, t, J¼
9.6 Hz, H-30), 4.27 (1H, m, H-2), 4.30 (1H, dd, J¼2.0 Hz,
J¼8.2 Hz, H-4), 4.57 (1H, t, J¼11.0 Hz, H-3), 5.50 (1H, d,
J¼5.5 Hz, H-1); 13C NMR (CDCl3): d 20.9, 24.4, 25.0,
26.0, 26.2, 60.4, 67.3, 68.7, 70.7, 70.8, 71.2, 71.2, 73.3,
74.2, 75.1, 75.3, 78.6, 82.7, 84.2, 96.2, 100.6, 108.5,
109.1; HRMS (ESI) m/z calcd for C47H56O11$Na+:
819.3715; found: 819.3764. Its b-form: colorless oil; [a]D23
5.4.9. 6-O-(1-C-Benzyl-2,3,4,6-tetra-O-benzyl-a-D-gluco-
pyranosyl)-1,2:3,4-di-O-isopropylidene-a-D-galacto-
23
465
pyranose (9d). Colorless oil; [a] +30.4 (c 1.85, CHCl3);
1H NMR (CDCl3): d 1.34 (3H, s, C(CH3)2), 1.37 (3H, s,
C(CH3)2), 1.46 (3H, s, C(CH3)2), 1.55 (3H, s, C(CH3)2),
3.09 (1H, d, J¼13.8 Hz, CCHaHbPh), 3.25 (1H, d, J¼
9.1 Hz, H-20), 3.27 (1H, d, J¼14.4 Hz, CCHaHbPh), 3.57
(1H, t, J¼9.6 Hz, H-40), 3.75–3.79 (2H, m, Ha-60, Ha-6),
3.84 (1H, dd, J¼3.4 Hz, J¼9.8 Hz, Hb-60), 3.92–3.96 (2H,
m, H-50, Hb-6), 4.06 (1H, m, H-5), 4.13 (1H, t, J¼9.6 Hz,
H-30), 4.31 (1H, dd, J¼2.7 Hz, J¼5.5 Hz, H-2), 4.40 (1H,
dd, J¼2.1 Hz, J¼8.7 Hz, H-4), 4.59–4.64 (3H, m, H-3,
OCH2Ph), 5.55 (1H, d, J¼5.5 Hz, H-1); 13C NMR
(CDCl3): d 24.4, 25.0, 26.0, 26.2, 39.5, 59.8, 67.2, 69.0,
70.7, 70.9, 71.1, 71.9, 73.1, 73.7, 74.5, 75.3, 78.6, 79.8,
83.2, 96.3, 102.5, 108.6, 109.1; HRMS (ESI) m/z calcd for
C53H60O11$Na+: 895.4028; found: 895.3995.
1
+23.5 (c 0.65, CHCl3); H NMR (CDCl3): d 1.26 (3H, s,
C(CH3)2), 1.31 (3H, s, C(CH3)2), 1.42 (3H, s, C(CH3)2),
1.48 (3H, s, CH3), 1.57 (3H, s, C(CH3)2), 3.53 (1H, m, H-
50), 3.58 (1H, d, J¼8.8 Hz, H-20), 3.62 (1H, dd, J¼8.9 Hz,
J¼9.6 Hz, H-40), 3.65–3.69 (3H, m, H-30, H-60), 3.84 (2H,
m, H-6), 4.00 (1H, m, H-5), 4.23 (1H, dd, J¼1.8 Hz,
J¼7.9 Hz, H-4), 4.29 (1H, dd, J¼2.4 Hz, J¼5.0 Hz, H-2),
4.53–4.58 (3H, m, H-3, OCH2Ph), 5.45 (1H, d, J¼5.0 Hz,
H-1); 13C NMR (CDCl3): d 17.0, 24.3, 25.0, 26.0, 26.1,
60.7, 67.5, 69.4, 70.7, 70.7, 71.3, 73.4, 78.2, 83.2, 83.9,
96.4, 102.3, 108.5, 109.1; HRMS (ESI) m/z calcd for
C47H56O11$Na+: 819.3715; found: 819.3739.
5.4.10. Phenethyl 2,3,4,6-tetra-O-benzyl-1-C-methyl-a-D-
glucopyranoside (12a). Colorless oil; [a]2D3 +45.5 (c 2.66,
CHCl3); H NMR (CDCl3): d 1.26 (3H, s, CH3), 2.93 (2H,
1
m, OCH2CH2Ph), 3.31 (1H, d, J¼9.5 Hz, H-2), 3.36 (1H,
m, H-5), 3.52–3.59 (3H, m, H-6, H-4), 3.61–3.66 (2H, m,
OCH2CH2Ph), 4.07 (1H, t, J¼9.3 Hz, H-3); 13C NMR
(CDCl3): d 21.0, 36.3, 62.0, 68.8, 71.4, 73.3, 74.7, 75.4,
75.5, 78.6, 83.0, 83.9, 100.3; HRMS (ESI) m/z calcd for
C43H46O6$Na+: 681.3192; found: 681.3197. Its b-form: col-
5.4.7. 6-O-(2,3,4,6-Tetra-O-benzyl-1-C-ethyl-a-D-gluco-
pyranosyl)-1,2:3,4-di-O-isopropylidene-a-D-galacto-
pyranose (9b). Colorless oil; [a]2D3 +11.3 (c 1.58, CHCl3);
1H NMR (CDCl3): d 0.81 (3H, t, J¼7.6 Hz, CH2CH3),
1.31 (3H, s, C(CH3)2), 1.32 (3H, s, C(CH3)2), 1.42 (3H, s,
C(CH3)2), 1.52 (3H, s, C(CH3)2), 1.79 (1H, m, CHaHbCH3),
1.88 (1H, m, CHaHbCH3), 3.52 (1H, d, J¼9.6 Hz, H-20),
3.61–3.67 (3H, m, H-40, Ha-60, Ha-6), 3.75–3.79 (2H, m,
Hb-60, Hb-6), 3.96 (1H, m, H-50), 4.01 (1H, t, J¼5.5 Hz,
H-5), 4.15 (1H, t, J¼9.6 Hz, H-30), 4.27 (1H, dd, J¼2.0 Hz,
J¼4.8 Hz, H-2), 4.31 (1H, dd, J¼2.0 Hz, J¼7.6 Hz, H-4),
4.57 (1H, dd, J¼2.1 Hz, J¼7.6 Hz, H-3), 5.50 (1H, d,
J¼5.5 Hz, H-1); 13C NMR (CDCl3): d 8.1, 24.4, 25.0, 25.5,
26.0, 26.2, 60.0, 67.4, 68.9, 70.7, 70.8, 71.2, 71.5, 73.1,
74.2, 74.4, 75.3, 78.7, 79.8, 83.0, 96.2, 102.2, 108.5, 109.1;
1
orless oil; [a]2D3 +21.4 (c 0.69, CHCl3); H NMR (CDCl3):
d 1.43 (3H, s, CH3), 2.91 (2H, t, J¼6.9 Hz, OCH2CH2Ph),
3.52–3.54 (1H, m, H-5), 3.55 (1H, d, J¼8.9 Hz, H-2), 3.62
(1H, t, J¼8.9 Hz, H-4), 3.65 (1H, t, J¼8.9 Hz, H-3), 3.69
(2H, d, J¼2.7 Hz, H-6), 3.86 (2H, m, OCH2CH2Ph); 13C
NMR (CDCl3): d 17.0, 36.7, 62.1, 69.4, 73.4, 73.4, 74.2,
75.0, 75.5, 78.2, 83.3, 83.9, 102.0; HRMS (ESI) m/z calcd
for C43H46O6$Na+: 681.3192; found: 681.3175.
5.4.11. Phenethyl 2,3,4,6-tetra-O-benzyl-1-C-ethyl-a-D-
glucopyranoside (12b). Colorless oil; [a]2D3 +54.0 (c 3.27,
CHCl3); 1H NMR (CDCl3): d 0.73 (3H, t, J¼7.6 Hz,

T. Yamanoi et al. / Tetrahedron 62 (2006) 10383–10392
10391
CH2CH3), 1.75 (1H, m, CHaHbCH3), 1.81 (1H, m,
CHaHbCH3), 2.92 (2H, m, OCH2CH2Ph), 3.41 (1H, dd,
J¼2.8 Hz, J¼10.3 Hz, H-5), 3.50 (1H, d, J¼9.7 Hz, H-2),
3.51–3.70 (4H, m, H-6, OCH2CH2Ph), 3.54 (1H, t,
J¼9.7 Hz, H-4), 4.12 (1H, t, J¼9.6 Hz, H-3): 13C NMR
(CDCl3): d 8.1, 25.5, 36.5, 61.5, 68.9, 71.7, 73.2, 74.7,
74.7, 75.4, 78.8, 79.6, 83.3, 102.0; HRMS (ESI) m/z calcd
for C44H48O6$Na+: 695.3343; found: 695.3346.
5.4.16. 2,3,4,6-Tetra-O-benzyl-a-D-glucopyranosyl 2,3,
4,6-tetra-O-benzyl-1-C-methyl-a-D-glucopyranoside
1
(18a). Colorless oil; [a]2D3 +70.0 (c 2.04, CHCl3); H NMR
(CDCl3): d 1.49 (3H, s, CH3), 3.29 (1H, d, J¼9.6 Hz,
H-20), 3.33–3.39 (3H, m, Ha-6, Hb-6, Ha-60), 3.55–3.58
(1H, m, Hb-60), 3.56 (1H, dd, J¼3.4 Hz, J¼10.3 Hz,
H-20), 3.64 (1H, dd, J¼9.6 Hz, J¼10.3 Hz, H-4), 3.68
(1H, t, J¼9.6 Hz, H-40), 4.03 (1H, t, J¼10.3 Hz, H-3),
4.05 (1H, t, J¼9.6 Hz, H-30), 4.17–4.19 (1H, m, H-50),
4.27–4.28 (1H, m, H-5), 5.34 (1H, d, J¼3.4 Hz, H-10);
13C NMR (CDCl3): d 22.7, 68.3, 68.5, 70.0, 71.0,
78.0, 78.6, 80.1, 81.8, 82.7, 85.1, 90.2, 101.0; HRMS
(ESI) m/z calcd for C69H72O11$Na+: 1099.4967; found:
1099.5006.
5.4.12. Phenethyl 2,3,4,6-tetra-O-benzyl-1-C-n-butyl-
a-D-glucopyranoside (12c). Colorless oil; [a]2D3 +38.2 (c
1
1.51, CHCl3); H NMR (CDCl3): d 0.76 (3H, t, J¼6.8 Hz,
CH2CH2CH2CH3), 0.91 (1H, m, CH2CHaHbCH2CH3),
1.05 (1H, m, CH2CH2CHaHbCH3), 1.15 (1H, m,
CH2CH2CHaHbCH3), 1.26 (1H, m, CH2CHaHbCH2CH3),
1.69 (2H, t, J¼8.2 Hz, CH2CH2CHaHbCH3), 2.94 (2H, m,
OCH2CH2Ph), 3.41 (1H, dd, J¼3.4 Hz, J¼10.3 Hz,
H-5), 3.48 (1H, d, J¼9.6 Hz, H-2), 3.53 (1H, t, J¼9.6 Hz,
H-4), 3.56 (1H, m, Ha-6), 3.60–3.63 (2H, m, Hb-6,
OCHaHbCH2Ph), 3.67–3.70 (1H, m, OCHaHbCH2Ph), 4.11
(1H, t, J¼9.6 Hz, H-3); 13C NMR (CDCl3): d 14.0, 23.0,
25.9, 32.7, 36.5, 61.5, 69.0, 71.7, 73.2, 74.8, 74.8, 75.4,
78.8, 80.0, 83.5, 101.8; HRMS (ESI) m/z calcd for
C46H52O6$Na+: 723.3656; found: 723.3648.
References and notes
1. Brockhaus, M.; Lehmann, J. Carbohydr. Res. 1977, 53, 21–
31.
2. Li, X. L.; Ohtake, H.; Takahashi, H.; Ikegami, S. Synlett 2001,
1885–1888.
3. For examples of chemical glycosidation, see: (a) Li, X. L.;
Ohtake, H.; Takahashi, H.; Ikegami, S. Tetrahedron 2001,
57, 4283–4295; (b) Lin, H.-C.; Yang, W.-B.; Gu, Y.-F.;
Chen, C.-Y.; Wu, C.-Y.; Lin, C.-H. Org. Lett. 2003, 5,
1087–1089; (c) Chang, C.-F.; Yang, W.-B.; Chang, C.-C.;
Lin, C.-H. Tetrahedron Lett. 2002, 43, 6515–6519; (d) Lin,
H.-C.; Du, W.-P.; Chang, C.-C.; Lin, C.-H. Tetrahedron
Lett. 2005, 46, 5071–5076; For enzymatic glycosidation,
see: (e) Schlesselmann, P.; Fritz, H.; Lehmann, J.; Uchiyama,
T.; Brewer, C. F.; Hehre, E. J. Biochemistry 1982, 21, 6606–
6614.
5.4.13. Phenethyl 1-C-benzyl-2,3,4,6-tetra-O-benzyl-a-D-
glucopyranoside (12d). Colorless oil; [a]2D3 +48.6 (c 1.33,
CHCl3); 1H NMR (CDCl3): d 2.96 (1H, m, OCH2CHaHbPh),
3.01 (1H, m, OCH2CHaHbPh), 3.03 (1H, d, J¼3.7 Hz,
CCHaHbPh), 3.23 (1H, d, J¼9.6 Hz, H-2), 3.27 (1H, d,
J¼3.7 Hz, CCHaHbPh), 3.47 (1H, t, J¼9.6 Hz, H-4), 3.49
(1H, m, H-5), 3.66 (1H, d, J¼11.0 Hz, Ha-6), 3.69 (1H,
dd, J¼3.4 Hz, J¼10.3 Hz, Hb-6), 3.82–3.86 (2H, m,
OCH2CH2Ph), 4.11 (1H, t, J¼9.7 Hz, H-3); 13C NMR
(CDCl3): d 36.6, 39.7, 61.7, 69.1, 71.9, 73.2, 74.0, 74.8,
75.8, 78.6, 79.9, 83.4, 102.4; HRMS (ESI) m/z calcd for
C49H50O6$Na+: 757.3500; found: 757.3549.
4. For example, see: (a) Czernecki, S.; Ville, G. J. Org. Chem.
1989, 54, 610–612; (b) Kraus, G. A.; Molina, M. T. J. Org.
Chem. 1988, 53, 752–753.
5. (a) Li, X. L.; Ohtake, H.; Takahashi, H.; Ikegami, S.
Tetrahedron 2001, 57, 4297–4309; (b) As the analogs of the
1-C-alkyl-hexopyranose derivatives, the glycosidation using
the 1-C-alkoxyalkyl-hexopyranose derivatives was reported.
See: Heskamp, B. M.; Veeneman, G. H.; van der Marel,
G. A.; van Boeckel, C. A. A.; van Boom, J. H. Tetrahedron
1995, 51, 5657–5670; (c) As the 1-C-alkyl-hexofuranose deriv-
ative, the glycosidation using 2,3:5,6-di-O-isopropylidene-
1-C-methyl-D-mannofuranosyl acetate was reported. See:
Dondoni, A.; Marra, A.; Rojo, I.; Scherrmann, M.-C. Tetra-
hedron 1996, 52, 3057–3074.
5.4.14. Phenyl 2,3,4,6-tetra-O-benzyl-1-C-methyl-a-D-
glucopyranoside (14a). Colorless oil; [a]2D3 +70.0 (c 4.90,
CHCl3); H NMR (CDCl3): d 1.26 (3H, s, CH3), 3.36 (1H,
1
d, J¼9.6 Hz, H-2), 3.63 (1H, t, J¼9.6 Hz, H-4), 3.66–3.70
(2H, m, H-6), 4.02–4.04 (1H, m, H-5), 4.16 (1H, t, J¼
9.0 Hz, H-3); 13C NMR (CDCl3): d 21.1, 69.1, 71.9, 73.4,
74.8, 75.6, 75.6, 78.6, 83.1, 84.2, 103.3; HRMS (ESI) m/z
calcd for C41H42O6$K+: 669.2613; found: 669.2661.
6. (a) Inazu, T.; Yamanoi, T. Chem. Lett. 1989, 69–72; (b) Yama-
noi, T.; Inazu, T. Chem. Lett. 1990, 849–852; (c) Yamanoi, T.;
Nakamura, K.; Takeyama, H.; Yanagihara, K.; Inazu, T. Chem.
Lett. 1993, 343–346; (d) Yamanoi, T.; Nakamura, K.; Sada, S.;
Goto, M.; Furusawa, Y.; Takano, M.; Fujioka, A.; Yanagihara,
K.; Satoh, Y.; Hosokawa, H.; Inazu, T. Bull. Chem. Soc. Jpn.
1993, 66, 2617–2622; (e) Yamanoi, T.; Nakamura, K.; Take-
yama, H.; Yanagihara, K.; Inazu, T. Bull. Chem. Soc. Jpn.
1994, 67, 1359–1366; (f) Yamanoi, T.; Fujioka, A.; Inazu, T.
Bull. Chem. Soc. Jpn. 1994, 67, 1488–1491.
7. (a) Yamanoi, T.; Iwai, Y.; Inazu, T. J. Carbohydr. Chem. 1998,
17, 819–822; (b) Yamanoi, T.; Iwai, Y.; Inazu, T. Heterocycles
2000, 53, 1263–1267; (c) Yamanoi, T.; Yamazaki, I.
Tetrahedron Lett. 2001, 42, 4009–4011.
8. Yamanoi, T.; Oda, Y.; Yamazaki, I.; Shinbara, M.; Morimoto,
K.; Matsuda, S. Lett. Org. Chem. 2005, 2, 242–246.
5.4.15. Methyl 6-O-(1-C-benzyl-2,3,4,6-tetra-O-benzyl-a-
D-glucopyranosyl)-2,3,4-tri-O-benzyl-a-D-glucopyrano-
1
side (17d). Colorless oil; [a]2D3 +50.0 (c 3.84, CHCl3); H
NMR (CDCl3): d 2.95 (1H, d, J¼14.4 Hz, CCHaHbPh),
3.14 (1H, d, J¼13.7 Hz, CCHaHbPh), 3.19 (1H, d,
J¼9.6 Hz, H-20), 3.33 (1H, dd, J¼8.9 Hz, J¼9.6 Hz, H-3),
3.36 (3H, s, OMe), 3.47 (1H, t, J¼9.6 Hz, H-40), 3.46–3.52
(2H, m, H-2, Ha-6), 3.63 (1H, d, J¼11.0 Hz, Ha-60), 3.69
(1H, dd, J¼3.4 Hz, J¼11.0 Hz, Hb-60), 3.86–3.90 (3H, m,
H-5, H-50, Hb-6), 3.98 (1H, t, J¼8.9 Hz, H-4), 4.05 (1H,
dd, J¼8.9 Hz, J¼9.6 Hz, H-30), 4.56–4.59 (2H, m, H-1,
OCHaHbPh); 13C NMR (CDCl3): d 39.7, 55.0, 60.6, 69.1,
70.3, 71.8, 78.6, 78.7, 79.8, 80.2, 82.3, 83.4, 97.6, 102.4;
HRMS (ESI) m/z calcd for C69H72O11$Na+: 1099.4967;
found: 1099.5003.

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9. (a) Yamanoi, T.; Matsuda, S.; Yamazaki, I.; Inoue, R.;
Hamasaki, K.; Watanabe, M. Heterocycles 2006, 68, 673–
677; (b) We also reported the Brønsted acid-catalyzed intra-
molecular b-glycosidation of 1-C-alkyl-D-hexopyranoses to
form the anhydroketopyranoses; Yamanoi, T.; Matsumura, K.;
Matsuda, S.; Oda, Y. Synlett 2005, 2973–2977.
10. Kuzuhara, H.; Fletcher, H. G., Jr. J. Org. Chem. 1967, 32,
2531–2534.
12. 2,3,4,6-Tetra-O-benzyl-1-C-methyl-a-D-glucopyranosyl ace-
tate has also been synthesized from 1 by a multistep reaction
sequence; Fukase, H.; Horii, S. J. Org. Chem. 1992, 57,
3642–3650.
13. It was reported that the acetylation of a ketopyranose derivative
with DMAP/Ac2O gave the open ring compound; Heskamp,
B. M.; Noort, D.; van der Marel, G. A.; van Boom, J. H.
Synlett 1992, 713–715.
11. Inazu, T.; Yamanoi, T. Jpn. Kokai Tokkyo Koho, JP 02240093,
1990.
14. Inanaga, J.; Yokoyama, Y.; Hanamoto, T. Tetrahedron Lett.
1993, 34, 2791–2794.