Novel Glycosidation of - D -Altropyranosides

Article abstract of DOI:10.1055/s-0029-1217073

A new glycosidation of α-d-altropyranosides, in which the 2-hydroxy group is not protected, was developed. The reaction proceeds via a 1,2 -β oxirane, which is formed in situ without extra steps for exchanging the 1-methoxy group to a more reactive leaving group. The glycoside bond of α-d-altropyranoside was shown to be weaker compared with those of α-d-glucopyranoside and α-d-mannopyranoside.

Full text of DOI:10.1055/s-0029-1217073

PAPER
43
Novel Glycosidation of a-D-Altropyranosides
N
ovel Glycosid
a
ation of
a
-
D
k
-Altropyra
n
a
osides hiro Nakayama, Kazusa Nishiyama, Hideaki Natsugari, Hideyo Takahashi*
School of Pharmaceutical Sciences, Teikyo University, Sagamiko, Sagamihara, Kanagawa 229-0195, Japan
Fax +81(426)853728; E-mail: hide-tak@pharm.teikyo-u.ac.jp
Received 21 July 2009; revised 1 September 2009
When the oxirane 14 was treated with methyl 2,3,4-tri-O-
benzyl-a-D-glucopyranoside (2)5 in the presence of excess
trimethylsilyl triflate, we found that the product, the ether-
linked sugar 3a,3 was gradually transformed into another
Abstract: A new glycosidation of a-D-altropyranosides, in which
the 2-hydroxy group is not protected, was developed. The reaction
proceeds via a 1,2-b-oxirane, which is formed in situ without extra
steps for exchanging the 1-methoxy group to a more reactive leav-
ing group. The glycoside bond of a-D-altropyranoside was shown to product. A detailed analysis of the isolated minor product
be weaker compared with those of a-D-glucopyranoside and a-D-
allowed us to determine the structure to be the three-pyr-
anose-linked sugar 4a. By extensive modification of the
reaction conditions, we succeeded in improving the yield
of 4a (Scheme 2). In this case, the addition of trimethyl-
silyl triflate was divided into two parts. The initial addi-
tion of trimethylsilyl triflate (1 equiv) was followed by a
mannopyranoside.
Key words: carbohydrates, glycosylations, epoxides, ring opening,
D-altropyranoside
Since coyolosa, a natural ether-linked sugar, was isolated second addition (1 equiv) to afford 4a (a/b = 1:5) in 71%
from Acrocomia mexicana as a unique 6,6¢-ether-linked yield. This is the first example of a three-pyranose-linked
sugar,1 we have investigated various syntheses of ether- sugar with ether and glycosidic linkages, which we have
linked pyranoses with the expectation of a new candidate tentatively named a ‘hybrid sugar’.
in the search for drugs to combat diabetes.2 Thus, we have
achieved the synthesis of a novel 3,6¢-ether-linked sugar
OH
BnO
(methyl a-D-altropyranoside) 3a by nucleophilic ring
O
BnO
1
opening of a 2,3-anhydro-a-D-mannopyranoside (ox-
3
2
TMSOTf (1.0 + 1.0 equiv)
CH2Cl2, –10 °C, 1 + 1 days
irane) 1 (Scheme 1).3 In the course of the study, a new
type of three-pyranose-linked sugar 4a with ether and gly-
cosidic linkages was found to form as a minor product.
Herein we describe the structure and mechanism of for-
mation of this unique sugar 4a, which led to a new gly-
cosidation of a-D-altropyranosides. We further consider
the interesting features of the glycosidic linkage in this
rare sugar.
+
O
OMe
O
BnO
BnO
2
BnO
OMe
3a
BnO
BnO
O
O
2
(TMSOTf)
1
2
4a
O
71%
α/β = 1:5
O
BnO
BnO
HO
O
BnO
BnO
MeOH
O
O
BnO
OMe
BnO
BnO
+
3
2
BnO
oxirane A
OMe
OMe
1
2
Scheme 2 One-pot formation of 4a by etherification–glycosidation
TMSOTf
CH2Cl2, –10 °C
Based on these results, we assumed that this reaction
might be a one-pot etherification–glycosidation, as shown
in Scheme 2. The initial addition of trimethylsilyl triflate
promoted nucleophilic ring opening of oxirane 1 with 2 to
provide the ether-linked sugar 3a, which subsequently re-
acted with 2 after the second addition of trimethylsilyl tri-
flate to give the hybrid sugar 4a via oxirane A. Formation
of 4a from oxirane A and 2 is consistent with a previous
report6 showing that glycosidation of 1,2-anhydro sugars
with similar acceptors gives glycosides.
OH
OH
BnO
BnO
BnO
BnO
O
O
O
3
2
2
3
O
+
BnO
O
O
OMe
O
BnO
O
BnO
BnO
BnO
BnO
BnO
OMe
BnO
BnO
OMe
OMe
3a
82%
4a
Scheme 1 Regioselective nucleophilic opening of 2,3-anhydro-a-
D-mannopyranoside 1 with methyl 2,3,4-tri-O-benzyl-a-D-glucopyra-
noside (2)
It is noteworthy that methyl a-D-altropyranoside 3a, in
which the 2-OH group is not protected, was glycosidated
easily. Such a 1,2-trans-D-altropyranoside appears to be a
good substrate for intramolecular cyclization to form the
oxirane A. Although the intermediate oxirane A was not
SYNTHESIS 2010, No. 1, pp 0043–0048
Advanced online publication: 26.10.2009
DOI: 10.1055/s-0029-1217073; Art ID: F14009SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
9

44
T. Nakayama et al.
PAPER
isolated, this sequence might be an alternative glycosida- while selectivity for the b-anomer was usually achieved in
tion of D-altropyranoside.7
dichloromethane, the ratio reversed in diethyl ether (a/b =
1:0.7) (entry 6). We next examined this glycosidation us-
ing methyl a-D-altropyranosides 3b (OR1 = OMe)3 and 3c
(OR1 = OBn)3 as glycosyl donors (entries 8 and 9). Fortu-
nately, the reaction proceeded smoothly to give 4b and 4c,
respectively. It is useful that methyl 3,4,6-tri-O-benzyl-a-
D-altropyranoside (3c) was converted into 4c in good
yield (77%, a/b = 1:2.9).
To confirm this reaction mechanism, we first examined
the latter glycosidation using 3a as the glycosyl donor. As
shown in Table 1, glycosidation of 3a proceeded under
acidic conditions to provide the three-pyranose-linked
sugar 4a. Although triflic acid (50%, a/b = 1:2.3) and
tin(IV) chloride (55%, a/b = 1:4) appeared to be effective
(entries 1 and 2), we found trimethylsilyl triflate to be the
most promising promoter.
All these things make it clear that the 1,2-trans-altropyra-
noside 3, in which the 2-OH group is not protected, actu-
ally reacted as a donor to give the sugar 4.8 It should be
emphasized that the stable 1-methoxy group reacts as an
excellent leaving group in this case, that is, there is no
need for extra steps to exchange the methoxy group for a
more reactive leaving group (e.g., Br, F).9
Table 1 Glycosidation of Methyl a-D-Altropyranosides 3a–c with
Methyl 2,3,4-Tri-O-benzyl-a-D-glucopyranoside (2)
OH
O
OH
O
BnO
BnO
BnO
BnO
promoter
OR2
R2OH
+
3
2
0 °C, 10 h
α, β
OR1 OMe
OR1
2
We also found that a longer reaction time changes the
product distribution (entry 3 vs 7). It is possible that the a-
anomer a-4a and b-anomer b-4a of 4a exist in an equilib-
rium state. To reveal the equilibrium state, each isolated
anomer was treated with trimethylsilyl triflate. The results
are shown in Table 2. After five hours in dichlo-
romethane, the pure a-4a anomer gave anomeric mixtures
of 4a (53%, a/b = 1:4) and cleaved alcohol 2 (39%) (entry
1). Similarly, b-4a provided anomeric mixtures of 4 (48%,
a/b = 1:9) and 2 (34%) (entry 3). It is clear that the glyco-
side bond in 4 is so weak that it was cleaved by trimethyl-
silyl triflate in dichloromethane and that the previously
cleaved alcohol 2 was glycosylated again in the presence
of trimethylsilyl triflate. In this equilibrium, the b-anomer
b-4a is preferred over the a-anomer a-4a. On the other
hand, in diethyl ether pure a-4a and b-4a were recovered
even after longer reaction times (entries 2 and 4). It is like-
ly that diethyl ether, which has higher Lewis basicity, de-
creased the Lewis acidity of trimethylsilyl triflate so that
glycoside bonds in a-4a and b-4a were retained at –10 °C.
A similar equilibrium was observed for the anomers of 4b
and 4c (entries 5–8). After treatment of the pure a-4b ano-
mer with trimethylsilyl triflate in dichloromethane for ten
hours, an anomeric mixture of 4b was obtained (22%,
a/b = 1:1.2) along with the alcohol 2 (63%) and a 1-OH D-
altrose derivative (entry 5). Pure b-4b also gave anomeric
mixtures of 4b (25%, a/b = 1:1.3), 2 (58%), and a 1-OH
D-altrose derivative (entry 6). In this case, since the
amount of cleaved alcohol 2 increased, 4b appeared to be
a less stable glycoside. Examination of a-4c and b-4c re-
sulted in similar recovery yields with an increase in the
preference for b-4c (entries 7 and 8). We assume that the
glycosidation of 4 was greatly affected by the bulky sub-
stitution at the 3-position of D-altropyranoside, which
might be responsible for the tendency for 1,2-cis-glycosi-
dation (i.e., b-4 form), especially in 4a (entries 1 and 3).
3a–c
(5.0 equiv)
4a–c
R1
:
a
R2
b
c
Me
Bn
O
O
BnO
BnO
BnO
BnO
BnO
OMe
BnO
OMe
Entrya Substrate Promoterb
Solvent
Product
Yield Ratioc
(%)
50
55
64
67
72
59
63
53
77
a/b
1
2
3
4
5
6
7f
8
9
3a
3a
3a
3a
3a
3a
3a
3b
3c
TfOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
4a
4a
4a
4a
4a
4a
4a
4b
4c
1:2.3
1:4
SnCl4
TMSOTf
TMSOTfd
TMSOTfe
TMSOTf
TMSOTf
TMSOTf
TMSOTf
1:2.4
1:4.6
1:2.3
1:0.7
1:4.7
1:2.3
1:2.9
CH2Cl2
CH2Cl2
CH2Cl2
a Reaction time was 10 h unless otherwise stated.
b 1.0 equivalent were used unless otherwise stated.
c Ratio of the isolated products.
d 2.0 equivalents were used.
e The molecular sieve MS4A was added.
f Reaction time of 44 h.
Reaction of 3a with 2 (5 equiv) in the presence of tri-
methylsilyl triflate (1 equiv) in dichloromethane at 0 °C
for ten hours afforded 4a (64%, a/b = 1:2.4) (entry 3).
While an excess amount of 2 (5 equiv) was necessary to
obtain the product efficiently, an excess amount of tri-
methylsilyl triflate did not increase the yield. Instead, the
ratio of anomers changed (a/b = 1:4.6) (entry 4). In con-
trast, the addition of molecular sieves (MS4A) increased
the yield (72%) without changing the ratio of anomers
(a/b = 1:2.3) (entry 5). A large solvent effect was observed;
As a whole, it should be stressed that a-D-altropyranoside
3, in which the 2-OH group is not protected, exists in an
equilibrium in acidic conditions. In other words, the gly-
coside bond in unprotected D-altropyranoside 3 is essen-
tially unstable.
Synthesis 2010, No. 1, 43–48 © Thieme Stuttgart · New York

PAPER
Novel Glycosidation of a-D-Altropyranosides
45
Table 2 Stability of D-Altropyranoside 4
OH
O
BnO
BnO
TMSOTf (1.0 equiv)
CH2Cl2, –10 °C
OR1
OR2
α-4a–c
OH
O
BnO
BnO
OR2
R2OH
+
α/β
OH
O
OR1
4a–c
BnO
BnO
2
OR2
β-4a–c
a
OR1
R1
R2
:
b
c
O
O
BnO
BnO
BnO
BnO
Me Bn
BnO
BnO
OMe
OMe
Entry
Substrate
Conditions
Solvent
Product
Recovered yield (%) of 4a Ratiob a/b
Time (h)
Yield (%) of 2
1
2
3
4
5
6
7
8
a-4a
a-4a
b-4a
b-4a
a-4b
b-4b
a-4c
b-4c
CH2Cl2
Et2O
5
5
53
89
48
93
22
25
15
36
1:4
39
–
1:0
CH2Cl2
Et2O
5
1:9
34
–
12
10
10
10
10
0:1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1:1.2
1:1.3
1:2.6
1:3.7
63
58
37
23
a Combined yield of a-4 and b-4.
b Determined using HPLC.
OH
We questioned whether the stereochemistry of the 1,2,3-
positions of the a-D-altropyranoside 3 were the key factor
in this glycosidation. To assess the importance of the con-
figuration at the 1,2,3-positions of pyranoside, methyl
3,4,6-tri-O-benzyl-a-D-glucopyranoside (5) and methyl
3,4,6-tri-O-benzyl-a-D-mannopyranoside (6)10 (Figure 1)
were selected for comparison and subjected to trimethyl-
silyl triflate promoted glycosidation conditions.
OH
O
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
O
O
1
2
3
OH
OMe
OMe
OBn OMe
α-D-altroside
3c
α-D-glucoside
α-D-mannoside
5
6
Figure 1 Three methyl a-D-pyranosides 3c, 5, and 6 with different
stereochemistry at the 2,3-positions
While the reaction of the a-D-glucoside 5 did not proceed
at all, the reaction of the a-D-mannoside 6 with 2 (4 equiv)
in the presence of trimethylsilyl triflate afforded the sole
product 7 (a-anomer)11 in 36% yield (Scheme 3). The re-
sult agrees with our speculation that the reaction proceeds
via the 1,2-b-oxirane formed in situ. In sharp contrast to
the a-D-altroside 3c, the mannoside 6 showed highly ro-
bust a-stereoselectivity. We further examined the stability
of 7 under acidic conditions. After treatment with trimeth-
ylsilyl triflate at –10 °C for ten hours, the glycoside 7 was
recovered completely. It is clear that the mannoside 7 is
more stable than the altroside 4c under acidic conditions
and that no equilibrium is observed in this case.
OH
BnO
O
BnO
6
BnO
TMSOTf (2.0 equiv)
+
O
CH2Cl2, r.t., 40 min
7
2
O
36%
BnO
BnO
BnO
OMe
TMSOTf (1.0 equiv)
CH2Cl2, –10 °C, 10 h
no reaction
Scheme 3 Trimethylsilyl triflate promoted glycosidation of methyl
3,4,6-tri-O-benzyl-a-D-mannopyranoside 6
Judging from the above results, we can safely say that
configuration of the 2-OH group in a-D-altroside and a-D-
mannoside 3 and 6 is necessary for this glycosidation. One
possible explanation for this glycosidation mechanism is
shown in Scheme 4.
Synthesis 2010, No. 1, 43–48 © Thieme Stuttgart · New York

46
T. Nakayama et al.
PAPER
OH
O
O
BnO
BnO
BnO
BnO
All reactions sensitive to air or moisture were conducted under an
argon atmosphere. Materials were obtained from commercial sup-
pliers. All anhydrous solvents were purified according to standard
methods. NMR spectra were recorded on a Jeol JNM-GSX600
spectrometer at 600 MHz for 1H NMR and 150 MHz for 13C NMR
with TMS as an internal standard. EI-MS spectra were measured on
a Jeol JMS-SX102A. FAB-MS were obtained with m-nitrobenzyl
alcohol as a matrix. Analytical TLC was carried out using Merck
silica gel 60 F254. Column chromatography was performed using sil-
ica gel Wakogel C-300 (45–60 mm).
O
– MeOH
1
2
3
OR1
OR1
OMe
HOR2
oxirane A
methyl α-D-altroside 3
R2OH
OH
O
O
O
BnO
BnO
BnO
BnO
α-4
OR1
OH
OR2
OR1
R2OH
α-D-altroside
oxonium ion B
BnO
BnO
Hybrid Sugar 4a; One-Pot Procedure
O
OR2
TMSOTf (25 mL, 0.14 mmol) was added to a mixture of 1 (50 mg,
0.14 mmol) and methyl 2,3,4-tri-O-benzyl-a-D-glucopyranoside (2,
652 mg, 1.40 mmol) in CH2Cl2 (1.4 mL) at –78 °C. The mixture was
warmed to –10 °C and stirred for 1 d, and then TMSOTf (25 mL,
0.14 mmol) was added at –78 °C. The mixture was stirred at –10 °C
for 1 d and then poured into a pH 7 phosphate buffer and extracted
with CH2Cl2. The organic phase was dried (Na2SO4) and concen-
trated in vacuo. The residual oil was subjected to column chroma-
tography (silica gel, hexane–EtOAc, 5:2) to give a-4a (21 mg,
12%), b-4a (103 mg, 59%), and 3a (22.2 mg, 19%).
β-4
OR1
β-D-altroside
OH
BnO
O
BnO
– MeOH
O
O
BnO
BnO
1
BnO
2
BnO
3
OMe
methyl α-D-mannoside 6
HOR2
oxirane A'
OH
O
BnO
BnO
R1O
7
α-D-mannoside
Hybrid Sugar 4a by Glycosidation of 3a with 2; Typical Proce-
dure
OR2
Scheme 4 Plausible reaction mechanisms of the glycosidation of 3
and 6
To a mixture of ether-linked sugar 3a (53 mg, 0.06 mmol), 2 (149
mg, 0.32 mmol), and activated MS4A (20 mg) in CH2Cl2, TMSOTf
(11 mL, 0.06 mmol) was added at –78 °C. The mixture was stirred
at –78 °C for 10 h, the mixture was poured into a pH 7 phosphate
buffer and extracted with CH2Cl2. The organic phase was dried
(Na2SO4) and concentrated in vacuo. The residual oil was subjected
to column chromatography (silica gel, hexane–EtOAc, 5:2) to give
The 1,2-trans-methyl a-D-altroside 3 and a-D-mannoside
6 appear to be good substrates for intramolecular cycliza-
tion to form the oxiranes A and A¢, respectively. Although
not isolated, the oxiranes A and A¢ would function as gly- a-4a (18 mg, 22%) and b-4a (40 mg, 50%).
cosyl donors. The reaction of oxirane A formed from 3
with an acceptor (R2OH) should stereoselectively yield
the a-altroside a-4 through axial attack at the anomeric
position in an SN2-like manner. Similarly, the methyl a-D-
mannoside 6 would stereoselectively provide the a-ano-
mer 7 via the oxirane A¢. In the case of the a-D-altroside
3, however, the a-anomer a-4 formed first is unstable so
that the glycoside bond would be cleaved under acidic
conditions to form the oxonium ion B. This is why a long-
er reaction time in the glycosidation step changes the
product distribution and yields the b-anomer b-4 in pref-
erence to the a-anomer a-4. Thus, it is possible that the
oxirane A, oxonium ion B, and anomers of the a-D-altro-
side exist in equilibrium. It seems reasonable that the 1,3-
diaxial strain in the a-anomer of a-D-altroside is so disad-
vantageous that the b-anomer is preferred in the reaction.
Although there is scope for investigation of this reaction
mechanism, we consider that the glycoside bond of a-D-
altroside, in which the 2-OH group is not protected, is es-
sentially weak. It is known that a-D-altrosides are not con-
tained in natural polysaccharides. The reason may reside
in the instability of the glycoside bond of a-D-altroside.
Methyl (Methyl 2,3,4-Tri-O-benyl-a-D-glucopyranoside)-
(6→3)-(4,6-di-O-benzyl-a-D-altropyranosyl)-(1→6)-2,3,4-tri-O-
benzyl-a-D-glucopyranoside (a-4a)
Rf = 0.23 (hexane–EtOAc, 1:1); [a]D22 +42.5 (c 0.5, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.26–7.15 (m, 40 H, Ar), 4.88 (d,
J = 10.8 Hz, 1 H, PhCH2), 4.87(d, J = 10.8 Hz, 1 H, PhCH2), 4.79
(d, J = 11.4 Hz, 1 H, PhCH2), 4.78 (d, J = 11.4 Hz, 1 H, PhCH2),
4.73 (d, J = 10.8 Hz, 1 H, PhCH2), 4.71 (d, J = 10.8 Hz, 1 H,
PhCH2), 4.67 (d, J = 12.0 Hz, 1 H, PhCH2), 4.64 (d, J = 4.8 Hz, 1 H,
H1), 4.62 (d, J = 11.4 Hz, 1 H, PhCH2), 4.62 (d, J = 11.4 Hz, 1 H,
PhCH2), 4.56 (d, J = 12.0 Hz, 1 H, PhCH2), 4.55 (d, J = 12.0 Hz, 1
H, PhCH2), 4.52 (d, J = 3.6 Hz, 1 H, H1¢), 4.51 (d, J = 12.0 Hz, 1 H,
PhCH2), 4.50 (d, J = 12.0 Hz, 1 H, PhCH2), 4.50 (d, J = 3.6 Hz, 1 H,
H1¢¢), 4.39 (d, J = 12.0 Hz, 1 H, PhCH2), 4.38 (d, J = 12.0 Hz, 1 H,
PhCH2), 4.29 (d, J = 12.0 Hz, 1 H, PhCH2), 3.98 (dd, J = 4.2, 9.6
Hz, 1 H, H5), 3.92 (dd, J = 4.8, 8.4 Hz, 1 H, H2), 3.92 (m, 1 H, H6¢),
3.89 (t, J = 9.6 Hz, 1 H, H3¢¢), 3.89 (t, J = 9.6 Hz, 1 H, H3¢), 3.80
(dd, J = 1.8, 10.8 Hz, 1 H, H6¢¢), 3.77 (dd, J = 3.6, 4.2 Hz, 1 H, H4),
3.69–3.66 (m, 2 H, H5¢, H5¢¢), 3.60–3.58 (m, 2 H, H6¢, H6¢), 3.53
(dd, J = 3.6, 8.4 Hz, 1 H, H3), 3.51 (t, J = 9.6 Hz, 1 H, H4¢¢), 3.43
(dd, J = 3.6, 9.6 Hz, 1 H, H2¢), 3.41 (t, J = 9.6 Hz, 1 H, H4¢), 3.39
(dd, J = 3.6, 9.6 Hz, 1 H, H2¢¢), 3.36–3.32 (m, 2 H, H6, H6), 3.26 (s,
3 H, OCH3), 3.24 (s, 3 H, OCH3).
13C NMR (150 MHz, CDCl3): d = {138.8, 138.7, 138.6, 138.4,
138.3, 138.2, 138.1, 137.9, 128.4, 128.4, 128.4, 128.4, 128.3, 128.3,
128.3, 128.2, 128.2, 128.0, 128.0, 128.0, 127.9, 127.9, 127.8, 127.8,
127.7, 127.7, 127.7, 127.6, 127.6, 127.5, 127.4} (Ar), 102.0 (C1),
97.9 (C1¢¢), 97.8 (C1¢), 82.2 (C3¢¢), 82.0 (C3¢), 80.1 (C2¢¢), 80.0
(C2¢), 79.5 (C3), 78.0 (C4¢¢), 77.7 (C4¢), {75.7, 75.7, 74.9, 74.9,
74.8, 73.3, 73.3, 72.3} (ArCH2), 73.0 (C4), 71.8 (C5), 70.6 (C2),
70.4 (C6¢¢), 70.1 (C5¢¢), 69.8 (C5¢), 69.5 (C6), 66.5 (C6¢), 55.1
(OCH3), 55.1 (OCH3).
In conclusion, a new glycosidation of a-D-altropyranoside
promoted by trimethylsilyl triflate was developed. The re-
action might proceed via a 1,2-b-oxirane. Most advanta-
geously, it is not necessary to exchange the stable
methoxy group at the 1-position for a more reactive leav-
ing group. We also found that the glycoside bond in D-al-
tropyranoside is essentially weak.
Synthesis 2010, No. 1, 43–48 © Thieme Stuttgart · New York

PAPER
Novel Glycosidation of a-D-Altropyranosides
47
HRMS (FAB, MeCN–NBA + NaI): m/z [M + Na] calcd for
C76H84O16Na: 1275.5657; found: 1275.5674.
Methyl (4,6-Di-O-benzyl-3-O-methyl-b-D-altropyranosyl)-
(1→6)-2,3,4-tri-O-benzyl-a-D-glucopyranoside (b-4b)
Rf = 0.39 (hexane–EtOAc, 1:1); [a]D22 +45.2 (c 0.25, CHCl3).
Methyl (Methyl 2,3,4-Tri-O-benzyl-a-D-glucopyranoside)-
(6→3)-(4,6-di-O-benzyl-b-D-altropyranosyl)-(1→6)-2,3,4-tri-O-
benzyl-a-D-glucopyranoside (b-4a)
1H NMR (600 MHz, CDCl3): d = 7.36–7.24 (m, 25 H, Ar), 4.96 (d,
J = 10.7 Hz, 1 H, PhCH2), 4.90 (d, J = 11.0 Hz, 1 H, PhCH2), 4.82
(d, J = 10.7 Hz, 1 H, PhCH2), 4.78 (d, J = 12.1 Hz, 1 H, PhCH2),
4.76 (d, J = 3.0 Hz, 1 H, H1), 4.71 (d, J = 11.0 Hz, 1 H, PhCH2),
4.65 (d, J = 12.1 Hz, 1 H, PhCH2), 4.60 (d, J = 11.2 Hz, 1 H,
PhCH2), 4.59 (d, J = 3.6 Hz, 1 H, H1¢), 4.51 (d, J = 11.2 Hz, 1 H,
PhCH2), 4.50 (d, J = 12.4 Hz, 1 H, PhCH2), 4.42 (d, J = 12.4 Hz, 1
H, PhCH2), 4.15 (ddd, J = 4.0, 4.0, 7.8 Hz, 1 H, H5), 4.02 (dd,
J = 3.0, 5.8 Hz, 1 H, H2), 3.99 (dd, J = 3.9, 11.3 Hz, 1 H, H6¢), 3.98
(t, J = 9.6 Hz, 1 H, H3¢), 3.88 (dd, J = 3.3, 7.8 Hz, 1 H, H4), 3.74
(ddd, J = 1.9, 3.9, 9.6 Hz, 1 H, H5¢), 3.63 (dd, J = 1.9, 11.3 Hz, 1 H,
H6¢), 3.58 (t, J = 9.6 Hz, 1 H, H4¢), 3.57 (dd, J = 3.3, 5.8 Hz, 1 H,
H3), 3.56 (dd, J = 4.0, 11.0 Hz, 1 H, H6), 3.52 (dd, J = 4.0, 11.0 Hz,
1 H, H6), 3.51 (dd, J = 3.6, 9.6 Hz, 1 H, H2¢), 3.42 (s, 3 H, OCH3),
3.35 (s, 3 H, OCH3).
13C NMR (150 MHz, CDCl3): d = {138.8, 138.5, 138.2, 138.2,
138.2, 138.0, 128.5, 128.4, 128.4, 128.4, 128.3, 128.3, 128.2, 128.1,
128.0, 128.0, 127.9, 127.8, 127.7, 127.6, 127.6, 127.6, 127.5,
127.0} (Ar), 101.3 (C1), 98.0 (C1¢), 82.2 (C3¢), 80.0 (C2¢), 78.3
(C3), 77.7 (C4¢), {75.7, 74.8, 73.4, 73.4, 71.6} (ArCH2), 71.6 (C4),
69.9 (C5¢), 69.3 (C5), 69.3 (C6), 68.6 (C2), 66.4 (C6¢), 58.0(OCH3),
55.1(OCH3).
Rf = 0.41 (hexane–EtOAc, 1:1); [a]D22 +27.8 (c 1.0, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.34–7.17 (m, 40 H, Ar), 4.97 (d,
J = 10.8 Hz, 1 H, PhCH2), 4.93 (d, J = 10.8 Hz, 1 H, PhCH2), 4.83
(d, J = 10.8 Hz, 1 H, PhCH2), 4.83 (d, J = 10.8 Hz, 1 H, PhCH2),
4.79 (d, J = 10.8 Hz, 1 H, PhCH2), 4.78 (d, J = 1.8 Hz, 1 H, H1),
4.76 (d, J = 10.8 Hz, 1 H, PhCH2), 4.76 (d, J = 12.6 Hz, 1 H,
PhCH2), 4.66 (d, J = 12.0 Hz, 1 H, PhCH2), 4.64 (d, J = 12.6 Hz, 1
H, PhCH2), 4.60 (d, J = 12.0 Hz, 1 H, PhCH2), 4.54 (d, J = 10.8 Hz,
1 H, PhCH2), 4.54 (d, J = 12.0 Hz, 1 H, PhCH2), 4.54 (d, J = 12.0
Hz, 1 H, PhCH2), 4.54 (d, J = 3.6 Hz, 1 H, H1¢), 4.52 (d, J = 10.8
Hz, 1 H, PhCH2), 4.51 (d, J = 3.6 Hz, 1 H, H1¢¢), 4.49 (d, J = 12.0
Hz, 1 H, PhCH2), 4.41 (d, J = 12.0 Hz, 1 H, PhCH2), 4.10 (dd,
J = 1.8, 10.8 Hz, 1 H, H6¢), 3.99–3.97 (m, 2 H, H5, H6¢¢), 3.97 (t,
J = 9.0 Hz, 1 H, H3¢), 3.93 (dd, J = 9.0, 9.6 Hz, 1 H, H3¢¢), 3.88 (dd,
J = 1.8, 4.8 Hz, 1 H, H2), 3.87 (dd, J = 4.8, 9.0 Hz, 1 H, H6), 3.82
(dd, J = 2.4, 9.0 Hz, 1 H, H6), 3.79 (ddd, J = 1.8, 6.0, 9.0 Hz, 1 H,
H5¢), 3.67–3.69 (m, 3 H, H3, H4, H5¢¢), 3.61 (dd, J = 5.4, 10.8 Hz,
1 H, H6¢¢), 3.59 (dd, J = 6.0, 10.8 Hz, 1 H, H6¢), 3.49 (dd, J = 3.6,
9.0 Hz, 1 H, H2¢), 3.45 (t, J = 9.0 Hz, 1 H, H4¢¢), 3.40 (t, J = 9.0 Hz,
1 H, H4¢), 3.38 (dd, J = 3.6, 9.6 Hz, 1 H, H2¢¢), 3.32 (s, 3 H, OCH3),
3.28 (s, 3 H, OCH3).
13C NMR (150 MHz, CDCl3): d = {137.7, 137.7, 137.7, 137.6,
137.6, 137.6, 137.1, 137.1, 128.5, 128.5, 128.5, 128.5, 128.5, 128.5,
128.4, 128.4, 128.4, 128.3, 128.3, 128.3, 128.1, 128.1, 128.1, 128.1,
128.1, 128.1, 128.0, 128.0, 128.0, 127.9, 127.9, 127.9} (Ar), 98.5
(C1), 97.9 (C1¢¢), 97.8 (C1¢), 82.0 (C3¢), 82.0 (C3¢¢), 80.1 (C4¢¢),
80.0 (C4¢), 78.0 (C2¢¢), 77.8 (C2¢), 76.2 (C5), {75.8, 75.7, 75.0,
73.4, 73.3, 73.3} (ArCH2), 73.3 (C6), {73.1, 73.0} (ArCH2), 71.6
(C3), 70.8 (C4), 70.5 (C6¢¢), 69.9 (C2), 69.8 (C5¢¢), 69.5 (C5¢), 68.2
(C6¢), 55.1(OCH3), 55.1(OCH3).
HRMS (FAB, MeCN–NBA + NaI): m/z [M + Na] calcd for
C49H56O11Na: 843.3721; found: 843.3715.
Methyl (3,4,6-Tri-O-benzyl-a-D-altropyranosyl)-(1→6)-2,3,4-
tri-O-benzyl-a-D-glucopyranoside (a-4c)
Rf = 0.56 (hexane–EtOAc, 1:1); [a]D20 +20.7 (c 0.28, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.28–7.14 (m, 30 H, Ar), 4.91 (d,
J = 11.0 Hz, 1 H, PhCH2), 4.79 (d, J = 12.1 Hz, 1 H, PhCH2), 4.78
(s, 1 H, H1¢), 4.72 (d, J = 11.0 Hz, 1 H, PhCH2), 4.70 (d, J = 12.1
Hz, 1 H, PhCH2), 4.60 (d, J = 12.1 Hz, 1 H, PhCH2), 4.57 (d,
J = 12.1 Hz, 1 H, PhCH2), 4.50 (d, J = 12.1 Hz, 1 H, PhCH2), 4.49
(d, J = 12.1 Hz, 1 H, PhCH2), 4.48 (d, J = 3.6 Hz, 1 H, H1), 4.45 (d,
J = 12.1 Hz, 1 H, PhCH2), 4.44 (d, J = 12.1 Hz, 1 H, PhCH2), 4.44
(d, J = 11.6 Hz, 1 H, PhCH2), 4.36 (d, J = 11.6 Hz, 1 H, PhCH2),
4.04 (dd, J = 1.7, 10.7 Hz, 1 H, H6), 3.95 (ddd, J = 2.5, 4.7, 9.1 Hz,
1 H, H5¢), 3.91 (t, J = 9.1 Hz, 1 H, H3), 3.89 (dd, J = 3.0, 4.1 Hz, 1
H, H3¢), 3.80 (m, 2 H, H2¢, H4¢), 3.71 (ddd, J = 1.7, 5.5, 9.1 Hz, 1
H, H5), 3.64 (dd, J = 2.5, 10.7 Hz, 1 H, H6¢), 3.60 (dd, J = 4.7, 10.7
Hz, 1 H, H6¢), 3.57 (dd, J = 5.5, 10.7 Hz, 1 H, H6), 3.42 (dd, J = 3.6,
9.1 Hz, 1 H, H2), 3.34 (t, J = 9.1 Hz, 1 H, H4), 3.25 (s, 3 H, OCH3).
13C NMR (150 MHz, CDCl3): d = {138.6, 138.3, 138.2, 138.0,
137.9, 128.4, 128.3, 128.3, 128.2, 128.2, 128.0, 127.9, 127.8, 127.7,
127.7, 127.7, 127.6, 127.6, 127.5, 127.4} (Ar), 98.5 (C1), 97.8
(C1¢), 82.0 (C3), 79.8 (C3¢), 77.9 (C2¢), 75.7 (C4¢), 75.0 (C4), {74.3,
73.4} (ArCH2), 73.3 (C5), 73.1 (C5¢), {73.0, 73.0, 71.8, 70.0}
(ArCH2), 69.7 (C6), 69.5 (C6¢), 68.1 (C2), 55.1 (OCH3).
HRMS (FAB, MeCN–NBA + NaI): m/z [M + Na] calcd for
C76H84O16Na: 1275.5657; found: 1275.5676.
Methyl (4,6-Di-O-benzyl-3-O-methyl-a-D-altropyranosyl)-
(1→6)-2,3,4-tri-O-benzyl-a-D-glucopyranoside (a-4b)
Rf = 0.66 (hexane–EtOAc, 1:1); [a]D20 +11.3 (c 0.4, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.36–7.25 (m, 25 H, Ar), 4.99 (d,
J = 11.0 Hz, 1 H, PhCH2), 4.88 (d, J = 11.0 Hz, 1 H, PhCH2), 4.81
(d, J = 11.0 Hz, 1 H, PhCH2), 4.78 (d, J = 12.1 Hz, 1 H, PhCH2),
4.76 (d, J = 1.4 Hz, 1 H, H1), 4.66 (d, J = 12.1 Hz, 1 H, PhCH2),
4.59 (d, J = 11.6 Hz, 1 H, PhCH2), 4.57 (d, J = 12.3 Hz, 1 H,
PhCH2), 4.56 (d, J = 3.6 Hz, 1 H, H1¢), 4.55 (d, J = 11.0 Hz, 1 H,
PhCH2), 4.53 (d, J = 12.3 Hz, 1 H, PhCH2), 4.50 (d, J = 11.6 Hz, 1
H, PhCH2), 4.11 (dd, J = 1.9, 10.7 Hz, 1 H, H6¢), 3.99 (t, J = 9.6 Hz,
1 H, H3¢), 3.93 (ddd, J = 2.8, 5.0, 9.1 Hz, 1 H, H5), 3.87 (dd,
J = 1.4, 4.4 Hz, 1 H, H2), 3.86 (dd, J = 3.0, 9.1 Hz, 1 H, H4), 3.79
(ddd, J = 1.9, 5.5, 10.1 Hz, 1 H, H5¢), 3.71 (dd, J = 2.8, 10.7 Hz, 1
H, H6), 3.68 (dd, J = 3.0, 4.4 Hz, 1 H, H3), 3.66 (dd, J = 5.0, 10.7
Hz, 1 H, H6), 3.63 (dd, J = 5.5, 10.7 Hz, 1 H, H6¢), 3.51 (dd, J = 3.6,
9.6 Hz, 1 H, H2¢), 3.43 (dd, J = 9.6, 10.1 Hz, 1 H, H4¢), 3.42 (s, 3 H,
OCH3), 3.35 (s, 3 H, OCH3).
13C NMR (150 MHz, CDCl3): d = {138.7, 138.4, 138.1, 138.1,
138.0, 128.5, 128.4, 128.4, 128.3, 128.3, 128.1, 128.0, 127.9, 127.8,
127.7, 127.7, 127.6, 127.5} (Ar), 98.6 (C1), 97.9 (C1¢), 82.1 (C3¢),
79.9 (C2¢), 77.9 (C4¢), 76.9 (C3), {75.8, 75.0, 73.4, 73.4} (ArCH2),
72.9 (C5), 72.6 (C4), 71.9 (ArCH2), 70.0 (C5¢), 69.7 (C6), 68.8
(C2), 68.2 (C6¢), 59.2 (OCH3), 55.1 (OCH3).
HRMS (FAB, MeCN–NBA + NaI): m/z [M + Na] calcd for
C55H60O11Na: 919.4034; found: 919.4033.
Methyl (3,4,6-Tri-O-benzyl-b-D-altropyranosyl)-(1→6)-2,3,4-
tri-O-benzyl-a-D-glucopyranoside (b-4c)
Rf = 0.27 (hexane–EtOAc, 1:1); [a]D22 +63.9 (c 0.925, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.36–7.16 (m, 30 H, Ar), 4.94 (d,
J = 11.0 Hz, 1 H, PhCH2), 4.78 (d, J = 2.5 Hz, 1 H, H1), 4.78 (d,
J = 11.0 Hz, 1 H, PhCH2), 4.77 (d, J = 12.1 Hz, 1 H, PhCH2), 4.71
(d, J = 11.3 Hz, 1 H, PhCH2), 4.65 (d, J = 12.1 Hz, 1 H, PhCH2),
4.65 (d, J = 11.8 Hz, 1 H, PhCH2), 4.60 (d, J = 11.3 Hz, 1 H,
PhCH2), 4.60 (d, J = 3.6 Hz, 1 H, H1¢), 4.59 (d, J = 11.8 Hz, 1 H,
PhCH2), 4.54 (d, J = 11.7 Hz, 1 H, PhCH2), 4.51 (d, J = 11.1 Hz, 1
H, PhCH2), 4.43 (d, J = 11.7 Hz, 1 H, PhCH2), 4.38 (d, J = 11.1 Hz,
HRMS (FAB, MeCN–NBA + NaI): m/z [M + Na] calcd for
C49H56O11Na: 843.3721; found: 843.3727.
Synthesis 2010, No. 1, 43–48 © Thieme Stuttgart · New York

48
T. Nakayama et al.
PAPER
1 H, PhCH2), 4.16 (ddd, J = 2.8, 3.9, 7.7 Hz, 1 H, H5), 4.08 (dd,
J = 2.5, 5.2 Hz, 1 H, H2), 4.00 (dd, J = 3.8, 11.5 Hz, 1 H, H6¢), 3.95
(t, J = 9.6 Hz, 1 H, H3¢), 3.88 (dd, J = 3.3, 7.7 Hz, 1 H, H4), 3.82
(dd, J = 3.3, 5.2 Hz, 1 H, H3), 3.73 (ddd, J = 1.9, 3.8, 9.6 Hz, 1 H,
H5¢), 3.60 (dd, J = 1.9, 11.5 Hz, 1 H, H6¢), 3.55 (t, J = 9.6 Hz, 1 H,
H4¢), 3.54 (dd, J = 3.9, 10.7 Hz, 1 H, H6), 3.48 (dd, J = 3.6, 9.6 Hz,
1 H, H2¢), 3.46 (dd, J = 2.8, 10.7 Hz, 1 H, H6), 3.31 (s, 3 H, OCH3).
13C NMR (150 MHz, CDCl3): d = {138.7, 138.5, 138.2, 138.1,
137.9, 128.3, 128.3, 128.2, 128.2, 128.0, 127.9, 127.8, 127.7, 127.7,
127.6, 127.5, 127.5, 127.4, 127.4, 127.3} (Ar), 101.4 (C1¢), 98.0
(C1), 82.1 (C3), 80.0 (C3¢), 77.6 (C2¢), 75.9 (C4¢), 75.6 (C4), {74.7,
73.4} (ArCH2), 73.4 (C5¢), 73.3(C5), {72.4, 72.0, 71.5, 69.9}
(ArCH2), 69.2 (C6), 69.1 (C6¢), 69.0 (C2), 55.1 (OCH3).
(2) (a) Takahashi, H.; Fukuda, T.; Mitsuzuka, H.; Namme, R.;
Miyamoto, H.; Ohkura, Y.; Ikegami, S. Angew. Chem. Int.
Ed. 2003, 42, 5069. (b) Takahashi, H.; Mitsuzuka, H.;
Nishiyama, K.; Ikegami, S. Synthesis 2006, 1415. Other
synthesis: (c) Haines, A. H. Org. Biomol. Chem. 2004, 2,
2352. (d) Haines, A. H. Tetrahedron Lett. 2004, 45, 835.
(3) Nishiyama, K.; Nakayama, T.; Natsugari, H.; Takahashi, H.
Synthesis 2008, 3761.
(4) Wu, X.; Kong, F.; Lu, D.; Li, G. Carbohydr. Res. 1992, 235,
163.
(5) Lipták, A.; Jodal, I.; Nanasi, P. Carbohydr. Res. 1975, 44, 1.
(6) (a) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc.
1989, 111, 6661. (b) Danishefsky, S. J.; Bilodeau, M. T.
Angew. Chem. Int. Ed. 1996, 35, 1380.
(7) Synthesis of D-altroside: (a) Fujita, K.; Ohta, K.; Ikegami,
Y.; Shimada, H.; Tahara, T.; Nogami, Y.; Koga, T.; Saito,
K.; Nakajiima, T. Tetrahedron Lett. 1994, 35, 9577.
(b) Ando, T.; Shinohara, H.; Luo, X.; Kandeel, M.; Kitade,
Y. Carbohydr. Res. 2007, 342, 2641.
HRMS (FAB, MeCN–NBA + NaI): m/z [M + Na] calcd for
C55H60O11Na: 919.4034; found: 919.4029.
Acknowledgment
(8) Glycosidation of 2-alkylated altrosides resulted in lower
yields.
(9) Recent report on glycosidation of methyl glycoside:
Vidadala, S. R.; Hotha, S. Chem. Commun. 2009, 2505.
(10) Franks, N. E.; Montgomery, R. Carbohydr. Res. 1968, 6,
286.
We wish to thank Ms. J. Shimode, Ms. A. Tonoki, and Ms. A.
Kawaji for spectroscopic measurements. This work was partially
supported by a Grant-in-Aid for Scientific Research from the Mini-
stry of Education, Science, Sports, Culture and Technology, Japan.
(11) Barresi, F.; Hindsgaul, O. Can. J. Chem. 1994, 72, 1447.
References
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R. Pharm. Acta Helv. 1997, 72, 105.
Synthesis 2010, No. 1, 43–48 © Thieme Stuttgart · New York