Stereoselective glycosylation using the long-range effect of a [2-(4-phenylbenzyl)oxycarbonyl]benzoyl group

Article abstract of DOI:10.1016/j.tetasy.2004.11.042

Highly α-selective glucosylation was effected by virtue of the solvent effect of cyclopentyl methyl ether and the long-range assistance of bulky 6-O-protective groups. Higher α-selectivity was obtained by the use of this solvent in comparison to conventio

Full text of DOI:10.1016/j.tetasy.2004.11.042

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 441–447
Stereoselective glycosylation using the long-range effect of a
[2-(4-phenylbenzyl)oxycarbonyl]benzoyl group
Hiroomi Tokimoto, Yukari Fujimoto, Koichi Fukase* and Shoichi Kusumotoꢀ
Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan
Received 8 November 2004;accepted 18 November 2004
Available online 21 December 2004
Abstract—Highly a-selective glucosylation was effected by virtue of the solvent effect of cyclopentyl methyl ether and the long-range
assistance of bulky 6-O-protective groups. Higher a-selectivity was obtained by the use of this solvent in comparison to conventional
diethyl ether. a-Selectivity was further improved with the influence of 6-O-substituents, such as TBDPS and phthaloyl groups, the
latter being mono esterified with a bulky alcohol.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Previously, we have reported an efficient method for gly-
cosylation using thioglycoside donors and hypervalent
iodine reagents prepared from PhIO and Lewis acids
as promoters.4–7 a-Glucosides were preferentially ob-
tained by virtue of the solvent effect of diethyl ether
and the a-directing effect of perchlorates, which have
been widely employed for selective a-glycosylations.4–9
We have also observed that long-range participa-
tion5–7,10 as well as steric demands6,7 of 6-O-protective
groups in glycosyl donors increased the a-selectivity of
the reaction (Fig. 1).3 Herein, we further develop this ap-
proach and have succeeded in securing higher a-selective
Stereoselective glycosylation has been an important
issue for efficient synthesis of oligosaccharides.1–3 In
particular, selective formation of 1,2-cis-glycosides is
generally a difficult issue, since no assisting effect such
as participation of a neighboring group is available.3
In the present study, we investigated a new practical
method for stereoselective 1,2-cis-a-D-glucosylation by
using bulky protecting groups for long-range stereocon-
trol. Among those tested a new phthaloyl ester proved
to be quite promising.
=
Bulky Group
R
O
O
BnO
BnO
R''
BnO
O
O R
O
O R
O
H
Activation
R''OH
BnO
BnO
BnO
BnO
R'
O
O
SPh
BnO
BnO
O
OR''
BnO
BnO
R''
BnO
O
H
= R'CO Acyl, alkoxy carbonyl, carbamoyl groups
R
Figure 1. a-Selective glucosylation by using the effects of 6-O-substituents.
*
Corresponding author. Tel.: +81 6850 5391;fax: +81 6850 5419;e-mail: koichi@chem.sci.osaka-u.ac.jp
ꢀ Present address: Fukui University of Technology, Gakuen 3-1-1, Fukui, Fukui 910-8505, Japan.
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.042

442
H. Tokimoto et al. / Tetrahedron: Asymmetry 16 (2005) 441–447
BnO
BnO
BnO
PhIO, Lewis acid
MS4A
O
BnO
BnO
BnO
HO
BnO
BnO
O
O
O
SPh
BnO
O
BnO
solvent
BnO
BnO
BnO
1
OMe
7
-20oC
BnO
9
OMe
Scheme 1.
glycosylation by the combined use of the favorable sol-
vent effect of cyclopentyl methyl ether and the steric
effect of bulky [2-(4-phenylbenzyl)oxycarbonyl]benzoyl
groups at the 6-position of glycosyl donors. This proce-
dure enables us to avoid the use of perchlorates many of
which are explosive and can cause serious problems in
laboratories.
Table 2. Effect of 6-O-substituents for a-selectivity
Entry Donor Acceptor Time Product Yield (%) a:b
1
2
3
4
5
2
3
4
5
6
7
7
7
7
7
6 h
5 h
10
11
53
85
79
53
83
100:0
90:10
97:3
45 min 12
1.5 h 13
45 min 14
100:0
100:0
6a
6
8
6 h 15
75
100:0
Glycosylation reactions were carried out by use of a donor (1.2 equiv),
PhIO (1.3 equiv), and TMSOTf (0.6 equiv) against an acceptor under
2. Results and discussion
˚
Ar atmosphere in the presence of molecular sieves 4 A at ꢀ20 ꢁC in
The solvent effect of cyclopentyl methyl ether (CPME),
a new solvent recently becoming available, was first
examined. 1,4-Dioxane was shown to be a more efficient
participating solvent than diethyl ether probably owing
to its structure, where the oxygen lone pair of the former
is more accessible for the participation.11 Since dioxane
is hygroscopic and thus not favorable for such reactions
where strictly anhydrous conditions are required, we
checked other less hygroscopic ethers and found that
tert-butyl methyl ether gave better a-selectivity than
diethyl ether.12 t-Butyl methyl ether is, however, not sta-
ble enough to strong acids often employed for glycosyl-
ation reactions. These results led us to examine a new
solvent, CPME. In view of its high stability against oxi-
dation and high boiling point (106 ꢁC), the use of this
solvent was expected to improve the safety of experi-
mental procedures and to be a good choice provided
that a sufficient a-orienting effect is exerted by this sol-
vent. In order to check the solvent effect, 2,3,4,6-tetra-
benzylated thioglycoside 1 was employed as a standard
donor, free methyl glycoside 8 with a free 6-OH group
as an acceptor, and Sn(OTf)2 as a Lewis acid. Glycosyl-
ation reactions were carried out using 1.3 equiv of PhIO,
0.6 equiv of Lewis acid, and 1.2 equiv of the donor 1
against the acceptor 8 under Ar atmosphere in the pres-
CPME.
a Reaction conditions, see text.
ide 9 (Scheme 1). As seen in Table 1 (entries 1 and 2),
higher a-selectivity was obtained using CPME than in
the corresponding reaction in diethyl ether.
The influence of Lewis acid catalysts was next examined.
In our previous papers, we showed that Lewis acid such
as SnCl2–AgClO4, SnCl4–AgClO4, SbCl3–AgClO4,
TMSClO4, Mg(ClO4)2 gave satisfactory a-selectivities
in glycosylation.5–7 As mentioned above, however,
perchlorates are explosive and their use should be
avoided. In the present study, various triflates were
examined in place of perchlorates. Though TMSOTf
gave the highest a-selectivity and chemical yield among
those tested (Table 1, entries 2–5), stereoselectivity was
greatly depressed from those obtained with perchlorates
and practically acceptable values were never obtained.
To improve the a-selectivity of triflate-promoted glyco-
sylation, the effect of 6-O-protective groups was exam-
ined with thioglucosyl donors having various
substituents at the 6-O-position (Scheme 2). As summa-
rized in Table 2, the reaction with 6-O-tert-butyldiphen-
ylsilylated donor 2 proceeded slowly but gave the
desired 10 with perfect a-selectivity (Table 2, entry 1).
The yield of the product was, however, moderate, since
a considerable amount of byproducts were formed.
Hence, phthaloyl half-esters were designed as new func-
tional groups for enhancing anomeric stereocontrol
(Fig. 2). The idea was based on our previous work on
successful stereoselective glycosylation using a ꢁmolecu-
lar clampꢂ method, where a bridge tethering acceptor
and donor components together controls their spatial
˚
ence of molecular sieves 4 A at ꢀ20 ꢁC to give disacchar-
Table 1. Reaction conditions and products of a-selective glycosylation
Entry Lewis acid Solvent Temp. Time
(ꢁC)
Yield a:b
(%)
1
2
3
4
5
Sn(OTf)2
Sn(OTf)2
TMSOTf
TBSOTf
TESOTf
Et2O
ꢀ20
<5 min 82
<5 min 80
72:28
78:22
84:16
79:21
66:34
CPME ꢀ20
CPME ꢀ20
CPME ꢀ20
CPME ꢀ20
1 h
89
80
82
5.5 h
2 h
PhIO, TMSOTf
RO
BnO
BnO
RO
BnO
BnO
HO
BnO
BnO
O
O
O
MS4A
O
SPh
O
BnO
BnO
BnO
BnO
BnO
OMe
CPME, -20 ºC
2-6
7
BnO
10-14
OMe
Scheme 2.

H. Tokimoto et al. / Tetrahedron: Asymmetry 16 (2005) 441–447
443
donors
BnO
R =
OMe 3
O
O
O
R
BnO
BnO
SPh
BnO
O
O
4
1
2
O
BnO
BnO
Ph
Ph
SPh
TBDPSO
5
BnO
HN
O
BnO
BnO
SPh
BnO
6
O
acceptors
HO
BnO
BnO
BnO
BnO
O
BnO
O
HO
BnO
OMe
OMe
7
8
products
BnO
BnO
BnO
TBDPSO
BnO
O
O
BnO
O
O
BnO
O
BnO
O
BnO
BnO
BnO
BnO
BnO
BnO
9
10
OMe
OMe
R =
OMe 11
O
O
O
O
O
O
R
O
12
O
O
O
BnO
BnO
BnO
BnO
O
Ph
Ph
OBn
O
BnO
O
BnO
BnO
BnO
13
HN
O
BnO
BnO
OMe
BnO
OMe
15
14
O
Figure 2. Structure of glycosyl donors, acceptors, and products.
arrangement, kinetically accelerates the glycosylation,
and allows a stereoselective reaction. Intramolecular
glycosylation between the donor and acceptor tethered
with a phthaloyl bridge at their 6-positions proceeded
smoothly to give the desired a(1!4) glycoside with high
stereoselectivity.13,14 A dipole repulsion between two
carbonyl groups in the phthaloyl moiety may have con-
trolled the direction of the two ester parts. This led us to
an idea that a phthaloyl half-ester part may cover the
upper face of the donor moiety to inhibit the attack of
an acceptor from the b-face of the former.
The glucosylation of an acceptor 8 possessing a more
hindered 4-hydroxyl group proceeded more slowly and
hydrolysis of the donor 6 was observed during the reac-
tion. When the reaction was accelerated by the use of
2.3 equiv of PhIO, 1.0 equiv of TMSOTf, and 2.0 equiv
of donor 6 against acceptor 8, the desired a(1!4) glyco-
side 15 was obtained in a satisfactory yield again with
perfect a-selectivity (Table 2, entry 6, Scheme 3).
Molecular modeling of the oxocarbenium ion intermedi-
ate of this reaction was carried out in order to explain
the high a-orienting effect of the 6-O-[2-(4-phenylbenz-
yl)oxycarbonyl]benzoyl group. A simplified structure
of the oxocarbenium ion intermediate was used for the
calculation: the benzyl ethers were changed to methyl
ethers and the biphenylmethyl group was changed to a
benzyl group. The lowest energy conformation was ex-
plored by using MacroModel (v7.1) Mixed MCMM/
LowMode Search using OPLS-AA force field and then
the geometry of energy minimum was optimized with
DFT calculation using B3LYP, 6–31G** (Jaguar v
4.1) (Fig. 3, A). In the lowest energy conformation A,
the phthaloyl half-ester part efficiently shields the upper
face of the pyranose ring and hence favor the attack of
the glycosyl acceptor from the opposite side to lead to
the preferential formation of a-glycosides. The confor-
mation B that can afford b-glycoside was 6.3 kJ less sta-
ble than A and hence considered to be a minor one.
The effect of a phthaloyl half-ester was examined by
using methyl ester 3 as a glycosyl donor. The yield was
very much improved from the value with TBDMS do-
nor 2 but the a-selectivity remained as low as 9:1 (Table
2, entry 2). Even so, the latter value indicates a slight but
positive a-directing influence of the 6-O-phthaloyl func-
tion as compared to the conventional benzyl function.
In fact, the a-selectivity was greatly improved when
more bulky 4-tert-butylbenzyl ester 4 was used as a
donor (Table 2, entry 3). Absolute a-selectivity was
obtained by using benzhydrylamide 5 as a donor but
the yield again dropped to an unsatisfactory, moderate
level (Table 2, entry 4). In the case of the biphenylmethyl
ester 6, the glycosylation proceeded smoothly to give the
desired a-glycoside 14 in a high yield with absolute a-
selectivity (Table 2, entry 5).

444
H. Tokimoto et al. / Tetrahedron: Asymmetry 16 (2005) 441–447
O
O
O
O
OBn
O
O
O
O
PhIO, TMSOTf
MS4A
O
O
O
HO
BnO
BnO
BnO
BnO
BnO
OBn
SPh
BnO
BnO
CPME, -20 ºC
BnO
OMe
O
BnO
BnO
OMe
Scheme 3.
TBDPSCl (121.6 mg, 114.7 lL, 442.2 lmol) at 0 ꢁC un-
der Ar atmosphere and the reaction mixture was stirred
at room temperature overnight. The reaction was then
worked up as usual. The residue was purified by silica-
gel
EtOAc = 15:1) to give 2 as a colorless syrup (272 mg,
flash
column
chromatography
(toluene/
95%). ESI-MS (positive) m/z = 803.3 [(M+Na)+]; 1H
NMR (400 MHz, CDCl3)
d
(ppm) = 7.77 (d,
Figure 3. The lowest energy conformation of oxocarbenium interme-
diate (A) and the conformation that shields a-face (B).
J = 6.84 Hz, 2H), 7.70 (d, J = 6.84 Hz, 2H), 7.60 (d,
J = 5.62 Hz, 1H), 7.60 (d, J = 7.32 Hz, 1H), 7.41–7.15
(m, 24H, aromatic), 4.90–4.84 (m, 4H, –CH2Ph · 2),
4.75–4.67 (m, 2H, –CH2Ph), 4.71 (d, J1,2 = 9.28 Hz,
1H, H-1), 3.96 (dd, J3,4 = 7.57 Hz, J3,2 = 8.71 Hz, 1H,
H-3), 3.93 (dd, J5,6 = 3.66 Hz, J5,4 = 5.75 Hz, 1H, H-5),
3.79 (dd, J6a,6b = 17.58 Hz, J6a,5 = 9.28 Hz, 1H, H-6a),
3.72 (dd, J6b,6a = 17.58 Hz, J6b,5 = 9.28 Hz, 1H, H-6b),
3.55 (dd, J2,3 = 8.79 Hz, J2,1 = 9.28 Hz, 1H, H-2), 3.40
(d, J4,3 = 7.57 Hz, 1H, H-4). Found: C, 75.10;H, 6.68;
S, 4.04. Calcd for C49H52O5SSi: C, 75.35;H, 6.71;S,
4.11.
3. Conclusion
In summary, a new practical and operationally simple
procedure has been developed for highly a-selective glu-
cosylation by using a phthaloyl group mono-esterified
with bulky biphenylmethanol and the solvent effect of
CPME. The phthaloyl half-ester and its structural ana-
logues may be useful as an auxiliary group for other dia-
stereoselective reactions as well.
4.2. Phenyl 2,3,4-tri-O-benzyl-6-O-[2-(methoxycar-
bonyl)benzoyl]-1-thio-a-D-glucopyranoside 3
4. Experimental section
1H NMR spectra were measured with JEOL JMN-GSX
400 or JEOL EX 270 spectrometers. The chemical shifts
in CDCl3 are given in d values from tetramethylsilane as
an internal standard. Mass spectra were obtained on
Applied Biosystem MarinarTM Biospectrometry Work-
station. Elemental analysis was performed by the staff
of the department. Silica-gel column chromatography
was carried out using Kieselgel 60 (Merck, 0.040–
0.063 mm) at medium pressure (2–4 kg/cm2). Precoated
Kieselgel 60 F254 (Merck, 0.5 mm) was used for pre-
parative thin layer chromatography. Anhydrous cyclo-
pentyl methyl ether was distilled from sodium.
Anhydrous Et2O was purchased from Kanto Chemicals,
To a solution of phenyl 2,3,4-tri-O-benzyl-6-O-(2-car-
bonylbenzoyl)-1-thio-a-D-glucopyranoside13 (30.0 mg,
43.0 lmol) in MeOH (1 mL) was added TMSCHN2
(30 lL, 60.0 lmol) at room temperature and the reac-
tion mixture was stirred for 30 min. The reaction was
quenched by addition of AcOH and concentrated in
vacuo. The residue was purified by silica-gel flash col-
umn chromatography (toluene/EtOAc = 10:1) to give 3
as a colorless syrup (22.7 mg, 75%). ESI-MS (positive)
1
m/z = 727.2 [(M+Na)+]; H NMR (400 MHz, CDCl3)
d (ppm) = 7.76–7.10 (m, 24H, aromatic), 5.59 (d,
J1,2 = 5.13 Hz, 1H, H-1), 5.03–4.61 (m, 6H,
–CH2Ph · 3), 4.55–4.44 (m, 3H, H-5, H-6a, H-6b),
3.95 (dd, J3,4 = J3,2 = 9.52 Hz, 1H, H-3), 3.88 (dd,
J2,3 = 9.52 Hz, J2,1 = 5.13 Hz, 1H, H-2), 3.78 (s, 3H,
–OCH3), 3.57 (dd, J4,5 = 9.03 Hz, J4,3 = 9.52 Hz, 1H,
H-4). Found: C, 71.48;H, 5.73;S, 4.46. Calcd for
C33H34O5S: C, 71.57;H, 5.72;S, 4.55.
˚
Tokyo. Molecular sieves 4 A was activated by heating at
250 ꢁC in vacuo for 3 h. The reactions were quenched by
addition of saturated aqueous NaHCO3 and extracted
with EtOAc and then the organic layer was washed with
H2O and brine, dried over Na2SO4, and concentrated in
vacuo, unless otherwise noted.
4.3. Phenyl 2,3,4-tri-O-benzyl-6-O-[[2-(4-tert-butylbenz-
yl)oxycarbonyl]benzoyl]-1-thio-a-D-glucopyranoside 4
4.1. Phenyl 2,3,4-tri-O-benzyl-6-O-tert-butyldiphenylsil-
yl-1-thio-b-D-glucopyranoside 2
To a solution of phenyl 2,3,4-tri-O-benzyl-6-O-(2-car-
bonylbenzoyl)-1-thio-a-D-glucopyranoside13 (50.0 mg,
72.4 lmol) in CH2Cl2 (1 mL) were added 4-tert-butyl-
benzyl alcohol (14.2 mg, 15.3 lL, 86.8 lmol), DIC
To a solution of phenyl 2,3,4-tri-O-benzyl-1-thio-D-
glucopyranoside13 (200.0 mg, 368.5 lmol) and imidazole
(30.1 mg, 442.2 lmol) in CH2Cl2 (3 mL) was added

H. Tokimoto et al. / Tetrahedron: Asymmetry 16 (2005) 441–447
445
(11.8 mg, 14.7 lL, 94.1 lmol) and DMAP (cat.) at room
temperature under Ar atmosphere and the reaction mix-
ture was stirred overnight. The reaction was quenched
by addition of AcOH and MeOH. Insoluble materials
were filtered through Celiteꢂ and the filtrate was concen-
trated in vacuo. The residue was purified by silica-gel
preparative thin layer chromatography (toluene/
EtOAc = 5:1) to give 4 as a colorless syrup (59.6 mg,
98%). ESI-MS (positive) m/z = 859.3 [(M+Na)+]; 1H
NMR (400 MHz, CDCl3) d (ppm) = 7.70–6.99(m, 28H,
aromatic), 5.52 (d, J1,2 = 5.13 Hz, 1H, H-1), 5.18 and
5.11 (each d, Jgem = 12.21 Hz, 2H, –CH2Ph), 4.93 and
4.77 (each d, Jgem = 12.45 Hz, 2H, –CH2Ph), 4.81
and 4.54 (each d, Jgem = 10.74 Hz, 2H, –CH2Ph), 4.67
and 4.59 (each d, Jgem = 11.72 Hz, 2H, –CH2Ph),
4.43–4.32 (m, 3H, H-5, H-6a, H-6b), 3.87 (dd,
J3,4 = J3,2 = 9.52 Hz, 1H, H-3), 3.81 (dd, J2,3 = 9.52 Hz,
J2,3 = 5.13 Hz, 1H, H-2), 3.48 (dd, J4,5 = 8.52 Hz,
J4,3 = 9.52 Hz, 1H, H-4), 1.20 (s, 9H, –C(CH3)3). Found:
C, 73.33;H, 6.23;S, 3.60. Calcd for C 52H52O8SÆ0.8H2O:
C, 73.35;H, 6.16;S, 3.77.
overnight. The reaction was quenched by addition of
AcOH and MeOH. Insoluble materials were filtered
through Celiteꢂ and the filtrate was concentrated in
vacuo. The residue was purified by silica-gel preparative
thin layer chromatography (toluene/EtOAc = 5:1) to
give 10 as a colorless syrup (59.9 mg, 97%). ESI-MS
1
(positive) m/z = 879.3 [(M+Na)+]; H NMR (400 MHz,
CDCl3) d (ppm) for a-anomer 7.75–7.63 (m, 28H,
aromatic), 5.58 (d, J1,2 = 5.13 Hz, 1H, H-1), 5.32 and
5.25 (each d, Jgem = 12.45 Hz, 2H, –CH2Ph), 4.99
and 4.78 (each d, Jgem = 10.74 Hz, 2H, –CH2Ph),
4.88 and 4.61 (each d, Jgem = 10.74 Hz, 2H, –CH2Ph),
4.73 and 4.64 (each d, Jgem = 11.72 Hz, 2H, –CH2Ph),
4.50–4.43 (m, 3H, H-5, H-6a, H-6b), 3.81 (dd,
J3,4 = 9.02 Hz, J3,2 = 9.77 Hz, 1H, H-3), 3.87 (dd,
J2,3 = 9.77 Hz, J2,1 = 5.13 Hz, 1H, H-2), 3.54 (t,
J4,5 = J4,3 = 9.03 Hz, 1H, H-4). Found: C, 74.95;H,
5.60;S, 3.74. Calcd for C 54H48O8SÆ0.5H2O: C, 74.89;
H, 5.59;S, 3.71.
4.6. Methyl 2,3,4,6-tetra-O-benzyl-D-glucopyranosyl-
(1!6)-2,3,4-tri-O-benzyl-a-D-glucopyranoside 9
4.4. Phenyl 2,3,4-tri-O-benzyl-6-O-[2-(diphenylmethyl-
aminocarbonyl)benzoyl]-1-thio-a-D-glucopyranoside 5
To a mixture of phenyl 2,3,4,6-tetra-O-benzyl-1-thio-b-
D-glucopyranoside 1 (81.7 mg, 129 lmol), methyl 2,3,4-
tri-O-benzyl-a-D-glucopyranoside 7 (50 mg, 108 lmol),
To a solution of phenyl 2,3,4-tri-O-benzyl-6-O-(2-car-
bonylbenzoyl)-1-thio-a-D-glucopyranoside13 (50.0 mg,
72.4 lmol) in CH2Cl2 (1 mL) were added Ph2CHNH2
(15.9 mg, 15 lL, 86.8 lmol), DIC (11.8 mg, 14.7 lL,
94.1 lmol) and DMAP (cat.) at room temperature un-
der Ar atmosphere and the reaction mixture was stirred
overnight. The reaction was quenched by addition of
AcOH and MeOH. Insoluble materials were filtered
through Celiteꢂ and the filtrate was concentrated in
vacuo. The residue was purified by silica-gel preparative
thin layer chromatography (toluene/EtOAc = 10:1) to
give 8 as a colorless syrup (55.2 mg, 89%). ESI-MS
˚
PhIO (30.8 mg, 140 lmol) and molecular sieves 4 A in
CPME (1 mL) was added Lewis acid (64.6 lmol) at
ꢀ20 ꢁC under Ar atmosphere. The reaction was then
worked up as usual. The residue was purified by silica-
gel preparative thin layer chromatography (toluene/
EtOAc = 5:1) to give 9 as a colorless syrup. ESI-MS
(positive) m/z = 1009.5 [(M+Na)+]; 1H NMR
(400 MHz, CDCl3) d (ppm) a-anomer 7.25–7.03 (m,
35H, aromatic), 4.90 (d, J1 ,2 = 3.66 Hz, 1H, H-10),
0
0
4.89–4.32 (m, 14H, –CH2Ph · 7), 4.47 (d, J1,2
=
0
0
0
0
3.42 Hz, 1H, H-1), 3.90 (t, J3 ,4 = J3 ,2 = 9.28 Hz, 1H,
H-30), 3.88 (t, J3,4 = J3,2 = 9.28 Hz, 1H, H-3), 3.76–3.48
(m, 8H, H-4, H-5, H-6a, H-6b, H-40, H-50, H-6a0,
1
(positive) m/z = 878.3 [(M+Na)+]; H NMR (400 MHz,
CDCl3) d (ppm) = 7.84 (d, JNH,CH = 7.81 Hz, 1H,
—CONH—), 7.73–7.01 (m, 32H, aromatic), 6.45–6.40
(m, 2H, aromatic), 6.28 (d, JCH,NH = 7.81 Hz, 1H,
–CHPh2), 5.28 (d, J1,2 = 5.13 Hz, 1H, H-1), 5.01 and
4.82 (each d, Jgem = 10.74 Hz, 2H, –CH2Ph), 4.91
and 4.63 (each d, Jgem = 10.99 Hz, 2H, –CH2Ph), 4.75
and 4.64 (each d, Jgem = 11.48 Hz, 2H, –CH2Ph), 4.57
(dd, J6a,6b = 11.72 Hz, J6a,5 = 2.20 Hz, 1H, H-6a), 4.45
(dd, J5,6b = 5.62 Hz, J5,4 = 9.52 Hz, 1H, H-5), 4.37 (dd,
J6b,6a = 11.72 Hz, J6b,5 = 5.62 Hz, 1H, H-6b), 3.95 (t,
J3,4 = J3,2 = 9.52 Hz, 1H, H-3), 3.29 (dd, J2,3 = 9.52 Hz,
J2,1 = 5.13 Hz, 1H, H-2), 3.55 (t, J4,5 = J4,3 = 9.52 Hz,
1H, H-4). Found: C, 74.76;H, 5.70;N, 1.73;S, 3.76.
Calcd for C54H49NO7SÆ0.7H2O: C, 74.73;H, 5.69;N,
1.61;S, 3.69.
H-6b0), 3.46 (dd, J2 ,3 = 9.28 Hz, J2 ,1 = 3.66 Hz, 1H,
H-20), 3.36 (dd, J2,3 = 9.28 Hz, J2,3 = 3.42 Hz, 1H, H-
2), 3.27 (s, 3H, –OCH3); b-anomer 3.24 (s, 3H,
–OCH3). Found: C, 74.86;H, 6.73. Calcd for
C62H66O11Æ0.5H2O: C, 74.81;H, 6.68.
0
0
0
0
4.7. Methyl 2,3,4-tri-O-benzyl-6-O-tert-butyldiphenylsil-
yl-D-glucopyranosyl-a-(1!6)-2,3,4-tri-O-benzyl-a-D-
glucopyranoside 10
To a mixture of 2 (34.1 mg, 43.7 lmol), 7 (16.9 mg,
36.4 lmol), PhIO (10.4 mg, 47.3 lmol) and molecu-
˚
lar sieves 4 A in CPME (0.5 mL) was added TMSOTf
(4.8 mg, 4.0 lL, 21.8 lmol) at ꢀ20 ꢁC under Ar atmo-
sphere. After the reaction mixture was stirred for 6 h,
the reaction was worked up as usual. The residue was
purified by silica-gel preparative thin layer chromatogra-
phy (toluene/EtOAc = 10:1) to give 10 as a colorless
syrup (19.4 mg, 53%, a:b = 100:0). ESI-MS (positive)
4.5. Phenyl 2,3,4-tri-O-benzyl-6-O-[[2-(4-phenylbenz-
yl)oxycarbonyl]benzoyl]-1-thio-a-D-glucopyranoside 6
To a solution of phenyl 2,3,4-tri-O-benzyl-6-O-(2-car-
bonylbenzoyl)-1-thio-a-D-glucopyranoside13 (50.0 mg,
72.4 lmol) in CH2Cl2 (1 mL) were added 4-biphenyl-
methanol (16.0 mg, 86.8 lmol), DIC (11.8 mg, 14.7 lL,
94.1 lmol) and DMAP (cat.) at room temperature un-
der Ar atmosphere and the reaction mixture was stirred
1
m/z = 1157.4 [(M+Na)+]; H NMR (400 MHz, CDCl3)
d (ppm) = 7.61 (dd, J = 1.47, 8.06 Hz, 2H), 7.57 (dd,
J = 1.47, 8.06 Hz, 2H), 7.51–7.05 (m, 36H, aromatic),
4.93 (d, J = 3.42 Hz, 1H, H-10), 4.90–4.46 (m, 12H,
0
0
0
0
–CH2Ph · 6), 3.92 (dd, J3 ,4 = 6.10 Hz, J3 ,2 = 9.52 Hz,

446
H. Tokimoto et al. / Tetrahedron: Asymmetry 16 (2005) 441–447
1H, H-30), 3.88 (dd, J3,4 = 6.10 Hz, J3,2 = 9.52 Hz,
1H, H-3), 3.74–3.69 (m, 4H, H-6a0, H6b0, H-6a, H-
6b), 3.67 (d, J5,6 = 3.66 Hz, 1H, H-5), 3.63 (d,
3.29 (dd, J2,3 = 9.52 Hz, J2,1 = 3.42 Hz, 1H, H-2), 3.34
(s, 3H, –OCH3), 1.29 (s, 9H, –C(CH3)3). b-anomer
3.31 (s, 3H, –OCH3). Found: C, 72.93;H, 6.64. Calcd
for C74H78O14Æ1.5H2O: C, 72.94;H, 6.46.
J5 ,6 = 5.37 Hz, 1H, H-50), 3.59 (d, J4,3 = 6.10 Hz, 1H,
0
0
H-3), 3.55 (d, J4 ,3 = 6.10 Hz, 1H, H-40), 3.46
0
0
(dd, J2 ,3 = 9.52 Hz, J2 ,1 = 3.42 Hz, 1H, H-20), 3.33
(dd, J2,3 = 9.52 Hz, J2,1 = 3.42 Hz, 1H, H-2), 3.28 (s,
3H, –OCH3), 0.95 (s, 9H, –C(CH3)3). Found: C, 74.21;
H, 6.89. Calcd for C71H78O11Si1Æ0.8H2O: C, 74.22;H,
6.84.
4.10. Methyl 2,3,4-O-tri-benzyl-6-O-[2-(diphenylmeth-
ylaminocarbonyl)benzoyl]-D-glucopyranosyl-a-(1!6)-
2,3,4-tri-O-benzyl-a-D-glucopyranoside 13
0
0
0
0
To a suspension of 5 (30.0 mg, 35.0 lmol), 7 (13.6 mg,
29.2 lmol), PhIO (8.3 mg, 38.0 lmol) and molecular
˚
sieves 4 A in CPME (0.3 mL) was added TMSOTf
4.8. Methyl 2,3,4-tri-O-benzyl-6-O-[2-(methoxycar-
bonyl)benzoyl]-D-glucopyranosyl-(1!6)-2,3,4-tri-O-benz-
yl-a-D-glucopyranoside 11
(3.9 mg, 3.2 lL, 17.5 lmol) at ꢀ20 ꢁC under Ar atmo-
sphere. After the reaction mixture was stirred for
1.5 h, the reaction was worked up as usual. The residue
was purified by silica-gel preparative thin layer chroma-
tography (toluene/EtOAc = 5:1) to give 13 as a colorless
syrup (7.8 mg, 53%, a:b = 100:0). ESI-MS (positive)
To a mixture of 3 (20.0 mg, 28.4 lmol), 7 (11.0 mg,
23.6 lmol), PhIO (6.8 mg, 30.7 lmol) and molecular
˚
sieves 4 A in CPME (0.5 mL) was added TMSOTf
1
(3.1 mg, 2.6 lL, 14.2 lmol) at ꢀ20 ꢁC under Ar atmo-
sphere. After the reaction mixture was stirred for 5 h,
the reaction was worked up as usual. The residue was
purified by silica-gel preparative thin layer chromatogra-
phy (toluene/EtOAc = 10:1) to give 11 as a colorless syr-
up (7 mg, 85%, a:b = 90:10). ESI-MS (positive)
m/z = 1232.6 [(M+Na)+]; H NMR (400 MHz, CDCl3)
d (ppm) = 7.82 (d, JNH,CH = 7.57 Hz, 1H, –CONH–),
7.78–7.12 (m, 42H, aromatic), 6.46–6.44 (m, 2H,
aromatic), 6.41 (d, JCH,NH = 7.57 Hz, 1H, –CHPh2),
4.97 and 4.75 (each d, Jgem = 11.23 0Hz, 2H, –CH2Ph),
0
0
4.94 (d, J1 ,2 = 3.66 Hz, 1H, H-1 ), 4.90 and 4.62
(each d, Jgem = 10.99 Hz, 2H, –CH2Ph), 4.84 and 4.58 (each
d, Jgem = 10.99 Hz, 2H, –CH2Ph), 4.76 and 4.71 (each
d, Jgem = 11.72 Hz, 2H, –CH2Ph), 4.68 and 4.43
(each d, Jgem = 12.21 Hz, 2H, –CH2Ph), 4.65 and 4.47
m/z = 1081.4 [(M+Na)+]; H NMR (400 MHz, CDCl3)
1
d (ppm) for a-anomer 7.60–7.08 (m, 34H, aromatic),
4.89 (d, J1 ,2 = 4.88 Hz, 1H, H-10), 4.87–4.50 (m, 12H,
–CH2Ph · 6), 4.47 (d, J1,2 = 3.42 Hz, 1H, H-1), 4.42–
4.33 (m, 3H, H-50, H-6a0, H-6b0), 3.94–3.87 (m, 3H,
H-3, H-30, H-40), 3.73 (s, 3H, –OCH3), 3.79–3.51 (m,
0
0
(each d, Jgem = 11.96 Hz, 2H, –CH2Ph), 4.54 (d, J1,2
=
3.66 Hz, 1H, H-1), 4.52–4.40 (m, 3H, H-50, H-6a0,
H-6b0), 4.03–3.90 (m, 3H, H-3, H-30, H-40), 3.81–3.75
(m, 2H, H-5, H-6a), 3.71–3.56 (m, 2H, H-4, H-6b),
0
0
4H, H-4, H-5, H-6a, H-6b), 3.43 (dd, J2 ,3 = 9.52 Hz,
J2 ,1 = 3.42 Hz, 1H, H-20), 3.32 (dd, J2,3 = 9.52 Hz,
J2,1 = 3.42 Hz, 1H, H-2), 3.27 (s, 3H, –OCH3). b-anomer
3.24 (s, 3H, –OCH3).
0
0
3.52 (dd, J2 ,3 = 9.52 Hz, J2 ,1 = 3.66 Hz, 1H, H-20),
3.40 (dd, J2,3 = 9.52 Hz, J2,1 = 3.66 Hz, 1H, H-2), 3.34
(s, 3H, –OCH3). Found: C, 72.41;H, 6.26;N, 1.12.
Calcd for C76H75NO13Æ2.8H2O: C, 72.45;H, 6.00;N,
1.11.
0
0
0
0
4.9. Methyl 2,3,4-tri-O-benzyl-6-O-[[2-(4-tert-butylbenz-
yl)oxycarbonyl]benzoyl]-D-glucopyranosyl-(1!6)-2,3,4-
tri-O-benzyl-a-D-glucopyranoside 12
4.11. Methyl 2,3,4-tri-O-benzyl-6-O-[[2-(4-phenylbenz-
yl)oxycarbonyl]benzoyl]-D-glucopyranosyl-a-(1!6)-
2,3,4-tri-O-benzyl-a-D-glucopyranoside 14
To a mixture of 4 (216 mg, 258 lmol), 7 (100 mg,
215 lmol), PhIO (61.6 mg, 280 lmol) and molecular
˚
sieves 4 A in CPME (2 mL) was added TMSOTf
(28.7 mg, 23.3 lL, 129 lmol) at ꢀ20 ꢁC under Ar atmo-
sphere. After the reaction mixture was stirred for
45 min, the reaction was worked up as usual. The resi-
due was purified by silica-gel flash chromatography (tolu-
ene/EtOAc = 5:1) to give 12 as a colorless syrup
(203 mg, 79%, a:b = 97:3). ESI-MS (positive)
To a suspension of 6 (221 mg, 258 lmol), 7 (100 mg,
215 lmol), PhIO (61.6 mg, 280 lmol) and molecular
˚
sieves 4 A in CPME (2 mL) was added TMSOTf
(28.7 mg, 23.3 lL, 129 lmol) at ꢀ20 ꢁC under Ar atmo-
sphere. After the reaction mixture was stirred for
45 min, the reaction was worked up as usual. The resi-
due was purified by silica-gel flash chromatography (tolu-
1
m/z = 1214.4 [(M+Na)+]; H NMR (400 MHz, CDCl3)
d (ppm) a anomer 7.70–7.13 (m, 38H, aromatic), 5.27
and 5.21 (each d, Jgem = 11.96 Hz, 2H, –CH2Ph),
ene/EtOAc = 5:1) to give 14 as a colorless syrup
25
(216 mg, 83%, a:b = 100:0). ½aŠ ¼ þ0:3 (c 1.37, CHCl3);
D
1
4.96 (d, J1 ,2 =3.17 Hz, 1H, H-1 ), 4.92 and 4.81 (each
d, Jgem = 10.25 Hz, 2H, –CH2Ph), 4.92 and 4.78 (each
d, Jgem = 10.50 Hz, 2H, –CH2Ph), 4.87 and 4.66
(each d, Jgem = 11.96 Hz, 2H, –CH2Ph), 4.87 and 4.60
(each d, Jgem = 11.23 Hz, 2H, –CH2Ph), 4.67 and 4.55
(each d, Jgem = 11.96 Hz, 2H, –CH2Ph), 4.65 (d,
ESI-MS (positive) m/z = 1232.4 [(M+Na)+]; H NMR
(400 MHz, CDCl3) d (ppm) = 7.72–7.15 (m, 43H, aro-
matic), 5.33 and 5.28 (each d, Jgem = 12.45 Hz, 2H,
0
0
0
–CH2Ph), 4.95 (d, J1 ,2 = 3.42 Hz, 1H, H-10), 4.94 and
4.79 (each d, Jgem = 10.74 Hz, 2H, –CH2Ph), 4.94
and 4.77 (each d, Jgem = 10.74 Hz, 2H, –CH2Ph), 4.89
and 4.65 (each d, Jgem = 11.96 Hz, 2H, –CH2Ph),
4.84 and 4.57 (each d, Jgem = 10.50 Hz, 2H, –CH2Ph),
4.67 and 4.53 (each d, Jgem = 12.21 Hz, 2H,
–CH2Ph), 4.64 (d, Jgem = 11.96 Hz, 2H, –CH2Ph · 2),
4.53 (d, J1,2 = 3.66 Hz, 1H, H-1), 4.46–4.41 (m, 2H, H-
0
0
Jgem = 11.21 Hz, 2H, –CH2Ph · 2), 4.53 (d, J1,2
=
3.42 Hz, 1H, H-1), 4.46–4.36 (m, 2H, H-6a0, H-6b0),
4.39 (dd, J5 ,6a = 11.78 Hz, J5 ,4 = 9.28 Hz, 1H, H-50),
0
0
0
0
4.02–3.94 (m, 3H, H-3, H-30, H-40), 3.82–3.69 (m, 3H,
H-5, H-6a, H-6b), 3.61 (t, J4,5 = J4,3 = 9.28 Hz, 1H, H-
0
6a0, H-6b0), 4.39 (dd, J5 ,6a = 11.96 Hz, J5 ,4 = 9.76 Hz,
0 0 0 0
0
0
0
4), 3.53 (dd, J2 ,3 = 6.59 Hz, J2 ,1 = 3.42 Hz, 1H, H-2 ),
0

H. Tokimoto et al. / Tetrahedron: Asymmetry 16 (2005) 441–447
447
1H, H-50), 4.01–3.94 (m, 3H, H-3, H-30, H-40), 3.81–3.69
(m, 3H, H-5, H-6a, H-6b), 3.60 (t, J4,5 = J4,3 = 9.28
Acknowledgements
0
0
0
0
Hz, 1H, H-4), 3.52 (dd, J2 ,3 = 9.03 Hz, J2 ,1 = 3.42 Hz, 1H,
H-20), 3.38 (dd, J2,3 = 9.52 Hz, J2,1 = 3.66 Hz, 1H, H-
2), 3.33 (s, 3H, –OCH3). Found: C, 73.61;H, 6.12. Calcd
for C76H74O14Æ1.6H2O: C, 73.66;H, 6.18.
The present work was financially supported in part by
the Grant-in-Aid for Scientific Research No. 15310149
from the Japan Society for the Promotion of Science
and by the Grant-in-Aid for Creative Scientific Research
ꢁIn vivo Molecular Science for Discovery of New Bio-
functions and Pharmaceutical Drugsꢂ No. 13NP0401
from the Ministry of Education, Science, Sports and
Culture, Japan. CPME used in this work was a generous
gift of ZEON Cooperation, R&D Center.15
4.12. Methyl 2,3,4-tri-O-benzyl-6-O-[[2-(4-phenylbenz-
yl)oxycarbonyl]benzoyl]-D-glucopyranosyl-a-(1!4)-
2,3,6-tri-O-benzyl-a-D-glucopyranoside 15
To a suspension of 6 (369 mg, 431 lmol), methyl 2,3,6-
tri-O-benzyl-a-D-glucopyranoside 8 (100 mg, 215 lmol),
PhIO (109 mg, 495 lmol) and molecular sieves 4 A in
˚
References
CPME (2 mL) was added TMSOTf (47.9 mg, 38.9 lL,
215 lmol) at ꢀ20 ꢁC under Ar atmosphere. After the
reaction mixture was stirred for 6 h, the reaction was
worked up as usual. The residue was purified by silica-
gel flash chromatography (toluene/EtOAc = 13:1) to
1. Toshima, K.;Tatsuta, K. Chem. Rev. 1993, 93, 1503–1531.
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7. Fukase, K.;Nakai, Y.;Egusa, K.;Porco, J. A., Jr.;
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give 6 as a colorless syrup (150 mg, 75%, a:b = 100:0).
25
D
½aŠ ¼ þ0:5 (c 1.81 CHCl3);ESI-MS (positive) m/z =
1233.5 [(M+Na)+]; 1H NMR (400 MHz, CDCl3) d
0
0
=
(ppm) = 7.71–7.11 (m, 43H, aromatic), 5.55 (d, J1 ,2
3.66 Hz, 1H, H-10), 5.26 and 5.22 (each d, Jgem = 12.21
Hz, 2H, –CH2Ph), 4.95 and 4.77 (each d, Jgem
=
11.72 Hz, 2H, –CH2Ph) 4.84 and 4.71 (each d,
Jgem = 10.74 Hz, 2H, –CH2Ph), 4.80 and 4.54 (each d,
Jgem = 10.99 Hz, 2H, –CH2Ph), 4.63 and 4.51 (each
d, Jgem = 11.96 Hz, 2H, –CH2Ph), 4.56 (d, Jgem
=
11.96 Hz, 4H, –CH2Ph · 2), 4.55 (d, J1,2 = 3.66 Hz,
1H, H-1), 4.44 and 4.38 (each d, Jgem = 11.96 Hz,
0
0
0
0
2H, –CH2Ph), 4.29 (d, J6a ,5 = J6b ,5 = 2.93 Hz, 2H, H-
6a0, H-6b0), 4.02 (t, J3,4 = J3,2 = 9.28 Hz, 1H, H-3),
12. Chiba, H.;Funasaka, S.;Mukaiyama, T. 83rd National
Meeting of the Chemical Society of Japan, Tokyo, March
2003;Abstr. No. 3D1–08.
0
0
0
3.95 (t, J4,5 = J4,3 = 9.28 Hz, 1H, H-4), 3.90 (t, J3 ,4
0
=
=
J3 ,2 = 9.28 Hz, 1H, H-30), 3.89 (td, J5 ,6a = J5 ,6b
2.93 Hz, J5 ,4 = 9.28 Hz, 1H, H-50), 3.79–3.73 (m, 3H,
0
0
0
0
0
0
13. Wakao, M.;Fukase, K.;Kusumoto, S.
1911–1914.
Synlett 1999,
H-5, H-6a, H-6b), 3.52 (dd, J2,3 = 9.28 Hz, J2,1
0
=
0
0
0
3.66 Hz, 1H, H-2), 3.45 (t, J4 ,5 = J4 ,3 = 9.28 Hz,
14. Wakao, M.;Fukase, K.;Kusumoto, S.
2002, 67, 8182–8190.
J. Org. Chem.
1H, H-40), 3.37 (dd, J2 ,3 = 9.28 Hz, J2 ,1 = 3.66 Hz,
1H, H-20), 3.33 (s, 3H, –OCH3). Found: C, 74.60;
H, 6.16. Calcd for C76H74O14Æ0.7H2O: C, 74.60;H,
6.10.
0
0
0
0
15. ZEON Corporation, R&D Center, 1-2-1 Yako, Kawa-
saki-ku, Kawasaki, Kanagawa 210-8507, fax: +81 44 276
3720.