An efficient synthesis of l-idose and l-iduronic acid thioglycosides and their use for the synthesis of heparin oligosaccharides

Article abstract of DOI:10.1016/j.carres.2007.12.015

Efficient preparations of thioglycoside derivatives of l-idose and l-iduronic acid are described. The method avoids the tedious chromatographic separations of furanose and pyranose anomeric mixtures, and affords the thioglycosides in a stereoselective man

Full text of DOI:10.1016/j.carres.2007.12.015

Available online at www.sciencedirect.com
Carbohydrate Research 343 (2008) 596–606
An efficient synthesis of L-idose and L-iduronic acid
thioglycosides and their use for the synthesis of
heparin oligosaccharidesI
a
a
b
a,
*
´
´
´
´
Janos Tatai, Gyorgyi Osztrovszky, Maria Kajtar-Peredy and Peter Fugedi
¨
¨
aDepartment of Carbohydrate Chemistry, Chemical Research Center, Hungarian Academy of Sciences,
Pusztaszeri u´t 59-67, H-1025 Budapest, Hungary
bNMR Laboratory, Chemical Research Center, Hungarian Academy of Sciences, Pusztaszeri u´t 59-67,
H-1025 Budapest, Hungary
Received 23 July 2007; received in revised form 16 December 2007; accepted 18 December 2007
Available online 25 December 2007
Presented in part at the 12th European Carbohydrate Symposium, Grenoble, France, July 6–11, 2003, Abstract OC012;
and at the 22nd International Carbohydrate Symposium, Glasgow, United Kingdom, July 23–27, 2004, Abstract C29.
Abstract—Efficient preparations of thioglycoside derivatives of L-idose and L-iduronic acid are described. The method avoids the
tedious chromatographic separations of furanose and pyranose anomeric mixtures, and affords the thioglycosides in a stereoselective
manner. The L-idose and L-iduronic acid thioglycosides having combinations of different protecting groups proved to be efficient
glycosyl donors in the synthesis of heparin disaccharides.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Heparin; L-Iduronic acid; Thioglycosides; Glycosylation; Oligosaccharide synthesis
1. Introduction
homogeneous HP/HS oligosaccharides. These oligosac-
charides are, however, accessible only with extreme dif-
ficulties by degradations of the natural polysaccharides.
Chemical synthesis is a viable option to provide well-
defined HP/HS oligosaccharide sequences for reviews
on the syntheses of heparin oligosaccharides.5–12
Whereas earlier synthetic approaches targeted a single
heparin oligosaccharide in each synthesis,5 more
recently synthetic strategies are being developed with
the aim of generating a series of heparin oligosaccha-
rides.13–20 We have developed21,22 a new synthesis strat-
egy based on orthogonal protection of the positions,
which are optionally sulfated in the target compounds.
In this way, from a single protected oligosaccharide, a
large number of differently sulfated derivatives could
be synthesized.
The structurally related heparin (HP) and heparan sul-
fate (HS), members of the glycosaminoglycan family
of polysaccharides, interact with a large number of pro-
teins of diverse biological functions.1,2 Heparin–protein
interactions modulate the biological activities of these
proteins and affect a series of physiological processes.
It is commonly assumed, though not rigorously proven,
that specific oligosaccharide structures within the heter-
ogeneous polysaccharide chains are responsible for the
binding to individual proteins.3,4
Identification of oligosaccharide ligands of individual
heparin-binding proteins would be most conveniently
done by screening the proteins against libraries of
Heparin and heparan sulfate are built up of alternating
D-glucosamine and hexuronic acid units, the latter being
either D-glucuronic acid or L-iduronic acid. Whereas
building blocks of D-glucosamine and D-glucuronic
q Synthesis of Glycosaminoglycan Oligosaccharides, Part 1.
*
Corresponding author. Fax: +36 1 438 1145; e-mail: pfugedi@
chemres.hu
0008-6215/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2007.12.015

J. Tatai et al. / Carbohydrate Research 343 (2008) 596–606
597
acid for oligosaccharide synthesis are accessible with
relative ease, the synthesis of L-iduronic acid
derivatives is more problematic. Neither L-idose and
L-iduronic acid nor their derivatives are available
commercially. Most of the synthetic methods for their
preparation start from some D-glucose or D-glucuronic
acid derivative and involve C-5 epimerization either on
the hexose23–27 or on the hexuronic acid28–34 stage,
though stereoselective procedures using chain-elonga-
tion of pentose derivatives have also been developed.35
For the appropriately protected derivatives required
for oligosaccharide synthesis, the introduction of the
protecting groups is normally done partly at the
D-gluco and partly at the L-ido stage. The use of D-
glucofuranose derivatives not only offers easy access
to C-5 for inversion by different methods but also
allows the ready introduction of some of the required
protecting groups. The furanose?pyranose switch,
however, is troublesome in these syntheses as high
proportions of the furanose anomers are formed both
with L-idose and L-iduronic acid derivatives, and the
separation of the different tautomers requires tedious
chromatographic separations and prevents large scale
synthesis. Although significant improvement has been
made36 by optimization of the reaction conditions for
the formation of a pyranose anomer on a particular
iduronic acid derivative, the generality of these condi-
tions for the preparation of other derivatives remains
to be seen.
erty of thioglycosides, which reduces the number of
monomers required for the synthesis of higher oligo-
saccharides, and the well-known stability of thio-
glycosides in protecting group transformations made
this type of compound attractive for our synthesis
strategy, which relies heavily on protecting group
manipulations.
For these reasons, we have developed a stereoselective
synthesis method for the preparation of phenyl 3-O-
benzyl-1-thio-a-L-idopyranoside, a key synthon in our
synthesis strategy, and prepared various L-idose and
L-iduronic acid derivatives from it. We also report on
the use of these compounds as glycosyl donors for the
synthesis of various protected heparin oligosaccharide
derivatives.
2. Results and discussion
The commercially available 1,2:5,6-di-O-isopropylidene-
a-D-glucofuranose (1) was converted into L-ido epoxide
(2) by the method of van Boeckel,23 which can readily
be performed on a 100 g scale (Scheme 1). Treatment
of the epoxide (2) with 1 M H2SO4 in dioxane at reflux
temperature afforded the 1,6-anhydro-b-L-idopyranose
derivative (3) in a single step via epoxide opening, iso-
propylidene hydrolysis and intramolecular glycosyla-
tion. In compound 3, the ring is fixed in the pyranose
form, and as the reaction product was readily isolated
by crystallization in 65% yield, the synthesis of this
intermediate eliminates the need for the tedious chro-
matographic separation of the furanose and pyranose
tautomers needed in other synthetic routes. Formation
of 1,6-anhydro-b-L-idopyranose from 5,6-anhydro-1,2-
O-isopropylidene-b-L-idofuranose under strongly acidic
conditions has been observed before43 and after present-
ing our results21,22 a similar synthesis of 3 has been
reported44 independently.
Until very recently21,22,37 almost invariably only
trichloroacetimidate derivatives of L-idose and L-
iduronic acid have been used as glycosyl donors in
the synthesis of heparin oligosaccharides. Attempted
use of thioglycosides was reported to be discouraging,38
due to difficulties in their preparation and inferior
results in glycosylations. Thioglycosides, in general,
can be advantageously used in oligosaccharide synthe-
ses,39–42 as they can be used both as glycosyl donors
and glycosyl acceptors, and as the thioglycoside func-
tion remains intact under most protecting group
manipulations. Both the dual donor–acceptor prop-
For the conversion of 3 into a thioglycoside, the
compound was first acetylated to give the crystalline
diacetate (4). Thiolysis of compound
4
with
O
O
O
OBn
Ref 23
OBn
O
a
HO
BnO
O
b
O
HO
O
O
O
O
O
3
2
1
SPh
SPh
OBn
O
OAc
O
c
AcO
AcO
BnO
O
AcO
+
AcO
OAc OAc
O
OAc OAc
6
4
5
Scheme 1. Synthesis of phenyl 2,4,6-tri-O-acetyl-3-O-benzyl-1-thio-a-L-idopyranoside. Reagents and conditions: (a) 1 M H2SO4, dioxane, 65%; (b)
Ac2O, pyridine, 93%; (c) (i) PhSSi(CH3)3, ZnI2, CH2Cl2, (ii) Ac2O, pyridine, 76%.

598
J. Tatai et al. / Carbohydrate Research 343 (2008) 596–606
45,46
trimethyl(phenylthio)silane in the presence of ZnI2
afforded the thioglycoside. As partial acetyl migration
was observed in the crude thiolysis product, the thio-
glycoside was isolated after acetylation in the form of
its triacetate (5) in 76% yield. The thiolysis reaction
was accompanied by partial debenzylation, which re-
sulted in the formation of the tetra-O-acetyl derivative
(6) as by-product isolated in 8% yield. The anomeric
configuration of 5 proved to be a, which was ascertained
tecting group at O-6 allowing later conversion to the
uronic acid. For the synthesis of an L-iduronosyl donor,
10 was oxidized with pyridinium dichromate in the pres-
ence of acetic anhydride and tert-butanol51 to give the
tert-butyl ester 12. In this reaction, the oxidation of the
sulfur to the corresponding sulfoxide and sulfone could
almost completely be avoided.
For the synthesis of higher oligosaccharides, L-idu-
ronic acid derivatives having a temporary protecting
group at O-4 are required. We have previously pro-
posed52 the use of the (1-naphthyl)methyl (1NAP) group
1
by the JC-1,H-1 value of 168 Hz, and no b thioglycoside
could be detected. The stereoselectivity of this thio-
glycosidation is noteworthy, as the reaction of 1,2,4,6-
tetra-O-acetyl-3-O-benzyl-L-idopyranose with thiols in
the presence of BF3ꢀEt2O gave anomeric mixtures of
thioglycosides (details not given). Non-stereoselective
formation of thioglycosides from 1,2,4,6-tetra-O-acet-
yl-3-O-benzyl-L-idopyranose has also been reported by
others recently.37,47,48 The preparative ease of the fura-
nose?pyranose transformation via 3 and the stereo-
selectivity of the thiolysis of 4 allowed the preparation
of large quantities of 5, which was the key compound
for further transformations.
as
a less expensive alternative of the (2-naph-
thyl)methyl53,54 regioisomer. (1-Naphthyl)methyl ethers
are readily prepared by, among others, reductive cleav-
age of (1-naphthyl)methylidene acetals, and the selective
removal of the (1-naphthyl)methyl group with ceric
ammonium nitrate can be accomplished in the presence
of benzyl groups.52 We have, therefore, synthesized 4-O-
(1-naphthyl)methylated L-iduronic acid thioglycosides,
which will allow chain elongation toward the nonreduc-
ing terminus.
The triol 7 was treated with 1-naphthaldehyde di-
methyl acetal to give the (1-naphthyl)methylidene deriv-
ative 13 (Scheme 3). After benzoylation, regioselective
reductive opening of the 4,6-O-(1-naphthyl)methylidene
acetal in 14 was carried out by our recently developed
method55 using BH3ꢀTHF and TMSOTf to give the
4-O-(1-naphthyl)methyl ether (15) in 92% yield. Oxida-
tion of 15, as for 12, gave the tert-butyl L-iduronate
thioglycoside 16.
The preparations of both the 4-O-benzylated and 4-O-
(1-naphthyl)methylated L-idose and L-iduronic acid
thioglycosides were readily performed on a 10 g scale.
The glycosylating capability of the L-idose and L-idu-
ronic acid thioglycosides was tested using D-glucosamine
To convert 5 to building blocks to be used in heparin
oligosaccharide synthesis, the compound was first
subjected to Zemplen deacetylation to give the triol (7)
´
(Scheme 2). Benzylidenation of 7 with benzaldehyde di-
methyl acetal in the presence of camphorsulfonic acid
in DMF afforded the crystalline acetal (8), which was
benzoylated to give 9. Compounds 7–9 were obtained
in crystalline form and had more negative optical rota-
tions than those published.38 Reductive opening of the
49
4,6-O-benzylidene acetal with BH3ꢀNMe3–AlCl3 in
ether–dichloromethane50 afforded the primary alcohol
10. Chloroacetylation of 10 gave the thioglycoside L-ido-
pyranosyl glycosyl donor (11) having a temporary pro-
SPh
SPh
SPh
OBn
O
OBn
O
OBn
O
a
c
b
AcO
HO
O
O
OH
OAc OAc
OH OH
8
7
Ph
5
SPh
OBn
O
ClAcO
e
SPh
SPh
OBn
O
OBn
O
OBn OBz
d
HO
11
O
O
OBz
OBn OBz
SPh
f
9
10
OBn
O
Ph
t
BuO2C
OBn OBz
12
Scheme 2. Synthesis of L-ido thioglycoside donors. Reagents and conditions: (a) NaOMe, MeOH, 99%; (b) PhCH(OMe)2, CSA, DMF, 88%; (c) BzCl,
pyridine, CH2Cl2, 85%; (d) BH3ꢀNMe3, AlCl3, CH2Cl2, Et2O, 71%; (e) ClCH2C(O)Cl, pyridine, CH2Cl2, 76%; (f) PDC, Ac2O, tBuOH, CH2Cl2, 62%.

J. Tatai et al. / Carbohydrate Research 343 (2008) 596–606
599
SPh
SPh
SPh
OBn
O
OBn
O
a
c
OBn
O
b
HO
O
O
O
OH
O
OBz
14
OH OH
1Naph
1Naph
13
7
SPh
SPh
OBn
OBn
O
d
HO
1NAPO
O
t
BuO2C
1NAPO
OBz
15
OBz
16
Scheme 3. Synthesis of tert-butyl (phenyl 2-O-benzoyl-3-O-benzyl-4-O-(1-naphthyl)methyl-1-thio-a-L-idopyranoside)uronate. Reagents and
conditions: (a) 1NaphCH(OMe)2, CSA, DMF, 98%; (b) BzCl, pyridine, CH2Cl2, 98%; (c) BH3ꢀTHF, TMSOTf, CH2Cl2, 92%; (d) PDC, Ac2O,
tBuOH, CH2Cl2, (74%).
derivatives 17,56 2057 and 2325 having O-4 free and
differing in their substituents at O-6 (Scheme 4). Reac-
tion of the L-idose thioglycoside 11 with 17 promoted
by DMTST58 proceeded smoothly and afforded disac-
charide 18 in 71% yield. The 1-naphthylmethylidene ace-
tal (14) could also be used as glycosyl donor. Its reaction
with 17 was performed using our recently developed
powerful promoter system59 of dimethyl disulfide–triflic
anhydride. The reaction proceeded at ꢁ40 °C within
10 min and gave disaccharide 19 in 90% yield.
chromatography, Silica Gel 60 (0.040–0.063 mm) (E.
Merck) was employed. Melting points were determined
in capillary tubes on a Griffin melting point apparatus
and are uncorrected. Optical rotations were measured
at 23 °C with an Optical Activity AA-10R polarimeter.
The NMR spectra were recorded on Varian Gemini
2000 (1H: 200 MHz; 13C: 50 MHz), Varian Gemini
3000 (1H: 300 MHz; 13C: 75 MHz), and Varian Unity-
Inova (1H: 400 MHz; 13C: 100 MHz) spectrometers at
ambient temperature in CDCl3. The chemical shifts were
1
Glycosylations of acceptors 20 and 17 with the L-
iduronic acid thioglycoside 12 were performed at room
temperature in the presence of DMTST, and afforded
disaccharides 21 and 22 in excellent yields (86% and
88%, respectively). Moreover, the 6-O-chloroacetylated
acceptor 23 was coupled with thioglycoside 16 under
the same conditions to give the disaccharide 24 in 71%
yield. The anomeric configuration of the interglycosidic
referenced to TMS (0.00 ppm for H) and to the central
line of CDCl3 (77.16 ppm for 13C) as internal standards.
Elemental analyses were performed with an Elementar
Vario EL III instrument at the Analytical Department
of the Chemical Research Center, Hungarian Academy
of Sciences.
3.2. 1,6-Anhydro-3-O-benzyl-b-L-idopyranose (3)
1
linkages was proved to be a by the JC-1,H-1 = 171 Hz
coupling constant. It is noteworthy that while uronic
acids, in general, tend to be poorer glycosyl donors than
the corresponding neutral sugars, no such difference
could be observed in the above cases. Our results clearly
show that thioglycosides of both L-idose and L-iduronic
acid can be used efficiently as glycosyl donors.
A solution of 2 (33.4 g, 114 mmol) in 2 M aq H2SO4
(70 mL) and dioxane (70 mL) was heated under reflux
overnight. The mixture was cooled to room tempera-
ture, neutralized with aq Ba(OH)2, the solid was re-
moved by filtration and was washed with EtOAc. The
filtrate was extracted with EtOAc (3 ꢂ 500 mL), the or-
ganic layers were combined and it was washed with
water, dried and concentrated. The residue was crystal-
lized from EtOH to afford 3 as a white solid (18.6 g,
65%); mp 155–156 °C, lit.60 158–159 °C; [a]D +66 (c
0.4, MeOH), lit.60 +69 (c 1.0, MeOH); 1H NMR
(200 MHz, CDCl3): d 7.40–7.26 (m, 5H, aromatic),
5.27 (d, 1H, J1,2 1.8 Hz, H-1), 4.95 and 4.73 (2d, 2H, J
11.7 Hz, PhCH2), 4.42 (t, 1H, J4,5ꢃJ5,6a 4.8 Hz, H-5),
4.04 (d, 1H, J6a,6b 7.7 Hz, H-6a), 3.87 (ddd, 1H, H-4),
3.72 (dd, 1H, J5,6b 5.1 Hz, H-6b), 3.65 (dt, 1H, H-2),
3.39 (t, 1H, J2,3ꢃJ3,4 8.0 Hz, H-3), 2.20 (d, 1H, J4,OH-4
3.3 Hz, OH-4), 2.05 (d, 1H, J2,OH-2 8.8 Hz, OH-2); 13C
NMR (50 MHz, CDCl3): d 138.4, 127.9, 127.6, 127.3
(aromatic), 101.8 (C-1), 83.3 (C-3), 75.4, 74.6 (C-2,
C-4), 74.5 (PhCH2), 70.8 (C-5), 64.5 (C-6).
The above disaccharides are important intermediates
in our syntheses of various heparin oligosaccharides.
3. Experimental
3.1. General methods
Organic solutions were dried over MgSO4 and concen-
trated under diminished pressure at 40 °C. Thin-layer
chromatography (TLC) was performed on Silica Gel
60 F254 plates (E. Merck, Darmstadt), the compounds
were detected under UV light and by spraying the plates
with a 0.02 M solution of resorcinol in 20% methanolic
H2SO4 solution followed by heating. For column

600
J. Tatai et al. / Carbohydrate Research 343 (2008) 596–606
OMPh
O
SPh
OMPh
O
O
a
OBn
O
BnO
OBn
O
ClAcO
+
ClAcO
HO
ZHN
OMe
BnO
ZHN
OBn OBz
OMe
OBn OBz
18
17
11
OMPh
O
O
SPh
BnO
OMPh
O
OBn
O
b
c
OBn
O
ZHN
OMe
+
HO
BnO
O
O
O
OBz
ZHN
O
OBz
14
OMe
1Naph
1Naph
17
19
OBn
O
O
SPh
BnO
OBn
O
OBn
O
OBn
O
ZHN
t
BuO2C
OMe
+
+
+
HO
t
BuO2C
BnO
OBn OBz
21
ZHN
OBn OBz
OMe
20
12
OMPh
O
O
BnO
SPh
OMPh
O
OBn
O
d
e
OBn
O
ZHN
t
BuO2C
OMe
HO
t
BuO2C
BnO
OBn OBz
ZHN
OBn OBz
OMe
12
17
22
OAcCl
O
O
BnO
SPh
OBn
O
OAcCl
O
OBn
O
ZHN
t
BuO2C
1NAPO
OMe
HO
t
BuO2C
1NAPO
BnO
OBz
24
ZHN
23
OBz
16
OMe
Scheme 4. Synthesis of heparin related disaccharides. Reagents and conditions: (a) DMTST, CH2Cl2, 71%; (b) Me2S2–Tf2O, DTBMP, CH2Cl2, 90%;
(c) DMTST, CH2Cl2, 86%; (d) DMTST, CH2Cl2, 88%; (e) DMTST, CH2Cl2, 71%.
3.3. 2,4-Di-O-acetyl-1,6-anhydro-3-O-benzyl-b-L-
idopyranose (4)
H-6b), 2.06 (s, 3H, CH3), 2.02 (s, 3H, CH3); 13C NMR
(50 MHz, CDCl3): d 170.2 (OC(O)CH3), 169.8 (OC(O)-
CH3), 138.2, 128.6, 127.9, 127.7 (aromatic), 99.4 (C-1),
77.2 (C-3), 76.3 (C-2), 74.6 (PhCH2), 72.8 (2C, C-4, C-
5), 65.7 (C-6), 21.02 (CH3), 20.97 (CH3). Anal. Calcd
for C17H20O7: C, 60.71; H, 5.99. Found: C, 60.68,
H, 5.98.
To a solution of 3 (13.5 g, 53.5 mmol) in dry pyridine
(90 mL), acetic anhydride (50 mL) was added at 0 °C.
The mixture was stirred at room temperature overnight,
after which the reaction was quenched with water. The
mixture was diluted with CH2Cl2 (500 mL), washed with
aq 2 M HCl, saturated aq NaHCO3, and water. The
organic phase was dried and concentrated. The residue
was crystallized from EtOAc–hexanes to afford 4 (16.7
g, 93%); mp 78–80 °C; [a]D +50 (c 0.2, CHCl3); 1H
NMR (200 MHz, CDCl3): d 7.41–7.23 (m, 5H, aro-
matic), 5.45 (d, 1H, J1,2 1.5 Hz, H-1), 5.05 (ddd, 1H,
J3,4 8.8 Hz, J4,5 4.4 Hz, J4,6b 1.1 Hz, H-4), 4.84 (dd,
1H, J2,3 8.4 Hz, H-2), 4.65 (s, 2H, PhCH2), 4.61 (dd,
1H, J5,6a 4.8 Hz, H-5), 4.03 (d, 1H, J6a,6b 7.7 Hz,
H-6a), 3.86 (t, 1H, H-3), 3.73 (ddd, 1H, J5,6b 4.8 Hz,
3.4. Phenyl 2,4,6-tri-O-acetyl-3-O-benzyl-1-thio-a-L-
idopyranoside (5)
To a solution of 4 (13.5 g, 40.1 mmol) in dry CH2Cl2
(150 mL), trimethyl(phenylthio)silane (22.7 mL, 121
mmol) and ZnI2 (25.6 g, 80.2 mmol) were added. The
mixture was stirred at room temperature overnight, fil-
tered through a pad of Celite. The filtrate was diluted
with CH2Cl2 (400 mL), after which a solution of HCl
in dioxane (18 mL) and water (10 mL) were added.

J. Tatai et al. / Carbohydrate Research 343 (2008) 596–606
601
The mixture was stirred at room temperature for 10 min,
the organic layer was washed with aq 2 M HCl, satu-
rated aq NaHCO3, and water, filtered and concentrated.
To the solution of the residue in dry pyridine (50 mL),
acetic anhydride (19 mL) was added at 0 °C. The mix-
ture was stirred at room temperature overnight, after
which the reaction was quenched with water. The mix-
ture was diluted with CH2Cl2, washed with aq 2 M
HCl, saturated aq NaHCO3, and water. The organic
layer was dried and concentrated. The residue was puri-
fied by column chromatography using 5:1 hexane–
acetone as eluent to give first 5 as a syrup (14.8 g,
76%); [a]D ꢁ105 (c 0.4, CHCl3), lit.38 ꢁ91 (c 0.56,
H-5), 4.42 (d, 1H, J2,OH 9.7 Hz, OH-2), 4.12 (m, 1H,
J2,3 2.9 Hz, J2,4 1.5 Hz, H-2), 4.07 (ddd, 1H, H-4), 4.04
(m, 1H, H-6a), 3.99 (m, 1H, H-6b), 3.74 (ddd, 1H, J3,4
3.5 Hz, H-3), 2.55 (dd, 1H, J6,OH 7.0 and 5.0 Hz, OH-
6); 13C NMR (100 MHz, CDCl3): d 137.5, 136.8,
131.1, 129.0, 128.5, 127.9, 127.7, 127.1 (aromatic), 90.1
(C-1), 74.3 (C-3), 72.3 (PhCH2), 71.0 (C-4), 68.8 (C-2),
66.3 (C-5), 65.5 (C-6).
3.6. Phenyl 3-O-benzyl-4,6-O-benzylidene-1-thio-a-L-
idopyranoside (8)
To a solution of 7 (15.2 g, 41.9 mmol) in dry DMF
(150 mL), benzaldehyde dimethyl acetal (9.5 mL,
62.9 mmol) and ( )-camphor-10-sulfonic acid (1.5 g,
6.5 mmol) were added. The mixture was stirred at
50 °C under diminished pressure (40 kPa) for 3 h, neu-
tralized with saturated aq NaHCO3 and concentrated.
The residue was dissolved in CH2Cl2 (500 mL) and
washed with water, then the organic phase was dried
and concentrated. The residue was purified by column
1
CHCl3), lit.47 ꢁ95 (c 1, CHCl3); H NMR (200 MHz,
CDCl3): d 7.59–7.24 (m, 10H, aromatic), 5.50 (d, 1H,
J1,2 1.3 Hz, H-1), 5.17 (dd, 1H, J2,3 2.6 Hz, H-2), 5.02
(ddd, 1H, J5,6a 7.5 Hz, J5,6b 5.3 Hz, H-5), 4.89 (dd,
1H, J4,5 2.0 Hz, H-4), 4.85 and 4.69 (2d, 2H, J
11.0 Hz, PhCH2), 4.28 (dd, 1H, J6a,6b 11.5 Hz, H-6a),
4.18 (dd, 1H, H-6b), 3.79 (ddd, 1H, J3,4 2.8 Hz, J1,3
1.1 Hz, H-3), 2.09 (s, 3H, CH3), 2.06 (s, 3H, CH3),
2.02 (s, 3H, CH3); 13C NMR (50 MHz, CDCl3): d
170.7 (OC(O)CH3), 170.2 (OC(O)CH3), 169.6 (OC(O)-
CH3), 137.2, 135.9, 131.5, 129.0, 128.6, 128.1, 127.8,
127.6 (aromatic), 86.0 (C-1, JC-1,H-1 168 Hz), 72.8
(PhCH2), 71.6, 68.9, 67.2, 64.7 (C-2, C-3, C-4, C-5),
62.9 (C-6), 21.1 (CH3), 20.9 (CH3), 20.8 (CH3).
chromatography (99:1 toluene–acetone) to give
8
(16.5 g, 88%); mp 118–119 °C (from EtOAc–hexanes);
[a]D ꢁ140 (c 0.3, CHCl3), lit.38 ꢁ91 (c 0.56, CHCl3),
1
lit.47 ꢁ145 (c 1, CHCl3); H NMR (200 MHz, CDCl3):
d 7.56–7.14 (m, 15H, aromatic), 5.68 (br s, 1H, H-1),
5.54 (s, 1H, PhCH), 4.85 and 4.60 (2d, 2H, J 11.7 Hz,
PhCH2), 4.45 (br s, 1H, H-5), 4.34 (dd, 1H, J5,6a
1.5 Hz, J6a,6b 12.5 Hz, H-6a), 4.17–4.07 (m, 3H, H-2,
H-4, H-6b), 3.85 (d, 1H, J2,OH 11.9 Hz, OH), 3.82 (m,
1H, H-3); 13C NMR (50 MHz, CDCl3): d 137.4,
137.33, 137.29, 130.3, 129.4, 129.2, 129.0, 128.7, 128.5,
128.2, 127.9, 126.9, 126.1 (aromatic), 101.7 (PhCH),
89.1 (C-1), 74.5, 73.8 (C-3, C-4), 72.5 (PhCH2), 70.2
(C-6), 67.8 (C-2), 60.8 (C-5).
Second eluted one was 6 (1.43 g, 8%), syrup; [a]D
1
ꢁ135 (c 0.5, CHCl3); H NMR (200 MHz, CDCl3): d
7.55–7.50 (m, 2H, aromatic), 7.34–7.26 (m, 3H, aro-
matic), 5.48 (d, 1H, J1,2 1.1 Hz, H-1), 5.06 (dd, 1H,
J2,3 3.3 Hz, H-2), 5.04–4.87 (m, 3H, H-3, H-4, H-5),
4.28 (dd, 1H, J5,6a 6.6 Hz, J6a,6b 11.5 Hz, H-6a), 4.21
(dd, 1H, J5,6b 5.5 Hz, H-6b), 2.20 (s, 3H, CH3), 2.13
(s, 3H, CH3), 2.10 (s, 3H, CH3), 2.04 (s, 3H, CH3);
13C NMR (50 MHz, CDCl3): d 170.6 (OC(O)CH3),
169.8 (OC(O)CH3), 169.3 (OC(O)CH3), 168.7
(OC(O)CH3), 134.7, 131.8, 129.1, 127.9 (aromatic),
85.5 (C-1), 68.4, 66.5, 66.4, 65.4 (C-2, C-3, C-4, C-5),
62.4 (C-6), 20.9 (2C, 2CH3), 20.8 (CH3), 20.7 (CH3).
Anal. Calcd for C25H28O8S: C, 61.46; H, 5.78; S, 6.56.
Found: C, 61.51, H, 5.73; S, 6.61.
3.7. Phenyl 2-O-benzoyl-3-O-benzyl-4,6-O-benzylidene-
1-thio-a-L-idopyranoside (9)
Benzoyl chloride (6.4 mL, 57.8 mmol) in CH2Cl2
(25 mL) was added dropwise to a solution of 8
(16.4 g, 36.5 mmol) in dry CH2Cl2 (75 mL) and dry pyr-
idine (25 mL) at 0 °C. The mixture was stirred at room
temperature overnight, after which the reaction was
quenched with water. The mixture was diluted with
CH2Cl2 (500 mL), washed with 2 M aq HCl, saturated
aq NaHCO3 and water, dried and concentrated. The
residue was purified by column chromatography (99:1
toluene–acetone) to give 9 (17.2 g, 85%); mp 136–
137 °C (from EtOAc–hexanes), lit.38 137–138 °C; [a]D
ꢁ89 (c 0.2, CHCl3), lit.38 ꢁ80 (c 1.1, CHCl3); 1H
NMR (400 MHz, CDCl3): d 8.02–7.95 (m, 2H, aro-
matic), 7.62–7.18 (m, 18H, aromatic), 5.82 (d, 1H, J1,2
1.3 Hz, H-1), 5.59 (s, 1H, PhCH), 5.53 (ddd, 1H, J2,3
2.5 Hz, J2,4 1.0 Hz, H-2), 4.98 and 4.71 (2d, 2H, J
11.7 Hz, PhCH2), 4.52 (dd, 1H, J5,6a 1.5 Hz, J5,6b
3.5. Phenyl 3-O-benzyl-1-thio-a-L-idopyranoside (7)
To a solution of 5 (18.9 g, 38.7 mmol) in dry MeOH
(200 mL), a catalytic amount of NaOMe was added.
The mixture was stirred overnight at room temperature,
neutralized with Amberlite IR 120 (H+) resin, filtered,
and concentrated to give 7 (13.9 g, 99%), mp 110–
111 °C (from EtOAc–hexanes); [a]D ꢁ191 (c 0.6,
1
CHCl3) lit.47 ꢁ151 (c 1, CHCl3); H NMR (400 MHz,
CDCl3): d 7.58–7.20 (m, 10H, aromatic), 5.57 (t, 1H,
J1,2ꢃJ1,3 1.3 Hz, H-1), 4.79 and 4.57 (2d, 2H, J
11.2 Hz, PhCH2), 4.56 (d, 1H, J4,OH 2.0 Hz, OH-4),
4.52 (ddd, 1H, J4,5 1.0 Hz, J5,6a 3.0 Hz, J5,6b 2.8 Hz,

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J. Tatai et al. / Carbohydrate Research 343 (2008) 596–606
2.0 Hz, H-5), 4.38 (dd, 1H, J6a,6b 12.3 Hz, H-6a), 4.20
(dd, 1H, H-6b), 4.12 (ddd, 1H, J4,5 1.6 Hz, H-4), 3.93
(dd, 1H, J3,4 2.6 Hz, H-3); 13C NMR (100 MHz,
CDCl3): d 165.7 (OC(O)Ph), 137.9, 137.3, 136.6, 133.1,
130.5, 130.1, 129.6, 129.0, 128.9, 128.6, 128.2, 128.1,
127.9, 127.0, 126.4 (aromatic), 101.1 (PhCH), 86.0 (C-
1), 73.3 (C-4), 73.2 (C-3), 72.5 (PhCH2), 70.0 (C-6),
67.9 (C-2), 60.7 (C-5).
J1,2 2.5 Hz, J1,3 1.0 Hz, H-1), 5.47 (ddd, 1H, J2,3
2.8 Hz, J2,4 0.8 Hz, H-2), 4.94 (d, 1H, J 11.7 Hz,
PhCH2), 4.93 (m, 1H, H-5), 4.63 (d, 1H, J 11.7 Hz,
PhCH2), 4.56 (dd, 1H, J5,6a 7.3 Hz, J6a,6b 10.8 Hz,
H-6a), 4.49 (d, 1H, J 11.5 Hz, PhCH2), 4.36 (dd, 1H,
J5,6b 4.4 Hz, H-6b), 4.28 (d, 1H, J 11.5 Hz, PhCH2),
3.99 (ddd, 1H, J3,4 3.0 Hz, H-3), 3.92 (m, 2H, CH2Cl),
3.49 (ddd, 1H, J4,5 2.3 Hz, H-4); 13C NMR (50 MHz,
CDCl3): d 167.1 (OC(O)CH2Cl), 165.8 (OC(O)Ph),
137.34, 137.27, 135.9, 133.4, 131.5, 130.1, 129.6, 129.2,
128.7, 128.51, 128.48, 128.4, 128.2, 128.11, 128.08,
127.5 (aromatic), 85.8 (C-1), 73.3 (C-4), 72.6 (PhCH2),
72.2 (PhCH2), 70.4, (C-3), 69.1 (C-2), 66.3, 65.4 (C-5,
C-6), 40.8 (CH2Cl). Anal. Calcd for C35H33ClO7S: C,
66.39; H, 5.25; S, 5.06. Found: C, 66.32; H, 5.28; S, 5.09.
3.8. Phenyl 2-O-benzoyl-3,4-di-O-benzyl-1-thio-a-L-
idopyranoside (10)
A solution of 9 (9.9 g, 17.9 mmol) and Me3NꢀBH3
(13.0 g, 179.0 mmol) in dry CH2Cl2 (90 mL) was stirred
˚
in the presence of 4 A molecular sieves (4 g). After
30 min,
a solution of aluminum chloride (9.6 g,
71.5 mmol) in dry ether (35 mL) was added dropwise
at 0 °C. After 3 h, the mixture was filtered through a
pad of Celite. The filtrate was diluted with CH2Cl2
(500 mL) and stirred with 2 M aq HCl (90 mL) for
1 h. The organic layer was washed with saturated aq
NaHCO3 and water, dried and concentrated. The
residue was purified by column chromatography (95:5
toluene–acetone) to give 10 as a syrup (7.1 g, 71%);
3.10. tert-Butyl (phenyl 2-O-benzoyl-3,4-di-O-benzyl-
1-thio-a-L-idopyranoside)uronate (12)
To a solution of 10 (6.0 g, 10.8 mmol) in CH2Cl2
(135 mL), pyridinium dichromate (8.1 g, 21.6 mmol),
Ac2O (10.2 mL, 108 mmol) and tert-butyl alcohol
(20 mL, 216 mmol) were added. The mixture was stirred
for 2 h at room temperature and it was then applied on
the top of a silica gel column in EtOAc, with a 10 cm
layer of EtOAc on top of the gel. The chromium com-
pounds were allowed to precipitate in the presence of
EtOAc and after 30 min the product was eluted with
EtOAc. After evaporating the solvent, the residue was
purified by column chromatography (98:2 toluene–
acetone) to give 12 (4.2 g, 62%); mp 90–93 °C (from
EtOAc–hexanes); [a]D ꢁ84 (c 0.2, CHCl3); 1H NMR
(400 MHz, CDCl3): d 7.94–7.88 (m, 2H, aromatic),
7.59–7.10 (m, 18H, aromatic), 5.77 (dd, 1H, J1,2
2.7 Hz, J1,3 1.0 Hz, H-1), 5.41 (ddd, 1H, J2,3 3.5 Hz,
J2,4 1.0 Hz, H-2), 5.11 (d, 1H, H-5), 4.89 (d, 1H, J
11.5 Hz, PhCH2), 4.65 (d, 1H, J 11.5 Hz, PhCH2), 4.54
(d, 1H, J 11.4 Hz, PhCH2), 4.51 (d, 1H, J 11.4 Hz,
PhCH2), 3.99 (ddd, 1H, J3,4 3.7 Hz, H-3), 3.95 (dd,
1H, J4,5 2.8 Hz, H-4), 1.48 (s, 9H, C(CH3)3); 13C
1
[a]D ꢁ98 (c 0.5, CHCl3); H NMR (400 MHz, CDCl3):
d 8.00–7.10 (m, 20H, aromatic), 5.65 (dd, 1H, J1,2
1.6 Hz, J1,4 0.6 Hz, H-1), 5.49 (ddd, 1H, J2,3 3.0 Hz,
J2,4 1.2 Hz, H-2), 4.92 (d, 1H, J 11.5 Hz, PhCH2), 4.72
(m, 1H, J5,6a 6.6 Hz, J5,6b 4.3 Hz, H-5), 4.65 (d, 1H, J
11.5 Hz, PhCH2), 4.49 (d, 1H, J 11.3 Hz, PhCH2), 4.32
(d, 1H, J 11.3 Hz, PhCH2), 4.01 (dd, 1H, J6a,6b
11.6 Hz, H-6a), 3.99 (ddd, 1H, J3,4 3.0 Hz, H-3), 3.78
(dd, 1H, H-6b), 3.57 (m, 1H, J4,5 2.3 Hz, H-4), 2.04
(br s, 1H, OH); 13C NMR (100 MHz, CDCl3): d 165.7
(OC(O)Ph), 137.3, 137.2, 135.7, 133.3, 131.7, 130.0,
129.5, 129.0, 128.5, 128.4, 128.3, 128.2, 128.04, 127.97,
127.4 (aromatic), 86.0 (C-1), 74.5 (C-4), 72.5 (PhCH2),
72.2 (PhCH2), 70.7 (C-3), 69.3 (C-2), 68.4 (C-5), 62.8
(C-6). Anal. Calcd for C33H32O6S: C, 71.20; H, 5.79;
S, 5.76. Found: C, 71.31; H, 5.75; S, 5.82.
NMR (100 MHz, CDCl3):
d 168.1 (C-6), 165.6
3.9. Phenyl 2-O-benzoyl-3,4-di-O-benzyl-6-O-chloro-
acetyl-1-thio-a-L-idopyranoside (11)
(OC(O)Ph), 137.6, 137.4, 135.8, 133.1, 131.1, 130.1,
129.4, 129.0, 128.6, 128.3, 128.14, 128.09, 127.7, 127.6,
127.3 (aromatic), 85.7 (C-1), 82.0 (C(CH3)3), 75.1
(C-4), 72.9 (2C, 2PhCH2), 72.3 (C-3), 69.4 (C-5), 69.1
(C-2), 28.2 (C(CH3)3). Anal. Calcd for C37H38O7S: C,
70.90; H, 6.11; S, 5.12. Found: C, 70.85; H, 6.11; S, 5.08.
Chloroacetyl chloride (0.31 mL, 3.96 mmol) in CH2Cl2
(3.0 mL) was added dropwise to a stirred solution of
10 (1.10 g, 1.98 mmol) in dry CH2Cl2 (75 mL) and dry
pyridine (3.0 mL) at ꢁ20 °C. After 30 min, the reaction
was quenched with water, and stirred for 20 min. The
mixture was diluted with CH2Cl2 (300 mL), washed with
2 M aq HCl, saturated aq NaHCO3 and water, dried
and concentrated. The residue was purified by column
chromatography (98:2 toluene–acetone) to give 11
3.11. Phenyl 3-O-benzyl-4,6-O-(1-naphthyl)methylidene-
1-thio-a-L-idopyranoside (13)
To a solution of 7 (13.9 g, 38.4 mmol) in dry DMF
(100 mL), 1-naphthaldehyde dimethyl acetal (12.1 mL,
57.3 mmol) and ( )-camphor-10-sulfonic acid (1.6 g,
7.0 mmol) were added. The mixture was stirred at
50 °C under diminished pressure (40 kPa) for 3 h,
1
(0.95 g, 76%) as a syrup; [a]D ꢁ97 (c 0.3, CHCl3); H
NMR (200 MHz, CDCl3): d 8.20–7.95 (m, 2H, aro-
matic), 7.58–7.08 (m, 18H, aromatic), 5.63 (dd, 1H,

J. Tatai et al. / Carbohydrate Research 343 (2008) 596–606
603
neutralized with saturated aq NaHCO3 and concen-
trated. The residue was dissolved in CH2Cl2 (500 mL),
washed with water, the organic layer was dried and con-
centrated. The residue was purified by column chroma-
tography (99:1 toluene–acetone) to give 13 (18.8 g, 98%)
(98:2?9:1 toluene–acetone) to give 15 (16.6 g, 92%) as
a
syrup; [a]D ꢁ113 (c 0.9, CHCl3); 1H NMR
(200 MHz, CDCl3): d 8.03–7.92 (m, 3H, aromatic),
7.85–7.73 (m, 2H, aromatic), 7.55–7.10 (m, 17H, aro-
matic), 5.65 (s, 1H, H-1), 5.49 (dd, 1H, J1,2 1.2 Hz, J2,3
3.3 Hz, H-2), 4.95 (d, 1H, J 11.7 Hz, ArCH2), 4.89 (d,
1H, J 11.7 Hz, ArCH2), 4.73 (d, 1H, J 11.7 Hz, ArCH2),
4.72 (m, 1H, H-5), 4.61 (d, 1H, J 11.7 Hz, ArCH2), 4.02
(dd, J3,4 2.6 Hz, H-3), 3.92 (ddd, 1H, J5,6a 6.9 Hz, J6a,6b
11.4 Hz, J6a,OH 3.3 Hz, H-6a), 3.64 (dd, J5,6b 4.7 Hz,
H-6b), 3.59 (dd, 1H, J4,5 2.0 Hz, H-4), 1.74 (dd, 1H,
OH); 13C NMR (50 MHz, CDCl3): d 165.8 (OC(O)Ph),
137.5, 135.9, 133.8, 133.4, 132.8, 131.8, 131.7, 130.1,
129.7, 129.16, 129.12, 128.8, 128.7, 128.5, 128.4, 128.2,
127.5, 127.2, 126.5, 126.1, 125.4, 125.1, 123.8 (aromatic),
86.1 (C-1), 73.8 (C-4), 72.6 (ArCH2), 70.8 (C-3), 70.5
(ArCH2), 69.6 (C-2), 68.8 (C-5), 62.6 (C-6). Anal. Calcd
for C37H34O6S: C, 73.24; H, 5.65; S, 5.28. Found: C,
73.18; H, 5.67; S, 5.32.
1
as a white foam; [a]D ꢁ121 (c 0.3, CHCl3); H NMR
(200 MHz, CDCl3): d 8.40 (d, 1H, aromatic), 7.89–7.80
(m, 2H, aromatic), 7.66–7.13 (m, 14H, aromatic), 5.99
1
(s, 1H, NaphCH), 5.75 (d, 1H, J1,2 1.5 Hz, H-1), 4.85
and 4.59 (2d, 2H, J 11.7 Hz, PhCH2), 4.54 (br s, 1H,
H-5), 4.42 (dd, 1H, J5,6a 1.5 Hz, J6a,6b 12.5 Hz, H-6a),
4.26–4.17 (m, 2H, H-4, H-6b), 4.12 (ddd, 1H, J2,3
2.9 Hz, H-2), 3.81 (d, 1H, J2,OH 11.7 Hz, OH), 3.79
(m, 1H, H-3); 13C NMR (50 MHz, CDCl3): d 137.5,
137.2, 134.1, 132.6, 130.8, 130.6, 130.3, 129.1, 128.8,
128.7, 128.4, 128.2, 128.0, 127.1, 126.8, 126.0, 125.4,
125.2, 125.0, 124.4 (aromatic), 102.6 (1NaphCH), 89.5
(C-1), 74.9, 74.1, 72.6 (C-3, C-4, PhCH2), 70.5 (C-6),
68.0 (C-2), 60.9 (C-5). Anal. Calcd for C30H28O5S: C,
71.98; H, 5.64; S, 6.41. Found: C, 72.02; H, 5.61; S, 6.44.
3.14. tert-Butyl (phenyl 2-O-benzoyl-3-O-benzyl-4-O-
(1-naphthyl)methyl-1-thio-a-L-idopyranoside)uronate (16)
3.12. Phenyl 2-O-benzoyl-3-O-benzyl-4,6-O-(1-naphthyl)-
methylidene-1-thio-a-L-idopyranoside (14)
Compound 15 (8.3 g, 13.7 mmol) was oxidized as
described for compound 12. The product was purified
by column chromatography (98:2 toluene–acetone) to
give 16 (6.9 g, 74%); [a]D ꢁ88 (c 0.3, CHCl3); 1H
NMR (200 MHz, CDCl3): d 7.93–7.70 (m, 5H, aro-
matic), 7.59–7.52 (m, 2H, aromatic), 7.45–7.07 (m,
15H, aromatic), 5.77 (d, 1H, J1,2 2.2 Hz, H-1), 5.39
(dd, 1H, J2,3 2.9 Hz, H-2), 5.16 (d, 1H, H-5), 5.02 (d,
1H, J 11.7 Hz, ArCH2), 4.91 (d, 1H, J 11.7 Hz, ArCH2),
4.83 (d, 1H, J 11.7 Hz, ArCH2), 4.57 (d, 1H, J 11.7 Hz,
ArCH2), 4.08 (t, 1H, J4,5 2.8 Hz, H-4), 3.97 (t, 1H, J3,4
3.0 Hz, H-3), 1.42 (s, 9H, C(CH3)3); 13C NMR
(50 MHz, CDCl3): d 168.2 (C-6), 165.6 (OC(O)Ph),
137.5, 135.7, 133.6, 133.2, 133.1, 131.4, 131.3, 130.1,
129.5, 129.1, 129.0, 128.6, 128.3, 128.2, 128.11, 128.08,
127.4, 126.3, 125.8, 125.4, 125.2, 123.8 (aromatic), 86.0
(C-1), 82.2 (C(CH3)3), 75.2 (C-4), 73.0 (ArCH2), 72.9
(C-3), 71.2 (ArCH2), 69.6, 69.4 (C-2, C-5), 28.2
(C(CH3)3). Anal. Calcd for C41H40O7S: C, 72.76; H,
5.96; S, 4.74. Found: C, 72.68; H, 5.93; S, 4.81.
Compound 13 (18.8 g, 37.6 mmol) was benzoylated as
described for compound 9. The product was purified
by column chromatography (98:2 toluene–EtOAc) to
give 14 (22.3 g, 98%); mp 135–136 °C (from EtOAc–
hexanes); [a]D ꢁ108 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3): d 8.33–7.01 (m, 22H, aromatic),
1
6.12 (s, 1H, NaphCH), 5.88 (t, 1H, J1,2ꢃJ1,3 1.2 Hz,
H-1), 5.55 (ddd, 1H, J2,3 2.5 Hz, J2,4 1.0 Hz, H-2), 5.00
and 4.72 (2d, 2H, J 11.8 Hz, PhCH2), 4.60 (dd, 1H,
J5,6a 1.5 Hz, J5,6b 2.0 Hz, H-5), 4.44 (dd, 1H, J6a,6b
12.5 Hz, H-6a), 4.31 (dd, 1H, H-6b), 4.22 (m, 1H, J4,5
1.0 Hz, H-4), 3.92 (ddd, 1H, J3,4 2.6 Hz, H-3); 13C
NMR (100 MHz, CDCl3): d 165.9 (OC(O)Ph), 137.3,
136.4, 133.8, 133.2, 133.0, 130.9, 130.6, 130.1, 129.7,
129.4, 129.1, 129.0, 128.6, 128.4, 128.10, 128.08,
127.96, 127.2, 126.4, 125.6, 124.9, 124.6 (aromatic),
100.8 (1NaphCH), 86.2 (C-1), 73.7 (C-4), 73.6 (C-3),
72.6 (PhCH2), 70.1 (C-6), 68.1 (C-2), 60.8 (C-5). Anal.
Calcd for C37H32O6S: C, 73.49; H, 5.33; S, 5.30. Found:
C, 73.32; H, 5.38; S, 5.39.
3.15. Methyl (2-O-benzoyl-3,4-di-O-benzyl-6-O-chloro-
acetyl-a-L-idopyranosyl)-(1?4)-3-O-benzyl-2-benzyloxy-
carbonylamino-2-deoxy-6-O-(4-methoxy)phenyl-a-D-
glucopyranoside (18)
3.13. Phenyl 2-O-benzoyl-3-O-benzyl-4-O-(1-naphthyl)-
methyl-1-thio-a-L-idopyranoside (15)
To a solution of 14 (18.0 g, 29.8 mmol) in dry CH2Cl2
(100 mL), 1 M BH3ꢀTHF in THF (58.7 mL, 58.7 mmol)
and TMSOTf (0.54 mL, 2.98 mmol) were added. The
mixture was stirred for 2 h at room temperature, cooled
to 0 °C, and quenched with triethylamine (20 mL) and
MeOH (100 mL). The solution was concentrated in
vacuo and co-evaporated three times with MeOH. The
residue was purified by column chromatography
A mixture of 11 (0.84 g, 1.32 mmol), 17 (0.55 g,
1.06 mmol), and 4 A molecular sieves (1.00 g) was stir-
˚
red in dry CH2Cl2 (10 mL) at 0 °C under argon for
30 min, then DMTST (1.37 g, 5.28 mmol) was added.
After 1 h, the reaction was quenched with triethylamine
(1 mL). The mixture was filtered through a pad of
Celite, the filtrate was diluted with CH2Cl2 (250 mL)

604
J. Tatai et al. / Carbohydrate Research 343 (2008) 596–606
and washed with 2 M aq HCl, saturated aq NaHCO3
and water, dried, and concentrated. The residue was
purified by column chromatography (9:1 toluene–
EtOAc) to give 18 (0.78 g, 71%) mp 145–146 °C (from
EtOAc–hexanes); [a]D +33 (c 0.2, CHCl3); 1H NMR
(400 MHz, CDCl3): d 7.82–7.78 (m, 2H, aromatic),
7.50 (m, 1H, aromatic), 7.37–7.08 (m, 22H, aromatic),
6.85–6.76 (m, 2H, aromatic), 6.65–6.56 (m, 2H, aro-
210 °C (from EtOAc–hexanes); [a]D ꢁ17 (c 0.8, CHCl3);
1H NMR (300 MHz, CDCl3): d 8.42–6.60 (m, 31H,
aromatic), 5.80 (s, 1H, 1NaphCH), 5.24 (d, 1H, J2 ;3
0
0
1.5 Hz, H-20), 5.13 (s, 1H, H-10), 5.07–4.98 (m, 3H,
PhCH2, NH), 4.81 (d, 1H, J 11.7 Hz, PhCH2), 4.77 (d,
1H, J1,2 4.4 Hz, H-1), 4.66 (s, 2H, PhCH2), 4.65 (d,
1H, J 11.7 Hz, PhCH2), 4.30–4.14 (m, 4H, H-2, H-4,
H-6a, H-6b), 4.06 (s, 1H, H-50), 4.00–3.90 (m, 3H,
matic), 5.18 (ddd, 1H, J2 ;3 3.3 Hz, J2 ;4 0.7 Hz, H-20),
H-5, H-40, H-6a0), 3.76 (t, 1H, J2 ;3 2.2 Hz, H-30), 3.63
(t, 1H, J3,4 9.5 Hz, H-3), 3.60 (s, 3H, ArOCH3), 3.42
0
0
0
0
0
0
0
0
5.06 (d, 1H, J 12.0 Hz, PhCH2), 5.04 (d, 1H, J1 ;2
2.2 Hz, H-10), 5.01 (d, 1H, J 12.0 Hz, PhCH2), 4.77 (d,
1H, J 11.6 Hz, PhCH2), 4.71 (d, 1H, J 11.5 Hz, PhCH2),
4.68 (d, 1H, J1,2 3.6 Hz, H-1), 4.64 (d, 1H, J2,NH
10.0 Hz, NH), 4.61 (d, 1H, J 11.6 Hz, PhCH2), 4.52
(s, 3H, OCH3), 3.19 (d, 1H, J6a0;6b 12.4 Hz, H-6b0); 13C
0
NMR (75 MHz, CDCl3): d 165.8 (OC(O)Ph), 155.9
(NHC(O)OCH2Ph), 154.0, 152.2, 138.4, 137.8, 136.3,
133.9, 133.5, 132.9, 130.6, 130.0, 129.7, 129.1, 128.5,
128.4, 128.3, 128.1, 127.99, 127.95, 127.9, 127.4, 127.3,
126.3, 125.6, 125.3, 125.1, 124.7, 115.8, 114.5 (aromatic),
101.4 (1NaphCH), 99.1 (C-10), 98.0 (C-1), 79.7 (C-3),
75.0 (C-30), 74.9 (PhCH2), 73.8, 73.6 (C-4, C-5), 72.2
(2C, 2PhCH2), 70.4 (C-40), 69.3 (C-60), 67.0, 66.9, 66.8
(C-20, C-6, NHC(O)OCH2Ph), 59.8 (C-50), 55.5, 55.4
(ArOCH3, OCH3), 55.3 (C-2). Anal. Calcd for
C60H59NO14: C, 70.78; H, 5.84; N, 1.38. Found: C,
70.53; H, 5.87; N, 1.39.
0
(d, 1H, J 11.3 Hz, PhCH2), 4.48 (ddd, 1H, J5 ;6a0
7.5 Hz, J5 ;6b 4.8 Hz, H-50), 4.48 (d, 1H, J 11.5 Hz,
PhCH2), 4.31 (d, 1H, J 11.3 Hz, PhCH2), 4.23 (dd,
0
0
1H, J6a0;6b 11.4 Hz, H-6a0), 4.16 (dd, 1H, H-6b0), 4.14
0
(dd, 1H, J4,5 9.9 Hz, H-4), 4.14 (dd, 1H, J6a,6b 11.0 Hz,
H-6a), 4.12 (dd, 1H, H-6b), 4.01 (ddd, 1H, J2,3
10.3 Hz, H-2), 3.98 and 3.92 (2d, 2H, J 14.8 Hz, CH2Cl),
3.88 (dd, 1H, J3 ;4 3.8 Hz, H-30), 3.87 (ddd, 1H, J5,6a
2.7 Hz, J5,6b 3.3 Hz, H-5), 3.60 (s, 3H, ArOCH3), 3.55
0
0
0
0
(dd, 1H, J3,4 9.2 Hz, H-3), 3.45 (ddd, 1H, J4 ;5 2.5 Hz,
H-40), 3.33 (s, 3H, OCH3); 13C NMR (100 MHz,
CDCl3): d 167.3 (OC(O)CH2Cl), 165.7 (OC(O)Ph),
155.8 (NHC(O)OCH2Ph), 154.0, 152.2, 138.2, 137.5,
137.4, 136.4, 133.2, 129.9, 128.50, 128.48, 128.41,
128.3, 128.23, 128.15, 128.11, 128.06, 128.02, 127.95,
127.4, 115.8, 114.4 (aromatic), 99.2 (C-1), 97.2 (C-10),
78.7 (C-3), 75.3 (PhCH2), 74.3 (C-4), 73.2 (C-40), 72.6
(PhCH2), 72.3 (C-30), 72.2 (PhCH2), 70.4 (C-5), 68.4
(C-20), 67.0 (NHC(O)OCH2Ph), 66.9 (C-6), 65.8 (C-50),
64.8 (C-60), 55.5 (ArOCH3), 55.2 (OCH3), 55.0
(C-2), 41.1 (CH2Cl). Anal. Calcd for C58H60ClNO15:
C, 66.56; H, 5.78; N, 1.34. Found: C, 66.51; H, 5.82;
N, 1.30.
3.17. Methyl [tert-butyl (2-O-benzoyl-3,4-di-O-benzyl-a-
L-idopyranosyl)uronate]-(1?4)-3,6-di-O-benzyl-2-benzyl-
oxycarbonylamino-2-deoxy-a-D-glucopyranoside (21)
A mixture of 12 (1.54 g, 2.46 mmol), 20 (1.00 g,
˚
1.97 mmol), and 4 A molecular sieves (1.00 g) was stir-
red in dry CH2Cl2 (18 mL) at 0 °C under argon for
30 min, then DMTST (2.91 g, 11.4 mmol) was added.
The mixture was allowed to attain room temperature
and after stirring overnight triethylamine (2 mL) was
added. The mixture was filtered through a pad of Celite,
diluted with CH2Cl2 (500 mL) and washed with 2 M aq
HCl, saturated aq NaHCO3 and water, dried, and con-
centrated. The residue was purified by column chroma-
tography (9:1 toluene–EtOAc) to give 21 (1.73 g, 86%);
[a]D +21.7 (c 0.9, CHCl3); 1H NMR (400 MHz, CDCl3):
d 7.90–7.80 (m, 1H, aromatic), 7.55–7.45 (m, 1H, aro-
3.16. Methyl [2-O-benzoyl-3-O-benzyl-4,6-O-(1-naph-
thyl)methylidene-a-L-idopyranosyl]-(1?4)-3-O-benzyl-
2-benzyloxycarbonylamino-2-deoxy-6-O-(4-methoxy)-
phenyl-a-D-glucopyranoside (19)
0
0
matic), 7.40–7.10 (m, 28H, aromatic), 5.53 (d, 1H, J1 ;2
4.6 Hz, H-10), 5.18 (ddd, J2 ;3 4.9 Hz, J2 ;4 0.8 Hz,
H-20), 5.01 (s, 2H, PhCH2), 4.87 (d, 1H, J 11.4 Hz,
PhCH2), 4.76 (d, 1H, J2,NH 10.4 Hz, NH), 4.75 (d, 1H,
J 11.5 Hz, PhCH2), 4.68 (d, 1H, J 11.5 Hz, PhCH2),
4.67 (d, 1H, J1,2 3.6 Hz, H-1), 4.64 (d, 1H, H-50), 4.58
(d, 1H, J 11.4 Hz, PhCH2), 4.54 (d, 1H, J 11.5 Hz,
PhCH2), 4.53 (d, 1H, J 11.5 Hz, PhCH2), 4.50 (d, 1H,
J 11.5 Hz, PhCH2), 4.49 (d, 1H, J 11.5 Hz, PhCH2),
0
0
0
0
A mixture of 14 (0.36 g, 0.60 mmol), 17 (0.26 g,
0.50 mmol), 2,6-di-tert-butyl-4-methylpyridine (0.10 g,
0.50 mmol), and 4 A molecular sieves (0.50 g) was stir-
˚
red in dry CH2Cl2 (10 mL) at ꢁ40 °C under argon for
30 min, then a 1 M solution of a mixture of Me2S2
and Tf2O in CH2Cl2 (0.90 mL, 0.90 mmol) was added.
After 10 min, the reaction was quenched with triethyl-
amine (1 mL). The mixture was filtered through a pad
of Celite, the filtrate was diluted with CH2Cl2
(250 mL) and washed with 2 M aq HCl, saturated aq
NaHCO3 and water, dried, and concentrated. The resi-
due was purified by column chromatography (98:2
CH2Cl2–EtOAc) to give 19 (0.46 g, 90%); mp 209–
0
0
4.08 (dd, 1H, J4,5 10.0 Hz, H-4), 4.02 (dd, 1H, J3 ;4
5.6 Hz, H-30), 4.00 (ddd, 1H, J2,3 10.6 Hz, H-2), 3.89
(ddd, 1H, J4 ;5 4.5 Hz, H-40), 3.70 (dd, 1H, J6a,6b
10.8 Hz, H-6a), 3.63 (ddd, 1H, J5,6a 4.5 Hz, J5,6b
2.0 Hz, H-5), 3.56 (dd, 1H, J3,4 8.8 Hz, H-3), 3.55 (dd,
1H, H-6b), 3.26 (s, 3H, OCH3), 1.36 (s, 9H, C(CH3)3);
0
0

J. Tatai et al. / Carbohydrate Research 343 (2008) 596–606
605
13C NMR (100 MHz, CDCl3): d 168.6 (C-60), 165.5
(OC(O)Ph), 155.8 (NHC(O)OCH2Ph), 138.8, 138.2,
137.9, 137.8, 137.7, 133.2, 130.0, 129.6, 129.1, 128.6,
128.4, 128.3, 128.2, 127.85, 127.79, 127.7, 127.6, 127.2,
of 21. After workup, the product was purified by column
chromatography (9:1 toluene–EtOAc) to give 24 (0.31 g,
71%); [a]D +9 (c 0.7, CHCl3); 1H NMR (200 MHz,
CDCl3): d 8.05–7.72 (m, 5H, aromatic), 7.58–7.10 (m,
125.3 (aromatic), 98.8 (C-1), 97.9 (JC-1 ;H-1 171 Hz,
C-10), 81.8 (C(CH3)3), 78.9 (C-3), 76.3 (C-40), 75.7 (C-4),
75.0 (C-30), 74.1 (PhCH2), 73.5 (PhCH2), 73.3 (PhCH2),
73.0 (PhCH2), 70.89 (C-50), 70.85 (C-20), 70.8 (C-5), 68.3
(C-6), 66.8 (NHC(O)OCH2Ph), 55.1 (OCH3), 54.3 (C-2),
28.0 (C(CH3)3). Anal. Calcd for C60H65NO14: C, 70.36;
H, 6.40; N, 1.37. Found: C, 70.24; H, 6.42; N, 1.38.
22H, aromatic), 5.56 (d, 1H, J1 ;2 5.5 Hz, H-10), 5.16
0
0
0
0
0
0
(d, 1H, J2 ;3 5.1 Hz, H-2), 5.12 (d, 1H, J 11.7 Hz,
PhCH2), 5.09 (d, 1H, J 11.7 Hz, PhCH2), 5.05 (d, 1H,
J4 ;5 2.9 Hz, H-50), 4.98 (d, 1H, J 11.7 Hz, PhCH2),
4.94 (d, 1H, J 11.4 Hz, PhCH2), 4.75 (d, 1H, J2,NH
9.9 Hz, NH), 4.64 (d, 1H, J 11.4 Hz, PhCH2), 4.64 (d,
1H, J1,2 2.9 Hz, H-1), 4.62 (d, 1H, J 11.0 Hz, PhCH2),
4.61 (d, 1H, J 11.0 Hz, PhCH2), 4.57 (d, 1H, J
11.4 Hz, PhCH2), 4.47 (dd, 1H, J5,6a 12.1 Hz, J6a,6b
3.3 Hz, H-6a), 4.29 (dd, 1H, J5,6b 1.5 Hz, H-6b), 4.28
and 4.09 (2d, 2H, J 18.3 Hz, CH2Cl), 4.10–3.87 (m,
4H, H-2, H-4, H-30, H-40), 3.68 (m, 1H, H-5), 3.55 (dd,
1H, J2,3 9.4 Hz, J3,4 9.9 Hz, H-3), 3.25 (s, 3H, OCH3),
1.39 (s, 9H, C(CH3)3); 13C NMR (50 MHz, CDCl3): d
169.3, 167.4 (C-60, OC(O)CH2Cl), 165.4 (OC(O)Ph),
156.0 (NHC(O)OCH2Ph), 138.7, 137.8, 136.5, 133.7,
133.4, 133.0, 131.4, 130.1, 129.4, 128.8, 128.64, 128.58,
128.5, 128.33, 128.28, 128.2, 128.0, 127.8, 127.4, 126.4,
125.9, 125.3, 123.7 (aromatic), 99.0 (C-1), 98.0 (C-10),
82.3 (C(CH3)3), 78.6 (C-3), 76.3, 76.2, 76.1 (C-4, C-30,
C-40), 74.8 (ArCH2), 73.8 (ArCH2), 72.0 (C-5), 71.8
(C-50), 71.3 (ArCH2), 68.8 (C-20), 67.0 (NHC(O)-
OCH2Ph), 64.0 (C-6), 55.4 (OCH3), 54.5 (C-2), 40.9
(OC(O)CH2Cl), 28.2 (C(CH3)3). Anal. Calcd for
C59H62ClNO15: C, 66.82; H, 5.89; N, 1.32. Found: C,
66.87; H, 5.84; N, 1.36.
0
0
3.18. Methyl [tert-butyl (2-O-benzoyl-3,4-di-O-benzyl-a-
L-idopyranosyl)uronate]-(1?4)-3-O-benzyl-2-benzyloxy-
carbonylamino-2-deoxy-6-O-(4-methoxy)phenyl-a-D-
glucopyranoside (22)
Compound 17 (1.2 g, 2.3 mmol) was glycosylated with
12 (1.8 g, 2.9 mmol), as described for the preparation
of 21. After workup, the product was purified by column
chromatography (9:1 toluene–EtOAc) to give syrupy 22
(2.1 g, 88%); [a]D +25 (c 0.4, CHCl3); 1H NMR
(400 MHz, CDCl3): d 7.83–6.62 (m, 29H, aromatic),
5.45 (d, 1H, J1 ;2 4.4 Hz, H-10), 5.16 (ddd, 1H, J2 ;3
0
0
0
0
4.1 Hz, J2 ;4 0.8 Hz, H-20), 5.02 (s, 2H, PhCH2), 4.90
(d, 1H, J 11.3 Hz, PhCH2), 4.79 (d, 1H, J2,NH 9.7 Hz,
NH), 4.74 (d, 1H, J 11.5 Hz, PhCH2), 4.71 (d, 1H, J1,2
3.6 Hz, H-1), 4.66 (d, 1H, H-50), 4.63 (d, 1H, J
11.5 Hz, PhCH2), 4.55 (d, 1H, J 11.3 Hz, PhCH2), 4.52
(d, 1H, J 11.5 Hz, PhCH2), 4.47 (d, 1H, J 11.5 Hz,
PhCH2), 4.20 (dd, 1H, J4,5 9.9 Hz, H-4), 4.13 (dd,
J6a,6b 10.5 Hz, 1H, H-6a), 4.11 (dd, 1H, H-6b), 4.05
0
0
Acknowledgments
0
0
(ddd, 1H, J2,3 10.5 Hz, H-2), 3.89 (dd, 1H, J3 ;4
4.8 Hz, H-30), 3.87 (dd, 1H, J4 ;5 3.8 Hz, H-40), 3.84
(ddd, 1H, J5,6a 3.8 Hz, J5,6b 3.0 Hz, H-5), 3.68 (s, 3H,
ArOCH3), 3.61 (dd, 1H, J3,4 8.9 Hz, H-3), 3.31 (s, 3H,
OCH3), 1.37 (s, 9H, C(CH3)3); 13C NMR (100 MHz,
0
0
This work was supported by projects 1/047/2001 NKFP
MediChem (Hungary), 1/A/005/2004 NKFP Medi-
Chem2, and Center of Excellence on Biomolecular
Chemistry QLK2-CT-2002-90436 (EU). The skillful
technical assistance of Ms. Katalin T. Palcsu is grate-
fully acknowledged.
CDCl3):
d
168.5 (C-60), 165.5 (OC(O)Ph), 155.8
(NHC(O)OCH2Ph), 154.0, 152.6, 138.8, 137.8, 137.6,
136.5, 133.1, 130.0, 128.5, 128.3, 128.2, 128.1, 128.0,
127.79, 127.7, 127.6, 127.2, 116.1, 114.4 (aromatic),
98.9 (C-1), 97.9 (C-10), 81.8 (C(CH3)3), 79.0 (C-3), 75.8
(C-40), 75.7 (C-4), 74.6 (C-30), 74.3 (PhCH2), 73.0
(PhCH2), 72.9 (PhCH2), 70.7 (2C, C-50, C-20), 70.0
(C-5), 67.1 (C-6), 66.9 (NHC(O)OCH2Ph), 55.6
(ArOCH3), 55.2 (OCH3), 54.4 (C-2), 28.1 (C(CH3)3).
Anal. Calcd for C60H65NO15: C, 69.28; H, 6.30; N,
1.35. Found: C, 69.32; H, 6.27; N, 1.33.
Supplementary data
NMR spectra of compounds (5, 11, 12, 16, 18, 19, 21,
22, 24). Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.carres.2007.12.015.
3.19. Methyl {tert-butyl [2-O-benzoyl-3-O-benzyl-4-O-
(1-naphthyl)methyl-a-L-idopyranosyl]uronate}-(1?4)-
3-O-benzyl-2-benzyloxycarbonylamino-2-deoxy-6-O-
chloroacetyl-a-D-glucopyranoside (24)
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