Regio- and chemoselective manipulation under mild conditions on glucosamine derivatives for oligosaccharide synthesis and its application toward N-acetyl-d-lactosamine and Lewis X trisaccharide

Article abstract of DOI:10.1016/j.tet.2008.07.048

Special emphasis on regio- and chemoselective manipulation on a new glucosamine scaffold was laid, toward the short-step and efficient synthetic routes for oligosaccharides. First, the blocking of two hydroxyl groups at C-1 and C-6 positions of N-protected glucosamine at once by silylation followed by an oxazolidinone formation between C-3 hydroxyl and C-2 amino groups were established, to lead an expeditious way for a glycosyl acceptor for lactosamine synthesis. Second, without any effect on acetyl protective groups in the same molecule, the ring-opening of oxazolidinone and hydrolysis of resulting carbonate under mild conditions allowed the C-3 hydroxyl group to be free, which is indispensable for further extension to oligosaccharides, such as a LeX trisaccharide.

Full text of DOI:10.1016/j.tet.2008.07.048

Tetrahedron 64 (2008) 9599–9606
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regio- and chemoselective manipulation under mild conditions on glucosamine
derivatives for oligosaccharide synthesis and its application toward N-acetyl- -
D
lactosamine and Lewis X trisaccharide
*
Yasuhito Nagai, Naoyuki Ito, Israt Sultana, Takeshi Sugai
Department of Chemistry, Keio University, 3-14-1 Hiyoshi, Yokohama 223-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 April 2008
Received in revised form 13 July 2008
Accepted 14 July 2008
Available online 18 July 2008
Special emphasis on regio- and chemoselective manipulation on a new glucosamine scaffold was laid,
toward the short-step and efficient synthetic routes for oligosaccharides. First, the blocking of two hy-
droxyl groups at C-1 and C-6 positions of N-protected glucosamine at once by silylation followed by an
oxazolidinone formation between C-3 hydroxyl and C-2 amino groups were established, to lead an ex-
peditious way for a glycosyl acceptor for lactosamine synthesis. Second, without any effect on acetyl
protective groups in the same molecule, the ring-opening of oxazolidinone and hydrolysis of resulting
carbonate under mild conditions allowed the C-3 hydroxyl group to be free, which is indispensable for
further extension to oligosaccharides, such as a LeX trisaccharide.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
conditions. The observation was contrasting to the fact that C-3, C-6
dibenzyloxy glucosamine derivatives have been good glycosyl ac-
Toward chemical syntheses of rare sugars and oligosaccharides,
it is important to provide versatile key intermediates with specific
free hydroxyl groups, on which introduction of other functional
groups, oxidation, stereochemical inversion, and glycosyl bond
formation are carried out. The protection and deprotection steps
should be as few as possible for the synthesis of such intermediates
to develop expeditious routes. Some years ago, we found an un-
expected transformation, which would meet such approach for
a new glucosamine derivative: a simultaneous TBDPS group pro-
tection of three hydroxyl groups on C-1, C-3, and C-6 positions of
ceptors.2,3 Then a less hindered glycosyl acceptor candidate 2b was
prepared, by substituting C-6 TBDPS group with acetyl group,
through a regioselective deprotection4 and the subsequent acety-
lation.5 The attempted glycosylation, however, resulted in almost
no reaction (Scheme 1). We realized that the TBDPS group at C-3
position should be replaced with sterically less hindered, but not
too electron-withdrawing group. In this paper, we designed a sugar
oxazolidinone 4 as a new acceptor, and the elaborated conditions
on the preparation and its subsequent manipulation are described
in detail.
N-acetyl-D
-glucosamine 1a.1 A tri-TBDPS ether 2a was obtained in
70% yield, where remarkable regioselectivity was observed for the
introduction of a silyl group at C-3 position leaving a free hydroxyl
group at C-4. This was effectively derived to N-acetyl-D-galactos-
amine through a stereochemical inversion at the liberated C-4
position.
The above tri-TBDPS ether 2a seemed attractive also as a lac-
tosamine precursor by way of glycosylation, however, the reactivity
of the free hydroxyl group turned out to be very low as an acceptor.
For example, we hardly observed any glycosylated product be-
tween various galactosyl or glucosyl donors involving a tri-
chloroactimidate 3, under protic or Lewis acidic activating
* Corresponding author. Faculty of Pharmacy, Keio University, 1-5-30, Shibakoen,
Minato-ku, Tokyo 105-8512, Japan. Tel./fax: þ81 3 5400 2665.
E-mail address: sugai-tk@pha.keio.ac.jp (T. Sugai).
Scheme 1. (a) TBDPSCl, imidazole, DMF, 70%; (b) AcCl, MeOH; (c) AcCl, collidine, 29%.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.048

9600
Y. Nagai et al. / Tetrahedron 64 (2008) 9599–9606
2. Results and discussion
give 4 in 85% yield. On this occasion, the concomitantly formed
p-nitrophenol, the leaving group, interferes the purification of 4,
due to the very similar chromatographic behavior of both products.
Then zinc powder was added immediately after acidification of the
reaction mixture to reduce p-nitrophenol into aminophenol, which
enabled easier removal of the obstinate by-product. Alternatively,
carbamylation–nitrosocyclization10 by way of a urea 5e provided
the same oxazolidinone (4, 51%), and in this case, the in-
expensiveness of reagents is advantageous. The oxazolidinone 4
was a crystalline material by virtue of the no contamination with
2.1. Regioselective introduction of TBDPS ethers on C-1 and C-
6 hydroxyl groups
The protection of hydroxyl groups located at C-6 and C-1 posi-
tions in one-shot with liberating C-3 and C-4 hydroxyl groups is the
first task. In the course of our previous study on the silylation on
GlcNAc 1a,1 at the very initial stage of the reaction, the desired di-
TBDPS ether 5a was observed by TLC analysis. The di-TBDPS ether
5a was, however, quickly transformed into tri-TBDPS ether 2a as the
major product. This observation suggested that the electron-
withdrawing nature of nitrogen function in C-2 position was
expected to lower the nucleophilicity of C-3 hydroxyl group. Based
on this consideration, our first attempt was the use of glucosamine
hydrochloride (1b) as the substrate. Due to the scarce solubility of
1b in the reaction mixture, the result was miserable, only to give
complex mixture, and the silylated products 5b as well as 6b were
only observed in trace amounts. Instead, the introduction of
strongly withdrawing substituent, trifluoroacetyl group6 on nitro-
gen atom (1c) turned the situation better, owing to the increase of
solubility of the substrate in DMF. The major product was, however,
monoprotected form 6c (75%), only whose C-6 hydroxyl group was
silylated, as the nucleophilicity of anomeric hydroxyl group turned
very low.
the corresponding
The glycosylation reaction of oxazolidinone 4 with 311 worked
very well to give 7a (87%) in exclusive formation of -linkage be-
a-anomer.
b
tween two sugars. Toward the introduction of the indispensable
N-acyl moiety often observed in oligosaccharides, one-pot two-step
transformation was also successful. Diisopropylethylamine fol-
lowed by acetyl chloride were added to the reaction mixture, when
the completion of the glycosylation was confirmed on TLC analysis.
Acetylated oxazolidinone 7b was obtained also as crystalline ma-
terial, in 80% yield (Scheme 3).
Then we considered the enhancement of the concentration of in
situ active silylating intermediate, TBDPS-imidazolinium chloride,7
by increasing the equivalence of imidazole to TBDPSCl from 1.1 to
2.2. The desired C-1, C-6 silylated product 5c became available in an
excellent yield (89%, Scheme 2). We tried another substrate 1d for
silylation, whose amino group was protected by a less electron-
withdrawing but sterically demanding Cbz group. The reaction
proceeded in a similar way, however, the isolated yield (71%) of 6d
was substantially lower. In both cases, the orientation of anomeric
TBDPS-oxy group exclusively settled in b, as had been observed for
N-acetyl derivatives 2a.1 Similar observation has been well known
for anomeric TMS ether formation in galactose.
Scheme 3. (a) LiOH, H2O, THF, quant.; (b) p-O2N(C6H4)OCOCl, NaHCO3, MeCN, H2O; (c)
Zn, AcOH, 85%; (d) KCNO, H2O; (e) NaNO2, AcOH, H2O, 51%; (f) 3, TMSOTf, MS 4 Å,
CH2Cl2; (g) AcCl, i-Pr2NEt, CH2Cl2, 80%.
2.3. The chemoselective deprotection to give liberated C-3
hydroxyl group
Toward the further glycosylated oligosaccharides based on
N-acetyl-D-lactosamine, the most important task is the liberation of
C-3 hydroxyl group of GlcNAc by the hydrolysis of oxazolidinone
ring. Kerns12,13 and Crich9,14 independently reported basic condi-
tions such as Cs2CO3 in alcohol,12,13 LiCl/LiOH,13 and Ba(OH)2.9,14 In
our case, the question is that under such strongly basic conditions,
the hydrolysis of oxazolidinone heterocycle is possible or not,
without any effect on many O-acetyl groups located in non-re-
ducing galactose moiety. Crich emphasized the chelation of metal
Scheme 2. (a) TBDPSCl, imidazole, DMF.
2.2. Elaboration to the oxazolidinone glycosyl acceptor
cation between N-acetyl carbonyl oxygen and b-oriented anomeric
oxygen to enhance the electrophilicity at oxazolidinone carbonyl
From recent literatures,8,9 the introduction of 2,3-oxazolidinone
functionality on 2-deoxyamino sugars do not interfere the glyco-
sylation at C-4 hydroxyl group. In our case, labile N-trifluoroacetyl
group in 5c worked advantageously toward the oxazolidinone ring
formation. Indeed, the protective group was easily removed to give
5b in quantitative yield under mildly basic conditions, while two
TBDPS protective groups were intact. Oxazolidinone formation
worked well by treatment with p-nitrophenyl chloroformate to
carbon.9 We had also experienced strongly electron-donating
property of the anomeric b-TBDPS oxygen atom in amino sugar
derivative.1 Our first attempt was then, the treatment of 7b with
a mixture of LiCl and LiOH13 in aqueous THF solution by choosing
small and strongly Lewis acidic lithium cation, however, gave no
desired hydrolyzed product. The replacement of H2O with H2O2
bearing an enhanced nucleophilicity,13 disappointingly, gave simi-
lar result.

Y. Nagai et al. / Tetrahedron 64 (2008) 9599–9606
9601
A very careful TLC analysis of the reaction was a clue to this
obstacle. When ethanol was added as a co-solvent for making the
reaction mixture to a homogeneous solution at the stage of the
initial reaction operations, a remarkable spot other than the start-
ing material appeared on TLC. The isolation and structural eluci-
dation revealed that the new product was an ethyl carbonate at C-3
position (8a) in 53% yield. This result was quite strange, as the
contrasting ‘carbamate formation’ had been reported12 by treat-
ment of some sugar oxazolidinones by Cs2CO3/ROH, but in our
N-iodosuccinimide (NIS, 3 equiv, based on 8c) and catalytic amount
of trifluoromethanesulfonic acid (TfOH, 0.1 equiv) in CH2Cl2 at 0 ꢀC
to room temperature to give a LeX trisaccharide derivative 10a in
44% yield. The addition of benzene as the co-solvent (1:1) sub-
stantially improved the yield to be 77%. The moderate yield ob-
served in less polar solvent was substantially due to the low
reactivity of the free hydroxyl group through the hydrogen bond
formation between the acetyl protective group on galactose moiety,
which was suggested by the IR spectrum of 8c. Furthermore, the
‘inversed procedure’, which had been proposed by Schmidt30 for
the highly active glycosylation intermediate, was very effective. The
yield reached as high as quantitative. "Through the experiments,
we observed that the acceptor 8c was almost insoluble in benzene.
The addition of donor...". phenylthio fucoside 9a as benzene solu-
tion was necessary to a pre-mixed solution of acceptor 8c and ac-
tivators in CH2Cl2 so as to the reaction smoothly proceeds. The
trichloroacetimidate donor 9b31 also worked well through the
inversed procedure with a similar CH2Cl2–Et2O solvent system, to
give 92% yield of the desired 10a.
hands, a clearly observed downfield-shifted H-3 (d 4.62) signal
supported well the structure of 8a. In previously reported Crich’s
experiments starting from acetylated oxazolidiones, no such car-
bonates had been observed, but those reactions were performed by
applying Ba(OH)2 in aqueous media at high temperature.9,14
We tried to put our experimental result into consideration. The
ring-opening carbonate formation became very slow under the
conditions that solid LiOH was added in a simple mixture of THF
and ethanol. Recently Niwayama have reported a controlled action
of alkali metal hydroxides in THF.15 Our observation suggests the
coordination of both of water and THF molecules on Lewis acidic
metal cation, to certain extent, is necessary.
Then, alcohols for ring-opening reactions were screened, whose
corresponding carbonates would selectively be removed under
very mild conditions. In this point of view, the first candidate as the
nucleophile was allyl alcohol. The reaction conditions were elabo-
rated, eventually to provide allyl carbonate 8b in 86% yield. The
selective palladium-catalyzed deprotection of allyl carbonate16 in
Throughout changing reaction conditions, the anomeric ratio
was constant (
a
/b
¼ca. 10:1) on the newly introduced fucosidic
linkage, with this acceptor 8c. The addition of DTBMP,32 a proton
scavenger, did not change either the yield or ratio, and in this case,
the glycosyl triflate formation and the subsequent SN2-like
cosylation pathway seems negligible.
b-gly-
As the major
a-anomer was crystalline, the product 10a was
easily purified by simple recrystallization. This derivative 10a car-
ries different protective groups on different sugar component, Ac
on Gal; Bn on Fuc; TBDPS on GlcNAc. Taking advantage of these
properties, two new derivatives 10b (92%) and 10c (quantitative)
were obtained, by treatment with sodium methoxide in methanol
and catalytic debenzylation, sequentially. The use of tri-
chloroacetoimidate fucosyl donor 9b was advantageous at this later
step, as the trace amount of sulfur contaminants, originated from
phenylthio fucosyl donor 9a, often interfered the smooth catalytic
hydrogenolysis (Scheme 5).
8b afforded the N-acetyl-D-lactosamine derivative 8c in 87% yield
(Scheme 4). The reactivity of oxazolidinone carbonyl group toward
nucleophilic alcohols was indeed very high. Even an electron-
withdrawing and sterically hindered trichloroethanol12 worked
very well to give a trichloroethyl carbonate (Troc) 8d in a quanti-
tative yield. This carbonate 8d could reductively cleaved by the
addition of zinc powder with acetic acid to afford 8c in two steps
and 90% yield. The ring-opening reaction worked well by applying
as low equivalent as 2.0 for trichloroethanol, and in this case,
successive two operations, ring-opening and hydrolysis of the
resulting carbonate were performed in one-pot. The attempt for the
use of another electron-withdrawing nucleophile, trifluoroethanol
was, however, unsuccessful, as the intermediates were too labile
and the reaction turned to complex mixture. A bulky, electron-
donating, tert-butyl alcohol did not work as the nucleophile.
Scheme 5. (a) 9a, NIS, TfOH, C6H6, CH2Cl2, qunat.; (b) 9b, NIS, TfOH, Et2O, CH2Cl2, 92%;
Scheme 4. (a) LiCl, LiOH, ROH, H2O, THF; (b) (Ph3P)4Pd, morpholine, THF, 87%; (c); Zn,
(c) MeONa, MeOH, 92%; (d) H2, Pd(OH)2, EtOH, quant.
AcOH, quant.
2.4. Application of the disaccharide as the further glycosyl
acceptor
3. Conclusion
We were successful to develop a route through a new amino
sugar scaffold 4 toward 2-deoxy-2-acetamido oligosaccharides, on
regioselective protection and chemoselective deprotection ap-
proach. The first key reaction was the protection of C-1, C-6 hy-
droxyl groups of glucosamine derivative at once with two TBDPS
Next, further glycosylation of above-mentioned disaccharide 8c
was examined. The target molecule is Lewis X trisaccharide,17–28
and the fucosylation of 8c would open a new route to provide de-
rivatives with different protective groups on individual sugar
components. The fucosylation was firstly performed with phenyl-
thio fucoside 9a.29 A mixture of 9a and 8c was treated with
groups, to provide single
b-anomer 5c in high yield. In another key
step, -oriented anomeric TBDPS-oxy group played a crucial role for
b

9602
Y. Nagai et al. / Tetrahedron 64 (2008) 9599–9606
the chemoselective deprotection of oxazolidinone ring in 7b, which
had not been available by treatment with conventionally basic
conditions,33 without any effect on other acetyl protective groups.
26.8, 57.9, 63.5, 71.8, 72.7, 76.3, 95.9, 127.1, 127.4, 127.7, 128.1, 129.5,
129.6, 129.8, 130.1, 132.3, 133.1, 133.1, 133.4, 135.3, 135.6, 135.8,
135.9, 169.4, 171.0; the signals between 26.6 and 26.8 included to-
tally 6 carbons, and ones between 127.1 and 135.9 included totally
24 carbons; IR nmax 3562, 3312, 1726, 1678 cmꢁ1. Anal. Calcd for
4. Experimental
C
42H53NO7Si2þ0.5H2O: C, 67.35; H, 7.27; N, 1.89. Found: C, 67.60; H,
4.1. Material and methods
7.49; N, 1.83.
Merck silica gel 60 F254 thin-layer plates (1.05744, 0.5 mm
thickness) and silica gel 60 (spherical and neutral; 100–210 mm,
37560-79) from Kanto Chemical Co. were used for preparative thin-
layer chromatography and column chromatography, respectively.
4.4. 1,6-Di-O-tert-butyldiphenylsilyl-2-deoxy-2-
trifluoroacetoamido-b-D-glucopyranose (5c) and 6-O-tert-
butyldiphenylsilyl-2-deoxy-2-trifluoroacetoamido-
glucopyranose (6c)
b-D-
4.2. Analytical methods
2-Trifluoroacetyl-D
-glucosamine6 (1c, 2.24 g, 8.14 mmol) and
imidazole (3.05 g, 44.8 mmol, 5.5 equiv) were dissolved in DMF
(24 mL) containing MS 4 Å (2.3 g) under Ar. The mixture was stirred
for 2 h at room temperature and tert-butyldiphenylsilyl chloride
(TBDPSCl, 6.49 g, 23.6 mmol, 2.9 equiv) in DMF (10 mL) was added
to the stirred solution. After stirring for 20 h at room temperature,
the mixture was quenched by the addition of brine. The solids were
filtered off and the filtrate was extracted with EtOAc, dried over
Na2SO4, and concentrated in vacuo. The residue was purified by
silica gel column chromatography (100 g). Elution with hexane–
All melting points are uncorrected. IR spectra were measured as
films for oils or KBr disks for solids on a Jasco FT/IR-410 spec-
trometer. 1H NMR spectra were measured in CDCl3 at 400 MHz on
a Jeol JNM GX-400 spectrometer and 13C NMR spectra were mea-
sured in CDCl3 at 100 MHz on a Jeol GX-400 spectrometer, unless
otherwise stated. High resolution mass spectra were recorded on
a Jeol JMS-GCmate spectrometer at 70 eV. Optical rotation values
were recorded on a P-1010 polarimeter.
EtOAc (2:1) afforded 5c (5.45 g, 89.0%) as amorphous solid, Rf 0.5
4.3. 2-Acetamido-6-O-acetyl-1,3-di-O-tert-butyldiphenylsilyl-
22
[hexane–EtOAc (3:2)]. [
a
]
ꢁ7.1 (c 1.00, EtOH); 1H NMR (270 MHz,
D
2-deoxy-b-D
-glucopyranose (2b)
CDCl3)
d
: 1.00 (s, 9H, t-Bu), 1.03 (s, 9H, t-Bu), 2.99 (dt, J4,5¼9.2 Hz,
J5,6¼4.6 Hz,1H, H5), 3.25 (d, J¼2.2 Hz,1H, OH), 3.45 (d, J¼4.1 Hz,1H,
OH), 3.51–3.71 (m, 4H, H3, H4, H6, H6), 3.79 (ddd, J1,2¼7.9 Hz,
J2,3¼10.1 Hz, J2,NH¼7.6 Hz, 1H, H2), 4.54 (d, 1H, H1), 6.49 (d, 1H, NH),
AcCl (270.0
mL) was added dropwise to MeOH (6.6 mL) and the
HCl solution obtained as above was cooled to 20 ꢀC. A solution of
the starting material 2a (199.3 mg, 0.21 mmol) in Et2O (6.6 mL) was
added and the mixture was stirred at room temperature for 8 h. The
reaction was monitored by silica gel TLC and developed with hex-
ane–EtOAc (2:1). The reaction mixture was concentrated in vacuo.
The residue was purified by silica gel column chromatography.
7.18–7.62 (20H, aromatic); 13C NMR (CDCl3, 100 MHz)
d: 19.1, 19.2,
26.8, 58.8, 64.1, 72.9, 73.8, 74.2, 95.2, 115.6, 127.4, 127.6, 127.8, 127.8,
129.8, 129.8, 129.8, 129.9, 132.3, 132.4, 132.5, 132.6, 135.4, 135.4,
135.6, 135.7, 157.8; the signal 26.8 included totally 6 carbons, and
ones between 127.4 and 135.7 included totally 24 carbons; IR nmax
3320, 2931, 1708 cmꢁ1; HRMS (EI): calcd for C36H59F3NO6Si2 [Mþ]:
694.2269; found m/z: 694.2268.
Elution with hexane–EtOAc (4:1) afforded the corresponding partly
20
desilylated product (56.5 mg, 38%). [
NMR (CDCl3, 400 MHz)
a]
ꢁ4.6 (c 1.00, CHCl3); 1H
D
d
: 1.03 (s, 18H, t-Bu), 1.31 (dd, J6,OH¼6.8 Hz,
In another run by applying lower equivalents of reagents,
monosilylated derivative 6c became the major product. Chro-
matographic separation on silica gel with hexane–EtOAc (2:3)
afforded 6c (75%) as amorphous solid, Rf 0.2 [hexane–EtOAc (3:2)].
1H, OH), 1.53 (s, 3H, Ac), 1.97 (d, J4,OH¼3.5 Hz, 1H, OH), 2.87 (m, 1H,
H5), 3.50 (m, 3H, H3, H6, H6), 3.61 (ddd, J3,4¼8.8 Hz, J4,5¼8.8 Hz,1H,
H4), 3.95 (ddd, J1,2¼7.8 Hz, J2,NH¼9.3 Hz, J2,3¼9.1 Hz, 1H, H2), 4.44
(d, 1H, H1), 4.66 (d, 1H, NH), 7.30–7.69 (20H, aromatic); 13C NMR
1H NMR (400 MHz, CDCl3)
H1
J1,2¼8.3 Hz, 1H, H1
d
: 1.04 (s, 9H, t-Bu), 5.22 (m, 1H, H1
). Upon acetylation, anomeric signals shifted to 5.65 (d,
) and 6.23 (d, J1,2¼3.9 Hz, 1H, H1 ), respectively.
a,
(CDCl3, 100 MHz) d: 19.0, 19.6, 23.5, 26.7, 26.9, 58.1, 62.3, 72.0, 74.5,
b
76.5, 96.2, 127.3, 127.5, 127.8, 128.2, 129.7, 129.7, 129.9, 130.2, 132.2,
133.0, 133.5, 133.7, 135.3, 135.5, 135.6, 135.9, 169.4; the signals be-
tween 26.7 and 26.9 included totally 6 carbons, and ones between
127.3 and 135.9 included totally 24 carbons; IR nmax 3566, 3367,
1668 cmꢁ1. This was employed for the next step without further
purification. The above-mentioned desilylated product (106.8 mg,
0.15 mmol) was dissolved in CH2Cl2 (1.9 mL) at ꢁ78 ꢀC. 2,4,6-Col-
b
a
4.5. 2-N-Benzyloxycarbonyl-1,6-di-O-tert-butyldiphenysilyl-
2-deoxy- -glucopyranose (5d) and 2-N-benzyloxycarbonyl-
6-O-tert-butyldiphenylsilyl-2-deoxy- -glucopyranose (6d)
b-D
b-D
lidine (40.4
mL, 0.30 mmol, 2.0 equiv) and acetyl chloride (13.1
m
L,
In the same manner as described for 5c, N-Cbz-D
-glucosamine22
0.18 mmol, 1.2 equiv) were added to the solution with stirring. The
reaction was monitored by silica gel TLC and developed with hex-
ane–EtOAc (2:1). After stirring for 3 h at ꢁ78 ꢀC and for 1 h at room
temperature, the mixture was quenched by the addition of water,
and the aqueous layer was extracted with EtOAc. The organic layers
were combined, washed with saturated NaHCO3 aq solution, water
and brine, dried over Na2SO4, and concentrated in vacuo. The res-
idue was purified by silica gel column chromatography. Elution
(1d, 454 mg, 1.45 mmol) was treated with TBDPSCl (1.34 g,
4.88 mmol, 3.4 equiv) and imidazole (516 mg, 7.58 mmol,
5.2 equiv) for 36 h. The crude residue was purified by silica gel
column chromatography (20 g). Elution with hexane–EtOAc (1:1)
afforded 5d (847 mg, 71%) and 6d (30.9 mg, 4%) as amorphous solid.
22
Compound 5d: Rf 0.5 [hexane–EtOAc (1:1)]; [
a
]
D
þ3.6 (c 1.00,
EtOH); 1H NMR (400 MHz, CDCl3)
d
: 1.01 (s, 9H, t-Bu), 1.04 (s, 9H, t-
Bu), 3.00 (br, 1H, OH), 3.03 (br, 1H, H5), 3.43 (br, 1H, H3), 3.54 (br,
1H, H2), 3.58 (br, 1H, OH), 3.66–3.72 (m, 3H, H4, H6, H6), 4.42 (d,
J1,2¼7.3 Hz, 1H, H1), 4.72 (d, J2,NH¼6.4 Hz, 1H, NH), 5.03 (d,
J¼18.6 Hz, 1H, Cbz), 5.03 (d, J¼18.6 Hz, 1H, Cbz), 7.17–7.64 (25H,
with hexane–EtOAc (4:1) afforded 2b (87.9 mg, 78%) as fine nee-
22
dles, mp 80.0–82.0 ꢀC. [
a
]
ꢁ8.2 (c 1.00, CHCl3); 1H NMR (CDCl3,
D
400 MHz) d: 1.01 (s, 18H, t-Bu), 1.46 (s, 3H, Ac), 1.99 (s, 3H, Ac), 2.12
(d, J4,OH¼3.9 Hz, 1H, OH), 3.05 (ddd, J4,5¼9.0 Hz, J5,6¼4.3 Hz,
J5,6¼4.3 Hz, 1H, H5), 3.50 (dd, J2,3¼9.2 Hz, J3,4¼8.9 Hz, 1H, H3), 3.55
(ddd, H4), 3.98 (ddd, J1,2¼7.8 Hz, J2,NH¼9.8 Hz, 1H, H2), 4.13 (m, 2H,
H6a, H6b), 4.32 (d, 1H, H1), 4.59 (d, 1H, NH), 7.27–7.71 (20H, aro-
aromatic); 13C NMR (CDCl3, 100 MHz)
d: 19.2, 19.3, 26.8, 59.6, 64.1,
67.2, 72.6, 74.5, 75.4, 95.8, 127.4, 127.6, 127.7, 127.7, 128.1, 128.4,
129.7, 129.7, 129.8, 132.6, 132.7, 132.7, 135.4, 135.5, 135.7, 135.8,
136.0, 156.9; the signal 26.8 included totally 6 carbons, and ones
between 127.4 and 136.0 included totally 30 carbons; IR nmax: 3394,
matic); 13C NMR (CDCl3, 100 MHz)
d: 19.0, 19.6, 20.8, 23.5, 26.6,

Y. Nagai et al. / Tetrahedron 64 (2008) 9599–9606
9603
1702 cmꢁ1. Anal. Calcd for C46H55NO7Si2þ0.5H2O: C, 69.14; H, 7.06;
N, 1.75. Found: C, 69.20; H, 7.17; N, 1.66.
3288, 1656, 1583 cmꢁ1. The crude urea 6e as above was employed
for next reaction without further purification and dissolved in
AcOH (3.0 mL) under Ar. Then, a solution of NaNO2 (65 mg,
0.94 mmol, 1.5 equiv) in water (0.1 mL) was added four times at
every 2 h intervals with stirring. The reaction was monitored by
silica gel TLC and developed with CHCl3–MeOH (8:1). After stirring
for 24 h at room temperature, the reaction was diluted with Et2O
and poured into NaOH aq solution (1.0 M). The aqueous layer was
extracted with Et2O and the combined organic layers were washed
with brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (20 g).
Elution with hexane–EtOAc (4:1) to EtOAc afforded 4 (217 mg, 51%
from 5c) as colorless fine needles together with the recovery of 5e
(91 mg, 21%). The physical and spectral data of 4 were coincided
with those mentioned as above.
Compound 6d: Rf 0.2 [hexane–EtOAc (1:2)]; 1H NMR (400 MHz,
CDCl3)
for 7c, upon acetylation, anomeric signal shifted to 5.58 (d,
J1,2¼8.3 Hz, 1H, H1 ) and 6.18 (d, J1,2¼3.4 Hz, 1H, H1 ), respectively.
d: 1.04 (s, 9H, t-Bu), 5.15 (br s, 1H, H1). In a similar manner
b
a
4.6. 2-Amino-1,6-di-O-tert-butyldiphenylsilyl-2-deoxy-
glucopyranose (5b) and 1,6-di-O-tert-butyldiphenylsilyl-2-
N,3-O-carbonyl-2-deoxy- -glucopyranose (4)
b-D-
b-D
To the stirred solution of silyl ether (5c, 5.35 g, 7.11 mmol) in THF
(24 mL) at 0 ꢀC, LiOH aq solution (2.0 M, 7.11 mL, 14.2 mmol,
2.0 equiv) was added. The mixture was stirred at 0 ꢀC, the reaction
was monitored by silica gel TLC, and developed with CHCl3–MeOH
(6:1). After 3.5 h, a small portion was extracted with EtOAc and the
formation of 5b was confirmed by the analysis of crude mixture. 1H
4.7. 20,30,40,60-Tetra-O-acetyl-
di-O-tert-butyldiphenylsilyl-2-N,3-O-carbonyl-2-deoxy-
glucopyranose (7a) and 20,30,40,60-tetra-O-acetyl-N-acetyl-
galactopyranosyl-(10-4)-1,6-di-O-tert-butyldiphenylsilyl-2-
N,3-O-carbonyl-2-deoxy- -glucopyranose (7b)
b-D
-galactopyranosyl-(10-4)-1,6-
NMR (400 MHz, CDCl3)
d: 0.95 (s, 9H, t-Bu), 1.00 (s, 9H, t-Bu), 2.67
b-D-
b-D-
(d, J1,2¼6.8 Hz, J2,3¼8.0 Hz, 1H, H2), 2.96 (ddd, J4,5¼9.2 Hz,
J5,6a¼4.4 Hz, J5,6b¼4.6 Hz, 1H, H5), 3.22 (dd, J3,4¼8.3 Hz, 1H, H3),
3.56–3.63 (m, 3H, H4, H6a, H6b), 4.29 (d, 1H, H1), 7.13–7.58 (20H,
aromatic); IR nmax 3363, 2930 cmꢁ1. To the rest of the reaction
mixture was added NaHCO3 (1.20 g, 14.2 mmol, 2 equiv) and ice
bath was removed. To the mixture, p-nitrophenyl chloroformate
(2.87 g, 14.2 mmol, 2.0 equiv) in CH3CN (10 mL) was added drop-
wise over 30 min. The reaction was monitored by silica gel TLC and
developed with hexane–EtOAc (2:1). After addition, the reaction
was further stirred for 2 h. AcOH (10 mL) and Zn dust (2.5 g) were
added portionwise to the reaction mixture with stirring for 1 h. The
mixture was then filtered to remove insoluble materials and the
filtrate was concentrated in vacuo. The residue was diluted with
Et2O and washed with NaOH aq solution (1.0 M) three times and
brine, dried over Na2SO4, and concentrated in vacuo. The crude
brown oil was purified by silica gel column chromatography
(200 g). Elution with hexane–EtOAc (4:1) afforded 4 (4.12 g, 85%) as
b-D
The oxazolidinone (4, 1.96 g, 2.87 mmol) and
a
tri-
chloroacetimidate (3, 1.83 g, 3.72 mmol, 1.3 equiv) were dissolved
in CH2Cl2 (35 mL) containing MS 4 Å (3.6 g) under Ar. After stirring
for 4 h at room temperature, the reaction mixture was cooled to
0 ꢀC and TMSOTf (0.1 mL, 0.574 mmol, 0.2 equiv) was added. The
mixture was gradually warmed up to room temperature and stir-
ring was continued for additional 2 h. After the complete con-
sumption of the substrate was confirmed by TLC analysis,
developed with hexane–EtOAc (1:1), the mixture was quenched by
the addition of Et3N. The solids were filtered off and the filtrate was
concentrated in vacuo. The residue was purified by silica gel column
chromatography (50 g). Elution with hexane–EtOAc (4:1) afforded
26
7a (2.57 g, 87%) as colorless fine needles, mp 189–190 ꢀC. [
a]
D
colorless oil. This was recrystallized from hexane and EtOAc to af-
ꢁ17.1 (c 1.00, CHCl3); 1H NMR (270 MHz, CDCl3)
d: 1.04 (s, 18H,
20
ford 4 (3.88 g, 80%) as fine needles, mp 177–179 ꢀC. [
a
]
ꢁ15.0 (c
t-Bu),1.63 (s, 3H, Ac),1.89 (s, 3H, Ac),1.93 (s, 3H, Ac), 2.05 (s, 3H, Ac),
3.15 (m, 1H, H5), 3.45 (dd, J1,2¼7.4 Hz, J2,3¼11.0 Hz, 1H, H2), 3.74–
3.76 (m, 3H, H3, H6, H6), 3.98–4.12 (m, 3H, H50, H60, H60), 4.25 (dd,
D
0.975, CHCl3); 1H NMR (400 MHz, CDCl3)
d: 1.04 (s, 9H, t-Bu),1.05 (s,
9H, t-Bu), 2.91 (s, 1H, OH), 3.19 (ddd, J4,5¼7.6 Hz, J5,6a¼4.0 Hz,
J5,6b¼5.2 Hz,1H, H5), 3.48 (dd, J1,2¼7.3 Hz, J2,3¼11.2 Hz,1H, H2), 3.76
(dd, J6a,6b¼10.8 Hz, 1H, H6b), 3.80 (dd, 1H, H6a), 3.94 (dd,
J3,4¼10.8 Hz, 1H, H3), 4.13 (dd, 1H, H4), 4.71 (d, 1H, H1), 4.96 (s, 1H,
0
0
0
J3,4¼8.4 Hz, J4,5¼9.7 Hz, 1H, H4), 4.53 (d, J1 ,2 ¼8.1 Hz, 1H, H1 ), 4.66
0
0
0
0
(d, 1H, H1), 4.71 (s, 1H, NH), 4.82 (dd, J2 ,3 ¼10.4 Hz, J3 ,4 ¼3.5 Hz, 1H,
H30), 5.03 (dd, 1H, H20), 5.25 (1H, H40), 7.12–7.62 (20H, aromatic);
NH), 7.12–7.62 (20H, aromatic); 13C NMR (100 MHz, CDCl3)
d: 19.1,
13C NMR (100 MHz, CDCl3)
d: 19.2, 19.5, 20.5, 20.6, 20.7, 20.7, 26.8,
19.2, 26.8, 61.3, 63.9, 69.4, 76.7, 81.9, 96.2, 127.5, 127.8, 129.9, 129.9,
130.0, 130.1, 132.1, 132.3, 132.4, 132.5, 135.4, 135.4, 135.5, 135.6,
159.4; the signal 26.8 included totally 6 carbons, and ones between
127.5 and 135.6 included totally 24 carbons; IR nmax 3367, 2931,
1774 cmꢁ1. Anal. Calcd for C39H47NO6Si2: C, 68.69; H, 6.95; N, 2.05.
Found: C, 68.47; H, 6.88; N, 2.06.
26.9, 61.3, 61.5, 61.6, 66.9, 68.8, 70.8, 70.9, 73.9, 77.5, 80.1, 95.8, 99.9,
127.7, 127.7, 127.8, 127.9, 129.7, 129.9, 130.1, 130.4, 132.0, 132.2, 132.4,
133.4, 135.3, 135.5, 135.6, 135.7, 158.8, 168.9, 169.8, 170.1, 170.3; the
signals between 26.8 and 26.9 included totally 6 carbons, and ones
between 127.7 and 135.7 included totally 24 carbons; IR nmax 3367,
2932, 1779, 1754 cmꢁ1. Anal. Calcd for C53H65NO15Si2þH2O: C,
61.79; H, 6.55; N, 1.36. Found: C, 61.84; H, 6.33; N, 1.37.
The glycosylation and the following N-acetylation could be
performed in one pot. In this case, when the glycosylation com-
pleted, the reaction mixture was cooled to 0 ꢀC and diisopropyle-
thylamine (6.0 mL, 35.0 mmol,12.0 equiv) was added. To the stirred
solution, acetyl chloride (1.25 mL, 17.5 mmol, 6.0 equiv) was added
dropwise over 1 h. The reaction was monitored by silica gel TLC and
developed with hexane–EtOAc (3:2). After stirring for 24 h at room
temperature, the mixture was quenched by the addition of satu-
rated NaHCO3 aq solution. The solids were filtered off and the fil-
trate was concentrated in vacuo. The residue was diluted with
EtOAc and washed with brine, dried over Na2SO4, and concentrated
in vacuo. The residue was purified by silica gel column chroma-
tography (100 g). Elution with hexane–EtOAc (3:1) afforded 7b
quantitatively as yellow gummy solid. This was recrystallized from
The oxazolidinone was alternatively prepared by way of a urea
intermediate 5e. In this case, when the reaction for preparing free
amine 5b (from 5c, 410 mg, 0.625 mmol) was completed, the
mixture was acidified by the addition of AcOH (1.5 mL). Then, KCNO
(505 mg, 6.25 mmol, 10.0 equiv) dissolved in water (1.0 mL) was
added dropwise over 1 h. The reaction was monitored by silica gel
TLC and developed with CHCl3–MeOH (8:1). After stirring for 4 h at
room temperature, the reaction was quenched by the addition of
NaHCO3 aq solution, and the aqueous layer was extracted with
CHCl3. The combined organic layers were washed with brine, dried
over Na2SO4, and concentrated in vacuo to afford urea 5e quanti-
tatively. Small portion of 5e was purified by preparative TLC [de-
veloped with CHCl3–MeOH (8:1)] to give an analytical sample, mp
203–205 ꢀC. 1H NMR (270 MHz, CDCl3)
d: 0.94 (s, 9H, t-Bu), 1.01 (s,
9H, t-Bu), 2.98 (m, 1H, H5), 3.28 (m, 1H, H2), 3.37 (dd, J2,3¼8.9 Hz,
J3,4¼8.9 Hz, 1H, H3), 3.53 (dd, J4,5¼8.5 Hz, 1H, H4), 3.65 (br, 2H, H6,
H6), 4.39 (d, J1,2¼7.2 Hz, 1H, H1), 7.12–7.60 (20H, aromatic); IR nmax
hexane and EtOAc to give 7b (2.42 g, 80%) as colorless fine needles,
20
mp 105–109 ꢀC. [
a]
ꢁ23.7 (c 0.950, EtOH); 1H NMR (270 MHz,
D

9604
Y. Nagai et al. / Tetrahedron 64 (2008) 9599–9606
0
0
0
CDCl3)
d
: 1.03 (s,18H, t-Bu),1.69 (s, 3H, Ac),1.89 (s, 3H, Ac),1.95 (s, 3H,
J1,2¼7.8 Hz, 1H, H1), 4.49 (d, J1 ,2 ¼7.8 Hz, 1H, H1 ), 4.52–4.64 (m, 3H,
0
0
0
0
0
Ac), 2.06 (s, 3H, Ac), 2.28 (s, 3H, Ac),03.09 (dt, J4,5¼9.1 Hz, J5,6¼6.4 Hz,
H3, Alloc–CH2), 4.72 (dd, J2 ,3 ¼10.3 Hz, J3 ,4 ¼3.4 Hz, 1H, H3 ), 4.91
(dd, 1H, H20), 5.14–5.20 (m, 3H, H40, Alloc–C]CH, NH), 5.28 (dd,
J¼1.5, 17.1 Hz, 1H, Alloc–C]CH), 5.86 (ddt, J¼5.4, 10.7 Hz, 1H, Alloc–
0
0
1H, H5), 3.55 (t, J5 ,6 ¼6.6 Hz,1H, H5 ), 3.65 (br, 2H, H6, H6), 3.77–4.10
(m, 4H, H2, H3, H60,0 H60), 4.19 (dd, J3,4¼6.6 Hz, 1H, 0H4), 4.47 (d,
0
0
J10 ,2 ¼8.1 Hz, 1H, H1 ), 4.74–4.79 (m, 2H, H1, 0 H3 ), 5.02 (dd,
CH]C), 7.15–7.62 (20H, aromatic); 13C NMR (100 MHz, CDCl3)
d:
0
0
0
0
J 2,3 ¼10.2 Hz,1H, H2 ), 5.22 (d, J3 ,4 ¼3.0 Hz,1H, H4 ), 7.14–7.60 (20H,
19.2, 19.5, 20.6, 20.6, 20.7, 20.7, 23.4, 26.7, 27.0, 55.2, 61.0, 61.2, 66.9,
68.5, 69.1, 70.5, 70.9, 74.1, 75.0, 76.8, 95.9, 100.0, 118.4, 127.5, 127.6,
127.7,127.9,129.7,129.8,129.9,131.4, 132.1,132.6,132.8,133.3,135.4,
135.8, 135.8,135.8, 154.9, 168.9, 169.6, 169.7, 170.0, 170.3; the signals
between 26.7 and 27.0 included totally 6 carbons, and ones be-
tween 118.4 and 135.8 included totally 26 carbons; IR nmax 2935,
1754, 1693 cmꢁ1. Anal. Calcd for C58H73NO17Si2: C, 62.63; H, 6.61; N,
1.26. Found: C, 62.30; H, 6.69; N, 1.18.
aromatic); 13C NMR (100 MHz, CDCl3)
d: 19.0, 19.5, 20.6, 20.7, 20.8,
20.8, 24.8, 26.7, 27.0, 61.2, 61.3, 61.6, 66.9, 68.8, 70.8, 70.8, 73.9, 77.2,
78.1, 97.0, 99.7, 127.3, 127.4, 127.8, 127.9, 129.7, 129.8, 129.9, 130.0,
132.3,132.5,132.8,133.1,135.4,135.7,135.9,135.9,154.0,168.9,169.8,
170.1,170.1,171.6; the signals between 26.7 and 27.0 included totally
6 carbons, and ones between 127.3 and 135.9 included totally 24
carbons; IR nmax 3446, 1797, 1754 cmꢁ1. Anal. Calcd for C55H69NO17
-
Si2þH2O: C, 61.60; H, 6.49; N, 1.31. Found: C, 61.50; H, 6.42; N, 1.33.
4.10. 20,30,40,60-Tetra-O-acetyl- -galactopyranosyl-(10-4)-2-
b-D
acetamido-1,6-di-O-tert-butyldiphenylsilyl-2-deoxy-b-D-
glucopyranose (8c)
4.8. 20,30,40,60-Tetra-O-acetyl-
acetamido-3-O-ethoxycarbonyl-1,6-di-O-tert-
butyldiphenylsilyl-2-deoxy- -glucopyranose (8a)
b-
D
-galactopyranosyl-(10-4)-2-
b-D
Allyl carbonate (8b, 928 mg, 0.846 mmol) was dissolved in
degassed THF (12 mL) under Ar. To the stirred solution, morpholine
(2 mL) and a catalytic amount of (Ph3P)4Pd were added, and the
mixture was stirred at 45 ꢀC for 12 h. The reaction was monitored
by silica gel TLC and developed with hexane–EtOAc (1:5). The
mixture was diluted with EtOAc and washed with brine, dried over
Na2SO4, and concentrated in vacuo. The residue was purified by
silica gel column chromatography (40 g). Elution with hexane–
EtOAc (3:1) and the subsequent recrystallization from hexane and
The oxazolidinone (7b, 80.6 mg, 0.0765 mmol) and LiCl (9.7 mg,
0.0229 mmol, 3 equiv) were dissolved in a mixture of EtOH and THF
(1:1, 3.2 mL). The mixture was cooled to ꢁ15 ꢀC and LiOH aq so-
lution (1.0 M, 0.01 mL, 1.3 equiv) was added. The reaction was
monitored by silica gel TLC and developed with hexane–EtOAc
(1:2). After stirring for 10 min, the mixture was poured into the
saturated NH4Cl solution and extracted with EtOAc. The organic
phase was washed with brine, dried over Na2SO4, and concentrated
in vacuo. The residue was purified by silica gel column chroma-
tography (4 g). Elution with hexane–EtOAc (2:1) afforded 8a
EtOAc afforded 8c (656 mg, 65% from 7b) as colorless prisms, mp
27
222–223 ꢀC. [
a]
ꢁ20.7 (c 0.950, CHCl3); 1H NMR (400 MHz, CDCl3)
D
(43.0 mg, 53%) as amorphous solid. 1H NMR (400 MHz, CDCl3)
d:
d: 1.08 (s, 9H, t-Bu), 1.10 (s, 9H, t-Bu), 1.68 (s, 3H, Ac), 1.86 (s, 3H, Ac),
1.01 (s, 9H, t-Bu), 1.04 (s, 9H, t-Bu), 1.23 (t, 3H, Et-CH3), 1.64 (s, 3H,
Ac), 1.75 (s, 3H, Ac), 1.89 (s, 3H, Ac), 1.97 (s, 3H, Ac), 2.02 (s, 3H, Ac),
2.93 (ddd, J4,5¼8.8 Hz, J5,6a¼2.0 Hz,0J5,6b¼2.0 Hz, 1H, H5), 3.60 (dd,
1.96 (s, 3H, Ac), 2.05 (s, 3H, Ac), 2.11 (s, 3H, Ac), 2.99 (dd, J4,5¼9.3 Hz,
J5,6a¼0.2 Hz, 1H, H5), 3.60 (dd, J2,3¼9.8 Hz, J3,4¼8.3 Hz, 1H, H3), 3.63
(s, 1H, OH), 3.65 (dd, J6a,6b¼11.2 Hz, 1H, H6a), 3.76 (d, 1H, H6b), 3.81
0
0
0
0
0
0
0
0
J5 ,6a ¼6.8 Hz, J5 ,6b ¼7.3 Hz, 1H, H5 ), 3.65 (dd, J6a,6b¼11.2 Hz, 1H,
(t, J5 ,6 ¼6.4 Hz, 1H, H5 ), 3.85–3.96 (m, 2H, H2, H4), 4.09 (d, 2H, H6 ,
0
0
H6a), 3.75 (dd, 1H, H6b), 3.97 (dd, J6a ,6b ¼11.2 Hz, 1H, H6a ), 4.03
H60), 4.59 (d, J1 ,2 ¼7.8 Hz, 1H, H1 ), 4.62 (d, J1,2¼7.8 Hz, 1H, H1), 4.85
0
0
0
0
(dd, 1H, H6b0), 4.07–4.18 (m, 4H, H2, H4, Et–CH2), 4.47 (d,
(dd, J2 ,3 ¼10.3 Hz, J3 ,4 ¼3.4 Hz, 1H, H3 ), 5.08 (dd, 1H, H2 ), 5.15 (d,
0
0
0
0
0
0
J1,2¼7.8 Hz, 1H, H1), 4.51 (d, J1 ,2¼8.3 Hz, 1H, H10), 4.62 (dd,
J2,NH¼8.8 Hz, 1H, NH), 5.30 (d, 1H, H40), 7.20–7.68 (20H, aromatic);
0
J2,3¼10.3 Hz, J3,4¼8.8 Hz, 1H, H3), 0 4.72 (dd, J3 ,4 ¼2.9 Hz,
13C NMR (100 MHz, CDCl3)
d: 19.2, 19.5, 20.5, 20.6, 20.7, 20.7, 23.7,
0
0
0
0
0
J2 ,3 ¼10.4 Hz, 1H, H3 ), 4.91 (d, 1H, H2 ), 5.17 (d, J2,NH¼9.8 Hz, 1H,
26.8, 27.0, 57.8, 61.1, 61.4, 66.8, 68.7, 70.6, 71.1, 72.2, 74.5, 78.8, 95.7,
100.4, 127.4, 127.6, 127.7, 127.9, 129.7, 129.9, 132.2, 132.8, 133.0,
133.4, 135.4, 135.8, 135.8, 135.8, 169.0, 169.7, 169.9, 170.0, 170.3; the
signals between 26.8 and 27.0 included totally 6 carbons, and ones
between 127.4 and 135.8 included totally 24 carbons; IR nmax 3405,
2932, 1757, 1736, 1692 cmꢁ1. Anal. Calcd for C54H69NO15Si2: C,
63.07; H, 6.76; N, 1.36. Found: C, 62.75; H, 6.81; N, 1.29.
NH), 5.20 (d, 1H, H40), 7.15–7.61 (20H, aromatic); 13C NMR
(100 MHz, CDCl3) d: 14.3, 19.1, 19.5, 20.6, 20.7, 20.7, 20.7, 23.4, 26.7,
26.9, 55.2, 60.9, 61.2, 64.1, 66.8, 69.0, 70.4, 70.9, 74.1, 74.9, 76.5, 95.9,
100.0,127.4,127.6,127.7,127.9,129.7,129.8,129.9,132.1,132.6,132.8,
133.3, 135.4, 135.8, 135.8, 135.8, 155.0, 168.9, 169.6, 169.7, 170.0,
170.3; the signals between 26.7 and 26.9 included totally 6 carbons,
and ones between 127.4 and 135.8 included totally 24 carbons; IR
nmax 2932, 1754, 1671 cmꢁ1
.
4.11. 20,30,40,60-Tetra-O-acetyl-
acetamido-3-O-trichloroethoxycarbonyl-1,6-di-O-tert-
butyldiphenylsilyl-2-deoxy- -glucopyranose (8d)
b-D
-galactopyranosyl-(10-4)-2-
4.9. 20,30,40,60-Tetra-O-acetyl-
acetamido-3-O-allyloxycarbonyl-1,6-di-O-tert-
butyldiphenylsilyl-2-deoxy- -glucopyranose (8b)
b-
D
-galactopyranosyl-(10-4)-2-
b-D
b-D
In a similar manner as described for 8a, the oxazolidinone (7b,
824 mg, 0.782 mmol) and LiCl (130 mg, 3.13 mmol, 4 equiv) were
In a similar manner as described above, the oxazolidinone (7b,
1.04 g, 0.984 mmol) and LiCl (125 mg, 2.95 mmol, 3 equiv) were
dissolved in a mixture of allyl alcohol and THF (1:3, 15 mL). The
mixture was cooled to 0 ꢀC and LiOH aq solution (1.0 M, 1.0 mL,
1.0 equiv) was added. The reaction was monitored by silica gel TLC
and developed with hexane–EtOAc (1:1). After stirring for 25 min,
the mixture was quenched, and the extraction and chromato-
dissolved in a mixture of 2,2,2-trichloroethanol (0.23 mL,
1.56 mmol, 2.0 equiv) and THF (8 mL). The mixture was cooled to
0 ꢀC and LiOH aq solution (1.0 M, 0.78 mL,1.0 equiv) was added. The
reaction was monitored by silica gel TLC and developed with hex-
ane–EtOAc (1:1). After stirring for 1 h, the mixture was quenched,
and the extraction and chromatographic purification provided 8d
quantitatively. 1H NMR (400 MHz, CDCl3)
d: 1.02 (s, 9H, t-Bu), 1.05
graphic purification provided 8b (928 mg, 86%) as colorless fine
(s, 9H, t-Bu), 1.66 (s, 3H, Ac), 1.71 (s, 3H, Ac), 1.89 (s, 3H, Ac), 1.97 (s,
3H, Ac), 2.05 (s, 3H, Ac), 2.92 (ddd, J4,5¼8.8 Hz, J5,6a¼2.0 Hz,
27
needles, mp 108–110 ꢀC. [
a
]
D
ꢁ31.5 (c 1.00, CHCl3); 1H NMR
0
0
0
0
0
(400 MHz, CDCl3)
d: 1.01 (s, 9H, t-Bu), 1.04 (s, 9H, t-Bu), 1.64 (s, 3H,
J5,6b¼2.0 Hz, 1H, H5), 3.59 (dd, J5 ,6a ¼6.8 Hz, J5 ,6b ¼6.8 Hz, 1H, H5 ),
Ac), 1.73 (s, 3H, Ac), 1.89 (s, 3H, Ac), 1.97 (s, 3H, Ac), 2.03 (s, 3H, Ac),
3.67 (dd, J6a,6b¼11.2 Hz, 1H, H6a), 3.75 (dd, 1H, H6b),0 3.98 (dd,
0
0
0
0
0
0
2.93 (ddd, J4,5¼8.8 Hz, 1H, H5), 3.60 (t, J5 ,6 ¼6.8 Hz, 1H, H5 ), 3.65
(dd, J5,6a¼2.0 Hz, J6a,6b¼11.2 Hz, 1H, H6), 3.75 (dd, J5,6b¼2.0 Hz, 1H,
H6), 3.97–4.02 (m, 2H, H60, H60), 4.10–4.17 (m, 2H, H2, H4), 4.46 (d,
J6a ,6b ¼11.2 Hz, 1H,0H6a ), 4.05–4.19 (m, H2, H4, 3H, H6b ), 4.52 (d,
0
0
J1 ,2 ¼7.8 Hz,1H, H1 ), 4.56 (d, J1,2¼7.3 Hz,1H, H1), 4.60 (d, J¼11.7 Hz,
0
0
0
0
0
1H, Troc–CH2), 4.70 (dd, J2 ,3 ¼10.3 Hz, J3 ,4 ¼3.4 Hz, 1H, H3 ), 4.75

Y. Nagai et al. / Tetrahedron 64 (2008) 9599–9606
9605
(dd, J2,3¼9.8 Hz, J3,4¼8.6 Hz, 1H, H3), 4.80 (d, 1H, Troc–CH2), 4.89
(dd, 1H, H20), 5.15 (d, 1H, J2,NH¼9.3 Hz, NH), 5.20 (d, 1H, H40), 7.14–
7.62 (20H, aromatic).
methoxide was added. The reaction was monitored by silica gel TLC
and developed with hexane–EtOAc (1:5). After stirring for 4 h at
room temperature, the reaction was quenched by the addition of
IR-120 resin (Hþ form). The insoluble materials were filtered off and
the filtrate was concentrated in vacuo. The residue was passed
Without any quenching and isolation, the trichloroethyl car-
bonate 8d as above was directly deprotected as follows. After stir-
ring for 1 h of the mixture for preparing 8d, AcOH (4 mL), and Zn
dust (1.2 g) were added. After the complete consumption of the
substrate was confirmed by TLC analysis, developed with hexane–
EtOAc (1:5), the mixture was neutralized with saturated NaHCO3 aq
solution. The mixture was then filtered to remove insoluble ma-
terials and the filtrate was extracted with EtOAc. The organic so-
lution was washed with brine, dried over Na2SO4, and concentrated
in vacuo. The residue was passed through a short column of silica
gel, followed by the recrystallization from hot EtOAc afforded 8c
(720 mg, 90% from 7b).
through a short column of silica gel to afford pure 10b (72 mg, 92%)
25
as amorphous solid. [
a]
ꢁ78.0 (c 0.950, MeOH); 1H NMR
D
(400 MHz, CDCl3) d:000.94 (s, 9H, t-Bu), 1.01 (s, 9H, t-Bu), 1.08 (d,
00 00
J5 ,6 ¼6.8 Hz, 3H, H6 ), 1.52 (s, 3H, Ac), 2.75 (d, J4,5¼9.3 Hz, 1H, H5),
0
00
0
0
0
0
2.96 (J2 ,3 ¼9.3 Hz, J3 ,4 ¼3.1 Hz, 1H, H3 ), 3.07 (br, 1H, H4 ), 3.33 (dd,
0
0
0
0
J1 ,2 ¼7.8 Hz, 1H, H2 ), 3.60–3.93 (m, 10H, H1, H2, H3, H6, H6, H4 ,
H50, H60, H60, H300), 3.99 (dd, J1 ,2 ¼2.5 Hz, J2 ,3 ¼9.8 Hz, 1H, H2 ),
4.08 (dd, J3,4¼8.8, 1H, H4), 4.22 (q, 1H, H500), 4.42 (d, 1H, H10), 4.52–
4.83 (m, 6H, Bn–CH2ꢂ3), 5.38 (d, 1H, H100), 5.45 (1H, d, J2,NH¼8.3 Hz,
00
00 00
00 00
NH), 7.06–7.58 (35H, aromatic); 13C NMR (100 MHz, CDCl3)
d: 16.8,
19.1, 19.5, 23.6, 26.7, 26.9, 27.0, 29.7, 61.6, 63.2, 67.3, 70.5, 71.7, 71.9,
72.7, 73.6, 74.3, 74.9, 75.1, 75.3, 76.2, 77.1, 77.2, 77.5, 79.8, 96.2, 96.7,
100.5, 127.1, 127.3, 127.3, 127.4, 127.5, 127.6, 127.6, 128.0, 128.0, 128.1,
128.2, 128.3, 128.3, 128.3, 128.5, 129.5, 129.6, 129.7, 132.5, 132.7,
133.4, 133.6, 135.5, 135.6, 135.6, 135.8, 135.8, 135.9, 137.7, 138.2,
138.3, 138.4, 138.5, 139.1, 170.0; the signals between 26.7 and 29.7
included totally 6 carbons, and ones between 127.1 and 139.1 in-
cluded totally 42 carbons; IR nmax 3411, 2931,1658 cmꢁ1. Anal. Calcd
for C73H89NO15Si2þH2O: C, 67.72; H, 7.08; N, 1.08. Found: C, 67.97;
H, 7.07; N, 1.17.
4.12. 20,30,40,60-Tetra-O-acetyl-
(10-4)-200,300,400-tri-O-benzyl-
acetamido-1,6-di-O-tert-butyldiphenylsilyl-2-deoxy-
-glucopyranose (10a)
b
-
D
-galactopyranosyl-
a-L
-fucopyranosyl-(100-3)-2-
b-D
The acceptor (8c, 298 mg, 0.290 mmol) was dissolved in CH2Cl2
(6.0 mL) containing MS 4 Å (800 mg) under Ar. After stirring for 2 h,
NIS (200 mg, 0.889 mmol) and TfOH (2 L, 0.029 mmol) were
m
added and the reaction mixture was cooled to 0 ꢀC. To the mixture,
the fucosyl donor (9a, 235 mg, 0.435 mmol) dissolved in benzene
(6 mL) was added dropwise over 30 min. The reaction was moni-
tored by silica gel TLC and developed with hexane–EtOAc (3:2). The
reaction was quenched by addition of Et3N. The solids were filtered
off and the filtrate was concentrated in vacuo. The residue was
diluted with EtOAc, washed with saturated Na2S2O3 aq solution and
brine, dried over Na2SO4, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (12 g). Elution
with hexane–EtOAc (4:1) afforded inseparable anomeric mixture of
10a (430 mg, ca. 10:1) quantitatively as amorphous solid. Re-
4.14.
b-D a-L
-Galactopyranosyl-(10-4)- -fucopyranosyl-(100-3)-2-
acetamido-1,6-di-O-tert-butyldiphenylsilyl-2-deoxy-b-D-
glucopyranose (10c)
A mixture of 10b (87.0 mg, 0.0681 mmol) and Pd(OH)2 (30 mg)
in EtOH (8.0 mL) was vigorously stirred under H2 at 40 ꢀC. The re-
action was monitored by silica gel TLC and developed with CHCl3–
MeOH (7:1). After stirring for 24 h, the catalyst was removed by
filtration. The filtrate and washings were concentrated and the
residue was passed through a short column of silica gel to afford 10c
(73 mg, quantitative) as colorless solid. This was recrystallized from
crystallization from hexane and EtOAc afforded pure a-anomer of
28
10a in regard to fucosyl unit as fine needles, mp 93–95 ꢀC. [
a]
D
ꢁ38.3 (c 1.20, CHCl3); 1H NMR (400 MHz, CDCl3)00 d: 0.97 (s, 9H, t-
hot EtOH to give 10c (44.2 mg, 65%) as colorless prisms, mp 255–
00 00
Bu), 1.04 (s, 9H, t-Bu), 1.10 (d, J5 ,6 ¼6.4 Hz, 3H, H6 ), 1.46 (s, 3H, Ac),
27
259 ꢀC. [
DMSO)
a
d
]
ꢁ49.8 (c 1.00, CHCl3/MeOH¼1:1); 1H NMR (400 MHz,
D
1.67 (s, 3H, Ac), 1.78 (s, 3H, Ac), 1.86 (s, 3H, Ac), 1.95 (s, 3H, Ac), 2.85
: 0.94–0.98 (m, 12H, H600, t-Bu), 1.01 (s, 9H, t-Bu), 1.76 (s,
0
0
(dd, J4,5¼8.3 Hz, J5,6a¼0.2 Hz, 1H, H5), 3.46 (dd, J5 ,6a ¼6.4 Hz,
0
0
0
3H, Ac), 2.83 (d, J4,5¼9.3 Hz, 1H, H5), 3.08 (t, J5 ,6 ¼6.4 Hz, 1H, H5 ),
0
0
0
00 00
J5 ,6b ¼6.4 Hz, 1H, H5 ), 3.52 (m, 1H, H2), 3.63 (d, J3 ,4 ¼2.0 Hz, 1H,
0
0
0
0
0
0
0
3.11 (dd, J2 ,3 ¼9.3 Hz, J3 ,4 ¼2.4 Hz, 1H, H3 ), 3.26 (dd, J1 ,2 ¼7.8 Hz,
1H, H20), 3.32–3.60 (m, 10H, H2, H3 H6a, H6b, H40, H60a, H60b, H200,
H300, H400), 3.90 (d, J3,4¼8.8 Hz,1H, H4), 4.19 (d, J1,2¼10.3 Hz,1H, H1),
H400), 3.69 (dd, J6a,6b¼11.7 Hz, 1H, H6a), 3.75 (d, 1H, H6b), 3.88 (dd,
0
00
0
0
00 00
J6a ,6b ¼10.7 Hz, 1H, H6 ), 3.91 (dd, J2 ,3 ¼10.0 Hz, 1H, H3 ), 3.90–
4.09 (m, 5H, H1, H3, H4, H60, H200), 4.49 (1H, q, H500), 4.50 (d0d,
4.54 (d, 1H, H10), 4.72 (q, J5 ,6 ¼6.8 Hz, 1H, H500), 4.85 (d,
00 00
0
0
0
0
0
0
0
J2 ,3 ¼10.3 Hz, J3 ,4 ¼4.4 Hz, 1H, H3 ), 4.57 (d, J1 ,2 ¼8.8 Hz, 1H, H1 ),
J1 ,2 ¼3.4 Hz, 1H, H100), 7.07–7.62 (20H, aromatic), 8.00 (d,
00 00
4.60–4.90 (m, 7H, H20, Bn–CH2ꢂ3), 4.96 (d, J1 ,2 ¼2.9 Hz, 1H, H1 ),
00
00 00
J2,NH¼9.2 Hz, 1H, NH); 13C NMR (100 MHz, DMSO)
d: 16.4, 18.8, 19.2,
5.15 (d, 1H, H40), 5.46 (d, J2,NH¼7.8 Hz, 1H, NH), 7.06–7.61 (35H,
23.1, 26.5, 26.7, 59.4, 59.4, 61.4, 65.6, 67.0, 68.3, 69.2, 70.7, 71.2, 72.8,
72.8, 73.4, 74.5, 75.3, 98.8, 98.8, 101.7, 127.3, 127.4, 127.7, 129.4,
129.5, 129.6, 129.7, 132.1, 132.2, 133.2, 133.2, 135.0, 135.1, 135.3,
135.4, 169.4; the signals between 26.5 and 26.7 included totally 6
carbons, and ones between 127.3 and 135.4 included totally 24
aromatic); 13C NMR (100 MHz, CDCl3)
d: 16.8, 19.2, 19.4, 20.5, 20.5,
20.6, 20.7, 23.3, 26.8, 26.9, 26.9, 29.4, 44.7, 60.5, 61.5, 66.2, 66.6,
66.6, 68.7, 70.2, 70.6, 72.6, 73.5, 74.0, 74.2, 75.0, 76.4, 77.2, 80.1, 97.8,
97.8, 98.9, 126.9, 127.2, 127.4, 127.4, 127.4, 127.6, 127.7, 128.0, 128.1,
128.2, 128.2, 128.4, 129.5, 129.6, 129.7, 130.0, 132.0, 132.7, 133.4,
133.5, 135.2, 135.6, 135.8, 135.9, 138.5, 138.8, 168.8, 169.6, 169.6,
169.7, 169.9; the signals between 26.8 and 29.4 included totally 6
carbons, and ones between 126.9 and 138.8 included totally 42
carbons; IR nmax 3429, 2931, 1667 cmꢁ1
. Anal. Calcd for
C
52H71NO15Si2þH2O: C, 60.97; H, 7.18; N, 1.37. Found: C, 61.05; H,
7.26; N, 1.25.
carbons; IR nmax 2932, 1756, 1674 cmꢁ1
81H97NO19Si2þH2O: C, 66.51; H, 6.82; N, 0.96. Found: C, 66.59; H,
7.04; N, 0.90.
. Anal. Calcd for
C
Acknowledgements
The authors thank Professor David Crich of Department of
Chemistry, University of Illinois at Chicago, for his valuable dis-
cussion. Professor Shigeru Nishiyama’s encouragement on this
study was acknowledged with thanks. This work was supported
both by a Grant-in-Aid for Scientific Research (No. 18580106) and
‘High-Tech Research Center’ Project for Private Universities:
matching fund subsidy 2006–2011 from the Ministry of Education,
4.13.
fucopyranosyl-(100-3)-2-acetamido-1,6-di-O-tert-
butyldiphenylsilyl-2-deoxy- -glucopyranose (10b)
b-D a-
-Galactopyranosyl-(10-4)-200,300,400-tri-O-benzyl-
b-D
To the stirred solution of trisaccharide 10a (89.3 mg,
0.0618 mmol) in MeOH (2 mL), a catalytic amount of sodium

9606
Y. Nagai et al. / Tetrahedron 64 (2008) 9599–9606
17. Nicolaou, K. C.; Hummel, C. W.; Buckovich, N. J.; Wong, C.-H. J. Chem. Soc., Chem.
Commun. 1991, 870–872.
18. Kameyama, A.; Ishida, H.; Kiso, M.; Hasegawa, A. J. Carbohydr. Chem. 1991, 10,
549–560.
Culture, Sports, Science, and Technology, Japan, and acknowledged
with thanks.
19. Numomura, S.; Iida, M.; Numata, M.; Sugimoto, M.; Ogawa, T. Carbohydr. Res.
1994, 263, C1–C6.
References and notes
20. Toepfer, A.; Kinzy, W.; Schmidt, R. R. Liebigs Ann. Chem. 1994, 449–464.
21. Nishimura, S.-I.; Matsuoka, K.; Furuike, T.; Nishi, N.; Tokura, S.; Nagami, K.;
Maruyama, S.; Kurita, K. Macromolecules 1994, 27, 157–163.
22. Danishefsky, S. J.; Gervay, J.; Peterson, J. M.; McDonald, F. E.; Koseki, K.; Griffith,
D. A.; Oriyama, T.; Marsden, S. P. J. Am. Chem. Soc. 1995, 117, 1940–1953.
23. Ehara, T.; Kameyama, A.; Yamda, Y.; Ishida, H.; Kiso, M.; Hasegawa, A. Carbo-
hydr. Res. 1996, 281, 237–252.
1. Ito, N.; Tokuda, Y.; Ohba, S.; Sugai, T. Bull. Chem. Soc. Jpn. 2004, 77, 1181–1186.
2. Bernlind, C.; Bennett, S.; Oscarson, S. Tetrahedron: Asymmetry 2000, 11, 481–492.
3. Mong, T. K.-K.; Huang, C.-Y.; Wong, C.-H. J. Org. Chem. 2003, 68, 2135–2142.
4. Nashed, E. M.; Glaudemans, C. P. J. J. Org. Chem. 1987, 52, 5255–5260.
5. Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1993, 58, 3791–3793.
6. Wolfrom, M. L.; Conigliaro, P. J. Carbohydr. Res. 1969, 11, 63–76.
´
´
24. Pohl, N. L.; Kiessling, L. L. Tetrahedron Lett. 1997, 38, 6985–6988.
25. Ellervik, U.; Magnusson, G. J. Org. Chem. 1998, 63, 9314–9322.
7. Arias-Perez, M. S.; Lopez, M. S.; Santos, M. J. J. Chem. Soc., Perkin Trans. 2 2002,
1549–1552.
´
26. de la Fuente, J. M.; Penades, S. Tetrahedron: Asymmetry 2002, 13, 1879–1888.
8. Kerns, R. J.; Zha, C.; Benakli, K.; Linag, Y.-Z. Tetrahedron Lett. 2003, 44, 8069–
8072.
9. Crich, D.; Vinod, A. U. J. Org. Chem. 2005, 70, 1291–1296.
10. Asano, M.; Nagasawa, C.; Suzuki, M.; Nishiyama, S.; Sugai, T. Biosci. Biotechnol.
Biochem. 2005, 69, 145–148.
27. Nishida, Y.; Turumi, T.; Sasaki, K.; Watanabe, K.; Dohi, H.; Kobayashi, K. Org. Lett.
2003, 5, 3775–3778.
28. Tanaka, H.; Matoba, N.; Tsukamoto, H.; Takimoto, H.; Yamada, H.; Takahashi, T.
Synlett 2005, 824–848.
29. Komba, S.; Ishida, H.; Kiso, M.; Hasegawa, A. Bioorg. Med. Chem. 1996, 4, 1833–
1847.
30. Schmidt, R. R.; Toepfer, A. Tetrahedron Lett. 1991, 32, 3353–3356.
31. Toepfer, A.; Schmidt, R. R. J. Carbohydr. Chem. 1993, 12, 809–822.
32. Kim, K. S.; Kim, J. H.; Lee, Y. J.; Lee, Y. J.; Park, J. J. Am. Chem. Soc. 2001, 123, 8477–
8488.
11. Amvam-Zollo, P.-H.; Sinay¨, P. Carbohydr. Res. 1986, 150, 199–212.
12. Benakli, K.; Zha, C.; Kerns, R. J. J. Am. Chem. Soc. 2001, 123, 9461–9462.
13. Wei, P.; Kerns, R. J. Tetrahedron Lett. 2005, 46, 6901–6905.
14. Crich, D.; Vinod, A. U. Org. Lett. 2003, 5, 1297–1300.
15. Niwayama, S.; Rimkus, A. Bull. Chem. Soc. Jpn. 2005, 78, 498–500.
16. Carvalho de Souza, A.; Halkes, K. M.; Meeldijk, J. D.; Verkleij, A. J.; Vliegenhtart,
J. F. G.; Kamerling, J. P. Eur. J. Org. Chem. 2004, 4323–4339.
33. Crich, D.; Li, W. J. Org. Chem. 2007, 72, 2387–2391.