Extended applications of di-tert-butylsilylene-directed α-predominant galactosylation compatible with C2-participating groups toward the assembly of various glycosides

Article abstract of DOI:10.1002/chem.200600832

The high versatility of di-tert-butylsilylene(DTBS)-directed α-predominant galactosylation have been extended to the construction of difficult glycan sequences. First, to investigate the compatibility of the α-predominant reaction with various glycosylation systems a variety of 4,6-O-DTBS-tethered galactosaminyl or galactosyl donors were synthesized efficiently, which have C2-participating groups with a wide variety of leaving groups such as alkylsulfenyl, halide, trichloroacetimidate groups. The results of the detailed examination of the glycosylation reaction using the glycosyl donors showed the wide scope of the 4,6-DTBS-directed α-galactosylation. In the next step, the stereoselective construction of α GalN-Ser/Thr sequences was examined by employing the DTBS-directed glycosylation. As a result, various types of serine and threonine derivatives were glycosylated α-selectively, producing α-GalN-Ser/Thr sequences in high yields. Moreover, the DTBS-directed galactosylation was successfully applied for the synthesis of α-tetrasaccharyl-Ser segment of glycophorin A.

Full text of DOI:10.1002/chem.200600832

DOI: 10.1002/chem.200600832
Extended Applications of Di-tert-butylsilylene-Directed a-Predominant
Galactosylation Compatible with C2-Participating Groups toward the
Assembly of Various Glycosides
[b]
Akihiro Imamura,[b] Akiyoshi Kimura,[b] Hiromune Ando,*[a] HideharuIshida, and
Makoto Kiso*[b]
Abstract: The high versatility of di-tert-
butylsilylene(DTBS)-directed a-pre-
alkylsulfenyl, halide, trichloroacetimi-
date groups. The results of the detailed
examination of the glycosylation reac-
tion using the glycosyl donors showed
the wide scope of the 4,6-DTBS-direct-
ed a-galactosylation. In the next step,
the stereoselective construction of a-
GalN-Ser/Thr sequences was examined
by employing the DTBS-directed gly-
cosylation. As a result, various types of
serine and threonine derivatives were
glycosylated a-selectively, producing a-
GalN-Ser/Thr sequences in high yields.
Moreover, the DTBS-directed galacto-
sylation was successfully applied for
the synthesis of a-tetrasaccharyl-Ser
segment of glycophorin A.
ACHTREUNG
dominant galactosylation have been ex-
tended to the construction of difficult
glycan sequences. First, to investigate
the compatibility of the a-predominant
reaction with various glycosylation sys-
tems a variety of 4,6-O-DTBS-tethered
galactosaminyl or galactosyl donors
were synthesized efficiently, which
have C2-participating groups with a
wide variety of leaving groups such as
Keywords: carbohydrates · glycosy-
lation · neighboring-group effect ·
oligosaccharides
Introduction
ical profiles are spurring efforts toward the synthesis of a-
galactosyl glycan sequences.[2]
a-Gal-type linkages are ubiquitously found in natural oligo-
saccharides such as globoseries and isogloboseries glycoli-
a-Gal-type linkages can be established using the anomeric
effect, often with the aid of the etheral solvent effect.[2c] To
minimize b-isomer formation, C2 hydroxyl or amino group
protection is limited to the nonparticipating mode. There-
fore, despite the elaborate procedure, the synthesis of 2-
azido-galactosyl donors became a part of the standard pro-
tocol to generate a-galactosaminyl linkages.[2a] However, the
anomeric selectivity and yield of conventional glycosylation
varies greatly depending on the structures of the coupling
partners; therefore difficult separation procedures are occa-
sionally required. In particular, this drawback causes the
drastic decrease in the overall yield of the a-galactosaminyl
glycan synthesis. In this context, Schmidt and co-worker
have described the nitroglycal-based approach toward the
synthesis of various mucin-type O-glycans to circumvent the
arduous preparation of the 2-azido-galactosyl donor.[3] Very
recently, Boons and co-workers have developed a novel gen-
eral method toward 1,2-cis glycosides synthesized by the
neighboring-group participation of the (1S)-phenyl-2-(phe-
nylsulfanyl)ethyl group at the C2-hydroxyl position.[4]
pids (Gala
A
teins (GalNHAca(1!)Ser/Thr core sequences). These oli-
gosaccharides are involved in a variety of important biologi-
cal processes[1] such as recognition of toxin receptors, the
innate immune response, malignant alteration. These biolog-
[a] Dr. H. Ando
Division of Instrumental Analysis
Life Science Research Center, Gifu University
1-1 Yanagido, Gifu-shi, Gifu 501-1193 (Japan)
Fax : (+81)58-293-2617
E-mail: hando@cc.gifu-u.ac.jp
[b] Dr. A. Imamura, A. Kimura, Prof. H. Ishida, Prof. M. Kiso
Department of Applied Bioorganic Chemistry
Faculty of Applied Biological Sciences, Gifu University and CREST
Japan Science and Technology Corporation (JST)
1-1 Yanagido, Gifu-shi, Gifu 501-1193 (Japan)
Fax : (+81)58-293-2916
E-mail: kiso@cc.gifu-u.ac.jp
Previously, we reported that the phenylthio glycoside of
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
4,6-di-tert-butylsilylene(DTBS)-protected galactose performs
A
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Chem. Eur. J. 2006, 12, 8862 – 8870

FULL PAPER
a-selective glycosidation despite the presence of participat-
ing groups at the C2 position (Scheme 1).[5] In this study, we
demonstrate that the new glycosylation method is a compre-
hensive and powerful method for the synthesis of a-galacto-
syl and galactosaminyl glycans.
indicated by the 1H NMR spectrum (d 5.76; d, J1,F
=
52.9 Hz), probably a result of the DTBS effect during the
fluorination. For the synthesis of other glycosyl donors, com-
pound 3 was subsequently hemiacetalized by NBS in aque-
ous acetone to produce 6. Then, the C1 hydroxyl in 6 was
transformed into trichloroacetimidate to form 7,[7] or acety-
lated to yield acetoxy derivative 8, which, upon the treat-
ment with 25% HBr solution in acetic acid, afforded galac-
tosaminyl bromide 9 with again predominant a-stereochem-
istry. Other types of glycosyl donors, namely, 10–12[8] and
13[5b] were also prepared in high yields. These compounds
were used with various coupling partners, namely, com-
pounds 14–22 (Figures 1 and 2).
Scheme 1. Di-tert-butylsilylene-directed a-galactosylation. Troc=2,2,2-tri-
chloroethoxycarbonyl, Phth=phthaloyl, Bz=benzoyl, NIS=N-iodosucci-
nimide, TfOH=trifluoromethanesulfonic acid, and MS=molecular
sieves.
Results and Discussion
Among the compatible protecting groups of the C2-amino
group, 2,2,2-trichloroethoxycarbonyl (Troc) was selected be-
cause of its easy introduction and chemoselective cleavage.
For C2 hydroxyl protection, a conventional benzoyl group
was used. The installation of the DTBS group on the 4,6-hy-
droxyl groups of the galactosides proceeded almost quanti-
tatively. As exemplified in Scheme 2, the thioglycosides of
Figure 1. DTBS-bridged galactosyl donors used in this study. Bz=benzo-
yl.
Figure 2. Various glycosyl acceptors used in this study. Hex=n-hexyl,
Cbz=benzyloxycarbonyl, Fmoc=9-fluorenylmethoxycarbonyl, All=
allyl, Pfp=pentafluorophenyl.
Scheme 2. a) i) DTBS(OTf)2/pyr, RT, 3 min; ii) subsequent addition of
G
TrocCl, 30 min, 93% (3) and 54% (4); b) 3, DAST, NBS/CH2Cl2, ꢀ158C,
5 h, 88%; c) 3, NBS/aq. acetone, RT, 30 min, 83%; d) 6, CCl3CN, DBU,
CH2Cl2, 08C, 30 min, 70%; e) 6, Ac2O, pyr, RT, 1 h, 94%; f) 8, 25% HBr
As summarized in Table 1, we have explored the versatili-
ty of the DTBS-directed a-galactosylation with a special
focus on a-galactosaminyl bond formation. First, the sily-
lene-bridged glycosyl donor 3 reacted with glucosyl acceptor
14 in various solvents affected by NIS/TfOH[9] (entries 1–5).
As a result, the a-selectivity of this DTBS-directed coupling
was found to be independent of solvent effects; thus, in all
cases the a-anomer 23 was stereoselectively produced in
84% to 100% de. Notably even the glycosidation in
CH3CN[10] exclusively yielded the a-glycoside (23%, 100%
de).
Next, in Table 2, various leaving groups such as the meth-
ylsulfenyl,[9,11] fluoride,[12,13] and trichloroacetimidate[14]
groups were examined. The glycosyl donors 3–7 were treat-
ed with 2-adamantanol (15). All stereochemical outcomes in
entries 1–7 were predominantly a with sufficiently high
in AcOH, CH2Cl2, RT, 2 h, 86%. DB=di-tert-butyl, DTBS(OTf)2 =di-
A
tert-butylsilyl bis(trifluoromethanesulfonate), DAST=(diethylamino)sul-
fur trifluoride, NBS=N-bromosuccinimide, DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene.
N-Troc-protected galactosamine 1 and 2, which were easily
prepared from galactosamine hydrochloride 1,[5b] successive-
ly reacted with DTBS(OTf)2[6] and 2,2,2-trichloroethyl chloro-
formate (TrocCl) in pyridine to produce 4,6-DTBS-protect-
ed 3 and 4 in almost quantitative yield, respectively. Further,
the phenylsulfenyl group of 3 could be successfully replaced
with fluoride by action of N-bromosuccinimide (NBS) and
(diethylamino)sulfur trifluoride (DAST), yielding 5 in 88%
yield. The anomeric arrangement of 5 was exclusively a, as
Chem. Eur. J. 2006, 12, 8862 – 8870
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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H. Ando, M. Kiso et al.
Table 1. Glycosidation of galactosyl donor 3 with glucosyl acceptor 14
under various condition.
Table 2. Examination of various leaving groups in DTBS-directed galac-
tosylation.
Entry Donor ROH
Promoter
T
t
Product Yield (a/
b)[a] [%]
[8C] [h]
1
2
3
4
3
3
4
5
15
15
15
15
NIS/TfOH
DMTST[b]
NIS/TfOH
SnCl2/
0
0
0
0
0.5
21
0.5
1.5
24
24
24
24
91:7
83:15
87:11
82:0
Entry
1[b]
2
3
4
Solvent
T [8C]
t [h]
Yield (a/b)[a] [%]
CH2Cl2
n-hexane
PhMe
CH3NO2
CH3CN
0
RT
0
0
0.5
8.0
0.5
0.5
22
96:3
58:3
91:7
93:6
23:0
[c]
AgClO4
5
5
15
Cp2HfCl2/
AgOTf[d]
TMSOTf
BF3·OEt2
ꢀ20 0.5
24
71:0
5
0!40
6
7
8
9
10
11
7
7
9
3
3
15
15
15
0
0
0.5
0.5
24
24
25
26
27
28
91:8
68:9
6:77
90:9
90:5
95:0
[a] Isolated yield. [b] ref. [5a]. Hex=n-hexyl
Ag-silicate[e] ꢀ20 2.0
MeOH NIS/TfOH
16
17
0
0
0
4.0
0.5
3.0
yields ranging from 68 to 91%. The results reveal the broad
compatibility of DTBS-directed coupling with various leav-
ing groups and promoters. Moreover, the results of en-
tries 4–7 where a-fluoride or a-imidate donors were used
ruled out the possibility that the a-anomeric selectivity of
the DTBS-directed reaction is attributed to the stereocon-
version of the b-glycosyl donor via SN2-like mechanism. In-
terestingly, in contrast to these results, when insoluble silver
silicate[15] was selected as a promoter for the glycosyl bro-
mide donor 9, the glycosylation predominantly produced the
corresponding b-anomeric outcome 25 at 77% yield
(entry 8). For entry 9, the smallest alkyl alcohol, that is,
methanol was a-selectively glycosylated with 3. In addition,
tertiary alcohol 16 and aryl alcohol 17[16] functioned as a-
predominant coupling partners, thus producing the corre-
sponding galactosides 27 and 28 in high yields (entries 10
and 11). At the final stage of this study, we attempted to di-
rectly a-galactosylate the hindered 1-hydroxyl of the ceram-
ide fragment 18 with the 2,3-benzoylated galactosyl donor
11. This reaction resulted in the successful synthesis of bio-
logically-important a-Gal-Cer frame 29 in a relatively high
yield (entry 12).[17]
NIS/TfOH
BF3OEt2/
Et3N[f]
10
12
11
18
TMSOTf
0
48
29
60:0
[a] Isolated yield. [b] See ref. [11]. [c] See ref. [12]. [d] See ref. [13].
[e] See ref. [15]. [f] See ref. [16]. DMTST=dimethyl(methylthio)sulfoni-
um trifluoromethanesulfonate.
Table 3. a-Predominant formation of GalN-Ser/Thr linkages.
Entry Donor ROH Promoter
t [h] Product Yield (a/b)[a] [%]
1
2
3
4
5
3
3
7
19
20
21
19
22
NIS/TfOH 0.5
NIS/TfOH 0.5
TMSOTf
NIS/TfOH 0.5
NIS/TfOH 1.0
30
31
32
33
34
95:2
93:0
97:0
65:0
88:0
0.5
12
13
[a] Isolated yield.
In accordance with the above-mentioned results, the
DTBS galactosyl donors have also been successfully used in
the efficient synthesis of a-galactosaminyl Ser/Thr sequences
(Table 3). Thus, various types of Ser derivatives, namely, 19,
21, and 22 as well as Thr derivative 20 were a-selectively
galactosylated by the GalNTroc donors 3 and 7 in high
yields (entries 1–3). The 2-acetamido-galactosyl donor 12
also served as an a-selective glycosylation unit to produce
an a-GalNAc-Ser linkage in a moderate yield (entry 4). In
entry 5, we found that the glycosidation of the Gal-GalN-
Troc disaccharide donor 13 with Ser derivative 22 yielded
the T-antigen structure 34 in 88% yield.
the GalN residue, the 4,6-DTBS group was cleaved by the
action of the fluoride anion released from n-tributylammoni-
um hydrogenfluoride (TBAHF)[18] without affecting the
Fmoc moiety. The resulting 4,6-diol glycan 38 was then sialy-
lated with the previously obtained N-Troc sialyl donor 39[19]
to afford the tetrasaccharide 40 in 88% yield. Finally, the
Troc groups within 40 were chemoselectively replaced by
acetyl groups to produce glycophorin A glycan frame 41.[20]
In summary, we have described the broad application of
the DTBS-directed glycosylation for use in the synthesis of
various a-galactosyl glycosides. As exemplified by the high
a-selectivity and high-yielding synthesis of biologically sig-
nificant a-Gal-Cer and glycophorin A glycan frames, this ap-
proach will greatly improve the efficiency of the general
strategy toward the synthesis of a-galactosyl glycan struc-
tures.
Moreover, the DTBS-containing trisaccharide 35[8] was
applied to the coupling of the Fmoc-Ser derivative 36
(Scheme 3). Fortunately, this coupling also confirmed our
expectations by producing
a
Neu5Aca
G
N
3)GalNa(1!)Ser sequence 37 as a single a-isomer in high
yield. Further, to establish an a-sialyl branch on the C6 of
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8862 – 8870

Oligosaccharides
FULL PAPER
Ph), 5.50 (d, 1H, J1,2 =10.5 Hz, H-1), 5.03, 4.90 (2d, 2H, Jgem =12.3 Hz,
OCH2CCl3), 4.85 (q, 2H, Jgem =12.3 Hz, OCH2CCl3), 4.82 (dd, 1H, J2,3
=
10.5, J3,4 =2.9 Hz, H-3), 4.74 (d, 1H, H-4), 4.24 (dd, 1H, Jgem =12.5 Hz,
H-6), 4.10 (q, 1H, H-2), 4.07 (dd, 1H, H-6’), 3.83 (s, 1H, H-5), 1.04, 0.96
(2s, 18H, 2 tBu); 13C NMR (100 MHz, CDCl3): d = 154.3, 152.7, 134.7,
129.1, 129.1, 126.6, 96.1, 94.8, 86.0, 78.2, 76.0, 73.3, 68.9, 66.6, 66.3, 49.4,
27.4, 27.2, 22.7, 20.2; MALDI MS: m/z: calcd for C26H35Cl6NO8SSiNa:
781.98; found: 781.95 [M+Na]+.
Methyl 2-deoxy-4,6-O-di-tert-butylsilylene-1-thio-2-(2,2,2-trichloroethoxy-
carbamoyl)-3-O-(2,2,2-trichloroethoxycarbonyl)-b-d-galactopyranoside
(4):
Di-tert-butylsilyl
bis(trifluoromethanesulfonate)
(1.32 mL,
3.62 mmol) was added at 08C under argon atmosphere to a solution of
compound 2 (1.16 g, 3.02 mmol) in pyridine (15 mL), and the mixture
was stirred for 3 min at ambient temperature. After the complete con-
sumption of the starting material was confirmed on TLC analysis
(CHCl3/MeOH 10:1), 2,2,2-trichloroethyl chloroformate (1.25 mL,
9.06 mmol) was added and stirred for 30 min (TLC: EtOAc/hexane 1:3).
The reaction mixture was coevaporated with toluene and extracted with
CHCl3. The organic phase was washed with 2m HCl, H2O, satd. aq.
Na2CO3 and brine, dried (Na2SO4) and concentrated. The residue was pu-
rified by chromatography on silica gel (EtOAc/hexane 1:5) to give 4
(1.13 g, 54%). [a]D =+33.38 (c 1.0, CHCl3); 1H NMR (500 MHz,
[D6]DMSO): d = 7.93 (d, 1H, NH), 4.97, 4.82 (2d, 2H, OCH2CCl3), 4.75
(dd, 1H, J2,3 =10.3, J3,4 =2.9 Hz, H-3), 4.72 (d, 1H, H-4), 4.53 (d, 1H,
J
1,2 =10.3 Hz, H-1), 4.25 (dd, 1H, Jgem =12.5 Hz, H-6), 4.07 (dd, 1H, H-
6’), 4.01 (q, 1H, H-2), 3.71 (s, 1H, H-5), 2.12 (s, 3H, Me), 1.02, 0.95 (2s,
18H, 2 tBu); 13C NMR (100 MHz, [D6]DMSO): d = 154.3, 152.8, 96.1,
94.8, 84.4, 79.2, 78.4, 76.1, 74.0, 73.3, 68.9, 66.6, 49.3, 27.4, 27.3, 23.0, 20.2,
12.5; MALDI MS: m/z: calcd for C21H33Cl6NO8SSiNa: 719.97; found:
720.04 [M+Na]+.
Scheme 3. a) NIS/TfOH, MS 4Š, CH2Cl2, 08C, 8 h, 88% (only a); b)
TBAHF, THF, H2O, RT, 5 h, 86%; c) NIS/TfOH, MS 3Š, CH3CN,
CH2Cl2, ꢀ358C, 31 h, 94% (a/b 73:21); d) i) Zn, AcOH, 408C, 3 h, 68%;
ii) Ac2O, pyr, RT, 11 h, 68%. MS=molecular sieves, TBAHF=tri-n-
2-Deoxy-4,6-O-di-tert-butylsilylene-2-(2,2,2-trichloroethoxycarbamoyl)-3-
O-(2,2,2-trichloroethoxycarbonyl)-a-d-galactopyranosyl fluoride (5): (Di-
ethylamino)sulfur trifluoride (260 mL, 1.97 mmol) and N-bromosuccini-
mide (303 mg, 1.7 mmol) at ꢀ158C under argon atmosphere were added
to a solution of compound 3 (1.00 g, 1.31 mmol) in CH2Cl2 (13 mL) and
the mixture was stirred for 5 h (TLC: EtOAc/hexane 1:3). The reaction
mixture was diluted with CHCl3 and satd. aq. NaHCO3 was added with
ice. The mixture was stirred for 5 min vigorously. The organic layer was
washed with water and dried over Na2SO4. After concentration, the re-
sulted residue was subjected to column chromatography on silica gel
butylammonium hydrogenfluoride.
R
Experimental Section
General procedures: 1H and 13C NMR spectra were taken by Varian
INOVA 400 and 500. Chemical shifts are expressed in ppm (d) relative
to the signal of either CHCl3 or Me4Si, adjusted to d 7.26 or 0.00 ppm, re-
spectively. MALDI-TOF MS spectra were recorded in positive ion mode
on a Bruker Autoflex with the use of a-cyano-4-hydroxycinnamic acid
(CHCA) as a matrix. Molecular sieves were purchased from Wako
Chemicals Inc. and dried at 3008C for 2 h in muffle furnace prior to use.
Drierite was powdered and dried at 3008C for 6 h in muffle furnace prior
to use. Solvents as reaction media were dried over molecular sieves and
used without purification. TLC analysis was performed on Merck TLC
(silica gel 60F254 on glass plate). Silica gel (80 mesh and 300 mesh) manu-
factured by Fuji Silysia Co. was used for flash column chromatography.
Quantity of silica gel was usually estimated as 100 to 150-fold weight of
sample to be charged. Solvent systems in chromatography were specified
in v/v. Evaporation and condensation were carried out in vacuo.
(EtOAc/hexane 1:8) to give
5 (778 mg, 88%). [a]D =+86.08 (c 1.0,
CHCl3); 1H NMR (400 MHz, [D6]DMSO): d = 8.38 (d, 1H, NH), 5.76
(d, 1H, J1,F =52.9 Hz, H-1), 5.08, 4.94 (2d, 2H, OCH2CCl3), 4.90 (dd, 1H,
H-3), 4.85 (m, 2H, OCH2CCl3), 4.82 (d, 1H, H-4), 4.30 (m, 2H, H-2, H-
6), 4.09 (s, 1H, H-5), 1.01, 0.97 (2s, 18H, 2 tBu); 13C NMR (100 MHz,
[D6]DMSO): d = 154.7, 152.6, 107.7, 105.5, 95.9, 94.8, 76.0, 73.8, 73.7,
68.7, 68.7, 68.5, 65.9, 48.5, 48.3, 27.2, 27.0, 22.7, 20.3; MALDI MS: m/z:
calcd for C20H30Cl6FNO8SSiNa: 691.97; found: 691.95 [M+Na]+.
2-Deoxy-4,6-O-di-tert-butylsilylene-2-(2,2,2-trichloroethoxycarbamoyl)-3-
O-(2,2,2-trichloroethoxycarbonyl)-a-d-galactopyranose (6): N-Bromosuc-
cinimide (2.33 g, 13.1 mmol) was added at ambient temperature to a solu-
tion of compound 3 (2.00 g, 2.62 mmol) in acetone (44 mL)/water (9 mL),
and the stirring was continued for 30 min until TLC analysis (EtOAc/
hexane 1:3) indicated the completion of the reaction. The reaction mix-
ture was concentrated. The residue was purified by column chromatogra-
phy on silica gel (EtOAc/hexane 1:5) to give 6 (1.45 g, 83%). 1H NMR
(500 MHz, CDCl3): mixture of rotamers 6a and 6b (a/b 3:1); 6a: d =
5.42 (d, 1H, J1,2 =2.9 Hz, H-1), 5.03 (d, 1H, NH), 4.86 (dd, 1H, J2,3 =11.0,
Phenyl 2-deoxy-4,6-O-di-tert-butylsilylene-1-thio-2-(2,2,2-trichloroethoxy-
carbamoyl)-3-O-(2,2,2-trichloroethoxycarbonyl)-b-d-galactopyranoside
(3):
Di-tert-butylsilyl
bis(trifluoromethanesulfonate)
(2.20 mL,
6.15 mmol) was added at 08C under argon atmosphere to a solution of
compound 1 (2.50 g, 5.59 mmol) in pyridine (110 mL), and the mixture
was stirred for 3 min at ambient temperature. After the complete con-
sumption of the starting material was confirmed on TLC analysis
(CHCl3/MeOH 10:1), 2,2,2-trichloroethyl chloroformate (1.15 mL,
8.39 mmol) was added and stirred for 30 min (TLC monitoring: EtOAc/
hexane 1:3). The reaction mixture was coevaporated with toluene and ex-
tracted with CHCl3. The organic phase was washed with 2m HCl, H2O,
satd. aq. Na2CO3 and brine, dried (Na2SO4) and concentrated. The resi-
due was purified by chromatography on silica gel (EtOAc/hexane 1:6) to
give 3 (3.05 g, 93%). [a]D =+27.78 (c 0.6, CHCl3); 1H NMR (500 MHz,
[D6]DMSO): d = 8.05 (d, 1H, J2,NH =9.3 Hz, NH), 7.40–7.24 (m, 5H,
J
3,4 =2.6 Hz, H-3), 4.84, 4.70 (2d, 2H, OCH2CCl3), 4.77 (d, 1H, H-4), 4.58
(td, 1H, H-2), 4.23 (m, 2H, H-6, H-6’), 4.01 (s, 1H, H-5), 2.92 (s, 1H,
OH), 1.08, 1.03 (2s, 18H, 2 tBu); 6b: d 5.41 (d, 1H, J1,2 =2.9 Hz, H-1),
5.29 (d, 1H, NH), 4.95 (dd, 1H, J2,3 =11.0, J3,4 =2.6 Hz, H-3), 4.84, 4.70
(2d, 2H, OCH2CCl3), 4.77 (dd, 1H, H-4), 4.58 (td, 1H, H-2), 4.32 (d, 1H,
H-6), 4.17 (d, 1H, H-6’), 4.01 (s, 1H, H-5), 2.86 (s, 1H, OH), 1.08, 1.03
(2s, 18H, 2 tBu); 13C NMR (125 MHz, CDCl3): d = 154.4, 154.0, 95.4,
94.4, 92.6, 75.8, 74.7, 70.2, 67.3, 67.0, 49.7, 49.2, 27.6, 27.5, 27.4, 23.4, 20.8;
MALDI MS: m/z: calcd for C20H31Cl6NO9SiNa: 689.97; found: 689.97
[M+Na]+.
Chem. Eur. J. 2006, 12, 8862 – 8870
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8865

H. Ando, M. Kiso et al.
2-Deoxy-4,6-O-di-tert-butylsilylene-2-(2,2,2-trichloroethoxycarbamoyl)-3-
O-(2,2,2-trichloroethoxycarbonyl)-a-d-galactopyranosyl trichloroacetimi-
date (7): Trichloroacetonitrile (1.0 mL, 10.4 mmol) and 1,8-diazabicyclo-
With glycosyl donor 5: Molecular sieves 4 Š (170 mg) under argon at-
mosphere was added to a solution of 5 (150 mg, 223 mmol) and 15
(22 mg, 144 mmol) in CH2Cl2 (3.7 mL). The mixture was stirred at room
temperature for 1 h. To the mixture were added SnCl2 (42 mg, 223 mmol)
and AgClO4 (55 mg, 267 mmol) at 08C, and the stirring was continued for
16 h at 08C. The precipitate was filtered off and washed with CHCl3. The
filtrate and washings were combined, and the solution was successively
washed with satd. aq. NaHCO3 and brine, dried (Na2SO4) and concen-
trated. Purification by column chromatography (PhCH3/EtOAc 130:1)
gave 22 (93 mg, 78%) and its b-isomer (12 mg, 10%).
A
of compound 6 (350 mg, 0.52 mmol) in CH2Cl2 (5.2 mL), and the mixture
was stirred for 30 min at ambient temperature (TLC: EtOAc/hexane
1:3). The reaction mixture was evaporated. The residue was purified with
column chromatography on silica gel (EtOAc/hexane 1:2) to give 7
1
(293 mg, 70%). H NMR (500 MHz, CDCl3); mixture of rotamers 7a and
7b (a/b 4:1); 7a: d = 8.75 (s, 1H, C=NH), 6.25 (d, 1H, J1,2 =3.5 Hz, H-
1), 5.14 (d, 1H, NH), 4.99 (dd, 1H, J2,3 =11.5, J3,4 =3.0 Hz, H-3), 4.80 (m,
5H, H-2, 2 OCH2CCl3), 4.75 (d, 1H, H-4), 4.26 (m, 2H, H-6, H-6’), 3.96
(s, 1H, H-5), 1.10, 1.04 (2s, 18H, 2 tBu); 7b: d = 8.79 (s, 1H, C=NH),
6.50 (d, 1H, J1,2 =2.9 Hz, H-1), 4.93 (d, 1H, NH), 4.99 (dd, 1H, J2,3 =11.5,
With glycosyl donor 7: Molecular sieves 4 Š (AW300) (170 mg) was
added under argon atmosphere to a solution of 7 (150 mg, 184 mmol) and
15 (19 mg, 124 mmol) in CH2Cl2 (3.1 mL). To the mixture was added tri-
methylsilyl trifluoromethanesulfonate (TMSOTf) (0.67 mL, 3.68 mmol) at
08C, and the stirring was continued for 1 h at 08C. A similar work-up
and purification as mentioned above gave 24 (91 mg, 91%) and its b-
isomer (8 mg, 8%). [a]D =+95.08 (c 1.9, CHCl3); 1H NMR (500 MHz,
CDCl3): d = 5.15 (d, 1H, NH), 5.11 (dd, 1H, J2,3 =11.2, J3,4 =2.7 Hz, H-
3), 5.10 (d, 1H, J1,2 =3.6 Hz, H-1), 4.85, 4.75 (2d, 2H, Jgem =11.4 Hz,
OCH2CCl3), 4.77, 4.70 (2d, 2H, Jgem =11.9 Hz, OCH2CCl3), 4.75 (d, 1H,
J
3,4 =3.0 Hz, H-3), 4.80 (m, 5H, H-2, 2 OCH2CCl3), 4.75 (d, 1H, H-4),
4.26 (m, 2H, H-6, H-6’), 3.96 (s, 1H, H-5), 1.10, 1.04 (2s, 18H, 2 tBu);
13C NMR (125 MHz, CDCl3): d = 160.4, 154.1, 154.0, 96.1, 95.2, 94.1,
90.9, 75.2, 74.6, 69.8, 69.5, 66.5, 49.3, 48.9, 31.6, 27.5, 27.2, 23.3, 21.0, 20.7;
MALDI MS: m/z: calcd for C22H31Cl9N2O9SiK: 848.86; found: 848.96
[M+K]+.
Acetyl 2-deoxy-4,6-O-di-tert-butylsilylene-2-(2,2,2-trichloroethoxycarba-
J
3,4 =2.7 Hz, H-4), 4.57 (td, 1H, J1,2 =3.6, J2,3 =11.2 Hz, H-2GalN), 4.28,
moyl)-3-O-(2,2,2-trichloroethoxycarbonyl)-a-D-galactopyranoside
(8):
4.16 (2dd, 2H, Jgem =12.8 Hz, H-6, 6’), 3.83 (s, 1H, H-5), 3.80 (t, 1H, H-
2adamantane), 2.07–1.54 (m, 14H, adamantane), 1.08, 1.02 (2s, 18H, 2 tBu);
13C NMR (100 MHz, CDCl3): d = 154.3, 154.1, 95.9, 80.1, 79.8, 76.9, 76.8,
76.5, 76.3, 75.2, 74.6, 70.1, 70.0, 67.5, 67.0, 49.3, 37.3, 36.7, 36.3, 33.6, 32.0,
31.8, 30.8, 27.6, 27.4, 27.3, 27.1, 23.4, 20.8; MALDI MS: m/z: calcd for
C30H45Cl6NO9SiNa: 824.08; found: 824.16 [M+Na]+.
Acetic anhydride (1.5 mL) was added at 08C to a solution of compound
6 (1.00 g, 1.49 mmol) in pyridine (1.5 mL), and the stirring was continued
for 1 h at ambient temperature (TLC: EtOAc/hexane 1:3). The reaction
mixture was coevaporated with toluene and extracted with EtOAc. The
organic phase was washed with 2m HCl, H2O, satd. aq. Na2CO3 and
brine, dried (Na2SO4) and concentrated. The residue was purified by
chromatography on silica gel (EtOAc/hexane 1:5) to give 8 (1.01 g,
94%). 1H NMR (500 MHz, CDCl3): mixture of rotamers 8a and 8b (a/b
3:1); 8a: d = 6.31 (d, 1H, J1,2 =3.7 Hz, H-1), 5.05 (d, 1H, NH), 4.94 (dd,
1H, J2,3 =11.4, J3,4 =2.9 Hz, H-3), 4.78 (m, 6H, H-2, H-4, 2 OCH2CCl3),
4.23 (2d, 2H, H-6, H-6’), 3.83 (s, 1H, H-5), 2.17 (s, 3H, Ac), 1.09, 1.03
(2s, 18H, 2 tBu); 8b: d 6.35 (d, 1H, J1,2 =3.3 Hz, H-1), 5.02 (d, 1H, NH),
4.88 (dd, 1H, J2,3 =7.0, J3,4 =2.9 Hz, H-3), 4.78 (m, 6H, H-2, H-4, 2
OCH2CCl3), 4.23 (m, 2H, H-6, H-6’), 3.83 (s, 1H, H-5), 2.16 (s, 3H, Ac),
1.09, 1.03 (2s, 18H, 2 tBu); 13C NMR (125 MHz, CDCl3): d = 169.0,
154.1, 96.3, 94.8, 94.2, 91.7, 75.3, 74.7, 70.1, 69.3, 66.6, 48.6, 48.2, 27.5,
23.3, 21.0, 20.8; MALDI MS: m/z: calcd for C22H33Cl6NO10SiNa: 731.99;
found: 731.95 [M+Na]+.
2-Adamantyl 2-deoxy-4,6-O-di-tert-butylsilylene-2-(2,2,2-trichloroethoxy-
carbamoyl)-3-O-(2,2,2-trichloroethoxycarbonyl)-b-d-galactopyranoside
(25): Molecular sieves 4 Š (180 mg) under argon atmosphere was added
to a solution of 9 (21 mg, 137 mmol) and Ag-silicate (180 mg) in CH2Cl2
(2.1 mL). The suspension was stirred for 1 h at room temperature. To the
suspension was added the solution of 15 (150 mg, 205 mmol) in CH2Cl2
(1.3 mL) at ꢀ208C dropwise, and the stirring was continued for 1 h at
ꢀ208C. The reaction was monitored by TLC (EtOAc/hexane 1:4). The
reaction mixture was diluted with CHCl3 and filtered through Celite. The
filtrate and washings were combined and concentrated. Purification by
column chromatography (PhCH3/EtOAc 130:1) gave 25 (85 mg, 77%)
and 24 (7 mg, 6%). [a]D =+22.08 (c 1.7, CHCl3); 1H NMR (500 MHz,
[D6]DMSO) d = 7.80 (d, 1H, NH), 5.04, 4.93 (2d, 2H, Jgem =12.5 Hz,
2-Deoxy-4,6-O-di-tert-butylsilylene-2-(2,2,2-trichloroethoxycarbamoyl)-3-
O-(2,2,2-trichloroethoxycarbonyl)-a-d-galactopyranosyl bromide (9):
25% HBr solution in acetic acid (182 mL, 0.56 mmol) was added at 08C
to a solution of compound 8 (200 mg, 0.28 mmol) in CH2Cl2 (1.4 mL),
and the mixture was stirred for 2 h at ambient temperature (TLC:
EtOAc/hexane 1:3). The reaction mixture was extracted with CHCl3. The
organic phase was washed with satd. aq. Na2CO3 and brine, dried
(Na2SO4) and concentrated. The residue was purified chromatography on
silica gel (EtOAc/hexane 1:20) to give 9 (177 mg, 86%). [a]D =+131.58
OCH2CCl3), 4.77 (q, 2H, Jgem =12.5 Hz, OCH2CCl3), 4.72 (dd, 1H, J3,4 =
3.4 Hz, H-3), 4.64 (d, 1H, H-4), 4.61 (d, 1H, J1,2 =8.0 Hz, H-1), 4.22, 4.04
(2dd, 2H, Jgem =11.2 Hz, H-6, 6’), 3.94 (pseudo q, 1H, J1,2 =8.0 Hz, H-2),
3.74 (brt, 1H, adamantane), 3.62 (s, 1H, H-5), 2.00–1.22 (m, 14H, ada-
mantane), 1.02, 0.95 (2s, 18H, 2 tBu); 13C NMR (100 MHz, [D6]DMSO):
d = 154.3, 152.9, 98.9, 96.1, 94.9, 79.8, 79.1, 77.6, 75.9, 73.6, 73.3, 69.4,
68.9, 66.6, 55.5, 50.9, 36.9, 35.9, 35.6, 32.9, 30.9, 30.8, 30.6, 29.0, 27.4, 27.1,
26.7, 26.5, 22.7, 20.4; MALDI MS: m/z: calcd for C30H45Cl6NO9SiNa:
824.08; found: 824.24 [M+Na]+.
(c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3): d
= 6.70 (d, 1H, J1,2 =
Methyl 2-deoxy-4,6-O-di-tert-butylsilylene-2-(2,2,2-trichloroethoxycarba-
3.4 Hz, H-1), 5.12 (d, 1H, NH), 4.99 (dd, 1H, J2,3 =10.9, J3,4 =2.3 Hz, H-
3), 4.79 (m, 5H, H-4, 2 OCH2CCl3), 4.67 (td, 1H, J2,NH =9.7 Hz, H-2),
4.07 (s, 1H, H-5), 1.07, 1.04 (2s, 18H, 2 tBu); 13C NMR (125 MHz,
CDCl3): d = 154.0, 153.9, 95.1, 94.8, 94.1, 75.8, 74.8, 72.3, 69.2, 66.2, 50.7,
29.7, 27.4, 27.1, 23.3, 21.0, 20.8.
moyl)-3-O-(2,2,2-trichloroethoxycarbonyl)-a-d-galactopyranoside
(26):
Molecular sieves 3 Š (500 mg) was added to a solution of compound 3
(100 mg, 131 mmol) and MeOH (10.6 mL, 262 mmol) in CH2Cl2 (1.3 mL).
The suspension was stirred for 1 h and cooled to 08C. To the mixture
were added N-iodosuccinimide (NIS) (59 mg, 262 mmol) and trifluorome-
thanesulfonic acid (TfOH) (2.3 mL, 26.2 mmol), and the stirring was con-
tinued for 4 h. The termination of reaction was confirmed by TLC
(EtOAc/hexane 1:3). The reaction mixture was filtered through Celite.
The combined filtrate and washings were extracted with CHCl3, and the
organic layer was washed with satd. aq. Na2CO3, satd. aq. Na2S2O3 and
brine, dried over Na2SO4 and concentrated. The residue was purified
with column chromatography on silica gel (EtOAc/hexane 1:30) to give
26 (72 mg, 90%) and the corresponding b-isomer (16 mg, 9%). [a]D =+
2-Adamantyl 2-deoxy-4,6-O-di-tert-butylsilylene-2-(2,2,2-trichloroethoxy-
carbamoyl)-3-O-(2,2,2-trichloroethoxycarbonyl)-a-d-galactopyranoside
(24): With glycosyl donor 3: Molecular sieves 4 Š (140 mg) was added
under argon atmosphere to a solution of 3 (120 mg, 157 mmol) and 15
(16 mg, 105 mmol) in CH2Cl2 (2.6 mL). The mixture was stirred at room
temperature for 2 h. To the mixture was added dimethyl(methylthio)sul-
fonium triflate (DMTST, 48%) (338 mg, 629 mmol) at 08C, and the stir-
ring was continued for 21 h at 08C. The reaction was monitored by TLC
(PhCH3/EtOAc 50:1). The precipitate was filtered off and washed with
CHCl3. The filtrate and washings were combined, and the solution was
successively washed with satd. aq. Na2CO3 and brine, dried and concen-
trated. Purification by column chromatography (PhCH3/EtOAc 130:1)
gave 24 (70 mg, 83%) and its b-isomer (13 mg, 15%).
1
85.58 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3): d = 5.22 (d, 1H, NH),
4.80 (m, 4H, H-1, H-3, OCH2CCl3), 4.58 (td, 1H, J1,2 =3.7, J2,3 =J2,NH
=
10.6 Hz, H-2), 4.24 (2d, 2H, H-6, H-6’), 3.73 (s, 1H, H-5), 3.41 (s, 3H,
OMe), 1.09, 1.03 (2s, 18H, 2 tBu); 13C NMR (125 MHz, CDCl3): d =
155.0, 154.7, 99.8, 96.2, 95.1, 75.4, 70.8, 68.0, 67.7, 56.4, 50.3, 49.8, 28.3,
8866
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8862 – 8870

Oligosaccharides
FULL PAPER
28.1, 24.1, 21.5; MALDI MS: m/z: calcd for C21H33Cl6NO9Si: 703.99;
found: 704.00 [M+Na]+; b-isomer: [a]D =+26.58 (c 1.0, CHCl3);
1H NMR (500 MHz, CDCl3): d = 7.87 (d, 1H, NH), 4.97–4.81 (4d, 4H, 2
OCH2CCl3), 4.72 (dd, 1H, H-3), 4.65 (d, 1H, H-4), 4.41 (d, J1,2 =8.0 Hz,
H-1), 4.17 (2d, 2H, H-6, H-6’), 3.89 (q, 1H, J2,3 =J2,NH =10.8 Hz, H-2),
3.66 (s, 1H, H-5), 3.37 (s, 3H, OMe), 1.01, 0.95 (2s, 18H, 2 tBu);
13C NMR (125 MHz, CDCl3): d = 154.0, 153.6, 100.8, 94.3, 70.8, 69.4,
67.0, 57.0, 52.3, 29.7, 27.4, 27.4, 23.3, 20.7; MALDI MS: m/z: calcd for
C21H33Cl6NO9SiNa: 703.99; found: 703.93 [M+Na]+.
and the organic layer was washed with satd. aq. Na2CO3 and brine, dried
over Na2SO4 and concentrated. The residue was purified with column
chromatography on silica gel (EtOAc/PhCH3 1:100) to give 29 (83 mg,
59%). [a]D =+96.58 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3): d =
8.02–7.33 (m, 15H, 3 Ph), 5.78 (d, 1H, NH), 5.76 (dd, 1H, J1,2 =3.7, J2,3
=
10.4 Hz, H-2GalN), 5.74 (m, 1H, J5,6 =6.8 Hz, H-5Cer), 5.56 (dd, 1H, J3,4
=
3.1 Hz, H-3GalN), 5.49 (m, 2H, H-3Cer, H-4Cer), 5.28 (d, 1H, H-1GalN), 4.88
(d, 1H, H-4GalN), 4.50 (m, 1H, J1,2 =4.6 Hz, H-2Cer), 4.28, 4.19 (2dd, 2H,
J
J
gem =12.6 Hz, H-6GalN, H-6’GalN), 3.92 (s, 1H, H-5GalN), 3.84 (dd, 1H,
gem =10.7 Hz, H-1’Cer), 3.70 (dd, 1H, Jgem =10.7 Hz, H-1Cer), 2.10 (m, 2H,
1-Adamantyl 2-deoxy-4,6-O-di-tert-butylsilylene-2-(2,2,2-trichloroethoxy-
carbamoyl)-3-O-(2,2,2-trichloroethoxycarbonyl)-a-d-galactopyranoside
(27): Molecular sieves 4 Š (170 mg) was added to a solution of com-
pound 3 (150 mg, 196 mmol) and compound 16 (20 mg, 131 mmol) in
CH2Cl2 (3.3 mL). The suspension was stirred for 1 h and cooled to 08C.
To the mixture were added NIS (88 mg, 392 mmol) and TfOH (3.4 mL,
13.1 mmol), and the stirring was continued for 30 min. A similar work-up
and purification by silica gel column chromatography (EtOAc/hexane
1:30) as described for 26 gave 27 (95 mg, 90%) and the corresponding b-
isomer (10 mg, 5%). [a]D =+85.58 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3): d = 5.33 (d, 1H, J1,2 =3.4 Hz, H-1), 5.07 (d, 1H, J2,NH =9.7 Hz,
NHCOCH2CH2), 1.98 (q, 2H, J5,6 =6.8 Hz, H-6Cer, H-6’Cer), 1.57 (m, 2H,
NHCOCH2CH2), 1.24 (m, 52H, CH2), 1.11, 0.96 (2s, 18H, 2 tBu), 0.88 (t,
6H, 2 CH2CH3); 13C NMR (100 MHz, CDCl3): d = 172.7, 166.2, 166.0,
165.2, 137.5, 133.2, 133.1, 133.0, 129.9, 129.8, 129.7, 129.7, 129.6, 129.4,
129.0, 128.4, 128.3, 128.3, 128.2, 124.6, 97.9, 74.4, 71.1, 70.9, 68.5, 67.7,
67.4, 66.8, 51.2, 36.9, 32.3, 31.9, 29.7, 29.7, 29.6, 29.6, 29.5, 29.5, 29.4, 29.4,
29.3, 29.2, 28.9, 27.5, 27.2, 25.8, 23.3, 22.7, 20.7, 14.1; MALDI MS: m/z:
calcd for C71H109NO11SiNa: 1202.77; found: 1202.96 [M+Na]+.
N-Benzyloxycarbonyl-O-[2-deoxy-4,6-O-di-tert-butylsilylene-2-(2,2,2-tri-
chloroethoxycarbamoyl)-3-O-(2,2,2-trichloroethoxycarbonyl)-a-d-galacto-
pyranosyl]-l-serine benzyl ester (30): Molecular sieves 4 Š (400 mg) was
added to a solution of compound 3 (277 mg, 364 mmol) and 19 (100 mg,
303 mmol) in CH2Cl2 (6.6 mL). The suspension was stirred for 1 h and
cooled to 08C. To the mixture were added NIS (163 mg, 728 mmol) and
TfOH (6.4 mL, 72.8 mmol) and stirring was continued for 0.5 h. The termi-
nation of reaction was confirmed by TLC (EtOAc/hexane 1:2). A similar
work-up as described for 26 and purification by silica gel column chroma-
tography (EtOAc/hexane 1:5) gave 30 (283 mg, 95%) and the corre-
sponding b-isomer (7 mg, 2%). [a]D =+68.28 (c 2.9, CHCl3); 1H NMR
NH), 4.85, 4.72 (2d, 2H, Jgem =12.1 Hz, OCH2CCl3), 4.83 (dd, 1H, J2,3
=
11.4, J3,4 =3.2 Hz, H-3), 4.77, 4.70 (2d, 2H, Jgem =12.0 Hz, OCH2CCl3),
4.75 (d, 1H, H-4), 4.50 (td, 1H, J1,2 =3.4, J2,3 =11.4, J2,NH =9.7 Hz, H-2),
4.28, 4.11 (2d, 2H, Jgem =12.8 Hz, H-6, H-6’), 3.92 (s, 1H, H-5), 2.16–1.56
(m, 15H, adamantane), 1.08, 1.02 (2s, 18H, 2 tBu); 13C NMR (125 MHz,
[D6]DMSO): d = 156.0, 155.8, 97.3, 96.2, 93.0, 92.8, 76.3, 71.9, 68.9, 68.8,
62.2, 51.3, 51.0, 44.2, 37.9, 32.4, 29.4, 29.1, 25.1, 22.9, 22.5, 16.0; MALDI
MS: m/z: calcd for C30H45Cl6NO9SiNa: 824.08; found: 824.08 [M+Na]+;
1
b-isomer: [a]D =+23.58 (c 1.0, CHCl3); H NMR (400 MHz, [D6]DMSO):
(500 MHz, [D6]DMSO): d = 7.86 (d, 1H, NHSer), 7.71 (d, 1H, J2,NH
=
d = 7.69 (d, 1H, NH), 5.15, 4.92 (2d, 2H, Jgem =11.9 Hz, OCH2CCl3),
4.85, 4.80 (2d, 2H, Jgem =12.3 Hz, OCH2CCl3), 4.77 (d, 1H, J1,2 =8.0 Hz,
H-1), 4.75 (dd, 1H, J3,4 =3.4 Hz, H-3), 4.63 (d, 1H, H-4), 4.23, 4.00 (2d,
2H, Jgem =11.4 Hz, H-6, H-6’), 3.78 (pseudo q, 1H, H-2), 3.60 (s, 1H, H-
9.0 Hz, NHGalN), 7.38–7.31 (m, 10H, 2 Ph), 5.12 (2 d, 2H, Jgem =12.4 Hz,
OCH2), 5.10, 5.05 (2 d, 2H, Jgem =12.2 Hz, OCH2), 5.04, 4.92 (2 d, 2H,
OCH2), 4.91, 4.65 (2 d, 2H, Jgem =12.2 Hz, OCH2), 4.87 (dd, 1H, J2,3
11.2, J3,4 =2.4 Hz, H-3), 4.83 (d, 1H, J1,2 =3.1 Hz, H-1), 4.65 (d, 1H, J3,4
=
=
5), 2.05–1.50 (m, 15H, adamantane), 1.02, 0.94 (2s, 18H,
2 tBu);
2.4 Hz, H-4), 4.49 (m, 1H, CHSer), 4.26 (td, 1H, H-2), 4.11, 3.97 (2 dd,
13C NMR (125 MHz, CDCl3): d = 154.1, 152.8, 96.3, 94.8, 93.7, 79.1, 77.6,
75.9, 73.9, 73.2, 69.3, 68.7, 66.9, 51.0, 41.1, 38.0, 29.9, 27.4, 27.1, 22.7, 20.3;
MALDI MS: m/z: calcd for C30H45Cl6NO9SiNa: 824.09; found: 824.08
[M+Na]+.
2H, Jgem =12.2 Hz, H-6, 6’), 3.82 (m, 2H, CH2Ser), 3.78 (s, 1H, H-5), 1.00,
0.95 (2s, 18H, 2 tBu); 13C NMR (100 MHz, [D6]DMSO): d
= 169.9,
156.1, 154.4, 152.8, 136.6, 135.6, 128.4, 128.3, 128.1, 127.9, 127.8, 127.3,
98.2, 95.9, 94.8, 79.1, 75.9, 74.9, 73.6, 69.3, 67.3, 66.6, 66.3, 65.8, 54.2, 48.5,
27.2, 27.1, 22.7, 20.3, 0.0; MALDI MS: m/z: calcd for
C38H48Cl6N2O13SiNa: 1001.09; found: 1001.08 [M+Na]+; b-isomer: [a]D =
ꢀ28.38 (c 0.3, CHCl3); 1H NMR (500 MHz, [D6]DMSO): d = 7.87 (d,
1H, J2,NH =9.0 Hz, NHGalN), 7.39–7.30 (m, 10H, 2 Ph), 7.20 (d, 1H,
p-Nitrophenyl 3-O-acetyl-2-deoxy-4,6-O-di-tert-butylsilylene-2-(2,2,2-tri-
chloroethoxycarbamoyl)-a-d-galactopyranoside (28): Molecular sieves
4 Š (700 mg) was added under argon atmosphere to a solution of com-
pound 10 (583 mg, 1.08 mmol) and 17 (100 mg, 721 mmol) in CH2Cl2
(18 mL). The suspension was stirred for 1 h and cooled to 08C. To the
mixture were added triethylamine (75 mL, 541 mmol) and BF3·Et2O com-
plex (340 mL, 2.70 mmol) and stirring was continued for 3 h at 08C. The
termination of reaction was confirmed by TLC (EtOAc/hexane 1:3). To
the reaction mixture, satd. aq. NaHCO3 was added. The mixture was ex-
tracted with CHCl3. The organic phase was washed with H2O and brine,
dried (Na2SO4) and concentrated. The residue was purified with column
chromatography on silica gel (EtOAc/PhCH3 1:50) to give 28 (450 mg,
95%). [a]D =+180.08 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d =
8.21, 7.20 (2d, 4H, Ar), 5.80 (d, 1H, J1,2 =3.2 Hz, H-1), 5.35 (d, 1H,
NHSer), 5.11 (q, 2H, Jgem =12.6 Hz, OCH2), 5.07, 5.02 (2 d, 2H, Jgem
=
12.6 Hz, OCH2), 5.02, 4.92 (2 d, 2H, Jgem =12.4 Hz, OCH2), 4.80, 4.65 (2
d, 2H, Jgem =12.4 Hz, OCH2), 4.74 (dd, 1H, J2,3 =10.9, J3,4 =2.9 Hz, H-3),
4.64 (d, 1H, H-4), 4.56 (d, 1H, J1,2 =8.3 Hz, H-1), 4.38 (m, 1H, CHSer),
4.24, 4.06 (2 dd, 2H, Jgem =10.4 Hz, H-6, 6’), 4.04, 3.82 (2 dd, 2H, Jgem
10.4 Hz, CH2Ser), 3.89 (q, 1H, H-2), 3.64 (s, 1H, H-5), 0.96, 0.94 (2s, 18H,
2 tBu); 13C NMR (100 MHz, CDCl3): d
169.5, 156.0, 153.9, 153.5,
=
=
136.1, 135.2, 128.6, 128.5, 128.4, 128.3, 128.1, 99.8, 96.2, 94.2, 92.7, 77.2,
74.3, 70.8, 69.3, 67.5, 67.1, 66.7, 54.2, 52.0, 29.6, 27.4, 27.3, 23.2, 20.6, 0.0;
MALDI MS: m/z: calcd for C38H48Cl6N2O13SiNa: 1001.09; found: 1001.09
[M+Na]+.
J
2,NH =9.8 Hz, NH), 5.22 (dd, 1H, J2,3 =10.9, J3,4 =2.5 Hz, H-3), 4.84, 4.63
(2d, 2H, Jgem =12.0 Hz, OCH2CCl3), 4.73 (td, 1H, H-2), 4.69 (d, 1H, H-
4), 4.22, 4.09 (2dd, 2H, Jgem =12.8 Hz, H-6, 6’), 3.79 (s, 1H, H-5), 2.15 (s,
3H, Ac), 1.12, 1.04 (2s, 18H, 2 tBu); 13C NMR (100 MHz, CDCl3): d =
171.3, 160.8, 154.3, 142.9, 125.8, 116.3, 96.8, 95.2, 74.5, 70.3, 70.0, 68.6,
66.5, 48.9, 27.4, 27.1, 23.2, 20.8, 20.7; MALDI MS: m/z: calcd for
C25H35Cl3N2O10SiNa: 679.10; found: 679.48 [M+Na]+.
N-(9-Fluorenylmethoxycarbonyl)-O-[2-deoxy-4,6-O-di-tert-butylsilylene-
2-(2,2,2-trichloroethoxycarbamoyl)-3-O-(2,2,2-trichloroethoxycarbonyl)-
a-d-galactopyranosyl]-l-threonine benzyl ester (31): [a]D =+72.08 (c 1.0,
CHCl3); 1H NMR (500 MHz, [D6]DMSO): d = 7.57 (d, 1H, NH), 7.52
(m, 14H, NHThr, Ph), 5.08 (q, 2H, OCH2CCl3), 4.98 (q, 2H, PhCH2), 4.84
(dd, 1H, H-3), 4.81 (q, 2H, OCH2CCl3), 4.80 (d, 1H, J1,2 =3.7 Hz, H-1),
4.69 (d, 1H, H-4), 4.52 (dd, 2H, CH2 of Fmoc), 4.36 (dd, 1H, CHThr),
4.26 (m, 3H, CH of Fmoc, CH2Thr), 4.25 (m, 1H, J1,2 =3.7 Hz, H-2), 4.11
(2 d, 2H, H-6, H-6’), 3.83 (s, 1H, H-5), 1.01, 0.98 (2s, 18H, 2 tBu);
13C NMR (100 MHz, [D6]DMSO): d = 170.7, 170.5, 157.5, 155.2, 153.6,
144.5, 144.3, 141.5, 141.4, 136.3, 129.6, 129.1, 129.0, 128.9, 128.8, 128.3,
128.2, 127.8, 126.0, 125.6, 120.9, 120.8, 96.7, 95.5, 79.9, 76.7, 75.9, 74.6,
74.4, 70.2, 67.4, 67.2, 66.9, 66.2, 59.3, 47.5, 28.0, 27.9, 27.8, 23.5, 21.7, 21.0,
19.3; MALDI MS: m/z: calcd for C46H54Cl6N2O13SiNa: 1103.14; found:
1103.04 [M+Na]+.
2,3-Di-O-benzoyl-4,6-O-di-tert-butylsilylene-a-d-galactopyranosyl-(1!1)-
(2S,3R,4E)-3-O-benzoyl-2-octadecanamido-4-octadecene-1,3-diol
(29):
Molecular sieves 4 Š AW-300 (200 mg) was added to a solution of com-
pound 11 (240 mg, 357 mmol) and compound 18 (80 mg, 119 mmol) in
CH2Cl2 (3.0 mL). The suspension was stirred for 1 h and cooled to 08C.
To the mixture was added TMSOTf (1.2 mL, 7.16 mmol) and the stirring
was continued for 48 h. The termination of reaction was confirmed by
TLC (EtOAc/hexane 1:5). The reaction mixture was filtered through
Celite. The combined filtrate and washings were extracted with CHCl3,
Chem. Eur. J. 2006, 12, 8862 – 8870
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8867

H. Ando, M. Kiso et al.
N-(9-Fluorenylmethoxycarbonyl)-O-[2-deoxy-4,6-O-di-tert-butylsilylene-
2-(2,2,2-trichloroethoxycarbamoyl)-3-O-(2,2,2-trichloroethoxycarbonyl)-
a-d-galactopyranosyl]-l-serine allyl ester (32): Molecular sieves 4 Š
(AW-300) (200 mg) was added to a solution of compound 7 (154 mg,
189 mmol) and 21 (46 mg, 126 mmol) in CH2Cl2 (3.1 mL). The suspension
was stirred for 1 h. To the mixture were added TMSOTf (0.68 mL,
3.78 mmol) and stirring was continued for 0.5 h. The termination of reac-
tion was confirmed by TLC (EtOAc/hexane 1:3). A similar work-up and
purification as described for 29 gave 32 (125 mg, 97%). [a]D =+81.18 (c
1.1, CHCl3); 1H NMR (500 MHz, CDCl3); mixture of rotamers 32a and
32b (a/b 2.3:1), 32a: d = 7.77–7.26 (m, 8H, Ph), 5.93 (m, 2H, CH2CH=
4.76, 4.59 (2 d, 2H, Jgem =12.2 Hz, OCH2CCl3), 4.63 (d, 1H, J3,4 =2.1 Hz,
H-4GalN), 4.42 (td, 1H, J2,3 =11.3, H-2GalN), 4.22–4.07 (m, 6H, H-6GalN
,
6’GalN, 6Gal, 6’Gal, CH2Ser), 3.90 (t, 1H, H-5Gal), 3.75 (dd, 1H, H-3GalN), 3.63
(s, 1H, H-5GalN), 2.13, 2.04, 2.00, 1.97 (4s, 12H, 4 Ac), 1.06, 1.05 (2s, 18H,
2 tBu); 34b: d = 7.36–7.26 (m, 5H, Ph), 5.84 (d, 1H, NHSer), 5.37 (d,
1H, J3,4 =3.4 Hz, H-4Gal), 5.25 (t, 1H, J1,2 =7.8, J2,3 =10.2 Hz, H-2Gal), 5.17
(brs, 2H, PhCH2), 4.98 (d, 1H, J1,2 =3.1 Hz, H-1GalN), 4.97 (dd, 1H, H-
3Gal), 4.94, 4.49 (2 d, 2H, Jgem =11.9 Hz, OCH2CCl3), 4.92 (m, 1H, CHSer),
4.71 (brs, 1H, H-4GalN), 4.66 (d, 1H, J2,NH =9.5 Hz, NHGalN), 4.64 (d, 1H,
H-1Gal), 4.50 (td, 1H, J2,3 =11.7 Hz, H-2GalN), 4.22–4.07 (m, 6H, H-6GalN
,
6’GalN, 6Gal, 6’Gal, CH2Ser), 3.90 (t, 1H, H-5Gal), 3.61 (s, 1H, H-5GalN), 3.55
(dd, 1H, H-3GalN), 2.13, 2.05, 2.00, 1.97 (4s, 12H, 4 Ac), 1.05, 1.03 (2s,
18H, 2 tBu); 13C NMR (100 MHz, CDCl3): d = 170.2, 170.1, 170.1, 169.6,
169.2, 166.7, 155.5, 154.1, 153.9, 142.1, 139.1, 136.7, 135.6, 128.6, 128.5,
128.2, 103.0, 101.5, 99.9, 99.1, 95.2, 79.1, 77.2, 76.4, 74.7, 74.6, 72.2, 71.1,
70.9, 70.8, 70.6, 69.5, 69.0, 68.8, 68.5, 67.6, 66.7, 61.4, 61.2, 54.3, 49.8, 49.6,
31.5, 29.6, 27.4, 27.2, 23.3, 22.6, 20.6, 20.5, 20.5, 14.1, 0.0; MALDI MS:
m/z: calcd for C48H58Cl3F5N2O20SiNa: 1233.22; found: 1233.24 [M+Na]+.
CH2, NHSer), 5.37, 5.31 (2 d, 2H, CH2CH=CH2), 5.22 (d, 1H, J2,NH
10.0 Hz, NHGalN), 4.94 (d, 1H, J1,2 =2.6 Hz, H-1), 4.83, 4.71 (2 d, 2H,
gem =11.9 Hz, OCH2CCl3), 4.82 (m, 1H, H-3), 4.80, 4.59 (2 d, 2H, Jgem
11.9 Hz, OCH2CCl3), 4.73 (d, 1H, 3,4 =2.1 Hz, H-4), 4.70 (d, 2H,
=
J
=
J
CH2CH=CH2), 4.65 (s, 1H, CHSer), 4.57 (td, 1H, J1,2 =2.6, J2,NH =10.0 Hz,
H-2), 4.47–4.35 (2 m, 2H, Jgem =10.4, J=7.0 Hz, CH2 of Fmoc), 4.22 (t,
1H, J=7.0 Hz, CH of Fmoc), 4.18–4.09 (m, 2H, H-6, 6’), 3.99 (brs, 2H,
CH2Ser), 3.74 (s, 1H, H-5), 1.07, 1.00 (2s, 18H, 2 tBu); 32b: d = 7.77–7.26
(m, 8H, Ph), 6.01 (d, 1H, NHSer), 5.93 (m, 1H, CH2CH=CH2), 5.37, 5.31
(2 d, 2H, CH2CH=CH2), 5.13 (d, 1H, J2,NH =10.0 Hz, NHGalN), 4.98 (d,
1H, J1,2 =2.6 Hz, H-1), 4.83, 4.71 (2 d, 2H, Jgem =11.9 Hz, OCH2CCl3),
4.82 (m, 1H, H-3), 4.80, 4.59 (2 d, 2H, Jgem =11.9 Hz, OCH2CCl3), 4.73
(d, 1H, J3,4 =2.1 Hz, H-4), 4.70 (d, 2H, CH2CH=CH2), 4.65 (s, 1H,
CHSer), 4.57 (td, 1H, J1,2 =2.6, J2,NH =10.0 Hz, H-2), 4.47–4.35 (2 m, 2H,
CH2 of Fmoc), 4.22 (t, 1H, CH of Fmoc), 4.18–4.09 (m, 2H, H-6, 6’), 3.99
(brs, 2H, CH2Ser), 3.74 (s, 1H, H-5), 1.03, 1.00 (2s, 18H, 2 tBu); 13C NMR
(100 MHz, CDCl3): d = 169.6, 155.7, 154.1, 153.7, 143.6, 143.5, 141.2,
131.0, 127.7, 127.0, 127.0, 124.99, 124.9, 120.0, 119.8, 99.1, 95.3, 94.2, 77.2,
76.8, 75.7, 74.9, 74.5, 69.7, 69.6, 67.7, 67.3, 66.6, 66.5, 54.3, 49.3, 48.8, 46.9,
27.4, 27.2, 23.2, 20.6, 0.0; MALDI MS: m/z: calcd for
C41H50Cl6N2O13SiNa: 1039.11; found: 1039.20 [M+Na]+.
N-(9-Fluorenylmethoxycarbonyl)-O-[(methyl 5-acetamido-4,7,8,9-tetra-
O-acetyl-3,5-dideoxy-d-glycero-a-d-galacto-2-nonulopyranosylonate)-
(2!3)-(6-O-acetyl-2,4-di-O-benzoyl-b-d-galactopyranosyl)-(1!3)-2-
deoxy-4,6-O-di-tert-butylsilylene-2-(2,2,2-trichloroethoxycarbamoyl)-a-d-
galactopyranosyl]-l-serine benzyl ester (37): Molecular sieves 4 Š
(320 mg) was added to a solution of compound 35 (270 mg, 183 mmol)
and 36 (51 mg, 122 mmol) in CH2Cl2 (3 mL). The suspension was stirred
for 1 h and cooled to 08C. To the mixture were added NIS (82 mg,
366 mmol) and TfOH (3.2 mL, 36.6 mmol) and stirring was continued for
8 h. The termination of reaction was confirmed by TLC (PhCH3/acetone/
MeOH 10:6:1). A similar work-up and purification with silica gel column
chromatography (PhCH3/acetone/MeOH 90:6:1) as described for 26 gave
37 (190 mg, 88%). [a]D =+72.08 (c 1.0, CHCl3); 1H NMR (500 MHz,
[D6]DMSO) d = 7.87 (d, 1H, NHSer), 7.66 (d, 1H, NHNeu), 7.61 (m, 23H,
Ph), 7.17 (d, 1H, NHGalN), 5.44 (m, 1H, H-8Neu), 5.35 (d, 1H, H-4Gal), 5.30
(q, 1H, H-2Gal), 5.18 (dd, 1H, H-7Neu), 5.12 (d, 1H, H-1Gal), 5.10 (s, 2H,
N-Benzyloxycarbonyl-O-(2-acetamido-3-O-acetyl-2-deoxy-4,6-O-di-tert-
butylsilylene-a-d-galactopyranosyl)-l-serine benzyl ester (33): Molecular
sieves 4 Š (120 mg) was added to a solution of compound 12 (90 mg,
182 mmol) and 19 (30 mg, 91.0 mmol) in CH2Cl2 (2.7 mL). The suspension
was stirred for 1 h and cooled to 08C. To the mixture were added NIS
(82 mg, 364 mmol) and TfOH (3.2 mL, 36.4 mmol) and stirring was contin-
ued for 3 h. The termination of reaction was confirmed by TLC (EtOAc/
hexane 2:1). A similar work-up and purification with silica gel column
chromatography as described for 26 gave 33 (42 mg, 65%). [a]D =
+103.38 (c 0.5, CHCl3); 1H NMR (500 MHz, [D6]DMSO): d = 7.81 (d,
1H, NHSer), 7.65 (d, 1H, J2,NH =8.7 Hz, NHGalN), 7.38–7.30 (m, 10H, 2
Ph), 5.10 (s, 2H, PhCH2), 5.08, 5.05 (2 d, 2H, Jgem =12.6 Hz, PhCH2), 4.84
(dd, 1H, J2,3 =11.4, J3,4 =2.6 Hz, H-3), 4.75 (d, 1H, J1,2 =3.6 Hz, H-1),
PhCH2), 4.83 (dd, 1H, H-3Gal), 4.74 (s, 1H, H-4GalN), 4.71 (d, 1H, J1,2
3.4 Hz, H-1GalN), 4.63 (m, 1H, H-4Neu), 4.53 (d, 1H,
gem =12.2 Hz,
OCH2CCl3), 4.41 (m, 3H, CHSer, CH2 of Fmoc), 4.25 (t, 1H, Jgem
=
J
=
12.7 Hz, H-9Neu), 4.16 (t, 1H, H-6Gal), 4.07 (td, 1H, H-2GalN), 4.03 (dd,
1H, H-9Neu), 4.02 (m, 5H, H-3GalN, H-6GalN, H-5Gal, H-6’Gal, CH of Fmoc),
3.74 (m, 5H, H-3GalN, H-6GalN, H-6Neu, CH2Ser), 3.73 (s, 3H, COOMe), 2.96
(d, 1H, Jgem =12.2 Hz, OCH2CCl3), 2.19 (dd, 1H, H-3eqNeu), 1.88 (6s, 18H,
6 Ac), 1.22 (m, 1H, H-3axNeu), 1.01, 0.92 (2s, 18H, 2 tBu); 13C NMR
(100 MHz, [D6]DMSO): d
= 170.4, 170.2, 170.2, 170.1, 170.0, 169.5,
169.2, 167.8, 165.0, 164.7, 156.3, 154.1, 153.0, 143.9, 141.0, 140.5, 137.5,
137.3, 135.8, 134.0, 133.5, 129.8, 129.7, 129.4, 129.1, 129.1, 129.0, 129.0,
128.8, 128.6, 128.4, 128.3, 128.0, 127.8, 127.3, 126.7, 125.5, 125.2, 125.0,
120.3, 105.1, 102.0, 100.9, 98.9, 98.0, 97.0, 96.9, 96.7, 95.9, 94.1, 86.3, 77.4,
75.4, 73.0, 72.6, 71.8, 71.2, 70.6, 70.1, 69.4, 68.7, 67.7, 67.5, 66.9, 66.4, 66.2,
65.9, 63.5, 62.0, 61.7, 59.6, 54.5, 53.6, 53.3, 52.0, 49.6, 47.6, 46.8, 39.0, 37.8,
37.3, 36.0, 27.4, 23.0, 22.9, 22.8, 22.7, 21.4, 21.2, 20.8, 20.6, 20.5, 20.4;
MALDI MS: m/z: calcd for C84H98Cl3N3O31SiNa: 1800.49; found: 1800.32
[M+Na]+.
4.52 (d, 1H, J3,4 =2.6 Hz, H-4), 4.44 (m, 1H, CHSer), 4.41 (td, 1H, J1,2
=
3.6, J2,3 =11.4, J2,NH =8.7 Hz, H-2), 4.08, 3.92 (2 dd, 2H, Jgem =11.7 Hz, H-
6, 6’), 3.80 (td, 2H, Jgem =11.2 Hz, CH2Ser), 3.76 (s, 1H, H-5), 2.01, 1.77
(2s, 6H,
2 Ac), 1.00, 0.96 (2s, 18H, 2
tBu); 13C NMR (100 MHz,
[D6]DMSO): d = 170.2, 169.9, 169.4, 156.1, 136.7, 135.5, 128.4, 128.3,
128.1, 127.9, 127.9, 127.9, 98.4, 70.2, 69.6, 67.3, 66.5, 66.4, 66.3, 65.7, 54.3,
45.8, 27.3, 27.1, 26.9, 22.7, 22.5, 20.7, 20.2, 1.1; MALDI MS: m/z: calcd
for C38H48Cl6N2O13SiNa: 737.18; found: 737.30 [M+Na]+.
N-(9-Fluorenylmethoxycarbonyl)-O-[(methyl 5-acetamido-4,7,8,9-tetra-
O-acetyl-3,5-dideoxy-d-glycero-a-d-galacto-2-nonulopyranosylonate)-
(2!3)-(6-O-acetyl-2,4-di-O-benzoyl-b-d-galactopyranosyl)-(1!3)-2-
deoxy-2-(2,2,2-trichloroethoxycarbamoyl)-a-d-galactopyranosyl]-l-serine
benzyl ester (38): A 1m solution of n-tributylammonium hydrogenfluori-
de·1.25H2O (0.80 mL, 0.80 mmol) was added to a flask containing com-
pound 37 (160 mg, 89.9 mmol), and the mixture was stirred at ambient
temperature for 5 h. The termination of reaction was confirmed by TLC
(CHCl3/MeOH 10:1). The reaction mixture was extracted with EtOAc,
and the organic layer was washed with 2m HCl, H2O, satd. aq. Na2CO3
and brine, dried over Na2SO4 and concentrated. The residue was purified
with column chromatography on silica gel (CHCl3/MeOH 70:1) to give
38 (126 mg, 86%). [a]D =+65.58 (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3): d = 7.75 (m, 23H, Ph), 6.31 (d, 1H, NHSer), 5.68 (m, 1H, H-
8Neu), 5.43 (t, 1H, H-2Gal), 5.23 (d, 1H, H-4Gal), 5.21 (dd, 1H, H-7Neu), 5.14
(q, 2H, PhCH2), 5.00 (d, 1H, NHNeu), 4.95 (d, 1H, H-1Gal), 4.88 (m, 2H,
N-Benzyloxycarbonyl-O-{2,3,4,6-tetra-O-acetyl-b-d-galactopyranosyl-(1!
3)-2-deoxy-4,6-O-di-tert-butylsilylene-2-(2,2,2-trichloroethoxycarbamoyl)-
a-d-galactopyranosyl}-l-serine pentafluorophenyl ester (34): Molecular
sieves 4 Š (80 mg) was added to a solution of compound 13 (54 mg,
59.2 mmol) and 22 (20 mg, 49.3 mmol) in CH2Cl2 (1.0 mL). The suspension
was stirred for 1 h and cooled to 08C. To the mixture were added NIS
(26 mg, 118 mmol) and TfOH (1.0 mL, 11.8 mmol) and the stirring was
continued for 1 h. The termination of reaction was confirmed by TLC
(EtOAc/hexane 2:3). A similar work-up and purification by silica gel
column chromatography (EtOAc/hexane 1:30) as described for 26 gave
34 (52 mg, 88%). [a]D =+61.38 (c 0.46, CHCl3); 1H NMR (500 MHz,
CDCl3): mixture of rotamers 34a and 34b (a/b 1.4:1); 34a: d = 7.36–7.26
(m, 5H, Ph), 5.88 (d, 1H, NHSer), 5.36 (d, 1H, J3,4 =3.4 Hz, H-4Gal), 5.24
(t, 1H, J1,2 =7.5, J2,3 =10.2 Hz, H-2Gal), 5.16 (brs, 2H, PhCH2), 5.11 (d,
1H, H-1GalN), 5.06 (d, 1H, J2,NH =7.8 Hz, NHGalN), 4.98 (dd, 1H, J3,4
3.4 Hz, H-3Gal), 4.93 (m, 1H, CHSer), 4.78 (d, 1H, J1,2 =7.5 Hz, H-1Gal),
=
H-3Gal, OCH2CCl3), 4.78 (d, 1H, J1,2 =2.9 Hz, H-1GalN), 4.77 (m, 1H, J3,4
=
8868
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8862 – 8870

Oligosaccharides
FULL PAPER
4.4 Hz, H-4Neu), 4.66 (d, 1H, NHGalN), 4.59 (d, 1H, CHSer), 4.41 (m, 3H,
H-9Neu, CH2 of Fmoc), 4.22 (m, 3H, H-2GalN, H-6Gal, CH of Fmoc), 4.11
(m, 4H, H-4Gal, H-5Gal, H-6’Gal, CH2Ser), 4.04 (d, 1H, H-4GalN), 3.88 (m,
3H, COOMe), 3.86 (m, 5H, H-6GalN, H-5Neu, H-9’Neu, CH2Ser, OCH2CCl3),
3.74 (dd, 1H, H-3GalN), 3.69 (m, 2H, H-5GalN, H-6’GalN), 3.65 (dd, 1H, H-
6Neu), 2.96 (s, 1H, OH-4GalN), 2.46 (dd, 1H, J3,4 =4.4, Jgem =12.7 Hz, H-
3eqNeu), 2.37 (s, 1H, OH), 1.88 (6s, 18H, 6 Ac), 1.62 (t, 1H, H-3axNeu);
13C NMR (125 MHz, CDCl3): d = 171.2, 170.8, 170.5, 170.2, 170.1, 170.0,
168.2, 166.0, 165.2, 156.0, 154.1, 143.7, 141.3, 135.1, 133.6, 133.4, 130.2,
130.1, 129.0, 128.8, 128.7, 128.6, 128.5, 127.8, 127.1, 125.1, 120.5, 101.0,
99.8, 96.8, 95.7, 93.0, 88.7, 78.8, 74.0, 72.0, 71.7, 71.2, 71.1, 70.6, 70.0, 69.2,
68.3, 68.0, 67.6, 67.2, 67.1, 66.8, 62.9, 62.7, 62.5, 54.7, 53.4, 50.0, 48.8, 47.1,
37.4, 37.1, 34.4, 33.1, 32.8, 31.9, 30.3, 30.1, 29.7, 29.4, 27.1, 23.1, 22.7, 21.6,
21.0, 20.7, 20.6, 20.4, 19.7, 14.2, 14.1; MALDI MS: m/z: calcd for
C76H82Cl3N3O31: 1660.39; found: 1660.25 [M+Na]+.
154.5, 154.0, 143.7, 141.3, 141.2, 137.8, 133.5, 133.4, 130.1, 130.0, 129.0,
128.7, 128.7, 128.6, 128.5, 128.2, 128.2, 127.9, 127.8, 127.7, 127.1, 127.1,
125.4, 125.3, 125.3, 125.2, 125.2, 120.3, 119.9, 100.8, 98.7, 98.2, 96.7, 95.6,
95.5, 78.0, 77.2, 74.2, 74.0, 72.1, 71.6, 71.4, 71.2, 71.0, 70.9, 69.1, 68.8, 68.4,
67.8, 67.6, 67.5, 66.7, 62.5, 61.9, 54.2, 53.3, 52.7, 51.0, 50.0, 48.8, 46.9, 37.5,
37.3, 37.1, 31.9, 30.0, 29.7, 29.3, 27.1, 23.1, 22.7, 21.5, 20.9, 20.8, 20.8, 20.7,
20.6, 20.5, 14.1; MALDI MS: m/z: calcd for C97H108Cl6N4O44Na: 2265.44;
found: 2265.36 [M+Na]+.
N-(9-Fluorenylmethoxycarbonyl)-O-[{(methyl 5-acetamido-4,7,8,9-tetra-
O-acetyl-3,5-dideoxy-d-glycero-a-d-galacto-2-nonulopyranosylonate)-
(2!3)-(6-O-acetyl-2,4-di-O-benzoyl-b-d-galactopyranosyl}-(1!3)-
{(methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-a-d-
galacto-2-nonulopyranosylonate)-(2!6)}-4-O-acetyl-2-deoxy-2-(2,2,2-tri-
chloroethoxycarbamoyl)-a-d-galactopyranosyl]-l-serine benzyl ester (41):
Zinc powder (280 mg) was added to a solution of compound 40a (28 mg,
12.5 mmol) in AcOH (0.2 mL). The suspension was stirred for 3 h at
408C. The termination of reaction was confirmed by TLC (CHCl3/
MeOH/PhCH3 10:1:1). The reaction mixture was filtered through Celite.
The combined filtrate and washings were extracted with CHCl3, and the
organic layer was washed with satd. aq. Na2CO3 and brine, dried over
Na2SO4 and concentrated. To the residue in pyridine (0.4 mL) was added
acetic anhydride (47 mL) at 08C under argon atmosphere, and the mix-
ture was stirred for 11 h at ambient temperature. The reaction mixture
was coevaporated with toluene and extracted with CHCl3. The organic
phase was washed with 2m HCl, H2O, satd. aq. Na2CO3 and brine, dried
(Na2SO4) and concentrated. The residue was purified by chromatography
on silica gel (CHCl3/MeOH/PhCH3 35:1:3.5) to give 41 (17 mg, 68%).
[a]D =+44.58 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3): d = 7.72 (m,
23H, Ph), 6.11 (d, 1H, NHSer), 5.69 (m, 1H, H-8c), 5.45 (d, 1H, NHa),
5.40 (s, 1H, H-4a), 5.34 (t, 1H, J1,2 =7.8 Hz, H-2b), 5.32 (m, 2H, H-7d,
H-8d), 5.22 (d, 1H, J3,4 =3.2 Hz, H-4b), 5.21, 5.02 (2 d, 2H, PhCH2), 5.15
N-(9-Fluorenylmethoxycarbonyl)-O-[{methyl 5-acetamido-4,7,8,9-tetra-
O-acetyl-3,5-dideoxy-D-glycero-a-d-galacto-2-nonulopyranosylonate-
(2!3)-6-O-acetyl-2,4-di-O-benzoyl-b-d-galactopyranosyl-(1!3)}-{methyl
4,7,8,9-tetra-O-acetyl-3,5-dideoxy-5-(2,2,2-trichloroethoxycarbamoyl)-d-
glycero-a-d-galacto-2-nonulopyranosylonate-(2!6)}-2-deoxy-2-(2,2,2-tri-
chloroethoxycarbamoyl)-a-d-galactopyranosyl]-l-serine benzyl ester (40):
Molecular sieves 3 Š (170 mg) was added to a solution of compound 39
(71 mg, 98.8 mmol) and 38 (108 mg, 65.9 mmol) in CH3CN/CH2Cl2 (1.5/
0.2 mL). The suspension was stirred for 1 h and cooled to ꢀ358C. To the
mixture were added NIS (45 mg, 198 mmol) and TfOH (2.0 mL,
19.8 mmol) and stirring was continued for 31 h. The termination of reac-
tion was confirmed by TLC (CHCl3/MeOH/PhCH3 10:1:1). The reaction
mixture was filtered through Celite. The combined filtrate and washings
were extracted with CHCl3, and the organic layer was washed with satd.
aq. Na2CO3, satd. aq. Na2S2O3 and brine, dried over Na2SO4 and concen-
trated. The residue was purified by column chromatography on silica gel
(CHCl3/MeOH/PhCH3 70:1:7) to give 40a (108 mg, 73%) and 40b
(32 mg, 21%). 40a: [a]D =+43.58 (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3): d = 7.65 (m, 23H, Ph), 6.11 (d, 1H, NHSer), 5.65 (m, 1H, H-8c),
5.42 (t, 1H, H-2b), 5.37 (m, 2H, H-7d, H-8d), 5.26 (d, 1H, H-4b), 5.20
(m, 1H, H-7c), 5.12 (q, 2H, PhCH2), 5.00 (d, 1H, NHc), 4.97 (m, 3H, H-
4d, NHd, OCH2CCl3), 4.96 (d, 1H, H-1b), 4.89 (d, 1H, OCH2CCl3), 4.84
(d, 1H, H-3b), 4.78 (m, 2H, H-1a, H-4c), 4.66 (m, 1H, NHa), 4.25 (t, 1H,
CHSer), 4.45 (d, 1H, OCH2CCl3), 4.40 (d, 1H, H-9c), 4.30 (m, 5H, H-2a,
H-6b, H-9d, CH2 of Fmoc), 4.15 (m, 5H, H-5b, H-6’b, H-6d, H-9’d, CH
of Fmoc), 4.04 (s, 1H, H-4a), 3.99 (m, 1H, H-6a), 3.94 (s, 1H, CH2Ser),
3.90 (m, 5H, H-3a, CH2Ser, COOMe), 3.82 (m, 3H, H-6’, H-5c, H-9’c),
3.73 (d, 1H, OCH2CCl3), 3.71 (s, 3H, COOMe), 3.65 (m, 2H, H-6c, H-
5d), 3.58 (t, 1H, H-5a), 2.77 (s, 1H, OH-4a), 2.64 (dd, 1H, Jgem =12.5 Hz,
H-3eqd), 2.46 (dd, 1H, Jgem =12.5 Hz,H-3eqc), 2.07 (10s, 30H, 10 Ac), 1.59
(t, 2H, Jgem =12.5 Hz, H-3axc, H-3axd); 13C NMR (100 MHz, CDCl3): d =
171.1, 171.0, 170.8, 170.7, 170.7, 170.4, 170.3, 170.3, 170.2, 170.1, 169.8,
168.2, 168.1, 167.8, 165.9, 165.2, 155.9, 154.0, 143.7, 143.6, 141.2, 137.8,
135.0, 133.5, 133.4, 130.0, 129.0, 129.0, 128.8, 128.7, 128.6, 128.2, 128.1,
127.7, 127.1, 125.3, 125.2, 125.0, 120.0, 100.8, 99.1, 98.6, 96.7, 95.6, 95.4,
78.4, 74.4, 73.9, 72.1, 72.0, 71.1, 70.7, 69.2, 68.8, 68.7, 68.4, 68.2, 67.5, 67.3,
67.0, 66.8, 63.7, 62.7, 62.1, 54.4, 53.3, 52.8, 51.5, 50.0, 48.7, 47.0, 37.5, 37.3,
37.1, 32.7, 31.9, 30.0, 29.7, 29.3, 27.0, 23.1, 22.7, 21.5, 21.4, 20.9, 20.8, 20.7,
20.7, 20.5, 20.4, 19.7, 14.1; MALDI MS: m/z: calcd for
C97H108Cl6N4O44Na: 2265.44; found: 2265.48 [M+Na]+; 40b: [a]D =+
44.08 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3): d = 7.68 (m, 23H,
Ph), 6.41 (d, 1H, NHa), 6.27 (d, 1H, NHd), 5.62 (m, 1H, H-8c), 5.50 (m,
2H, H-4d, H-7d), 5.44 (t, 1H, H-2b), 5.35 (m, 1H, H-8d), 5.29 (d, 1H, H-
4b), 5.18 (m, 3H, H-7c, PhCH2), 4.99 (d, 1H, H-1b), 4.96 (d, 1H, NHc),
4.86 (m, 2H, H-3b, OCH2CCl3), 4.83 (d, 1H, J1,2 =2.7 Hz, H-1a), 4.73 (m,
4H, NHa, H-4c, H-9d, CHSer), 4.36 (m, 3H, H-9d, CH2 and CH of
Fmoc), 4.32 (td, 1H, J1,2 =2.7 Hz, H-2a), 4.24 (s, 3H, H-4a, H-6b, H-6’b),
4.14 (m, 4H, H-6d, H-9’d, OCH2CCl3), 4.06 (t, 1H, H-5b), 4.02 (dd, 1H,
CH2Ser), 3.95 (d, 1H, OCH2CCl3), 3.91 (dd, 1H, H-9’c), 3.87 (s, 3H,
COOMe), 3.79 (m, 5H, H-3a, H-6a, H-6’a, H-5c, CH2Ser), 3.71 (s, 3H,
COOMe), 3.65 (m, 2H, H-5a, H-6c), 2.93 (s, 1H, OH), 2.59 (dd, 1H, H-
(dd, 1H, H-7c), 5.11 (d, 1H, NHc), 4.96 (d, 1H, NHc), 4.91 (d, 1H, J1,2
7.8 Hz, H-1b), 4.87 (d, 1H, J1,2 =2.9 Hz, H-1a), 4.84 (m, 1H, H-4d), 4.77
(dd, 1H, H-4c), 4.75 (dd, 1H, J3,4 =3.2 Hz, H-3b), 4.57 (m, 1H, CHSer
=
,
4.41 (m, 5H, J1,2 =2.9 Hz, H-2a, H-6b, H-6’b, H-9d, CH of Fmoc), 4.26
(m, 2H, H-5b, H-9d), 4.07 (m, 6H, H-3a, H-5d, H-6d, H-9’d, CH2 of
Fmoc), 3.92 (m, 5H, H-5a, CH2Ser, CO(O)CH3), 3.79 (m, 7H, H-6a, H-5c,
H-9’c, CH2Ser, CO(O)CH3), 3.61 (dd, 1H, H-6c), 3.37 (dd, 1H, H-6’a),
2.55 (dd, 1H, H-3eqd), 2.47 (dd, 1H, H-3eqc), 1.99 (13s, 39H, Ac), 1.97 (t,
1H, H-3axd), 1.63 (t, 1H, H-3axc); 13C NMR (125 MHz, CDCl3): d
=
171.1, 170.9, 170.8, 170.6, 170.3, 170.2, 170.1, 170.0, 169.9, 169.6, 168.2,
167.8, 165.7, 164.8, 156.1, 143.8, 143.7, 141.3, 134.9, 133.4, 133.3, 130.3,
130.2, 130.1, 129.4, 128.9, 128.8, 128.5, 128.4, 127.8, 127.1, 125.1, 120.0,
117.1, 116.9, 116.6, 100.8, 99.9, 98.6, 96.8, 75.0, 72.6, 71.9, 71.3, 71.2, 71.0,
69.3, 69.1, 68.9, 68.5, 68.2, 67.4, 67.2, 67.1, 64.2, 63.0, 62.2, 61.8, 54.6, 53.3,
52.8, 49.3, 48.9, 48.7, 47.1, 37.5, 37.2, 37.1, 32.8, 31.9, 30.4, 30.0, 29.7, 29.4,
27.5, 27.1, 23.2, 23.1, 22.7, 22.2, 21.5, 21.1, 21.0, 20.8, 20.7, 20.6, 20.3, 14.1;
MALDI MS: m/z: calcd for C97H112N4O43Na: 2043.66; found: 2043.67
[M+Na]+.
Acknowledgements
This work was financially supported in part by MEXT of Japan (Grant-
in-Aid for Scientific Research to H.A., no. 16780083, H.I., no.
16580086, and M.K., no. 1701007), and Mitsubishi Chemical Corpora-
tion Fund (H.A.). We thank Ms. Kiyoko Ito for technical assistance.
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Chem. Eur. J. 2006, 12, 8862 – 8870
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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Received: June 14, 2006
Published online: August 22, 2006
8870
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Chem. Eur. J. 2006, 12, 8862 – 8870