Solid-phase synthesis of complex oligosaccharides using azidoglucose as a glycosyl acceptor

Article abstract of DOI:10.1002/ejoc.200400111

The solid phase synthesis of oligosaccharides 1-3 was performed on Merrifield resin. These syntheses are based on the hydroxymethylbenzyl benzoate spacer-linker system and, for regioselective chain extension, the use of O-glycosyl trichloroacetimidates as glycosyl donors containing temporary O-Fmoc protection. The important lactosamine-containing oligosaccharides 1-3 are accessible in excellent yields by using a 2-azidoglucose residue as the glucosamine building block adjacent to the spacer-linker system. Only standard amounts of the glycosyl donor are employed in this solid phase oligosaccharide synthesis and we did not have to resort to any capping procedures. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400111

FULL PAPER
Solid-Phase Synthesis of Complex Oligosaccharides Using Azidoglucose as a
Glycosyl Acceptor
Xiangyang Wu[a] and Richard R. Schmidt[a]
Keywords: Azidoglucose / Carbohydrates / Oligosaccharides / Solid phase / Synthesis / Trichloroacetimidates
The solid phase synthesis of oligosaccharides 1−3 was per-
formed on Merrifield resin. These syntheses are based on the
hydroxymethylbenzyl benzoate spacer-linker system and, for
regioselective chain extension, the use of O-glycosyl trichlo-
roacetimidates as glycosyl donors containing temporary O-
Fmoc protection. The important lactosamine-containing oli-
gosaccharides 1−3 are accessible in excellent yields by using
a 2-azidoglucose residue as the glucosamine building block
adjacent to the spacer-linker system. Only standard amounts
of the glycosyl donor are employed in this solid phase oligos-
accharide synthesis and we did not have to resort to any cap-
ping procedures.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
group as a latent amino functionality, because this group
has proven, in solution phase oligosaccharide synthesis, to
Oligosaccharides, which play an important role in various have great versatility and efficiency and it can be trans-
biological processes, including inflammation, immune re- formed readily into an N-acetylamino group.[24,25] Hence,
sponse, metastasis, and fertilization, have attracted a lot of we selected an azido group-containing glucosamine residue
interest in recent years[1Ϫ3] and, as a consequence, oligosac- for the solid phase synthesis of target molecules 1؊3
charide synthesis has become an important task.[4Ϫ8] Re- (Scheme 1), which are constituents of various oligosacchar-
cently, successful solid phase oligosaccharide syntheses ide types.
(SPOS) have been developed by several research
groups[9Ϫ20] because SPOS exhibits inherent advantages
over solution phase synthesis, such as higher reaction yields
because of the use of excess building blocks and/or reagents,
shorter times for the completion of the syntheses, and more
convenient purification procedures. In contrast to oligopep-
tides and oligonucleotides, which are routinely prepared on
automated synthesizers, no general strategy has yet ap-
peared for the efficient construction of various complex oli-
gosaccharides on polymer supports, which, therefore, limits
the use of automated synthesizers. To this end, quite a deal
of fine tuning of the SPOS methodology is still required.
One of the problems that we encountered recently is the
low reactivity of N-phthaloyl- or N-dimethylmaleoyl-pro-
tected, 4-O-unprotected glucosamine residues as acceptors,
particularly when these residues are positioned next to the
resin linkage. Therefore, in our previous approaches to the
syntheses of N-glycan, lactosamine, and oligolactosamine
oligosaccharides, we have introduced a novel capping pro-
cedure to overcome the low reactivity of this acceptor and,
thus, to avoid the accumulation of undesired by-
products.[21Ϫ23] Alternatively, a reactivity increase of the ac-
ceptor moiety can be envisaged by introducing the azido
Scheme 1. Target molecules 1؊3
Results and Discussion
Attachment of target molecules 1؊3 to the Merrifield re-
sin (for instance, to carboxylic acid 5) will lead to inter-
mediate 4a (Scheme 2, which also exhibits the synthesis
strategy).
[a]
Fachbereich Chemie, Universität Konstanz,
Fach M 725, 78457 Konstanz, Germany
Fax: (internat) ϩ49-7531-88-3135
E-mail: Richard.Schmidt@uni-konstanz.de
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400111
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Solid-Phase Synthesis of Complex Oligosaccharides
FULL PAPER
Scheme 2. Synthesis strategy and building blocks required for the synthesis of 1؊3
This strategy is based on our hydroxymethylbenzyl ben-
The Fmoc group was introduced using Fmoc-Cl and a
zoate spacer-linker system[26] with 4b as the decisive inter- catalytic amount of Steglich’s reagent (DMAP) in pyridine
mediate and O-Fmoc protected O-glycosyl trichloroacetimi- at room temperature (Ǟ12). 1-O-Desilylation using an ex-
dates as the glycosyl donors; hence, we required building cess of HF·pyridine complex in THF furnished 1-O-unpro-
blocks 6؊10 for the synthesis of 1؊3.
tected 13, which we transformed subsequently into trichlo-
roacetimidate 14 by treatment with trichloroacetonitrile in
the presence of sodium hydride (0.1 equiv.). Glycosylation
of linker 15[29] in dichloromethane/acetonitrile, 1:1, in the
presence of TMSOTf as catalyst, led, as a result of the ni-
trile effect,[30] to β-glycoside 16, which we transformed into
Synthesis of Building Blocks 6؊10
Building blocks 7, 9, and 10 are readily available by fol-
lowing previously reported procedures.[27] The sugar-linker
building block 6 (Scheme 3) was prepared from the known
2-azido-3,6-di-O-benzyl-2-deoxy-glucose derivative 11,
which was obtained from -glucosamine in five steps.[28]
building block
6 by desilylation with an excess of
HF·pyridine complex in THF.
The synthesis of the galactosyl donor 8 was based on the
known galactoside 18 (Scheme 4).[27]
Scheme 4. Synthesis of building block 8; reagents and conditions:
(a) DCC, DMAP, CH2Cl2, quant.; (b) 1. BH3·THF, Bu2BOTf, 74%;
2. FmocCl, pyridine, 90%; (c) 1. HF·pyridine, THF, 98%; 2.
CCl3CN, HaH, 70%.
Scheme 3. Synthesis of sugar-linker building block 6; reagents and
conditions: (a) FmocCl, pyridine, DMAP, 95%; (b) HF·pyridine,
THF, 95%; (c) Cl3CCN, NaH, 95%; (d) CH2Cl2/CH3CN, 1:1,
TMSOTf, 60%; (e) HF·pyridine, THF, 78%
4-Nitrophenoxyacetic acid (PNPA-OH) 17 was obtained
by following a published procedure.[31] Treatment of 17 and
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X. Wu, R. R. Schmidt
FULL PAPER
18 with DCC as condensing agent and a catalytic amount sin-bound disaccharide 22. Generally, we monitored the
of DMAP in dichloromethane afforded 19 in quantitative progress of the reaction by performing TLC and MALDI-
yield. Reductive opening of the 4,6-O-benzylidene group TOF analyses of the crude cleavage product (NaOMe,
containing ring with borane in the presence of dibutylbor- CH2Cl2/MeOH) obtained from a small sample of resin
ane triflate[32] afforded the desired 6-O-unprotected inter- (2 mg). Preparative cleavage of resin 22 and per-O-acety-
mediate, which on treatment with Fmoc-Cl in pyridine fur- lation of the product afforded, after flash chromatography,
nished the 1-O-silyl-protected glycoside 20 that carries two the desired lactosamine disaccharide 1 in 81% yield from 6
temporary protecting groups (Fmoc and PNPA) for orthog- (96% per step over five steps); this result suggests that resin
onal cleavage. Removal of the 1-O-silyl group using an ex- 21, which has a 2-azido group in the glucosamine residue,
cess of HF·pyridine complex in THF, and then reaction is an excellent acceptor.
with trichloroacetonitrile in the presence of sodium hydride
(0.1 equiv.) as base, gave the desired galactosyl donor 8.
A β-(1Ϫ3)-linked N-acetyllactosamine chain is a fre-
quently occurring structural unit in, for instance, human
milk. Therefore, we repeated the previous synthesis up to
resin 22, which contains one lactosamine residue and an
Fmoc unit as a temporary protecting group at the 3b-O for
chain extension. Treatment of resin 22 with triethylamine
in dichloromethane (for selective Fmoc removal) and then
glycosylation with glucosamine donor 9 in the presence of
TMSOTf as catalyst afforded the trisaccharide resin 23.
After washing with dichloromethane/THF, 1:1, and then
performing Fmoc removal and glycosylation with donor 7
as described before, we obtained tetrasaccharide resin 24. A
final preparative cleavage of resin 24 using NaOMe/MeOH,
and then O-acetylation of the cleavage product using acetic
anhydride in pyridine, afforded, after flash chromatography,
target molecule 2 in a satisfactory yield of 21% from 6 (84%
per step over nine steps). Investigations with the 2-azidoglu-
cose donor 14, rather than the 2-phthalimidoglucose donor
9, led to higher product yields, but, to our surprise, the gly-
cosylation step on the polymer support, although carried
out in a 1:1-mixture of dichloromethane/acetonitrile at low
temperature, was not fully β-selective.
Solid Phase Synthesis of Target Molecules 1؊3
The SPOS was initiated by attaching primary alcohol 6
to the solid support 5 through a condensation reaction with
N,N-diisopropylcarbodiimide (DIC) and a catalytic amount
of DMAP in dichloromethane; unchanged carboxylate
functions were transformed into their methyl esters as de-
scribed previously (Scheme 5).[27]
For the synthesis of target molecule 3, again we first
treated resin 4b with triethylamine to remove the 4-O-Fmoc
group; the subsequent glycosylation with galactosyl donor
8 (3 equiv.) in the presence of TMSOTf (0.3 equiv.) as cata-
lyst in dichloromethane at Ϫ20 °C furnished disaccharide
resin 25. The Fmoc group was then removed selectively in
Scheme 5. Synthesis of oligosaccharides 1 and 2; reagents and con-
ditions: (a) 1. DIC, DMAP, CH2Cl2; 2. MeOH; (b); NEt3/CH2Cl2,
8:1; (c) CH2Cl2, Ϫ40 °C, TMSOTf; (d) NaOMe/MeOH; (e)
Ac2O, pyridine.
We determined the loading of the resin 4b to be
0.12 mmol/g resin after recycling and purification of the
starting material 6. Treatment of resin 4b with triethylamine
in dichloromethane afforded the 4-O-unprotected resin 21,
which we subjected to glycosylation with 3 equiv. of donor
Scheme 6. Synthesis of trisaccharide 3; reagents and conditions:
(a) NEt3/CH2Cl2, 8:1; (b) TMSOTf, Ϫ20 °C, CH2Cl2; (c) NaOMe/
7[27] and TMSOTf (0.3 equiv.) as catalyst to furnish the re- MeOH; (d) Ac2O, pyridine.
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Solid-Phase Synthesis of Complex Oligosaccharides
FULL PAPER
772.5 [M ϩ Naϩ]. C43H51N3O7Si (749.9): calcd. C 68.87, H 6.85,
N 5.60; found C 68.87, H 6.86, N 5.60.
the presence of the PNPA group using triethylamine in di-
chloromethane. After washing with dichloromethane/THF,
1:1, glycosylation with the mannosyl donor 10[26,27] af-
forded the trisaccharide resin 26. A final preparative cleav-
age and O-acetylation, as described above, afforded, after
flash chromatography, the trisaccharide 3 in 63% overall
2-Azido-3,6-di-O-benzyl-2-deoxy-4-O-(9-fluorenylmethoxy-
carbonyl)-α/β-
D-glucopyranose
(13):
HF·pyridine
(7.0 mL,
50.7 mmol) was added dropwise at room temperature to a solution
of 12 (3.8 g, 5.07 mmol) in dry THF (30 mL), and then the mixture
yield from 6 (95% per step over seven steps). Thus, with this was stirred overnight. The solution was diluted with ethyl acetate
(50 mL), neutralized with solid calcium carbonate and water
(1 mL), and poured into water (50 mL) and then the layers were
separated. The aqueous layer was extracted with ethyl acetate (3 ϫ
50 mL) and the combined organic layers were dried over mag-
nesium sulfate and concentrated in vacuo. The residue was purified
by flash chromatography (petroleum ether/ethyl acetate, 4:1) to af-
ford 13 (2.9 g, 95%) as a white foam. TLC (petroleum ether/ethyl
addition to our previously introduced SPOS methodology,
oligosaccharides containing glucosamine residues at their
reducing end also can be obtained in excellent yields
(Scheme 6).
1
Conclusion
acetate, 2:1): Rf ϭ 0.43. [α]D ϭ ϩ5.9 (c ϭ 1.0, CHCl3). H NMR
(250 MHz, CDCl3): δ ϭ 3.18 (d, 1 H, OH), 3.39Ϫ3.62 (m, 4 H, 2-
H, 5-H, 6-H, 6Ј-H), 4.08 (t, 3J ϭ 7.2, 3J ϭ 9.6 Hz, 1 H, 3-H),
The use of a 4-O-unprotected 2-azidoglucose acceptor,
rather than a corresponding 2-phthalimido- or 2-dimeth-
ylmaleimido-glucose acceptor, close to the resin linkage
greatly improved the SPOS results when applied to our pre-
viously introduced methodology. Hence, the amount of gly-
cosyl donor required for high-yielding glycosylation is re-
2
4.18Ϫ4.34 (d, J ϭ 7.2 Hz, 2 H), 4.48 (s, 2 H, CH2Ph), 4.57 (t, 1
H), 4.65 (d, 2J ϭ 9.3 Hz, 1 H, 1/2 CH2Ph), 4.84 (dd, 3J ϭ 9.6, 3J ϭ
7.7 Hz, 1 H, 4-H), 5.3 (br., 1 H, 1-H), 7.18Ϫ7.75 (m, 18 H, Ar)
ppm. MALDI-MS: m/z ϭ 629.9 [M ϩ Naϩ]. C35H33N3O7 (607.7):
calcd. C 69.18, H 5.48, N 6.91; found C 69.14, H 5.59, N 6.93.
duced and the capping of the unchanged acceptor after the 2-Azido-O-[3,6-di-O-benzyl-2-deoxy-4-O-(9-fluorenylmethoxy-
carbonyl)-α/β-D-glucopyranosyl] Trichloroacetimidate (14): Com-
glycosylation step, to reduce by-product formation and to
ease product purification, is not required.
pound 13 (2.4 g, 3.95 mmol) was dissolved in a mixture of dichloro-
methane (10 mL) and Cl3CCN (10 mL), and then sodium hydride
(2 mg) was added at 0 °C. After 30 min, the mixture was neu-
tralized with silica gel and concentrated at low pressure. The resi-
due was purified by flash chromatography (petroleum ether/ethyl
acetate, 4:1) to afford 14 (2.8 g, 95%) as a white foam. TLC (petro-
leum ether/ethyl acetate, 2:1): Rf ϭ 0.67 (β). [α]D ϭ Ϫ1.4 (c ϭ 1.0,
Experimental Section
General Remarks: Each solvent was purified and dried in the usual
manner. All reactions were performed using dry solvents and under
argon unless otherwise stated. TLC was performed on plastic plates
of silica gel 60 F254. Detection was achieved by treatment with a
solution of ammonium molybdate (20 g) and cerium() sulfate
(0.4 g) in 10% H2SO4 (400 mL), or with 15% H2SO4, and then heat-
ing at 150 °C. Flash chromatography was carried out on silica gel
(Baker 30Ϫ60 mm). Adsorption of crude reaction products was
performed using silica gel (Baker 60Ϫ200 mm). Petroleum ether
was used in the boiling range 35Ϫ70 °C; toluene, CH2Cl2, MeOH,
and EtOAc were distilled. Optical rotations were determined at 21
°C using a PerkinϪElmer 241/MC polarimeter (1-dm cell). NMR
spectra were recorded using Bruker 600 DRX instruments; tetra-
methylsilane was the internal standard. MS spectra were recorded
using a MALDI-kompakt (Kratos) instrument operating in the
positive mode; 2,5-dihydroxybenzoic acid in THF was the matrix.
Microanalyses were performed in the microanalysis unit at the
Fachbereich Chemie, Universität Konstanz.
1
CHCl3). H NMR (250 MHz, CDCl3): δ ϭ 3.54Ϫ3.78 (m, 4 H, α/
β, 2-H, 5-H, 6-H, 6Ј-H), 4.03Ϫ4.14 (m, 1 H, α/β, 3-H), 4.27Ϫ4.33
(m, 2 H), 4.45Ϫ4.49 (m, 2 H, CH2Ph), 4.65Ϫ4.80 (m, 2 H, CH2Ph),
3
3
4.93Ϫ5.00 (dd, J ϭ 9.3, J ϭ 9.6 Hz, 1 H, 4-Hβ), 5.08Ϫ5.17 (dd,
3J ϭ 9.5, J ϭ 10.0 Hz, 1 H, 4-Hα), 5.63 (d, J1,2 ϭ 8.3 Hz, 1 H, 1-
3
Hβ), 6.41 (d, J1,2 ϭ 3.5 Hz, 1 H, 1-Hα), 7.06Ϫ7.75 (m, 18 H, Ar),
8.72 (s, 1 H, NHα), 8.75 (s, 1 H, NHβ) ppm. MALDI-MS: m/z ϭ
629.3 [M Ϫ Cl3CCN ϩ Naϩ]. C37H33Cl3N4O7 (752.2): calcd. C
58.08, H 4.42, N 7.45; found C 58.02, H 4.11, N 7.55.
4-(tert-Butyldiphenylsilyloxymethyl)benzyl 2-Azido-3,6-di-O-benzyl-
2-deoxy-4-O-(9-fluorenylmethoxycarbonyl)-β-D-glucopyranoside
(16): A solution of 15[29] (170 mg, 0.45 mmol) and 14 (444 mg,
0.5 mmol) in a mixture of CH2Cl2/CH3CN, 1:1 (5 mL) was stirred
˚
in the presence of 4-A molecular sieves under argon at room tem-
perature for 5 min. TMSOTf (3 µL, 0.015 mmol) was slowly added
dropwise and then the reaction mixture was stirred for 30 min. The
solution was filtered and the filtrates were concentrated in vacuo.
The residue was purified by flash chromatography (petroleum
ether/ethyl acetate, 6:1) to afford 16 (260 mg, 60%). TLC (petro-
leum ether/ethyl acetate, 4:1): Rf ϭ 0.57. [α]D ϭ Ϫ21.2 (c ϭ 1.0,
CHCl3). 1H NMR (250 MHz, CDCl3): δ ϭ 1.04 (s, 9 H, tBu),
3.36Ϫ3.57 (m, 5 H), 4.09 (t, 3J ϭ 7.1 Hz, 1 H) 4.22Ϫ4.26 (dd, 3J ϭ
7.5 Hz, 2 H), 4.32 (d, J1,2 ϭ 7.7 Hz, 1 H, 1-H), 4.48 (s, 2 H,
CH2Ph), 4.56Ϫ4.66 (t, 2J ϭ 12.9 Hz, 2 H, CH2Ph), 4.71 (s, 2 H,
CH2Ph), 4.75Ϫ4.90 (m, 3 H, 4-H, CH2Ph), 7.14Ϫ7.72 (m, 32 H,
Ar) ppm. MALDI-MS: m/z ϭ 989.9 [M ϩ Naϩ]. C59H59N3O8Si
(966.2): calcd. C 73.34, H 6.15, N 4.35; found C 73.64, H 6.26,
N 4.37.
Dimethylthexylsilyl 2-Azido-3,6-di-O-benzyl-2-deoxy-4-O-(9-fluor-
enylmethoxycarbonyl)-β-D-glucopyranoside (12): FmocCl (7.0 g,
27.5 mmol) and DMAP (24 mg, 0.2 mmol) were added at room
temperature to a solution of 11[28] (2.9 g, 5.5 mmol) in pyridine
(20 mL). After 2 h, the mixture was concentrated at low pressure,
and the residue purified by flash chromatography (petroleum ether/
ethyl acetate, 20:1) to afford 12 (3.9 g, 95%) as a white foam. TLC
(petroleum ether/ethyl acetate, 10:1): Rf ϭ 0.33. [α]D ϭ Ϫ21.6 (c ϭ
1
1.0, CHCl3). H NMR (250 MHz, CDCl3): δ ϭ 0.08, 0.11 (2 s, 6
H, 2 CH3), 0.78Ϫ0.81 (m, 12 H, 4 CH3), 1.57 [m, 1 H, CH(CH3)2],
3.3 (m, 2 H, 3-H, 2-H), 3.48Ϫ3.60 (m, 3 H, 5-H, 6-H, 6Ј-H), 4.18
2
(d, J ϭ 7.2 Hz, 2 H), 4.20 (m, 1 H), 4.33 (d, J1,2 ϭ 7.2 Hz, 1 H,
1-H), 4.40Ϫ4.57 (m, 3 H, 3/2 CH2Ph), 4.67Ϫ4.74 (m, 2 H, 4-H, 1/ 4-(Hydroxymethyl)benzyl 2-Azido-3,6-di-O-benzyl-2-deoxy-4-O-(9-
2 CH2Ph), 7.11Ϫ7.69 (m, 18 H, Ar) ppm. MALDI-MS: m/z ϭ fluorenylmethoxycarbonyl)-β- -glucopyranoside (6): HF·pyridine
D
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X. Wu, R. R. Schmidt
FULL PAPER
(0.35 mL, 2.28 mmol) was added dropwise at room temperature to
a solution of 16 (220 mg, 0.228 mmol) in dry THF (10 mL), and
then the mixture was stirred overnight. The solution was diluted
with ethyl acetate (10 mL), neutralized with solid calcium carbon-
ate and water (0.5 mL), and then poured into water (10 mL); the
TLC (petroleum ether/ethyl acetate, 2:1): Rf ϭ 0.43. [α]D ϭ ϩ16.1
(c ϭ 1.0, CHCl3). H NMR (250 MHz, CDCl3): δ ϭ 0.01, 0.10 (2
1
s, 6 H, 2 CH3), 0.63Ϫ067 (m, 12 H, 4 CH3), 1.41Ϫ1.46 [m, 1 H,
CH(CH3)2], 3.67Ϫ3.83 (t, 3J ϭ 6.5 Hz, 1 H, 5-H), 3.94 (d, 3J ϭ
2.9 Hz, 1 H, 4-H), 4.07Ϫ4.46 (m, 7 H), 4.64 (s, 2 H, CH2OPh),
3
combined organic layers were dried with magnesium sulfate and 4.78 (d, J1,2 ϭ 7.5 Hz, 1 H, 1-H), 5.23 (dd, J ϭ 3.2 Hz, 1 H, 3-
3
concentrated in vacuo. The residue was purified by flash chroma-
H), 5.4 (dd, J ϭ 7.5 Hz, 1 H, 2-H), 6.6Ϫ7.9 (m, 22 H, Ar) ppm.
tography (petroleum ether/ethyl acetate, 2:1) to afford 6 (130 mg, MALDI-MS: m/z ϭ 940.6 [M ϩ Naϩ]. C51H55NO13Si (918.1):
78%) as a white oil. TLC (petroleum ether/ethyl acetate, 2:1): Rf ϭ
0.25. [α]D ϭ Ϫ15.4 (c ϭ 1.0, CHCl3). 1H NMR (250 MHz, CDCl3):
calcd. C 66.72, H 6.04, N 1.53; found C 66.44, H 5.89, N 1.60.
O-[2-O-Benzoyl-4-O-benzyl-6-O-(9-fluorenylmethoxycarbonyl)-3-O-
(4-nitrophenoxyacetyl)-α/β-D-galactopyranosyl] Trichloroacetimid-
3
δ ϭ 3.32Ϫ3.56 (m, 5 H, 2-H, 3-H, 5-H, 6-H, 6Ј-H), 4.04 (t, J ϭ
3
7.1 Hz, 1 H), 4.22 (dd, J ϭ 7.6 Hz, 2 H), 4.27 (d, J1,2 ϭ 7.8 Hz, 1
ate (8): HF·pyridine (1.4 mL, 9 mmol) was added dropwise at room
temperature to a solution of 20 (1.65 g, 1.8 mmol) in dry THF
(20 mL), and then the mixture was stirred overnight. The solution
was diluted with ethyl acetate (50 mL), neutralized with solid cal-
cium carbonate and water (1 mL), and poured into water (50 mL)
and then the layers were separated. The aqueous layer was ex-
tracted with ethyl acetate (3 ϫ 50 mL) and the combined organic
layers were dried over magnesium sulfate and concentrated in va-
cuo. The residue was purified by flash chromatography (petroleum
ether/ethyl acetate, 2:1) to afford 2-O-benzoyl-4-O-benzyl-6-O-(9-
fluorenylmethoxycarbonyl)-3-O-(4-nitrophenoxyacetyl)-α/β--
galactopyranose (1.38 g, 98%) as a white foam. TLC (petroleum
ether/ethyl acetate, 2:1): Rf ϭ 0.36 (α). [α]D ϭ ϩ61.5 (c ϭ 1.0,
CHCl3). 1H NMR (250 MHz, CDCl3): δ ϭ 3.0 (s, 1 H, OH),
4.1Ϫ4.7 (m, 11 H), 5.50-5.57 (dd, 3J ϭ 3.5 Hz, 1 H, 2-H), 5.64 (m,
H, 1-H), 4.45 (s, 2 H, CH2Ph), 4.53Ϫ4.62 (m, 4 H, 2 CH2Ph),
4.68Ϫ4.88 (m, 3 H, 4-H, CH2Ph), 7.12, 7.69 (m, 22 H, Ar) ppm.
MALDI-MS: m/z ϭ 749 [M ϩ Naϩ]. C43H41N3O8 (726.9): calcd.
C 70.09, H 5.70, N 5.75; found C 70.32, H 5.77, N 6.00.
Dimethylthexylsilyl 2-O-Benzoyl-4,6-O-benzylidene-3-O-(4-nitrophen-
oxyacetyl)-β-D
-galactopyranoside (19): A solution of 18[27] (3.0 g,
5.84 mmol) and 17[31] (1.38 g, 7 mmol) in dry CH2Cl2 (20 mL) was
treated with a catalytic amount of DMAP (70 mg, 0.58 mmol) and
DCC (2.4 g, 11.7 mmol). After 2 h, the reaction mixture was con-
centrated at low pressure, and the residue was purified by flash
chromatography (petroleum ether/ethyl acetate, 3:1) to afford 19
(4.8 g, quant.) as a white foam. TLC (petroleum ether/ethyl acetate,
2:1): Rf ϭ 0.43. [α]D ϭ ϩ57.7 (c ϭ 1.0, CHCl3). 1H NMR
(250 MHz, CDCl3): δ ϭ 0.08Ϫ0.19 (2 s, 6 H, 2 CH3), 0.71 (m, 12
H, 4 CH3), 1.51 [m, 1 H, CH(CH3)2], 3.57 (s, 1 H, 5-H), 4.07 (m,
3
1 H, 1-H), 5.73Ϫ5.78 (dd, J ϭ 3.0 Hz, 1 H, 3-H), 6.6Ϫ8.1 (m, 22
2
3
H, Ar) ppm. MALDI-MS: m/z ϭ 797.0 [M ϩ Naϩ]. C43H37NO13
(775.8): calcd. C 66.57, H 4.81, N 1.81; found C 66.22, H 4.94,
N 1.70.
1 H, 6-H), 4.32 (d, J ϭ 11.9 Hz, 1 H, 6Ј-H), 4.45 (d, J ϭ 3.6 Hz,
1 H, 4-H), 4.56-4-72 (dd, 2J ϭ 16.6 Hz, 2 H, CH2OPh), 4.93 (d,
J1,2 ϭ 7.6 Hz, 1 H, 1-H), 5.26 (dd, J ϭ 3.7 Hz, 1 H, 3-H), 5.52 (s,
3
1 H, PhCH), 5.60Ϫ5.67 (dd, 3J ϭ 7.6 Hz, 1 H, 2-H), 6.6Ϫ8.0 (m, 14
H, Ar) ppm. MALDI-MS: m/z ϭ 717.2 [M ϩ Naϩ]. C36H43NO11Si
(693.7): calcd. C 62.33, H 6.24, N 2.02; found C 62.19, H 6.23,
N 2.32.
2-O-Benzoyl-4-O-benzyl-6-O-(9-fluorenylmethoxycarbonyl)-3-O-
(4-notrophenoxyacetyl)-α/β--galactopyranose
(300 mg,
0.39
mmol) was dissolved in a mixture of dichloromethane (5 mL) and
Cl3CCN (5 mL) and then sodium hydride (2 mg) was added at 0
°C. After 0.5 h, the mixture was neutralized with silica gel and con-
centrated at low pressure. The residue was purified by flash chro-
matography (petroleum ether/ethyl acetate, 5:1) to afford 8 (250 mg,
70%) as a white foam. TLC (petroleum ether/ethyl acetate, 2:1):
Dimethylthexylsilyl 2-O-Benzoyl-4-O-benzyl-6-O-(9-fluorenylmeth-
oxycarbonyl)-3-O-(4-nitrophenoxyacetyl)-β-D-galactopyranoside
(20): 19 (1.4 g, 2.0 mmol) was dissolved in dry dichloromethane
(10 mL) under argon and then 1  BH3·THF (20 mL, 20 mmol)
and 1  dibutylborane triflate (2 mL, 2 mmol) were slowly added
dropwise at 0 °C before the reaction mixture was stirred for 4 h.
The solution was concentrated at low pressure, and the residue was
purified by flash chromatography (petroleum ether/ethyl acetate,
3:1) to afford dimethylthexylsilyl 2-O-benzoyl-4-O-benzyl-3-O-(4-
1
Rf ϭ 0.28 (α). H NMR (250 MHz, CDCl3): δ ϭ 4.18 (s, 1 H, 4-
H), 4.41Ϫ4.30 (m, 2 H, 6-H, 6Ј-H), 4.35Ϫ4.58 (m, 6 H), 4.73 (s,
2HCH2OPh), 5.80 (m, 2 H, 2-H, 3-H), 6.66Ϫ6.71 (m, 3 H),
7.12Ϫ7.95 (m, 20 H, Ar), 8.53 (s, 1 H, NH) ppm. C45H37Cl2N2O13
(920.3): calcd. C 58.73, H 4.05, N 3.04; found C 58.64, H 4.13,
N 3.04.
nitrophenoxyacetyl)-β--galactopyranoside (1.53 g, 74%) as
a
white oil. TLC (petroleum ether/ethyl acetate, 2:1): Rf ϭ 0.25.
[α]D ϭ ϩ11.9 (c ϭ 1.0, CHCl3). 1H NMR (250 MHz, CDCl3): δ ϭ
0.03, 0.13 (2 s, 6 H, 2 CH3), 0.67Ϫ0.70 (m, 12 H, 4 CH3), 1.47Ϫ1.53
[m 1 H, CH(CH3)2], 3.64Ϫ3.68 (m, 2 H, 5-H, 6-H), 3.86 (m, 1 H,
6Ј-H), 3.97 (d, 3J ϭ 3.2 Hz, 1 H, 4-H), 4.34Ϫ4.52 (dd, 2J ϭ
16.5 Hz, 2 H, CH2Ph), 4.62Ϫ4.74 (dd, 2J ϭ 12.1 Hz, 2 H,
CH2OPh), 4.83 (d, J1,2 ϭ 7.5 Hz, 1 H, 1-H), 5.26 (dd, 3J ϭ 3.2 Hz,
1 H, 3-H), 5.57Ϫ5.64 (dd, 3J ϭ 7.5 Hz, 1 H, 2-H), 6.6Ϫ7.98 (m, 14
H, Ar) ppm. MALDI-MS: m/z ϭ 719.3 [M ϩ Naϩ]. C36H45NO11Si
(693.7): calcd. C 62.15, H 6.52, N 2.01; found C 62.10, H 6.61,
N 2.23.
4-(Polystyrene-divinylbenzene-carbonyloxymethyl)benzyl 2-Azido-
3,6-di-O-benzyl-4-O-(9-fluorenylmethoxycarbonyl)-2-deoxy-β-
glucopyranoside (4b): Carboxyl-PS-resin (1.0 g, loading
D-
ϭ
5
2 mmol/g) was swollen under argon in a mixture of primary alcohol
6 (100 mg, 0.137 mmol) and dichloromethane (6 mL) and then it
was shaken for 10 min. DIC (1.6 mL, 10 mmol) and DMAP
(24 mg, 0.2 mmol) were added to the resin solution, which was then
shaken for 1 day. MeOH (0.5 mL) was added to the resin solution,
which was then shaken for 24 h. The resin 4b was filtered off,
washed with CH2Cl2 (4 ϫ 10 mL) and THF (4 ϫ 10 mL), and dried
under high vacuo (10 h, 60 °C oil bath). The loading of resin was
determined to be 0.12 mmol/g by recycling the unchanged acceptor
and also by a very clean preparative cleavage of NaOMe (4 equiv.)
for 6.0 h.
A catalytic amount of DMAP (3 mg, 0.02 mmol) and FmocCl
(2.1 g, 8.2 mmol) were added at room temperature to a solution of
dimethylthexylsilyl 2-O-benzoyl-4-O-benzyl-3-O-(4-nitrophenoxya-
cetyl)-β--galactopyranoside (1.43 g, 2.06 mmol) in pyridine
(15 mL). After 2 h, the mixture was concentrated at low pressure
and the residue was purified by flash chromatography (petroleum
General Procedure for Fmoc Deprotection (Procedure A): Fmoc de-
protection was performed according to the procedure previously
ether/ethyl acetate, 4:1) to afford 20 (1.7 g, 90%) as a white foam. described.[27]
2830
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2826Ϫ2832

Solid-Phase Synthesis of Complex Oligosaccharides
FULL PAPER
3
General Procedure for the Solid Phase Glycosylation (Procedure B):
Solid phase glycosylation was performed according to the pro-
cedure previously described.[27]
5.35 (t, J ϭ 10.3 Hz, 1 H, 2b-H), 5.43 (s, 1 H, CHPh), 5.46 (s, 1
H, CHPh), 6.9Ϫ7.41 (m, 38 H, Ar) ppm. 13C NMR (150.9 MHz,
CDCl3): δ ϭ 63.9 (C-2a), 65.8 (C-2c), 65.9 (C-5b), 66.5 (C-5d), 67.3
(C-6c), 68.4 (C-6a, C-6d), 68.3 (C-6b), 69.2 (C-2b), 70.6 (C-2d),
71.9 (C-3b), 73.0 (C-4b), 75.0 (C-5a, C-5c), 75.6 (C-4d), 76.8 (C-
4c), 77.0 (C-3d), 77.4 (C-4a), 81.1 (C-4a), 81.1 (C-3c), 82.6 (C-3a),
100.3 (C-1c), 100.7 (C-1d), 100.8 (C-1b), 102.7 (C-1a) ppm.
MALDI-MS: m/z ϭ 1669.7 [M ϩ Naϩ]. C90H92N4O26 (1645.7).
General Procedure for Cleavage (Procedure C): Cleavage was per-
formed according to the procedure previously described.[27]
Resin 21: The Fmoc group of 4b was removed using procedure A.
Resin 22: Resin 21 was glycosylated with donor 7 according to pro-
cedure B using 0.3 equiv. of TMSOTf at Ϫ40 °C.
Resin 25: Resin 21 was glycosylated with donor 8 according to pro-
cedure B using 0.3 equiv. of TMSOTf at Ϫ20 °C.
4-(Acetoxymethyl)benzyl 2,3-O-Di-acetyl-4,6-O-benzylidene-β-
D-
Resin 26: The Fmoc group of 25 was removed using procedure A.
Chain elongation with donor 10 was then performed according to
procedure B using 0.3 equiv. of TMSOTf at Ϫ20 °C.
galactopyranosyl-(1Ǟ4)-2-azido-3,6-di-O-benzyl-2-deoxy-β- -gluco-
D
pyranoside (1): Resin 22 (36 µL) was treated as described in pro-
cedure C. After removal of the solvents in vacuo, the crude cleavage
residue was treated with Ac2O (1 mL) and pyridine (2 mL) for 10 h.
The resulting mixture was concentrated in vacuo and coevaporated
twice with toluene. The residue was purified by flash chromatogra-
phy (petroleum ether/ethyl acetate, 2:1) to furnish 1 (25.6 mg, 81%
overall yield) as an amorphous solid. TLC (petroleum ether/ethyl
4-(Acetoxymethyl)benzyl 2-O-Acetyl-3,4,6-tri-O-benzyl-α-
pyranosyl-(1Ǟ6)-(2,3-di-O-acetyl-4-O-benzyl-β- -galacto-
pyranosyl)(1Ǟ4)-2-azido-3,6-di-O-benzyl-2-deoxy-β- -glucopy-
D-manno-
D
D
ranoside (3): Resin 26 (24 µL) was treated as described in procedure
C. After removal of the solvents in vacuo, the crude cleavage resi-
due was treated with Ac2O (1 mL) and pyridine (2 mL) for 10 h.
The resulting mixture was concentrated in vacuo and coevaporated
twice with toluene. The residue was purified by flash chromatogra-
phy (petroleum ether/ethyl acetate, 2:1) to furnish 3 (20 mg, 63%
overall yield) as an amorphous solid. TLC (petroleum ether/ethyl
1
acetate, 2:1): Rf ϭ 0.60. [α]D ϭ Ϫ3.4 (c ϭ 1.7, CHCl3). H NMR
(600 MHz, CDCl3): δ ϭ 1.92Ϫ2.03 (m, 9 H, 3 Ac), 3.04 (s, 1 H,
3
5b-H), 3.24 (d, J ϭ 8.0 Hz, 1 H, 5a-H), 3.32 (m, 1 H, 3a-H), 3.41
(m, 1 H, 2a-H), 3.67Ϫ3.74 (m, 2 H, 6a-H, 6Јa-H), 3.82 (d, 2J ϭ
11.5 Hz, 1 H, 6b-H), 3.94 (t, 3J ϭ 9.1 Hz, 1 H, 4a-H), 4.12 (d, 2J ϭ
1
2
acetate, 1:1): Rf ϭ 0.44. [α]D ϭ ϩ1.1 (c ϭ 1.0, CHCl3). H NMR
12.1 Hz, 1 H, 6Јb-H), 4.20 (m, 1 H, 4b-H), 4.22 (d, J ϭ 8.1 Hz, 1
3
H, 1a-H), 4.41 (d, 2J ϭ 12.0 Hz, 1 H, 1/2 CH2Ph), 4.53 (d, J ϭ
(600 MHz, CDCl3): δ ϭ 1.98Ϫ2.16 (m, 12 H, 4 Ac), 3.26Ϫ3.32 (m,
3 H, 3a-H, 5c-H, 6b-H), 3.37 (m, 1 H, 5b-H), 3.44Ϫ3.49 (m, 2 H,
8.0 Hz, 1 H, 1b-H), 4.59 (d, 2J ϭ 12.1 Hz, 1 H, 1/2 CH2Ph),
4.66Ϫ4.70 (m, 4 H, 3b-H, 3/2 CH2Ph), 4.85 (d, 2J ϭ 12.1 Hz, 1 H,
1/2 CH2Ph), 5.03 (m, 4 H, 2 CH2Ph), 5.25 (m, 1 H, 2b-H), 5.38 (s,
1 H, CHPh), 7.14Ϫ740 (m, 19 H, Ar) ppm. 13C NMR (150.9 MHz,
CDCl3): δ ϭ 66.1 (C-2a), 66.58 (C-5b), 67.56 (C-6a), 68.6 (C-6b),
69.4 (C-2b), 73.36 (C-4b), 75.2 (C-5a), 75.8 (C-3b), 77.1 (C-4a),
81.2 (C-3a), 100.56 (C-1a), 100.62 (C-1b), 101.03 (CϪCHPh) ppm.
MALDI-MS: m/z ϭ 905.3 [M ϩ Naϩ]. C47H51NO14 (881.9).
3
2a-H, 6a-H), 3.53 (m, 1 H, 6Јb-H), 3.60 (d, J ϭ 9.7 Hz, 1 H, 5a-
H), 3.71Ϫ3.73 (m, 3 H, 6Јa-H, 6c-H, 6Јc-H), 3.85 (m, 2 H, 3c-H,
4b-H), 3.93Ϫ3.95 (m, 2 H, 4a-H, 4c-H), 4.23 (d, J1,2 ϭ 8.1 Hz, 1
H, 1a-H), 4.38Ϫ4.50 (m, 5 H, 5/2 CH2Ph), 4.52 (s, 1 H, 1c-H), 4.55
(d, J1,2 ϭ 8.0 Hz, 1 H, 1b-H), 4.61Ϫ4.66 (m, 4 H, 2 CH2Ph), 4.72
(d, 2J ϭ 12.0 Hz, 1 H, 1/2 CH2Ph), 4.79Ϫ4.93 (m, 5 H, 3b-H, 2
3
CH2Ph), 5.09 (s, 2 H, CH2Ph), 5.21 (s, 1 H, 2c-H), 5.30 (dd, J ϭ
3
8.3, J ϭ 10.1 Hz, 1 H, 2b-H), 7.16Ϫ7.35 (m, 34 H, Ar) ppm. 13C
Resin 23: The Fmoc group of 22 was removed using procedure A.
Chain elongation with donor 9 was then performed according to
procedure B using 0.3 equiv. of TMSOTf at Ϫ40 °C.
NMR (150.9 MHz, CDCl3): δ ϭ 64.8 (C-6b), 65.4 (C-2a), 67.5 (C-
6c), 68.1 (C-6a), 68.5 (C-2c), 70.3 (C- 2b), 71Ϫ4 (C-5a), 72.5 (C-
5b), 73.8 (C-3b, C-4a), 73.9 (C-4b), 74.9 (C-5c), 75.7 (C-4c), 77.8
(C-3c), 81.1 (C-3a), 97.9 (C-1c), 100.0 (C-1b), 100.4 (C-1a) ppm.
MALDI-MS: m/z ϭ 1381.5 [M ϩ Naϩ]. C76H83N3O20 (1358.5).
Resin 24: The Fmoc group of 23 was removed using procedure A.
Chain elongation with donor 7 was then performed according to
procedure B using 0.3 equiv. of TMSOTf at Ϫ40 °C.
Acknowledgments
4-(Acetoxymethyl)benzyl
2,3-Di-O-acetyl-4,6-O-benzylidene-β-D-
We thank the European Community (Grant No. FAIR-
CT97Ϫ3142), the Bundesministerium für Bildung und Forschung
(Grant N° 0311229), the Deutsche Forschungsgemeinschaft, and
the Fond der Chemischen Industrie for financial support of this
work. The help of A. Friemel in structural assignments is grate-
fully acknowledged.
galactopyranosyl-(1Ǟ4)-(3,6-di-O-benzyl-2-deoxy-2-phthalimido-β-
D
-glucopyranosyl-(1Ǟ3)-(2-O-acetyl-4,6-O-benzylidene-β-
D
D
-
-
galactopyransyl)(1Ǟ4)-2-azido-3,6-di-O-benzyl-2-deoxy-β-
glucopyranoside (2): Resin 24 (24 µL) was treated as described in
procedure C. After removal of the solvents in vacuo, the crude
cleavage residue was treated with Ac2O (1 mL) and pyridine (2 mL)
for 10 h. The resulting mixture was concentrated in vacuo and co-
evaporated twice with toluene. The residue was purified by HPLC
(ethyl acetate/hexane, 6:5) to furnish 2 (8.3 mg, 21% overall yield)
as an amorphous solid. TLC (petroleum ether/ethyl acetate, 1:1):
Rf ϭ 0.35. 1H NMR (600 MHz, CDCl3): δ ϭ 1.86Ϫ2.10 (m, 12 H,
4 Ac), 3.03 (s, 1 H, 5d-H), 3.14 (s, 1 H, 5b-H), 3.19 (d, 1 H, 5c-H),
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3
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1d-H), 4.47 (d, 2J ϭ 12.1 Hz, 1 H, 1/2 CH2Ph), 4.51Ϫ4.65 (m, 5
H, 1a-H, 2 CH2Ph), 4.68 (d, J1,2 ϭ 8.0 Hz, 1 H, 1b-H), 4.71-4-75
(dd, 2J ϭ 11.8 Hz, 2 H, CH2Ph), 4.80 (dd, 1 H, 3b-H), 4.88 (d,
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2831

X. Wu, R. R. Schmidt
FULL PAPER
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Received February 18, 2004
2832
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2826Ϫ2832