Synthesis of a carbohydrate-centered C-glycoside cluster

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SYNTHESIS OF A CARBOHYDRATE-CENTERED C-
GLYCOSIDE CLUSTER
a
b
Michael Dubber & Thisbe K. Lindhorst
a
Institut für Organische Chemie, Christian-Albrechts-Universität zu Kiel , Otto-Hahn-
Platz 4, Kiel, D-24098, Germany
b
Institut für Organische Chemie, Christian-Albrechts-Universität zu Kiel , Otto-Hahn-
Platz 4, Kiel, D-24098, Germany
Published online: 16 Aug 2006.
To cite this article: Michael Dubber & Thisbe K. Lindhorst (2001) SYNTHESIS OF A CARBOHYDRATE-CENTERED C-GLYCOSIDE
CLUSTER , Journal of Carbohydrate Chemistry, 20:7-8, 755-760
To link to this article: http://dx.doi.org/10.1081/CAR-100108288
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J. CARBOHYDRATE CHEMISTRY, 20(7&8), 755–760 (2001)
COMMUNICATION
SYNTHESIS OF A CARBOHYDRATE-CENTERED
C-GLYCOSIDE CLUSTER1
Michael Dubber and Thisbe K. Lindhorst*
Institut für Organische Chemie, Christian-Albrechts-Universität zu
Kiel, Otto-Hahn-Platz 4, D-24098 Kiel, Germany
The carbohydrate moieties of glycoconjugates are involved in numerous
recognition events in biological systems both in a physiological as well as a patho-
2
,3
4
logical context. In these processes, multivalency of molecular interactions plays
an important role because certain sugar epitopes are frequently displayed in a poly-
valent manner. With regard to the multiple-copy design of natural oligosaccha-
rides, many means for clustering of carbohydrate ligands have been sought in or-
der to provide synthetic mimetics which are more easily obtained than their natural
5
, 4c
counterparts, while possibly equally active.
During our attempts to inhibit the
6
adhesion of Escherichia coli bacteria to high mannose-type structures, we have
employed different pathways for glycocluster synthesis comprising glycosidation,
peptide coupling, thiourea bridging, and photoaddition reactions. In order to in-
crease the stability of such compounds in a physiological environment, C-glyco-
sides instead of O-glycosides can be employed in the design of carbohydrate-based
7
8
9
10
11
antiadhesives.
1
2
Here we present the synthesis of the first carbohydrate-centered C-glyco-
side cluster (5) using two spacer-modified carbohydrate derivatives (1 and 4) and
peptide coupling in the ligation step. Two possible pathways for the synthesis of
peptide bond-ligated glycoclusters can be envisaged. Either an oligocarboxylic
acid is employed as the core molecule and coated with an amino-functionalized
carbohydrate derivative, or an oligoamine core is peptide-coupled to a carboxy-
lated saccharide epitope. In either of these two pathways, according to observations
*Corresponding author.
7
55
Copyright © 2001 by Marcel Dekker, Inc.
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DUBBER AND LINDHORST
made in our laboratory, a powerful coupling reagent has to be chosen to achieve
multiple peptide coupling in good yields.
For the synthesis of glycodendrimers and glycoclusters using amide connec-
tivities, HATU (N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methy-
lene]-N-methylmethanaminium hexafluorophosphate N-oxide) was shown to be
1
3
superior to other onium salts. In a peptide coupling reaction, HATU has to
Scheme 1. a. Bu
3 2
SnH, AIBN, methyl acrylate, toluene; NaOMe, MeOH, 24%. b. LiOH, H O.
c. HATU, DIPEA, DMF, 68% (two steps).

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CARBOHYDRATE-CENTERED C-GLYCOSIDES
757
react first with the carboxylic acid component. This has to be a fast reaction in or-
1
4
der to avoid decomposition of the expensive reagent. In order to prepare a clus-
ter glycoside by peptide coupling, it is therefore not advisable to use an oligocar-
boxylic acid but rather a polyamine as the core molecule. The latter was reacted
with a carboxy-functionalized C-glycoside (4) as the acid component (Scheme 1).
C-Mannoside 4 (Scheme 1) was synthesized, starting from the glycosyl bromide 2
1
5
in a classical radical reaction using methyl acrylate. This reaction furnished
1
6
methyl ester 3, which in turn was saponified to give the corresponding acid 4 in
1
1
situ. This is a known compound, which has, however, never been used in glyco-
cluster synthesis. Here, it could be readily ligated to the glucose-centered pen-
10
taamino hydrochloride 1, which was selected as the core pentaamine in the pep-
tide coupling reaction from a spectrum of different possibilities. 1.5 Equivalents of
the acid 4 were used per amino group to obtain the C-glycosidically linked man-
nose cluster 5 in good yield. It is worthwhile to point out that due to the chiral core
unit, NMR spectra of this type of molecules can be unequivocally solved (Scheme
2).
In conclusion, it was shown that a novel carbohydrate-centered C-mannoside
glycocluster could be readily obtained by the peptide-coupling reaction of a
branched oligoamine represented by 1 and a carboxylated C-mannoside such as 4,
involving a number of one-pot procedures en route to the product 5. The method
can be recommended for the multi-100 mg synthesis of the respective glycoclus-
ters and will be further explored in our group.
Scheme 2.

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DUBBER AND LINDHORST
EXPERIMENTAL
General methods. TLC was performed on silica gel plates (GF254, Merck).
Detection was effected by UV irradiation and subsequent charring with 10% sul-
phuric acid in ethanol followed by heat treatment. Flash chromatography was per-
formed on silica gel 60 (230–400 mesh, particle size 0.040–0.063 mm, Merck). Op-
tical rotations were measured on a Perkin-Elmer 241 polarimeter (sodium-D-line:
5
4
1
89 nm, length of cell 1 dm) in water. NMR spectra were recorded on Bruker AMX
1
13
1
00 (400.13 MHz for H, 100.61 MHz for C) and DRX 500 (500.13 MHz for H,
13
25.76 MHz for C). Assignment of the peaks was achieved with the aid of 2D-
1
1
NMR techniques ( H- H-COSY and HMQC). MALDI-TOF-mass spectra were
recorded on a Bruker Biflex III with 19 kV acceleration voltage and DHB (2,4-di-
hydroxy benzoic acid) as matrix (c ꢀ 10 ꢁg/ꢁL in 40% acetonitrile/water). Ionisa-
tion was effected with a nitrogen laser at 337 nm. Elemental analyses were carried
out in the Institute of Inorganic Chemistry, Christian-Albrechts-University Kiel.
Methyl 3-(ꢂ-D-mannopyranosyl)propanoate (3). A solution of 2,3,4,6-
tetra-O-acetyl-ꢂ-D-mannopyranosyl bromide (2) (17.72 g, 43.1 mmol) and methyl
acrylate (19.5 mL, 215.2 mmol) in degassed toluene (50 mL) was stirred at 85 °C
and a solution of Bu SnH (22.8 mL, 86.2 mmol) and AIBN (400 mg) in toluene (30
3
mL) was added dropwise over 1 h. Then stirring was continued for 0.5 h at 85 °C.
The solution was concentrated and the residue dried in high vacuum. The residual
syrup was dissolved in acetonitrile, washed with hexane, concentrated and purified
by column chromatography (1:1 toluene-EtOAc; R 0.42). The crude acetylated
f
product was dissolved in dry MeOH and stirred for 2 h with 1M NaOMe in MeOH.
ꢃ
The solution was neutralized with Dowex-H , filtered and purified by column chro-
matography (9:1 EtOAc-MeOH) to yield 1,5-anhydro-D-mannitol (470 mg, 7 %, Rf
0
.06) as side product and the title compound 2 (2.62 g, 24 %, R 0.15) as a white
f
1
solid: [ꢂ] ꢃ18.7° (c 1.4, H O); mp 77.7 °C; H NMR (400 MHz, D O) ꢄ 3.80-3.95
D
2
2
(
m, 2H, H-1, H-2), 3.80–3.85 (m, 2H, H-3, H-6), 3.74 (ddꢀt, 1H, J 6.1 Hz, H-4),
.71 (s, 3H, OMe), 3.65 (ddꢀt, 1H, J 9.4 Hz, H-6ꢅ), 3.51 (ddd, 1H, J 2.5, 6.1, 9.2
Hz, H-5), 2.43–2.58 (m, 2H, OCH CH CO Me), 2.11 (m, 1H, OCHHCH CO Me),
3
2
2
2
2
2
1
3
1
.83 (m, 1H, OCHHCH CO Me) ppm; C-NMR (100.67 MHz, D O) ꢄ 176.9
2 2 2
(
CO Me), 78.0 (CH, C-1), 74.1 (C-5), 71.7 (C-2), 71.3 (C-3), 67.7 (C-4), 61.6 (C-
2
6
), 52.7 (OMe), 30.6 (OCH CH CO Me), 23.3 (OCH CH CO Me) ppm.
2 2 2 2 2 2
1
0-ꢂ-D-Mannopyranosyl-8-oxo-4-thia-7-azadecyl-2,3,4,6-tetra-O-[10-
ꢀ
-D-mannopyranosyl-8-oxo-4-thia-7-azadecyl]-ꢀ-D-glucopyranoside (5).
The octopus glycoside 3-(2-aminoethylthio)propyl-2,3,4,6-tetra-O-3(2-amino-
9
ethylthio)propyl-ꢂ-D-glucopyranoside (1) (54 mg, 0.057 mmol) and diisopropy-
lethyl amine (DIPEA, 0.1 mL, 0.580 mmol) were dissolved in dry DMF (4 mL) and
stirred for 1 d. In the meantime 3 (110 mg, 0.44 mmol) was dissolved in methanol
(
6 mL) and water (4 mL) and LiOH ꢆ H O (102 mg, 2.4 mmol) was added. The
2
solution was stirred at 0 °C until ester cleavage was completed (TLC, MeOH). Ad-
ditional water was added (20 mL) and the solution was neutralized at 0 °C with 2M
hydrochloric acid and freeze dried to yield 4, which was used as a crude product.

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CARBOHYDRATE-CENTERED C-GLYCOSIDES
759
Then, a solution of 3 in DMF (4 mL) was added to the earlier prepared solution of
. The coupling reagent HATU (N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-
1
b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate N-ox-
ide, 167 mg, 0.44 mmol) and DIPEA (0.15 ml, 0.88 mmol) were added and the so-
lution was stirred for 36 h at rt. For work-up, the solution was passed over a
Sephadex LH-20 column with methanol as the eluent, to yield 5 (82 mg, 68 %) as
1
a colorless syrup: [ꢂ] ꢃ22.0° (c 1.4, H O); H NMR (D O) ꢄ 4.95 (d, 1H, J 3.5
D
2
2
1,2
Hz, H-1 ), 3.93–3.48 (m, 49H, 5 (glc)OCH , H-3 , H-5 , H-6 , H-6ꢅ , 5 H-
glc
2
glc
glc
glc
glc
1man, 5 H-2man, 5 H-3man, 5 H-4man, 5 H-5man, 5 H-6man, 5 H-6ꢅman), 3.43–3.35 (m,
1
0HꢃMeOH, SCH CH N), 3.31–3.25 (m, 2H, H-2 , H-4 ), 2.75–2.64 (m, 20H,
2 2 glc glc
5
(glc) OCH CH CH SCH ), 2.45–2.29 (m, 10H, 5 (man)CH CH ), 2.13–2.01
2
2
2
2
2
2
(
m, 5H, 5 (man)CHH), 2.00–1.80 (m, 15H, 5 (man)CHH, 5 (glc)OCH CH ) ppm;
2 2
1
3
C-NMR (125.77 MHz, D O): ꢄ 99.1 (C-1 ), 84.0 (C-3 ), 83.0 (C-2 ), 80.4
2
glc
glc
glc
(
C-4 ), 78.7 (5ꢆ) (5 C-1man), 77.4 (5ꢆ) (5 C-5man), 74.0 (5ꢆ), 74.0 (5ꢆ) (5 C-
glc
2man, 5 C-3man), 72.9 (C-5 ), 73.5, 72.0 (2ꢆ), 71.9, 71.3, 68.5 (C-6 , (glc)CH ),
glc
glc
2
7
0.7 (5ꢆ) (5 C-4man), 64.2 (5ꢆ) (5 C-6man), 41.5 (5ꢆ) (5 SCH CH N), 34.5 (5ꢆ)
2 2
(
(
(
5 (man)CH CH ), 33.3–33.2 (5ꢆ) (5 SCH CH N), 32.9, 32.5, 32.4, 32.0, 31.6 (5
2 2 2 2
glc)OCH CH ), 30.7, 30.6 (2ꢆ), 30.5 (2ꢆ) (5 (glc)OCH CH CH S), 27.3 (5ꢆ)
2
2
2
2
2
ꢃ
5(man)CH ) ppm; MALDI-TOF-MS m/z 1879.4 ((MꢃNa) calcd 1855.8).
2
Anal.Calcd for C H N O S (1857.24): C 49.15, H 7.44, N 3.77; Found
76 137 5 36 5
C 48.61, H 7.24, N 3.36%.
ACKNOWLEDGMENTS
Support of this work by the Fonds der Chemischen Industrie (FCI) is grate-
fully acknowledged. We are indebted to Dr. V. Sinnwell and to Dr. C. Wolff for
performing the NMR experiments.
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2
-building blocks
2
Received June 7, 2001
Accepted August 21, 2001

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