Glyco-SAMs as glycocalyx mimetics: Synthesis of L-fucose- and D-mannose-terminated building blocks

Article abstract of DOI:10.1002/ejoc.200400239

In the course of a project on the supramolecular functions of the glycocalyx present on eukaryotic cell surfaces, it has been our goal to prepare spacer glycosides and cluster glycosides that are suitable for the formation of self-assembled monolayers (SAMs) on gold. We have selected amino-functionalized D-mannose and L-fucose derivatives for peptide coupling to thio-functionalised alkane and alkane-oligoethylene glycol spacers such as 12 and 15. Thus, a variety of thiospacered glycosides (16-19) and cluster glycosides (23, 24, 26, 28, and 29) were synthesized, which can be assembled on gold wafers to serve as glycocalyx mimetics. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400239

FULL PAPER
Glyco-SAMs as Glycocalyx Mimetics: Synthesis of
L
-Fucose- and -Mannose-
D
Terminated Building Blocks
Mike Kleinert,[a] Niels Röckendorf,[a] and Thisbe K. Lindhorst*[a]
Keywords: Carbohydrates / Cell adhesion / Dendrimers / Glycocalyx / Monolayers
In the course of a project on the supramolecular functions of
the glycocalyx present on eukaryotic cell surfaces, it has
lene glycol spacers such as 12 and 15. Thus, a variety of thio-
spacered glycosides (16−19) and cluster glycosides (23, 24,
been our goal to prepare spacer glycosides and cluster glyco- 26, 28, and 29) were synthesized, which can be assembled
sides that are suitable for the formation of self-assembled
monolayers (SAMs) on gold. We have selected amino-func-
on gold wafers to serve as glycocalyx mimetics.
tionalized
D-mannose and
L-fucose derivatives for peptide
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
coupling to thio-functionalised alkane and alkane-oligoethy- Germany, 2004)
Introduction
Self-assembled monolayers (SAMs) were first introduced by
Whitesides et al. in 1988[9] and have found wide applications
since then,[10] especially in surface plasmon resonance.[11]
The target molecules of our study consist of a thio- or
thioacetate-functionalised linear spacer to allow formation
of a stable SϪAu bond upon SAM formation on a gold
wafer, and a carbohydrate part as the terminal moiety. The
design of these building blocks, which are suitable for the
formation of glyco-functionalized SAMs, is based on pep-
tide-coupling of the various components (Figure 1). A
hexaethylene glycol (EG6) moiety is included to eliminate
nonspecific binding of proteins.[12] To allow a facile access
to more complex glyco-SAMs, we decided to use the well-
established cluster glycosides[13] to serve as oligosaccharide
mimetics, in addition to simple monosaccharides to termin-
ate the S-functionalised spacers. From the armada of bio-
logically important carbohydrates, we have selected -man-
nose and -fucose for our study, firstly because we are es-
pecially interested in mannose-specific proteins such as
Concanavaline A[14] and type 1 fimbriae of bacteria,[15] and
secondly because -fucose is an important glycocalyx com-
ponent associated with many sugar-related diseases and a
monosaccharide with a demanding chemistry due to its lab-
ile glycosidic bond.
All eukaryotic cells are covered by a thick layer com-
posed of complex carbohydrates. This sugar layer is called
the ‘‘glycocalyx’’ and possesses a thickness of up to 100 nm
and more. The elucidation of the biological functions of the
glycocalyx has opened up the field of glycobiology.[1] Cur-
rent investigations are concentrated on the analysis of the
molecular recognition and interactions of protein receptors,
like the lectins[2] and selectins,[3] and their carbohydrate li-
gands. Such carbohydrateϪprotein interactions[4] are
characterized by dissociation constants (KD) in the millimo-
lar or high micromolar range and it has been understood
that it is multivalency of the respective molecular interac-
tions[5] on a supramolecular level which leads to a biologi-
cally effective signal.[6] Numerous target-designed carbo-
hydrate ligands, glycomimetics and multivalent neoglyco-
conjugates have been synthesized and investigated in bind-
ing studies of various kinds.[7] However, it has remained
difficult to address the supramolecular chemistry that is
most likely involved in the biology of a nano-sized array of
molecules such as in the glycocalyx.[8] As it is our goal to
check out the biological functions of glycocalyx carbo-
hydrates beyond the investigation of more or less specific
interactions of single molecules, we have started a project
to utilize the phenomenon of self-assembly of thio-func-
tionalised molecules on gold surfaces to mimic the expan-
sion of a cell surface glycocalyx at least in two dimensions.
Results and Discussion
To obtain sugar-modified building blocks suitable for the
formation of self-assembled monolayers on gold wafers, we
planned to attach monovalent saccharides and eventually
trivalent cluster glycosides to a thio-functionalized spacer
by peptide coupling. Thus, the two essential moieties of
such molecules — the saccharide and the spacer part —
had to be functionalized with an amino function, which was
[a]
Institut für Organische Chemie, Christian-Albrechts-
Universität zu Kiel,
Otto-Hahn-Platz 3, 24098 Kiel, Germany
Fax: ϩ 49-431-880-7410
E-mail: tklind@oc.uni-kiel.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2004, 3931Ϫ3940
DOI: 10.1002/ejoc.200400239
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M. Kleinert, N. Röckendorf, T. K. Lindhorst
FULL PAPER
Figure 1. Architecture of thio-spacered cluster glycosides and monosaccharides, respectively, for the construction of ‘‘glyco-SAMs’’
chosen for the sugar portion, and a carboxy group, which ditions[18] and then the Cbz group was removed by hydro-
was selected as the spacer terminus. Our first task was to genolysis, making the unprotected aminoalkyl glycoside 5
prepare the amino-functionalized glycosides of the man- available. Interestingly, when this deprotection sequence was
nose and fucose series — the β-fucosides 5 and 6 and the repeated, the N-isopropyl(aminopentyl)fucoside
6
was
α-mannoside 10.
formed as the only product. This finding can be explained
by the presence of acetone in the reaction mixture, leading
to 6 as a result of reductive amination. This undesired prod-
uct 6 eventually became a valuable tool for the elaboration
of the synthesis and purification of spacered cluster glyco-
sides (vide infra).
Then, aminoethyl mannoside 10 was easily obtained from
the known[19] bromoethyl mannoside 7, which was trans-
formed into the protected azide 8, deacetylated to the OH-
free mannoside 9, and finally reduced to the target amine
10 by hydrogenolysis in good yields (Scheme 1).
Synthesis of Amino-Functionalized Glycosides
We decided to prepare glycosides carrying the amino
function in the aglycon part. Therefore, fucose tetraacetate
(1) was first converted into Fmoc-protected 2-aminoethyl-
β--fucoside 3 (Scheme 1) via the fucosyl bromide 2. How-
ever, the low yields of this reaction sequence prompted us to
change the amino-protecting group to benzyloxycarbonyl
(Cbz). Thus, following a procedure described in the litera-
ture,[16] fucosyl bromide 2 was reacted with N-Cbz-5-amin-
opentanol[17] under Helferich conditions to obtain the Cbz-
protected 5-aminopentyl-β--fucoside 4 in good yield. To
prevent OǞN acetyl-group migration, the fully protected
Synthesis of ω-Thio-Functionalized Spacers
The spacers needed for the eventual immobilization of
´
compound was first deacetylated under Zemplen con- the targeted glycosides on gold have to carry a terminal
Scheme 1. Synthesis of aminoalkyl glycosides 5, 6 and 10; reaction conditions: a) HBr/HOAc (33%), DCM, 0 °C to room temp., 3 h,
quant.; b) HO(CH2)2NHFmoc, Ag2CO3, DCM, room temp., 4 h, 20%; c) HO(CH2)5NHCbz, NO2CH3/toluene (1:1), Hg(CN)2, room
temp., 65%; d) 1. MeOH, NaOMe, room temp., 3 h, 2. MeOH, H2, Pd/C, 4 h, 70% over 2 steps; e) 1. MeOH, NaOMe, room temp., 3 h,
2. MeOH, acetone, H2, Pd/C, 3 h, 90%; f) NaN3, DMF, Bu4NBr, room temp., 12 h, 89%; g) MeOH, NaOMe, room temp., 2 h; h) MeOH,
H2, Pd/C, 4 h, 90%
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Glyco-SAMs as Glycocalyx Mimetics
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thiol or thioacetyl function. In addition, a carboxy function coupling was attempted to obtain saccharides suitable for
is required for the attachment to the various sugar deriva- the formation of SAMs. Preliminary coupling experiments
tives by peptide coupling. The commercially available and with the thio-functionalized undecanoic acid 12 revealed
inexpensive ω-thioundecanoic acid 11 was chosen as a suit- that the products of this reaction are difficult to purify due
able molecule in this regard. S-Acetylation to 12 was ac- to their amphiphilic character. However, when the experi-
complished in a facile, quantitative reaction using Zn in ments were carried out with the N-isopropyl-substituted
combination with acetic acid and acetyl chloride amine 6, purification and characterization of the product
(Scheme 2). The resulting thioester could be used in crude mixture was easier. Therefore, peptide-coupling conditions
form, making tedious purification procedures, as docu- were optimized utilizing the secondary amine 6. When the
mented in the literature,[20] unnecessary.
water-soluble carbodiimide EDC was treated with HOBt in
DMF, peptide 16 was obtained in only moderate yields of
around 40% (Scheme 3). After the evaluation of the guanid-
inium-type coupling reagents HBTU and HATU, the mixed
anhydride method[16] using isobutyl chloroformate under
basic conditions was finally identified as an optimal pro-
cedure for this case, yielding 16 in an improved yield of
60%.
These conditions were eventually applied for the peptide-
coupling reaction of the valuable hexaethylene glycol car-
boxylic acid 15 and the aminopentyl fucoside 5 to yield the
target glycoside 17, which is a suitable building block for
SAM formation, in 54% yield. In analogy, the spacered
mannosides 18 and 19 could be obtained in 65% and an
excellent 94% yield, respectively.
Synthesis of Spacered Cluster Glycosides
The first part of this work led to the four thio-func-
tionalized molecules 16Ϫ19, each carrying a monosacchar-
ide moiety, for the formation of glyco-SAMs. Our next goal
was to use cluster glycosides along the same synthetic route.
The well-established trifunctional dendron 20[24] was chosen
as scaffold molecule for the synthesis of cluster glycosides
by peptide coupling. This ester was easily obtained, even on
a multigram scale, from nitromethane and acrylic acid tert-
butyl ester after reduction of the nitro group with Raney-
Ni in ethanol.[25] The aminotriester 20 was then converted
into the N-Fmoc-protected triacid 21 in a one-pot reaction
in dichloroethane (Scheme 4). Dichloroethane is the solvent
of choice for this reaction because its boiling point is high
enough that TFA is not concentrated upon evaporation.
Thus, the N-protected triacid 21 was obtained in 62% yield
over two steps after reversed-phase chromatography (RP-
18).
Various coupling conditions were elaborated for the pep-
tide-coupling reaction of aminoalkyl glycosides to the N-
protected triacid 21. When carbodiimide-mediated methods
were applied, products with structural defects were pre-
dominantly observed. Finally, HATU turned out to be a
powerful coupling reagent for this case, leading to the fuco-
side clusters 22 and 25 in the presence of a threefold excess
of the fucosides 5 and 6, respectively (Scheme 4). Steric hin-
drance due to the N-isopropyl group of 6 was no problem
in this reaction. Purification of these cluster fucosides was
difficult due to the extreme acid lability of the fucosidic
bond. However, gel-permeation chromatography with a Se-
phadex medium and neat methanol as eluent was success-
Scheme 2. Synthesis of thio-functionalized alkane and hexaethyl-
ene glycol spacers; reaction conditions: a) Zn/HOAc, AcCl, DCM,
0 °C to room temp., 1 h, quant.; b) AcSH, THF, room temp., hν,
4 h, 96%; c) succinic anhydride, DIPEA, DCM, reflux 1 h, quant.
For biological investigations with SAMs it is important
to avoid unspecific adhesion of biomolecules to the molecu-
lar monolayer. Biorepulsive monolayers are obtained when
hexaethylene glycol (EG6) spacers are utilized.[9,21] An oli-
goethylene moiety resembles a polar unit of the monolayer,
covering the gold wafer as a tight film, thus preventing un-
wanted interactions between the gold surface and proteins
used in a bioassay.
The alkene-terminated hexaethylene glycol 13 served as
starting material for the synthesis of a thio-functionalized
EG-carboxylic acid. It was easily obtained in a substitution
reaction involving hexaethylene glycol and 11-bromounde-
cene.[22] Then, thioacetylation was achieved in a photoreac-
tion with thioacetic acid in THF using AIBN as radical
initiator. The reaction mixture was irradiated with a 295 nm
UV-filter and a standard Hg-pressure UV-lamp, giving the
alcohol 14 in nearly quantitative yields.[23] This procedure
also facilitated the critical purification step. The terminal
hydroxy group of 14 was then esterified in a reaction with
succinic anhydride to form the desired carboxylic acid 15 in
72% overall yield starting from hexaethylene glycol.
Synthesis of ω-Thio-Functionalized Spacered
Monosaccharides
With the desired aminoalkyl glycosides and the ω-thio- fully used for purification. Once again, it turned out that
functionalized carboxylic acid spacers at hand, peptide purification of the cluster fucoside 22, derived from the sec-
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M. Kleinert, N. Röckendorf, T. K. Lindhorst
FULL PAPER
Scheme 3. Synthesis of ω-thio-functionalized spacered glycosides; reaction conditions: a) acid 12 or 15, isobutyl chloroformate, NPr3,
DMF, 0 °C to room temp., 3Ϫ6 h, 16: 60%; 17: 54%; 18: 65% and 19: 94%).
Scheme 4. Synthesis of ω-thio-functionalized spacered cluster glycosides; reaction conditions: a) FmocCl, C2H4Cl2, room temp., 3 h; b)
TFA, C2H4Cl2, room temp., 1 h, 62% over 2 steps; c) 6, HATU, DIPEA, DMF, room temp., 3 h, 66%; d) 5, HATU, DIPEA, DMF, room
temp., 3 h, 39%; e) morpholine, DMF, room temp., 2 h, quant.; f) 12, HATU, DIPEA, DMF, room temp., 3 h, 62%; g) 15, isobutyl
chloroformate, NPr3, DMF, 0 °C to 45 °C, 4 h, 63%; h) 15, HATU, DIPEA, DMF, room temp., 3 h, 5%; j) 10, HATU, DIPEA, DMF,
room temp., 3 h, 54%; k) 12, isobutyl chloroformate, NPr3, DMF, 0 °C to room temp., 18 h, 32%; l) 15, isobutyl chloroformate, NPr3,
DMF, 0 °C to room temp., 2 h, 32%.
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Glyco-SAMs as Glycocalyx Mimetics
FULL PAPER
ondary N-isopropylamine 6, was easier than purification of our studies on the basis of the results that have been re-
25. This observation might be explained by the higher mo- ported here.
lecular weight of 22 and its modulated polarity compared
to 25.
HATU-mediated peptide coupling using mannoside 10 Experimental Section
also led to the analogous mannoside cluster 27 in compar-
able 54% yield. Purification of the trivalent mannoside clus-
Abbreviations: See ref.[27]
ter 27 was possible applying preparative reversed-phase
HPLC using an acetonitrile/water gradient containing 0.1%
under argon or nitrogen and using distilled solvents, unless other-
General Remarks: Reactions were carried out in dried glassware
TFA. The same procedure as above caused degradation of
the fucosyl clusters.
wise noted. THF was dried by distillation from sodium/potassium
ketyl, methanol by distillation from magnesium turnings, and di-
chloromethane by distillation from calcium hydride, all under ar-
gon. Commercially available starting materials, reagents and pure
DMF were used without further purification. TLC was performed
on GF254 silica gel plates (Merck), detection was effected by the
use of UV light (254 nm and 366 nm) and with mixtures of either
10% sulfuric acid in ethanol or cerium() sulfate and phosphor-
molybdate in 10% sulfuric acid followed by heat treatment. Flash
chromatography was performed on silica gel 60 (230Ϫ400 mesh,
particle size 0.040Ϫ0.063 mm, Merck). NMR spectra were re-
corded on Bruker DRX 500 (500 MHz for 1H, 125.47 MHz for
Next, the trivalent cluster glycosides 22, 25, and 27 were
coupled to the linear thioacetates 12 and 15, respectively, at
the focal amino group. First, Fmoc-deprotection was car-
ried out in a quantitative reaction with 20% morpholine in
DMF. Then, HATU was successfully applied in the peptide-
coupling reaction with the acid 12, leading to the alkyl-
spacered target thioacetate 23 in 62% yield. The anhydride
method delivered the EG-spacered thioacetate 24 in 63%
yield after peptide coupling of the amine derived from 22
with the acid 15. It turned out that these spacered cluster
glycosides possess tensidic properties, with all the associated
difficulties regarding their purification. Furthermore, NMR
analysis is tricky as in the case of the amide-coupled cluster
glycosides 22 and 23, which occur as two major amide ster-
eoisomers[26] as reflected by two signal sets in the NMR
spectrum. High temperature NMR experiments in meth-
anol up to 330 K did not lead to simplification of the spec-
tra. Unfortunately, the EG-spacered fucoside cluster 26
could be obtained in pure form in only 5% yield. This low
yield is mainly due to the difficult purification procedure of
the acid-labile compound, involving a GPC-HPLC se-
quence. Only partial purification was achieved by gel chro-
matography on Sephadex, and subsequent HPLC separ-
ation on RP-18 material led to the pure target molecule in
reduced yield. On the other hand, the thio-spacered target
mannosides 28 and 29 were prepared in 32% and 19% yield,
respectively, according to the anhydride route. This finding
again shows that the less-sensitive mannosides can be much
more conveniently handled than the analogous fucosides.
1
13C) and ARX 300 instruments (300 MHz for H, 75.47 MHz for
13C). Spectra were calibrated with respect to the solvent peak
1
(CDCl3: δ ϭ 7.24 ppm for H and δ ϭ 77.0 ppm for 13C; [D4]me-
1
thanol: δ ϭ 3.35 ppm for H and δ ϭ 49.30 ppm for 13C). Assign-
ment of the peaks was achieved with the aid of 2D NMR tech-
1
niques (1H,1H-COSY and H,13C-HSQC). Peak values that could
not be unequivocally assigned to one atom, and may therefore be
interchangeable, are marked with an asterisk. Hydrogen and car-
bon atoms within the scaffold are indexed as follows: The sugar
residue is numbered as usual from 1 to 6 with the anomeric position
being number 1, the atoms of the anomeric spacer moiety then
receive higher numbers by consequent numbering starting from the
glycoside bond. This is depicted for compound 29 in Figure 2. In
the sugar-free spacer molecules the thioacetate is defined as the
terminus of the molecule, as exemplified for 15 (Figure 2).
MALDI-TOF mass spectra were recorded on a Bruker Biflex III
19 kV instrument, norharmane (9H-pyrido[3,4-b]indole) in THF
was used as matrix. For sample preparation, a drop of matrix solu-
tion was first placed on the target and left to evaporate. Afterwards,
a solution of the sample in THF or in methanol was placed on the
pre-crystallized matrix.
Even though NMR studies showed no contamination within the
samples, correct elemental analyses could not be obtained for most
of the reported substances. Even samples that contained no im-
purities according to analytical HPLC failed to give correct values.
Therefore, ESI-MS measurements were also conduced to prove pu-
rity and record high-resolution mass spectra. These were performed
on a Mariner (Part-No. V800600) instrument. For analytical HPLC
chromatography a MerckϪHitachi machine with a diode array de-
tector L-7455 was used with either LiChrosorb RP-8 7 µm silica
or a Chromolith performance RP-18 100-4.6 mm column. Pre-
parative HPLC chromatography was carried out on a Shimadzu
system with Merck columns Hibar RT250-25 mm with LiChro-
sorb RP-8 7 µm silica.
Conclusion
In conclusion, we have reported the synthesis of spacered
monosaccharides and trivalent cluster glycosides of the -
mannose and -fucose series. Our ongoing work utilizing
these molecules has shown that they indeed form SAMs,
with varying characteristics, which are currently under
investigation, as is a biological evaluation of this system.
It is important to note that the purification of the target
molecules such as 17 and 19, 26 and 29 is hampered by
their amphiphilic character, a fact which often leads to dis-
appointing isolated yields. The β-fucosidic bond proved to
be a problem due to its sensitivity towards lowered pH.
However, the applied synthetic concept was shown to be a
General Procedure A. Peptide Coupling using the Mixed Anhydride
Method: The carboxylic acid (1 equiv.) was dissolved 1Ϫ3 mL of
dry DMF under a nitrogen atmosphere and cooled to 0 °C. Iso-
butyl chloroformate (1.2 equiv.) and tripropylamine (2.0 equiv.)
were added with a syringe and the reaction mixture was stirred for
30 min prior to the addition of a concentrated solution of the am-
valuable and highly flexible one. We are currently extending ine (1.2 equiv.) in DMF and final addition of tripropylamine (1.0
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M. Kleinert, N. Röckendorf, T. K. Lindhorst
FULL PAPER
Succinic Acid Mono[ω-(11-thioacetylundecyl)hexaethylene glycol]
Ester (15): DIPEA (20.5 µL, 15.18 mg, 0.117 mmol) was added to
a stirred solution of alcohol 15 (100 mg, 0.196 mmol) and succinic
anhydride (25.5 mg, 0.255 mmol) in 1.3 mL of dry dichloromethane
under nitrogen. The reaction mixture was refluxed for 4 h and sub-
sequently the solvent was removed in vacuo. The obtained reddish
oil was dissolved in diethyl ether, acidified with 5 mL of aqueous
1  HCl and extracted three times with diethyl ether, dried over
sodium sulfate and used without further purification. Yield 115 mg
(0.188 mmol, M ϭ 610.799) 97%. 1H NMR (500 MHz, CDCl3,
TMS): δ ϭ 4.27 (m, 2 H, 2 H-5). 3.66 [mc, 20 H, 2 (H-7, H-8, H-
9, H-10, H-11, H-12, H-13, H-14, H-15, H-16)], 3.58Ϫ3.57 (m, 2
H, 2 H-6), 3.45 (t, J ϭ 6.85 Hz, 2 H, 2 H-17), 2.86 (t, J ϭ 7.30 Hz,
2 H, 2 H-27), 2.65 [m, 4 H, 2 (H-2, H-3)], 2.32 (s, 3 H, 3 H-29),
1.56 [mc, 4 H, 2 (H-18, H-26)], 1.26 [br. m, 14 H, 2 (H-19, H-20,
H-21, H-22, H-23, H-24, H-25)] ppm. 13C NMR (125 MHz,
CDCl3, TMS): δ ϭ 196.21 (C-28), 175.00 (C-1), 172.05 (C-4), 71.55
(C-17), 70.67Ϫ70.00 (C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14,
C-15, C-16), 68.94 (C-6), 63.85 (C-5), 33.75 (C-2), 30.59 (C-29),
29.64 (C-3), 29.56Ϫ28.80 (C-18, C-20, C-21, C-22, C-23, C-24, C-
25, C-26, C-27), 26.05 (C-19) ppm. IR (KBr): ν˜ ϭ 2929 s, 2854 s,
1784 m, 1736 s, 1691 s, 1454 m, 1350 m, 1249 m, 1134 s, 1100 s,
1046 m, 953 m, 907 w, 860, w, 731 w, 627m. CI-MS: m/z (%) ϭ 611
(1.16) [M ϩ H]ϩ, 551 (1.33), 511 (10.88), 435 (1.33), 365 (1.22),
187 (3.81). ESI-MS: m/z ϭ 633.29 [M ϩ Naϩ] (M ϭ 633.32 calcu-
lated for C29H54O11S ϩ Na): m/z ϭ 649.26 [M ϩ Kϩ] (M ϭ 649.30
calculated for C29H54O11S ϩ K).
FucC5NiPrC11SAc (16):[27] The reaction was carried out according
to the general procedure A using carboxylic acid 12 (51.8 mg,
0.200 mmol) in 1.5 mL of DMF, isobutyl chloroformate (32.8 mg,
0.240 mmol) and tripropylamine (76.1 µL 0.400 mmol). After
20 min a solution of fucoside 5 (59.8 mg, 0.240 mmol) and triprop-
ylamine (38.01 µL, 0.200 mmol) in 0.5 mL of DMF was syringed
in dropwise. After 6 h the solvent was evaporated and the pale-
yellow crude oil was purified by flash chromatography (MeOH/
DCM, 1:20 Ǟ 1:10). Yield 59 mg (0.120 mmol, M ϭ 491.68) 60%.
1H NMR (500 MHz, CDCl3, TMS): δ ϭ 4.21 (mc, 1 H, H-1), 4.04
(m, 1 H, H-12), 3.90 (mc, 1 H, H-7), 3.71 (br., 1 H, H-4), 3.64Ϫ3.53
(m, 3 H, H-2, H-3, H-5), 3.51 (mc, 1 H, H-7Ј), 3.12 (mc, 2 H, 2 H-
11), 2.86 (t, J ϭ 7.33 Hz, 2 H, 2 H-25), 2.32 (m, 4 H, 3 H-27, H-
15), 2.26 (mc, 1 H, H-15Ј), 1.64 (mc, 2 H, 2 H-8), 1.60Ϫ1.52 [mc, 6
H, 2 (H-10, H-16, H-24)], 1.375 (m, 2 H, 2 H-9), 1.33 (d, J ϭ
6.41 Hz, 3 H-6), 1.27 [mc, 14 H, 2 (H-17, H-18, H-19, H-20, H-21,
H-22, H-23)], 1.18 (d, J ϭ 6.60 Hz, 3 H, 3 H-13), 1.12 (d, J ϭ
6.62 Hz, 3 H, 3 H-13) ppm. 13C NMR (125 MHz, CDCl3, TMS):
δ ϭ 196.02 (C-26), 172.91 (C-14), 172.56 (C-14Ј), 103.01 (C-1),
74.00 (C-3), 71.49 (C-4), 71.39 (C-2), 70.45 (C-5), 69.64 (C-7), 48.25
(C-12), 40.92 (C-11), 33.82 (C-15), 31.27 (C-16), 30.58 (C-26), 29.44
(C-10), 29.40Ϫ29.10 (C-17, C-18, C-19, C-20, C-21, C-22, C-23),
28.91 (C-8), 28.73, 25.52, 23.92, 21.32 (C-13, C-13Ј), 16.32 (C-6)
ppm. MALDI-TOF: m/z ϭ 556 [M ϩ Na]ϩ and m/z ϭ 572 [M ϩ
K]ϩ (M ϭ 533.34 calculated for C27H51NO7S).
Figure 2. Numbering of hydrogen and carbon atoms for assign-
ment of NMR spectroscopic data
equiv.) at 0 °C. The reaction mixture was then allowed to warm to
room temp. and stirred for 2Ϫ6 h.
5-Aminopentyl-N-isopropyl-β-l-fucopyranoside (6): Fucoside
4
(143 mg, 0.57 mmol) was dissolved in 10 mL of methanol, a cata-
lytic amount of NaOMe was added and the reaction mixture was
stirred for 3 h at room temp. Amberlite IR 120 was then added for
neutralization, filtered off, washed several times with methanol and
then the solvent was evaporated. The oily crude product was dis-
solved in 10 mL of methanol containing acetone, Pd/charcoal was
added and the reaction mixture was subsequently stirred for 3 h at
room temp. The suspension was filtered through a thin bed of celite
and the solvent was removed in vacuo to yield 6 as a white foam.
Yield: 152 mg (0.52 mmol, M ϭ 291.38) 91%. 1H NMR (500 MHz,
CDCl3, TMS): δ ϭ 4.21 (m, 1 H, H-1), 3.89 (dt, J ϭ 6.60, J ϭ
9.54 Hz, 1 H, H-7), 3.67Ϫ3.63 (m, 2 H, H-3, H-5), 3.57 (dt, J ϭ
6.61, J ϭ 9.53 Hz, 1 H, H-7Ј), 3.50Ϫ3.49 (m, 2 H, H-2, H-4), 2.88
(sep, J ϭ 6.23 Hz, 1 H, H-12), 2.64 (m, 2 H, 2 H-11), 1.69 (q, J ϭ
6.79 Hz, 2 H, 2 H-8), 1.61Ϫ1.55 (m, 2 H, 2 H-10), 1.50Ϫ1.44 (m, FucC5NHsucEG6C11SAc (17): The reaction was carried out accord-
2 H, 2 H-9), 1.30 (d, J ϭ 6.60 Hz, 3 H, 3 H-6), 1.13 (d, J ϭ 6.42 Hz, ing to the general procedure A using carboxylic acid 15 (370 mg,
6 H, 6 H-13) ppm. 13C NMR (125 MHz, CDCl3, TMS): δ ϭ 104.81 0.605 mmol) in 3 mL of DMF, isobutyl chloroformate (94.3 mg,
(C-1), 75.17 (C-2), 73.01 (C-4), 72.31 (C-3), 71.82 (C-5), 70.51 (C- 0.727 mmol) and tripropylamine (230.5 µL, 1.21 mmol). After
7), 49.89 (C-12), 47.89 (C-11), 30.58 (C-10), 30.11 (C-8), 24.90 (C- 15 min a solution of fucoside 5 (181.2 mg, 0.727 mmol) and tripro-
9), 22.18 (2 C-13), 16.77 (C-6) ppm. CI-MS: m/z (%) ϭ 292 (100) pylamine (115 µL, 0.606 mmol) in 0.5 mL of DMF was syringed
[M ϩ H]ϩ, 248 (1.50), 174 (4.46), 146 (24.72) (M ϭ 291.20 calcu-
in dropwise. After 6 h the solvent was evaporated and the yellow,
lated for C14H29NO5). ESI-MS: m/z ϭ 292.18 [M ϩ Hϩ] (M ϭ highly viscous crude oil was purified by flash chromatography
292.21 calculated for C14H29NO5 ϩ H); m/z ϭ 314.16 [M ϩ Naϩ]
(M ϭ 314.19 calculated for C14H29NO5 ϩ Na).
(MeOH/DCM, 1:20 Ǟ 1:10). Yield 280 mg (0.333 mmol, M ϭ
1
841.49) 55%. H NMR (500 MHz, CDCl3, TMS): δ ϭ 4.23 (m, 2
3936
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3931Ϫ3940

Glyco-SAMs as Glycocalyx Mimetics
FULL PAPER
H, 2 H-16), 4.18 (mc, 1 H, H-1), 3.86 (dt, J ϭ 6.05, J ϭ 9.54 Hz,
1 H, H-7), 3.71 (mc, 2 H, 2 H-17), 3.65 [mc, 20 H, H-3, H-5, 2 (H-
18, H-19, H-20, H-21, H-22, H-23, H-24, H-25, H-26)], 3.60Ϫ3.57
H, 2 H-35), 2.64 (m, 2 H, 2 H-10), 2.53 (mc, 2 H, 2 H-11), 2.30 (s,
3 H, 3 H-37), 1.59Ϫ1.53 [m, 4 H, 2 (H-26, H-34)], 1.26 [br., 14 H,
2 (H-27, H-28, H-29, H-30, H-31, H-32, H-33)] ppm. 13C NMR
(m, 4 H, H-2, H-4, 2 H-27), 3.53 (dt, J ϭ 6.40, J ϭ 9.54 Hz, 1 H, (125 MHz, CDCl3, TMS): δ ϭ 197.43 (C-36), 174.40 (C-9), 174.18
H-7Ј), 3.44 (m, 2 H, 2 H-28), 3.18 (m, 2 H, 2 H-11), 2.89 (mc, 2 H, (C-12), 101.61 (C-1), 74.68 (C-5), 73.61, 72.49 (C-3), 72.30 (C-25),
2 H-38), 2.64 (t, J ϭ 6.97 Hz, 2 H, 2 H-13), 2.49 (t, J ϭ 6.96 Hz, 71.99 (C-2), 70.51Ϫ71.10 (C-15, C-16, C-17, C-18, C-19, C-20, C-
2 H, 2 H-14), 2.32 (s, 3 H, 3 H-40), 1.65 (mc, 2 H, 2 H-8), 1.59Ϫ1.50 21, C-22, C-23, C-24), 68.60 (C-4), 67.20 (C-7), 64.82 (C-13), 62.89
[m, 6 H, 2 (H-10, H-29, H-37)], 1.46Ϫ1.42 (m, 2 H, 2H-9), (C-6), 62.17, 40.30 (C-8), 31.29 (C-10), 30.68 (C-11), 30.63Ϫ29.81
1.35Ϫ1.31 [mc, 14 H, 2 (H-30, H-31, H-32, H-33, H-34, H-35, H-
(C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34), 29.73 (C-
36)], 1.27 (d, J ϭ 6.6 Hz, 3 H, 3 H-6) ppm. 13C NMR (125 MHz,
35), 27.15 ppm. MALDI-TOF: m/z ϭ 838 [M ϩ Na]ϩ (M ϭ 815.43
CDCl3, TMS): δ ϭ 197.61 (C-39), 174.24 (C-12), 174.11 (C-15), calculated for C37H69NO16S). ESI-MS: m/z ϭ 838.38 [M ϩ Naϩ]
104.82 (C-1), 75.19 (C-2), 73.05 (C-3), 72.37 (C-4), 72.35 (C-28),
71.86 (C-5), 71.57 (C-18, C-19, C-20, C-21, C-22, C-23, C-24, C-
25, C-26), 71.17 (C-27), 70.49 (C-7), 70.08 (C-17), 64.85 (C-16),
40.37 (C-11), 31.49 (C-14), 30.75 (C-40), 30.56Ϫ30.40 (C-13, C-30,
C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38), 30.12 (C-29),
29.78 (C-10), 27.23 (C-8), 24.42 (C-9), 16.78 (C-6) ppm. MALDI-
TOF: m/z ϭ 864 [M ϩ Na]ϩ (M ϭ 841.49 calculated for
C40H75NO15S). ESI-MS: m/z ϭ 664.42 [M ϩ Naϩ] (M ϭ 664.47
calculated for C40H75NO15S ϩ Na).
(M ϭ 838.42 calculated for C37H69NO16S ϩ Na).
4-(2-Carboxyethyl)-4-(9-fluorenylmethoxycarbonylamino)heptane-
1,7-diacid (21): Fmoc chloride (1.21 g, 4.64 mmol) was mixed with
aminotriester 20 (1.93 g, 4.64 mmol) and dissolved in 40 mL of
dichloromethane. DIPEA (1 mL) was then added and the mixture
was stirred for 1 h at room temp. The solvent was removed in va-
cuo, the residue was taken up in 10 mL of DCM and 5 mL of TFA
was added. After 3 h of additional stirring the solution was diluted
with 50 mL of C2H4Cl2 and the solvent was removed in vacuo at
room temp. Column chromatography on RP-18 silica gel (MeCN/
H2O, 1:1) and subsequent lyophilization yielded a colourless pow-
ManC2NHC11SAc (18): The reaction was carried out according to
the general procedure
A using carboxylic acid 15 (77 mg,
der. Yield: 1.36 g (2.89 mmol, M ϭ 469.35) 62%. HPLC: tR
ϭ
0.296 mmol) in 1.5 mL of DMF, isobutyl chloroformate (46 µL,
0.355 mmol) and tripropylamine (112 µL, 0.6 mmol). After 30 min
amine 10 (79.2 mg, 0.355 mmol) in 0.5 mL of DMF and tripropyla-
mine (56 µL, 0.3 mmol) were added to the clear reaction mixture
which was then warmed to room temp. over 2 h and stirred over-
night. The solvent was removed in vacuo and the residue was taken
up in 15% acetonitrile (aq.) and purified by HPLC chromatography
water/acetonitrile, 30% Ǟ 70% acetonitrile, 60 min, 10 mL/min,
tR ϭ 35 min) to yield a white foam. Yield: 89.4 mg (192 mmol,
M ϭ 465.60) 65%. 1H NMR (500 MHz, CDCl3, TMS): δϭ 4.75
(br. d, 1 H, H-1), 3.82 (dd, J ϭ 2.2, J ϭ 9.53 Hz, 1 H, H-6), 3.80
(dd, J ϭ 1.65, J ϭ 3.48 Hz, 1 H, H-2), 3.74 (mc, 1 H, H-7), 3.67
(mc, 2 H, H-3, H-6Ј), 3.59 (m, ‘‘t’’, J ϭ 9.54 Hz, 1 H, H-4), 3.52
(mc, 2 H, H-5, H-7Ј), 3.41Ϫ3.34 (m, 2 H, 2 H-8), 2.85 (t, J ϭ
7.16 Hz, 2 H, 2 H-19), 2.30 (s, 3 H, 3 H-21), 2.19 (t, J ϭ 2.52 Hz,
2 H, 2 H-10), 1.59 (mc, 2 H, 2 H-18), 1.53 (mc, 2 H, 2 H-11), 1.30
[br., 12 H, 2 (H-12, H-13, H-14, H-15, H-16, H-17)] ppm. 13C
NMR (125 MHz, CDCl3, TMS): δ ϭ 197.67 (C-20), 176.58 (C-9),
101.72 (C-1), 74.80 (C-5), 72.56 (C-3), 72.11 (C-2), 68.80 (C-4),
67.30 (C-7), 62.93 (C-6), 40.27 (C-8), 37.10 (C-10), 30.80 (C-21),
30.54Ϫ29.83 (C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18),
27.07 (C-19) ppm. MALDI-TOF: m/z ϭ 488 [M ϩ Na]ϩ (M ϭ
465.24 calculated for C21H39NO8S). ESI-MS: m/z ϭ 488.19 [M ϩ
Naϩ] (M ϭ 488.22 calculated for C21H39NO8S ϩ Na).
24.38 min [250/4 LiChrosorb 7 µm C8, water/acetonitrile, 10% Ǟ
80% acetonitrile, 60 min, 1 mL/min]. 1H NMR (300 MHz, MeOD):
δ ϭ 7.77 (d, J ϭ 7.08 Hz, 2 H, Ar-H), 7.08 (d, J ϭ 7.19 Hz, 2 H,
Ar-H), 7.32 (mc, 4 H, Ar-H), 4.35 (m, 2 H, 2 H-6), 4.18 (m, 1 H,
H-7), 2.24 (mc, 6 H, 6 H-2), 1.94 (mc, 6 H, 6 H-3) ppm. 13C NMR
(75.47 MHz, MeOD): δ ϭ 177.10 (C-1), 156.52 (C-5), 145.36,
142.60, 128.73, 128.16, 126.18, 120.88 (Ar-C), 66.78 (C-6), 57.42
(C-4), 30.55, 29.11 (C-2, C-3). ESI-MS: m/z ϭ 492.12 [M ϩ Naϩ]
(M ϭ 492.16 calculated for C25H27NO8 ϩ Na).
(FucC5NiPr)3NHFmoc (22): Fucoside 6 (123 mg, 0.42 mmol) was
mixed with triacid 21 (66 mg, 0.14 mmol) and HATU (171 mg,
0.45 mmol). The mixture was dissolved in 2 mL of dry DMF, the
solution cooled to 0 °C, (92 µL, 0.54 mmol) of DIPEA added and
the reaction mixture stirred for 6 h at room temp. The solvent was
removed in vacuo and the residue was taken up in methanol and
purified by gel-permeation chromatography on Sephadex LH-20 to
yield a white foam. Yield: 120 mg (93 µmol, M ϭ 1289.59) 66%.
1H NMR (500 MHz, MeOD): δ ϭ 7.81 (m, 2 H, Ar-H), 7.69 (m,
2 H, Ar-H), 7.39 (m, 2 H, Ar-H), 7.32 (m, 2 H, Ar-H), 4.52 (mc, 1
H, H-12), 4.31 (mc, 2 H, 2 H-19), 4.21 (mc, 3 H, 2 H-12, H-20),
4.15 (m, 3 H, 3 H-1), 3.79 (mc, 3 H, 3 H-7), 3.58 (m, 6 H, 3 H-4,
3 H-5), 3.51 (mc, 3 H, 3 H-7), 3.44 (mc, 6 H, 3 H-2, 3 H-3), 3.16
(mc, 6 H, 6 H-11), 2.36 (m, 6 H, 6 H-15), 1.97 (m, 6 H, 6 H-16),
1.63 (m, 6 H, 6 H-8), 1.56 (m, 6 H, 6 H-9), 1.36 (m, 6 H, 6 H-10),
1.25 (m, 9 H, 9 H-6), 1.15 (m, 18 H, 18 H-13).13C NMR
(125.47 MHz, MeOD): δ ϭ 174.79, 174.21 (C-14), 156.96 (C-18),
145.33, 142.64, 128.88, 128.26, 126.26, 121.06 (Ar-C), 104.84,
104.81 (C-1), 75.19 (C-2), 73.06, 7302 (C-4), 72.33, (C-3), 71.84 (C-
5), 70.55, 70.35 (C-7), 67.32 (C-20), 58.11 (C-17), 50.01, 49.85 (C-
12), 47.83, 45.04, 42.32 (C-11), 32.14, 31.48, 30.51 (C-15, C-16),
30.39, 30.29, 24.84, 24.62 (CH2), 21.53, 20.65 16.82, 16.79 (CH3)
ppm. MALDI-TOF: m/z ϭ 1313 [M ϩ Na]ϩ (M ϭ 1288.76 calcu-
lated for C67H108N4O20). ESI-MS: m/z ϭ 1311.68 [M ϩ Naϩ] (M ϭ
1311.74 calculated for C67H108N4O20 ϩ Na).
ManC2NHsucEG6C11SAc (19): The reaction was carried out ac-
cording to the general procedure A using carboxylic acid 15
(226 mg, 0.370 mmol) in 1.5 mL of DMF, isobutyl chloroformate
(57.6 µL, 0.444 mmol) and tripropylamine (140 µL, 0.740 mmol).
After 30 min a solution of mannoside 10 (99.1 mg, 0.444 mmol)
and tripropylamine (70 µL, 0.370 mmol) in 1 mL of DMF was
syringed in dropwise. After 3 h the solvent was evaporated and the
yellow, highly viscous crude oil was purified by flash chromatogra-
phy (MeOH/DCM, 1:20 Ǟ 1:10). Yield 304 mg (0.373 mmol, M ϭ
1
815.43) 94%. H NMR (500 MHz, CDCl3, TMS): δ ϭ 4.77 (br., 1
H, H-1), 4.22 (m, 2 H, 2 H-13), 3.8 (dd, J ϭ 2.40, J ϭ 11.74 Hz,
1 H, H-6), 3.81 (mc, 1 H, H-2), 3.75 (m, 1 H, H-7), 3.71Ϫ3.69 (m, (FucC5NiPr)3C11SAc (23): Fmoc-protected fucoside 22 (120 mg, 93
4 H, H-3, H-6Ј, 2 H-14), 3.64 [br., 20 H, 2 (H-15, H-16, H-17, H- µmol) was dissolved in 4 mL of dry DMF, 1 mL of morpholine
18, H-19, H-20, H-21, H-22, H-23, H-24)], 3.58 (mc, 2 H, H-4, H- was added and the solution was stirred for 1 h at room temp. The
5), 3.53 (mc, 1 H, H-7Ј), 3.45 (m, ‘‘t’’, J ϭ 7.78 Hz, 2 H, 2 H-25),
3.42 (mc, 1 H, H-8), 3.37 (mc, 1 H, H-8Ј), 2.86 (t, J ϭ 7.34 Hz, 2
solvent was removed in vacuo, the residue was mixed with 11-
thioacetylundecanoic acid 12 (30 mg, 0.12 mmol) and HATU
Eur. J. Org. Chem. 2004, 3931Ϫ3940
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3937

M. Kleinert, N. Röckendorf, T. K. Lindhorst
FULL PAPER
(46 mg, 0.12 mmol) and subsequently the mixture was dried for 1 h
in vacuo. Under an argon atmosphere the compounds were dis-
34), 72.30 (C-5), 71.81Ϫ71.13 (C-7, C-23, C-24, C-25, C-26, C-27,
C-28, C-29, C-30, C-31, C-32), 64.82 (C-22), 59.01 (C-17), 49.96
solved in 5 mL of dry DMF, DIPEA (25 µL, 0.15 mmol) was added (C-12), 47.79 (C-12Ј), 45.0 (C-11), 42.27 (C-11Ј), 32.10 (C-20),
and the solution was stirred for 18 h at room temp. The solvent
was removed in vacuo, the residue was taken up in methanol and
purified by gel-permeation chromatography on Sephadex LH-20 to
yield a colourless foam. Yield: 76 mg (58 µmol, M ϭ 1309.73) 62%.
HPLC: tR ϭ 24.75 min [250/4 LiChrosorb 7µm C8, water/aceto-
32.09 (C-8), 31.90 (C-16), 30.71Ϫ30.51 (C-10, C-35, C-36, C-37, C-
38, C-39, C-40, C-41, C-42, C-43, C-46), 30.15 (C-19), 29.84 (C-
44), 29.78 (C-15), 27.10 (C-9), 21.67 (C-13), 20.67 (C-13Ј), 16.80
(C-6). MALDI-TOF: m/z ϭ 1683.62 [M ϩ Na]ϩ (M ϭ 1682.00
calculated for C81H150N4O28S ϩ Na); m/z ϭ 1698.64 [M ϩ K]ϩ
nitrile, 20% Ǟ 90% acetonitrile, 60 min, 1 mL/min]. The NMR (M ϭ 1698.12 calculated for C81H150N4O28S ϩ K). ESI-MS: m/z ϭ
spectroscopic data showed clearly the presence of two amide rota-
1682.07 [M ϩ Naϩ] (M ϭ 1682.01 calculated for C81H150N4O28S ϩ
mers in a 1:0.9 ratio, which can undoubtedly be assigned in accord- Na).
ance to the doubled set of signals for the isopropyl group and the
(FucC5NH)3NHFmoc (25): Fucoside 5 (105 mg, 0.42 mmol) was
methylene signals close to it. Here, the chemical shifts of both iso-
mers are listed. H NMR (500 MHz, 300 K, CDCl3): δ ϭ 4.53 (br.
1
mixed with triacid 21 (66 mg, 0.14 mmol) and HATU (171 mg,
0.45 mmol). The mixture was dissolved in 2 mL of dry DMF, the
solution cooled to 0 °C, DIPEA (92 µL, 0.54 mmol) added and
the reaction mixture stirred for 6 h at room temp. The solvent was
removed in vacuo, the residue was taken up in methanol and puri-
fied by gel-permeation chromatography on Sephadex LH-20 to
yield a white foam. Yield: 64 mg (55 µmol, M ϭ 1163.35) 39%.
HPLC: tR ϭ 39.41 min [250/4 LiChrosorb 7 µm C8, water/aceto-
nitrile, 0% Ǟ 70% acetonitrile, 60 min, 1 mL/min]. 1H NMR
(500 MHz, MeOD): δ ϭ 7.82 (br. d, J ϭ 7.52 Hz, Ar-H), 7.69 (m,
2 H, Ar-H), 7.39 (m, 2 H, Ar-H), 7.31 (m, 2 H, Ar-H), 4.32 (m, 2
H, 2 H-17), 4.20 (m, 1 H, H-18), 4.16 (m, 3 H, 3 H-1), 3.84 (m, 3
H, 3 H-7), 3.58 (m, 6 H, 3 H-4, 3 H-5), 3.51 (mc, 3 H, 3 H-7Ј),
3.45 (m, 6 H, 3 H-2, 3 H-3), 3.15 (m, 6 H, 6 H-11), 2.16 (m, 6 H,
6 H-13), 1.92 (m, 6 H, 6 H-14), 1.62 (m, 6 H, 6 H-8), 1.51 (m, 6
H, 6 H-9), 1.41 (m, 6 H, 6 H-10), 1.25 (d, J ϭ 6.4 Hz, 9 H, 9 H-
6) ppm. 13C NMR (125.47 MHz, MeOD): δ ϭ 175.69, 175.58 (C-
12), 145.44, 142.61, 128.78, 128.19, 126.31, 120.95 (Ar-C), 104.79
(C-1), 75.16 (C-2), 73.04 (C-4), 72.33, (C-3), 71.84 (C-5), 70.64 (C-
7), 67.11 (C-17), 57.89 (C-15), 40.42 (C-11), 30.39, 30.08 (C-13, C-
14), 30.71 (C-8), (C-9), 24.44 (C-10), 16.81 (C-6) ppm. MALDI-
TOF: m/z ϭ 1186 [M ϩ Na]ϩ (M ϭ 1162.61 calculated for
C58H90N4O20). ESI-MS: m/z ϭ 1185.55 [M ϩ Naϩ] (M ϭ 1185.60
calculated for C58H90N4O20 ϩ Na).
sept, 3 H, 3 H-12), 4.19 (mc, 3 H, 3 H-1), 4.06 (br. sept, 2 H, 3 H-
12), 3.91 (mc, 3 H, 3 H-7), 3.72 (mc, 3 H, 3 H-4), 3.59 [mc, 9 H, 3
(H-2, H-3, H-5)], 3.49 (mc, 3 H, 3 H-7Ј), 3.13 (br. m, H-11), 2.83
(br. t, 2 H, H-28), 2.35 (mc, 6 H, CH2), 2.31 (br. s, 3 H, 3 H-30),
2.15 (mc, 8 H, CH2), 1.60 (mc, 16 H, CH2, H-27), 1.28 (mc, 13 H,
CH2, 9 H-6), 1.18 (d, J ϭ 6.42 Hz, 9 H, 9 H-13), 1.12 (d, J ϭ
6.79 Hz, 9 H, 9 H-13) ppm. 13C NMR (125.47 MHz, CDCl3): δ ϭ
196.21 (C-29), 173.61 (C-14), 173.44 (C-14), 172.97 (C-18), 103.34
(C-1), 103.17 (C-1), 74.43, 74.11, 71.77, 71.71, 71.45, 70.62 (C-2,
C-3, C-4, C-5), 69.03 (C-7), 57.62 (C-17), 48.66, 46.18 (C-12),
43.88, 41.15, 37.72, 31.10, 30.78 (C-30), 29.63Ϫ28.95, 26.18, 26.03,
24.16, 23.52 (CH2), 21.50, 20.65 (C-13), 16.56 (C-6) ppm. MALDI-
TOF: m/z ϭ 1332 [M ϩ Na]ϩ (M ϭ 1308.82 calculated for
C65H120N4O20S).
(FucC5NiPr)3sucEG6C11SAc (24): The protected cluster 22 (60 mg,
0.046 mmol) was dissolved in 1.5 mL of DMF at room temp. under
nitrogen, 0.3 mL of morpholine was added and the reaction mix-
ture was stirred for 2 h. The solvents were removed in vacuo and
50 mg of a colourless solid was obtained and used without further
purification. The coupling was performed according to procedure
A using carboxylic acid 15 (25.8 mg, 0.042 mmol) in 0.5 mL of
DMF, isobutyl chloroformate (6 µL, 0.046 mmol) and tripropylam-
ine (16 µL, 0.082 mmol). After 30 min free amine (50 mg,
0.046 mmol) was dissolved in 1 mL of DMF and added to the
solution. Stirring was maintained at room temp. overnight prior to
solvent removal in vacuo. The crude yellow oily product was sub-
(FucC5NH)3sucEG6C11SAc (26): Fmoc-protected fucoside 25
(60 mg, 37 µmol) was dissolved in 4 mL of dry DMF, 1 mL of
morpholine was added and the solution was stirred for 1 h at room
jected to HPLC purification (tR ϭ 48.20 min; A ϭ water, B ϭ temp. The solvent was removed in vacuo, the residue was mixed
acetonitrile, 0% B Ǟ 70% B, 5 min, 70% B Ǟ 30% B, 60 min,
with EG6-alkyl thioacetate 15 (271 mg, 0.44 mmol) and HATU
10 mL/min) to give a colourless oil. Yield: 48 mg (0.029 mmol,
(171 mg, 0.45 mmol), and then the mixture was dried for 1 h in
M ϭ 1659.02) 63%. The NMR spectroscopic data clearly showed vacuo. Under argon atmosphere the compounds were dissolved in
the presence of two amide rotamers in a 1:0.8 ratio, which can
undoubtedly be assigned in accordance to the doubled set of sig-
5 mL of dry DMF, DIPEA (85 µL, 0.5 mmol) was added and the
solution was stirred for 48 h at room temp. The solvent was re-
nals for the isopropyl group and the methylene signals close to moved in vacuo, the residue was taken up in methanol and purified
it. Here, the chemical shifts of both isomers are listed. 1H NMR
by gel-permeation chromatography on Sephadex LH-20. Prepara-
(500 MHz, MeOD): δ ϭ 4.54 (mc, 1 H, H-12), 4.25Ϫ4.20 (m, 7 H,
tive HPLC of the residue on RP-8 silica gel (A ϭ water, B ϭ aceto-
3 H-1, 2 H-12, 2 H-22), 3.89 (mc, 3 H, 3 H-7), 3.73 (mc, 3 H, 3 H- nitrile, 5% B Ǟ 80% B, 10 mL/min, 60 min, tR ϭ 52 min) yielded
23), 3.68 [mc, 21 H, 3 H-5, 2 (H-24, H-25, H-26, H-27, H-28, H- a colourless foam. Yield: 24 mg (15 µmol, M ϭ 1533.89) 5%. 1H
29, H-30, H-31, H-32)], 3.64 (mc, 3 H, 3 H-4), 3.62 (m, 2 H, 2 H-
NMR (500 MHz, MeOD): δ ϭ 4.22 (mc, 2 H, 2 H-20), 4.17 (mc, 3
33), 3.57 (mc, 3 H, 3 H-7Ј), 3.51 (mc, 8 H, 3 H-2, 3 H-3, 2 H-34),
H, 3 H-1), 3.85 (mc, 3 H, 3 H-7), 3.70 (mc, 2 H, 2 H-21), 3.64 [23
3.28 (m, 3 H, 3 H 11), 3.20 (m, 3 H, 3 H-11Ј), 2.90 (t, J ϭ 7.15 Hz, H, 3 H-5, 2 (H-22, H-23, H-24, H-25, H-26, H-27, H-28, H-29, H-
2 H, 2 H-44), 2.68 (mc, 2 H, 2 H-19), 2.53 (mc, 2 H, 2 H-20), 2.45 30, H-31)], 3.59 (5 H, 3 H-4, 2 H-32), 3.53 (mc, 3 H, 3 H-7Ј), 3.46
(mc, 3 H, 3 H-15), 2.39 (mc, 3 H, 3 H-15Ј), 2.35 (s, 3 H, 3 H-46), (mc, 6 H, 3 H-2, 3 H-3), 3.17 (mc, 6 H, 6 H-11), 2.86 (t, J ϭ
2.05 (mc, 6 H, 6 H-16), 1.68 (m, 9 H, 6 H-8, 3 H-10), 1.60 (m, 7 7.20 Hz, 2 H, 2 H-42), 2.65 (mc, 2 H, 2 H-17), 2.50 (mc, 2 H, 2 H-
H, 3 H-10Ј, 2 H-35, 2 H-43), 1.49Ϫ1.34 [m, 20 H, 6 H-9, 2 (H-36, 18), 2.30 (s, 3 H, 3 H-44), 2.18 (mc, 6 H, 6 H-13), 1.96 (mc, 6 H, 6
H-37, H-38, H-39, H-40, H-41, H-42)], 1.30 (d, J ϭ 6.42 Hz, 9 H, H-14), 1.64 (quint, J ϭ 6.97 Hz, 6 H, 6 H-8), 1.54 (mc, 10 H, 6 H-
9 H-6), 1.26 (d, J ϭ 6.61 Hz, 10 H, 10 H-13), 1.20 (d, J ϭ 6.78 Hz, 10, 3 H-33, 3 H-41), 1.41 (mc, 6 H-9), 1.31 (mc, H-34, H-35, H-36,
8 H, 8 H-13Ј) ppm. 13C NMR (125 MHz, MeOH, TMS): δ ϭ
H-37, H-38, H-39, H-40), 1.26 (d, J ϭ 6.45 Hz, 12 H, 12 H-6) ppm.
197.56 (C-45), 174.78 (C-14), 174.30 (C-18), 143.60 (C-21), 104.80 13C NMR (125.47 MHz, MeOH): δ ϭ 175.77 (C-19), 174.89 (C-
(C-1), 75.19 (C-33), 75.16 (C-3), 73.02 (C-4), 72.33 (C-2), 72.31 (C- 16), 104.83 (C-1), 75.21 (C-2), 73.06 (C-4), 72.37 (C-3), 71.86 (C-
3938
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 3931Ϫ3940

Glyco-SAMs as Glycocalyx Mimetics
FULL PAPER
5), 71.58, 71.17, 70.46 (C-7), 70.08 (C-18), 64.99 (C-17), 59.04 (C- 30.42Ϫ29.84 (C-16, C-17, C-18, C-19, C-20. C-21), 29.78 (C-23),
15), 40.42 (C-11), 31.75, 31.31, 30.74 (C-13, C-14), 30.74, 30.69, 27.15 (C-15) ppm. MALDI-TOF: m/z ϭ 1127.83 [M ϩ Na]ϩ (M ϭ
30.57, 30.42, 30.19, 30.13, 29.86, 29.79 (C-30), 24.77 (C-42), 16.81
1104.52 calculated for C47H84N4O23S). ESI-MS: m/z ϭ 1127.46
(C-6) ppm. MALDI-TOF-MS: m/z ϭ 1557 [M ϩ Na]ϩ (M ϭ [M ϩ Naϩ] (M ϭ 1127.51 calculated for C47H84N4O23S ϩ Na).
1532.87 calculated for C72H132N4O28S). ESI-MS: m/z ϭ 789.38 [M
(ManC2)3sucEG6C11SAc (29): The reaction was carried out accord-
ϩ2 Naϩ] (M ϭ 789.42 calculated for C72H132N4O28S ϩ2 Na);
ing to procedure A but with DIPEA instead of NPr3 and carboxylic
m/z
C72H132N4O28S ϩ Na).
ϭ 1555.82 [M ϩ ϭ 1555.86 calculated for
Naϩ] (M
acid 15 (45.5 mg, 0.0745 mmol) in 1.5 mL of DMF, isobutyl chloro-
formate (11.6 µL, 0.0894 mmol) and DIPEA (28.4 µL,
0.149 mmol). After 30 min of stirring amine 10 (77 mg,
0.0894 mmol) and 14.2 µL of DIPEA were added. This mixture
was stirred for 2 h prior to solvent removal in vacuo. The crude
product was purified by gel-permeation chromatography on Se-
(ManC2)3NHFmoc (27): Mannoside 10 (100 mg, 0.45 mmol) was
mixed with triacid 21 (70 mg, 0.15 mmol) and HATU (171 mg,
0.45 mmol). The mixture was dissolved in 10 mL of dry DMF, the
solution cooled to 0 °C, 100 µL of DIPEA added and the reaction
mixture tirred for 4 h at room temp. The solvent was removed in
vacuo, the residue was taken up in 15% acetonitrile (aq.) and puri-
fied by HPLC chromatography (A ϭ water, B ϭ acetonitrile, 20%
B Ǟ 50% B, 70 min, 10 mL/min, tR ϭ 32 min) to yield a white
phadex LH-20 to yield
a colourless oil. Yield: 20.4 mg
(0.014 mmol, M ϭ 1455.65) 19%. 1H NMR (500 MHz, MeOD):
δ ϭ 4.77 (m, 3 H, 3 H-1), 4.24 (mc, 2 H, 2 H-17), 3.85 (dd, J ϭ
2.1, 11.5 Hz, 3 H, 3 H-6), 3.82 (dd, J ϭ 1.6, 3.3 Hz, 3 H, 3 H-2),
3.77 (mc, 3 H, 3 H-7), 3.70 (mc, 8 H, 3 H-3, 3 H-6Ј, 2 H-18), 3.64
[mc, 18 H, 2 (H-19, H-20, H-21, H-22, H-23, H-24, H-25, H-26,
H-27)], 3.64 (mc, 3 H, 3 H-4), 3.59 (mc, 3 H, 3 H-5), 3.55 (mc, 5
H, 3 H-7Ј, 2 H-28), 3.46 (t, J ϭ 6.6 Hz, 2 H, 2 H-29), 3.40 (mc, 6
H, 6 H-8), 2.86 (t, J ϭ 7.34 Hz, 2 H, 2 H-39), 2.67 (mc, 2 H, 2 H-
15), 2.50 (mc, 2 H, 2 H-14), 2.30 (s, 3 H, 3 H-41), 2.21 (mc, 6 H, 6
H-10), 1.97 (mc, 6 H, 6 H-11), 1.55 (mc, 4 H, 2 H-38, 2 H-30), 1.30
[mc, 14 H, 2 (H-31, H-32, H-33, H-34, H-35, H-36, H-37)] ppm.
13C NMR (125.47 MHz, MeOD): δ ϭ 197.64 (C-40), 176.06 (C-9),
175.04 (C-13), 173.78 (C-16), 101.69 (C-1), 74.82 (C-5), 72.54 (C-
3), 72.37 (C-18), 72.06 (C-2), 71.52, 71.12, 70.04, 68.72 (3 C-4),
67.26 (3 C-7), 65.07 (C-17), 62.98 (C-6), 59.09 (C-12), 40.39 (C-8),
31.81 (C-11), 31.62 (C-15), 31.33 (C-10), 30.74, 30.71 (C-38, C-30),
30.68, 30.59, 30.56, 30.18 (C-41), 29.85 (C-14), 29.77 (C-39), 27.19.
ESI-MS: m/z ϭ 1477.70 [M ϩ Naϩ] (M ϭ 1477.71 calculated for
C63H114N4O31S ϩ Na).
foam. Yield: 90 mg (82 µmol, M ϭ 1085.11) 54%. HPLC: tR
ϭ
18.91 min [250/4 LiChrosorb 7 µm C8, A ϭ water, B ϭ acetonitrile,
0% B Ǟ 0% B 10 min, 0% B Ǟ 75% B, 50 min, 1 mL/min]. 1H
NMR (500 MHz, MeOD): δ ϭ 7.79 (m, 2 H, Ar-H), 7.68 (m, 2 H,
Ar-H), 7.37 (m, 2 H, Ar-H), 7.31 (m, 2 H, Ar-H), 4.76 (d, J ϭ
1.4 Hz, 3 H, 3 H-1), 4.34 (br. d, 2 H, 2 H-14), 4.19 (br. t, 1 H, H-
15), 3.84 (dd, J ϭ 2.2, J ϭ 11.7 Hz, 3 H, 3 H-6), 3.84 (dd, J ϭ 1.8,
J ϭ 3.5 Hz, 3 H, 3 H-6), 3.76 (m, 3 H, 3 H-7), 3.69 (mc, 6 H, 3 H-
3, 3 H-6Ј), 3.58 (m, ‘‘t’’, 3 H, 3 H-4), 3.55 (mc, 6 H, 3 H-5, 3 H-
7Ј), 3.37 (mc, 6 H, 6 H-8), 2.15 (mc, 6 H, 6 H-10), 1.95 (mc, 6 H,
6 H-11) ppm. 13C NMR (125.47 MHz, MeOD): δ ϭ 175.99 (C-9),
156.66 (C-13), 145.43, 142.61, 128.76, 128.19, 126.31, 120.92 (Ar-
C), 101.64 (C-1), 74.83 (C-5), 72.51 (C-3), 72.05 (C-2), 68.67 (C-4),
67.22 (C-7), 67.08 (C-14), 62.98 (C-6), 57.88 (C-12), 40.39 (C-8),
31.95 (C-10), 31.26 (C-11) ppm. MALDI-TOF: m/z [M ϩ Na]ϩ
(M ϭ 1084.46 calculated for C49H72N4O23). ESI-MS: m/z ϭ
1107.39 [M ϩ Naϩ] (M ϭ 1107.45 calculated for C49H72N4O23
ϩ
Na).
Acknowledgments
(ManC2)3C11SAc (28): The protected cluster 27 (80 mg,
0.093 mmol) was dissolved in 1.5 mL of DMF at room temp. under
nitrogen, 0.3 mL morpholine was added and the reaction mixture
was stirred for 2 h. The solvents were removed in vacuo and a
colourless solid was obtained and used without further purifi-
cation. The coupling reaction was carried out according to the gen-
eral procedure A using acid 12 (22 mg, 0.0843 mmol) in 0.5 mL of
DMF, tripropylamine (32 µL, 0.169 mmol) and isobutyl chloro-
formate (11 µL, 0.0927 mmol) at 0 °C. After 30 min the previously
deprotected amine in 1 mL of DMF and 16 µL of NPr3 was added
and the reaction mixture was warmed to room temp. and stirred
for 90 h. The solvent was removed in vacuo, the residue was taken
up in 15% acetonitrile (aq.) and purified by HPLC chromatography
(A ϭ water, B ϭ acetonitrile, 15% B Ǟ 70% B, 60 min, 10 mL/min,
tR ϭ 22.73 min) to yield a white foam. Yield 30 mg (0.027 mmol,
M ϭ 1104.52) 32%. 1H NMR (500 MHz, MeOD): δ ϭ 4.76 (d, J ϭ
1.65 Hz, 3 H, 3 H-1), 3.85 (dd, J ϭ 2.2, J ϭ 11.74 Hz, 3 H, 3 H-
6), 3.82 (dd, J ϭ 1.65, 3.3 Hz, 3 H, 3 H-2), 3.76 (mc, 3 H, 3 H-7),
3.70 (mc, 6 H, 3 H-3, 3 H-6Ј), 3.59 (dd, J ϭ 9.35, J ϭ 9.72 Hz, 3
H, 3 H-4), 3.55 (mc, 6 H, 3 H-5, 3 H-7Ј), 3.43 (mc, 6 H, 3 H-8),
3.37 (mc, 6 H, 3 H-8Ј), 2.85 (t, J ϭ 7.20 Hz, 2 H, 2 H-23), 2.30 (s,
3 H, 3 H-25), 2.18 (mc, 8 H, 6 H-10, 2 H-14), 1.98 (mc, 6 H, 6 H-
11), 1.60 (mc, 2 H, 2 H-15), 1.55 (m, 2 H, 2 H-22), 1.30 [br., 12 H,
2 (H-16, H-17, H-18, H-19, H-20, H-21)] ppm. 13C NMR
(125.47 MHz, MeOD): δ ϭ 197.77 (C-24), 176. 06 (C-9), 176.00
(C-13), 101.63 (C-1), 74.81 (C-5), 72.50 (C-3), 72.05 (C-2), 68.66
(C-4), 67.21 (C-7), 63.00 (C-6), 58.89 (C-12), 40.38 (C-8), 37.86 (C-
14), 31.79 (C-11), 31.30 (C-10), 30.74 (C-22), 30.49 (C-25),
This work has partly been supported by the DFG in the frame of
the collaborative network SFB 470. We would like to thank Mrs.
Elwira Klima-Bartczak for her valuable technical assistance and
PD Dr. Andreas Terfort for his kind advice.
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3939

M. Kleinert, N. Röckendorf, T. K. Lindhorst
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3940
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 3931Ϫ3940