Synthesis of benzaldehyde-functionalized glycans: A novel approach towards glyco-SAMs as a tool for surface plasmon resonance studies

Article abstract of DOI:10.1002/chem.200902693

In recent years the interest in tools for investigating carbohydrateprotein (CPI) and carbohydrate-carbohydrate interactions (CCI) has increased significantly. For the investigation of CPI and CCI, several techniques employing different linking methods are available. Surface plasmon resonance (SPR) imaging is a most appropriate tool for analyzing the formation of self-assembled monolayers (SAM) of carbohydrate derivatives, which can mimic the glycocalyx. In contrast to the SPR imaging methods used previously to analyze CPI and CCI, the novel approach reported herein allows a facile and rapid synthesis of linker spacers and carbohydrate derivatives and enhances the binding event by controlling the amount and orientation of ligand. For immobilization on biorepulsive amino-functionalized SPR chips by reductive amination, diverse aldehyde-functionalized glycan structures (glucose, galactose, mannose, glucosamine, cellobiose, lactose, and lactosamine) have been synthesized in several facile steps that include olefin metathesis. Effective immobilization and the first binding studies are presented for the lectin concanavalin A.

Full text of DOI:10.1002/chem.200902693

FULL PAPER
DOI: 10.1002/chem.200902693
Synthesis of Benzaldehyde-Functionalized Glycans: A Novel Approach
Towards Glyco-SAMs as a Tool for Surface Plasmon Resonance Studies
Sebastian Kopitzki,[a] Knud J. Jensen,[b] and Joachim Thiem*[a]
Abstract: In recent years the interest in
tools for investigating carbohydrate–
protein (CPI) and carbohydrate-carbo-
hydrate interactions (CCI) has in-
creased significantly. For the investiga-
tion of CPI and CCI, several tech-
niques employing different linking
methods are available. Surface plasmon
resonance (SPR) imaging is a most ap-
propriate tool for analyzing the forma-
tion of self-assembled monolayers
(SAM) of carbohydrate derivatives,
which can mimic the glycocalyx. In
contrast to the SPR imaging methods
used previously to analyze CPI and
CCI, the novel approach reported
herein allows a facile and rapid synthe-
sis of linker spacers and carbohydrate
derivatives and enhances the binding
event by controlling the amount and
orientation of ligand. For immobiliza-
tion on biorepulsive amino-functional-
ized SPR chips by reductive amination,
diverse aldehyde-functionalized glycan
structures (glucose, galactose, mannose,
glucosamine, cellobiose, lactose, and
lactosamine) have been synthesized in
several facile steps that include olefin
metathesis. Effective immobilization
and the first binding studies are pre-
sented for the lectin concanavalin A.
Keywords: amination
·
carbohy-
drates · metathesis · monolayers ·
surface plasmon resonance
Introduction
recognition events can be classified into carbohydrate–pro-
tein-interactions (CPI), especially between sugars and lec-
tins[5] and also selectins,[6] and carbohydrate–carbohydrate
interactions (CCI).[7]
Carbohydrates conjugated to proteins or lipids are structural
constituents of all eukaryotic cell surfaces. This layer, which
is composed of glycoproteins, glycolipids, complex oligosac-
charides as well as proteoglycans and other glycoconjugates,
is called the “glycocalyx” and has a thickness of up to
100 nm.[1] The molecular interactions of these glycoconju-
gates play a crucial role in various cellular processes, includ-
ing bacterial and viral infection, cancer metastasis, modula-
tion and activation of the immune system, tissue differentia-
tion and development, and many other intercellular recogni-
tion events.[2–4] In addition, carbohydrate-associated cellular
Both types of interactions are typically weak in in vitro
testing (KD values in the millimolar or high micromolar
range) compared with antigen–antibody interactions (KD
ꢀ10ꢁ8 to 10ꢁ12 m).[8–10] However, a multivalent presentation
of carbohydrate recognition units can increase the binding
affinity dramatically.[11,12] Although the elucidation and bio-
logical assignment of the glycocalyx has been well advanced
by glycobiology, the development of a general mechanistic
concept for carbohydrate recognition is still hampered by
difficulties in studying these interactions.
Thus, novel analytical and synthetic approaches such as
chemoenzymatic and automated solid-phase synthesis of oli-
gosaccharides and glycomimics as well as chemical tools, mi-
croarrays, glyconanoparticle technology, and molecular
modeling could facilitate the study of carbohydrate-based
recognition events.[13–20] The phenomenon of self-assembly
of thiol-functionalized molecules on gold surfaces, first de-
veloped by Bain and Whitesides in 1988,[21] is quite advanta-
geous for mimicking the glycocalyx. In particular, the con-
cept of glyco-self-assembled monolayers (glyco-SAMs) is
well suited to the investigation of the molecular interactions
of carbohydrates: It allows the density and orientation of
carbohydrate ligands to be controlled, and there are several
[a] Dipl.-Chem. S. Kopitzki, Prof. Dr. J. Thiem
Department of Chemistry, Faculty of Sciences
University of Hamburg
Martin-Luther-King-Platz 6, 20146 Hamburg (Germany)
Fax : (+49)40-42383-4325
E-mail: thiem@chemie.uni-hamburg.de
[b] Prof. Dr. K. J. Jensen
IGM, Faculty of Life Sciences, Centre for Carbohydrate
Recognition and Signalling
University of Copenhagen, Thorvaldsensvej 40
1871 Frederiksberg (Denmark)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902693.
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methods for their characterization.[22] Furthermore, glyco-
SAMs on gold can be advantageously studied by spectro-
scopic techniques such as surface plasmon resonance (SPR),
ellipsometry, atomic force microscopy (AFM), and X-ray
photoelectron spectroscopy.[23,24]
glycosides by cross metathesis. Olefin metathesis has
become a mainstay in organic synthesis.[27,28] Cross-metathe-
sis (CM), however, is less developed, especially in carbohy-
drate chemistry, than ring-closing metathesis (RCM) and
ring-opening metathesis polymerization (ROMP).[29] En-
couraged by recent reports, which solved the problems of
self-metathesis and accepted the challenges of aqueous
CM,[30,31] olefin metathesis was applied to modify the carbo-
hydrate derivatives. Glyco-SAMs could successfully be pre-
pared by the incubation of plain gold sensor surfaces with
amino-functionalized and biorepulsive spacers and subse-
quent attachment of the glycoderivates by reductive amina-
tion. The evidence for effective immobilization of carbohy-
drates was supplied by initial binding experiments of the
lectin concanavalin A to modified SAMs carrying a-manno-
pyranoside structures.
The novel systematic approach to the immobilization of
synthetic glycosides reported herein is based on 1) the con-
trol of the orientation by well-defined tethers, 2) the control
of the binding event by calculable tether length and provi-
sion of functionalization by the preparation of mixed SAMs
in different ratios, 3) a facile in situ immobilization through
thioalkanes on gold as SAMs, and 4) a facile in situ attach-
ment of glycoderivatives by reductive amination (Scheme 1).
To achieve these aims benzaldehyde-functionalized glyco-
structures were chosen to attach carbohydrate head groups
to amine-bearing SAMs diluted with biorepulsive spacers to
control the ligand interdistance. The two essential require-
ments for these biorepulsive compounds synthesized for
self-assembly are a long alkane chain and a terminal oligo-
ethylene glycol moiety. The first is needed to form strong
van der Waals interactions between spacers, which promotes
accurate SAM formation.[25] The oligoethylene glycol moiety
was introduced to prevent the nonspecific adhesion of bio-
material to the SAM[26] and an anchor group is provided by
the insertion of the amino function. The approach used to
obtain the aldehyde-linking partner for covalent immobiliza-
tion by reductive amination does not depend on convention-
al glycosylation, which usually leads to a/b mixtures and re-
quires tedious chromatographic purification. Instead, the al-
dehyde function is introduced into anomerically pure allyl
Results and Discussion
The use of reductive amination as a coupling procedure for
glyco-SAM formation requires the amino functionalization
of spacers and aldehyde derivatization of anomerically pure
glycosides. Thus, the target compounds were synthesized by
a convergent building block approach. Following the prepa-
ration of a series of allyl mono- and disaccharides, the next
step was benzaldehyde functionalization by cross metathesis.
Synthesis of monosaccharide allyl glycosides: Sugars were
suspended in commercially available allyl alcohol and by
Scheme 1. Schematic depiction of glyco-SAMs for surface plasmon resonance studies: a) cleaned SPR sensor chips are incubated with different thiofunc-
tionalized spacers 44 and 49 in a ratio of 9:1; b) preformed SAMs with amino-functionalized head groups allows the presentation of bioactive compounds
in a well-defined manner; c) covalent immobilization of carbohydrates by imine formation and subsequent reductive amination.
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Synthesis of Benzaldehyde-Functionalized Glycans
FULL PAPER
simple Fischer glycosylation the corresponding allyl glyco-
sides of monosaccharides 1, 2, 5, and 6 were obtained, inter-
estingly in both anomeric forms.[32,33] Subsequent acetylation
allowed the isolation of anomerically pure glycosides 3, 4, 7,
and
8
in good yields by column chromatography
(Scheme 2). Thus, a fairly large repertoire of monomeric
building blocks can be obtained in only two steps (see the
Supporting Information for experimental procedures).
Scheme 2. Synthesis of peracetylated monosaccharide allyl glycosides.
Reagents and conditions: a) 1. Allyl alcohol, conc. H2SO4, 808C, 3–4 h;
2. Ac2O, Py, RT, 16–18 h; 2 steps. Yields: 3a: 36%; 3b: 25%; 4a:34%;
4b: 21%; 7a: 41%; 7b: 21%; 8a: 34%; 8b: 15%.
Scheme 4. Synthesis of peracetylated allyl N-acetyllactosaminide 18. Re-
agents and conditions: a) 1-methylimidazole, Zn, ethyl acetate, reflux,
3 h; 15: 87%; b) CuACHTNUTRGNEG(UN OAc)2, I2, AcOH, 808C, 6 h; 16: 96%; c) TMS-N3,
TMS-OTf, dichloromethane, RT, 16 h; 17: 94%; d) allyl alcohol, PPh3, di-
chloromethane, 08C to RT, 4 h; e) DOWEX (OHꢁ), EtOH, column fil-
tration; f) NaOMe, MeOH, RT, 12 h; g) Ac2O, Py, 12 h; 18: three steps
82%.
Synthesis of disaccharide allyl glycosides: In the case of di-
ACHTUNGTRENNUNGsaccharides, allylation has to be carried out by following the
Koenigs–Knorr procedure.[34] Thus, the peracetates of cello-
biose 9 and lactose 10 were converted into the glycosyl bro-
mides 11 and 12 by treatment with hydrogen bromide in gla-
cial acetic acid. The bromides 11 and 12 were then treated
with allyl alcohol in the presence of silver carbonate to
afford only the b-configured compounds 13 and 14
(Scheme 3; see the Supporting Information for experimental
procedures).
glycals.[36] The 1-O-acetyl-2-iodo derivative 16 was obtained
by the addition of a slight excess of iodine in the presence
of cupric acetate in acetic acid at 808C. Complete trans ste-
reoselectivity led to the manno-configured derivative, as de-
1
termined by H and 13C NMR spectroscopy and by compari-
son with the literature data.[37] Treatment of 16 with trime-
thylsilyl azide and trifluoromethanesulfonate afforded the
corresponding mannopyranosyl azide 17 in nearly quantita-
tive yield with conservation of the a-anomeric configuration.
The 1H and 13C NMR data were in agreement with those
previously reported.[38] The azide 17 was treated with triphe-
nylphosphine and allyl alcohol to generate an (allyl 2-ami-
nophosphonium b-glucopyranosyl) iodide, which was sub-
jected to anion exchange with DOWEX 2X8 (OHꢁ). Re-
maining acetyl groups were removed with NaOMe in dry
methanol. Reacetylation under classic conditions with acetic
anhydride and dry pyridine afforded the desired product 18
(see the Supporting Information for experimental proce-
dures). In this way, the target compound 18 was isolated in a
yield of 82% over four steps without separation of inter-
mediates
Scheme 3. Synthesis of peracetylated allyl glycosides of cellobiose 9 and
lactose 10. Reagents and conditions: a) Ac2O, AcOH, HBr, 08C, 4 h; 11:
85%; 12: 92%; b) allyl alcohol, Ag2CO3, CH2Cl2, RT, 12 h; 13: 75%; 14:
71%.
Because N-acetyllactosamine is rather expensive, precur-
sor 18 was synthesized by following the procedure of Lafont
et al. (Scheme 4).[35] Thus, the bromide 12 was converted
into the lactal 15 by reductive elimination using zinc and 1-
methylimidazole in ethyl acetate at reflux. trans iodoacet-
ACHTUNGTRENNUNGoxyACHTUNGTRENNUNGlation can be achieved by using either iodine and a
metal acetate in acetic acid or N-iodosuccinimide, most
often in acetic acid to prepare 2-deoxy-2-iodo sugars from
Synthesis of benzaldehyde-functionalized carbohydrates by
cross metathesis: To attach the glycoderivatives to the
amino-functionalized SAMs, readily accessible allylic sac-
charides were chosen. This approach is not limited to attach-
ment just through the anomeric position of the carbohy-
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J. Thiem et al.
Table 1. Optimization of the cross metathesis reaction conditions for the
synthesis of the benzaldehyde-linked glycoderivatives.[a]
drates. The aldehyde linker was introduced by olefin meta-
thesis.[39] This approach was used to take advantage of the
high diversity of potential coupling partners to form larger
libraries of tethered glycans. Another advantage of this
transformation is the tolerance towards various protecting
groups. Furthermore, recent developments in the field of
aqueous olefin metathesis has led to novel possible applica-
tions for the use of unprotected carbohydrates.[40]
The required simple aldehyde linker 21 was obtained by
nucleophilic substitution of allyl bromide with 4-hydroxy-
benzaldehyde (19) and acetalization with trimethyl orthofor-
mate (TMoF) in nearly quantitative yield (Scheme 5).[41,42]
Entry
T [8C]
t [h]
Yield [%][b]
1
2
3
25
40
40
40
40
3
3
6
12
6
36
55
92
89
54
4
5[c]
[a] Unless otherwise noted, the reactions were carried out in degassed an-
hydrous dichloromethane with coupling partner 21 and catalyst 23.
[b] Only the E configuration was observed by 1H NMR spectroscopy.
[c] With catalyst 22.
Scheme 6. Ruthenium catalysts applied in cross metathesis: Grubbs
second-generation catalyst 22 and Grubbs–Hoveyda second-generation
catalyst 23.
assumed that catalyst activity was lost by self-metathesis.
Thus, the Grubbs catalyst 22 was replaced by the Grubbs–
Hoveyda catalyst 23 in the hope of increased activity and
stability. However, a substantial improvement in the yields
was not observed, and this also applies to studies with in-
creased amounts of catalyst (results not shown). Hence, the
conditions applied by Meinke and Thiem in the synthesis of
potential sialyltransferase inhibitors[46] with less self-meta-
thesis under dilution were considered. The best results were
obtained when the more active and stable catalyst 23 was
used in cross metathesis under reflux conditions in dry di-
chloromethane for 6 hours (Table 1, entry 3).
The optimized conditions were accordingly applied to link
allyl glycosides 4, 7, and 8 to obtain the corresponding ben-
zaldehyde-functionalized derivatives 25, 26, and 27
(Table 2). With disaccharides, decreased yields were ob-
served and thus further optimization of the reaction condi-
tions was needed for oligosaccharides. In contrast to the ob-
servations of Roy and Das, homodimerization of the carbo-
hydrate moieties was never detected.[47]
The glycoderivatives 31–37 required for surface plasmon
resonance studies were obtained by deacetalization of ben-
zaldehyde dimethyl acetal followed by hydrogenolysis cata-
lyzed by palladium on charcoal poisoned with diphenyl sul-
fite and subsequent classical Zemplꢁn deprotection
(Table 3). In this way, the desired target products were ob-
tained and purified by column chromatography and charac-
terized by NMR spectroscopy and high-resolution mass
spectrometry. To remove the dimethyl acetal the tethered
glycoderivatives were dissolved in aqueous THF containing
0.1% trifluoroacetic acid.[42] After stirring for 1 hour the re-
action was stopped by dilution with CH2Cl2 and the addition
of triethylamine. The reaction mixture was then concentrat-
Scheme 5. Synthesis of benzaldehyde-functionalized glucoderivative 24.
Reagents and conditions: a) Allyl bromide, K2CO3, acetone, reflux, 17 h;
20: 94%; b) pTSA, TMoF, RT, 6 h ; 21: 98%; c) for reaction conditions,
see Table 1.
Unlike the widely used ring-closing metathesis procedure,
cross metathesis gives the desired compounds along with
several byproducts.[43] Cross metathesis has only recently at-
tracted more attention in carbohydrate chemistry because
novel and more active catalysts have only just become avail-
able.[44] The desired cross-products, which are usually ob-
tained as mixtures of E and Z isomers, compete with the for-
mation of the two self-metathesis products, each one being a
mixture of E and Z isomers. To be useful in synthesis, a
method had to be developed to obtain a well-defined prod-
uct without any byproducts. Thus, the reaction conditions
were optimized by using the allyl glucopyranoside 3b and
compound 21 (Table 1). As mentioned above, in every case
of cross metathesis, only products with the E configuration
were observed. To explore the efficiency of the reaction, the
two ruthenium catalysts 22 and 23 were studied (Scheme 6).
The initial cross-metathesis experiments performed under
conditions described by Wong and co-workers to construct a
glycolipid library yielded the desired cross-product 24.[45] No
dimerization of 3b was observed, however, self-metathesis
of the corresponding coupling partner 21 was detected and a
significant amount of starting material was reisolated. It was
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Synthesis of Benzaldehyde-Functionalized Glycans
FULL PAPER
Table 2. Formation of benzaldehyde-linked glycoderivatives by olefin
metathesis.[a]
bromide in commercially available w-bromoundecene (38)
with tri- or hexaethylene glycol (39 or 40; Scheme 7). To
prevent disubstitution the glycoderivatives were used in
Product
Yield [%][b]
87
4
7
75
81
Scheme 7. Synthesis of amino-functionalized spacers. Reagents and con-
ditions: a) NaH, DMF, 08C to RT, 12 h; 39: 95%; 40: 96%; b) 45, NaH,
DMF, 08C for 2 h then 08C to RT, 15 h; 46: 78%; c) TsCl, Py, 08C to RT,
15 h; 50: 92%; d) NaN3, TBAI, DMF, 708C, 2 h; 47: 82%; 51: 85%;
e) AcSH, AIBN, THF, hn, 3 h; 43: quant.; 44: quant.; 48: 95%; 52: 96%;
f) LAH, Et2O, 0 8C to RT, 2–3 h; 49: 64%; 53: 66%.
8
13
46
52
12
two-fold excess.[26] The oligoethylene glycol capped alkenes
41 and 42 were obtained in almost quantitative yields after
flash chromatographic purification. Both dilution molecules
were thioacetylated by photoreaction with thioacetic acid in
THF using AIBN as radical initiator.[50] After irradiation
with a standard UV mercury pressure lamp over a short
period the required dilution molecules 43 and 44 were ob-
tained in nearly quantitative yields in only two steps.
14
18
In addition, an amino function is required for attachment
of the benzaldehyde-functionalized glycoderivatives to SPR
sensor chips by reductive amination. Thus, alkene-terminat-
ed hexaethylene glycol 42 served as the starting material for
the synthesis of attachment spacers 49 and 53. In one case
an additional tether was introduced into the alcohol 42 by
employing a slightly modified procedure developed for teth-
ering sugars to cisplatin as antitumor agents.[51] The halogen
derivative 46 was obtained by nucleophilic monosubstitution
of 1-bromo-4-chlorobutane (45) with glycol 42 and sodium
hydride in DMF in a yield of 78%. Then the chloride was
substituted by azide in DMF at 708C to give compound 47
in a yield of 82%. After photochemical thioacetylation and
reduction of the azide by lithium aluminum hydride in di-
ethyl ether at 08C, the amino-functionalized spacer 49 was
isolated in a nonoptimized yield of 64%.
These conditions were also applied to the synthesis of the
attachment molecule 53, except for the first step, in which
the azide function was introduced by nucleophilic substitu-
tion of tosylate 50, which in turn was obtained by reaction
of alcohol 42 with tosyl chloride in pyridine in a yield of
92%. Following the procedure used to elaborate compound
49, the second nontethered attachment molecule 53 was ob-
tained in a yield of 66%.
[a] Unless otherwise noted, reactions were carried out in degassed anhy-
drous dichloromethane with coupling partner 21 and catalyst 23. [b] Only
1
E-configured products were observed by H NMR spectroscopy.
ed. To convert the double bond into an alkane motif the pal-
ladium catalyst was poisoned with diphenyl sulfite and dry
ethyl acetate was used as the solvent otherwise the benzal-
dehyde function could be transformed into an undesired
methylene group.[48] After filtration and evaporation the
acetyl groups were removed by the addition of a methanolic
sodium methoxylate solution (0.1m) under Zemplꢁn condi-
tions.[49] Subsequent treatment with Amberlite IR 120 (H+
form) and evaporation of the solvent gave a syrupy residue.
Removal of salts and further purification followed by lyo-
philization conclude this advantageous, facile, and rapid
work-up protocol.
Synthesis of amino-functionalized spacers: For glyco-SAM
formation two types of spacers, dilution and attachment
molecules, are needed. To avoid nonspecific adhesion of bio-
molecules in biological investigations using SAMs both
types of spacers have to carry a terminal oligoethylene
glycol (OEG) unit. Thus, initially, dilution molecules 43 and
44 carrying thioacetyl functions to allow SAM formation on
gold were synthesized by nucleophilic substitution of the
SPR experiments: Cell surface glycans play a crucial role in
many different recognition events and thus various efficient
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J. Thiem et al.
Table 3. Deprotection of aldehyde-functionalized glycoderivatives.[a]
cell systems. Houseman and
Mrksich formed SAMs with
OEG-capped and benzoqui-
none-functionalized
prior to immobilizing carbohy-
drate–cyclopentadiene conju-
gates by Diels–Alder reactions.
However, in their work, non-
functionalized chips showed un-
specific protein binding.[63]
spacers
Product
Yield [%][b]
91
24
The
approach
presented
25
26
92
89
herein anticipates nonspecific
binding and uses on-chip immo-
bilization of carbohydrates to
ensure accurate SAM forma-
tion and avoid the use of heavy
metals by attachment by reduc-
tive amination. Furthermore, to
the best of our knowledge, this
is the first example of the
online observation of SAM for-
mation and carbohydrate at-
tachment.
27
28
80
82
Online SAM formation: In the
preparation of glyco-SAMs the
first step was to form accurate
monolayers containing attach-
ment and dilution molecules at
a well-defined distance. Thus, a
100 mm solution of compounds
44 and 49 (25:1 ratio) in phos-
phate-buffered saline (pH 7.4)
was prepared. Prior to use, the
plain gold sensor chips were
cleaned by treatment with pira-
29
30
89
79
[a] Reagents and conditions: 1) THF, TFA, H2O, RT, 1 h; 2) Pd/C, H2, DPS, EtOAc, RT, 24–48 h; 3) NaOMe,
MeOH, RT, 24 h. [b] Overall yields.
tools for analyzing these processes are required. Surface
plasmon resonance is one of the most important techniques
used in this area and a number of groups have developed
different approaches for the immobilization of carbohy-
drates on sensor chips.[52–55] In many cases SAMs are formed
by the covalent binding of thiols to gold.[56–59] For example,
Zhi et al. reported a concept that could be applied to syn-
thetic glycosides and glycans from natural sources.[57] How-
ever, the approach reported herein focused on well-defined
synthetic saccharides. Recently, Penades and co-workers
used long-chain alkenyl N-acetylglucosaminopyranosides
and 11-mercapto-1-undecanol as a reference for the forma-
tion of SAMs.[60] A disadvantage of this approach is the lack
of any biorepulsive spacer unit. A building block system was
established by Kleinert and co-workers; both azide- and
alkyne-derivatized glycol and biorepulsive OEG spacer
structures were synthesized and the construction and modifi-
cation of the glyco-SAMs were carried out by copper-cata-
lyzed “click” chemistry before SAM formation occurred di-
rectly on sensor chips.[61,62] Owing to its cytotoxicity, the use
of copper could be a drawback in SPR assays in the study of
nha solution. These blank chips were incubated with the
thiol solution inside the SPR instrument by injecting the
thiol over a minimum period of 45 min (Figure 1). SAM for-
mation was observed online. After an initial washing proce-
dure in which buffer solution was passed over the gold chips
for 10 min, the premixed thiols were injected at a flow rate
of 5 mLminꢁ1. SAM formation was observed by the increase
in the response unit (RU). After injection, the RU increased
rapidly as a result of a quick adsorption of thiols on the gold
surface. Then reorganization of the SAM is shown by a
slight growth of the RU. After saturation and accurate SAM
formation, as indicated by a horizontal line (zero gradient),
injection was interrupted. No significant decrease in the RU
was observed. This indicates that the SAM formed by in-
system incubation with thiols is well arranged.
The biorepulsive nature of the coated sensor chips carry-
ing amino functions was proven by adhesion experiments
with the proteins bovine serum albumin (BSA) and conca-
navalin A (ConA). Neither BSA nor ConA were adsorbed
at the surface (data not shown). Also, comparison of the
online-coated surface with surfaces resulting from standard
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Synthesis of Benzaldehyde-Functionalized Glycans
FULL PAPER
of NaBH3CN was injected,
which resulted in a sharp peak
in the sensorgram (Figure 2).
The flow rate in this process
was 10 mLminꢁ1 and the contact
time required for the reaction
to form a stable amino function
was 4 min. Afterwards the flow
cell was thoroughly washed
with PBS buffer to remove un-
reacted residues. Then the
eluent was changed to HEPES
buffer for lectin binding studies.
The stabile base line indicated
the success of immobilization of
mannopyranoside 25.
The immobilization of man-
nopyranoside 25 was proven by
a lectin binding assay employ-
ing ConA (Figure 3). Thus, so-
Figure 1. Online SAM formation observed by an increase in the response unit (RU) after injection of 100 mm
solution of 44 and 49 (ratio 25:1), with SAM formation completed after saturation.
ACHUTNGRENNUlG uACTHUNGTRENNUtG ions of ConA and BSA at
various concentrations (6.25–
100 mm) were eluted over the
glyco-SAM. Only in the case of
ConA was a binding event ob-
served, as shown in Figure 3.
The
adsorption
coefficient
(Kads) of ConA with the man-
nose-functionalized surface was
determined to be (5.2ꢂ1.5)ꢂ
106 mꢁ1 and this is similar to pre-
viously observed data (Kads
=
(5.6ꢂ1.7)ꢂ106 and (3.1ꢂ1.4)ꢂ
106 mꢁ1).[23,64] The data for BSA
are not shown. From the sen-
sorgram in Figure 3, the first
qualitative results have been
unequivocally demonstrated for
the binding ConA to manno-
pyranoside-functionalized SPR
Figure 2. Online glycol-SAM formation and attachment of mannopyrano-
side 25.
SAM formation with ethanolic solutions of thiols showed
the advantage of this approach.
Online carbohydrate attachment and lectin binding studies:
After the SAMs had been successfully formed the following
attachment procedure was applied to immobilize benzalde-
hyde-functionalized mannopyranoside 25 to the sensor sur-
face. The glycoside was dissolved in PBS buffer and injected
at a flow rate of 10 mLminꢁ1. After no further imine forma-
tion was observed, as indicated by a horizontal RU curve,
injection of the carbohydrate conjugate was interrupted and
the irreversible linkage was established by reductive amina-
tion with sodium cyanoborohydride. Hence, a 0.1m solution
Figure 3. Binding studies of ConA to mannopyranoside-functionalized
SPR sensorchips. A: Equilibration phase; B1: association (50 mm ConA);
B2: association (100 mm ConA); C: dissociation; D: regeneration (0.1%
SDS solution).
Chem. Eur. J. 2010, 16, 7017 – 7029
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7023

J. Thiem et al.
sensor chips (see the Supporting Information for details and
the difference sensorgram).
Conclusion
Benzaldehyde-functionalized glycoderivatives and amino-
functionalized spacers for glyco-SAM formation have been
synthesized. The successful use of CM for the modification
of sugars has enhanced the opportunities of this reaction
type in carbohydrate chemistry and especially in the con-
struction of larger libraries of tethered glycans. The immobi-
lization of carbohydrates on sensor chips by reductive ami-
nation has circumvented the disadvantages of previously re-
ported attachment procedures. In a preliminary experiment,
proof-of-concept evidence for the attachment of mannose
was provided by binding studies with the well-known lectin
ConA.
This novel and advantageous immobilization method is
presently being employed in various biomimetic studies of
carbohydrates and in the development of a carbohydrate-
based array for diagnostics and screening. We are currently
exploring the scope of this approach with other biologically
important systems as well as extending it to other applica-
tions such as glyconanoparticles.
Scheme 8. Numbering of hydrogen and carbon atoms for the assignment
of NMR data.
use they were cleaned by treatment with piranha solution (conc. H2SO4/
30% H2O2, 1:1) for 10 min. After rinsing with twice-distilled water and
ethanol the plain gold chips were dried in a flow of nitrogen. The SAM
formation was effected immediately after cleaning by elution (flow
5 mLminꢁ1) with 100 mm solutions of 44/49 (ratio 25:1) for a minimum of
45 min. The following general procedure was used for immobilizing car-
bohydrate conjugates on to amino-functionalized SPR sensor chips by re-
ductive amination: 100 mm solutions of 25 in PBS buffer were injected
(flow rate 10 mLminꢁ1) over a period of 30 min. When a sensorgram ex-
hibited saturation, the injection was stopped and the reduction was initi-
ated by adding a NaCNBH3-solution (4 min at 10 mLminꢁ1). For the bind-
ing studies, the lectin concanavalin A (ConA/mannose positive) was
used. The measurements were carried out in HEPES-buffered saline
(150 mm NaCl, 10 mm NaHEPES, 0.005% Tween 20/pH 7.4) containing
Ca2+ (1 mm CaCl2·2H2O) and Mn2+ (1 mm MnCl2·4H2O) ions for ConA
activation. ConA was dialyzed for 2 d in HEPES buffer to remove any
remaining mannose. Solutions of ConA as well as BSA in HEPES buffer
(6.25, 12.5, 25, 50, and 100 mm) were injected over 3 min at a flow rate of
20 mLminꢁ1. The injection of 60 mL of 0.1% SDS solution was appropri-
ate to regenerate the sensor surface.
Experimental Section
General procedure A—Cross metathesis with allyl glycosides: Peracety-
lated allyl glycoside (1 mmol) and a five- to eight-fold excess of the cor-
responding coupling partner 37 (5–8 mmol) were dissolved in dry and de-
gassed dichloromethane (49 mL) and placed in a flame-dried flask con-
taining activated molecular sieves (4 ꢄ) using standard Schlenk tech-
niques. Grubbs catalyst 23 (0.10 mmol) dissolved in dry and degassed di-
chloromethane (1 mL) was added through a syringe or as a solid to attain
a 0.02m solution. The reaction mixture was heated at reflux for 6 h. Con-
version of the starting material was detected by TLC. The solution was
concentrated under reduced pressure and the crude product was directly
purified by column chromatography by using silica and a petroleum
ether/ethyl acetate gradient (4:1!2:1/1:1 for disaccharides).
General procedure B—Deprotection and hydrogenolysis of benzalde-
hyde-functionalized glycosides: The CM products (90–870 mmol) were
dissolved in a mixture of THF, water, and TFA (90:9.9:0.1, v/v; solvent
A) to obtain a 0.2m solution. After stirring for 1 h the reaction mixture
was diluted with CH2Cl2 (100 mL) and the reaction was stopped by the
addition of triethylamine (2 mL) and then water (100 mL). The organic
layer was separated and dried over Na2SO4. The solvent was removed
under reduced pressure and the crude product was used in the next trans-
formation step without further purification. For hydrogenolysis, the alde-
hyde was dissolved in anhydrous EtOAc and placed in a flame-dried
flask containing palladium (10%) on charcoal and diphenyl sulfide
(0.01 equiv). The suspension was degassed and after purging with hydro-
gen the mixture was stirred for 12 h. Then the suspension was filtered
and thoroughly dried before the residue was redissolved in a methanolic
sodium methoxide solution (20 mL, 0.1m). The solution was stirred for
6 h at room temperature and the mixture was then neutralized with Am-
berlite IR 120 (H+) resin. After filtration and evaporation of the solvent
the crude products were purified by flash chromatography using silica
and dichloromethane/methanol (5:1) as eluent.
General: Reagents of commercial quality were purchased from Aldrich,
Sigma, or Merck and were used without further purification. Solvents
were dried according to standard methods. All reactions were carried out
under an argon atmosphere with dry solvents under anhydrous conditions
unless otherwise noted. Analytical thin-layer chromatography (TLC) was
performed on precoated aluminum plates (silica gel 60 F254, Merck5554)
and compound spots were visualized by UV light (254 nm) and by stain-
ing with
a yellow solution containing CeACHNUTGRTEG(NUNN NH4)2ACHTUGNRTNEN(UGN NO3)6 (0.5 g) and
(NH4)6Mo7O24·4H2O (24.0 g) in 6% H2SO4 (500 mL) or with 10% H2SO4
in ethanol followed by heat treatment. For column chromatography,
silica gel 60 (230–400 mesh, 40–63 mm) (Merck) was used.
1H and 13C NMR spectra were recorded on Bruker AMX-400 (400 MHz
for 1H, 100.6 MHz for 13C) and DRX-500 (500 MHz for 1H, 125.8 MHz
for 13C) spectrometers at 300 K. Chemical shifts were calibrated against
solvent residual peaks (CDCl3: d=7.24 and 77.0 ppm for 1H and 13C, re-
spectively; [D4]methanol: d=3.35 and 49.30 ppm for 1H and 13C, respec-
tively). The signals were assigned by 1H–1H COSY, HSQC, HMBC, and,
if necessary, NOESY experiments. Hydrogen and carbon atoms are in-
dexed 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 numbers with the index “bu” for butyl and
“ar” for aromatic with the numbering starting from the glycosidic bond.
This is shown for compound 30 in Scheme 8. In the sugar-free spacer
molecules, the thiol function is defined as the terminus of the molecule,
as exemplified for 49 (Scheme 8).
Optical rotations were measured by using
a Krꢃss Optronic P8000
(589 nm) instrument at 208C. MALDI-TOF MS was performed on a Bru-
kerBiflex III spectrometer with dihydroxybenzoic acid or trihydroxyan-
thracene as the matrix in positive reflector mode. FAB HRMS was per-
formed on a Thermo Finnigan MAT95 XL mass spectrometer.
SPR measurements: The BIACORE T100 SPR imaging instrument was
used in the study of the carbohydrate arrays described herein. Uncoated
gold surfaces (BIACORE SIA kit Au) were used as sensor chips. Before
(E)-4-(4-Dimethoxymethylphenoxy)but-2-enyl 2,3,4,6-tetra-O-acetyl-b-d-
glucopyranoside (24): The reaction was carried out according to general
7024
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 7017 – 7029

Synthesis of Benzaldehyde-Functionalized Glycans
FULL PAPER
procedure A using compound 3b (388 mg, 1.00 mmol) and compound 21
(1.04 g, 5.00 mmol) with catalyst 23 (63 mg, 0.10 mmol). The product 24
was obtained as a colorless syrup (523 mg, 92%). Rf =0.36 (petroleum/
1H; 4-H), 4.80 (d, 3J1,2 =8.5 Hz, 1H; 1-H), 4.52–4.50 (m, 1H; 1a-Hbu),
3
4.40–4.36 (m, 1H; 1b-Hbu), 4.27 (m, 3H; 4-Hbu, 6b-H), 4.09 (dd, J5,6b
=
2.4, 3J6a,6b =12.2 Hz, 1H; 6a-H), 3.82 (dd, 3J1,2 =8.5, 3J2,3 =10.5 Hz, 1H; 2-
H), 3.80 (ddd, 3J5,6a =5.0, 3J5,6b =2.5, 3J6a,6b =12.2 Hz, 1H; 5-H), 3.29 (s,
6H; OCH3), 2.05 (s, 3H; Hac),1.99 (s, 3H; Hac), 1.97 (s, 3H; Hac),
1.88 ppm (s, 3H; Hac); 13C NMR (126 MHz, CDCl3, 258C): d=170.6
(CH3CO), 170.3 (CH3CO), 170.2 (CH3CO), 169.1 (CH3CON), 132.0
(Carom), 129.3 (Carom), 128.0 (Carom), 126.9 (Carom), 114.7 (C-2bu), 114.1 (C-
3bu), 102.9 (Cacetal), 99.4 (C-1), 71.8 (C-3), 71.0 (C-5), 68.8 (C-4), 68.7 (C-
EtOAc, 1:1); [a]2D0 =ꢁ15.3 (c=1.0 in CHCl3); 1H NMR (500 MHz,
3
CDCl3, 258C): d=7.32 (d, 3JAr =8.4 Hz, 2H; 1-Harom), 6.86 (d, JAr
=
8.4 Hz, 2H; 2-Harom), 5.96–5.80 (m, 2H; 2-Hbu, 3-Hbu), 5.32 (s, 1H; Hacetal),
3
5.18 (dd, 3J2,3 =9.4, 3J3,4 =9.6 Hz, 1H; 3-H), 5.06 (dd, 3J3,4 =9.6, J4,5
=
9.9 Hz, 1H; 4-H), 4.99 (dd, 3J1,2 =7.9, 3J2,3 =9.4 Hz, 1H; 2-H), 4.53 (d,
3J1,2 =7.9 Hz, 1H; 1-H), 4.50–4.48 (m, 2H; 4-Hbu), 4.38–4.32 (m, 1H; 1a-
H
bu), 4.23 (dd, 3J5,6b =4.7, 2J6a,6b =12.3 Hz, 1H; 6b-H), 4.15–4.03 (m, 2H;
1bu), 67.7 (C-4bu), 61.9 (C-6), 53.9 (C-5), 52.6 (OCH3), 22.7 (CH3CON),
1b-Hbu ,6a-H), 3.65 (ddd, 3J4,5 =9.9, 3J5,6a =2.4, 3J5,6b =4.7 Hz, 1H; 5-H),
3.28 (s, 6H; OCH3), 2.06 (s, 3H; Hac), 2.01 (s, 3H; Hac), 2.00 (s, 3H; Hac),
1.98 ppm (s, 3H; Hac); 13C NMR (126 MHz, CDCl3, 258C): d=170.5
(CH3CO), 170.1 (CH3CO), 169.3 (CH3CO), 169.2 (CH3CO), 130.6
(Carom), 128.4 (Carom), 128.2 (Carom), 127.9 (Carom), 114.2 (C-2bu), 114.1 (C-
20.8 (CH3CO), 20.7 (CH3CO), 20.6 ppm (CH3CO); HRMS (FAB): calcd.
for C27H38NO12+: 568.2389 [M+H]+; found: 568.2370.
(E)-4-(4-Dimethoxymethylphenoxy)but-2-enyl
2,2’,3,3’,4’,6,6’-hepta-O-
acetyl-b-cellobioside (28): The reaction was carried out according to gen-
eral procedure A using compound 13 (677 mg, 1.00 mmol) and compound
21 (1.67 g, 8.00 mmol) with catalyst 23 (63 mg, 0.10 mmol). The product
28 was obtained as a colorless syrup (394 mg, 46%). Rf =0.25 (petro-
3
4
bu), 102.9 (Cacetal), 99.6 (C-1), 72.8 (C-3), 71.7 (C-5), 71.2 (C-2), 68.8 (C-
bu), 68.3 (C-4), 67.5 (C-1bu), 61.8 (C-6), 52.5 (OCH3), 20.7 (CH3CO), 20.6
leum/EtOAc, 1:1); [a]2D0 =ꢁ21.1 (c=1.0 in CHCl3); 1H NMR (500 MHz,
(CH3CO), 20.5 (CH3CO), 20.4 ppm (CH3CO); HRMS (FAB): m/z: calcd.
for C27H37O13+: 569.2229 [M+H]+; found: 569.2157.
3
CDCl3, 258C): d=7.34 (d, 3JAr =8.5 Hz, 2H; 1-Harom), 6.86 (d, JAr
=
(E)-4-(4-Dimethoxymethylphenoxy)but-2-enyl 2,3,4,6-tetra-O-acetyl-a-d-
mannopyranoside (25): The reaction was carried out according to the
general procedure A using compound 4a (388 mg, 1.00 mmol) and com-
pound 21 (1.04 g, 5.00 mmol) with catalyst 23 (63 mg, 0.10 mmol). The
product 25 was obtained as a colorless syrup (495 mg, 87%). Rf =0.30
(petroleum/EtOAc, 1:1); [a]2D0 =+32.6 (c=1.0 in CHCl3); 1H NMR
(500 MHz, CDCl3, 258C): d=7.29 (d, 3JAr =8.4 Hz, 2H; 1-Harom), 6.95 (d,
8.5 Hz, 2H; 2-Harom), 5.95–5.85 (m, 2H; 2-Hbu, 3-Hbu), 5.32 (s, 1H; Hacetal),
5.20–5.10 (m, 2H; 3-H, 3’-H), 5.04 (dd, 3J3’,4’ =9.6, 3J4’,5’ =9.8 Hz, 1H; 4’-
H), 4.94–4.86 (m, 2H; 2-H, 2’-H), 4.52–4.46 (m, 3J1,2 =7.6, 3J1’,2’ =7.6 Hz,
3
3
5H; 1-H, 1’-H, 6a-H, 4-Hbu), 4.35 (dd, J5,6a =4.3, J6a,6b =12.3 Hz, 1H; 6b-
H), 3.78–3.74 (m, 3H;4-H, 1-HBu), 3.64 (ddd, 3J4’,5’ =9.8 Hz, 3J5’,6’a =4.2,
3J5’,6’b =2.2 Hz, 1H; 5’-H), 3.55 (ddd, 3J4,5 =9.9, 3J5,6a =4.3, 3J5,6b =1.9 Hz,
1H; 5-H), 3.29 (s, 6H; OCH3), 2.11 (s, 3H; Hac), 2.07 (s, 3H; Hac), 2.01
(s, 3H; Hac), 2.00 (s, 3H; Hac), 1.99 (s, 3H; Hac), 1.96 ppm (s, 3H; Hac);
13C NMR (126 MHz, CDCl3, 258C): d=170.4 (CH3CO), 170.3 (CH3CO),
170.2 (CH3CO), 169.8 (CH3CO), 169.5 (CH3CO), 169.2 (CH3CO), 169.0
(CH3CO), 132.0 (Carom), 129.3 (Carom), 128.0 (Carom), 126.9 (Carom), 114.7
(C-2bu), 114.1 (C-3bu), 103.5 (Cacetal), 100.7 (C-1’), 99.3 (C-1’), 76.4 (C-4),
72.9 (C-5), 72.6 (C-3’), 72.5 (C-3), 71.94 (C-5’), 71.6 (C-2’), 71.5 (C-2),
68.3 (C-1bu), 67.7 (C-4’), 67.5 (C-4bu), 61.8 (C-6), 61.5 (C-6’), 20.8
(CH3CO), 20.7 (CH3CO), 20.6 (CH3CO), 20.5 ppm (CH3CO); HRMS
(FAB): calcd. for C39H53O21+: 857.3074 [M+H]+; found: 857.3000.
3JAr =8.4 Hz, 2H; 2-Harom), 5.95–5.82 (m, 2H; 2-Hbu, 3-Hbu), 5.30 (dd,
3
3J3,4 =9.8, 3J4,5 =10.0 Hz, 1H; 4-H), 5.28 (s, 1H; Hacetal), 5.24 (dd, J2,3
=
3
3
3
2.7, J3,4 =9.8 Hz, 1H; 3-H), 5.28 (s, 1H), 5.19 (dd, J1,2 =1.4, J2,3 =2.7 Hz,
1H; 2-H), 4.80 (d, 3J1,2 =1.4 Hz, 1H; 1-H), 4.54–4.50 (m, 1H; 1a-Hbu),
4.28–4.18 (m, 2H; 1b-Hbu, 6-Ha), 4.08–3.98 (m, 3H; 4-Hbu, 6-Ha), 3.94
(ddd, 3J4,5 =10.0, 3J5,6a =3.1, 3J5,6b =5.6 Hz, 1H; 5-H), 3.24 (s, 6H; OCH3),
2.09 (s, 3H; Hac), 2.03 (s, 3H; Hac), 1.98 (s, 3H; Hac), 1.93 ppm (s, 3H;
Hac); 13C NMR (126 MHz, CDCl3, 258C): d=170.6 (CH3CO), 170.0
(CH3CO), 169.8 (CH3CO), 169.6 (CH3CO), 131.9 (Carom), 130.7 (Carom),
129.1 (Carom), 127.9 (Carom), 114.9 (C-2bu), 114.2 (C-3bu), 103.0 (Cacetal), 96.7
(C-1), 69.5 (C-2), 69.0 (C-4), 68.6 (C-5), 68.6 (C-1bu), 67.5 (C-4bu), 66.1
(E)-4-(4-Dimethoxymethylphenoxy)but-2-enyl
2,2’,3,3’,4’,6,6’-hepta-O-
acetyl-b-lactoside (29): The reaction was carried out according to general
procedure A using compound 14 (677 mg, 1.00 mmol) and compound 21
(1.67 g, 8.00 mmol) with catalyst 23 (63 mg, 0.10 mmol). The product 29
was obtained as a colorless syrup (446 mg, 52%). Rf =0.27 (petroleum/
(C-3), 62.4 (C-6), 52.6 (OCH3), 20.8 (CH3CO), 20.7 (CH3CO), 20.6 ppm
+
(CH3CO); HRMS (FAB): calcd. for C27H37O13
:
569.2229 [M+H]+;
found: 569.2258.
(E)-4-(4-Dimethoxymethylphenoxy)but-2-enyl 2,3,4,6-tetra-O-acetyl-b-d-
galactopyranoside (26): The reaction was carried out according to general
procedure A using compound 5b (395 mg, 1.02 mmol) and compound 21
(1.18 g, 5.65 mmol) with catalyst 23 (63 mg, 0.10 mmol). The product 26
was obtained as a colorless syrup (435 mg, 75%). Rf =0.32 (petroleum/
EtOAc, 1:1); [a]2D0 =+33.1 (c=1.0 in CHCl3); 1H NMR (500 MHz,
3
CDCl3, 258C): d=7.35 (d, 3JAr =8.5 Hz, 2H; 1-Harom), 6.88 (d, JAr
=
8.5 Hz, 2H; 2-Harom), 5.95–5.80 (m, 2H; 2-Hbu, 3-Hbu), 5.36–5.33 (m, 2H;
4’-H, Hacetal), 5.19 (dd, 3J2,3 =10.5, 3J3,4 =9.8 Hz, 1H; 3-H), 4.94–4.86 (m,
2H; 2-H, 2’-H), 5.10 (dd, 3J1’,2’ =7.9, 3J2’,3’ =10.4 Hz, 1H; 2’-H), 4.94–4.86
1
3
3
EtOAc, 1:1); [a]2D0 =+9.8 (c=1.0 in CHCl3); H NMR (500 MHz, CDCl3,
(m, 2H; 2-H, 3’-H), 4.52–4.46 (m, J1,2 =7.6, J1’,2’ =7.6 Hz, 5H; 1-H, 1’-H,
6a-H, 4-Hbu), 4.35–4.33 (m, 1H; 1a-Hbu), 4.15–4.00 (m, 4H; 1b-Hbu, 6b-H,
6’ab-H), 3.87 (ddd, 3J4’,5’ =0.8, 3J5’,6’a =6.4, 3J5’,6’b =6.5 Hz, 1H; 5’-H), 3.80
(dd, 3J3,4 =9.4, 3J4,5 =9.5 Hz, 1H; 4-H), 3.58 (ddd, 3J5,6a =1.9, 3J5,6b =4.9,
3J4,5 =9.5 Hz, 1H; 5-H), 3.31 (s, 6H; OCH3), 2.16 (s, 3H; Hac), 2.15 (s,
3H; Hac), 2.11 (s, 3H; Hac), 2.05 (s, 3H; Hac), 2.04 (s, 3H; Hac), 2.03 (s,
3H; Hac), 1.96 ppm (s, 3H; Hac); 13C NMR (126 MHz, CDCl3, 258C): d=
170.4 (CH3CO), 170.3 (CH3CO), 170.2 (CH3CO), 169.8 (CH3CO), 169.5
(CH3CO), 169.2 (CH3CO), 169.0 (CH3CO), 132.0 (Carom), 129.3 (Carom),
128.0 (Carom), 126.9 (Carom), 114.7 (C-2bu), 114.1 (C-3bu), 103.0 (Cacetal),
101.0 (C-1’), 99.4 (C-1), 76.23 (C-4), 72.8 (C-3), 72.6 (C-5’), 71.6 (C-2),
70.9 (C-3’), 70.6 (C-5’’), 69.1 (C-2’), 68.88 (C-1bu), 67.62 (C-4bu), 66.61 (C-
258C): d=7.35 (d, 3JAr =8.5 Hz, 2H; 1-Harom), 6.88 (d, 3JAr =8.5 Hz, 2H;
3
2-Harom), 5.99–5.85 (m, 2H; 2-Hbu, 3-Hbu), 5.38 (dd, 3J3,4 =3.9, J4,5
=
0.9 Hz, 1H; 4-H), 5.28 (s, 1H; Hacetal), 5.24 (dd, 3J1,2 =7.9, 3J2,3 =10.5 Hz,
3
3
1H; 2-H), 5.01 (dd, J2,3 =10.5, J3,4 =3.9 Hz, 1H; 3-H), 4.58–4.54 (m, 1H;
3
1a-Hbu), 4.51 (d, J1,2 =7.9 Hz, 1H; 1-H), 4.44–4.36 (m, 1H; 1b-Hbu), 4.20–
4.08 (m, 4H; 4-Hbu, 6-Ha,b), 3.89 (ddd, 3J4,5 =0.9, 3J5,6a =6.7, 3J5,6b =6.8 Hz,
1H; 5-H), 3.30 (s, 6H; OCH3), 2.09 (s, 3H; Hac), 2.03 (s, 3H; Hac), 1.98
(s, 3H; Hac), 1.93 ppm (s, 3H; Hac); 13C NMR (126 MHz, CDCl3, 258C):
d=170.3 (CH3CO), 132.0 (Carom), 129.3 (Carom), 128.0 (Carom), 126.9
(Carom), 114.9 (C-2bu), 114.3 (C-3bu), 103.1 (Cacetal), 100.4 (C-1), 70.9 (C-3),
70.7 (C-5), 68.8 (C-2), 68.7 (C-1bu), 67.9 (C-4bu), 67.0 (C-4), 61.2 (C-6),
52.7 (OCH3), 20.8 (CH3CO), 20.7 (CH3CO), 20.6 ppm (CH3CO); HRMS
(FAB): calcd. for C27H37O13+: 569.2229 [M+H]+; found: 569.2230.
4’), 61.9 (C-6), 60.7 (C-6’), 52.6 (OCH3), 20.8 (CH3CO), 20.7 (CH3CO),
+
20.6 (CH3CO), 20.5 ppm (CH3CO); HRMS (FAB): calcd. for C39H53O21
857.3074 [M+H]+; found: 857.3052.
:
(E)-4-(4-Dimethoxymethylphenoxy)but-2-enyl 2-acetamido-3,4,6-tri-O-
acetyl-2-deoxy-d-glucopyranoside (27): The reaction was carried out ac-
cording to general procedure A using compound 6b (387 mg, 1.00 mmol)
and compound 21 (1.04 g, 5.00 mmol) with catalyst 23 (63 mg,
0.10 mmol). The product 27 was obtained as a colorless syrup (494 mg,
81%). Rf =0.10 (petroleum/EtOAc, 1:1); [a]2D0 =ꢁ14.7 (c=1.0 in CHCl3);
1H NMR (500 MHz, CDCl3, 258C): d=7.34 (d, 3JAr =8.5 Hz, 2H; 1-
Harom), 6.87 (d, 3JAr =8.5 Hz, 2H; 2-Harom), 5.92–5.85 (m, 2H; 2-Hbu, 3-
(E)-4-(4-Dimethoxymethylphenoxy)but-2-enyl
2-acetamido-3,6-di-O-
acetyl-4-O-(2,3,4,6-tetra-O-acetyl-b-d-galactopyranosyl)-2-deoxy-b-d-glu-
copyranoside (30): The reaction was carried out according to general pro-
cedure A using compound 18 (720 mg, 1.07 mmol) and compound 21
(1.67 g, 8.00 mmol) with catalyst 23 (63 mg, 0.10 mmol). The product 30
was obtained as a colorless solid (110 mg, 12%). Rf =0.21 (EtOAc); m.p.
1
878C; [a]2D0 =ꢁ9.4 (c=0.5 in CHCl3); H NMR (500 MHz, CDCl3, 258C):
3
3
H
bu), 5.29–5.21 (m, 2H; Hacetal, 3-H), 4.97 (dd, 3J3,4 =10.5, 3J4,5 =10.5 Hz,
d=7.36 (d, JAr =8.5 Hz, 2H; 1-Harom), 6.92 (d, JAr =8.5 Hz, 2H; 2-Harom),
Chem. Eur. J. 2010, 16, 7017 – 7029
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7025

J. Thiem et al.
3
3
3
5.92–5.85 (m, 2H; 2-Hbu, 3-Hbu), 5.68 (d, JNH,2 =6.4 Hz, 1H; NH), 5.31 (s,
2H; 3-H, 4-H), 3.23 (ddd, 3J5,6a =2.5, J5,6b =5.0, J4,5 =10.5 Hz, 1H; 5-H),
1.96 (s, 3H; HNHAc), 1.92–1.85 (m, 2H; 3-Hbu), 1.84–1.76 ppm (m, 2H; 2-
Hbu); 13C NMR (126 MHz, CDCl3, 258C): d=192.9 (Cald), 129.0 (Carom),
115.1 (Carom), 98.5 (C-1), 73.6 (C-4), 73.1 (C-5), 68.2 (C-1bu), 68.7 (C-3),
67.3 (C-4bu), 62.5 (C-6), 55.3 (C-2), 27.3 (C-3bu), 27.2 (C-3bu), 22.8 ppm
(CH3CON); HRMS (FAB): calcd. for C19H28NO8+: 398.1809 [M+H]+;
found: 398.1812.
1H; Hacetal), 5.29–5.20 (m, 2H; 4-H, 3-H), 5.07 (dd, 3J2’,3’ =7.6 Hz, 1H; 2’-
H), 4.90 (dd, 3J2’,3’ =7.6, J3’,4’ =3.6 Hz, 1H; 3’-H), 4.50–4.40 (m, 3H; 1’-H,
3
1-Hbu), 4.42 (d, 3J1,2 =8.1 Hz, 1H; 1-H), 4.39 (dd, 3J5,6a =5.7, J6a,’b
=
3
12.3 Hz, 1H; 6a-H), 4.28–4.12 (m, 3H; 2-H, 4-Hbu), 4.05–3.99 (m, 3H;
6b-H, 6a’b’-H), 3.83–3.78 (m, 2H; 5-H, 5’-H), 3.70 (dd, 3J3,5 =9.9, J4,54
=
3
9.9 Hz, 1H; 4-H), 2.15 (s, 3H; Hac), 2.14 (s, 3H; Hac), 2.13 (s, 3H; Hac),
2.06 (s, 3H; Hac), 2.05 (s, 3H; Hac), 1.88 ppm (s, 3H; HNHAc); 13C NMR
(126 MHz, CDCl3, 258C): d=170.4 (CH3CO), 170.3 (CH3CO), 170.2
(CH3CO), 169.8 (CH3CON), 169.5 (CH3CO), 169.2 (CH3CO), 169.0
(CH3CO), 132.0 (Carom), 129.3 (Carom), 128.0 (Carom), 126.9 (Carom), 114.7
(C-2bu), 114.1 (C-3bu), 103.5 (Cacetal), 100.2 (C-1’), 95.2 (C-1), 75.3 (C-4),
70.6 (C-3), 70.00 (C-3’), 69.5 (C-5), 68.3 (C-4bu), 68.2 (C-2’), 67.5 (C-4bu),
67.2 (C-5’), 65.5 (C-4’), 60.9 (C-6), 59.7 (C-6’), 52.7 (OCH3), 51.0 (C-2),
4-(4-Formylphenoxy)butyl b-cellobioside (35): The reaction was carried
out according to general procedure B using compound 28 (300 mg,
350 mmol). The product 35 was obtained as a colorless solid (149 mg,
82%). Rf =0.16 (CH2Cl2/MeOH, 5:1); m.p. 1208C; [a]2D0 =+20.4 (c=1.0
in MeOH); 1H NMR (500 MHz, CDCl3, 258C): d=9.80 (s, 1H; Hald),
7.84 (d, 3JAr =8.7 Hz, 1H; 1-Harom), 7.10 (d, 3JAr =8.8 Hz, 1H; 2-Harom),
4.52 (d, 3J1,2 =7.9 Hz, 1H; 1-H), 4.43 (d, 3J1,2 =7.9 Hz, 1H; 1’-H), 4.20 (t,
3J3bu,4bu =6.7 Hz, 2H; 4-Hbu), 3.86–3.57 (m, 6H; 6-H, 6’-H, 1-Hbu), 3.50–
3.30 (m, 8H; 2-H, 3-H, 4-H, 5-H, 2’-H, 3’-H, 4’-H, 5’-H), 1.92–1.85 (m,
2H; 3-Hbu), 1.84–1.76 ppm (m, 2H; 2-Hbu); 13C NMR (126 MHz, CDCl3,
258C): d=192.9 (Cald), 129.0 (Carom), 115.1 (Carom), 103.4 (C-1’), 102.2 (C-
1), 80.7 (C-4), 77.1 (C-3’), 77.0 (C-5’), 75.3 (C-3’), 74.9 (C-5), 73.8 (C-2’),
73.5 (C-2), 70.7 (C-4’), 68.8 (C-1bu), 67.6 (C-4bu), 66.6 (C-4’), 63.9 (C-6’),
63.0 (C-6), 27.3 (C-2bu), 27.2 ppm (C-3bu); HRMS (FAB): calcd. for
C23H35O13+: 519.2072 [M+H]+; found: 519.2066.
20.8 (CH3CO), 22.8 (CH3CON), 20.6 (CH3CO), 20.5 ppm (CH3CO);
HRMS (FAB): calcd. for C39H54NO20
856.3239.
+
:
856.3234 [M+H]+; found:
4-(4-Formylphenoxy)butyl b-d-glucopyranoside (31): The reaction was
carried out according to the general procedure B using compound 24
(500 mg, 879 mmol). The product 31 was obtained as a colorless syrup
(285 mg, 91%). Rf =0.45 (CH2Cl2/MeOH, 5:1); [a]2D0 =+42.5 (c=1.0 in
MeOH); 1H NMR (500 MHz, CDCl3, 258C): d=9.81 (s, 1H; Hald), 7.84
(d, JAr =8.8 Hz, 1H; 1-Harom), 7.07 (d, JAr =8.8 Hz, 1H; 2-Harom), 4.27 (d,
3J1,2 =7.9 Hz, 1H; 1-H), 4.12 (t, 3J3bu,4bu =6.7 Hz, 2H; 4-Hbu), 4.05–3.95
(m, 1H; 1a-Hbu), 3.90–3.83 (m, 1H; 1b-Hbu), 3.66 (dd, J5,6a =5.03, J6a,6b
3
3
4-(4-Formylphenoxy)butyl b-lactoside (36): The reaction was carried out
according to general procedure
B using compound 29 (400 mg,
3
2
=
446 mmol). The product 36 was obtained as a colorless solid (206 mg,
85%). Rf =0.15 (CH2Cl2/MeOH, 5:1); m.p. 1148C; [a]2D0 =+20.4 (c=1.0
in MeOH); 1H NMR (500 MHz, CDCl3, 258C): d=9.81 (s, 1H; Hald),
7.84 (d, 3JAr =8.8 Hz, 1H; 1-Harom), 7.11 (d, 3JAr =8.8 Hz, 1H; 2-Harom),
4.50 (d, 3J1,2 =8.0 Hz, 1H; 1’-H), 4.42 (d, 3J1,2 =7.7 Hz, 1H; 1-H), 4.17 (t,
3J3bu,4bu =6.6 Hz, 2H; 4-Hbu), 3.95 (dd, 3J5,6a =1.7, 2J6a,6b =12.2 Hz, 1H; 6a-
H), 3.89 (dd, 3J3’,4’ =3.1, 3J4’,5’ =0.7 Hz, 1H; 4’-H), 3.78–3.65 (m, 5H; 6-H,
6’ab-H, 1-Hbu), 3.52 (dd, 3J3„4 =8.9, 3J4,5 =9.8 Hz, 4-H), 3.50–3.30 (m, 6H;
2-H, 3-H, 5-H, 2’-H, 3’-H, 5’-H), 1.95–1.86 (m, 2H; 3-Hbu), 1.83–1.77 ppm
(m, 2H; 2-Hbu); 13C NMR (126 MHz, CDCl3, 258C): d=192.9 (Cald),
129.0 (Carom), 115.1 (Carom), 105.8 (C-1’), 103.9 (C-1), 81.3 (C-4), 78.3 (C-
5’), 77.6 (C-5), 77.3 (C-3), 75.9 (C-2), 74.8 (C-3’), 73.6 (C-2’), 70.7 (C-4’),
3
12.17 Hz, 1H; 6a-H), 3.40–3.23 (m, 3H; 3-H, 4-H, 6b-H), 3.17 (dd, J1,2
=
7.9, 3J2,3 =8.9 Hz, 1H; 2-H), 1.96–1.87 (m, 2H; 3-Hbu), 1.85–1.75 ppm (m,
2H; 2-Hbu); 13C NMR (126 MHz, CDCl3, 258C): d=192.9 (Cald), 133.1
(Carom), 116.0 (Carom), 104.4 (C-1), 78.1 (C-4), 77.9 (C-5), 75.1 (C-2), 71.7
(C-1bu), 70.31 (C-4bu), 69.39 (C-3), 62.85 (C-6), 27.2 (C-3bu), 26.9 ppm (C-
2bu); HRMS (FAB): calcd. for C17H25O8+: 357.1544 [M+H]+; found:
357.1548.
4-(4-Formylphenoxy)butyl a-d-mannopyranoside (32): The reaction was
carried out according to general procedure
(400 mg, 704 mmol). The product 32 was obtained as a colorless oil.
(230 mg, 92%). Rf =0.44 (CH2Cl2/MeOH, 5:1); [a]2D0 =+10.2 (c=1.0 in
MeOH); 1H NMR (500 MHz, CDCl3, 258C): d=9.83 (s, 1H; Hald), 7.86
(d, JAr =8.7 Hz, 1H; 1-Harom), 7.08 (d, JAr =8.8 Hz, 1H; 2-Harom), 4.77 (d,
3J1,2 =1.3 Hz, 1H; 1-H), 4.13 (t, 3J3bu,4bu =6.7 Hz, 2H; 4-Hbu), 3.93–3.65
(m, 4H; 6ab-H, 1-H), 3.55–3.46 (m, 4H; 2-H, 3-H, 4-H, 5-H), 1.92–1.85
(m, 2H; 3-Hbu), 1.84–1.76 ppm (m, 2H; 2-Hbu); 13C NMR (126 MHz,
CDCl3, 258C): d=192.9 (Cald), 129.0 (Carom), 115.1 (Carom), 101.6 (C-1),
74.6 (C-5), 72.7 (C-4), 72.3 (C-2), 68.81 (C-1bu), 68.7 (C-3), 68.3 (C-4bu),
62.9 (C-6), 27.3 (C-3bu), 27.2 ppm (C-2bu); HRMS (FAB): calcd. for
C17H25O8+: 357.1544 [M+H]+; found: 357.1539.
B using compound 25
68.8 (C-1bu), 67.6 (C-4bu), 66.6 (C-4’), 63.9 (C-6’), 63.0 (C-6), 27.3 (C-2bu),
27.2 ppm (C-3bu); HRMS (FAB): calcd. for C23H35O13
3
3
+
:
519.2072
[M+H]+; found: 519.2063.
4-(4-Formylphenoxy)butyl
2-acetamido-4-O-b-d-galactopyranosyl)-2-
deoxy-b-d-glucopyranoside (37): The reaction was carried out according
to general procedure B using compound 30 (80 mg, 93 mmol). The prod-
uct 37 was obtained as a colorless solid (41 mg, 79%). Rf =0.25 (CH2Cl2/
MeOH, 3:1); m.p. 1508C; [a]2D0 =+20.4 (c=1.0 in MeOH); 1H NMR
3
(500 MHz, CDCl3, 258C): d=9.85 (s, 1H; Hald), 7.80 (d, JAr =8.8 Hz, 1H;
4-(4-Formylphenoxy)butyl b-d-galactopyranoside (33): The reaction was
carried out according to general procedure
(400 mg, 704 mmol). The product 33 was obtained as a colorless oil
(223 mg, 89%). Rf =0.45 (CH2Cl2/MeOH, 5:1); [a]2D0 =- 4.5 (c=1.0 in
MeOH); 1H NMR (500 MHz, CDCl3, 258C): d=9.80 (s, 1H; Hald), 7.83
(d, JAr =8.8 Hz, 1H; 1-Harom), 7.06 (d, JAr =8.8 Hz, 1H; 2-Harom), 4.22 (d,
3J1,2 =7.4 Hz, 1H; 1-H), 4.11 (t, 3J3bu,4bu =6.4 Hz, 2H; 4-Hbu), 4.02–3.93
(m, 1H; 1a-Hbu), 3.82 (dd, 3J3,4 =3.1, 3J4,5 =0.5 Hz, 1H; 4-H), 3.74–3.70
(m, 2H; 6ab-H), 3.65–3.57 (m, 1H; 1a-Hbu), 3.53–3.42 (m, 3H; 2-H, 3-H,
5-H), 1.95–1.85 (m, 2H; 3-Hbu), 1.82–1.75 ppm (m, 2H; 2-Hbu); 13C NMR
(126 MHz, CDCl3, 258C): d=193.0 (Cald), 133.1 (Carom), 116.0 (Carom),
105.0 (C-1), 76.6 (C-3), 75.0 (C-5), 72.6 (C-2), 70.3 (C-4), 70.2 (C-1bu),
69.3 (C-4bu), 62.5 (C-6), 27.3 (C-3bu), 26.9 ppm (C-2bu); HRMS (FAB):
calcd. for C17H25O8+: 357.1544 [M+H]+; found: 357.1551.
1-Harom), 7.08 (d, 3JAr =8.8 Hz, 1H; 2-Harom), 4.60 (d, 3J1’,2’ =7.8 Hz, 1H;
1’-H), 4.49 (d, 3J1„2 =7.8 Hz, 1H; 1-H), 4.12 (t, 3J3bu,4bu =6.6 Hz, 2H; 4-
B using compound 26
H
bu), 4.02–3.93 (m, 2H; 6a-H, 1a-Hbu), 3.94 (dd, 3J3’,4’ =3.1, 3J4’5’ =0.6 Hz,
1H; 4’-H), 3.85 (dd, 3J5,6b =5.5, 2J6a,6b =12.3 Hz, 1H; 6b-H), 3.80–3.65 (m,
7H; 3-H, 4-H, 2’-H, 3’-H, 5’-H, 6’-H), 3.62–3.60 (m, 2H; 5-H, 1b-Hbu),
3.55 (d, 3J1„2 =7.8, 3J2„3 =9.9 Hz, 1H; 2-H), 2.05 (s, 3H; HNHAc), 1.95–1.86
(m, 2H; 3-Hbu), 1.83–1.77 ppm (m, 2H; 2-Hbu); 13C NMR (126 MHz,
CDCl3, 258C): d=193.0 (Cald), 174.5 (CH3CON), 133.1 (Carom), 116.0
(Carom), 102.8 (C-1’), 100.0 (C-1), 78.4 (C-4), 75.3, 74.7, 72.4, 70.9 (C-3, C-
2’, C-3’, C-5’), 70.4 (C-4’), 68.8 (C-1bu), 68.5 (C-5), 67.6 (C-4bu), 61.0 (C-6),
3
3
60.0 (C-6’), 55.0 (C-2), 27.3 (C-2bu), 26.9 (C-2bu), 22.1 ppm (CH3CON);
HRMS (FAB): calcd. for C25H33NO13
560.2330.
:
560.2338 [M+H]+; found:
+
Undec-10-enyl triethylene glycol (41): Sodium hydride (217 mg,
9.02 mmol) was added slowly to a solution of triethylene glycol (39;
1.33 g, 8.81 mmol) in dry DMF (8 mL). After stirring for 30 min at room
temperature the suspension was cooled to 08C and a solution of 11-bro-
moundec-2-ene (38; 1.03 g, 4.41 mmol) in dry DMF (4 mL) was added
slowly. After warming to room temperature, the mixture was stirred for
12 h. The reaction was quenched with a sat. NH4Cl solution (10 mL) and
then diluted with ethyl acetate (20 mL). The aqueous layer was extracted
with ethyl acetate (3ꢂ20 mL) and the combined organic layers were
washed with a sat. NaCl solution and dried over Na2SO4. After filtration
4-(4-Formylphenoxy)butyl
2-acetamido-2-deoxy-b-d-glucopyranoside
(34): The reaction was carried out according to general procedure B
using compound 27 (450 mg, 793 mmol). The product 34 was obtained as
a colorless syrup (252 mg, 80%). Rf =0.21 (CH2Cl2/MeOH, 5:1); [a]D20
=
ꢁ4.5 (c=1.0 in MeOH); 1H NMR (500 MHz, CDCl3, 258C): d=9.80 (s,
1H; Hald), 7.84 (d, 3JAr =8.7 Hz, 1H; 1-Harom), 7.10 (d, 3JAr =8.8 Hz, 1H;
2-Harom), 4.42 (d, 3J1,2 =8.5 Hz, 1H; 1-H), 4.10 (t, 3J3bu,4bu =6.7 Hz, 2H; 4-
Hbu), 3.86 (dd, 3J5,6b =2.5, 2J6a,6b =12.3 Hz, 1H; 6a-H), 3.65–3.50 (m, 3H;
6b-H, 1-Hbu), 3.32 (dd, 3J1,2 =8.5, 3J2,3 =12.3 Hz, 1H; 2-H), 3.26–3.21 (m,
7026
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 7017 – 7029

Synthesis of Benzaldehyde-Functionalized Glycans
FULL PAPER
the solvents were evaporated and the crude product was purified by
column chromatography using silica and dichloromethane/methanol
(20:1) as eluent to yield the title compound 39 as a yellowish oil (1.27 g,
4.19 mmol, 95%). Rf =0.43 (CH2Cl2/MeOH, 10:1); 1H NMR (500 MHz,
CDCl3, 258C): d=5.73 (ddt, 3J2,3 =6.8, 3Jcis =10.3, 3Jtrans =16.9 Hz, 1H; 2-
H); 4.89 (dq, 4J1,3 =2.0 Hz, 3Jtrans =16.9 Hz, 2H; 1-H), 3.61–3.50 (m, 12H;
2.03–2.00 (m, 2H; 3-H), 1.84–1.80 (m, 1H; 3’-H), 1.73–1.71 (m, 2H; 2’-
H), 1.58–1.55 (m, 2H; 10-H), 1.36–1.27 ppm (m, 16H; 4-H, 5-H, 6-H, 7-
H, 8-H, 9-H, 11-H, 1’-H); 13C NMR (126 MHz, CDCl3, 258C): d=139.5
(C-2), 114.4 (C-1), 77.3–69.2 (C-11, C-12, C-13, C-14, C-15, C-16, C-17,
C-18, C-19, C-20, C-21, C-22, C-23, C-1’), 45.2 (C-4’), 34.1–26.4 ppm (C-3,
C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-2’, C-3’).
12-H, 13-H, 14-H, 15-H, 16-H, 17-H), 3.38 (t, 3J10,11 =7.1 Hz, 2H; 11-H),
O-(4’-Azidobutyl)-(w-undec-10-enyl) hexaethylene glycol (47): The chlo-
ride 46 (500 mg, 952 mmol), sodium azide (250 mg, 3.80 mmol), and tetra-
butylammonium iodide (175 mg, 476 mmol) were dissolved in abs. DMF
(20 mL) and were heated at 708C for 2 h with stirring. Then the solvents
were removed under reduced pressure and the crude material was puri-
fied by flash chromatography on silica using petroleum/ethyl acetate
(1:1). The title compound 47 was obtained as a colorless oil (415 mg,
82%). Rf =0.68 (CH2Cl2/MeOH, 10:1); 1H NMR (500 MHz, CDCl3,
3
2.60 (brs, 1H; OH), 1.96 (q, 3J2,3 =6.8 Hz, 2H; 3-H), 1.51 (t, J10,11
=
7.1 Hz, 2H; 10-H), 1.28–1.21 ppm (m, 12H; 4-H, 5-H, 6-H, 7-H, 8-H, 9-
H); 13C NMR (126 MHz, CDCl3, 258C): d=139.2 (C-2), 114.1 (C-1), 72.5
(C-16), 71.5 (C-11), 70.6–70.0 (C-12–C-16), 61.7 (C-17), 36.4 (C-3), 33.8–
26.0 ppm (C-4–C-10).
Undec-10-enyl hexaethylene glycol (42): Following the procedure used
for the synthesis of compound 41, hexaethylene glycol (40; 2.50 g,
8.85 mmol) and sodium hydride (218 mg, 9.10 mmol) were suspended in
dry DMF (8 mL) and then 11-bromoundec-2-ene (38; 1.05 g, 4.50 mmol)
in dry DMF (4 mL) was added. After washing and purification, com-
pound 42 was obtained as a yellowish oil (1.88 g, 4.32 mmol, 96%). Rf =
3
258C): d=5.80 (ddt, 3J2,3 =6.8, Jcis 2 =10.2, 3J,trans =16.9 Hz, 1H; 2-H),
5.01–4.92 (m, 2H; 1-H), 3.64–3.42 (m, 26H; 12-H, 13-H, 14-H, 15-H, 16-
3
H, 17-H, 18-H, 19-H, 20-H, 21-H, 22-H, 23-H, 1’-H), 3.39 (t, J1,2 =5.8 Hz,
2H; 4’-H), 2.03–2.00 (m, 2H; 3-H), 1.73–1.71 (m, 2H; 2’-H),1.62–1.60 (m,
2H; 3’-H), 1.58–1.55 (m, 2H; 10-H), 1.36–1.27 ppm (m, 12H; 4-H, 5-H,
6-H, 7-H, 8-H, 9-H); 13C NMR (126 MHz, CDCl3, 258C): d=139.9 (C-2),
114.0 (C-1), 77.3–69.2 (C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-
19, C-20, C-21, C-22, C-23, C-1’), 51.2 (C-4’), 34.1–26.4 ppm (C-3, C-4, C-
5, C-6, C-7, C-8, C-9, C-10, C-2’, C-3’).
0.56 (CH2Cl2/MeOH, 10:1); 1H NMR (500 MHz, CDCl3, 258C): d=5.80
4
(ddt, 3J2,3 =6.8, 3Jcis =10.3, 3Jtrans =16.9 Hz, 1H; 2-H), 4.95 (dq, J1,3
=
2.0 Hz, 3Jtrans =16.9 Hz, 2H; 1-H), 3.68–3.56 (m, 24H; 12-H, 13-H, 14-H,
3
15-H, 16-H, 17-H, 18-H, 19-H, 20-H, 21-H, 22-H, 23-H), 3.44 (t, J10,11
=
6.8 Hz, 2H; 11-H), 2.60 (brs, 1H; OH), 2.02 (m, 2H; 3-H), 1.56 (t,
3J10,11 =6.8 Hz, 2H; 10-H), 1.33–1.22 ppm (m, 12H; 4-H, 5-H, 6-H, 7-H,
8-H, 9-H); 13C NMR (126 MHz, CDCl3, 258C): d=139.2 (C-2), 114.9 (C-
1), 72.5 (C-22), 71.5 (C-11), 71.5–70.0 (C-3, C-12–C-20), 61.7 (C-23), 36.4
(C-10), 33.8–26.0 9 (C-3–C-11).
O-(4’-Azidobutyl)-(w-11-thioacetylundecyl) hexaethylene glycol (48):
Following the procedure used for the synthesis of compound 43, com-
pound 47 (400 mg, 752 mmol), thioacetic acid (160 mL, 2.26 mmol), and
AIBN (100 mg, 600 mmol) were allowed to react in THF (15 mL) to yield
a colorless oil (434 mg, 95%). Rf =0.52 (CH2Cl2/MeOH, 10:1); 1H NMR
11-Thioacetylundecyl triethylene glycol (43): Thioacetic acid (740 mL,
10.4 mmol) and AIBN (450 mg, 2.74 mmol) were added to a stirred solu-
tion of alkene 41 (1.05 g, 3.47 mmol) in abs. THF (20 mL) and the mix-
ture was irradiated with UV light for 3 h at room temperature. The sol-
vents were evaporated and the yellow crude product was purified by
chromatography with a CH2Cl2/methanol gradient (20:1 ! 18:1) to yield
a colorless oil (1.31 g, quant.). Rf =0.40 (CH2Cl2/MeOH, 10:1); 1H NMR
(500 MHz, CDCl3, 258C): d=3.66 (m, 2H; 17-H), 3.61–3.51 (m, 10H; 12-
H, 13-H, 14-H, 15-H, 16-H), 3.38 (t, 3J10,11 =6.8 Hz, 2H; 11-H), 2.79 (t,
3J1,2 =7.3 Hz, 2H; 1-H), 2.45 (m, 2H; 16-H), 2.25 (s, 3H; OSCCH3), 1.49
(m, 2H; 8-H), 1.25–1.16 ppm (m, 12H; 9-H, 10-H, 11-H, 12-H, 13-H, 14-
H); 13C NMR (126 MHz, CDCl3, 258C): d=196.1 (OSCCH3), 70.0- 72.5
(C-11, C-12, C-13, C-14, C-15, C-16), 61.8 (C-17), 30.6 (C-1), 26.0–
29.5 ppm (C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10).
(500 MHz, CDCl3, 258C): d=3.64–3.45 (m, 26H; 12-H, 13-H, 14-H, 15-
3
H, 16-H, 17-H, 18-H, 19-H, 20-H, 21-H, 22-H, 23-H, 1’-H), 3.40 (t, J1,2
=
7.4 Hz, 2H; 11-H), 3.39 (t, 3J1,2 =5.8 Hz, 2H; 4’-H), 2.85 (t, 3J1,2 =7.4 Hz,
2H; 1-H), 2.67–2.65 (m, 2H; 2-H), 1.73–1.70 (m, 2H; 2’-H), 1.62–1.60 (m,
2H; 3’-H), 1.58–1.55 (m, 2H; 10-H), 1.36–1.27 ppm (m, 14H; 3-H, 4-H,
5-H, 6-H, 7-H, 8-H, 9-H); 13C NMR (126 MHz, CDCl3, 258C): d=77.3–
69.2 (C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-19, C-20, C-21, C-
22, C-23, C-1’), 51.2 (C-4’), 34.1–26.4 ppm (C-1, C-2, C-3, C-4, C-5, C-6,
C-7, C-8, C-9, C-10, C-2’, C-3’, CH3); MS (MALDI-TOF): m/z: calcd for
C29H57N3O8S: 607.39 [M+Na]+; found: 630.9.
O-(4’-Aminobutyl)-(w-11-mercaptoundecyl) hexaethylene glycol (49): A
suspension of lithium aluminum hydride (105 mg, 2.76 mmol) in dry THF
(10 mL) was cooled to 08C. Then a solution of compound 47 (420 mg,
691 mmol) in dry THF (5 mL) was added slowly. The reaction was al-
lowed to warm to room temperature and stirred for 3 h and then
quenched by adding water (5 mL). The suspension was filtered and the
residue extracted by THF (100 mL). The combined organic layers were
evaporated under reduced pressure and the crude product was purified
by chromatography with a CH2Cl2/methanol gradient (20:1 ! 18:1) to
yield a pale-yellow oil (239 mg, 64%). Rf =0.33 (CH2Cl2/MeOH, 5:1);
1H NMR (500 MHz, CDCl3, 258C): d=3.64–3.45 (m, 26H; 12-H, 13-H,
14-H, 15-H, 16-H, 17-H, 18-H, 19-H, 20-H, 21-H, 22-H, 23-H, 1’-H), 3.40
11-Thioacetylundecyl hexaethylene glycol (44): Following the procedure
used for the synthesis of compound 43, alkene 42 (1.56 g, 3.59 mmol),
thioacetic acid (770 mL, 10.8 mmol), and AIBN (470 mg, 2.87 mmol) were
allowed to react in THF (20 mL) to yield a colorless oil (1.83 g, quant.).
Rf =0.35 (CH2Cl2/MeOH, 10:1); 1H NMR (500 MHz, CDCl3, 258C): d=
3.71–3.69 (m, 2H; 23-H), 3.66–3.52 (m, 22H; 12-H, 13-H, 14-H, 15-H, 16-
H, 17-H, 18-H, 19-H, 20-H, 21-H, 22-H), 3.42 (t, 3J=6.8 Hz, 1H; 11-H),
3
2.83 (t, J1,2 =7.4 Hz, 2H; 1-H), 2.30 (s, 3H; OSCCH3), 1.53 (m, 4H; 2-H,
10-H), 1.33–1.23 ppm (m, 14H; 3-H, 4-H, 5-H, 6-H, 7-H, 8-H, 9-H);
13C NMR (126 MHz, CDCl3, 258C): d=196.1 (OSCCH3), 70.0–72.5 (C-
11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-19, C-20, C-21, C-22),
61.8 (C-23), 30.6 (CH3), 29.5–26.5 ppm (C-1, C-2, C-3, C-4, C-5, C-6, C-7,
C-8, C-9, C-10).
3
3
3
(t, J1,2 =7.4 Hz, 2H; 11-H), 3.39 (t, J1,2 =5.8 Hz, 2H; 4’-H), 2.85 (t, J1,2
=
7.4 Hz, 2H; 1-H), 2.66–2.63 (m, 2H; 2-H), 1.73–1.70 (m, 2H; 2’-H), 1.62–
1.60 (m, 4H; 2-H, 3’-H), 1.58–1.55 (m, 2H; 10-H), 1.36–1.27 ppm (m,
14H; 3-H, 4-H, 5-H, 6-H, 7-H, 8-H, 9-H); 13C NMR (126 MHz, CDCl3,
258C): d=77.3–69.2 (C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-
19, C-20, C-21, C-22, C-23, C-1’), 42.3 (C-4’), 39.4 (C-1), 34.1–26.4 ppm
(C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-2’, C-3’); HRMS (FAB):
m/z: calcd. for C27H57NO7S: 539.3856 [MꢁNa]+; found: 562.3802.
O-Tosyl-(w-undec-10-enyl) hexaethylene glycol (50): A stirred solution
of the alcohol 42 (2.01 g, 4.62 mmol) in dry pyridine (20 mL) was cooled
to 08C and then tosyl chloride (1.76 g, 9.24 mmol) was added portion-
wise. The mixture was warmed to room temperature, stirred for 15 h, and
then concentrated. The crude product was purified by column chroma-
tography using silica and a petroleum/ethyl acetate gradient (1:1 ! 1:2).
The product 51 was obtained as a pale-yellow oil (2.50 g, 92%). Rf =0.60
(CH2Cl2/MeOH, 10:1); 1H NMR (500 MHz, CDCl3, 258C): d=7.79 (d,
3JAr =8.4 Hz, 2H; 1-Harom), 7.39 (d, 3JAr =8.4 Hz, 2H; 2-Harom), 5.80 (ddt,
3J2,3 =6.8, 3Jcis =10.0, 3Jtrans =16.8, 1H; 2-H), 5.00–4.91 (m, 2H; 1-H), 4.15
O-(4’-Chlorobutyl)-(w-undec-10-enyl) hexaethylene glycol (46): Alcohol
42 (632 mg, 1.45 mmol) was dissolved in dry DMF (15 mL) and cooled to
08C. A suspension of sodium hydride (68 mg, 1.68 mmol) in DMF (5 mL)
was added slowly to the solution. After stirring for 30 min a solution of
1-bromo-4-chlorobutane (45; 1.75 mL, 15.2 mmol) in dry DMF (15 mL)
was added dropwise. The reaction mixture was maintained at 08C for 2 h,
then allowed to warm to room temperature, and stirred for 15 h. After
quenching the reaction with a sat. NH4Cl solution (5 mL) the mixture
was concentrated under reduced pressure. The residue was purified by
chromatography on silica using CH2Cl2/methanol (30:1) as eluent to yield
a colorless oil (594 mg, 78%). Rf =0.68 (CH2Cl2/MeOH, 10:1); 1H NMR
3
(500 MHz, CDCl3, 258C): d=5.80 (ddt, 3J2,3 =6.8, Jcis 2 =10.2, 3J
=
,trans
16.9 Hz, 1H; 2-H), 5.00–4.91 (m, 2H; 1-H), 3.64–3.42 (m, 26H; 12-H, 13-
H, 14-H, 15-H, 16-H, 17-H, 18-H, 19-H, 20-H, 21-H, 22-H, 23-H, 4’-H),
Chem. Eur. J. 2010, 16, 7017 – 7029
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7027

J. Thiem et al.
(t, 3JH22,23 =4.8 Hz, 2H; 23-H), 3.69–3.56 (m, 22H; 12-H, 13-H, 14-H, 15-
H, 16-H, 17-H, 18-H, 19-H, 20-H, 21-H, 22-H), 3.44 (t, 3JH11,10 =6.8 Hz,
2H; 11-H), 2.44 (s, 3H; Ar-CH3), 2.03 (q, 2H; 3-H), 1.58–1.53 (m, 2H;
10-H), 1.36–1.27 ppm (m, 12H; 4-H, 5-H, 6-H, 7-H, 8-H, 9-H); 13C NMR
(126 MHz, CDCl3, 258C): d=144.7 (C-1arom), 139.2 (C-2), 132.9 (C-2arom),
129.8 (C-2arom), 127.9 (C-2arom), 114.1 (C-1), 71.5 (C-22), 70.5–70.0 (C-13,
C-14, C-15, C-16, C-17, C-18, C-19, C-20, C-21), 69.7 (C-23), 69.2 (C-12),
68.6 (C-11), 33.7 (C-3), 29.1–26.0 (C-4, C-5, C-6, C-7, C-8, C-9, C-10),
21.6 ppm (CH3); MS (MALDI-TOF): m/z: calcd for C30H52O9S: 588.33
[M+Na]+; found: 611.5.
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Azido-(w-undec-10-enyl) hexaethylene glycol (51): The tosylate 50
(2.05 g, 3.48 mmol), sodium azide (905 mg, 13.9 mmol), and tetrabutylam-
monium iodide (642 mg, 1.74 mmol) were dissolved in abs. DMF (40 mL)
and the mixture was heated at 708C for 2 h with stirring. Then the sol-
vents were removed under reduced pressure and the crude material was
purified by flash chromatography on silica using petroleum/ ethyl acetate
(1:1) as eluent. The title compound 51 was obtained as a colorless oil
(1.36 g, 85%). Rf =0.41 (CH2Cl2/MeOH, 10:1); 1H NMR (500 MHz,
CDCl3, 258C): d=5.80 (ddt, 3J2,3 =6.8, 3Jcis =10.3, 3Jtrans =17.1, 1H; 2-H),
4.98 (ddt, 4J1,3a =1.6, 4J1,3b =2.2, 3Jtrans =17.1 Hz, 1H; 1a-H), 4.98 (ddt,
4J1,3a =1.1, 4J1,3b =2.0, 3Jtrans =10.3 Hz, 1H; 1a-H), 3.69–3.62 (m, 22H; 12-
H, 13-H, 14-H, 15-H, 16-H, 17-H, 18-H, 19-H, 20-H, 21-H, 22-H), 3.44 (t,
3
3JH11,10 =6.8 Hz, 2H; 11-H), 3.38 (t, J22, 23 =5.1 Hz, 2H; 23-H), 2.05–2.05
(m, 2H; 3-H), 1.58–1.53 (m, 2H; 10-H), 1.36–1.27 ppm (m, 12H; 4-H, 5-
H, 6-H, 7-H, 8-H, 9-H); 13C NMR (126 MHz, CDCl3, 258C): d=139.3 (C-
2), 114.0 (C-1), 71.5 (C-11), 70.5–70.0 (C-13, C-14, C-15, C-16, C-17, C-
18, C-19, C-20, C-21, C-22), 50.6 (C-23), 33.7 (C-3), 29.1–26.0 ppm (C-4,
C-5, C-6, C-7, C-8, C-9, C-10); MS (MALDI-TOF): m/z: calcd for
C23H45N3O6: 459.33 [M+Na]+; found: 482.6.
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Azido-(w-11-thioacetylundecyl) hexaethylene glycol (52): Following the
procedure used for the synthesis of compound 43, compound 51 (1.10 g,
2.39 mmol), thioacetic acid (510 mL, 7.17 mmol), and AIBN (314 mg,
1.91 mmol) were allowed to react in THF (15 mL) to yield a colorless oil
(1.22 g, 96%). Rf =0.38 (CH2Cl2/MeOH, 10:1); 1H NMR (500 MHz,
CDCl3, 258C): d=3.69–3.66 (m, 20H; 12-H, 13-H, 14-H, 15-H, 16-H, 17-
3
H, 18-H, 19-H, 20-H, 21-H), 3.57–3.55 (m, 2H; 22-H), 3.43 (t, J10,11
=
6.8 Hz, 2H; 11-H), 3.38 (t, 3J22,23 =5.0 Hz, 2H; 23-H), 2.85 (t, J1,2
=
3
7.4 Hz, 2H; 1-H), 2.31 (s, 3H; OSCCH3), 1.53–1.51 (m, 4H; 2-H, 10-H),
1.33–1.23 ppm (m, 14H; 3-H, 4-H, 5-H, 6-H, 7-H, 8-H, 9-H); 13C NMR
(126 MHz, CDCl3, 258C): d=196.0 (OSCCH3), 72.5–70.1 (C-11, C-12, C-
13, C-14, C-15, C-16, C-17, C-18, C-19, C-20, C-21, C-22), 50.6 (C-23),
30.6 (CH3), 29.5–26.5 ppm (C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-
10); MS (MALDI-TOF): m/z: calcd for C25H49N3O7S: 535.33 [M+Na]+;
found: 558.9.
Amino-(w-11-mercaptoundecyl) hexaethylene glycol (53): Following the
procedure used for the synthesis of compound 49, compound 52 (850 mg,
1.59 mmol) and lithium aluminum hydride (241 mg, 6.36 mmol) were al-
lowed to react in THF (30 mL) to yield a colorless oil (491 mg, 66%).
Rf =0.32 (CH2Cl2/MeOH, 5:1); 1H NMR (500 MHz, CDCl3, 258C): d=
1H NMR (400 MHz, CDCl3): d=3.69–3.66 (m, 20H; 12-H, 13-H, 14-H,
15-H, 16-H, 17-H, 18-H, 19-H, 20-H, 21-H), 3.57–3.55 (m, 2H; 22-H),
3.40 (t, 3J10,11 =6.8 Hz, 2H; 11-H), 2.80 (t, 3J22,23 =6.2 Hz, 2H; 23-H), 2.65
(t, 3J1,2 =7.4 Hz, 2H; 1-H), 1.51–1.49 (m, 2H; 10-H), 1.33–1.23 ppm (m,
16H; 2-H, 3-H, 4-H, 5-H, 6-H, 7-H, 8-H, 9-H); 13C NMR (126 MHz,
CDCl3, 258C): d=72.5–70.1 (C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-
18, C-19, C-20, C-21, C-22), 41.8 (C-23), 29.5–26.5 ppm (C-1, C-2, C-3, C-
4, C-5, C-6, C-7, C-8, C-9, C-10); HRMS (FAB): m/z: calcd. for
C23H49NO6S: 467.3281 [MꢁNa]+; found: 490.3155.
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Support of this work by the Deutsche Forschungsgemeinschaft (SFB 470,
A5) is gratefully acknowledged.
7028
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Chem. Eur. J. 2010, 16, 7017 – 7029

Synthesis of Benzaldehyde-Functionalized Glycans
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Received: September 30, 2009
Revised: February 22, 2010
Published online: April 29, 2010
Chem. Eur. J. 2010, 16, 7017 – 7029
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7029