Antagonists of the myelin-associated glycoprotein: A new class of tetrasaccharide mimics

Article abstract of DOI:10.1016/j.bmc.2006.03.007

The tetrasaccharide substructure 1 of the ganglioside GQ1bα shows a remarkable affinity for the myelin-associated glycoprotein (MAG). In the search for structurally simplified and pharmacokinetically improved mimics of 1, biphenyl was identified as a feas

Full text of DOI:10.1016/j.bmc.2006.03.007

Bioorganic & Medicinal Chemistry 14 (2006) 4944–4957
Antagonists of the myelin-associated glycoprotein: A new
class of tetrasaccharide mimics
Daniel Schwizer,a Heiko Ga¨thje,b Soerge Kelm,b Michele Porro,a
Oliver Schwardta and Beat Ernsta,*
aInstitute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland
bCentre for Biomolecular Interactions Bremen, University of Bremen, Leobener Str., 28359 Bremen, Germany
Received 3 October 2005; revised 2 March 2006; accepted 8 March 2006
Available online 31 March 2006
Abstract—The tetrasaccharide substructure 1 of the ganglioside GQ1ba shows a remarkable affinity for the myelin-associated gly-
coprotein (MAG). In the search for structurally simplified and pharmacokinetically improved mimics of 1, biphenyl was identified as
a feasible replacement for the core disaccharide Galb(1–3)GalNAc according to saturation transfer difference (STD) NMR and
molecular modeling investigations. Using Suzuki coupling, a convergent synthesis of the mimics was achieved. To optimize the
yields of the coupling reactions, the catalytic effects of microwave irradiation and conventional heating were compared. The biolog-
ical evaluation of mimics 3 and 4 was performed in a competitive target-based assay. It was found that the relative inhibitory poten-
cy (rIP) of antagonist 3 was clearly enhanced in comparison to the reference trisaccharide 2, despite the former having a much
simpler structure. In addition to the improved synthetic feasibility, an increase of the partition coefficient between octanol and water
(log P), and therefore a beneficial change in the pharmacokinetic properties of 3 and 4 was achieved.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
MAG hasbeen identified as asialic acid-binding immuno-
globulin-like lectin (Siglec-4). Its role,11 as one of several
myelin components inhibiting axonal regrowth after inju-
ry, has drawn a lot of attention.12 Although the mecha-
nism is still unclear, it is believed that reverting this
inhibitory activity of MAG could be a way of supporting
the regeneration after injury to the central nervous sys-
tem. Schnaar13 reported that a limited set of structurally
related gangliosides, known to be expressed on myelinat-
ed neurons in vivo, are functional ligands of MAG. The
gangliosides GD1a, GT1b, and GQ1ba (Fig. 2) have been
synthesized in preparative amounts14 and have therefore
been available for the establishment of a structure–affinity
relationship (SAR). Thereafter, the SAR profile was re-
fined by numerous synthetic contributions based on neu-
raminic acid derivatives and ganglioside fragments.15 The
recently reported ability to reverse MAG inhibition with
monovalent glycosides16 encourages further exploration
of glycans and glycan mimics as inhibitors of MAG-med-
iated axonal outgrowth inhibition.
The adult mammalian central nervous system (CNS)
has—unlike the peripheral nervous system (PNS)—no
capacity for regeneration.1 It was believed that this lack
of regeneration is inherent to the CNS. However, it is
now known that neurite outgrowth is principally possi-
ble,2 but actively inhibited by inhibitor proteins ex-
pressed by myelinating glia cells, oligodendrocytes and
Schwann cells.3 Three inhibitor proteins have been iden-
tified so far: Nogo A,4 oligodendrocyte myelin glycopro-
tein (OMpg)5 and myelin-associated glycoprotein
(MAG).6 It appears that these three proteins all bind
to the same receptor, Nogo-66,7 that then forms a com-
plex with the coreceptor p75NTR
.
This leads to the
8
transduction of the inhibitory signal into the cytosol of
the neuron, where it activates RhoA,9 which in turn
causes growth cone collapse. This cascade has also been
proved to be triggered by MAG binding to gangliosides
with p75NTR as coreceptor10 (Fig. 1).
In conclusion, although several potential binding part-
ners for MAG have been identified, the full biological
role of its sialic acid-binding activity has remained un-
clear. A potent and selective inhibitor of this activity
would provide the tool required to investigate this
Keywords: Axonal regeneration; Binding affinity; Carbohydrate-bind-
ing epitope; Myelin-associated glycoprotein (MAG); Biphenyl; Suzuki
coupling; Miyaura boronation.
*
Corresponding author. Tel.: +41 267 15 51; fax: +41 267 15 52;
e-mail: beat.ernst@unibas.ch
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.03.007

D. Schwizer et al. / Bioorg. Med. Chem. 14 (2006) 4944–4957
4945
Figure 1. MAG, Nogo-66, and oligodendrocyte myelin glycoprotein (OMgp) all bind to the Nogo-66 receptor (NgR). The inhibitory signal is
transduced into the cytosol of the neuron via the coreceptor p75NTR. MAG also binds to GT1b with p75NTR as coreceptor and thereby transduces
the inhibitory signal into the cytosol. Intracellularly, the small GTPase RhoA is activated, which leads to a collapse of the growth cone.
question. Furthermore, although numerous sialic acid
derivatives and oligosaccharides with antagonistic activ-
ity are available,15 no MAG antagonist mimicking the
carbohydrate nature of the physiological ligands and
at the same time having drug-like properties has been
published so far.
linked sialic acid, the only sizeable STD effect detected
stems from the N-acetyl group. In analogy to the knowl-
edge gained from the crystal structure of the N-terminal
domain of sialoadhesin (Siglec-1) in complex with
30-sialyllactose,18 we can assume that the carboxylic acid
of the a(2–3)-linked sialic acid forms an important salt
bridge with Arg118.19 In addition, docking of tetrasac-
charide 1 to a homology model of MAG20 indicates that
the carboxylic acid of the a(2–6)-linked sialic acid forms
a second salt bridge with Lys67.20 Finally, the low STD
values found for protons of the core disaccharide
Galb(1–3)GalNAc indicate that only marginal contribu-
tions to binding originate from this part of tetrasaccha-
ride 1. We therefore decided to replace the core
disaccharide by a linker, which positions the two sialic
acid residues in the required spacial orientation
(Fig. 2, mimic 3), and at the same time improves the
pharmacokinetic properties of lead structure 1. Molecu-
lar modeling revealed that a biphenyl core would fulfill
such spacial requirements. In addition, a dramatic
reduction of the high polarity of 1, and therefore an
improvement of log P, can be expected. It has been
reported that, in the search for selectin antagonists,
the biphenyl moiety has already successfully been ap-
plied for mimicking the core disaccharide Galb(1–
4)GlcNAc of sialyl Lewisx.21
In an earlier study,17 we investigated the binding proper-
ties of the terminal tetrasaccharide of GQ1ba (see 1,
Fig. 2). In the present study, mimics of the tetrasaccha-
ride 1, where the core disaccharide Galb(1–3)GalNAc is
replaced by a non-carbohydrate linker, are presented.
2. Results and discussion
By comparing the carbohydrate structures of the gan-
gliosides GD1a, GT1b, and GQ1ba, tetrasaccharide 1
was identified as the relevant part for binding to
MAG.13,17 Recently, the binding, that is, the proximity
of individual parts of 1 to MAG (see 1, Fig. 2), has been
determined by Saturation Transfer Difference (STD)
17
NMR.
The largest STD response was observed at
the N-acetyl function of the a(2–3)-linked sialic acid.
Further significant interactions originate from H-6 and
H-7 of the a(2–3)-linked sialic acid. For the a(2–6)-

4946
D. Schwizer et al. / Bioorg. Med. Chem. 14 (2006) 4944–4957
HO
OH
OH
AcHN
COOH
O
HO
OH
O
HO
HO
HO
O
O
AcHN
HO
O
O
O
O
OH
AcHN
OH
O
OH
OH
O
COOH
OH
HO
O
HO
O
C13H27
HO
O
O
AcHN
HO
HN
C17H35
OH
O
OH
COOH
HO
O
HO
GQ1ba
O
AcHN
HO
COOH
OH
HO
OH
O
OH
H3C
OH
HN
HO
O
COONa
CH3
OH
OH
OH
O
O
HO
HO
HO
HO
O
HO
HO
O
O
O
O
HN
AcHN
O
O
O
OSE
O
O
OSE
OH
OH
NHAc
NHAc
OH
OH
H
OH
HO
HO
COONa
COONa
H
OH
OH
1
2
OH
OH
AcHN
HO
COONa
O
COONa
O
O
HO
HO
AcHN
OH
AcHN
O
O
O
O
OH
OH
HO
HO
COONa
COONa
OH
3
4
Figure 2. GQ1ba, bis-sialylated lead structure 1, reference compound 2, and biphenyl derivatives 3 and 4. In 1 the pharmacophores are indicated in
bold-face type.
With the second mimic, the contribution of the a(2–
6)-linked sialic acid was explored. Since its interaction
with MAG is limited to a lipophilic contact of the
N-acetyl group and a salt bridge formed by the
carboxylate, its replacement by (S)-phenyllactic acid
was envisaged (Fig. 2, mimic 4). Models for the
3D-structures of lead 1 and mimic 3 were generated
using MacroModel 5.0,22 optimized in aqueous
solution on the basis of the improved AMBER 4.0
force field for carbohydrates published by Still,23 and
partially modified by Kolb and Ernst.24 The superim-
position was performed manually with the PrGen soft-
ware.25 The illustrations were finally prepared with
SAMOAꢀ (Fig. 3).
26
For the synthesis of 3 and 4, a convergent approach
based on Suzuki coupling27 was anticipated. The build-
ing blocks for this approach, phenylhalides 8–10 and 12,
and the boronic esters 13 were obtained by standard
procedures.

D. Schwizer et al. / Bioorg. Med. Chem. 14 (2006) 4944–4957
4947
a
b
3
1
c
1 +3
Figure 3. Replacement of the Galb(1–3)GalNAc core of 1 by biphenyl; (a) 3D-structure of 1; (b) 3D-structure of 3; (c) superposition of the
3D-structure of 1 (red) and 3 (green).
31
Although phase transfer catalysis (PTC) proved to be a
valuable method for synthesizing the aryl galactosides
8a and 8b starting from the commercially available tet-
ra-O-acetyl-a-D-galactopyranosylbromide (5) (Scheme
1, Table 1), it gave unsatisfactory yields in the glucose
series due to a competing 1,2-elimination reaction.28
However, acceptable yields of the b-isomers 9a–c were
obtained by using BF3Æetherate as catalyst.29 The sialo-
sides 10a–c were prepared by PTC30 from sialylchloride
7. For the synthesis of the phenylbromide 12, benzyl
(R)-phenyllactate 11 was treated with 3-bromophenol
(Scheme 2) under Mitsunobu conditions.32
For the boronation of the phenylbromides 8a,b, 9a,b
and 10b (Scheme 1, Table 1), the procedure published
by Miyaura32,33,35 was optimized using microwave tech-
nique. The best results were obtained with PdCl2(dppf)
catalysis in the presence of additional dppf in dioxane.
RO
O
X1
O
O
RO
RO
KOAc, PdCl2(dppf)
O
O
5, 6 or 7
dppf, dioxane
A or B
+
O
O
O
O
X2
B
B
O
X2
B
HO
O
X2: Br, I
phenylhalides
8, 9 and 10
boronic esters
13
OAc
OAc
OAc
AcO
AcO
Cl
AcO
OAc
O
O
AcO
AcO
COOMe
O
OAc
AcHN
AcO
AcO
AcO
Br
5
6 [34]
7 [31]
Scheme 1. Synthesis of the reactants for the Suzuki coupling: phenylhalides and boronic esters. (See above-mentioned references for further
information).34

4948
D. Schwizer et al. / Bioorg. Med. Chem. 14 (2006) 4944–4957
Table 1. Synthesis of the reactants for the Suzuki coupling
Glycosyl donor
Glycosyl acceptor
Method
A
Phenylhalide
Yield (%)
77
Reaction conditions
Boronic ester
Yield (%)
89
5
8a, b
1.5 h, 120 ꢁC, lW
13a, b
HO
Br
Br
8b, b
9a, b
9b, b
9c, b
74
56
49
49
40
56
46
1.5 h, 120 ꢁC, lW
13b, b
13c, b
13d, b
—
86
80
89
—
—
85
—
HO
HO
6
B
2 h, 120 ꢁC, lW
Br
Br
2.25 h, 120 ꢁC, lW
HO
HO
—
I
7
A
10a, a
10b, a
10c, a
—
—
HO
Br
Br
0.75 h, 120 ꢁC, lW
13e, a
—
HO
HO
—
I
Method A, phase transfer catalysis starting from sugar halides; method B, Lewis acid-catalysis starting from peracetylated b-D-glucose.
OH
OBn
O
a)
b)
O
Br
O
B
O
OBn
OBn
O
O
O
11
12
13f
Scheme 2. Synthesis of the (S)-phenyl-lactic acid derivative 13f. Reagents and conditions: (a) PPh3, DEAD, THF, 3-bromophenol (66%); (b)
bis(picanolato)diborane, KOAc, PdCl2(dppf), dppf, dioxane, 80 ꢁC (66%).
The boronide 13f was obtained by standard procedures.
Finally, all boronides were purified by filtration through
a short silica column, although slight decomposition
could not be avoided.
not lead to improved yields. Also the addition of 2,6-di-
tert-butyl-p-cresol as a radical scavenger did not affect
the outcome of the reaction,37 Stronger bases like Cs2CO3
or Ag2CO3, however, had a significant impact on the
yields of Suzuki coupling with galactose and glucose
derivatives (see entries 2 and 7–9). With Ag2CO3, a 77%
yield of 16 was obtained (entry 14), whereas Cs2CO3 led
to the formation of various side products (entry 15). In
general, iodides gave slightly higher yields than the corre-
sponding bromides (entries 8 and 9 vs 2 and 7), and the use
of cesium carbonate resulted in shorter reaction times
compared to silver carbonate (entries 2 and 9 vs 7 and 8)
(Scheme 3).
In a first step, the Suzuki coupling leading to the biphenyl
derivative 14 was carefully optimized with the glucose
derivatives 9a,c and the boronic ester of galactose 13b.
(Table 2, entries 1–9). Initially, the influence of elevated
temperature (oil bath) and microwave irradiation on the
Suzuki coupling was compared in two test reactions (en-
tries 1 and 2). As expected,36 microwave irradiation gave
an improvement in the yield by more than 50% compared
to conventional heating. To prevent deprotection of the
reactants, mild bases like K3PO4 or NaHCO3 were initial-
ly used,27 However, only modest yields were obtained for
galactose or glucose derivatives (entries 3–6), and even
lower yields for the more sensitive sialic acid derivatives
10a–c (entries 10–13). Change of solvent (entry 6) or pro-
longed reaction times at lower temperature (entry 13) did
Deprotection of 14, 15, and 16 was performed under
´
standard Zemplen conditions to afford 3 (56%), 4
(52%), and 17 (91%). After transformation into the cor-
responding sodium salts, the biphenyls were purified by
filtration through a size-exclusion column (P-2) prior to
biological testing.

D. Schwizer et al. / Bioorg. Med. Chem. 14 (2006) 4944–4957
4949
Table 2. Microwave-assisted Suzuki coupling leading to the formation of the biphenyl core of 14, 15, and 16
Entries
Reactants
Pd-catalyst
Ligand
Base
Solvent
Time, conditions
Prod.
Yielda (%)
c
1
2
9a + 13b
Pd(PPh3)4
Pd(PPh3)4
—
—
Cs2CO3
Cs2CO3
NaHCO3
K3PO4
K3PO4
K3PO4
Ag2CO3
Ag2CO3
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
Ag2CO3
Cs2CO3
Dioxane
Dioxane
4.5 h, 120 ꢁCd
14
14
14
14
14
14
14
14
14
16
15
16
16
16
16
54
83
39
38
40
41
73
83
87
8
c
4.5 h, 120 ꢁC, lW
10 h, 150 ꢁC, lW
1.75 h, 170 ꢁC, lW
1.75 h, 170 ꢁC, lW
1.75 h, 170 ꢁC, lW
8 h, 120 ꢁC, lW
8 h, 120 ꢁC, lW
4.5 h, 120 ꢁC, lW
1.75 h, 170 ꢁC, lW
2.25 h, 170 ꢁC, lW
1.5 h, 170 ꢁC, lW
58.5 h, 100 ꢁC, lW
7 h, 120 ꢁC, lW
7 h, 120 ꢁC, lW
c
3
Pd(PPh3)4
—
H2O/dioxane
Dioxane
4
PdCl2(dppf)b
PdCl2(dppf)b
PdCl2(dppf)b
dppf
dppf
dppf
—
5
Dioxane/BHT
THF
Dioxane
6
c
7
Pd(PPh3)4
Pd(PPh3)4
c
8
9c + 13b
—
—
Dioxane
Dioxane
c
9
Pd(PPh3)4
10
11
12
13
14
15
10a + 13e
10b + 13f
10c + 13e
PdCl2(dppf)b
PdCl2(dppf)b
PdCl2(dppf)b
PdCl2(dppf)b
dppf
dppf
dppf
dppf
—
Dioxane/BHT
Dioxane/BHT
Dioxane/BHT
Dioxane/BHT
Dioxane
28
10
12
77
11
b
Pd(PPh3)4
Pd(PPh3)4
c
—
Dioxane
a Isolated yield.
b 0.03 equiv of the catalyst was used.
c 0.01 equiv of the catalyst was used.
d Reaction heated in oil-bath.
RO
RO
O
OR
OR
OR
O
RO
RO
Pd-catalyst, ligand
base, solvent
O
O
9a,c + 13b
(table 2)
OR
14, R=Ac
17, R=H
a)
CO2R3
O
R1O
OR1
Pd-catalyst, ligand
base, solvent
AcHN
R1O
O
O
10b + 13f
COOR2
(table 2)
OR1
15, R1=Ac, R2=Me, R3=Bn
4, R1=H, R2=Na
b)
OR1
OR1
OR1
AcHN
R1O
O
CO2R2
O
R1O
OH
AcHN
R1O
O
O
Pd-catalyst, ligand,
base, solvent
COOR2
OR1
10a,c + 13e
(table 2)
16, R1=Ac, R2=Me
3, R1=H, R2=Na
b)
Scheme 3. Reagents and conditions: (a) 1 M NaOMe, MeOH, 17 h, rt (91%); (b) i—1 M NaOMe, MeOH, 17 h, rt, ii—addition of H2O, 6 h, rt,
iii—Dowex 50 · 8 (Na+), 3, 52%; 4, 56%.

4950
D. Schwizer et al. / Bioorg. Med. Chem. 14 (2006) 4944–4957
Table 3. Rel. inhibitory potencies (rIP) and C log P values36 of parent
compound 1, reference 2, and mimics 3 and 4
bioavailability of 3 and 4, that is, C log P, could decisively
be improved by six and ten orders of magnitude, respec-
tively, compared to the parent tetrasaccharide 1 (Table
3). A further important issue to be addressed is the meta-
bolic stability of the presented sialosides. In general, the
substrate specificity of sialidases from mammalian tissues
is determined by the type of bond at the terminal sialic
acid residue (2–3, 2–6 or 2–8) and does not depend on
the structure of the glycoconjugate chain.40 Therefore, it
cannot be excluded that the presented mimics 3 and 4
are cleaved metabolically by sialidases.
Compound
1
2a
1.0
ꢀ5.54
3
4
rIP
C log P36
3.30
ꢀ8.91
1.38
ꢀ2.55
0.91
+1.68
a Compound 238 was used as reference compound with a relative rIP
of 1.
For the biological evaluation, a competitive target-based
assay was used.15,17 The relative inhibitory potentials
(rIP) of mimics 3 and 4 were determined in microtiter
plates containing covalently attached sialic acids. To
determine the bound MAG, the Fc-part of MAG was
complexed with alkaline phosphatase-labeled anti-Fc
antibodies. The amount of MAG bound to the sialylat-
ed plates was then determined by the initial velocity of
fluorescein release from fluorescein diphosphate. The
affinities were determined relative to trisaccharide 2,38
which was used as a standard compound, and has a
relative inhibitory potency (rIP) of 1.
The data presented in this study constitute an important
step toward the development of potent and drug-like oli-
gosaccharide mimics. A further optimization of the core
replacement by modified biphenyls and phenoxyphenyls
is currently being investigated.
4. Experimental
4.1. General
The rIP of compound 3 is less (1.38) than that of its tet-
rasaccharide counterpart 1 (3.3). However, compound 3
is still more active than the reference trisaccharide 2.
Replacement of the a(2–6)-linked sialic acid with (S)-
phenyllactic acid results in a lower biological activity
in comparison to 3. The decline in potency of com-
pounds 3 and 4 can be rationalized by a spacial shift
Optical rotations were measured at 21 ꢁC on a Perkin-
Elmer 241 polarimeter with a path length of 1 dm. Con-
centrations are given in g/100 ml. NMR spectra were ob-
tained on a Bruker Avance 500 Ultra Shield in CDCl3,
D2O or CD3OD with either solvent peak (H1 NMR:
CDCl3 7.26 ppm, CD3OD 3.31 ppm, D2O 4.79 ppm;
13C NMR: CDCl3 77.0 ppm, CD3OD 49.0 ppm) or
dioxane (13C NMR: 67.2 ppm) as an internal reference.
Infrared spectra were recorded on a Perkin-Elmer
FT-IR spectrometer. Microwave-assisted reactions were
carried out with CEM Discover and Explorer. Electron
spray ionization mass spectra (ESI-MS) were obtained
on a Waters micromass ZQ. Reactions were monitored
by TLC using glass plates coated with silica gel 60 F254
(Merck) and visualized by using UV light and/or by
charring with Mostain (a 0.02 M solution of ammonium
cerium sulfate dihydrate and ammonium molybdate tet-
rahydrate in aqueous 10% H2SO4). Column chromato-
graphy was performed on Fluka silica gel C60 40/60
or Merck LiChroprepꢂ RP-18 40/60. Methanol (MeOH)
and dioxane were dried by refluxing with sodium meth-
oxide and sodium, respectively, and distilled immediate-
ly before use. Dimethylformamide (DMF) and
dimethylsulfoxide (DMSO) were freshly distilled from
CaH2. Dichloromethane (CH2Cl2), toluene, and tetra-
hydrofurane (THF) were dried by filtration over Al2O3
(Fluka, type 5016A basic).
˚
of ca. 1 A for the carboxylate of the a(2–6)-linked sialic
acid and the (S)-phenyllactic acid (see Fig. 3), when
compared to its original position in the tetrasaccharide
1. However, the ease of synthesis and the assumed
improvement in the pharmacokinetic properties of com-
pounds 3 and 4 (for C log P,39 see Table 3) may counter-
vail the modest increase in potency for mimic 3 and the
decrease in biological activity for compound 4.
3. Conclusions
Two mimics of the tetrasaccharide Siaa(2–3)Galb(1–
3)[Siaa(2–6)]GalNAc (1) were prepared. Based on STD
data17 and molecular modeling considerations,20 the
core disaccharide Galb(1–3)GalNAc was substituted
with a biphenyl moiety. Employing Suzuki coupling, a
convergent synthesis of the biphenyl structures 3 and 4
could be achieved. To improve the yields of the coupling
reaction, the catalytic effect of microwave irradiation
and conventional heating was compared.
4.2. 30-Bromophenyl 2,3,4,6-tetra-O-acetyl-b-D-galacto-
pyranoside (8a)
The biological evaluation of mimics 3 and 4 was per-
formed in a competitive target-based assay. It was found
that the rIP of antagonist 3 was clearly enhanced com-
pared to that of the reference trisaccharide 2, despite the
former having a much simpler structure. Mimics 4, how-
ever, showed an rIP similar to the reference compound,
indicating that the (S)-phenyllactate moiety is only
incompletely mimicking the a(2–6)-linked sialic acid.
At room temperature, NaOH (1.25 M, 10 ml) was added
to a stirred solution of 2,3,4,6-tetra-O-acetyl-a-D-galac-
topyranosylbromide (5) (2.00 g, 4.86 mmol), benzyltri-
ethylammonium bromide (1.11 g, 4.07 mmol), and 3-
bromophenol (1.68 g, 9.73 mmol) in CH2Cl2 (80 ml).
The reaction mixture was refluxed for 4 h at 40 ꢁC.
The layers were separated and the aqueous layer was
extracted with CH2Cl2 (2· 40 ml). The combined organ-
ic layers were then washed with NaOH (1.25 M, 4·
In addition to the improved synthetic feasibility, a benefi-
cial change in the pharmacokinetic properties of both
mimics could be achieved. Thus, a critical parameter for

D. Schwizer et al. / Bioorg. Med. Chem. 14 (2006) 4944–4957
4951
30 ml) and water (30 ml), and dried over Na2SO4. The
solvent was rotavaped off to yield 8a (1.89 g, 77%),
which was used in the Suzuki coupling without further
purification.
C(O)CH3), 3.89 (ddd, J = 2.4, 6.0, 10.0 Hz, 1H, H-5),
4.19 (dd, J = 2.4, 12.3 Hz, 1H, H-6a), 4.25 (dd, J = 6.0,
12.3 Hz, 1H, H-6b), 5.06 (d, J = 7.5 Hz, 1H, H-1), 5.14
(m, 1H, H-4), 5.26 (dd, J = 7.5, 9.3 Hz, 1H, H-2), 5.30
(m, 1H, H-3), 6.91–6.93, 7.14–7.22 (m, 4H, C6H4); 13C
NMR (CDCl3, 125.8 MHz) d: 20.6, 20.6, 20.7 (4
C(O)CH3), 62.0 (C-6), 68.3 (C-4), 71.0 (C-2), 72.2 (C-
5), 72.6 (C-3), 98.8 (C-1), 116.0 (aromat. C–Br), 120.1,
122.7, 126.4, 130.7 (aromat. C–H), 157.4 (aromat. C–
O), 169.3, 169.4, 170.6 (4 C@O); IR (KBr) m: 3474,
2969, 1752 (C@O), 1589, 1475, 1434, 1370, 1228,
21
D
½aꢁ
+1.0 (c 0.64, CHCl3); 1H NMR (CDCl3,
500.1 MHz) d: 2.01, 2.07, 2.09, 2.18 (4 s, 12H, 4
C(O)CH3), 4.08 (m, 1H, H-5), 4.20 (m, 2H, H-6a,b),
5.02 (d, J = 7.9 Hz, 1H, H-1), 5.48 (m, 1H, H-4), 5.48
(dd, J = 7.9, 10.4 Hz, 1H, H-2), 5.10 (dd, J = 3.5,
10.4 Hz, 1H, H-3), 6.92–7.22 (m, 4H, C6H4); 13C
NMR (CDCl3, 125.8 MHz) d: 20.6, 20.6, 20.7 (4
C(O)CH3), 61.6 (C-6), 66.9 (C-4), 68.5 (C-2), 70.7 (C-
3), 71.3 (C-5), 99.4 (C-1), 115.9 (aromat. C–Br), 120.0,
122.7, 126.4, 130.7 (aromat. C–H), 157.4 (aromat. C–
O), 169.3, 170.1, 170.2, 170.5 (4 C@O); IR (KBr) m:
3469, 2982, 1752 (C@O), 1590, 1477, 1429, 1371, 1227,
1063 cmꢀ1
.
4.5. 40-Bromophenyl 2,3,4,6-tetra-O-acetyl-b-D-glucopyr-
anoside (9b)
Penta-O-acetyl-b-D-glucopyranose (6) (601 mg, 1.54 mmol)
was treated with 4-bromophenol (293 mg, 1.69 mmol)
and BF3ÆEt2O (20.5 ll, 0.154 mmol) according to the
procedure for 9a. The residue was purified by flash chro-
matography (petroleum ether/EtOAc, 4:1 to 2:1) to
afford 9b (383 mg, 49%) as a colorless solid.
1080 cmꢀ1
.
4.3. 40-Bromophenyl 2,3,4,6-tetra-O-acetyl-b-D-galacto-
pyranoside (8b)
2,3,4,6-Tetra-O-acetyl-a-D-galactopyranosylbromide (5)
(0.540 g, 1.31 mmol) was treated with 4-bromophenol
(0.455 g, 2.63 mmol), benzyltriethylammonium bromide
(0.298 g, 1.09 mmol), and NaOH (1.25 M, 2.71 ml)
according to the above procedure to afford the colorless
solid 8b (489 mg, 74%).
21
D
½aꢁ
ꢀ16.8 (c 0.54, CHCl3); 1H NMR (CDCl3,
500.1 MHz) d: 2.03, 2.05, 2.06, 2.08 (4 s, 12H, 4
C(O)CH3), 3.85 (ddd, J = 2.4, 5.4, 9.9 Hz, 1H, H-5),
4.16 (dd, J = 2.4, 12.3 Hz, 1H, H-6a), 4.28 (dd, J = 5.4,
12.3 Hz, 1H, H-6b), 5.03 (d, J = 7.4 Hz, 1H, H-1), 5.16
(m, 1H, H-4), 5.25 (m, 1H, H-2), 5.28 (m, 1H, H-3),
6.87–6.89, 7.39–7.41 (m, 4H, C6H4); 13C NMR (CDCl3,
125.8 MHz) d: 20.6, 20.6, 20.7 (4 C(O)CH3), 61.9 (C-6),
68.2 (C-4), 71.1 (C-3), 72.1 (C-5), 72.6 (C-2), 99.1 (C-1),
115.9 (aromat. C–Br), 118.8 (2 aromat. C–H), 132.5 (2
aromat. C–H), 155.8 (aromat. C–O), 169.4, 170.2,
170.5 (4 C@O); IR (KBr) m: 3482, 2960, 1749 (C@O),
21
D
½aꢁ
+5.7 (c 0.56, CHCl3); 1H NMR (CDCl3,
500.1 MHz) d: 2.01, 2.06, 2.07, 2.18 (4s, 12H, 4
C(O)CH3), 4.05 (m, 1H, H-5), 4.15 (dd, J = 6.2,
11.4 Hz, 1H, H-6a), 4.22 (dd, J = 7.0, 11.4 Hz, 1H, H-
6b), 4.99 (d, J = 8.0 Hz, 1H, H-1), 5.10 (dd, J = 3.4,
10.4 Hz, 1H, H-3), 5.45 (m, 1H, 4-H), 5.48 (dd,
J = 8.0, 10.4, 1H, H-2), 6.88–6.90, 7.39–7.41 (m, 4H,
C6H4); 13C NMR (CDCl3, 125.8 MHz) d: 20.6, 20.7,
20.7 (4 C(O)CH3), 61.3 (C-6), 66.8 (4 C(O)CH3), 68.5
(C-2), 70.7 (C-3), 71.1 (C-5), 99.6 (C-1), 115.9 (aromat.
C–Br), 118.8 (2 aromat. C–H), 132.5 (2 aromat. C–H),
164.0 (aromat. C–O), 170.3 (4 C@O); IR (KBr) m:
3482, 2983, 1753 (C@O), 1582, 1488, 1432, 1371, 1228,
1490, 1441 1378, 1235, 1055 cmꢀ1
.
4.6. 30-Iodophenyl 2,3,4,6-tetra-O-acetyl-b-D-glucopyr-
anoside (9c)
Penta-O-acetyl-b-D-glucopyranose (6) (501 mg, 1.28 mmol)
was treated with 3-iodophenol (311 mg, 1.41 mmol)
and BF3ÆEt2O (17.1 ll, 0.136 mmol) according to the
procedure for 9a. The crude product was purified by
flash chromatography (petroleum ether/EtOAc, 4:1 to
2:1) to afford 9c (344 mg, 49%) as a colorless solid.
1165, 1067 cmꢀ1
.
4.4. 30-Bromophenyl 2,3,4,6-tetra-O-acetyl-b-D-glucopyr-
anoside (9a)
21
D
To a stirred solution of penta-O-acetyl-b-D-glucose (6)
(0.601 g, 1.54 mmol) and 3-bromophenol (0.292 g,
1.69 mmol) in toluene (5 ml) under argon, BF3ÆEt2O
(20.5 ll, 0.154 mmol) was added. The reaction was stir-
red at room temperature for 48 h and then diluted with
toluene (5 ml) and quenched with water (10 ml). The
layers were separated and the aqueous layer was extract-
ed with toluene (3· 20 ml). The combined organic layers
were then washed with NaOH (1.25 M, 2· 20 ml) and
water (20 ml), dried over Na2SO4, and concentrated.
The residue was purified by flash chromatography
(petroleum ether/EtOAc, 5:1 to 2:1) to yield 9a
(437 mg, 56%) as a white foam.
½aꢁ
ꢀ16.4 (c 0.59, CHCl3); 1H NMR (CDCl3,
500.1 MHz) d: 2.03, 2.05, 2.06, 2.12 (4 s, 12H, 4
C(O)CH3), 3.88 (ddd, J = 2.4, 5.9, 10.0 Hz, 1H, H-
5), 4.18 (dd, J = 2.4, 12.3 Hz, 1H, H-6a), 4.25 (dd,
J = 5.9, 12.3 Hz, 1H, H-6b), 5.06 (d, J = 7.5 Hz, 1H,
H-1), 5.13 (m, 1H, H-4), 5.25 (dd, J = 7.6, 9.3 Hz,
1H, H-2), 5.29 (m, 1H, H-3), 6.94–7.42 (m, 4H,
C6H4); 13C NMR (CDCl3, 125.8 MHz) d: 20.6, 20.6,
20.8 (4 C(O)CH3), 62.0 (C-6), 68.2 (C-4), 71.0 (C-
2), 72.2 (C-5), 72.6 (C-3), 94.1 (aromat. C–I), 98.8
(C-1), 116.6, 125.9, 130.9, 132.5 (aromat. C), 157.1
(aromat. C–O), 169.4, 170.2, 170.6 (4 C@O); IR
(KBr) m: 3474, 2960, 1759 (C@O), 1585, 1474, 1369,
1226, 1039 cmꢀ1; Anal. Calcd for C20H23O10I: C,
43.65; H, 4.21; O, 29.07. Found: C, 43.82; H, 4.22;
O, 29.18.
21
D
½aꢁ
ꢀ15.4 (c 0.80, CHCl3); 1H NMR (CDCl3,
500.1 MHz) d: 2.03, 2.05, 2.07, 2.11 (4 s, 12H, 4

4952
D. Schwizer et al. / Bioorg. Med. Chem. 14 (2006) 4944–4957
4.7. Methyl (30-bromophenyl 5-acetamido-4,7,8,9-tetra-
O-acetyl-3,5-dideoxy-D-glycero-a-D-galacto-2-nonulopyr-
anosid)onate (10a)
O), 167.9, 170.0, 170.1, 170.2, 170.6, 170.9 (6 C@O); IR
(KBr) m: 3381, 3073, 2961, 1748 (C@O), 1663 (N–C@O),
1542, 1486, 1371, 1220, 1131, 1040 cmꢀ1; Anal. Calcd
for C26H32NO13Br: C, 48.31; H, 4.99; N, 2.17. Found:
C, 48.13; H, 4.75; N, 2.03.
NaOH (0.2 M, 75 ml) was added to a stirred solution
of methyl 2-deoxy-2-chloro-4,7,8,9-tetra-O-acetyl-N-
acetyl-neuraminidate (7) (1.47 g, 2.88 mmol), benzyltrie-
thylammonium bromide (1.73 g, 6.35 mmol), and 3-bro-
mophenol (2.49 g, 14.4 mmol) in CH2Cl2 (60 ml). The
mixture was refluxed for 2.5 h at 40 ꢁC. The layers were
separated and the aqueous layer was extracted with
CH2Cl2 (3· 20 ml). The combined organic layers were
washed with NaOH (0.2 M, 2· 40 ml) and water
(20 ml), and dried over Na2SO4. The solvent was re-
moved at high vacuo and the residue was purified by
flash chromatography (CH2Cl2/MeOH, 80:1 to 16:1) to
yield 10a (738 mg, 40%) as a white foam.
4.9. Methyl (30-iodophenyl 5-acetamido-4,7,8,9-tetra-O-
acetyl-3,5-dideoxy-D-glycero-a-D-galacto-2-nonulopyr-
anosid)onate (10c)
Methyl 2-deoxy-2-chloro-4,7,8,9-tetra-O-acetyl-N-ace-
tyl-neuraminidate (7) (0.670 g, 1.31 mmol) was treated
with 3-iodophenol (1.46 g, 6.64 mmol), benzyltriethyl-
ammonium bromide (0.797 g, 2.93 mmol), and NaOH
(0.2 M, 34 ml) according to the procedure for 10a. The
residue was purified by flash chromatography
(CH2Cl2/MeOH, 1:0 to 25:1) to afford 10c (442 mg,
46%) as a colorless solid.
21
D
½aꢁ
+12.1 (c 0.61, CHCl3); 1H NMR (CDCl3,
21
D
500.1 MHz) d: 1.91, 2.04, 2.05, 2.13, 2.14 (5 s, 15H, 5
C(O)CH3), 2.18 (m, 1H, H-3ax), 2.67 (dd, J = 4.7,
13.0 Hz, 1H, H-3eq), 3.70 (s, 3H, OCH3), 4.06 (m, 1H,
H-5), 4.18 (dd, J = 4.6, 12.5 Hz, 1H, H-9a), 4.31 (dd,
J = 2.2, 12.5 Hz, 1H, H-9b), 4.36 (dd, J = 1.0, 10.6 Hz,
1H, H-6), 4.97 (m, 1H, H-4), 5.22 (d, J = 10.0 Hz, 1H,
NH), 5.33 (m, 1H, H-7), 5.36 (m, 1H, H-8), 7.04–7.24
(m, 4H, C6H4); 13C NMR (CDCl3, 125.8 MHz) d:
20.8, 20.8, 20.8, 21.0, 23.2 (5 C(O)CH3), 37.7 (C-3),
49.4 (C-5), 53.1 (OCH3), 62.0 (C-9), 67.3 (C-7), 68.6
(C-4), 69.1 (C-8), 73.4 (C-6), 100.0 (C-2), 118.8, 122.3,
124.0, 127.4, 130.5 (aromat. C), 154.2 (aromat. C–O),
167.8, 170.0, 170.0, 170.2, 170.6, 170.9 (6 C@O); IR
(KBr) m: 3374, 3070, 2960, 1748 (C@O), 1666 (N–
C@O), 1586, 1542, 1472, 1434, 1370, 1218, 1131,
1040 cmꢀ1; Anal. Calcd for C26H32NO13Br: C, 48.31;
H, 4.99; N, 2.17. Found: C, 48.27; H, 4.79; N, 2.39.
½aꢁ
+19.9 (c 0.54, CHCl3); 1H NMR (CDCl3,
500.1 MHz) d: 1.91, 2.04, 2.05, 2.13, 2.14 (5 s, 15H, 5
C(O)CH3), 2.17 (m, 1H, H-3ax), 2.67 (dd, J = 4.7,
13.0 Hz, 1H, H-3eq), 3.70 (s, 3H, OCH3), 4.06 (m, 1H,
H-5), 4.18 (dd, J = 4.6, 12.4 Hz, 1H, H-9a), 4.31 (m,
1H, H-9b), 4.35 (dd, J = 0.9, 10.8 Hz, 1H, H-6), 4.96
(ddd, J = 4.6, 10.4, 12.0 Hz, 1H, H-4), 5.22 (d,
J = 10.0 Hz, 1H, NH), 5.35 (m, 2H, H-7, H-8), 6.99–
7.44 (m, 4H, C6H4); 13C NMR (CDCl3, 125.8 MHz) d:
20.3, 20.8, 20.8, 21.0, 23.2 (5 C(O)CH3), 37.7 (C-3),
49.4 (C-5), 53.1 (OCH3), 61.9 (C-9), 67.3 (C-7), 68.6
(C-4), 69.1 (C-8), 73.4 (C-6), 100.0 (C-2), 93.6 (aromat
C–I), 119.5, 129.9, 130.8, 133.3 (4 aromat C), 153.9 (aro-
mat C–O), 167.8, 170.0, 170.0, 170.2, 170.9 (6 C@O); IR
(KBr) m: 3373, 3067, 2959, 1748 (C@O), 1665 (N–C@O),
1580, 1468, 1436, 1371, 1219, 1131, 1040 cmꢀ1; ESI-MS
Calcd. for C26H33INO13 [M+H+]: 694.1; Found: 694.1.
4.8. Methyl (40-bromophenyl 5-acetamido-4,7,8,9-tetra-
O-acetyl-3,5-dideoxy-D-glycero-a-D-galacto-2-nonulopyr-
anosid)onate (10b)
4.10. Benzyl (S)-2-(30-bromophenoxy)-3-phenylpropano-
ate (12)
To a cooled (0 ꢁC) solution of benzyl D-3-phenyllactate
Methyl 2-deoxy-2-chloro-4,7,8,9-tetra-O-acetyl-N-ace-
tyl-neuraminidate (7) (2.00 g, 3.92 mmol) was treated
with 4-bromophenol (3.40 g, 19.7 mmol), benzyltriethy-
lammonium bromide (2.35 g, 8.63 mmol), and NaOH
(0.2 M, 100 ml) according to the procedure for 10a.
The residue was purified by flash chromatography
(CH2Cl2/MeOH, 80:1 to 20:1) to afford 10b (1.43 g,
56%) as a colorless solid.
(420 mg,
2.55 mmol),
1.64 mmol), 3-bromophenol
and triphenylphosphine
(441 mg,
(643 mg,
2.45 mmol) in THF was added diethylazodicarboxylate
(382 ll, 2.46 mmol). The mixture was stirred at room
temperature for 2 12 h. The solvent was evaporated in
vacuo and the resulting residue was suspended in
20 ml of hexane and diethyl ether (1:1), and then filtered.
The triphenylphosphine oxide crystals were thoroughly
washed with a hexane-diethyl ether-mixture (60 ml,
1:1). The filtrate was washed with 0.6 M NaOH (2·
15 ml) and water (15 ml), dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by flash chro-
matography (toluene/petroleum ether, 1:1 to 2:1) to give
448 mg (66%, 1.09 mmol) of crystalline 12.
21
D
½aꢁ
+6.4 (c 0.51, CHCl3); 1H NMR (CDCl3,
500.1 MHz) d: 1.91, 2.04, 2.05, 2.13, 2.15 (5 s, 15H, 5
C(O)CH3), 2.21 (m, 1H, H-3ax), 2.70 (dd, J = 4.6,
13.0 Hz, 1H, H-3eq), 3.65 (s, 3H, OCH3), 4.08 (m, 1H,
H-5), 4.14 (dd, J = 4.9, 12.5 Hz, 1H, H-9a), 4.27 (m,
1H, H-9b), 4.43 (m, 1H, H-6), 4.94 (ddd, J = 4.6, 10.4,
12.2 Hz, 1H, H-4), 5.21 (d, J = 10.0 Hz, 1H, NH), 5.35
(m, 1H, H-7), 5.36 (m, 1H, H-8), 6.94–6.95, 7.37–7.39
(m, 4H, C6H4); 13C NMR (CDCl3, 125.8 MHz) d:
20.8, 20.8, 20.8, 21.0, 23.2 (5 C(O)CH3), 38.3 (C-3),
49.4 (C-5), 53.1 (OCH3), 62.0 (C-9), 67.2 (C-7), 68.6
(C-4), 68.9 (C-8), 73.4 (C-6), 100.0 (C-2), 116.7 (aromat.
C–Br), 121.5, 132.3 (4 aromat. C–H), 152.9 (aromat. C–
21
D
½aꢁ
+17.3 (c 0.53, CHCl3); 1H NMR (CDCl3,
500.1 MHz) d: 3.22–3.24 (m, 2H, H-3), 4.81 (dd,
J = 5.7, 7.4 Hz, 1H, H-2), 5.10–5.17 (m, 2H, H-10),
6.71–6.73, 6.98–7.08 (m, 4H, C6H4), 7.19–7.34 (m,
10H, 2· C6H5); 13C NMR (CDCl3, 125.8 MHz) d: 38.9
(C-3), 67.2 (C-10), 77.9 (C-2), 114.0, 118.9, 123.4,
124.9, 127.1, 128.4, 128.5, 128.6, 129.4, 130.6 (15

D. Schwizer et al. / Bioorg. Med. Chem. 14 (2006) 4944–4957
4953
aromat. C), 135.0, 135.9 (2 aromat. C–C), 158.3 (aro-
mat. C–O), 170.5 (C-1); IR (KBr) m: 3464, 3062, 3031,
2961, 2925, 1743 (C@O), 1585, 1470, 1454, 1388, 1357,
11.4 Hz, 1H, H-6b), 5.09 (d, J = 8.0 Hz, 1H, H-1), 5.11
(dd, J = 3.4, 10.5 Hz, 1H, H-3), 5.41 (m, 1H, H-4),
5.50 (dd, J = 7.9, 10.5 Hz, 1H, H-2), 6.97–6.99, 7.75–
7.76 (m, 4H, C6H4); 13C NMR (CDCl3, 125.8 MHz) d:
20.6, 20.7, 20.7, 20.7 (4 C(O)CH3), 24.8, 24.8 (2
C(CH3)2), 61.5 (C-6), 66.9 (C-4), 68.6 (C-2), 70.8 (C-
3), 71.1 (C-5), 83.8 (2 C(CH3)2), 99.1 (C-1), 115.9 (2 aro-
mat. C–H), 136.5 (2 aromat. C–H), 159.3 (aromat. C–
O), 169.4, 170.1, 170.2, 170.4 (4 C@O); IR (KBr) m:
3475, 2981, 2937, 1755 (C@O), 1605, 1575, 1514, 1364,
1280, 1232, 1198, 1172, 1061 cmꢀ1
.
4.11. General procedure for the preparation of boronides
A microwave tube was charged with the appropriate
phenylbromide (1 mmol), potassium acetate (3 mmol),
bis(picanolato)diborane
(1.2 mmol),
PdCl2(dppf)
(3 mol%), and dppf (3 mol%). The tube was closed,
evacuated through a needle, and flushed with argon.
Dioxane (2.5 ml) was added with vigorous stirring.
The solvent was degassed in an ultrasonic bath for
15 min and flushed with argon for another 5 min. The
tube was heated by microwave irradiation to 120 ꢁC
for 1.5 to 2.25 h. The solvent was evaporated in vacuo
and the residue dissolved in CH2Cl2 (50 ml), washed
with brine (2· 25 ml), dried (Na2SO4), and concentrated.
The residue was purified by flash chromatography.
1322 (B-O), 1229, 1166, 1144, 1076 cmꢀ1
.
4.14. 30-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-
phenyl 2,3,4,6-tetra-O-acetyl-b-D-glucopyranoside (13c)
Phenylbromide 9a (100 mg, 0.199 mmol) was treated
with bis(picanolato)diborane (60.9 mg, 0.240 mmol) fol-
lowing the general procedure (lW, 120 ꢁC, 2 h). The res-
idue was purified by flash chromatography (toluene/
ethyl acetate, 7:1) to afford 87.9 mg (80%, 0.160 mmol)
of 13c as a colorless solid.
4.12. 30-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-
phenyl 2,3,4,6-tetra-O-acetyl-b-D-galactopyranoside
(13a)
21
D
½aꢁ
ꢀ12.4 (c 0.76, CHCl3); 1H NMR (CDCl3,
500.1 MHz) d: 1.33 (s, 12H, 4 CH3), 2.01, 2.07,
2.07, 2.19 (4 s, 12H, 4 C(O)CH3), 4.09 (m, 1H, H-
5), 4.17 (dd, J = 6.0, 11.3 Hz, 1H, H-6a), 4.22 (dd,
J = 7.2, 11.3 Hz, 1H, H-6b), 5.11 (d, J = 8.0 Hz, 1H,
H-1), 5.12 (m, 1H, H-4), 5.46 (m, 1H, H-2), 5.50
(dd, 1H, J = 7.9, 10.5 Hz, H-3), 7.09–7.53 (m, 4H,
C6H4); 13C NMR (CDCl3, 125.8 MHz) d: 20.6, 20.6,
20.7, 20.7 (4 C(O)CH3), 24.8, 24.9 (2 C(CH3)2),
62.0 (C-6), 68.3 (C-4), 71.2 (C-2), 72.0 (C-5), 72.8
(C-3), 84.0 (2 C(CH3)2), 98.9 (C-1), 120.1, 122.4,
129.1, 129.8 (4 aromat. C–H), 156.3 (aromat. C–O),
170.7 (4 C@O); IR (KBr) m: 3475, 2981, 1760
(C@O), 1577, 1492, 1433, 1357, 1322 (B-O), 1224,
Phenylbromide 8a (103 mg, 0.204 mmol) was treated
with bis(picanolato)diborane (60.6 mg, 0.239 mmol) fol-
lowing the general procedure (lW, 120 ꢁC, 1.5 h). The
residue was purified by flash chromatography (toluene/
ethyl acetate, 5:1) to afford 100 mg (89%, 0.182 mmol)
of 13a as a colorless solid.
21
D
½aꢁ
+1.3 (c 0.54, CHCl3); 1H NMR (CDCl3,
500.1 MHz) d: 1.33 (s, 12H, 4 CH3), 2.03, 2.05, 2.06,
2.08 (4 s, 12H, 4 C(O)CH3), 3.89 (ddd, J = 2.3, 5.5,
10.0 Hz, 1H, H-5), 4.16 (dd, J = 2.3, 12.3 Hz, 1H, H-
6a), 4.28 (dd, J = 5.5, 12.3 Hz, 1H, H-6b), 5.14 (d,
J = 7.5 Hz, 1H, H-1), 5.17 (m, 1H, H-3), 5.26–5.32 (m,
2H, H-2, H-4), 7.08–7.52 (m, 4H, C6H4); 13C NMR
(CDCl3, 125.8 MHz) d: 20.6, 20.7, 20.7, 20.6 (4
C(O)CH3), 24.8, 24.9 (2 C(CH3)2), 61.5 (C-6), 67.0 (C-
4), 68.7 (C-2), 70.9 (C-3), 71.0 (C-5), 84.0 (2 C(CH3)2),
99.4 (C-1), 120.2, 122.3, 129.0, 129.8 (4 aromat. C–H),
156.4 (aromat. C–O), 169.4, 170.1, 170.3, 170.4 (4
C@O); IR (KBr) m: 3444, 2981, 2937, 1753 (C@O),
1577, 1491, 1431, 1372, 1356, 1321 (B-O), 1225, 1145,
1145, 1046 cmꢀ1
.
4.15. 40-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-
phenyl 2,3,4,6-tetra-O-acetyl-b-D-glucopyranoside (13d)
Phenylbromide 9b (101 mg, 0.201 mmol) was treated
with bis(picanolato)diborane (60.4 mg, 0.238 mmol) fol-
lowing the general procedure (lW, 120 ꢁC, 2.25 h). The
residue was purified by flash chromatography (toluene/
ethyl acetate, 5:1) to afford 98.2 mg (89%, 0.178 mmol)
of 13d as a colorless solid.
1078 cmꢀ1
.
21
D
4.13. 40-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-
phenyl 2,3,4,6-tetra-O-acetyl-b-D-galactopyranoside
(13b)
½aꢁ
ꢀ9.6 (c 0.69, CHCl3); 1H NMR (CDCl3,
500.1 MHz) d: 1.33 (s, 12H, 4 CH3), 2.03, 2.04, 2.05,
2.08 (4 s, 12H, 4 C(O)CH3), 3.89 (ddd, J = 2.3, 5.6,
10.0 Hz, 1H, H-5), 4.16 (dd, J = 2.2, 12.3 Hz, 1H,
H-6a), 4.27 (dd, J = 5.5, 12.3 Hz, 1H, H-6b), 5.12 (d,
J = 7.5 Hz, 1H, H-1), 5.15 (m, 1H, H-4), 5.26–5.32
(m, 2H, H-2, H-3), 6.96–6.98, 7.74–7.76 (m, 4H,
C6H4); 13C NMR (CDCl3, 125.8 MHz) d: 20.6, 20.6,
20.7 (4 C(O)CH3), 24.8 (2 C(CH3)2), 62.0 (C-6), 68.3
(C-4), 71.1 (C-2), 72.1 (C-5), 72.7 (C-3), 83.8 (2
C(CH3)2), 98.6 (C-1), 115.9 (2 aromat. C–H), 136.5
(2 aromat. C–H), 159.3 (aromat. C–O), 169.4, 170.2,
170.6 (4 C@O); IR (KBr) m: 3476, 2980, 1748
(C@O), 1605, 1366, 1323 (B-O), 1231, 1143,
Phenylbromide 8b (102 mg, 0.203 mmol) was treated
with bis(picanolato)diborane (61.0 mg, 0.240 mmol) fol-
lowing the general procedure (lW, 120 ꢁC, 1.5 h). The
residue was purified by flash chromatography (toluene/
ethyl acetate, 4:1) to afford 95.6 mg (86%, 0.174 mmol)
of 13b as a colorless solid.
21
D
½aꢁ
+6.6 (c 0.56, CHCl3); 1H NMR (CDCl3,
500.1 MHz) d: 1.33 (s, 12H, 4 CH3), 2.01, 2.05, 2.07,
2.18 (4 s, 12H, 4 C(O)CH3), 4.09 (m, 1H, H-5), 4.17
(dd, J = 6.0, 11.4 Hz, 1H, H-6a), 4.21 (dd, J = 7.3,
1062 cmꢀ1
.

4954
D. Schwizer et al. / Bioorg. Med. Chem. 14 (2006) 4944–4957
4.16. Methyl [40-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-phenyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dide-
oxy-D-glycero-a-D-galacto-2-nonulopyranosid]onate (13e)
needle, and flushed with argon. Dioxane (1 ml) was add-
ed under vigorous stirring. The solvent was degassed in
ultrasonic bath for 20 min and flushed with argon for
another 10 min. The tube was heated by microwave irra-
diation to 120 ꢁC for an appropriate time. The solvent
was evaporated in vacuo. The residue was dissolved in
CH2Cl2 (20 ml), washed twice with brine (2· 30 ml),
dried (Na2SO4), and concentrated in vacuo. The residue
was purified by flash chromatography to yield the corre-
sponding biphenyl.
Phenylbromide 10b (251 mg, 0.388 mmol) was treated
with bis(picanolato)diborane (118 mg, 0.465 mmol) fol-
lowing the general procedure (lW, 120 ꢁC, 0.75 h).
The residue was purified by flash chromatography (tol-
uene/CH2Cl2/2-propanol, 15:10:0.1 to 15:10:3) to afford
228 mg (85%, 0.329 mmol) of 13e as a brownish solid.
21
D
½aꢁ
+16.4 (c 0.59, CHCl3); 1H NMR (CDCl3,
4.19. 4-(2,3,4,6-Tetra-O-acetyl-b-D-galactopyranosyl)-30-
(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-biphenyl (14)
500.1 MHz) d: 1.33 (s, 12H, 4 CH3), 1.92, 2.04, 2.06,
2.12, 2.17 (5 s, 15H, 5 C(O)CH3), 2.22 (m, 1H, H-3ax),
2.68 (m, 1H, H-3eq), 3.63 (s, 3H, OCH3), 4.11 (m, H-
5), 4.16 (m, 1H, H-9a), 4.28 (m, 1H, H-9b), 4.51 (m,
1H, H-6), 4.96 (m, 1H, H-4), 5.23 (m, 1H, N-H), 5.33
(m, 2H, H-7, H-8), 7.02–7.04, 7.71–7.73 (m, 4H,
C6H4); 13C NMR (CDCl3, 125.8 MHz) d: 20.7, 20.8,
20.9, 21.0, 24.6 (5 C(O)CH3), 24.8, 24.9 (2 C(CH3)2),
38.3 (C-3), 49.4 (C-5), 53.0 (CH3), 62.0 (C-9), 67.4 (C-
7), 68.7 (C-4), 69.3 (C-8), 73.6 (C-6), 83.7 (2 C(CH3)2),
99.6 (C-2), 118.3 (2 aromat. C–H), 136.3 (2 aromat.
C–H), 159.5 (aromat. C–O), 168.4, 170.1, 171.0 (6
C@O); IR (KBr) m: 3373, 2979, 1750 (C@O), 1663 (N–
C@O), 1604, 1542, 1448, 1365, 1321 (B–O), 1223,
Phenylhalide 9c (50.2 mg, 91.2 lmol) and boronide 13b
(45.6 mg, 82.9 lmol) were treated with cesium carbonate
(81.1 mg, 249 lmol) and Pd(PPh3)4 (1.4 mg, 1.21 lmol)
in dioxane (1 ml) according to the general procedure
(lW, 120 ꢁC, 4.5 h). The residue was purified by flash
chromatography (toluene/ethyl acetate, 3:1 to 2.5:1) to
afford 61.0 mg (87%, 72.0 lmol) of 14 as a colorless
solid.
21
D
½aꢁ
ꢀ1.6 (c 0.55, CHCl3); 1H NMR (CDCl3,
500.1 MHz) d: 1.98, 2.02, 2.03, 2.04, 2.06, 2.06, 2.08,
2.19 (8 s, 24H, 8 C(O)CH3), 3.88 (m, 1H, H-50), 4.08
(m, 1H, H-5), 4.15–4.28 (m, 4H, H-6, H-60), 5.08 (d,
J = 7.9 Hz, 1H, H-1), 5.12 (dd, J = 3.5, 10.5 Hz, 1H,
H-3), 5.15 (d, J = 7.6 Hz, 1H, H-10), 5.16 (m, 1H, H-
40), 5.29–5.31 (m, 2H, H-20, H-30), 5.47 (dd, J = 0.7,
3.4 Hz, 1H, H-4), 5.51 (dd, J = 7.9, 10.5 Hz, 1H, H-2),
6.94–7.49 (m, 8H, 2· C6H4); 13C NMR (CDCl3,
125.8 MHz) d: 20.5, 20.6, 20.6, 20.6, 20.7 (8
C(O)CH3), 61.3 (C-6), 62.0 (C-60), 66.8 (C-4), 68.3 (C-
40), 68.6 (C-2), 70.8 (C-3), 71.0 (C-5), 71.1 (C-30), 72.0
(C-50), 72.7 (C-20), 98.9 (C-10), 99.6 (C-1), 115.2, 115.7,
121.9, 129.9, 117.2, 128.3 (8 aromat. C–H), 135.7,
142.2 (2 aromat. C–C), 156.6, 157.1 (2 aromat. C–O),
169.3, 169.4, 170.1, 170.2, 170.3, 170.5 (8 C@O); Anal.
Calcd for C40H46O20: C, 56.74; H, 5.48. Found: C,
56.60; H, 5.73.
1145, 1083, 1039 cmꢀ1
.
4.17. Benzyl (S)-2-[30-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)-phenoxy]-3-phenylpropanoate (13f)
A flask was charged with phenylbromide 12 (300 mg,
0.729 mmol), potassium acetate (215 mg, 2.19 mmol),
dppf (13.3 mg, 24.0 lmol), and dioxane (15 ml). The
flask was flushed with argon and degassed in ultrasonic
bath for 15 min. Bis(picanolato)diborane (278 mg,
1.09 mmol) and PdCl2(dppf) (17.9 mg, 21.9 lmol) were
added and the mixture was heated to 80 ꢁC for 27 h.
The solvent was evaporated in vacuo. The residue was
dissolved in CH2Cl2 (25 ml), washed with water (2·
20 ml), dried (Na2SO4), and concentrated in vacuo.
The residue was purified by flash chromatography
(petroleum ether/toluene/ethyl acetate, 10:1:0.5) to af-
ford 221 mg (66%, 0.482 mmol) of 13f as a yellowish oil.
4.20. Methyl (30-(S)-(1-benzyloxycarbonyl-2-phenyl-2-
ethoxy)-biphenyl-4-yl 5-acetamido-4,7,8,9-tetra-O-acetyl-
3,5-dideoxy-D-glycero-a-D-galacto-2-nonulopyrano-
sid)onate (15)
21
D
½aꢁ
ꢀ9.1 (c 0.56, CHCl3); 1H NMR (CDCl3,
500.1 MHz) d: 1.32 (s, 12H, 4 CH3), 3.21–3.29 (m, 2H,
H-3), 4.93 (dd, J = 5.4, 7.6 Hz, 1H, H-2), 5.09–5.14
(m, 2H, H-10), 6.91–7.40 (m, 14H, C6H4, 2· C6H5);
13C NMR (CDCl3, 125.8 MHz) d: 24.8, 24.9 (2
C(CH3)2), 39.1 (C-3), 67.0 (C-10), 77.4 (C-2), 83.8 (2
C(CH3)2), 118.4, 120.8, 126.9, 128.1, 128.3, 128.4,
128.5, 129.0, 129.5 (14 aromat. C), 135.2, 136.9 (2 aro-
mat. C–C), 157.1 (aromat. C–O), 171.1 (C-1); IR
(KBr) m: 3492, 3064, 3032, 2978, 2931, 1752 (C@O),
Phenylhalide 10b (282 mg, 436 lmol) and boronide 13f
(220 mg, 480 lmol) were treated with K3PO4 (280 mg,
1.32 mmol), dppf (7.7 mg, 13.9 lmol), BHT (67.7 mg,
307 lmol), and PdCl2(dppf) (12.0 mg, 14.7 lmol) in
dioxane (6.5 ml) according to the general procedure
(lW, 170 ꢁC, 2.5 h). The mixture was heated with micro-
waves to 170 ꢁC for 2 1/4 h. The residue was purified by
flash chromatography (toluene/CH2Cl2/2-propanol,
15:10:0 to 15:10:2) to afford 108 mg (28%, 120 lmol)
of 15 as colorless solid.
1575, 1491, 1430, 1358, 1272, 1215, 1145, 1085 cmꢀ1
.
4.18. General procedure for Suzuki coupling
21
D
½aꢁ
+5.0 (c 0.54, CHCl3); 1H NMR (CDCl3,
A microwave tube was charged with phenylboronide
(0.109 mmol), the appropriate phenylhalogenide
(0.120 mmol), base (0.326 mmol), and catalyst
(1.09 lmol). The tube was closed, evacuated through a
500.1 MHz) d: 1.86, 1.96, 1.98, 2.06, 2.08 (5 s, 15H, 5
C(O)CH3), 2.17 (m, 1H, H-3ax), 2.73 (dd, J = 4.6,
12.9 Hz, 1H, H-3eq), 3.17–3.25 (m, 2H, H-30), 3.62 (s,
3H, OCH3), 4.04 (m, 1H, H-5), 4.11 (dd, J = 4.9,

D. Schwizer et al. / Bioorg. Med. Chem. 14 (2006) 4944–4957
4955
12.5 Hz, 1H, H-9a), 4.21 (m, 1H, H-9b), 4.26 (dd,
J = 2.4, 12.5 Hz, 1H, H-6), 4.85 (dd, J = 5.4, 7.7 Hz,
1H, H-20), 4.92 (m, 1H, 4-H), 5.04–5.11 (m, 2H, H-100),
5.29–5.34 (m, 2H, H-7, H-8), 5.35 (d, J = 5.0 Hz, 1H,
N-H), 6.67–7.34 (m, 18H, 2· C6H4, 2· C6H5); 13C
NMR (CDCl3, 125.8 MHz) d: 20.7, 20.9, 21.0, 23.1 (5
C(O)CH3), 38.0 (C-3), 39.1 (C-30), 49.4 (C-5), 53.0
(OCH3), 62.0 (C-9), 67.0 (C-100), 67.3 (C-7), 68.8 (C-4),
69.2 (C-8), 73.3 (C-6), 77.8 (C-20), 100.0 (C-2), 113.5,
114.2, 114.3, 116.7, 118.0, 120.1, 120.5, 121.5, 126.9,
128.0, 128.3, 128.4, 128.5, 128.5, 129.5, 129.7, 132.3,
135.1, 136.1, 136.3, 141.9 (22 aromat. C), 153.3, 158.0
(2 aromat. C–O), 168.1, 170.6, 170.9, 171.0 (8 C@O);
HR-MS calcd for C48H51NNaO16 [M+Na+]: 920.3100;
Found: 920.3074.
4.23. 3,40-Di-[sodium (5-acetamido-3,5-dideoxy-D-glyce-
ro-a-D-galacto-2-nonulopyranosid)onat-2-yl]-biphenyl (3)
Biphenyl 16 (31.6 mg, 27.9 lmol) was treated according
to the general procedure to afford 12.7 mg (56%,
15.6 lmol) of 3 as a colorless solid.
1H NMR (D2O, 500.1 MHz) d: 1.95 (m, 2H, H-3ax,
H-30ax), 2.04 (s, 6H, 2 C(O)CH3), 2.91 (m, 2H, H-3eq,
H-30eq), 3.63 (m, 2H, H-7, H-70), 3.65 (m, 2H, H-9a,
H-90a), 3.77 (m, 2H, H-4, H-40), 3.80–3.89 (m, 2H, H-
9b, H-90b), 3.92 (m, 2H, H-5, H-50), 3.87–3.94 (m, 4H,
H-6, H-60, H-8, H-80), 6.86–7.60 (m, 8H, 2· C6H4);
13C NMR (D2O, 125.8 MHz) d: 22.5 (2 CH3), 52.1 (C-
5, C-50), 63.3 (C-9, C-90), 68.7 (C-7, C-70, C-4, C-40),
72.5 (C-8, C-80), 73.9 (C-6, C-60), 103.2, 103.1 (C-2, C-
20), 114.4, 115.1, 116.7, 119.2, 119.8, 120.2, 122.4,
122.9, 128.4, 128.7, 130.5, 131.0 (12 aromat. C); HR-
MS calcd for C23H26NO10 [MꢀSia]: 476.1562; Found:
476.1542.
4.21. 3,40-Di-[methyl (5-acetamido-4,7,8,9-tetra-O-ace-
tyl-3,5-dideoxy-D-glycero-a-D-galacto-2-nonulopyrano-
sid)onat-2-yl]-biphenyl (16)
Phenylhalide 10c (61.2 mg, 88.3 lmol) and boronide 13e
(41.6 mg, 60.0 lmol) were treated with silver carbonate
(47.9 mg, 174 lmol) and Pd(PPh3)4 (2.2 mg, 1.91 lmol)
in dioxane (1 ml) according to the general procedure
(lW, 120 ꢁC, 7 h). The residue was purified by flash
chromatography (toluene/CH2Cl2/2-propanol, 15:10:1
to 15:10:2.5) to afford 52.6 mg (77%, 46.4 lmol) of 16
as colorless solid.
4.24. Sodium [30-(S)-(sodium 2-hydroxy-3-phenylpropio-
nate-2-O-yl)-biphenyl-4-yl 5-acetamido-3,5-dideoxy-D-
glycero-a-D-galacto-2-nonulopyranosid]onate (4)
Biphenyl 15 (85.0 mg, 94.7 lmol) was treated according
to the general procedure to afford 33.2 mg (52%,
49.6 lmol) of 4 as a colorless solid.
21
D
21
D
½aꢁ
+16.6 (c 0.52, CHCl3); 1H NMR (CDCl3,
½aꢁ +24.0 (c 0.52, H2O); 1H NMR (D2O, 500.1 MHz) d:
500.1 MHz) d: 1.89, 1.91, 2.01, 2.02, 2.03, 2.05, 2.10,
2.12, 2.14 (9 s, 30H, 10 C(O)CH3), 2.17–2.26 (m,
2H, H-3ax, H-3a0 x), 2.67–2.73 (m, 2H, H-3eq, H-3e0 q),
3.66, 3.70 (2 s, 6H, 2 OCH3), 4.05–4.19 (m, 4H, H-
5, H-50, H-9a, H-9a0 ), 4.29–4.36 (m, 2H, H-9b, H-90b),
4.36–4.45 (m, 2H, H-6, H-60), 4.95–4.99 (m, 2H, H-
4, H-40), 5.33–5.40 (m, 4H, H-7, H-70, H-8, H-80),
5.46–5.50 (m, 2H, N-H, N0-H), 7.06–7.49 (m, 8H, 2·
C6H4); 13C NMR (CDCl3, 125.8 MHz) d: 20.6, 20.7,
20.8, 21.0, 23.1 (10 C(O)CH3), 37.5, 38.1 (C-3, C-30),
49.4 (C-5, C-50), 53.0, 53.4 (2 OCH3), 62.0 (C-9, C-
90), 67.3, 67.5 (C-7, C-70), 68.8, 68.9 (C-4, C-40),
69.1, 69.6 (C-8, C-80), 73.3 (C-6, C-60), 99.9, 100.0
(C-2, C-20), 118.7, 119.2, 122.7, 129.6, 120.0, 127.9
(8 aromat. C–H), 153.4, 153.8 (2 aromat. C–O),
135.9, 141.6 (2 aromat. C–C), 168.1, 168.2, 170.1,
170.1, 170.6, 171.0 (12 C@O); Anal. Calcd for
C52H64N2O26: C, 55.12; H, 5.69; N, 2.47. Found: C,
55.11; H, 5.75; N, 2.39.
1.95 (m, 1H, H-3ax), 2.05 (1 s, 3H, C(O)CH3), 2.90 (dd,
J = 4.0, 12.4 Hz, 1H, H-3eq), 3.16–3.29 (m, 2H, H-30),
3.61 (m, 1H, H-7), 3.66 (m, 1H, H-9a), 3.78 (m, 1H,
H-4), 3.87–3.89 (m, 1H, H-9b), 3.91–3.92 (m, 3H, H-5,
H-6, H-8), 4.80 (m, 1H, H-20), 6.84–7.58 (m, 13H, 2·
C6H4, C6H5); 13C NMR (D2O, 125.8 MHz) d: 22.8
(CH3), 41.2 (C-3), 52.5 (C-5), 63.3 (C-9), 68.9 (C-7),
68.6 (C-4), 72.4 (C-8), 74.0 (C-6), 80.5 (C-20), 114.1,
114.2, 120.1, 122.1, 127.1, 128.2, 128.8, 129.6, 130.8
(18 aromat. C); Anal. Calcd for C32H33NO12Na2Æ5H2O:
C, 50.59; H, 5.71; N, 1.84. Found: C, 50.83; H, 5.66; N,
2.02.
4.25. 4-b-D-Galactopyranosyl-30-b-D-glucopyranosyl-bi-
phenyl (17)
Biphenyl 14 (93.1 mg, 110 lmol) was treated according
to the general procedure without addition of water to
afford 51.2 mg (91%, 100 lmol) of 17 as a colorless
solid.
4.22. General procedure for deprotection
21
D
1
½aꢁ ꢀ62.0 (c 0.58, H2O); H NMR (D2O, 500.1 MHz)
To a solution of the biphenyl derivative (0.095 mmol) in
methanol (3 ml) was added 1 M NaOMe in methanol
(1 ml). After stirring at room temperature for 17 h,
water (1 ml) was added and stirring continued for 6 h.
The mixture was neutralized with Dowex 50 · 8 (H+),
filtered, and concentrated in vacuo. The residue was
purified by reversed-phase chromatography (gradient
methanol/water), treated with Dowex 50 · 8 (Na+),
and purified on a P2 column to give the sodium salt of
the biphenyl derivative after a final lyophilization from
dioxane/water.
d: 3.49 (m, 1H, H-30), 3.60 (m, 2H, H-20, H-50), 3.62–
3.67 (m, 1H, H-40), 3.72–3.81 (m, 2H, H-6), 3.78 (m,
1H, H-3), 3.83 (m, 1H, H-2), 3.88 (m, 1H, H-5), 3.92
(m, 2H, H-60), 4.00 (m, 1H, H-4), 5.08 (d, 1H,
J = 7.6 Hz, H-1), 5.16 (d, 1H, J = 7.3 Hz, H-10), 7.10–
7.65 (m, 8H, 2· C6H4); 13C NMR (D2O, 125.8 MHz)
d: 61.2 (C-60), 61.4 (C-6), 69.1 (C-4), 70.2 (C-30), 71.2
(C-2), 73.2, 73.6 (C-3), 76.1 (C-5), 76.2, 76.8, 100.8 (C-
10), 101.3 (C-1), 115.3, 116.0, 117.6, 122.2, 129.0, 131.1
(12 aromat. C); Anal. Calcd for C24H30O12Æ2.5H2O: C,
51.89; H, 6.35. Found: C, 52.25; H, 6.16.

4956
D. Schwizer et al. / Bioorg. Med. Chem. 14 (2006) 4944–4957
13. Yang, L. J.-S.; Zeller, C. B.; Shaper, N. L.; Kiso, M.;
Acknowledgments
Hasegawa, A.; Shapiro, R. E.; Schnaar, R. L. Proc. Natl.
Acad. Sci. U.S.A. 1996, 93, 814.
We are grateful to the Volkswagen Foundation for their
generous support of this work. In addition, we thank
Mr. Werner Kirsch, Microanalytical Services of the
Organic Institute of the University of Basel, for per-
forming the microanalysis, Prof. Dr. Michael Przybyl-
ski, Department of Chemistry, University of
Konstanz/D for the high-resolution MS, and Alexander
Vo¨gtli for the graphic art (Fig. 1). The authors would
like to express their gratitude to Mr. Oleg Khorev for
thorough reading of the manuscript.
14. (a) Hotta, K.; Ishida, H.; Hasegawa, A. J. Carbohydr.
Chem. 1995, 14, 491; (b) Ito, H.; Ishida, H.; Ando, S.;
Kiso, M. Glycoconjugate J. 1999, 16, 585; (c) Ito, H.;
Ishida, H.; Kiso, M. J. Carbohydr. Chem. 2001, 20,
207.
15. (a) Kelm, S.; Brossmer, R.; Isecke, R.; Gross, H.-J.;
Strenge, K.; Schauer, R. Eur. J. Biochem. 1998, 255,
663; (b) Strenge, K.; Schauer, R.; Bovin, N.; Hasegawa,
A.; Ishida, H.; Kiso, M.; Kelm, S. Eur. J. Biochem.
1998, 258, 677; (c) Sawada, N.; Ishida, H.; Collins, B.
E.; Schnaar, R. L.; Kiso, M. Carbohydr. Res. 1999, 316,
1; (d) Collins, B. E.; Ito, H.; Sawada, N.; Ishida, H.;
Kiso, M.; Schnarr, R. L. J. Biol. Chem. 1999, 274,
37637.
References and notes
16. Vyas, A. A.; Blixt, O.; Paulson, J. C.; Schnaar, R. L. J.
Biol. Chem. 2005, 280, 16305.
17. Schwardt, O.; Gao, G.-P.; Kelm, S.; Ga¨thje, H.; Meyer,
B.; Shin, S.-Y.; Peters, T.; Bhunia, A.; Ernst, B.,
submitted.
1. Ramon y Cajal, S. Degeneration and Regeneration of
the Nervous System; Oxford Univ. Press: London,
1928.
2. (a) Tello, F. Trab. Lab. Invest. Biol. 1911, 9, 123; (b)
Davies, S. J.; Goucher, D. R.; Doller, C.; Silver, J.
J. Neurosci. 1999, 19, 5810.
18. May, A. P.; Robinson, R. C.; Vinson, M.; Crocker, P. R.;
Jones, E. Y. Mol. Cell 1998, 1, 719.
3. (a) Schwab, M. E.; Caroni, P. J. Neurosci. 1988, 8, 2381;
(b) Caroni, P.; Savio, T.; Schwab, M. E. Prog. Brain Res.
1988, 78, 363.
19. The numbering of the amino acids was done according
to Sato, S.; Fujita, N.; Kurihara, T.; Kuwano, R.;
Kakahashi, Y.; Miyatake, T. Biochem. Biophys. Res.
Commun. 1989, 163, 1473; see also Swiss-Prot entry
P20916.
4. (a) Caroni, P.; Schwab, M. E. Neuron 1988, 1, 85; (b)
Caroni, P.; Schwab, M. E. J. Cell Biol. 1988, 106, 128; (c)
Chen, M. S.; Huber, A. B.; van der Haar, M. E.; Frank,
M.; Schnell, L.; Spillmann, A. A.; Christ, F.; Schwab, M.
E. Nature 2000, 403, 434; (d) GrandPre, T.; Nakamura, F.;
Vartanian, T.; Strittmatter, S. M. Nature 2000, 403, 439.
5. (a) Kottis, V.; Thibault, P.; Mikol, D.; Xiao, Z. C.; Zhang,
R.; Dergham, P.; Braun, P. E. J. Neurochem. 2002, 82,
1566; (b) Wang, K. C.; Koprivica, V.; Kim, J. A.;
Sivasankaran, R.; Guo, Y.; Neve, R. L.; He, Z. Nature
2002, 417, 941.
20. Personal communication from Prof. Thomas Peters, Med.
University of Lubeck.
¨
21. Kogan, T. P.; Duprey, B.; Keller, K. M.; Scott, I. L.; Bui,
H.; Market, R. V.; Beck, P. J.; Voytus, J. A.; Revelle, B.
M.; Scott, D. J. Med. Chem. 1995, 38, 4976.
22. Mohamadi, F.; Richards, N. G. J.; Guida, W. C.;
Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.;
Hendrickson, T.; Still, C. W. J. Comp. Chem. 1990, 11,
440.
6. (a) McKerracher, L.; David, S.; Jackson, D. L.; Kottis, V.;
Dunn, R. J.; Braun, P. E. Neuron 1994, 13, 805; (b)
Mukhopadhyay, G.; Doherty, P.; Walsh, F. S.; Crocker,
P. R.; Filbin, M. T. Neuron 1994, 13, 757; (c) Vinson, M.;
Strijbos, P. J. L. M.; Rowles, A.; Facci, L.; Moore, S. E.;
Simmons, D. L.; Walsh, F. S. J. Biol. Chem. 2001, 276,
20280.
7. Fournier, A. E.; GrandPre, T.; Strittmatter, S. M. Nature
2001, 409, 341.
8. (a) Wang, K. C.; Kim, J. A.; Sivasankaran, R.; Segal, R.;
He, Z. Nature 2002, 420, 74; (b) Wong, S. T.; Henley, J.
R.; Kanning, K. C.; Huang, K. H.; Bothwell, M.; Poo, M.
M. Nat. Neurosci. 2002, 5, 1302.
23. Senderowitz, H.; Parish, C.; Still, W. C. J. Am. Chem. Soc.
1996, 118, 2078.
24. Kolb, H. C.; Ernst, B. Chem. Eur. J. 1997, 3, 1571; Kolb,
H. C.; Ernst, B. Pure Appl. Chem. 1997, 69, 1879.
25. Zbinden, P.; Dobler, M.; Folkers, G.; Vedani, A. Quant.
Struct.-Act. Relat. 1998, 17, 122.
26. Schmid, S.; Vedani, A.; Ernst, B., unpublished.
27. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; (b)
Suzuki, A. J. Organomet. Chem. 1999, 576, 147; (c)
Suzuki, A. Proc. Jpn. Acad. 2004, 80B, 359.
28. Dess, D.; Kleine, H. P.; Weinberg, D. V.; Kaufman, R. J.;
Sidhu, R. S. Synthesis 1981, 883.
29. Sokolov, V. M.; Zakharov, V. I.; Studentsov, E. P. Russ.
J. Gen. Chem. 2002, 72, 806.
30. Rothermel, J.; Faillard, H. Carbohydr. Res. 1990, 196, 29.
31. Kuhn, R.; Lutz, P.; MacDonald, D. L. Chem. Ber. 1966,
99, 611.
9. Mi, S.; Lee, X.; Shao, Z.; Thill, G.; Ji, B.; Relton, J.;
Levesque, M.; Allaire, N.; Perrin, S.; Sands, B.; Crowell,
T.; Cate, R. L.; McCoy, J. M.; Pepinsky, R. B. Nat.
Neurosci. 2004, 7, 221.
10. Yamashita, T.; Higuchi, H.; Tohyama, M. J. Cell Biol.
2002, 157, 565.
32. Ishiyama, T.; Ishida, K.; Miyaura, N. Tetrahedron 2001,
57, 9813.
11. (a) Kelm, S.; Pelz, A.; Schauer, R.; Filbin, M. T.; Tang,
S.; de Bellard, M. E.; Schnaar, R. L.; Mahoney, J. A.;
Hartnell, A.; Bradfield, P.; Crocker, P. R. Curr. Biol.
1994, 4, 965; (b) Crocker, P. R.; Clark, E. A.; Filbin,
M. T.; Gordon, S.; Jones, Y.; Kehrl, J. H.; Kelm, S.; Le
Douarin, N. M.; Powell, L.; Roder, J.; Schnaar, R. L.;
Sgroi, D.; Stamenkovic, I.; Schauer, R.; Schachner, M.;
Tedder, T.; van den Berg, T. K.; van der Merwe, P. A.;
Watt, S. M.; Varki, A. Glycobiology 1998, 8, Glycofo-
rum 2 v-vi.
33. (a) Takaoka, S.; Nakade, K.; Fukuyama, Y. Tetrahe-
dron Lett. 2002, 43, 6919; (b) Ishiyama, T.; Itoh, Y.;
Kitano, T.; Miyaura, N. Tetrahedron Lett. 1997, 38,
3447.
34. Whistler, R. L.; Wolfram, M. L. Reactions of Carbohy-
drates. In Methods in Carbohydrate Chemistry; Academic
Press, Inc.: New York, 1993; Vol. 2, p 212.
35. Ishiyama, T.; Murata, M.; Miyaura, N. I. J. Org. Chem.
1995, 60, 7508.
36. Kappes, O. C. Angew. Chem. Int. Ed. 2004, 43, 6250.
37. Coudret, C.; Mazenc, V. Tetrahedron Lett. 1997, 38,
5293.
12. McKerracher, L. Proc. Natl. Acad. Sci. U.S.A. 2002, 99,
7811.

D. Schwizer et al. / Bioorg. Med. Chem. 14 (2006) 4944–4957
4957
38. Schwardt, O.; Gao, G.-P.; Visekruna, T.; Rabbani, S.;
Gassmann, E.; Ernst, B. J. Carbohydr. Chem. 2004, 23, 1.
39. Hoekman, D.; Leo, A. J. CLOGP; 4.3. ed.; BioByte Corp.;
Claremont, CA.
40. Bieberich, E.; Liour, S. S.; Yu, R. K. Methods
Enzymol. 2000, 312B, 339; Kopitz, J.; Sinz, K.;
Brossmer, R.; Cantz, M. Eur. J. Biochem. 1997, 248,
527.