Bis C-glycosylated diphenylmethanes for stable glycoepitope mimetics

Article abstract of DOI:10.1055/s-1999-2738

Bis C-glycosylated diphenylmethanes, in which two sugar units protrude from a diphenylmethane scaffold by C-glycosylated bonds, were synthesized as versatile glycoepitope mimetics using C-glycosylated aryl tins and C- glycosylated benzyl bromides. The syn

Full text of DOI:10.1055/s-1999-2738

LETTER
737
Bis C-Glycosylated Diphenylmethanes for Stable Glycoepitope Mimetics
Takeshi Kuribayashia, Sayako Gohyaa, Yumiko Mizunoa, Masayuki Shimojimab, Kazuhiro Itob, Susumu Satoha*
aExploratory Chemistry Research Laboratories
bBiological Research Laboratories, Sankyo Co. Ltd., 2-58 Hiromachi 1-chome, Shinagawa-ku, Tokyo 140-8710 Japan
Fax +81(3)-5436-8570; E-mail: ssatoh@shina.sankyo.co.jp
Received 19 March 1999
Peracetylated sugars were coupled with 4-methoxytolu-
ene using tin (IV) chloride-silver trifluoroacetate combi-
nation to afford the b-C-glycosylated toluenes.7
Subsequent brominations at the benzyl position of the
C-glycosylated toluenes using N-bromosuccinimide and
azobisisobutyronitrile afforded the C-glycosylated benzyl
bromides (1).
Abstract: Bis C-glycosylated diphenylmethanes, in which two sug-
ar units protrude from a diphenylmethane scaffold by C-glycosyl-
ated bonds, were synthesized as versatile glycoepitope mimetics us-
ing C-glycosylated aryl tins and C-glycosylated benzyl bromides.
The synthetic method was applied to the synthesis of a sLeX mimet-
ic. Besides, triphenylphosphine oxide was found to be a crucial ad-
ditive in the Stille coupling reaction.
Key words: Stille coupling reaction, additive, aryl C-glycoside, sia-
lyl Lewis X, mimetic
SnCl4
AgOTfa
O
O
+
Glycoconjugates expressed on cell surfaces or extracellu-
lar matrices have been recognized to be deeply involved
in numerous cellular processes.1 Although glycoconju-
gates are huge and complex biomolecules, some small
specific epitopes on them are thought to be responsible for
some specific activity. Identification and extraction of
pharmacophore of those glycoepitopes and effective pre-
sentation of the extracts on a small scaffold will permit the
reproduction of some properties of huge glycoconjugates
by simple glycoepitope mimetics. Many groups have re-
ported the successful production of glycoepitope mimet-
ics by linking several monosaccharides on various
scaffolds with O-linkage or by replacing a sialic acid with
a carboxylic acid;2 few groups, however, have reported on
the examination of C-glycosides for glycoepitope
mimetics2,3 in spite of several advantages of C-glycoside
glycomimetics over natural oligosaccharides, such as in-
creased physiological stability, in vivo half-time, and bio-
availability.
OAc
(AcO)n
(AcO)n
CH2Cl2
OMe
(Fuc: 89%, Gal: 78%)
OMe
MeO
O
NBS, AIBN
CCl4
Br
(AcO)n
C-glycosylated benzyl bromides (1)
(Fuc: 65%, Gal: 71%)
Scheme 1 Synthesis of C-Glycosylated Benzyl Bromides
Of several trials searching for good coupling conditions
for C-galactosylated aryl tin, 3 equivalent C-galactosylat-
ed benzyl bromide, tetrakis(triphenylphosphine)palladi-
um (0), and potassium carbonate in refluxing 1,4-dioxane
were found to afford the bis C-glycosylated diphenyl-
methane in good yield (Condition A). 1 Equivalent C-ga-
lactosylated benzyl bromide decreased the coupling yield
from 80% to 33%. The coupling of a number of C-glyco-
sylated aryl tins with C-galactosylated benzyl bromide
was examined using Condition A. The results are summa-
rized in the Table.
We report here the facile preparation of bis C-glycosylat-
ed diphenylmethanes, wherein each sugar unit component
is intentionally changed, and two sugar units are arranged
on a diphenylmethane scaffold in such a way as to pro-
trude from the scaffold. The synthesis was carried out by
the Stille coupling4 of C-glycosylated aryl tins,5 including
C-sialylated aryl tin, with C-glycosylated benzyl bro-
mides (1) that are newly designed as benzyl electrophiles
bearing C-glycoside. Besides, in searching for good cou-
pling conditions, triphenylphosphine oxide was found to
be a crucial additive for excellent coupling yields.
Likewise, a C-fucosylated aryl tin and a C-glucosylated
aryl tin reacted with the C-galactosylated benzyl bromide
and afforded the bis C-glycosylated diphenylmethanes in
yields of 97% and 64%, respectively (entries 2, and 3).
The sugar part of C-glycosylated aryl tins, however, was
found to be quite sensitive for the coupling yield. In the
case of N-phthaloyl-D-glucosamine- and L-rhamnose-de-
rived aryl tins, Condition A afforded the bis C-glycosylat-
ed diphenylmethanes in low yields (22% and 28%,
respectively) (entries 4, and 5). Moreover, the C-sialylat-
ed aryl tin did not afford the bis C-glycosylated diphenyl-
methane at all. It only afforded a destannylated product8
of the C-sialylated aryl tin in 79% yield.
Having previously investigated the coupling of C-glyco-
sylated aryl tins with various benzyl bromides under the
Stille reaction condition,6 we designed C-glycosylated
benzyl bromides (1) as counterparts for the palladium me-
diated cross-coupling. The C-glycosylated benzyl bro-
mides (1) were synthesized as follows (Scheme 1).
Synlett 1999, No. 6, 737–740 ISSN 0936-5214 © Thieme Stuttgart · New York

738
T. Kuribayashia et al.
LETTER
Table Synthesis of Bis C-Glycosylated Diphenylmethanes
MeO
O
AcO
MeO
AcO
AcO
MeO
O
(AcO)n
O
SnBu3
OAc
O
+
AcO
AcO
(AcO)n
Br
OAc
C-glycosylated aryl tins
C-galactosylated benzyl bromides
OAc
OMe
Condition Aa
Condition Bb
Entry
C-glycosylated aryl tins
bis C-glycosylated diphenylmethanes
OMe
OAc
AcO
O
OMe
OMe
OMe
OMe
OAc
O
AcO
AcO
OAc
AcO
80%
1
2
3
4
AcO
OMe
OAc
OAc
SnBu3
O
AcO
OAc
OMe
OMe
OMe
OMe
OMe
OMe
O
OAc
O
OAc
AcO
OAc
97%
64%
22%
OAc
AcO
OMe
AcO
OAc
SnBu3
O
AcO
OAc
OMe
OAc
AcO
AcO
OMe
OMe
OMe
OMe
OMe
OMe
O
OAc
O
AcO
AcO
OAc
AcO
OMe
OAc
OAc
O
SnBu3
SnBu3
SnBu3
AcO
OAc
OMe
NPhth
AcO
AcO
O
NPhth
O
AcO
AcO
OAc
82%
AcO
AcO
OMe
OAc
OAc
O
OAc
OMe
O
AcO
AcO
O
OAc
AcO
AcO
28%
5
6
7
76%
63%
76%
AcO
OMe
OAc
OAc
O
AcO
OAc
OMe
OAc
OAc
AcHN
AcO
MeO2C
O
AcO
O
OAc
CO2Me
SnBu3
OMe
OAc
AcO
<1%
AcO
AcO OAc
O
MeO
AcHN
AcO OAc
MeO
OMe
OMe
O
OMe
OMe
AcO
OAc
AcO
O
AcO
OAc
AcO
AcO
AcO
OMe
OAc
O
SnBu3
OAc
OMe
a Condition A: all reaction were carried out in refluxing 1,4-dioxane using C-glycosylated aryl tin, C-glycosylated benzyl bromide, Pd(PPh3)4
and K2CO3 under the following equivalency (1: 3 : 0.1 : 2). b Condition B: 1 eq. of O:PPh3 was added to Condition A.
Synlett 1999, No. 6, 737–740 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Bis C-Glycosylated Diphenylmethanes for Stable Glycoepitope Mimetics
739
After a number of trials using various additives under The reaction afforded the bis C-glycosylated diphenyl-
Condition A for the coupling of C-sialylated aryl tin and methane in 76% yield under Condition B. Deprotection of
C-galactosylated benzyl bromide, augmenting the pro- the product according to the conventional method11 af-
cess with 1 equivalent triphenylphosphine oxide (Condi- forded compound (2). We believe this is one of the short-
tion B) was found to increase the coupling yield est synthesis of physiologically stable C-linked sLeX
dramatically from <1% to 63%; no reduction in the prod- mimetics.
uct of C-sialylated aryl tin was observed by TLC analysis
The sLeX mimetic (2) and a sLeX derivative [NeuAca2-
(entry 6).
3Galb1-3(Fuca1-4)GlcNAcb1-(O(CH2)8CO2Me)], which
In the case of the N-phthaloyl-D-glucosamine- and the L- showed selectin antagonistic activities of 0.75, 0.033 and
rhamnose-derived aryl tins, triphenylphosphine oxide as a 0.015 mM for E-, L- and P-selectins, respectively (IC50,
further additive was found to improve the coupling yield. Foxall’s ELISA assay12), inhibited binding of sLeX (con-
Condition B increased the coupling yield of the N-phtha- jugated with [3H]-polyacrylamide) to guinea pig eosino-
loyl-D-glucosamine-derived aryl tin and the C-galactos- phils by 56% at 7.2 mM and IC50 of 15 mM, respectively.
ylated benzyl bromide from 22% to 82% (entry 4). L- This assay established by us uses [3H]-polyacrylamide as
Rhamnose- and D-xylose-derived aryl tins also afforded a determinant; therefore, IC50 value in this assay is com-
the corresponding bis C-glycosylated diphenylmethanes, paratively higher than that in the ELISA assay.
both in yields of 76% (entries 5, and 7). This result shows
that the addition of triphenylphosphine oxide is quite in-
dispensable in the synthesis of these particular bis C-gly-
cosylated diphenylmethanes. A study on this effect of
triphenylphosphine oxide is now under way in our labora-
tory.
In conclusion, we established the synthetic method
of the novel class of C-glycosides. Their potential
utility for glycoepitope mimetics was demonstrated in
the synthesis of sLeX mimetic (2) which showed good
selectin antagonistic activity. Further application of
this method in various glycoepitopes is currently under
As sialylated oligosaccharides are involved in a large va- investigation.
riety of biological events, a facile synthesis of sialylated
glycomimetics may offer the possibility for the discovery
of lead compounds having novel biological activities and
pharmaceutical value.
References and Notes
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Stuttgart, 1998.
As one example, we tried to synthesize sialyl Lewis X
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and fucose residue are critical for the binding with selec-
tins, we decided to couple a sialic acid and a fucose on a
diphenylmethane scaffold with C-linkage using our meth-
od (Scheme 2).
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OMe
OAc
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MeO2C
O
AcO
O
SnBu3
OMe
OAc
+
AcHN
AcO
OAc
AcO
OAc
MeO
Br
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HO
MeO
OH
OH
Pd(PPh3)4
O:PPh3
K2CO3
O
1) NaOMe
2) NaOH aq.
HO2C
O
/ dioxane
OH
HO
OMe
(54%)
(76%)
AcHN
HO
MeO
OH
2
Scheme 2 The Coupling of C-Sialylated Aryl Tin and C-Fucosylated
Benzyl Bromide
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T. Kuribayashia et al.
LETTER
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Article Identifier:
1437-2096,E;1999,0,06,0737,0740,ftx,en;Y06099ST.pdf
Synlett 1999, No. 6, 737–740 ISSN 0936-5214 © Thieme Stuttgart · New York