Parallel synthesis of sialyl Lewis X mimetics on a solid phase: Access to a library of fucopeptides

Article abstract of DOI:10.1002/(SICI)1521-3773(19980703)37:12<1707::AID-ANIE1707>3.0.CO;2-V

A novel anchoring group p-(acyloxymethyl)benzylidene acetal (p-AMBA) enables the bidirectional functionalization of glycosylated amino acid derivatives and thus the rapid parallel synthesis of fucopeptides as sialyl Lewis X mimetics on a solid phase [Eq.

Full text of DOI:10.1002/(SICI)1521-3773(19980703)37:12<1707::AID-ANIE1707>3.0.CO;2-V

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d) T. Ohkuma, H. Ikehira, T. Ikariya, R. Noyori, Synlett 1997, 467 ±
468; e) T. Ohkuma, H. Doucet, T. Pham, K. Mikami, T. Korenaga, M.
Terada, R. Noyori, J. Am. Chem. Soc. 1998, 120, 1086 ± 1087.
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Ã
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Parallel Synthesis of Sialyl Lewis X Mimetics on
a Solid Phase: Access to a Library of
Fucopeptides**
[10] X-ray crystallographic analysis was performed with a Rigaku AFC
diffractometer (graphite monochromator, MoKa radiation). The
structures were solved with PATTY and DIRDIF94. (R),(R,R)-2d:
C62H56Cl2N2P2Ru, Mr ˆ 1063.06, orange crystal, 0.1  0.1  0.1 mm,
monoclinic, space group C2 (no. 5), a ˆ 24.50(1), b ˆ 20.533(9), c ˆ
Thomas F. J. Lampe, Gabriele Weitz-Schmidt, and
Chi-Huey Wong*
24.80(1) Š
b ˆ 119.20(3)8, Vˆ 10908(10) Š3,
Z ˆ 8,
1calcd
ˆ
1,
1.294 gcm 3, m(MoKa) ˆ 4.84 m
T ˆ 296 K. 9880 reflections were
independent and unique, and 6220 with I > 3.00s(I) (2qmax ˆ 508) were
used for the solution of the structure. All hydrogen atoms were
calculated from ideal geometries, fixed, and included in the calcu-
lation of the structural factor. R ˆ 0.034, Rw ˆ 0.034. (R),(S,S)-2e:
C62H56Cl2N2P2Ru, Mr ˆ 1063.06, orange crystal, 0.1  0.1  0.2 mm,
monoclinic, space group C2 (no. 5), a ˆ 24.74(2), b ˆ 20.49(1), c ˆ
In response to injury or inflammation the damaged tissue
releases cytokines, which trigger the expression of P-selectin
followed by E-selectin on the endothelium. The initial
recognition of the tetrasaccharide sialyl Lewis X (sLex) of
the terminal unit of surface glycoconjugates by the selectins
leads to leukocyte ªrollingº followed by protein ± protein
interactions (integrins CD11/18, ICAM-1 ligand) and extrav-
asation of leukocytes into the endothelium.[1] Thus, blocking
the sLex/selectin interactions at an early stage of the
inflammatory cascade, especially the P-selectin/ligand inter-
actions, has been considered to be an effective way of treating
acute and perhaps chronic inflammatory diseases.[2]
Although sLex is being clinically evaluated for the treat-
ment of reperfusion injury, it must be administered by
injection at high doses, as it binds the selectins weakly and
is orally inactive and unstable in the blood. However, the
structure of sLex has served as a useful guide for designing
simpler and better low molecular weight compounds as
25.04(1) Š
b ˆ 120.79(4)8, Vˆ 10908(11) Š3,
Z ˆ 8,
1calcd
ˆ
1,
1.294 gcm 3, m(MoKa) ˆ 4.84 m T ˆ 296 K. 12862 reflections were
independent and unique, and 7807 with I > 3.00s(I) (2qmax ˆ 558) were
used for the solution of the structure. All hydrogen atoms were
calculated from ideal geometries, fixed, and included in the calcu-
lation of the structural factor. R ˆ 0.034, Rw ˆ 0.033. Crystallographic
data (excluding structure factors) for the structures reported in this
paper have been deposited with the Cambridge Crystallographic Data
Center as supplementary publication no. CCDC-101399. Copies of the
data can be obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB21EZ, UK (fax: (‡44)1223-336-033; e-mail:
deposit@ccdc.cam.ac.uk).
[11] W. A. Herrmann, B. Cornils, Angew. Chem. 1997, 109, 1074 ± 1095;
Angew. Chem. Int. Ed. Engl. 1997, 36, 1048 ± 1067.
[12] The turnover number (TON) is the number of moles of product per
mole of catalyst. The turnover frequency (TOF) is the TON per hour
or second.
[13] Reaction with the diastereomeric isomer (R),(S,S)-2e, either pre-
formed or formed in situ, gave the S alcohol in 15 Æ 2%.
[*] Prof. Dr. C.-H. Wong, Dr. T. F. J. Lampe
The Scripps Research Institute
[14] Various alkaline bases, such as KOH, (CH3)2CHOK, (CH3)2CHONa,
(CH3)3COK, and K2CO3 can be used as cocatalysts. For reactions with
a high S/C, acidic impurities should be carefully removed from
substrates and solvents.
Department of Chemistry
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax : (‡ 1)619-784-2409
Dr. G. Weitz-Schmidt
Novartis Pharma AG
Preclinical Research
[15] Reaction of [RuCl2{(S)-TolBINAP}(dmf)n] and (S,S)-DPEN in
DMF at 508C (method B) gave a mixture of (S),(S,S)-2d and its cis
isomer (31P NMR, d ˆ 50.2 (d, J ˆ 38.0 Hz), 57.0 (d, J ˆ 38.0 Hz)).
Hydrogenation of 5g with the cis isomer showed comparable
reactivity to (S),(S,S)-2d, to give (R)-6 g with 97% ee.
CH-4002 Basel (Switzerland)
[**] We gratefully acknowledge financial support of our work by Novartis
Pharma AG and the NSF and the award of a DFG-Stipendium to
T.F.J.L. by the Deutsche Forschungsgemeinschaft.
[16] a) K. Mori, P. Puapoomchareon, Liebigs Ann. Chem. 1991, 1053 ±
1056; b) R. Croteau, F. Karp In Perfumes: Art, Science and Technology
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selectin antagonists.[3] On the basis of the crystal structure of
E-selectin, NMR studies of the conformations of sLex in
solution and bound to E-, P-, and L-selectin,[5] and structure/
activity studies on sLex derivatives and mimetics,[6] the
essential functional groups and their spatial arrangement
required for binding of the sLex epitope to the selectins have
been elucidated. By using this recognition model, numerous
structurally diverse low molecular weight sLex mimetics have
been prepared (Figure 1).[3, 7] Some of them exhibit an affinity
towards the selectins equal to or higher than that of sLex.
HO
HO
OBn
O
HO
O
O
O
HO
a-e
f, g
OBn
SEt
OH
OAll
O
O
FmocNH
OH
L-fucose
O
3
4
Scheme 1. a) Ac2O, 4-DMAP, pyridine, 0 !208C; b) EtSH, BF3 ´ Et2O,
0 !208C (60%, two steps); c) NaOMe (cat.) in MeOH, 208C; d) 2,2-
dimethoxypropane, cat. p-TsOH ´ H2O, CH2Cl2, 208C (94%, two steps, a/
b ˆ 1:7); e) NaH, BnBr, TBAI (cat.), THF (84%, 100% b); f) Fmoc-Thr-
OAll, CuBr2/TBAI, CH2Cl2, DMF; g) aqueous AcOH, (80%, 1% TFA).
All ˆ allyl, Bn ˆ benzyl, 4-dmap ˆ 4-(dimethyamino)pyridine, Fmoc ˆ 9-
fluorenylmethyloxycarbonyl, TBAI ˆ tetrabutylammonium iodide, TFA ˆ
trifluoroacetic acid, Thrˆ threonine, Ts ˆ toluenesulfonate.
HO
HO
HO
OH
OH
OH
O
O
HO
HO
NHAc
OH
O
3 (five steps, 47% overall yield) by standard methods. By
using CuI2/[Bu4N]I,[12] Fmoc-protected l-threonine allyl ester
was glycosylated with 3 to give selectively the a anomer
(a/b ꢀ 9/1). Cleavage of the acetonide with 80% aqueous
acetic acid containing 1% TFA followed by column chroma-
tography gave fucoside 4 as the pure a anomer (64% yield,
two steps).
OH
O
O
O
O
O
OH
HO2C
O
O
OEt
OH
OH
HO
N
CO HN
HO
HO
O
H
O
1
2
OH
OH
AcHN
Figure 1. The tetrasaccharide sialyl Lewis X (1) and the fucopeptide 2 as
an oligosaccharide mimic.
Treatment of the diol 4 with the dimethyl acetal 7 and a
catalytic amount of p-TsOH ´ H2O gave a diastereomeric
mixture of benzylidene acetals 5 (Scheme 2). The bifunctional
linker 7 was easily derived from commercially available 4-
formylbenzoic acid by formation of the dimethyl acetal and
reduction of the acid group (62%, two steps). By using a
moderate excess (2.1equiv) of the alcohol 5 and DIC/4-
DMAP activation, 5 was immobilized nearly quantitatively
Recently, interest in solid-phase syntheses has increased
dramatically, since they allow combinatorial chemistry to be
performed for the discovery of biologically active compounds
and for optimization of lead structures.[8] In particular, the
parallel synthesis of individual compounds on solid phases is
considered to be a promising approach to rapid optimization
of previously identified lead structures. Here we report on our
efforts to develop new strategies for the parallel and/or
combinatorial synthesis of a substance library of O- and C-
fucosylpeptides structurally related to 2, which is nearly as
active as sLex towards E-selectin.[7a]
1
(0.24 mmolg ) on a carboxyl-functionalized poly(ethylene
glycol) graft copolymer resin(PEG-PS) to give 6.[13] The
loading was determined by photometric analysis of the
cleaved Fmoc groups and gravimetrically by means of the
product released from the resin with aqueous acetic acid
(80% ‡ 2% TFA). The diol 4 was liberated quantitatively
without any detectable cleavage of the acid-sensitive a-
fucosidic bond. Thus, the combination of the para-acylox-
ymethylbenzylidene acetal (p-AMBA) anchor group and
PEG-PS solid support achieved maximal loading, recovery
of excess reagent, appropriate swelling of the solid support,
desirable stability of the acetal linkage during synthesis, and
selective cleavage by a weak acid.
Fucose, which contains the three hydroxyl groups required
for recognition of sLex by E-selectin, was retained as the only
carbohydrate moiety in the mimic, while GlcNAc was
replaced by l-threonine and its derivatives. Anchoring the
fucose ± GlcNAc surrogate through its 3,4-cis-diol unit[9]
enables the bidirectional elongation of the glycosylated amino
acid while bound to the solid support. N-terminal elongation
allows the elaboration of optimal substitutions for the
galactose and sialic acid residues. C-terminal modifications[10]
can be used to install additional functionalities that interact
with new groups in selectins.[7b, 11] The use of Fmoc ± peptide
chemistry and the application of an orthogonal protective-
group strategy (R1 ˆ All, R2 ˆ
Starting with 0.8 mmol resin-bound 6, we conducted a
parallel synthesis of sLex mimetics 8 on a preparative scale
(Scheme 3). At branching points of the synthesis, the material
Fmoc, R3 ˆ Bn; for abbrevia-
p-AMBA
PEG-PS
OH
tions, see legends to schemes),
as well as the reversible immobi-
O
HO
O
HO
O
O
MeO
MeO
OBn
OBn
O
O
O
lization of the 3,4-cis-diol moiety
of fucose by a highly acid labile
linker group, enable the rapid
and bidirectional assembly of
fucosylpeptides.
The synthesis of orthogonally
protected a-fucoside 4 is depict-
ed in Scheme 1. l-Fucose was
converted into ethylthiofucoside
OBn
O
OH
O
HO
O
PEG-PS
7
a
O
b
OAll
OAll
FmocNH
FmocNH
OAll
FmocNH
O
O
O
5
6
4
Scheme 2. Immobilization of fucoside 4 on a carboxyl-functionalized PEG-PS resin by anchor group 7. a) 7, p-
TsOH (cat.), CH2Cl2, 208C; b) DIC, 4-DMAP (cat.), CH2Cl2, 208C, 18 h, 100% (0.24 mmolg 1). p-AMBA ˆ p-
(acyloxymethyl)benzylidene acetal anchor group, DIC ˆ diisopropylcarbodiimide, PEG-PS ˆ poly(ethylene
glycol) graft copolymer; for other abbreviations, see legend to Scheme 1.
1708
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biological activity of the fucopepti-
des towards E-selectin decreased
with increasing chain length of the
C-terminal residue (XR1), the oppo-
site was observed in the P-selectin
assay: Binding affinity generally in-
creased significantly on addition of a
tris(ethylene glycol) decyl ether res-
idue (ester or amide linkage). The
ester derivative 9c binds 53 times
more strongly than the ethyl deriva-
tive 9a. An increase of biological
activity is also observed for the
corresponding amide 9d, which
binds 100 times more strongly than
9a. The influence of the N-terminal
residue R3 on binding to P-selectin
seems to be limited; the phospho-
nate fucopeptide 9h (IC50 ˆ 17mm)
has the highest activity. Comparing
the values for the two selectins shows
that fucosylpeptides 9d ( ꢀ 100-fold)
and 9h (almost 200-fold) inhibit P-
selectin significantly more strongly
than E-selectin.
p-AMBA
OBn
p-AMBA
OBn
PEG-PS
p-AMBA
OBn
PEG-PS
PEG-PS
O
O
O
O
O
O
O
O
O
c, d
a, b
O
O
O
O
FmocHN
X
OAll
X
R1
FmocNH
R1
N
H
FmocNH
R2
O
O
O
6
R1 = Et,
X = O, NH
Me
8
O
3
e, f
OBn
R2
=
=
OH
O
P
O
BnO
R3
BnO
,
,
BnO
OH
O
BnO
p-AMBA
OBn
PEG-PS
HO
HO
HO
HO
O
O
OBn
O
O
O
O
O
g
h
O
O
O
O
H
H
N
H
R3
N
X
R3
X
X
R3
N
R1
N
H
R1
N
R1
N
H
H
R2
O
O
R2
O
O
R2
O
O
9
8
O
P
O
OH
in 9: R2
, R3
=
HO
HO
HO
(n = 2,3),
=
OH
n
Scheme 3. a) [Pd(PPh3)4] (cat.), dimedone, THF, 208C, 18 h; b) R1OH, 2,6-dichlorobenzoyl chloride,
pyridine, CH2Cl2/DMF (1/1), 208C, 18 h; or R1NH2, HBTU, HOBT, NMM, CH2Cl2/DMF (1/1), 208C, 4.5 h;
c) DMF/morpholine (1/1), 208C, 1 h; d) FmocNHCHR2CO2H, HBTU, HOBT, NMM, DMF, 208C, 4 h;
e) DMF/piperidine (3/2), 208C, 10 min; f) R3CO2H, HBTU, HOBT, NMM, DMF, 208C, 4 h; g) aqueous
AcOH (80%, 2% TFA), 208C, 2  18 ± 22 h; h) H2, 10% Pd/C, EtOH/THF/H2O, 208C, 3 ± 4 h. HBTU ˆ 2-
(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, HOBTˆ 1-hydroxybenzotria-
zole, NMM ˆ N-methylmorpholine; for other abbreviations, see legend to Scheme 1.
We have developed a new synthet-
ic strategy for the parallel synthesis
of fucopeptides as sLex mimetics on
a solid phase. Linking the sugar
through a highly acid sensitive 1,2-
diol protecting and anchoring group
was divided into equal parts in the dry state. Allyl cleavage[14]
with Pd0 and dimedone as a scavenger liberated the
C-terminus of the fucosyl ± threonine conjugate, which was
subsequently modified. Esterification was best accomplished
with a large excess of alcohol and activation by a mixed
anhydride,[15] and amide bonds were formed by standard
methods of peptide synthesis. Our model studies revealed
that C-terminal functionalization on solid phase proceeds
with high yield and no racemization. A peptide synthesis
consisting of removal of the Fmoc groups, amino acid
coupling, and cleavage of the benzylidene acetal anchor
groups under weakly acidic conditions afforded the protected
fucosylpeptides 8 in high yields (Table 1). Diketopiperazines
and compounds formed by cleavage of the a-fucosidic bond
were not detected on analysis of the crude cleavage products
by mass spectrometry. To obtain homogeneous materials for
biological evaluation, fucosylpeptides 8 were purified by
chromatography on silica gel. Yields of 8 range from 47 to
65% (based on the initial loading); this corresponds to an
average yield of 90 ± 94% per step. Removal of the benzylic
protecting groups by catalytic hydrogenation afforded the
mimetics 9.
(p-AMBA) enables variable functionalization of the N- and
C-termini of glycopeptides. This provides access to a library of
sLex mimetics by parallel or combinatorial synthesis and
allows rapid optimization of the biological activity of a known
lead structure. Some members of the fucopeptide library
exhibit high selectivity and activity against P-selectin in cell-
free assay systems. Work is in progress to test the versatility of
p-AMBA based immobilization methodology in other syn-
thetic areas involving 1,2- and 1,3-diol units, for example, the
synthesis of complex oligosaccharides on solid phases.
Experimental Section
1
Immobilization of 5: Carboxyl-functionalized resin (3.85 g, 0.26 mmolg
,
corresponding to 1.0 mmol of functional groups) was dried for several
hours under high vacuum. Then 4-DMAP (12.2 mg, 0.1 mmol), DIC
(1.5 mmol), and a solution of alcohol 5 (1.545 g, 2.1 mmol) in dry CH2Cl2
(16 mL) were added, and the suspension was gently shaken for 14 h at room
temperature. The reaction mixture was transferred into a peptide synthesis
vessel, filtered, and the resin washed thoroughly with dry CH2Cl2 and dried
under high vacuum to give 4.32 g of material. The combined filtrate was
concentrated in vacuo, and unchanged alcohol 5 (740 mg, 1.0 mmol, 48%)
was recovered after purification by column chromatography on silica gel.
Cleavage of the Fmoc groups from the dry resin followed by photometric
1
analysis revealed a loading of ꢀ 0.24 mmolg ( ꢀ 1.04 mmol on resin,
Fucosylpeptides 9a ± h were tested against E- and P-
selectins in a cell-free assay system.[16] With polyvalent sLea
attached to a polyacrylamide[16a] in the E-selectin binding
assay, all members of the fucosylpeptide library showed only
moderate binding affinities, whereby phosphonate fucopep-
tide 9h was the most active (IC50 ˆ 0.7mm). While the
100% functionalization).
Fmoc cleavage and amino acid coupling: After swelling in DMF and
removal of excess DMF, the resin was suspended in DMF/morpholine (1/1,
0.6 mL per 100 mg dry resin) and shaken for 1 h at room temperature
(step c, Scheme 3) or suspended in DMF/piperidine (3/2) and shaken for
10 min at room temperature (step e, Scheme 3). After washing with dry
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Table 1. Structures, yields, and biological activities of the sLex mimics 8 and 9.
8 or 9[a]
Yield
of 8[b]
Yield
of 9[c]
XR1
R3 [d]
E-selectin
IC50 [mm] [e]
P-selectin
IC50 [mm] [e]
a
b
c
d
e
f
62
65
47
58
49
51
65
88
97
76
67
81
95
94
OEt
OEt
0.8
4.0
3.2
4.1
1.8
3.2
0.7
3.0
0.66
0.057
0.030
0.059
0.256
g
OEt
> 1.0
h
55
90
4.1
0.017
[a] In this series R2 remains constant, and Fmoc-protected g-benzyloxy-l-allo-threonine[17] was used as amino acid building block. [b] Yields based on
purified fucopeptides 8. [c] Yields based on purified 9 after fractional precipitation of crude hydrogenation products from MeOH/Et2O (9a ± f), ion-exchange
chromatography (9g and 9h) and lyophilization from H2O. [d] The substituents shown refer to 9; compounds 8 contain the corresponding benzylated
substituents. [e] The activities were measured according to the procedure described previously with sLea ± polyacrylamide conjugate. The values are an
average of three measurements, Æ 10%.; IC50 for sLex ˆ 0.8mm towards E-selectin and >3mm towards P-selectin).[16a]
DMF (6 Â , 1 mL per 100 mg dry resin ), a pre-stirred (5 ± 10 min) solution
of the acids used for coupling (3equiv for step d and 6 equiv for step f,
Scheme 4), HOBT, NMM, and HBTU (1.6 equiv, 2.2 equiv and 1.05 equiv,
based on the amount of acid) in dry DMF (0.2 ± 0.25m in acid) was added to
the resin. After shaking for 4 ± 4.5 h at room temperature, the coupling
reaction was terminated by filtration, and the resin was washed with DMF
and CH2Cl2 (6 Â each).
Cleavage from the resin: A suspension of resin in aqueous AcOH (80%,
0.9 mL per 100 mg dry resin) containing 2% TFA was shaken for 18 ± 22 h
at room temperature. After filtration and washing three times with AcOH
(80%), the cleavage procedure was repeated. The filtrate was concentrated
in vacuo, and residual AcOH and H2O were removed by coevaporating
twice with dry toluene. The colorless to slightly yellow oil or solid was
purified by column chromatography on silica gel to afford material that was
homogeneous according to HR-MS, 1H, and 13C NMR spectroscopy.
Keywords: glycopeptides ´ parallel synthesis ´ sialyl Lewis X
mimetics ´ solid-phase synthesis
[1] a) T. A. Springer, Cell 1994, 76, 301, and references therein; b) J. C.
Paulson in Adhesion: Its Role in Inflammatory Disease (Ed.: L.
Harlow, D. Liu), Freemann, New York, 1992.
[2] a) M. Buerke, A. S. Weyrich, Z. Zheng, F. C. A. Gaeta, M. J. Forrest,
A. M. Lefer, J. Clin. Invest. 1994, 1140; b) A. Giannis, Angew. Chem.
1994, 106, 188; Angew. Chem. Int. Ed. Engl. 1994, 33, 178.
[3] For a comprehensive review on sLex mimetics, see E. E. Simanek, G. J.
McGarvey, J. A. Jablonowski, C.-H. Wong, Chem. Rev., in press and
references therein.
[4] B. J. Graves, R. L. Crowther, C. Chandran, J. M. Rumberger, S. Li, K.-
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Nature 1994, 367, 532.
9b: colorless hygroscopic solid; 1H NMR (500 MHz, D2O): d ˆ 4.95 (d, J ˆ
3.5 Hz, 1H), 4.68 (brs, 1H), 4.54 (d, J ˆ 7.2 Hz, 1H), 4.44 (q, J ꢀ 6.1 Hz,
1H), 4.22 (dq, J ˆ 10.6, 7.2 Hz, 1H), 4.12 (dq, J ˆ 10.6, 7.2 Hz, 1H), 3.97 (m,
1H), 3.74 ± 3.69 (m, 5H), 3.60 (dd, J ˆ 12.1, 6.4 Hz, 1H), 2.62 ± 2.52 (m, 4H),
1.24 (t, J ˆ 7.1 Hz, 3H), 1.15 (brd, J ꢀ 6.4 Hz, 6H); HR-MS: m/z calcd for
[5] For solution conformations, see a) Y. Ichikawa, Y. C. Lin, D. P. Dumas,
G. J. Shen, E. Garcia-Junceda, M. A. Williams, R. Bayer, C. Ketcham,
L. E. Walker, J. C. Paulson, C.-H. Wong, J. Am. Chem. Soc. 1992, 114,
9283; for conformations bound to E-selectin, see b) R. M. Cooke, R. S.
Hale, S. G. Lister, G. Shah, M. P. Weir, Biochemistry 1994, 33, 10591;
c) L. Scheffler, B. Ernst, A. Katopodis, J. L. Magnani, W. J. Wang, R.
Weisema, T. Peters, Angew. Chem. 1995, 107, 2034; Angew. Chem. Int.
Ed. Engl. 1995, 34, 1841; for conformations bound to E-, P-, and L-
selectins, see d) L. Poppe, G. S. Brown, J. S. Philo, P. V. Nikrad, B. H.
Shah, J. Am. Chem. Soc. 1997, 119, 1727.
[6] a) B. K. Bradley, M. Kiso, S. Abbas, P. Nikrad, O. Strivastava, C.
Foxall, Y. Oda, A. Hasegawa, Glycobiology, 1993, 3, 633; b) W. Stahl,
U. Sprengard, G. Kretzschmar, H. Kunz, Angew. Chem. 1994, 106,
2186; Angew. Chem. Int. Ed. Engl. 1994, 33, 2096; c) S. A. DeFrees,
F. C. A. Gaeta, Y. C. Lin, Y. Ichikawa, C.-H. Wong, J. Am. Chem. Soc.
1993, 115, 7549.
‡
C20H34O13N2Cs: 643.1115 [M‡Cs] , found: 643.1139. 9d: colorless hygro-
1
scopic solid; H NMR (500 MHz, D2O): d ˆ 4.94 (d, J ˆ 3.7 Hz, 1H), 4.53
(d, J ˆ 9.0 Hz, 1H), 4.44 (brs, 1H), 4.41 (d, J ˆ 6.3 Hz, 1H), 3.89 ± 3.87 (m,
1H), 3.75 ± 3.52 (m, 16H), 3.43 (t, J ˆ 6.7 Hz, 2H), 3.31 ± 3.36 (m, 2H), 2.29
(t, J ꢀ 7.1 Hz, 2H), 2.24 (t, J ˆ 7.4 Hz, 2H), 1.81 (t, J ꢀ 7.3 Hz, 2H), 1.55 ±
1.50 (m, 2H), 1.28 ± 1.21 (m, 14H), 1.18 (d, J ˆ 6.1 Hz, 3H), 1.14 (d, J ˆ
6.4 Hz, 3H), 0.83 (brt, J ꢀ 6.6 Hz, 3H); HR-MS: m/z calcd for
‡
C35H65O15N3Cs: 900.3470 [M‡Cs] , found: 900.3498. 9e: colorless hygro-
1
scopic solid; H NMR (500 MHz, D2O): d ˆ 4.94 (d, J ˆ 3.5 Hz, 1H), 4.70
(brs, 1H), 4.58 (d, J ˆ 7.2 Hz, 1H), 4.42 ± 4.35 (m, 2H), 4.18 ± 4.16 (m, 1H),
3.97 ± 3.96 (m, 1H), 3.74 ± 3.55 (m, 16H), 3.42 (t, J ˆ 6.5 Hz, 2H), 2.64 ± 2.53
(m, 4H), 1.53 (brs, 2H), 1.30 ± 1.23 (m, 14H), 1.17 (d, J ˆ 6.1 Hz, 3H), 1.15
(d, J ˆ 6.4 Hz, 3H), 0.85 (brt, J ꢀ 6.5 Hz, 3H); HR-MS: m/z calcd for
[7] a) S.-H. Wu, M. Shimazaki, C.-C. Lin, L. Qiao, W. J. Moree, G. Weitz-
Schmidt, C.-H. Wong, Angew. Chem. 1996, 108, 106; Angew. Chem.
Int. Ed. Engl. 1996, 35, 88; b) C.-H. Wong, F. Moris-Varas, S.-C. Hung,
T. G. Maron, C.-C. Lin, K. W. Gong, G. Weitz-Schmidt, J. Am. Chem.
Soc. 1997, 119, 8152; c) H. C. Kolb, B. Ernst, Chem. Eur. J. 1997, 3,
‡
C34H62O16N2Cs: 887.3154 [M‡Cs] , found: 887.3184.
Received: January 16, 1998 [Z11372IE]
German version: Angew. Chem. 1998, 110, 1761 ± 1764
1710
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Angew. Chem. Int. Ed. 1998, 37, No. 12

COMMUNICATIONS
1571; d) For early work on glycopeptides as mannose 6-phosphate
mimics, see M. K. Christensen, M. Meldal, K. Bock, H. Cordes, S.
Mouristen, H. Elsner, J. Chem. Soc. Perkin Trans. 1 1994, 1299.
[8] a) M. A. Gallop, R. W. Barrett, W. P. Dower, S. P. A. Fodor, E. M.
Gordo, J. Med. Chem. 1994, 37, 1233; b) E. M. Gordon, R. W. Barrett,
W. J. Dower, S. P. A. Fodor, M. A. Gallop, ibid. 1994, 37, 1385; c) J. S.
Früchtel, G. Jung, Angew. Chem. 1996, 108, 19; Angew. Chem. Int. Ed.
Engl. 1996, 35, 17; d) F. Balkenhohl, C. von dem Bussche-Hünnefeld,
A. Lansky, C. Zechel, ibid. 1996, 108, 2436; 1996, 35, 2288;
e) Combinatorial Peptide and Nonpeptide Libraries (Ed.: G. Jung),
VCH, Weinheim, 1996; f) K. S. Lam, M. L. V. Krchnak, Chem. Rev.
1997, 97, 411; g) A. Nefzi, J. M. Ostresh, R. A. Houghten, ibid. 1997, 97,
449.
Complex Fluids Based on the Flexible One-
Dimensional Mineral Polymers [K(MPS4)]1
(M ˆ Ni, Pd): Autofragmentation to Concave,
Cyclic (PPh4)3[(NiPS4)3]**
Julien Sayettat, Lucy M. Bull, Jean-Christophe P.
Â
Gabriel, Stephane Jobic, Franck Camerel, Anne-Marie
Â
Marie, Marc Fourmigue, Patrick Batail,* Raymond
Â
Brec,* and Rene-Louis Inglebert
In memory of Jean Rouxel
[9] Anchoring of 1,3- and 1,2-diols on solid supports: a) J. M. J. Frechet, G.
Pelle, J. Chem. Soc. Chem. Commun. 1975, 225; b) E. Seymour, J. M. J.
Frechet, Tetrahedron Lett. 1976, 3669; c) S. Hanessian, T. Ogawa, Y.
Guindon, J. L. Kamennof, R. Roy, Carbohydr. Res. 1974, 38, C15; d) Y.
Palom, E. Alazzouzi, F. Gordillo, A. Grandas, E. Pedroso, Tetrahedron
Lett. 1993, 34, 2195; e) G. T. Wang, S. Li, N. Wideburg, G. A. Krafft,
D. J. Kempf, J. Med. Chem. 1995, 38, 2995.
[10] Although C-terminal modified peptide amides and esters are acces-
sible by using specific linker groups, the approaches reported so far are
not adaptable to combinatorial methodologies. More synthetic
flexibility has been introduced by the concept of postsynthetic C ± N
inversion on the solid phase: a) M. Davies, M. Bradley, Angew. Chem.
1997, 109, 1135; Angew. Chem. Int. Ed. Engl. 1997, 36, 1097; b) R. S.
Kania, R. N. Zuckermann, C. K. Marlowe, J. Am Chem. Soc. 1994,
116, 8835.
[11] a) J. Y. Ramphal, M. Hiroshige, B. Lou, J. J. Gaudino, M. Hayashi,
S. M. Chen, L. C. Chiang, F. C. A. Gaeta, S. A. DeFrees, J. Med.
Chem. 1996, 39, 1357; b) H. Tsujishita, Y. Hiramatsu, N. Kondon, H.
Ohmoto, H. Kondo, M. Kiso, A. Hasegawa, ibid. 1997, 40, 362.
[12] S. Sato, M. Mori, Y. Ito, T. Ogawa, Carbohydr. Res. 1986, 155,
C6.
[13] E. Bayer, Angew. Chem. 1991, 103, 117; Angew. Chem. Int. Ed. Engl.
1991, 30, 113.
[14] H. Kunz, H. Waldmann, Angew. Chem. 1984, 86, 49; Angew. Chem.
Int. Ed. Engl. 1984, 23, 71.
The discovery of the lyotropic nematic phase of LiMo3Se3 in
N-methylformamide,[1] a rare example of a liquid crystal
based on a mineral core, was achieved 70 years after the
pioneering work of the German physicist H. Zocher.[2] This
event, soon followed by the study of the nematic behavior of
V2O5 ribbons[3] and smectic clays[4] in water, has aroused acute
interest in the development of solution-phase chemistry of
charged, all-inorganic molecules. The motivation for such
investigations is the prospect of unraveling the organic/
inorganic interfacial chemistry and physics of unprecedented
anisotropic fluids based on one- and two-dimensional, charg-
ed, extended mineral polymers.[5, 6]
The solid-state chemistry of transition metal chalcoge-
nides[7] is abound with low-dimensional motifs, such as
11[Mo3Se3] . Their dimensionality arises from the balance
between the strong covalent character of the transition
metal ± chalcogen bonds within the negatively charged chains
or slabs and their effective ionic screening by alkali metal
cations.[8, 9] A recent example is the series of transition metal
chalcogenide phosphates KMPS4 (M ˆ Ni, Pd) with infinite
anionic chains 11[MPS4] .[10] Here we demonstrate 1) that
KMPS4 compounds are soluble in polar organic solvents such
as dimethylformamide (DMF) and dimethyl sulfoxide
(DMSO), and form complex fluids made up of flexible
inorganic polymers; 2) that [(NiPS4)3]3 Ðan unprecedented,
concave trimetallic thiophosphate molecular trianion adopt-
ing pseudo-C3v symmetryÐis formed in DMF at room
temperature from the autofragmentation and rearrangement
of 11[NiPS4] ; and 3) that it is possible to follow the dissolution
and fragmentation processes with mass spectrometry, solu-
tion-state 31P NMR spectroscopy, and transmission electron
microscopy (TEM). Thus, the contrasting behavior and
stability of the Ni and Pd phases can be revealed.
[15] P. Sieber, Tetrahedron. Lett. 1987, 28, 6147.
[16] a.) G. Weitz-Schmidt, D. Sockmaier, G. Scheel, N. E. Nifantꢁev, A. B.
Tuzikov, N. V. Bovin, Anal. Biochem. 1996, 238, 184; All compounds
were active against P-selectin with IC50 values in the range of 1 ± 7mm
in the sLea polylysine conjugate assay: b) G. Thoma, J. L. Magnani, R.
Ohrlein, B. Ernst, F. Schwarzenbach, R. Duthaler, J. Am. Chem. Soc.
1997, 119, 7414.
[17] g-Benzyloxy-l-allo-threonine was prepared by l-threonine aldolase-
catalyzed aldol condensation of benzyloxyglyceraldehyde and glycine:
V. P. Vassilev, T. Uchiyama, T. Kajimoto, C.-H. Wong, Tetrahedron
Lett. 1995, 36, 4081. It has been shown to be a good replacement for
Gal.[7a]
In accordance with their highly anisotropic bonding,
KNiPS4 and KPdPS4 are soluble in polar organic solvents
[*] Dr. P. Batail, Prof. R. Brec, Dr. J. Sayettat, Dr. L. M. Bull, Dr. J.-C. P.
Â
Gabriel, Dr. S. Jobic, F. Camerel, Dr. A.-M. Marie, Dr. M. Fourmigue
Â
Institut des Materiaux de Nantes
Â
UMR 6502 CNRS-Universite de Nantes
BP 32229, 44322 Nantes (France)
Fax: (‡33)240-373-995
E-mail: batail@cnrs-imn.fr
Dr. R.-L. Inglebert
Â
GREMI, UFR Faculte des Sciences
Â
rue de Chartres, BP 6759, 45067 Orleans (France)
[**] This work was supported by the CNRS. L.M.B. wishes to thank the
Â
Region Pays de Loire and the CNRS for a postdoctoral fellowship and
a visiting scientist grant, respectively.
Angew. Chem. Int. Ed. 1998, 37, No. 12
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1433-7851/98/3712-1711 $ 17.50+.50/0
1711