Convergent route to organometallic dendrimers composed of platinum- acetylide units

Article abstract of DOI:10.1002/(SICI)1521-3773(19990301)38:5<689::AID-ANIE689>3.0.CO;2-D

The third-generation dendrimer with 45 platinum atoms (shown schematically) was synthesized efficiently by a convergent methodology in which two different trialkylsilyl groups (symbolized by the nodal points) are used to protect the bridging triethynylben

Full text of DOI:10.1002/(SICI)1521-3773(19990301)38:5<689::AID-ANIE689>3.0.CO;2-D

COMMUNICATIONS
[1] a) F. A. Troy II, Glycobiology 1992, 2, 5 ± 23; b) U. Rutishauser, A.
Acheson, A. K. Hall, D. M. Mann, J. Sunshine, Science 1988, 240, 53 ±
57; c) K. Kitajima, S. Inoue, Y. Inoue, F. A. Troy II, J. Biol. Chem. 1988.
263, 18269 ± 18276; d) C. Zuber, P. M. Lackie, W. A. Caterall, J. Roth, J.
Biol. Chem. 1992, 267, 9965 ± 9971; e) S. Inoue, M. Iwasaki, Biochem.
Biophys. Res. Commun. 1978, 83, 1018 ± 1023; f) J. B. Robbin, G. H.
McCracken, Jr., E. C. Gotschlich, F. érskov, I. érskov, L. A. Hanson,
N. Engl. J. Med. 1974, 290, 1216 ± 1220; g) M. S. Schiffer, E. Oliverira,
M. P. Glode, G . H. McCracken, Jr., L. M. Sarff, J. B. Robbin, Pediatr.
Res. 1976, 10, 82 ± 87.
[2] a) M. R. Lifely, A. S. Gilbert, C. Moreno, Carbohydr. Res. 1981, 94,
193 ± 203. b) M. R. Lifely, A. S. Gilbert, C. Moreno, Carbohydr. Res.
1984, 134, 229 ± 243.
[3] a) L. Riboni, S. Sonnino, D. Acquotti, A. Malesci, R. Ghidoni, H. Egge,
S. Mingrino, G. Tettamanti, J. Biol. Chem. 1986, 261, 8514 ± 8519;
b) G. A. Nores, T. Dohi, M. Taniguchi, S. Hakomori, J. Immunol. 1989,
139, 3171 ± 3176; c) R. Bassi, L. Riboni, S. Sonnino, Carbohydr. Res.
1989, 193, 141 ± 146.
closely related to sialic acid. On the other hand, such an
interaction is not possible for the side chains of the other two
sugar units since the rigidity is created by the glycosidic
linkage fixed at C-8. Other possible explanations cannot be
simply ruled out. For example, the different pKa values of
these carboxyl groups[8] may result in such regioselectivity.
However, our speculation waits for the isolation and purifi-
cation of both monolactone trimers for further NMR stud-
ies;[6] computer modeling is currently in progress.
In conclusion, two different methods are presented to
obtain the two possible monolactones of an a-2,8-linked
trisialic acid with regioselectivity. The neuraminidase hydrol-
ysis demonstrates a novel way to distinguish both regioisom-
ers from each other. The methods developed here can be
further extended and applied to prepare other lactonized
oligomers for the investigation of their unknown biological
functions.
[4] S. Ando, R. K. Yu, J. N. Scarsdale, S. Kusunoki, J. H. Prestegard, J. Biol.
Chem. 1989, 264, 3478 ± 3483.
[5] a) R. K. Yu, T. A. W. Koerner, S. Ando, H. C. Yohe, J. H. Prestegard, J.
Biochem. 1985, 98, 1367 ± 1373; b) B. Maggio, T. Agria, R. K. Yu,
Biochemistry 1990, 29, 8729 ± 8734.
[6] Based on the results of 2D NMR experiments, the partial assignment of
compound 2 is given in the following. The detailed and complete NMR
characterizations are currently in progress and will be published in due
Experimental Section
course. 1H NMR (500 MHz, HOD): d ˆ 1.694 (1H, t, J3a-3e
ˆ
Reagents: N-Acetylneuraminic acid trimer ([!8Neu5Aca2!]3) was
obtained from NGK Biochemical Ltd. (Handa, Japan) with the help of
Prof. Yasuo Inoue. Neuraminidase from Anthrobacter ureafaciens was
purchased from Sigma (St. Louis, USA). All other reagents for reactions
and high-performance capillary electrophoresis (HPCE) were of the
highest grade commercially available.
J3e-4 ˆ 12 Hz, H-3a[II]), 1.740 (1H, t, J3a-3e ˆ J3e-4 ˆ 12 Hz, H-3a[III]),
1.830 (1H, t, J3a-3e ˆ J3e-4 ˆ 13 Hz, H-3a[I]), 2.065 (6H, s, 2acetyl), 2.088
(3H, s, acetyl), 2.229 (1H, dd, J3e-3a ˆ 12, J3e-4 ˆ 4.5 Hz, H-3e[I]), 2.254
(1H, dd, J3e-3a ˆ 12, J3e-4 ˆ 4.5 Hz, H-3e[III]), 2.814 (1H, dd,
J3e-3a ˆ 12, J3e-4 ˆ 4.5 Hz, H-3e[II]), 3.625 (1H, m, H-4[II]), 3.651 (1H,
m, H-4[III]), 3.802 (1H, m, H-5[III]), 3.895 (1H, m, H-5[I]), 3.973 (1H,
m, H-5[II]), 4.022 (1H, m, H-4[I]). [I] is defined as the sugar unit
located at the reducing terminal of 2, and [III] is at the nonreducing
Lactonization of the a-2,8-linked tri-N-acetylneuraminic acid: Free trimers
of [a2!8] N-acetylneuraminic acid (25 mg) were incubated in glacial acetic
acid (1 mL) at room temperature. The reaction mixtures were frozen with
liquid nitrogen and then dried immediately by SpeedVac (Savant, USA) to
remove acetic acid. Dried samples were dissolved in doubly distilled water,
and an aliquot (5 mL) of the mixture was analyzed by HPCE.
Â
end. For this assignment, see also T. Ercegovic, G. Magnusson, J. Org.
Chem. 1996, 61, 179 ± 184; ref. [4].
[7] a) C.-H. Lin, B. W. Murray, I. R. Ollmann, C.-H. Wong, Biochemistry
1997, 36, 780 ± 785. b) T. Sugai, C.-H. Lin, G.-J. Shen, C.-H. Wong,
Bioorg. Med. Chem. 1995, 3, 313 ± 320.
[8] A. E. Manzi, H. H. Higa, S. Diaz, A. Varki, J. Biol. Chem. 1994, 269,
23617 ± 23624.
Preparation of the dilactone 4: free trimers of [a2!8] N-acetylneuraminic
acid (25 mg) were left in glacial acetic acid (1 mL) at room temperature for
8 h, frozen with liquid nitrogen, and then dried immediately by SpeedVac
(Savant, USA) to remove acetic acid.
Hydrolysis of 4: A sample of 4 (50 mg) was dissolved in 0.1n (NH4)2CO3
(500 mL) at 378C. After 20, 40, and 80 min an aliquot was removed, frozen
with liquid nitrogen, and then dried by SpeedVac (Savant, USA). Dried
samples were dissolved in doubly distilled water, and an aliquot (5 mL) of
the mixture was analyzed by HPCE.
Convergent Route to Organometallic
Dendrimers Composed of Platinum ± Acetylide
Units**
Chromatographic analysis: Capillary electrophoreses (CE) were per-
formed on a Beckman capillary electrophoresis system (P/ACE 2100) with
a fused silica capillary (118 cmÂ75 mm (inner diameter)) at 20 kV and
258C. Phosphate buffer (50 mm, pH 8.0) was used as the running buffer.
The UV absorption at 200 nm was monitored. Samples were injected into
the capillary under a high pressure of nitrogen (1.3 bar) for 3 s. The
capillary was regenerated by washing with doubly distilled water for 3 min
and then 0.1n NaOH for 5 min.
Kiyotaka Onitsuka, Masanori Fujimoto,
Nobuaki Ohshiro, and Shigetoshi Takahashi*
There is increasing interest in the development of new
strategies to synthesize well-defined nanosize macromole-
cules with specific functions. Dendrimers have a regularly
branched architecture and have large, spherical dimensions to
meet the requirements for new materials.[1] One method for
the functionalization of dendrimers is the incorporation of
Neuraminidase hydrolysis: Partially lactonized samples (10 mg) in 100mm
ammonium acetate buffer (pH 5) were digested with neuraminidase
(1 mU) from Anthrobacter ureafaciens in 20-mL CE vials at room temper-
ature. The progress of hydrolysis was monitored by HPCE at regular time
intervals.
Fast atom bombardment (FAB) mass spectrometry: Negative-mode FAB
mass spectra of the samples were obtained on an Autospec OA-TOF mass
spectrometer (Micromass, UK) fitted with a cesium ion gun operated at
26 kV. Samples were dissolved in Milli Q water for loading on to the probe
tip coated with monothioglycerol as matrix.
[*] Prof. Dr. S. Takahashi, Dr. K. Onitsuka, M. Fujimoto, N. Ohshiro
The Institute of Scientific and Industrial Research
Osaka University, Mihogaoka, Ibaraki, Osaka 567 ± 0047 (Japan)
Fax : (‡ 81)6-6879-8459
E-mail: takahashi@sanken.osaka-u.ac.jp
Received: July 29, 1998 [Z12220IE]
German version: Angew. Chem. 1999, 111, 746 ± 749
[**] This work was partly supported by a Grant-in-Aid for Scientific
Research on Priority Areas (No. 10149228 ªMetal-assembled Com-
plexesº) from the Ministry of Education, Science, Sports, and Culture.
Keywords: capillary electrophoresis ´ lactones ´ sialic acids
Angew. Chem. Int. Ed. 1999, 38, No. 5
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3805-0689 $ 17.50+.50/0
689

COMMUNICATIONS
transition metals that exhibit some characteristic properties.
Most organometallic dendrimers reported previously, how-
ever, contain metal atoms either only at the core[2] or at the
surface,[3] and organometallic dendrimers with transition
metals in every generation have so far been less studied.[4]
Since such organometallic dendrimers are built up by
successive organometallic reactions, the strategy is severely
limited because of the low stability of organometallic
complexes relative to organic compounds.
We reported previously the synthesis of platinum ± acety-
lide dendrimers, which utilized triethynylmesitylene as a
bridging ligand to build up a heneicosanuclear complex, which
is a second generation dendrimer.[5] Metal ± acetylide den-
drimers may have potential applicability as new materials,
since some metal acetylides are known to show unique
properties.[6] However, it would be difficult to extend the
method that we employed previously to synthesize higher
generation dendrimers, because of the large effort required to
isolate the resulting dendrimers from the reaction mixture
when no protecting groups were used. Herein we wish to
report an efficient route for the synthesis of an organometallic
dendrimer composed of platinum ± acetylide units in the main
chain by a convergent method. The methodology involves the
use of two kinds of trialkylsilyl protecting groups, trimethyl-
silyl and tri(isopropyl)silyl, of the terminal acetylene unit for
the synthesis of platinum ± acetylide dendrimers.[7]
alent of tri(isopropyl)silylacetylene at room temperature in
the presence of a [PdCl2(PPh3)2]/CuI catalyst in diethylamine
led to the selective formation of the mono(silylethynyl)
derivative 2, which was converted quantitatively into a
tri(silylethynyl) derivative 3 by the reaction with excess
trimethylsilylacetylene in triethylamine under reflux.[8] Since
a tri(isopropyl)sily group is less reactive towards a base than a
trimethylsilyl group,[7] selective desilylation of the trimethyl-
silyl group was performed with K2CO3 in acetone to give
compound 4, which had two terminal acetylenic groups in the
molecule. p-Methoxyphenylethynylplatinum groups, which
would eventually become the chain-end groups of our
dendrimers, were introduced by the reaction of 4 with two
equivalents of the platinum complex 5 in the presence of a
CuCl catalyst at room temperature to give the dinuclear
acetylide complex 6.[9] Removal of the tri(isopropyl)silyl
group in 6 by the treatment with Bu4NF gave the first
generation dendron 7. The molecular structure of 7 was
determined by X-ray analysis (Figure 1).[10]. The Pt ± C bond
distances are in the range of 1.992(9) ± 2.01(1) Š, which are
The triethynylbenzene derivatives, which were used as the
bridging ligand, were protected as shown in Scheme 1.
Treatment of 1,3-dibromo-5-iodobenzene (1) with one equiv-
Figure 1. Molecular structure of the first generation dendron 7. Hydrogen
atoms are omitted for clarity.
slightly longer than those of the triethynylmesitylene-bridged
triplatinum complex 8 because of the strong trans influence of
an ethynyl group relative to a chloride ligand.[5] The coordi-
nation planes around the Pt atoms in 7 are approximately
perpendicular to the aromatic plane of the central bridge and
parallel to the aromatic plane of p-methoxyphenylethynyl
groups, while in 8 the former arrangement has dihedral angles
of about 608.[5]
The first-generation dendrimer 9, which contained nine
platinum atoms, was prepared by the reaction of 7 with the
core complex 8 in a 3:1 molar ratio (Scheme 2). The 1H NMR
spectrum of 9 showed two singlets at d ˆ 2.57 and 3.78 in a 1:2
integral ratio; the former signal is assignable to the methyl
protons of the central mesitylene group and the latter to the
methoxy protons of the end group. The 31P{1H} NMR
spectrum of 9 exhibited two singlets at d ˆ 10.88 (JPt,P
ˆ
2381 Hz) and 11.10 (JPt,P ˆ 2392 Hz) in a 2:1 integral ratio,
which correspond to the phosphane groups bound to the six
outer and to three inner platinum atoms, respectively. These
data are consistent with the expected structure of 9, which is
also supported by IR and elemental analyses.
The first-generation dendron 7 was successfully grown to a
second-generation dendron 11 by the reaction with 10 in a 2:1
molar ratio, followed by desilylation of the tri(isopropyl)silyl
group (Scheme 3). The similar reaction of 10 with 11 resulted
in the formation of the third generation dendron 12.
Reactions of 11 and 12 with 8 in a 3:1 molar ratio led to the
formation of the second and third-generation dendrimers 13
ꢀ
Scheme 1. Synthesis of the first-generation dendron 7. a) HC CSiiPr3,
[Pd(PPh3)2Cl2] (cat.), CuI (cat.), Et2NH, RT, quantitative yield;
ꢀ
b) HC CSiMe3, [Pd(PPh3)2Cl2] (cat.), CuI (cat.), Et3N, benzene, reflux,
90%; c) K2CO3 (aq), acetone, reflux, 95%; d) Cl(Et3P)2Pt CC6H4OMe 5
(2 equiv), CuI (cat.), Et2NH, RT, 96%; e) Bu4NF, THF, 788C !RT, 95%.
ꢀ
690
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3805-0690 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1999, 38, No. 5

COMMUNICATIONS
Scheme 2. Synthesis of the first generation dendrimer 9.
Scheme 4. Synthesis of the second- and third-generation dendrimers 13
and 14.
showed only two signals at d ˆ 10.84 (JPt,P ˆ 2381 Hz) and
11.04 (the coupling constant JPt,P could not be determined
since the satellite signals were too weak to be detected) in an
about 14:1 integral ratio. The latter signal is assigned to the
central six phosphanes, and the the former to the other eighty
four phosphane atoms. To the best of our knowledge 14, which
contains 45 platinum atoms in a molecule, is one of the largest
organotransition metal dendrimers and belongs to nanosize
materials.
In summary, a methodology for the efficient synthesis of
very large platinum ± acetylide dendrimers that contain up to
45 platinum atoms has been developed by a convergent
method that uses two kinds of trialkylsilyl groups. The method
presented here may be applied to the synthesis of metal ±
acetylide dendrimers other than platinum, since several stable
transition metal ± acetylide complexes are already known.[9, 11]
Scheme 3. Synthesis of the second- and third-generation dendrimers 11 and
12, respectively. a) CuI (cat.), Et2NH, RT; b) Bu4NF, THF, 788C !RT.
and 14, respectively (Scheme 4). The 1H NMR spectrum of 14
(Figure 2) is very simple in spite of it being an extremely large
molecule (Mr ˆ 25840), which indicates a highly symmetric
structure. Two singlet signals are observed at d ˆ 2.57 and 3.77
from the central mesitylene group and the methoxy end
group, respectively, in a 1:8 integral ratio, which supports the
proposed structure of 14. The 31P{1H} NMR spectrum of 14
Received: September 9, 1998 [Z12396IE]
German version: Angew. Chem. 1999, 111, 737 ± 739
Keywords: alkyne complexes ´ dendrimers ´ platinum
Angew. Chem. Int. Ed. 1999, 38, No. 5
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3805-0691 $ 17.50+.50/0
691

COMMUNICATIONS
[3] a) J. W. J. Knapen, A. W. van der
Made, J. C. de Wilde, P. W. N. M.
van Leeuwen, P. Wijkens, D. M.
Grove, G. van Koten, Nature
1994, 372, 659; b) D. Seyferth,
T. Kugita, A. L. Rheingold, Or-
ganometallics 1995, 14, 5362;
c) Y.-H. Liao, J. R. Moss, Orga-
nometallics 1996, 15, 4307; d) M.
Bardaji, M. Kustos, A.-M. Cami-
nade, J.-P. Majoral, B. Chaudret,
Organometallics 1997, 16, 403;
e) I. Cuadrado, C. M. Casado,
Â
B. Alonso, M. Moran, J. Losada,
V. Belsky, J. Am. Chem. Soc. 1997,
119, 7613.
[4] a) S. Campagna, G. Denti, S.
Serrori, A. Juris, M. Venturi, V.
Ricevuto, V. Balzani, Chem.
Eur. J. 1995, 1, 211; b) S. Achar,
J. J. Vittal, R. J. Puddephatt, Or-
ganometallics 1996, 15, 43;
c) W. T. S. Huck, L. J. Prins,
R. H. Fokkens, N. M. M. Nibber-
ing, F. C. J. M. van Veggel, D. N.
Reinhoudt, J. Am. Chem. Soc.
1998, 120, 6240.
[5] a) N. Ohshiro, F. Takei, K. Onit-
suka, S. Takahashi, Chem. Lett.
1996, 871; b) N. Ohshiro, F. Takei,
K. Onitsuka, S. Takahashi, J. Or-
ganomet. Chem. 1998, 569, 195.
[6] a) S. Takahashi, Y. Takai, H.
Morimoto, K. Sonogashira, N.
Hagihara, Mol. Cryst. Liq. Cryst.
1982, 82, 139; b) S. Takahashi, Y.
Takai, H. Morimoto, K. Sonoga-
shira, J. Chem. Soc. Chem. Com-
mun. 1984, 3; c) T. Kaharu, H.
Matsubara, S. Takahashi, J. Ma-
ter. Chem. 1992, 2, 43; d) T.
Kaharu, R. Ishii, T. Adachi, T.
Yoshida, S. Takahashi, J. Mater.
Chem. 1995, 5, 687.
[7] a) Y.-F. Lu, C. W. Harwig, A. G.
Fallis, J. Org. Chem. 1993, 58,
4202; b) O. Lavastre, L. Ollivier,
P. H. Dixneuf, S. Sibandhit, Tet-
rahedron 1996, 52, 5495; c) M. M.
Haley, M. L. Bell, J. J. English,
C. A. Johnson, T. J. R. Weakley,
J. Am. Chem. Soc. 1997, 119, 2956.
[8] S. Takahashi, Y. Kuroyama, K.
Sonogashira, N. Hagihara, Syn-
thesis 1980, 627.
1
[9] K. Sonogashira, T. Yatake, Y.
Tohda, S. Takahahi, N. Hagihara,
Figure 2. Structure and H NMR spectrum (in CDCl3) of the third-generation dendrimer 14.
[1] For reviews, see a) D. A. Tomalia, A. M. Naylor, W. G. A. God-
dard III, Angew. Chem. 1990, 102, 119; Angew. Chem. Int. Ed. Engl.
1990, 29, 138; b) J. Issberner, R. Moors, F. Vögtle, Angew. Chem. 1994,
106, 2507; Angew. Chem. Int. Ed. Engl. 1994, 33, 2413; c) G. R.
Newkome, C. N. Moorefield, F. Vögtle, Dendritic Molecules. Concepts,
Syntheses, Perspectives, VCH, Weinheim, 1996; d) H.-F. Chow, T. K.-
K. Mong, M. F. Nongrum, C.-W. Wan, Tetrahedron 1998, 54, 8543; e)
M. Fischer, F. Vögtle, Angew. Chem./Angew. Chem. Int. Ed. 1999, in
press.
J. Chem. Soc. Chem. Commun. 1977, 291.
[10] Crystallographic data for 7: C54H78O2P4Pt2 (Mr ˆ 1273.28), monoclinic,
space group P21/c (No. 14), aˆ 24.461(3), bˆ 10.286(3), cˆ 22.814(4) Š,
b ˆ 106.50(1)8, Vˆ 5503(1) Š3, Z ˆ 4, 1calcd ˆ 1.536 g cm 3, m(MoKa) ˆ
1
52.10 cm
,
758C, w ± 2q scan, 6 < 2q < 558, R (Rw) ˆ 0.051 (0.061)
determined by full-matrix least-squares method for 559 parameters
against 6391 reflections with I > 3.0s(I) from 12638 unique reflections
(Rint ˆ 0.037), GOF ˆ 1.07. Crystallographic data (excluding structure
factors) for the structure reported in this paper have been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-102875. Copies of the data can be obtained free
of charge on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK (fax: (‡44)1223-336-011; e-mail: deposit@ccdc.cam.ac.uk).
[11] M. I. Bruce, M. G. Humphrey, J. G. Matisons, S. K. Roy, A. G.
Swincer, Aust. J. Chem. 1984, 37, 1955.
[2] a) G. R. Newkome, R. Güther, C. N. Moorefield, F. Cardullo, L.
Â
Echegoyen, E. Perez-Cordero, H. Luftmann, Angew. Chem. 1995, 107,
2159; Angew. Chem. Int. Ed. Engl. 1995, 34, 2023; b) V. J. Catalano, N.
Parodi, Inorg. Chem. 1997, 36, 537; c) C. B. Gorman, B. L. Parkhurst,
W. Y. Su, K.-Y. Chen, J. Am. Chem. Soc. 1997, 119, 1141; d) C. M.
Cardona, A. E. Kaifer, J. Am. Chem. Soc. 1998, 120, 4023.
692
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3805-0692 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1999, 38, No. 5