Synthesis of Selectively Functionalized Carbosilane Dendrimers with a Carbohydrate Core

Article abstract of DOI:10.1021/ol9910619

(Matrix presented) First-generation members of a novel family of dendrimers schematically shown above have been synthesized. They display carbohydrate-centered carbosilanes in which one functional group (FG) is discriminated from the others. This will eve

Full text of DOI:10.1021/ol9910619

ORGANIC
LETTERS
1999
Vol. 1, No. 12
1925-1927
Synthesis of Selectively Functionalized
Carbosilane Dendrimers with a
Carbohydrate Core
Mike M. K. Boysen and Thisbe K. Lindhorst*
Institute of Organic Chemistry, UniVersity of Hamburg, Martin-Luther-King-Platz 6,
D-20146 Hamburg, Germany
tklind@chemie.uni-hamburg.de
Received September 17, 1999
ABSTRACT
First-generation members of a novel family of dendrimers schematically shown above have been synthesized. They display carbohydrate-
centered carbosilanes in which one functional group (FG) is discriminated from the others. This will eventually allow their utilization in the
synthesis of labeled carbosilanes or as selectively functionalized scaffolds for the preparation of multivalent glycomimetics.
Dendrimers1 combine the advantages of monodisperse
molecules with an especially large number of functionalities
of one kind, assembled in the periphery of the molecule.
However, a major disadvantage of the principles of dendritic
growth is that chemical discrimination of one functionality
from the others present in a particular dendrimer is difficult.2
Selectively functionalized dendrimers would allow a number
of attractive options such as immobilization of the molecule
or its labeling with a reporter group; therefore searching for
synthetic avenues to selectively functionalized dendrimers
is an important task.
ers.3 Using carbohydrates as core molecules for dendrimer
synthesis offers promising advantages for the preparation of
selectively functionalized analogues, since the anomeric
position of monosaccharides can be easily discriminated from
the other ring hydroxyls by glycosidation prior to the
construction of dendritic layers. Thus, glycosides can serve
as core scaffolds for the synthesis of selectively function-
alized dendrimers. This is the focus of our current work.
Because we are also utilizing this chemistry for the
synthesis of multivalent glycomimetics, which are designed
as inhibitors of bacterial adhesion,4,5 the choice of the spacer
characteristics being used in such a molecule is relevant. To
design rather flexible glycodendrimer antennae and avoid
intramolecular interactions of spacers, we have selected
We have been dealing with the preparation of dendrimers
with carbohydrate cores for various purposes and introduced
chiral glucose-based poly(amidoamine) (PAMAM) dendrim-
(1) For an overview, see: (a) Matthews, O. A.; Shipway, A. N.; Fraser
Stoddart, J. Prog. Polym. Sci. 1998, 23, 1-56. (b) Fischer, M.; Vo¨gtle, F.
Angew. Chem. 1999, 111, 934-955; Angew. Chem., Int. Ed. Engl. 1999,
38, 884-905.
(2) (a) Hawker, C. J.; Fre´chet, J. M. J. Macromolecules 1990, 23, 4726-
4729. (b) Wooley, K.; Hawker, C. J.; Fre´chet, J. M. J. J. Chem. Soc., Perkin
Trans. 1 1991, 1059-1076.
(3) Dubber, M.; Lindhorst, Th. K. Chem. Commun. 1998, 1265-1266.
(4) (a) Beachey, E. H. J. Infect. Dis. 1981, 143, 325-345. (b) Krogfeld,
K. A. ReV. Infect. Dis. 1991, 13, 721-735. (c) Karlsson, K.-A. Curr. Opin.
Struct. Biol. 1991, 1, 732-740.
(5) For multivalency in biological systems, see: Mammen, M.; Choi,
S.-K.; Whitesides, G. M. Angew. Chem. 1998, 110, 2908-2953; Angew.
Chem., Int. Ed. Engl. 1998, 37, 2754-2794.
10.1021/ol9910619 CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/24/1999

carbosilane dendrimers6 for this program, rather than the
nitrogen-based PAMAM dendrimers.
The applied synthetic route comprises per-allylation of
suitable glucosides and subsequent application of a hydro-
silylation-Grignard addition protocol, which is used for
growing carbosilane dendrimer generations.
Compounds 1 and 2 were selected as the starting gluco-
sides. They were obtained by glycosylation of the corre-
sponding alcohols using glucosyl trichloroacetimidate as
glycosyl donor under standard conditions.7 Per-allylation of
1 under Williamson conditions afforded tetraallylated gly-
coside 3 (Scheme 1).
7 using TBDMS-OTf (Scheme 2). Glucoside 7 can now also
survive the reaction conditions necessary for build up of
carbosilane generations.
For construction of the carbosilane dendrimers, dichloro-
methylsilane and allylmagnesium bromide were chosen as
reagents. Hydrosilylation9 of the allylic groups was ef-
fectively catalyzed by hexachloroplatinic acid in 2-propanol
(Speier’s catalyst10) to afford chlorosilanes 8 and 9. These
were submitted to the Grignard reaction without purification,
which finally led to the first-generation carbosilane den-
drimers 10 and 11 (Scheme 3).11
Scheme 3a
Scheme 1a
a
(a) NaH, allyl bromide, DMF.
The analogous procedure applied to 2 gave a mixture of
esters 4 and 5,8 which can be separated by means of flash
chromatography. However, they are better used as a mixture,
since they yield the same product in the following step
(Scheme 2).
Scheme 2a
a (a) HSiMeCl2, H2PtCl6‚6 H2O/i-PrOH, THF; (b) allylMgBr,
Et2O.
Proton NMR spectra of 10 and 11 display large areas of
overlapping signals due to the asymmetric character of these
carbohydrate-centered representatives of carbosilane den-
drimers. However, key signals for the allylic protons, the
silyl-methyl groups, and the benzylic protons as well as the
anomeric H-1 clearly allow the determination of integration
ratios which confirm complete conversion of four allyl
functions in 3 and 7. 13C NMR spectra, on the other hand,
are well-resolved and allow the assignment of each peak.
a (a) LiAlH4, Et2O; (b). TBDMS-OTf, MeCN.
The aglycon moiety of glucoside 3 can be directly
submitted to the hydrosilylation-Grignard addition sequence.
Esters 4 and 5, on the other hand, first must be reduced to
alcohol 6, which was subsequently protected as the silyl ether
(6) (a) van der Made, A. W.; van Leeuwen, P. W. N. M. J. Chem. Soc.,
Chem. Commun. 1992, 1400-1401. (b) Zhou, L.-L.; Roovers, J. Macro-
molecules 1993, 26, 963-968. (c) Seyferth, D.; Son, D. Y.; Rheingold, A.
L.; Ostrander, R. L. Organometallics 1994, 13, 2682-2690. (d) Kim, C.;
Park, E.; Kang, E. Bull. Korean Chem. Soc. 1996, 17, 419-424.
(7) Schmidt, R. R.; Kinzy, W. AdV. Carbohydr. Chem. Biochem. 1994,
50, 21-123.
(9) (a) Muslof, M. C.; Speier, J. L. J. Org. Chem. 1964, 29, 2519-
2524. (b) Chalk, A. J.; Harrod, J. F. J. Am. Chem. Soc. 1965, 87, 16-21.
(c) Ojima I. In The Chemistry of Organic Silicon Compounds; Patai, S.,
Rappoport, Z., Eds.; Wiley: New York, 1989; pp 1479-1526. (d)
Marciniec, B.; Gulinski, J. J. Organomet. Chem. 1993, 446, 15-23.
(10) (a) Benkeser, R. A.; Kang, J. J. Organomet. Chem. 1980, 185, C9-
C12. (b) Lewis, L. N.; Lewis, N. J. Am. Chem. Soc. 1986, 108, 7228-
7232. (c) Lewis, L. N. J. Am. Chem. Soc. 1990, 112, 5998-6004.
(8) Boysen, M. M. K.; Lindhorst, Th. K. J. Carbohydr. Chem., in press.
1926
Org. Lett., Vol. 1, No. 12, 1999

Structures of 10 and 11 were furthermore approved by
MALDI-TOF analysis.12
In summary, we have introduced the first carbosilane
dendrimers with carbohydrate cores, exemplified by the first-
generation representatives 10 and 11. Our synthetic strategy
allows for selective functionalization of these molecules at
the glucoside aglycon moiety. Further research will be
directed toward the preparation of higher generations within
this dendrimer family and the modification of their peripheral
functions.
(11) General Procedure for the Preparation of Carbosilan Dendrim-
ers from Tetraallylated Glucosides. For both reactions in this two-step
protocol, except for the final workup, the Schlenk technique is required.
Hydrosilylation. The tetraallylated compound (3 or 7) was dissolved in
dry THF (0.11-0.37 mol/L). After addition of dichloromethylsilane (6
equiv) and 1-4 drops of Speier’s catalyst, the mixture was stirred at rt for
1 h and then under reflux for another 10 h. After cooling to rt, the solvent
and excess dichloromethylsilane were removed under vacuum as completely
as possible. The resulting oily crude product (chlorosilane 8 or 9) which
still contained residual solvent and silane reagent was used in the next
synthetic step without any further purification. Grignard Addition of
Allylmagnesiumbromide to Si-Cl Bonds. The crude chlorosilane (8 or
9) was dissolved in dry diethyl ether under an atmosphere of nitrogen (0.11-
0.22 mol/L). To this solution was added dropwise allylmagnesiumbromide
in diethyl ether (1 mol/L, 1.5 equiv per Si-Cl bond; a larger excess of
Grignard reagent should be used because of residual dichloromethylsilane
in the crude product). Precipitation of magnesium salts resulted instantly.
After the addition was finished, the mixture was stirred under reflux for 12
h and then cooled to rt and poured onto an ice-cold saturated ammonium
chloride solution. The aqueous phase was extracted three times with diethyl
ether, and the combined organic phases were then twice washed with water
and finally once with brine. Drying over magnesium sulfate, filtration, and
evaporation of the solvent yielded the crude product which was purified
by flash chromatography on silica gel.
Acknowledgment. We thank the DFG, which financially
supported this work in the frame of the Graduiertenkolleg
Glycoconjugate. A Graduiertenkolleg stipendium for M.M.K.B.
is gratefully acknowledged. We also thank Dr. Andreas
Terfort and Carola Gosch for their valuable help concerning
inert gas technology.
Supporting Information Available: Full experimental
details and 1H NMR as well as 13C NMR spectroscopic data
for compounds 3-7, 10, and 11 and MALDI-TOF spectro-
metric data for compounds 10 and 11. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL9910619
3
CH2CH2Si), -0.02, -0.03, -0.05 (12H, each s, 4 SiCH3) ppm; J1,2
≈
3J2,3 ) 8.1 Hz; 13C NMR (CDCl3) δ ) 138.3 (C, aryl-C), 134.6, 134.5
(CH, 8 CH2dCHCH2), 128.3, 127.6, 127.5 (CH, 4 aryl-C), 113.3, 113.2
(CH2, 8 CH2dCHCH2), 103.7 (CH, C-1), 84.8, 78.1, 75.0 (CH, C-3, -4,
-5), 82.3 (CH, C-2), 76.4, 75.8, 75.6, 74.6 (CH2, 4 OCH2CH2CH2Si), 73.1
(CH2, CH2Ph), 69.8, 69.3, 68.9 (CH2, C-6, CH2OCH2Ph, su OCH2), 24.6,
24.5, 24.4, 23.8 (CH2, 4 OCH2CH2CH2Si), 21.2 (CH2, 8 CH2dCHCH2),
9.1, (CH2, 4 OCH2CH2CH2Si), -5.9 (CH3, SiCH3) ppm; MALDI-TOF MS
m/z 1001.7 ((M + Na)+, calcd 1001.6), 1017.7 ((M + K)+, calcd 1017.6)
for C55H94O7Si4 (M ) 978.6), 875.6 ((C48H80O7Si3Na)+, calcd 876.1).
(12) Detailed analytical data for target compound 10, also representative
for compound 11: yield 52% (1.13 g, 1.15 mmol, two steps); 1H NMR
(CDCl3) δ ) 7.25-7.34 (5H, m, 5 aryl-H), 5.67-5.81 (8H, m, 8
CH2dCHCH2), 4.78-4.88 (16H, m, 8 CH2dCHCH2), 4.50-4.58 (2H, m,
CH2Ph), 4.26 (1H, d, H-1), 3.96-4.03 (1H, ddd ≈ m, su () sugar moiety)
OCHAHB), 3.14-3.84 (16H, m, H-3, H-4, H-5, H-6, H-6′, 4 OCH2CH2-
CH2Si, CH2OCH2Ph, su OCHAHB), 3.07 (1H, dd ≈ t, H-2), 1.46-1.61 (24H,
m, 8 CH2dCHCH2, 4 OCH2CH2CH2Si), 0.42-0.56 (8H, m, 4 OCH2-
Org. Lett., Vol. 1, No. 12, 1999
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