Synthesis of chiral carbohydrate-centered dendrimers

Article abstract of DOI:10.1039/a800560e

D-Glucose was converted into its per-O-(2-aminoethyl)-functionalized derivative 4, which served as initiator core for the construction of the chiral, monodisperse PAMAM-type carbohydrate-centered hybrid dendrimer 7.

Full text of DOI:10.1039/a800560e

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Synthesis of chiral carbohydrate-centered dendrimers
Michael Dubber and Thisbe K. Lindhorst*†
Institut fu¨r Organische Chemie der Universita¨t Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany
D-Glucose was converted into its per-O-(2-aminoethyl)-
functionalized derivative 4, which served as initiator core for
the construction of the chiral, monodisperse PAMAM-type
carbohydrate-centered hybrid dendrimer 7.
MeOH reaction mixture10 to yield the desired penta-hemiacetal
after reduction with PPh3. This was characterized as the
corresponding pentahydrate by NMR spectroscopy in D2O. The
penta-hemiacetal was submitted to a reductive amination
reaction: application of BnNH2 led to nearly inseparable
mixtures comprised of cyclic amines, due to intramolecular
reactions. However, the use of Bn2NH and sodium acetoxybor-
ohydride11 as the reducing agent gave the desired benzyl cluster
3 at 210 °C in high yields without purification problems. Then
3 was converted into the pentaamine 4 by heterogeneous
catalytic transfer hydrogenation reaction12 with ammonium
formate and Pd (10% on charcoal) in MeOH in a clean reaction.
Thus the target compound 4 could be synthesized starting from
allyl glucoside (1) in 43% overall yield.
The glucose derivative 4 represents a stereochemically well-
defined, oligofunctional molecule with five uniformly function-
alized spacers. It may serve as core molecule for the synthesis of
carbohydrate-centered glycoclusters13 or of carbohydrate-cen-
tered dendrimers. It was submitted to the reaction sequence
leading to PAMAM dendrimer generations, consisting of the
exhaustive Michael addition of the polyamine to methyl
acrylate, followed by amidation of the resulting methyl esters
with ethylenediamine.14 Indeed reaction of 4 with methyl
acrylate led to the decaester 5 in quantitative yield, which was
quantitatively converted into the first generation hybrid
PAMAM dendrimer 6 with ethylenediamine (Scheme 2).
Further branching at the amino functions at the periphery of the
molecule led to the eicosaester 7, also in quantitative yield. The
monodisperse structures of 5–7 could unequivocally be con-
firmed by NMR spectroscopy as 1H–13C HMBC NMR allowed
the detection of each individual branch of every molecule.‡ All
synthesized compounds are chiral.§ However, the specific
rotation values of the carbohydrate-centered dendrimers de-
crease with increasing generation, according to observations
made in the literature,15 whereas the molar rotation values
remain in the same range (ca. 400).
Dendrimer chemistry is a rapidly developing field of research.1
Dendrimers offer the prospect of novel materials with ad-
vantagous properties, allowing them to serve as soluble
catalysts,2 dendritic boxes3 or other supramolecular dendritic
arrangements. Furthermore, new applications such as enantio-
selective synthesis with chiral dendrimers, or favourable
bioapplications such as in transfection4 and glycobiology, are
currently being explored. Dendrimer chemistry has been
combined with carbohydrate chemistry in order to form
multivalent glycomimetics5 (glycodendrimers) with antiadhe-
sive properties or other carbohydrate containing dendrimers.6
Other than from the point of view of glycobiology, the
combination of carbohydrates and dendrimers is attractive for
the manipulation of dendritic structures leading to modified
properties of, as yet, unestimated value. Carbohydrate cores are
especially appealing for the design of dendrimers due to their
easy availibility from the chiral pool and renewable resources,
biocompatibility, low toxicity and natural polyfunctionality. In
addition, intrinsic chirality may be introduced into dendrimers
by using carbohydrate cores.7 Furthermore, the stereochemical
shape of dendrimers may be easily manipulated by choosing
differently configurated monosaccharides, and the core multi-
plicity may be altered by utilizing mono-, di- or even oligo-
saccharides as carbohydrate cores, such as trehalose or
raffinose. This is of special interest as the shape and composi-
tion of dendrimers may dramatically affect their host–guest
relationships.8
Here we report the first synthesis of a carbohydrate-centered
Starburst® PAMAM dendrimer based on a reaction sequence
which is suited to converting reducing sugars into carbohydrate
derivatives which can serve as initiator cores for the develop-
ment of PAMAM generations. This was exemplified with
d-glucose. First, allyl a-d-glucoside 1, which was obtained by
Fischer glycosylation, was perallylated to 2 under phase transfer
catalysis (Scheme 1). Partially allylated products were not
formed as the allylation rate increases with the extent of
allylation of the starting material under these conditions.9
Ozonolysis of the resulting allyl 2,3,4,6-tetra-O-allyl-a-d-
glucoside (2) was performed in a NaHCO3-buffered CH2Cl2–
In conclusion, a reaction sequence has been elaborated which
is generally applicable for the facile and uniform conversion of
free saccharides into fully O-(2-aminoethyl)-functionalized
derivatives such as 4. These are suited for dendritic expansion,
opening the door into a wide array of structurally diverse, but
well-defined, carbohydrate-centered PAMAM dendrimers. The
new hybrid dendrimers may be custom-designed by choice of
the carbohydrate core giving rise to possible advantageous
N
O
NH2
N
H2N
O
O
O
OH
i
iv
ii, iii
O
O
O
O
HO
HO
O
O
O
O
O
O
O
O
O
OH
O
O
O
N
N
H2N
H2N
H2N
N
1
2
3
4
Scheme 1 Reagents and conditions: i, allyl chloride (5 equiv.), 40% aq. NaOH, Bu4NBr (1 equiv.), 35 °C, 16 h, 76%; ii, O3, NaHCO3, CH2Cl2–MeOH 6:1,
work-up with PPh3; iii, Na(AcO)3BH, AcOH, Bn2NH, THF, work-up with 1 m NaOH, 74% (2 steps); iv, Pd–C (10%), NH4HCO2, MeOH, 76%
Chem. Commun., 1998
1265

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NH2
O
O
O
O
NH
NH
OMe
OMe
O
O
i
ii
O
O
N
4
N
NH2
5
5
6
5
iii
MeO
MeO
O
O
MeO
N
MeO
O
O
O
OMe
NH
N
N
MeO
O
O
N
HN
OMe
O
HN
O
O
O
N
OMe
MeO
MeO
MeO
NH
O
O
O
O
N
OMe
N
O
O
O
O
O
O
NH
NH
O
N
N
H
N
O
N
N
N
HN
O
O
O
O
O
O
N
O
OMe
O
N
NH
HN
MeO
O
OMe
O
N
O
MeO
OMe
MeO
O
O
OMe
MeO
7
Scheme 2 Reagents and conditions: i, methyl acrylate (22 equivs.), MeOH, 3 d, room temp., quant.; ii, ethylendiamine (600 equivs.), MeOH, 5 d, +5 °C,
quant. iii, methyl acrylate (60 equivs.), MeOH, 3 d, room temp., quant.
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properties compared to classical PAMAMs, such as altered
solubilities and overall shapes, better biodegradibility, lower
toxicity and chirality.
The authors wish to thank Dr V. Sinnwell for NMR
experiments, Professor Dr J. Thiem for his assistance and the
Fonds der Chemischen Industrie (FCI) for financial support.
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Notes and References
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† E-mail: tklind@chemie.uni-hamburg.de
‡ All compounds showed consistent NMR and mass spectral data. Selected
data for 7: MALDI-TOF (positive) [Calc. for C146H257N25O56: 3258.8.
Found 3261.0 (M + 1)]; dH(500 MHz, CD3OD) 5.02 (d, 1 H, J1,2 3.2, H-1),
4.03–3.93 (m, 2 H, OCH2CH2N), 3.88–3.59 (m, 73 H, H-5, H-6, H-6A, 4
OCH2CH2N, 20 OCH3), 3.54 (dd ≈ t, 1 H, J2,3 9.2, J3,4 9.2, H-3), 3.34–3.27
[m, 21 H, H-2, 10 C(O)NCH2CH2N], 3.26 (dd ≈ t, 1 H, J4,5 9.2, H-4),
3.0–2.89 [m, 20 H, 10 NCH2CH2C(O)N], 2.89–2.76 (dd ≈ t, 50 H, 5
OCH2CH2N, 20 NCH2CH2CO2Me), 2.64–2.57 [dd
C(O)NCH2CH2N], 2.54–2.49 (dd t, 40 H, 20 NCH2CH2CO2Me),
≈ t, 20 H, 10
≈
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175.7–175.5 (10 CO2N), 99.2 (C-1), 84.5 (C-3), 83.2 (C-2), 80.9 (C-4), 73.1
(C-5), 73.0, 72.9, 72.5, 71.8, 70.7, 68.3 (C-6, 5 OCH2CH2N), 55.7, 55.6,
55.5, 55.0, 54.7 (5 OCH2CH2N), 55.0 [20 C(O)NCH2CH2N], 53.4 (20
CO2CH3), 52.7, 52.6, 52.6, 52.5, 52.5 [10 NCH2CH2C(O)N], 51.7 (20
NCH2CH2CO2Me), 39.7 [10 C(O)NCH2CH2N], 35.8, 35.7, 35.6, 35.6, 35.5
[10 NCH2CH2C(O)N], 34.8 (20 NCH2CH2 CO2Me).
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§ Selected specific optical rotations: 1 [a]2D0 +160.5 (c 1.09, MeOH); 3 [a]2D7
+35.2 (c 1.18, CHCl3); 5 [a]D27 +34.6 (c 0.96, MeOH); 7 [a]2D5 +13.1 (c 0.38,
MeOH).
Received in Liverpool, UK, 20th January 1998; 8/00560E
1266
Chem. Commun., 1998