Synthesis of carbosilane dendritic wedges and their use for the construction of dendritic receptors

Article abstract of DOI:10.1039/b514583j

A divergent route for the synthesis of carbosilane wedges that contain either a bromine or amine as focal point has been developed. These new building blocks enable the construction of various core-functionalized carbosilane dendrimers. As a typical example carbosilane dendrimers up to the third generation containing a N,N′,N″-1,3,5-benzenetricarboxamide core (G1-G3) have been synthesized. This new class of molecules has been studied as host molecules and they have been found to bind protected amino acids as guest molecules via hydrogen bonding interactions. A decrease in the association constants was observed for the higher generation dendritic hosts, which is attributed to the increased steric hindrance around the core where the binding site is located. The binding properties of the dendritic host molecules can be tuned by modifying the binding motif at the core of the carbosilane dendrimers. A higher association constant for N-CBZ-protected glutamic acid 1-methyl ester (5) was observed when the third generation N,N′,N″-1,3,5-tris(l- alaninyl)benzenetricarboxamide core-functionalized carbosilane dendrimer (G3′) was used as the host molecule compared to G3. Different association constants for the formation of the diastereomeric G3′·l-5 (K = 295 M^-1) and G3′·d-5 (K = 236 M^-1) host-guest complexes were observed, pointing to a small enantioselective recognition effect. The difference between the association constants for the formation of the G3′·(l-5)₂ and G3′·(d-5)₂ host-guest complexes was much more pronounced, K = 37 M^-1 versus K = 10 M^-1, respectively. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b514583j

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of carbosilane dendritic wedges and their use for the construction
of dendritic receptors
Rieko van Heerbeek, Paul C. J. Kamer, Piet N. M. W. van Leeuwen and Joost N. H. Reek*
Received 14th October 2005, Accepted 15th November 2005
First published as an Advance Article on the web 14th December 2005
DOI: 10.1039/b514583j
A divergent route for the synthesis of carbosilane wedges that contain either a bromine or amine as
focal point has been developed. These new building blocks enable the construction of various
core-functionalized carbosilane dendrimers. As a typical example carbosilane dendrimers up to the
ꢀ
ꢀꢀ
third generation containing a N,N ,N -1,3,5-benzenetricarboxamide core (G1–G3) have been
synthesized. This new class of molecules has been studied as host molecules and they have been found
to bind protected amino acids as guest molecules via hydrogen bonding interactions. A decrease in the
association constants was observed for the higher generation dendritic hosts, which is attributed to the
increased steric hindrance around the core where the binding site is located. The binding properties of
the dendritic host molecules can be tuned by modifying the binding motif at the core of the carbosilane
dendrimers. A higher association constant for N-CBZ-protected glutamic acid 1-methyl ester (5) was
ꢀ
ꢀꢀ
observed when the third generation N,N ,N -1,3,5-tris(L-alaninyl)benzenetricarboxamide
ꢀ
core-functionalized carbosilane dendrimer (G3 ) was used as the host molecule compared to G3.
ꢀ
−1
Different association constants for the formation of the diastereomeric G3 ·L-5 (K = 295 M ) and
ꢀ
−1
G3 ·D-5 (K = 236 M ) host–guest complexes were observed, pointing to a small enantioselective
ꢀ
recognition effect. The difference between the association constants for the formation of the G3 ·(L-5)
2
ꢀ
−1
−1
and G3 ·(D-5)
2
host–guest complexes was much more pronounced, K = 37 M versus K = 10 M ,
respectively.
Introduction
the hydrosilylation with either mono-, di- or trichlorosilanes. The
distance between the branching points depends on the choice of the
x-alkenylation reagent. In principle, it is possible to alter the degree
of branching as well as the branch-length at every generation. The
presence of either silicon-chloride or allyl end-groups can be used
for the introduction of a functionality at the periphery of the
dendrimer. This versatility offered by carbosilane dendrimers, has
led to the extensive use of carbosilane dendrimers as scaffolds with
various functional groups. Functional materials such as liquid
Dendrimers are interesting macromolecules owing to their well-
defined, highly branched structures and physical properties,
and they have drawn the attention of chemical, biological and
materials scientists for more than two decades. The propensity
of dendrimers to enclose guest molecules and their potential
application in drug delivery and gene therapy has been studied
since the early developments in dendrimer chemistry. Dendrimers
specifically designed for the molecular recognition of substrates,
including chiral ones, are generally synthesized by connecting
1
2
3
8
9
10
11
crystals, catalysts, sensors and unimolecular micelles have
been synthesized by functionalization of carbosilane dendrimers
4
wedges (dendrons) to receptors.
12
with mesogens, catalysts, metal-complexes and water-soluble
Within the different dendrimer families known, the carbosilane
dendrimers form a special class. The physical properties of the
carbosilane dendrimers, such as their viscosity, core-accessibility,
the size of the internal voids and the generation at which
surface congestion occurs, can be tuned easily by choosing the
groups, respectively.
Surprisingly, little attention has been devoted to core-
functionalized carbosilane dendrimers. The reaction conditions
applied during the carbosilane synthesis impose strong limita-
tions to the functional groups that can be present in the core
during the synthesis. Polar groups such as amides and esters are
neither compatible with the Grignard nor with the hydrosilylation
reactions. Therefore the number of core-functionalized carbosi-
lane dendrimers directly obtained through divergent carbosilane
5,6
appropriate building blocks for the dendrimer growth sequence.
Furthermore, carbosilane dendrimers are robust, highly apolar
macromolecules with low glass transition temperatures. The syn-
thesis of carbosilane dendrimers consists of a repetitive sequence
of x-alkenylations, using either Grignard or lithium reagents,
13
dendrimer synthesis starting from a core-functionality is scarce.
7
and platinum-catalyzed hydrosilylations with chlorosilanes. The
Convergent dendrimer synthesis, pioneered by Hawker and
degree of branching can be varied between 1–3 by performing
14
Fr e´ chet, follows a strategy in which dendritic wedges are first
prepared, which subsequently can be connected to functional
building blocks leading to core-functionalized dendrimers. This
synthetic route has led to the synthesis of a large number of
Van’t Hoff Institute for Molecular Sciences, University of Amsterdam,
Nieuwe Achtergracht 166, 1018 WV Amsterdam, The Netherlands. E-mail:
reek@science.uva.nl; Fax: (+31)20-5256422; Tel: (+31)20-5256437
15
core-functionalized dendrimers. The availability of carbosilane
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wedges would greatly facilitate the synthesis of core-functionalized
carbosilane dendrimers. A first example of a core-functionalized
hyper-branched carbosilane polymer—obtained through a con-
trichlorosilane in 70% yield after vacuum distillation, which
gave 1 after a Grignard reaction with allylmagnesium bro-
mide. The catalyst used in the hydrosilylation reaction was
bis(tetrabutylammonium)platinum hexachloride (Lukevics cata-
16
vergent approach—has been reported by Lach et al. They
synthesized an oxazoline core-functionalized hyper-branched car-
bosilane polymer, which subsequently was condensed to 1,3,5-
24
lyst, 0.002 mol%). The side-product of the hydrosilylation of
allyl bromide is propyltrichlorosilane, which is also observed in
ꢀ
ꢀꢀ
25
benzenetricarboxylic acid yielding a N,N ,N -1,3,5-benzenetri-
carboxamide core-functionalized hyper-branched carbosilane
polymer. Gossage et al. reported the divergent synthesis of
phenol core-functionalized carbosilane dendritic wedges up to
the synthesis of (3-chloropropyl)trichlorosilane, and originates
from the hydrosilylation of propene that is generated via a
platinum-catalyzed H/Br exchange of allyl bromide (yielding
propene and SiBrCl ). Wedge 1 could be grown in the same
3
17
the third generation. The first generation wedge was con-
densed successfully with 1,3,5-benzenetricarbonyl trichloride.
Oosterom et al. synthesized p-bromophenyl core-functionalized
wedges starting from p-bromostyrene. These dendritic build-
ing blocks were used for the synthesis of core-functionalized
way as described for the synthesis of carbosilane dendrimers by
7
Van der Made and Van Leeuwen, i.e. via a repetitive sequence
of hydrosilylation with trichlorosilane followed by a Grignard
reaction with allylmagnesium bromide. No cross-coupling of the
bromine functionalized wedges with the Grignard reagent was
observed within the duration of the experiment (5–6 hours).
Wedges up to the third generation were prepared in quantitative
conversion, 73–89% isolated yield.
18
dendritic phosphines.
M u¨ ller et al. synthesized an o-
diphenylphosphinophenol core-functionalized carbosilane wedge
and applied this wedge as a ligand in the nickel-catalyzed Shell
19
Higher Olefin Process.
The use of the Lukevics catalyst in the hydrosilylation reactions
gave 100% selectivity for the linear hydrosilylated products. It is
well-established that hydrosilylation reactions might suffer from
induction periods of variable length and the need for small
amounts of oxygen to activate the catalyst, depending on the
This article describes the synthesis of three generations of 3-
bromopropyl core-functionalized carbosilane dendritic wedges
(
1–3) as useful building blocks for the synthesis of core-
functionalized dendrimers. Bromine was selected as a focal
point of the carbosilane wedges because it is inert towards the
conditions applied in the dendrimer growth sequence and can
26
alkene and hydrosilane reagents. In the current reaction the
activity of the hydrosilylation catalyst was rather unpredictable,
but it was proven that it required the presence of oxygen in the
20
readily be modified via simple substitution reactions. These
wedges have been used previously to synthesize a number of core-
functionalized dendrimers in collaboration with the groups of
27
reaction mixture. Although the selectivity in all cases remained
the same (100% linear product), the reaction could take over
one week to run to completion and sometimes required additional
catalyst. The poor reproducibility of the activity is most likely
related to the oxygen sensitivity of the catalyst. Stein et al. showed
that, for poorly coordinating olefins (1-hexene), oxygen is required
2
1
22
23
Nolte, Jer oˆ me and van Maarseveen. In this article we illustrate
the versatility of the building blocks by the facile synthesis
ꢀ
ꢀꢀ
of three generation N,N ,N -1,3,5-benzenetricarboxamide core-
functionalized carbosilane dendrimers (G1–G3). The dendrimers
G1–G3 have been used as hosts for the binding of (amino) acid
guests. The effect of the introduction of an L-alanine spacer,
between the core and the wedge of G3, on the binding of chiral
guest molecules is evaluated.
26
to prevent the formation of inactive, multi-nuclear Pt species.
Furthermore Kleyer et al. showed that the hydrosilylation rate
can be controlled by the amount of oxygen present in the
reaction mixture (introduced as a 1–5 weight percent mixture
28
with an inert gas such as nitrogen or argon). The addition of
either an insufficient amount or an excess of oxygen can lead
to lower reaction rates or the formation of inactive species. The
hydrosilylation reactions were performed as follows: the wedges
were dissolved together with 0.01 mol% Lukevics catalyst (with
respect to the allyl groups) under an inert atmosphere of nitrogen
in a mixture of dichloromethane (in order to dissolve the catalyst)
and diethyl ether (good solvent for the dendritic wedges), after
which trichlorosilane was added to the reaction mixture. Oxygen
was allowed to diffuse into the reaction mixture via a calcium
chloride tube on the reaction vessel after closing the nitrogen
Results and discussion
Synthesis of carbosilane wedges and core-functionalized
dendrimers
(
3-Bromopropyl)triallylsilane 1 was prepared as the smallest
wedge and starting compound for the synthesis of the higher
generations (Scheme 1). A platinum-catalyzed hydrosilylation
of allyl bromide with trichlorosilane yielded (3-bromopropyl)-
29
inlet. By performing the hydrosilylation in this fashion sufficient
time is offered for the platinum complex to be reduced, after which
diffusion of air from the head space into the reaction mixture
slowly increases the oxygen content, thereby passing through the
optimal oxygen concentration.
Substitution of the bromine focal point by an amine could
be achieved by stirring the different generations of bromine
functionalized wedges in a large excess of liquid ammonia at
◦
70
C under 15 bar of pressure, resulting in a new series
of functionalized wedges. Importantly, the reactions should be
performed at sufficiently high dilution (≤0.11 M) since otherwise
secondary and tertiary amines are formed as a result of the
Scheme 1 Synthesis of higher generation carbosilane wedges from 1
(
(
third generation wedge 3 is shown). Reaction conditions: (i) HSiCl
Bu N) PtCl , rt; (ii) (allyl)MgBr, Et O, rt, 5–6 h.
3
,
4
2
6
2
2
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higher nucleophilicity of the product compared to ammonia. The
dendritic wedges 2 and 3 are immiscible with liquid ammonia and
require the addition of diethyl ether as a co-solvent. In the absence
of co-solvent the reaction with liquid ammonia gave a mixture of
the starting compound and the primary, secondary and tertiary
amine products. For example, the reaction of 2.50 g of 2 in 50 mL
◦
liquid ammonia (0.07 M) at 70 C yielded a mixture of 20% 2,
5
0% of the desired primary amine product, 30% of the secondary
and traces of tertiary amine products after 20 hours, indicating
that the reaction is taking place in a dispersion rather than in
a homogeneous solution. When performed under the optimized
conditions, the amine wedges could be isolated as colorless oils in
Fig. 1 GPC traces of carbosilane dendrimers G1 (—), G2 (· · ·) and
90–96% yield.
G3 (-·-). Inset: calculated logM
retention times of G1–G3.
w
of G1–G3 as function of the GPC
The amine functionalized wedges were condensed with 1,3,5-
benzenetricarbonyl trichloride in dry CH
2
2
Cl in the presence
of triethylamine yielding carbosilane dendrimers containing an
ꢀ
ꢀꢀ
N,N ,N -1,3,5-benzenetricarboxamide core (G1–G3) in 85–94%
The mass spectrum of G1 (Fig. 2a) displays a peak at m/z =
ꢀ
ꢀꢀ
yield after column chromatography (Scheme 2). N,N ,N -1,3,5-
Tributylbenzenetricarboxamide G0 was prepared using similar
conditions. The quality of the silica gel used for the column
chromatography is of great influence on the isolated yields
obtained. The silica gel should not be too acidic since this
leads to lower yields as a result of the de-allylation of the
carbosilane dendrimer. The Si–OH groups present on the silica
gel surface lead to immobilization of the dendrimer via Si–O–
Si bond formation. In fact Shimada et al. used this hydrolytic
procedure with functionalized allylsilanes for the covalent linking
+
8
90 with the isotope pattern corresponding to [M + Ag] and a
+
peak at m/z = 769 corresponding to [M − (3 × allyl) + Ag] .
In the case of G2 the mass spectrum (Fig. 2b) displays peaks
at m/z = 2259 with an isotope pattern corresponding to [M +
+
+
Ag] , and at m/z = 2368 corresponding to the [M + 2Ag] ion.
For G3 three peaks are observed in the mass spectrum (Fig. 2c),
+
+
corresponding to [M] (m/z = 6267), [M + Ag] (m/z = 6375) and
+
[
M + 2Ag] (m/z = 6484) respectively. The resolution of the mass
spectrum of G3 is insufficient for identification of a clear isotope
pattern, which indicates that at higher generations the ionization
becomes increasingly more difficult. This effect has been observed
30
of functional groups to silica gel.
32
previously for carbosilane dendrimers.
Synthesis of a carbosilane dendrimer with an extended core
Focal point manipulation of the amine core-functionalized den-
dritic wedges can be used to introduce different binding motifs
in the core of the carbosilane dendrimers, for example by
introducing amino acid spacers using standard peptide chemistry.
This provides easy access to new dendritic receptors, which are
expected to have different affinities for guest molecules since
the introduction of an amino acid spacer increases the number
of H-bond donors/acceptors present in the core and enlarges
the volume of the void inside the dendrimer. Furthermore, the
introduction of a chiral amino acid generates a chiral binding
site that might be able to discriminate between two enantiomeric
guest molecules. Therefore, an analogue of carbosilane dendrimer
G3 containing an L-alanine spacer between the aromatic core and
Scheme 2 Synthesis of different generations of carbosilane dendrimers
containing an N,N ,N -1,3,5-benzenetricarboxamide core.
ꢀ
ꢀꢀ
Both G0 and G1 are white solids, whereas G2 and G3 are color-
1
ꢀ
less oils. All dendrimers were characterized by IR spectroscopy, H
the carbosilane wedges (G3 , Scheme 3) was synthesized, applying
the convergent strategy.
1
3
and C NMR spectroscopy and elemental analysis. GPC analysis
Fig. 1) revealed that the dendrimers obtained are monodisperse.
(
To this end a third generation carbosilane wedge, with saturated
peripheral groups and an amine focal point was functionalized
with L-alanine and a subsequent condensation reaction with 1,3,5-
The plot of the logarithm of the calculated molecular weight of
the dendrimers as function of their GPC retention times shows
a linear correlation, as is commonly observed for molecules of
different molecular weights that have similar shapes.
The carbosilane dendrimers were subjected to MALDI-TOF
MS analysis and satisfactory mass spectra were obtained after
ꢀ
benzenetricarboxylic acid yielded G3 (Scheme 4). The Gabriel
33
synthesis was used to introduce the primary amine as the focal
point. The bromine focal point was substituted by a phthaloyl
group by reacting dendritic wedge 3 with potassium phthalimide
+
31
◦
Ag labeling of the dendrimers with silver trifluoroacetate and
using dithranol (1,8,9-anthracenetriol) as the matrix (Fig. 2a–c).
in DMF at 80 C. The substituted product (7) was obtained in 56%
yield after column chromatography. The allylic peripheral groups
were fully hydrogenated using palladium on carbon under an
atmospheric pressure of hydrogen. Hydrazinolysis of the saturated
wedge 8 and an alkaline work-up afforded the amine focal point
+
In all cases the peak corresponding to the [M + Ag] ion was
the most abundant one and arises from the cation–p interaction
+
between Ag and the allylic end groups or the aromatic core.
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+
Fig. 2 MALDI-TOF MS spectra recorded after Ag labeling with silver trifluoroacetate using dithranol as the matrix: (a) G1; (b) G2; (c) G3. Insets:
calculated and observed isotope patterns.
functionalized wedge 9 in quantitative conversion, 94% isolated
yield. Next BOC-protected L-alanine was coupled to the wedge via
a DCC coupling, affording wedge 10 in 82% yield. The BOC-group
was removed by stirring the wedge in a 50% (v/v) TFA solution
in dichloromethane, affording wedge 11 in quantitative yield.
Condensation of the amine functionalized wedge 11 with 1,3,5-
benzenetricarboxylic acid (trimesic acid) using benzotriazol-1-yl-
oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) as
the carboxylic acid activating reagent yielded dendrimer G3 in
ꢀ
93% yield after column chromatography. NMR and IR dilution
ꢀ
experiments show that G3 does not self-associate in apolar
34
solvents, in contrast to its lower generation analogues.
2
14 | Org. Biomol. Chem., 2006, 4, 211–223
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Scheme 3 Schematic representation and CPK-representation of a com-
ꢀ
ꢀꢀ
puted structure of N,N ,N -tris(L-alaninyl)-1,3,5-benzenetricarboxamide
ꢀ
core-functionalized carbosilane dendrimer G3 .
Fig. 3 CPK-representations of computed structures of the carbosilane
dendrimers G1–G3.
Binding studies were performed in dry chloroform-d with G0–
G3 at a concentration of 5 mM using FMOC-glycine 4, N-CBZ-
L-glutamic acid 1-methyl ester (L-5) and propionic acid (6) as the
guest molecules. The IR spectra of 5 mM solutions of G0 and G1
in chloroform-d showed N–H stretching vibrations at 3455 and
−
1
3
451 cm , respectively, characteristic of non-hydrogen bonded
amides, indicating that these molecules do not self-associate in
36
this solvent at this concentration. The IR spectra of the guest
37
molecules 4 (13 mM) and 5 (25 mM) in chloroform-d also showed
only non-hydrogen bonded amide stretching vibrations at 3454
−
1
and 3430 cm , respectively, indicating that these molecules do
not aggregate under the conditions applied in the NMR titration
1
experiments. H NMR titration experiments were employed to
−
1
determine the association constants K (M ) and complexation
a
induced shifts DdCIS (Hz), defined as the chemical shift difference
of a proton of the host–guest complex and that of the free
host. The shifts of the aromatic and amide proton resonances of
the dendrimers were monitored during the titration experiments
(
Table 1). The titration curves were fitted assuming the formation
of 1:1 complexes, using a non-linear least-squares fitting proce-
dure, and satisfactory fits were obtained.
ꢀ
ꢀꢀ
Scheme 4 Synthesis of N,N ,N -1,3,5-tris(L-alaninyl)benzenetricarbox-
ꢀ
amide core-functionalized dendrimer G3 . Reagents: (i) potassium phthal-
◦
imide, DMF, 80 C; (ii) H
2
, Pd/C (10%), EtOAc; (iii) H
2
NNH
2
·H
2
O,
EtOH, reflux followed by HCl (aq), reflux, alkaline work-up; (iv) BOC-L-
The observed shifts of the NMR resonances belonging to the
amide protons present in the dendrimers clearly indicate that
binding of the guest molecules is based on H-bonding. This is
alanine, DCC, DMAP, CH
PyBOP, DiPEA, THF.
2 2 2 2
Cl ; (v) TFA–CH Cl (1:1); (vi) trimesic acid,
−
1
substantiated by IR measurements on G2 (mNH = 3448 cm )
Binding studies
−
1
showing a new amide N–H stretching vibration at 3385 cm
ꢀ
ꢀꢀ
The N,N ,N -1,3,5-benzenetricarboxamide core can be used as a
upon complexation with 6. The low association constant found
for 6 suggests that the amide bonds in 4 and L-5 contribute to the
binding with the dendrimer core.
The association constants of G0 to G2 reveal that the binding of
guests 4 and L-5 is slightly weaker in higher generation dendrimers,
while for G3 hardly any binding is observed. These observations
reflect the increase in steric hindrance imposed by the dendritic
35
binding site for guest molecules. CPK models of the dendrimers
G1–G3 show that the cores in the higher generation dendrimers are
more shielded from the environment by the dendritic carbosilane
wedges (Fig. 3). In order to study the ability of these dendrimers
to accommodate guest molecules, the binding of three different
1
guest molecules was studied by IR and H NMR spectroscopy.
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a
Table 1 Association constants K and complexation induced shifts DdCIS
of the dendrimer–guest complexes in chloroform-d calculated from the
shifts of the aromatic and amide proton resonances of the dendrimer
−
1 a
Dendrimer
Guest
K
a
(M
)
DdCIS,ArH (ppm)
DdCIS,NH (ppm)
G0
G1
G2
G3
G0
G1
G2
G3
G2
4
87
69
65
5
40
38
10
5
0.31
0.26
0.19
1.17
0.99
0.63
Scheme 5 Synthesis of optically enriched D-5. Reaction conditions:
4
(
2 2 2 2
i) DCC, DMAP (11%), MeOH, CH Cl ; (ii) TFA, CH Cl .
4
4
L-5
L-5
L-5
L-5
6
b
b
obtained in 87% overall yield and 61% optical purity (determined
from the specific optical rotation by comparison with optically
pure L-5).
0.33
0.29
0.32
1.05
0.94
1.14
ꢀ
A Job plot analysis of G3 with L-5 was performed to determine
24
0.47
1.39
the binding stoichiometry of the host–guest complex formed
a
b
39
Estimated error 5%. Estimated K values. The small shifts prohibited
accurate determination of the association constant.
(Fig. 4). The shift of the resonance of the aH of L-5 was monitored
ꢀ
as a probe in solutions containing different [G3 ]:[L-5] ratios while
ꢀ
keeping [G3 ] + [L-5] constant. The maximum of the Job plot is
found at a mole fraction L-5 of 0.50, indicating the formation of a
wedges in the higher generation dendrimers, shielding the binding
site located at the core of the dendrimer. In G3 the carbosilane
wedges almost fully encapsulate the binding site, as can be seen
from the CPK model (Fig. 3), hampering the binding of the guest
molecules.
1
:1 host–guest complex.
The calculated changes in the free energy of formation of the
◦
host–guest complexes (DG ) range from −2.6 (G0) to −0.95 kcal
−
1
mol (G3), indicating that the binding is based on one H-bonding
interaction (the energy of a hydrogen bond typically varies between
−
1
2
–5 kcal mol depending on the distance between the donor
and acceptor atom). Amino acid L-5 is bound weaker than 4,
which might be explained by a difference in the binding geometry.
Complexation induced shift values provide some structural infor-
mation about the binding geometry and a different trend in DdCIS
within the dendrimer series G0–G2 is observed for 4 compared
to L-5. A drop in the DdCIS value (upon complexation with 4)
is observed for the higher generation hosts, indicating that the
geometry of the host–guest complex of G2 differs from that of G0
and G1. Most likely this change in binding geometry is induced
by steric hindrance of the dendritic wedges. The different binding
geometry, however, reduces the association constant within the
dendrimer series to a smaller extent compared to L-5. No drop
in DdCIS is observed for L-5 within the dendrimer series G0–G2,
suggesting that the host–guest complexes have a similar geometry.
The inability to adopt a different binding geometry might explain
the relatively large drop in association constant observed for L-5
within the dendrimer series compared to 4 and might be attributed
to the steric bulk around the amide bond in L-5. The increased
steric hindrance in the higher generation dendrimer might hamper,
for example, the formation of the hydrogen bond between the
dendritic host and the amide bond of L-5 leading to a lower
association constant.
ꢀ
Fig. 4 Job plot analysis of a titration of G3 with L-5.
1
H NMR titration experiments (300 MHz) were employed to
ꢀ
determine the association constants of G3 with both enantiomers
of 5 (Table 2). The shifts of the resonances belonging to the
aromatic protons, the aH of the alaninyl spacer and the amide
ꢀ
proton adjacent to the wedge of G3 were monitored during the
titration experiment. Although the Job plot analysis revealed a
1:1 binding stoichiometry, the best results in the non-linear least-
squares fitting procedure were obtained when the formation of
a 1:2 host–guest complex was assumed. This discrepancy can
be explained by the fact that the binding of the second guest
is relatively weak, and consequently the shift is too small to be
detected in the Job plot titration experiment.
ꢀ
The association constant for the formation of the G3 ·L-5 host–
−
1
guest complex (K = 295 M ) is considerable higher than the
1
formation of the G3·L-5 host–guest complex (estimated K =
a
−
1
5
M ), which clearly indicates that extending the core leads to
Binding studies on a carbosilane dendrimer with an extended core
a better accessibility of guest molecules. Compared to the hosts
G0 and G1, the association constant for the binding of L-5 in the
dendritic host G3 is a factor of 7 higher, which can be attributed to
ꢀ
The binding behavior of dendrimer G3 with both L- and D-5
1
ꢀ
was studied using H NMR spectroscopy. D-5 was synthesized
starting from commercially available N-CBZ-D-glutamic acid c-
tert-butyl ester by subsequent esterification with methanol, via
a DCC coupling, and de-esterification of the tert-butyl ester
using TFA (Scheme 5). Partial racemization was observed, which
is probably the result of direct abstraction of the aH by 4-
the number of H-bonds involved in the complexation. IR spectra
ꢀ
of G3 containing guest 5 showed N–H stretching vibrations at
−
1
3333 and 3306 cm , confirming that the binding is based on H-
bonding interactions involving the amide bonds (a non-hydrogen
bonded N–H stretching vibration belonging to free 5 was found
38
−1
dimethylaminopyridine (DMAP). Optically enriched D-5 was
at 3437 cm ).
2
16 | Org. Biomol. Chem., 2006, 4, 211–223
This journal is © The Royal Society of Chemistry 2006

View Article Online
ꢀ
Table 2 Association constants K
1
and K
2
and complexation induced shifts DdCIS 1,2 of the dendritic host G3 –guest 5 complexes in chloroform-d calculated
1
from H NMR titration experiments
b
c
DdArH (ppm)
DdNH (ppm)
CIS
DdCH (ppm)
CIS
−
1
a
−1
a
Guest
K
1
(M
)
K
2
(M
)
CIS
1
CIS
2
1
CIS
2
1
CIS
2
L-5
D-5
295
236 (221)
37
10 (3.3)
0.045
0.038
0.47
1.2
0.27
0.21
3.5
4.9
−0.076
−0.048
−0.95
−1.4
d
d
a
b
c
Estimated error 5%. Complexation induced shifts of the amide protons adjacent to the aromatic core. Complexation induced shifts of the aH of the
d
alaninyl spacer. Value corrected for optically pure D-5.
The two enantiomers of 5 are bound in the dendritic host
G3 with different association constants, demonstrating that the
unless mentioned otherwise. Solvents were dried and distilled
under nitrogen; Et O from sodium–benzophenone and CH Cl
from CaH
[(Bu N) PtCl
cedure. Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexa-
fluorophosphate (PyBOP) and N-(benzyloxycarbonyl)-D-
glutamic acid 5-tert-butyl ester were purchased from NovaBio-
chem. Other chemicals were purchased from Acros Organics
or the Aldrich Chemical Company. Allyl bromide was distilled
ꢀ
2
2
2
chiral core can discriminate between the two enantiomers through
2
.
Bis(tetrabutylammonium)platinum hexachloride
] was synthesized according to a literature pro-
0
diastereomeric interactions. The calculated DG for the formation
4
2
24
6
ꢀ
ꢀ
of the G3 ·L-5 and G3 ·D-5 host–guest complexes are −3.34 kcal
mol and −3.17 kcal mol , respectively, corresponding to DDG
DG ) = −0.17 kcal mol . In a racemic mixture of 5,
− DG
7% of the bound guest is the L-5 enantiomer, indicating that the
−
1−
−1
−
1
(
5
L
D
enantioselective recognition of the first guest molecule is small.
Interestingly, the binding of the first guest molecule enhances the
enantioselective binding of the second guest molecule, which is
expressed by a larger DDG of 1.4 kcal mol− calculated for the
prior to use. Allylmagnesium bromide was prepared in Et O
2
42
according to modified literature procedures. The molarity of the
Grignard was determined prior to use via a titration with a 0.50 M
isopropanol solution in xylenes using 1,10-phenanthroline as an
indicator. Silica 60 (SDS Chromagel, 70–200 lm) was used for
column chromatography. Melting points were determined on a
Gallenkamp apparatus. Optical rotations were measured with a
1
formation of the 1:2 host–guest complexes (DG
L
= −2.1 kcal
= −0.70 kcal mol ). Consequently, in a racemic
mixture of 5, 92% of the L-5 would be bound as the second guest
−
1
−1
mol ; DG
D
40
molecule, which can be considered significant. This enhanced
enantioselective recognition in the binding of the second guest
molecule might be attributed to the presence of the first guest
molecule preorganizing the binding site for the binding of the
second guest molecule, leading to a higher energy barrier between
the ‘match’ and ‘mismatch’ diastereomeric interactions.
−
1
2
Perkin Elmer 241 Polarimeter. [a]
D
values are given in 10 deg cm
−
1
g . IR spectra were measured on a BioRad FT-IR (FTS-7)
1
13
spectrophotometer. H and C NMR spectra were collected on
a Bruker AMX 300 spectrometer, a Varian Mercury 300 or a
Varian Inova 500 spectrophotometer. The chemical shift values
d are given in ppm, the values of the coupling constants J in
Hz. GC/MS spectra were recorded on a Hewlett Packard 5890/
Conclusions
5
971-GC/MS (split/splitless injector, ZB-5 15 m column, film
thickness 0.25 lm, carrier gas: 0.2 bar He). FAB mass spectra
were recorded on a JOEL JMS SX/SX102A four sector mass
spectrometer coupled to a JOEL MS-MP7000 data system using
Carbosilane dendritic wedges both with a bromine or amine
focal point have been prepared and shown to be useful building
blocks for the construction of core-functionalized carbosilane
dendrimers that are otherwise difficult to obtain. Substitution
of the bromide focal point or using standard peptide chemistry
with the amine focal point can be used to synthesize carbosilane
dendrimers in a convergent manner. We have synthesized two
types of core-functionalized carbosilane dendrimers, which can
be used for the (enantioselective) molecular recognition of guest
molecules. The modular approach used enables the construction
of carbosilane dendrimers containing a variety of binding sites,
based on various amino acids, which might result in systems
that can bind guest molecules with higher enantioselectivities
and binding constants. These carbosilane dendrimers containing
amino acids may be used as novel recyclable organocatalysts by
3
-nitrobenzyl alcohol as a matrix. MALDI-TOF mass spectra
were collected on a Voyager-DE Biospectrometry Workstation
PerSeptive Biosystems Inc., Framingham, MA, USA) mass
spectrometer equipped with a nitrogen laser emitting at 337 nm
3 ns pulses). The samples were labeled using silver trifluoroacet-
(
(
31
ate and analyzed using dithranol as the matrix. Gel permeation
chromatography (GPC) was performed on a Shimadzu apparatus
equipped with three Waters Styragel Columns (HR-1, HR-2 and
HR-4) connected in series and with a RID-10A refractive index
detector and a SPD-10A VP UV/Vis detector.
CAUTION: Hydrosilylation reactions are highly exothermic
and good care should be taken. It is our experience that the occur-
rence of a vigorous reaction seems to be completely unpredictable
41
binding and converting substrate molecules or as new materials
for the resolution of amino acid derivatives.
(if this happened, it was always between 10 and 90 minutes) and
a dry ice–acetone bath should be kept at hand when adding the
trichlorosilane as a precaution.
Experimental section
(
3-Bromopropyl)trichlorosilane. A 250 mL flame-dried three-
necked round bottom flask equipped with a nitrogen inlet was
charged with allyl bromide (25.0 mL, 0.288 mol), dry CH Cl
(250 mL) and dry Et O (12.5 mL). To this solution was added
General remarks
All reactions were carried out in flame-dried glassware and under
a dry nitrogen atmosphere using standard Schlenk techniques
2
2
2
This journal is © The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 211–223 | 217

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0
.55 mL of a freshly prepared 0.050 M solution of (Bu
4
N)
. Subsequently trichlorosilane
36.5 mL, 0.362 mol) was added to the solution. A calcium
2
PtCl
6
Carbosilane wedge Br[G3](allyl)27 3. To a solution of 2 (4.00 g,
−
5
(
(
0.60 × 10 mol) in dry CH
2
Cl
2
5.48 mmol) in dry CH
2
Cl
2
(7.8 mL) and dry Et O (4.75 mL)
2
was added 0.099 mL of a freshly prepared 0.050 M solution
−
6
chloride-tube was installed and the nitrogen inlet was closed. After
0 minutes an exothermic reaction occurred and the reaction vessel
of (Bu
4
N)
2
PtCl
6
(5.0 × 10 mol) in dry CH
2
Cl . Subsequently
2
1
trichlorosilane (6.5 mL, 64.4 mmol) was added to the solution, a
calcium chloride tube was introduced and the nitrogen inlet was
closed. The reaction mixture was stirred for one week after which
was cooled using a dry ice–acetone bath if it became too vigorous.
After the exothermic reaction had subsided the reaction mixture
was stirred overnight after which it was concentrated in vacuo. The
crude product was purified by vacuum distillation, affording the
1
a H NMR spectrum showed complete conversion of all the allylic
end groups. The solvents were evaporated and the residue was
title compound as a colorless liquid (52.4, 70%). d
CDCl ) 3.47 (2H, t, J 6.6, BrCH ), 2.13 (2H, m, BrCH
.58 (2H, m, CH Si). d (75 MHz, CDCl ) 35.7, 27.1 and 24.6.
H
(300 MHz,
dissolved in dry Et
dropwise to a 1.1 M solution of allylmagnesium bromide in Et O
(150 mL, 0.165 mol) over a period of 30 minutes and subsequently
stirred for 6 hours. The reaction mixture was poured slowly into
an ice-cold 10% ammonium chloride solution in water (250 mL),
the layers were separated and the water layer was extracted with
2
O (10 mL). The silane solution was added
3
2
2
CH ) and
2
2
1
2
C
3
(
3-Bromopropyl)triallylsilane 1. (3-Bromopropyl)trichlorosi-
lane (52.4 g, 0.204 mol) was added dropwise over a period of
Et
MgSO
crude product by flash chromatography over silica using hexanes–
Et O (9:1) as an eluent gave 3 (9.1 g, 79%) as a viscous, colorless oil
Found: C, 68.63; H, 10.17. Calc. for C120 213Si13Br; C, 68.60; H,
) 5.78 (27H, m, SiCH ),
), 3.38 (2H, t, J 6.9, BrCH
CH=CH
Si(allyl)
Si) and 0.57 (26H, m, BrCH CH
134.5, 113.7,
2
O (3 × 50 mL). The combined organic layers were dried on
1
2
1
hours to a 1.1 M allylmagnesium bromide solution in Et O
2
4
, filtered and concentrated in vacuo. Purification of the
(
612 mL, 0.673 mol). The reaction mixture was stirred for 5 hours
at room temperature after which it was hydrolyzed by carefully
pouring it into an ice-cold 10% ammonium chloride solution in
water (400 mL). The layers were separated and the water layer
2
(
H
1
4
0.22%). d
.86 (54H, m, SiCH
CH
24H, m, (3-bromopropyl)Si(CH
H
(300 MHz, CDCl
3
2
CH=CH
2
was washed with Et
layers were dried on MgSO
2
O (3 × 200 mL). The combined ethereal
CH=CH
), 1.82
), 1.35
2
2
2
4
, filtered and concentrated in vacuo.
(
(
2H, m, BrCH
2
2
), 1.59 (54H, d, J 8.1, SiCH
and CH
2
2
Purification of the crude product by flash chromatography over
silica using hexanes as an eluent gave 1 (40.6 g, 73%) as a colorless
2
)
3
2
3
), 0.66 (24H,
CH and
m, SiCH
2
CH
2
CH
2
1
2
2
2
liquid. (Found: C, 52.80; H, 7.67. Calc. for C12
.75%). d (300 MHz, CDCl ) 5.77 (3H, m, SiCH
6H, m, SiCH ), 3.37 (2H, t, J 6.9, BrCH
CH=CH
BrCH CH ), 1.61 (6H, d, J 8.1, SiCH ) and 0.71 (2H,
CH=CH
m, BrCH CH CH Si). d (75 MHz, CDCl ) 135.3, 115.4, 38.2,
8.8, 20.9 and 12.2. m/z (GC/MS) 231 (M − allyl).
H
21SiBr; C, 52.74; H,
CH=CH
), 4.88
), 1.89 (2H, m,
3
{
CH
2
Si(CH
2
)
3
}
3
). C NMR (75 MHz, CDCl
3
) d
C
7
H
3
2
2
3
7.4, 28.3, 19.9, 18.8, 18.5, 18.0, 17.9, 17.7, 16.8 and 11.8. m/z
(
2
2
2
+
(
MALDI-TOF) 2164 (M + Ag − allyl).
2
2
2
2
2
2
2
C
3
+
2
(3-Aminopropyl)triallylsilane. A stainless steel autoclave was
charged with 1 (1.50 g, 5.49 mmol) and liquid ammonia (50 mL).
◦
The solution was heated to 75 C and stirred overnight (p ≈ 15
Carbosilane wedge Br[G2](allyl)
.0366 mol) was dissolved in dry CH
9
2. Compound 1 (10.0 g,
Cl (17.5 mL) and dry Et
bar). The reaction mixture was cooled to room temperature and
the ammonia was evaporated. Water (15.0 mL) was added to the
0
2
2
2
O
(
0
10.5 mL). To the solution was added 0.22 mL of a freshly prepared
residue and the water layer was extracted with Et
The combined ethereal layers were dried on MgSO
concentrated in vacuo, affording the title compound (1.15 g,
quantitative) as a slightly yellow liquid. d (300 MHz, CDCl )
2
O (4 × 10 mL).
−
5
.05 M solution of (Bu
4
N)
2
PtCl
6
(1.1 × 10 mol) in dry CH
2
Cl ,
2
4
, filtered and
followed by trichlorosilane (14.0 mL, 0.139 mol). The flask was
equipped with a calcium chloride tube and the nitrogen inlet was
closed. The reaction mixture was stirred overnight after which a
H
3
5
2
.68 (3H, m, SiCH
.59 (2H, t, J 7.0, NH
CH=CH
Si). d (75 MHz, CDCl
and 8.6. m/z (GC/MS) 168 (M − allyl).
2
CH=CH
CH ), 2.57 (2H, broad s, NH
), 1.41 (2H, m, NH CH
) 134.2, 113.8, 45.1, 27.0, 19.6
2
), 4.78 (6H, m, SiCH
2
CH=CH
), 1.51 (6H,
) and 0.50
2
),
1
H NMR spectrum showed complete conversion of all the allylic
2
2
2
end groups. The reaction mixture was concentrated in vacuo and
d, J 8.2, SiCH
2H, m, CH
2
2
2
2
CH
2
dissolved in dry Et
to a 2.9 M solution of allylmagnesium bromide solution in Et
140 mL, 0.406 mol) over a period of 1 hour. The reaction mixture
2
O (14.0 mL). The solution was added dropwise
(
2
C
3
2
O
+
(
was stirred for 5 hours after which it was poured slowly into an
ice-cold 10% ammonium chloride solution in water (300 mL). The
organic layer was separated and the water layer was extracted
Second generation carbosilane wedge H
less steel autoclave was charged with 2 (0.60 g, 0.82 mmol), Et
2
N[G2](allyl)
9
. A stain-
2
O
with Et
on MgSO
crude product by flash chromatography over silica using hexanes–
Et O (9:1) as an eluent gave 2 (23.7 g, 89%) as a colorless oil.
Found: C, 63.85; H, 9.43. Calc. for C39 Br; C, 64.15; H,
) 5.82 (9H, m, SiCH ),
), 3.38 (2H, t, J 6.9, BrCH
CH=CH
2
O (3 × 150 mL). The combined organic layers were dried
(5 mL) and liquid ammonia (50 mL). The solution was heated to
◦
4
, filtered and concentrated in vacuo. Purification of the
75 C and stirred overnight (p ≈ 15 bar). The reaction mixture was
cooled to room temperature and the ammonia was evaporated.
To the residue was added water (5.0 mL) and the water layer
2
(
9
4
(
(
H
69Si
4
was extracted with Et
layers were dried on MgSO
affording the title compound (0.46 g, 96%) as a colorless oil. d
2
O (4 × 3 mL). The combined ethereal
.52%). d
.91 (18H, m, SiCH
CH
Si(allyl)
Si(CH ). d
9.9, 18.4, 17.5, 16.8 and 11.9. m/z (MALDI-TOF) 795 (M +
Ag − allyl).
H
(300 MHz, CDCl
3
2
CH=CH
2
4
, filtered and concentrated in vacuo,
CH=CH
), 1.83
), 1.38
2
2
2
H
2H, m, BrCH
6H, m, CH
2
2
), 1.61 (18H, d, J 8.2, SiCH
), 0.69 (6H, SiCH CH CH
(75 MHz, CDCl ) 134.5, 113.7, 37.2, 28.2,
2
2
(300 MHz, CDCl
m, SiCH
CH=CH
d, J 8.0, SiCH
CH=CH
and SiCH CH CH Si), 0.65 (8H, m, CH
m, Si(CH ) and 0.46 (2H, m, NH CH CH
3
) 5.67 (9H, m, SiCH
), 2.65 (2H, t, J 7.0, NH
), 1.34 (10H, m, NH
Si(allyl)
CH ). d
2
CH=CH
2
), 4.87 (18H,
), 1.57 (18H,
CH , NH
), 0.56 (6H,
(75 MHz,
2
3
2
2
2
Si) and 0.61 (8H,
2
2
2
CH
2
m, CH
2
2
)
3
C
3
2
2
2
CH
2
2
2
+
1
2
2
2
2
3
2
)
3
2
2
2
2
C
2
18 | Org. Biomol. Chem., 2006, 4, 211–223
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View Article Online
CDCl
3
) 134.5, 113.7, 45.9, 28.4, 19.8, 18.4, 17.6, 16.7 and 9.65.
(6H, m, NHCH
0.66 (6H, m, CH
28.3, 114.2, 43.7, 24.0, 19.7 and 9.0. m/z (MALDI-TOF) 890
2
CH
2
), 1.62 (18H, d, J 8.0, SiCH
2
CH=CH
2
) and
+
m/z (FAB) 666.472 (M + H. Calc. for C39
H
72NSi
4
666.474).
2
Si). d
C
(75 MHz, CDCl ) 165.8, 135.4, 134.3,
3
1
+
+
Third generation carbosilane wedge H N[G3](allyl)27
less steel autoclave was charged with 3 (1.10 g, 0.524 mmol), Et
2
.
A stain-
(M + Ag). m/z (FAB) 784.476 (M + H. Calc. for C45
H
70
N
3
O
3
Si
3
2
O
784.472).
(
7
5 mL) and liquid ammonia (50 mL). The solution was heated to
5 C and stirred overnight (p ≈ 15 bar). The reaction mixture was
◦
ꢀ
ꢀꢀ
Second generation N,N ,N -1,3,5-benzenetricarboxamide core-
functionalized dendrimer G2. solution of (0.200 g,
N (0.070 mL, 0.50 mmol) in CH Cl (1.0 mL)
cooled to room temperature and the ammonia was evaporated.
To the residue was added water (5.0 mL) and the water layer was
extracted with Et
dried on MgSO , filtered and concentrated in vacuo, affording the
title compound (1.06 g, 99%) as a colorless oil (Found: C, 70.52;
H, 10.22; N, 0.68. Calc. for C120 215Si13N; C, 70.75; H, 10.64; N,
0
4
1
A
5
0.300 mmol) and Et
3
2
2
◦
2
O (4 × 3 mL). The combined ethereal layers were
was cooled to 0 C. To the solution was added dropwise 1,3,5-
benzenetricarbonyl trichloride (0.0241 g, 0.0909 mmol) in CH
(1.0 mL). The reaction mixture was warmed to room temperature
and stirred overnight. The resulting white suspension was poured
into water (5.0 mL) and the layers were separated. The water layer
4
2
Cl
2
H
.69%). d
.89 (54H, m, SiCH
.59 (54H, d, J 8.2, SiCH
H
(300 MHz, CDCl
CH=CH
CH=CH
, NH
Si), 0.56 (24H, m, {CH
CH CH ). d (75 MHz, CDCl
13.7, 45.8, 28.5, 19.9, 18.8, 18.5, 18.1, 18.0, 17.7, 16.8
3
) 5.78 (27H, m, SiCH
), 2.66 (2H, t, J 7.0, NH
), 1.35 (28H, m, NH CH
and CH Si(allyl) ), 0.66
Si(CH
) 134.5,
2
CH=CH
2
),
),
2
2
2
CH
2
was extracted with CH
layers were dried on MgSO
Purification of the crude product by column chromatography over
silica using hexanes–Et O (2:1) as an eluent gave G2 (0.148 g, 94%)
as a colorless oil. (Found: C, 69.99, H, 10.01, N, 1.91. Calc. for
2
Cl
2
(3 × 3.0 mL). The combined organic
2
2
2
2
CH
2
4
, filtered and concentrated in vacuo.
and (3-aminopropyl)Si(CH
24H, m, SiCH CH CH
and 0.50 (2H, NH CH
2
)
3
2
2
3
(
2
2
2
2
2
)
3
}
3
)
2
2
2
2
2
C
3
−
1
1
C
126
H
213
N
3
O
3
Si12: C, 70.22, H, 9.96, N, 1.95%). mmax(KBr)/cm
3354 (broad), 3075, 2994, 2970, 2914, 2876, 2795, 1790, 1667,
629 and 1519. d (300 MHz, CDCl ) 8.35 (3H, s, ArH), 6.44
(3H, t, J 5.6, NH), 5.77 (27H, m, SiCH ), 4.88 (54H,
CH=CH
m, SiCH ), 3.44 (6H, q, J 6.7, NHCH ), 1.58 (6H, m,
CH=CH
NHCH CH ), 1.58 (54H, d, J 8.0, SiCH ), 1.36 (18H,
CH=CH
m, CH Si(allyl) ), 0.67 (18H, m, SiCH CH CH Si), 0.59 (18H, m,
CH Si(CH ) and 0.54 (6H, m, NHCH CH CH ). d (75 MHz,
CDCl ) 165.4, 135.3, 134.6, 128.0, 113.7, 43.9, 24.6, 19.9, 18.4,
17.5, 16.8 and 10.1. m/z (MALDI-TOF) 2261 (M + Ag).
and 9.5.
1
H
3
ꢀ
ꢀꢀ
N,N ,N -1,3,5-Tributylbenzenetricarboxamide G0. To a solu-
2
2
tion of 1,3,5-benzenetricarbonyl trichloride (0.250 g, 0.942 mmol)
and Et
2
2
2
3
N (0.475 mL, 3.41 mmol) in THF (5.0 mL) was added
2
2
2
2
dropwise a solution of 1-aminobutane (0.279 mL, 2.83 mmol)
in THF (10 mL). The reaction mixture was stirred overnight
after which a white suspension had formed. The reaction mixture
was poured into water (30 mL). The water layer was extracted
with Et
dried on MgSO
G0 (0.332 g, 94%) as a white solid. (Found: C, 66.86; H,
8
1
2
2
3
2
2
2
2
2
)
3
2
2
2
C
3
+
2
O (4 × 10 mL). The combined ethereal layers were
ꢀ
ꢀꢀ
4
, filtered and concentrated in vacuo, affording
Third generation N,N ,N -1,3,5-benzenetricarboxamide core-
functionalized dendrimer G3. solution of (0.137 g,
N (0.030 mL, 0.21 mmol) in CH Cl (1.0 mL)
was cooled to 0 C. To the solution was added dropwise 1,3,5-
benzenetricarbonyl trichloride (5.4 mg, 0.020 mmol) in CH
A
6
.76; N, 11.22. Calc. for C21
1.19%). Mp 197.5–197.9 C. mmax(KBr)/cm 3241 (broad), 3076,
H
33
N
3
O
3
; C, 67.17; H, 8.86; N,
0.0673 mmol) and Et
3
2
2
◦
−1
◦
961, 2932, 2873, 1642 and 1561. d
H
(300 MHz, CDCl
3
) 7.65
2
Cl
2
(
3H, s, ArH), 7.33 (3H, broad t, NH), 3.38 (6H, q, J 6.4,
NHCH ), 1.57 (6H, quintet, J 7.3, NHCH CH ), 1.38 (6H,
sextet, J 7.4, NHCH CH CH ) and 0.95 (9H, t, J 7.3, CH ).
(75 MHz, CDCl ) 165.9, 135.6, 128.1, 40.3, 31.8, 20.3 and
4.0. m/z (FAB) 376.260 (M + H. Calc. for C21
76.260).
(1.0 mL). The reaction mixture was warmed to room temperature
and stirred overnight. The reaction mixture was poured into
water (5.0 mL) and the layers were separated. The water layer
2
2
2
2
2
2
3
d
1
3
C
3
was extracted with CH
layers were dried on MgSO
Purification of the crude product by column chromatography
over silica using hexanes–Et O (19:1) as an eluent gave G3
(0.106 g, 85%) as a colorless oil. (Found: C, 70.52, H, 10.22, N,
0.68. Calc. for C369 Si39; C, 70.71, H, 10.37, N, 0.67%).
max(KBr)/cm 3431, 3076, 3059, 2996, 2971, 2913, 2877, 2795,
1793, 1674, 1629 and 1517. d (300 MHz, CDCl ) 8.35 (3H, s,
ArH), 6.43 (3H, broad t, NH), 5.77 (81H, m, SiCH
4.89 (162H, m, SiCH ), 3.42 (6H, q, J 5.8, NHCH
CH=CH
1.59 (168H, d, J 8.1, NHCH CH CH and SiCH
CH=CH
(72H, m, NHCH CH CH Si(CH and CH Si(allyl) ), 0.66 (72H,
m, SiCH CH CH Si) and 0.61 ppm (78H, m, NHCH CH CH
Si(CH ). d (75 MHz, CDCl ) 165.2, 135.2, 134.9,
2
Cl
2
(3 × 3 mL). The combined organic
+
H
34
N
3
O
3
4
, filtered and concentrated in vacuo.
2
ꢀ
ꢀꢀ
First generation N,N ,N -1,3,5-benzenetricarboxamide core-
functionalized dendrimer G1. A solution of 4 (0.590 g, 2.82 mmol)
and Et
H
645
N
3
O
3
−
1
3
N (0.404 mL, 2.90 mmol) in CH
C. To the solution was added dropwise 1,3,5-benzenetricarbonyl
Cl (1.0 mL). The reaction
2
Cl
2
(1.0 mL) was cooled to
m
◦
0
H
3
trichloride (0.224 g, 0.845 mmol) in CH
2
2
2
CH=CH
2
2
),
),
mixture was warmed to room temperature and stirred overnight
after which the reaction mixture was poured into water (5 mL).
The layer were separated and the water layer was extracted with
CH
on MgSO
column chromatography over silica using CH
an eluent gave G1 (0.600 g, 91%) as a white solid. (Found: C,
6
8
2
2
2
2
2
2
2
2
), 1.36
2
2
2
2
)
3
2
3
2
Cl
2
(3 × 3 mL). The combined organic layers were dried
, filtered and concentrated in vacuo. Purification by
Cl –Et O (4:1) as
2
2
2
2
2
2
4
and {CH
2
2
)
3
}
3
C
3
2
2
2
134.6, 113.8, 44.2, 24.7, 19.6, 18.5, 18.3, 17.9, 17.7, 16.8 and 10.2.
+
m/z (MALDI-TOF) 6375 (M + Ag).
8.34; H, 8.59; N, 5.51. Calc. for C45
H
69
N
3
O
3
Si
.87, N, 5.36%). mmax(KBr)/cm 3247 (broad), 3085, 2995, 2972,
920, 2883, 1634 and 1560. d (300 MHz, CDCl ) 8.37 (3H, s,
CH=CH
),
), 3.45 (6H, J 6.7, NHCH ), 1.63
3
; C, 68.91; H,
−
1
Carbosilane wedge Pht[G3](allyl)27 7. Compound 3 (5.03 g,
H
3
2.39 mmol) and potassium phthalimide (0.58 g, 3.13 mmol)
◦
ArH), 6.54 (3H, t, J 5.6, NH), 5.78 (9H, m, SiCH
.90 (18H, m, SiCH
CH=CH
2
2
were suspended in DMF (25 mL) and heated to 80 C for a
4
2
2
2
period of 1 hour. The reaction mixture was poured into water
This journal is © The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 211–223 | 219

View Article Online
(
200 mL) and extracted with Et
ethereal layers were washed with water (2 × 60 mL), dried on
MgSO , filtered and concentrated in vacuo. Purification of the
crude product by flash column chromatography using hexanes–
Et O (9:1) as an eluent gave 7 (2.90 g, 56%) as a colorless oil.
Found: C, 70.90; H, 10.15; N, 0.72. Calc. for C128
C, 70.94; H, 10.09; N, 0.65%). d (500 MHz, CDCl
m, ArH), 7.68 (2H, m, ArH), 5.73 (27H, m, SiCH
2
O (3 × 80 mL). The combined
a colorless oil. (Found: C, 68.11; H, 12.47; N, 1.20. Calc. for
2
0
◦
C
128
H
282
N
2
O
3
Si13; C, 67.94; H, 12.56; N, 1.24%). [a] −3.7 (c
D
−
1
4
1.0 in CHCl
3
). mmax(CHCl )/cm 3442, 2956, 2919, 2869, 2795,
3
1700 and 1676. d
H
(500 MHz, CDCl ) 6.03 (1H, broad t, NH),
3
2
5.02 (1H, broad s, NH), 4.13 (1H, broad m, CH), 3.28 (1H,
ꢀ
(
H
217NO
2
Si13
;
dt, J 13.5 and 6.6, NHCHH ), 3.20 (1H, dt, J 13.5 and 6.6,
ꢀ
H
3
) 7.81 (2H,
NHCHH ), 1.47 (12H, s, CH
3
(BOC and Ala)), 1.34 (80H, m,
and SiCH CH CH Si), 0.98 (81H,
), 0.59 (48H, m, CH SiCH ) and 0.52
and NHCH CH CH ). d (125.8 MHz,
) 179.8, 172.4, 43.1, 31.2, 28.6, 24.6, 18.9, 18.8, 18.5, 18.1,
CH=CH
),
),
NHCH
t, J 7.0, SiCH
(56H, m, SiCH
CDCl
CH
, SiCH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
3
2
2
2
4
1
(
.86 (54H, m, SiCH
.57 (56H, d, J 8.1, SiCH
2
CH=CH
2
), 3.62 (2H, t, J 7.5, NCH
2
2
2
3
2
2
CH=CH
and NCH
Si(allyl) ), 0.64 (24H,
CH CH and
) 168.4, 134.7, 134.0,
CH
), 1.33
2
2
2
2
2
2
3
2
2
2
C
24H, m, {3-(Pht)propyl}SiCH
2
and CH
2
3
3
m, SiCH
2
CH
2
CH
2
Si) and 0.56 (26H, m, PhtCH
(125.8 MHz, CDCl
2
2
2
18.0, 17.9, 17.8, 15.7 and 10.0.
{
1
1
CH
2
Si(CH
2
)
3
}
3
). d
C
3
Carbosilane wedge L-alaninyl[G3](propyl)27 ammonium trifluo-
roacetate salt 11. A solution of 10 (0.668 g, 0.295 mmol) in
32.5, 123.3, 113.8, 41.4, 23.6, 19.9, 18.8, 18.5, 18.1, 17.9, 17.7,
6.9 and 9.9. m/z (MALDI-TOF) 2126.4 (M − C
+
3
6
H ).
CH
(CaCl
2
Cl
2
(10.0 mL) was cooled under dry, aerobic conditions
tube) to 0 C using an ice–water bath. To this solution
◦
Carbosilane wedge Pht[G3](propyl)27 8. To
7
(3.91 g,
2
1
.80 mmol) and Pd on C (10%, 0.26 g) was added EtOAc (90 mL).
and
was added TFA (5.0 mL) in 1.0 mL portions. The reaction was
stirred for 10 minutes at 0 C, followed by stirring for 1 hour
◦
The mixture was placed under an atmospheric pressure of H
2
stirred overnight. The reaction mixture was filtered over Celite and
concentrated in vacuo, affording 8 (3.61, 90%) as a colorless oil.
at room temperature. To the reaction mixture was added toluene
(15 mL) and the solvents were removed in vacuo. The residue
was re-dissolved and evaporated to dryness twice using toluene
(15mL)andonceusingdiethylether(20mL), affording 10(0.671g,
quantitative) as a colorless oil. (Found: C, 63.88; H, 12.42; N, 0.96.
(
6
Found: C, 69.34; H, 12.45; N, 0.62. Calc. for C128
9.20; H, 12.30; N, 0.63%). d (500 MHz, CDCl
ArH), 7.68 (2H, m, ArH), 3.63 (2H, t, J 7.5, NCH
NCH CH ), 1.29 (78H, m, SiCH CH CH and SiCH
.94 (81H, t, J 7.1, CH ), 0.55 (48H, m, CH
56H, m, SiCH CH CH and Pht–CH CH CH
H
271NO Si13; C,
2
H
3
) 7.82 (2H, m,
), 1.64 (2H, m,
CH CH Si),
SiCH ) and 0.48
). d (125.8 MHz,
2
2
0
2
2
2
2
3
2
2
2
Calc. for C125
H
275
F
3
N
2
O
3
Si13; C, 65.95; H, 12.18; N, 1.23%). [a]
D
◦
−1
0
(
3
2
2
2
−0.9 (c 1.0 in CHCl
3
). mmax(CHCl
3
)/cm 3280, 2956, 2918, 2869,
2
2
3
2
2
C
2795 and 1676. d
H
(500 MHz, CDCl
3
) 6.35 (1H, broad s, NH), 4.09
ꢀ
CDCl
3
) 168.2, 133.7, 132.3, 123.1, 41.2, 23.4, 18.7 (2C), 18.5, 18.2,
(1H, broad s, CH), 3.38 (1H, broad m, NHCHH ), 3.14 (1H, broad
ꢀ
+
1
7.9, 17.8, 17.7, 17.5, 15.5 and 9.8. m/z (MALDI-TOF) 2179
m, NHCHH ), 1.57 (83H, m, NH
3
CH
2
CH
2
, SiCH
CH
) and 0.52 (56H, m, SiCH CH
(125.8 MHz, CDCl ) 179.7, 169.2, 134.5,
2
CH
CH
CH
2
CH
), 0.59
and
3
and
+
(
M − C
3
H
6
).
SiCH
48H, m, CH
NHCH CH CH
2
CH
2
CH
2
Si), 0.98 (81H, t, J 7.3, SiCH
2
2
3
(
2
SiCH
). d
2
2
2
3
Carbosilane wedge H
2
N[G3](propyl)27 9. Compound 8 (3.50 g,
.58 mmol) was dissolved in EtOH (85 mL) and hydrazine
2
2
2
C
3
1
4
9.7, 43.8, 24.2, 18.9, 18.1, 18.0, 17.8, 15.7 and 10.2. m/z (FAB)
monohydrate (0.79 mL, 16 mmol) was added. The solution was
+
2162.9 (M − CF
3
COO).
◦
heated to 90 C and the resulting white dispersion was stirred
ꢀ
ꢀꢀ
overnight. The reaction mixture was cooled to room temperature
after which a concentrated HCl solution (15 mL) was added to
N,N ,N -1,3,5-Tris(L-alaninyl)benzenetricarboxamide
core-
ꢀ
functionalized dendrimer G3 . 1,3,5-Benzenetricarboxylic acid
(0.0192 g, 0.0914 mmol), 11 (0.635 g, 0.279 mmol) and PyBOP
(0.145 g, 0.279 mmol) were suspended in THF (10.0 mL). To
the suspension was added DiPEA (0.107 mL, 0.614 mmol) after
which a clear solution was obtained. The reaction mixture was
stirred overnight. The solvent was removed in vacuo. Purification
of the residue by column chromatography over silica using
◦
the dispersion. The resulting mixture was heated at 90 C for
5
hours after which a white, crystalline precipitate had formed.
The mixture was cooled and poured into an ice-cold NaOH
solution (1.5 M, 125 mL). The mixture was partially concentrated
and subsequently extracted with Et
2
O (3 × 40 mL). The organic
layer was washed with water (2 × 40 mL), dried on MgSO
4
,
ꢀ
filtered and concentrated in vacuo, affording 9 (3.10 g, 94%) as
hexanes–EtOAc (4:1) as an eluent gave G3 (0566 g, 93%), as
a colorless oil. (Found: C, 68.40; H, 13.04; N, 0.61. Calc. for
a colorless oil. (Found: C, 68.39; H, 12.72; N, 1.42. Calc. for
2
0
◦
C
2
(
120
H
269NSi13; C, 68.91; H, 12.96; N, 0.67%). d
.66 (2H, t, J 6.8, NH CH ), 1.41 (2H, m, NH
80H, m, SiCH CH CH , SiCH CH CH Si and NH
), 0.56 (48H, m, CH SiCH ) and 0.50 (56H, m,
and NH CH CH CH ). d (125.8 MHz, CDCl
5.9, 28.7, 18.7, 18.6, 18.1, 17.9, 17.8, 17.5, 15.4 and 9.5. m/z
H
(500 MHz, CDCl
CH CH ), 1.31
), 0.96 (81H,
3
)
C
378
H
822
N
6
O
6
Si39; C, 68.33; H, 12.47; N, 1.26%). [a]D −2.5 (c 1.0
(500 MHz, CDCl ) 8.40 (3H, s, ArH), 7.12 (3H, d,
J 7.0, ArC(O)NH), 5.72 (3H, broad s, C(O)NHCH
2
2
2
2
2
in CHCl
3
). d
H
3
2
2
3
2
2
2
2
2
), 4.62 (3H,
ꢀ
t, J 7.3, CH
SiCH
4
3
2
2
quintet, J 7.0, CH), 3.45 (3H, dt, J 11.7 and 3.8, NHCHH ),
3.08 (3H, dt, J 9.6 and 3.5, NHCHH ), 1.50 (15H, d, J 7.0,
ꢀ
2
CH
2
CH
3
2
2
2
2
C
3
)
CH
and SiCH
(
3
(Ala) and NHCH
CH CH Si), 0.95 (243, t, J 7.3, SiCH
144H, m, CH SiCH ) and 0.50 (168H, m, SiCH
CH ). d (125.8 MHz, CDCl ) 171.8, 165.2, 135.1,
2
CH
2
), 1.31 (234H, m, SiCH
CH CH
CH CH
2
CH
), 0.56
and
2
CH
3
+
(
MALDI-TOF) 2093 (M + H).
2
2
2
2
2
3
2
2
2
2
3
Carbosilane wedge BOC-L-alaninyl[G3](propyl)27 10. Com-
NHCH
2
CH
2
2
C
3
pound
9
(0.796 g, 0.381 mmol), BOC-L-Ala (0.0720 g,
.381 mmol), DCC (0.0785 g, 0.381 mmol) and DMAP (4.65 mg,
.0381 mmol) were dissolved in CH Cl (10 mL) and stirred for
hours. The solution was concentrated in vacuo. Purification of
1
1
28.9, 49.7, 43.4, 24.5, 19.5, 18.9, 18.8, 18.5, 18.1, 18.0, 17.9, 17.8,
5.7 and 10.2. m/z (MALDI-TOF) 6669 (M + Na).
0
0
2
+
2
2
N-(Benzyloxycarbonyl)-D-glutamic acid 5-tert-butyl ester 1-
the crude product by column chromatography over silica using
hexanes–EtOAc (9:1) as an eluent gave 10 (0.707 g, 82%) as
methyl ester. To a solution of N-(benzyloxycarbonyl)-D-glutamic
acid 5-tert-butyl ester (0.25 g, 0.742 mmol), DCC (0.135 g,
2
20 | Org. Biomol. Chem., 2006, 4, 211–223
This journal is © The Royal Society of Chemistry 2006

View Article Online
0
.741 mmol) and DMAP (9.6 mg, 79 lmol) in CH
2
Cl
2
(4.0 mL)
[H]:[G] while keeping [H] + [G] constant were prepared in NMR
was added MeOH (50.0 lL, 1.23 mmol). The reaction mixture was
stirred for 2 hours after which the solvent was removed in vacuo.
Purification of the crude product by column chromatography
over silica using EtOAc–hexanes (99:1) as an eluent gave the title
tubes by mixing the stock solution in different proportions (total
1
volume: 500 lL). H NMR spectra were recorded for each NMR
tube. The Dd values were calculated by subtracting the chemical
shift of the aH resonance of L-5 in the spectrum (d
x
) from the same
2
0
◦
compound (0.246 g, 95%) as a colorless oil. [a] −3.7 (c 1.0
resonance of the pure L-5 solution (d ). A graph of the Dd value
0
D
−
1
in CHCl
723. d
NH), 5.07 (2H, s, PhCH
3
). mmax(CDCl
3
)/cm 3431, 3008, 2982, 2961, 2937 and
as function of the mole fraction L-5 was plotted. The maximum
corresponds to 0.5 mole fraction, corresponding to a 1:1 binding
stoichiometry.
1
H
(300 MHz, CDCl
3
) 7.31 (5H, m, ArH), 5.49 (1H, d, J 8.1,
), 4.36 (1H, q, J 8.1, CH), 3.71 (3H, s,
2
C(O)OCH
3
), 2.29 (2H, q, J 6.9, CH
2
C(O)OtBu), 2.11 (1H, m,
(BOC)).
ꢀ
ꢀ
CHCHH ), 1.92 (1H, m, CHCHH ) and 1.40 (9H, s, CH
3
Acknowledgements
d
C
(75 MHz, CDCl
3
) 172.7, 172.2, 156.2, 136.4, 128.7, 128.4, 128.3,
8
1.0, 67.2, 53.7, 52.7, 31.6, 28.2 and 27.8. m/z (GC/MS) 295
The authors would like to thank Dr Roel H. Fokkens for
measurement of the MALDI-TOF MS spectra. The Netherlands
Organization for Scientific Research (NWO/STW) is acknowl-
edged for financial support (RvH).
+
(
M − tBu).
N-(Benzyloxycarbonyl)-D-glutamic acid 1-methyl ester D-5. N-
Benzyloxycarbonyl)-D-glutamic acid 5-tert-butyl ester 1-methyl
(
ester (0.161 g, 0.457 mmol) was dissolved under a dry atmosphere
CaCl tube) in CH Cl (6.0 mL). The solution was cooled
(
2
2
2
References
with an ice–water bath and TFA (1.0 mL) was added to the
◦
1 For some general reading on dendrimers see: Dendrimers and Other
Dendritic Polymers, ed. J. M. J. Fr e´ chet and D. A. Tomalia, John Wiley
solution. The reaction mixture was stirred for 10 minutes at 0 C
and subsequently 1 hour at room temperature. To the reaction
mixture was added toluene (10 mL) after which the solvents were
removed in vacuo. Purification of the crude product by column
chromatography over silica using EtOAc–hexanes (19:1) as an
&
Sons, Ltd., West Sussex, 2001; G. R. Newkome, C. N. Moorefield
and F. V o¨ gtle, Dendrimers and Dendrons, Wiley-VCH, Weinheim, 2001;
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1
97, vii; J. P. Majoral and A.-M. Caminade, Chem. Rev., 1999, 99, 845;
2
D
0
◦
eluent gave D-5 (0.124 g, 92%) as a white solid. [a] −4.8 (c 1.0 in
A. W. Bosman, H. M. Janssen and E. W. Meijer, Chem. Rev., 1999, 99,
43
−1
CHCl
3
), 61% optical purity.
m
max(CDCl )/cm 3511, 3430, 3036,
3
1665.
2
For reviews on gene therapy and/or drug delivery see: J. M. Loutsch,
D. Ong and J. M. Hill, Drugs Pharm. Sci., 2003, 130, 467; P. K. Tripathi,
A. J. Khopade, T. Dutta, R. B. Umamaheshewari, S. Jain, D. K. Saraf
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Syst., 2002, 17, 462; M. J. Cloninger, Curr. Opin. Chem. Biol., 2002, 6,
2
5
951, 2856 and 1716. d
.43 (1H, d, J 7.8, NH), 5.10 (2H, s, PhCH
H
(300 MHz, CDCl
3
) 7.34 (5H, m, ArH),
), 4.43 (1H, q, J 7.2,
2
CH), 3.74 (3H, s, C(O)OCH
3
), 2.44 (2H, q, J 7.0, CH
2
COOH),
(75 MHz,
ꢀ
ꢀ
2
.20 (1H, m, CHCHH ) and 1.97 (1H, m, CHCHH ). d
C
CDCl ) 177.5, 172.5, 156.2, 136.3, 128.8, 128.5, 128.3, 67.4, 53.4,
3
52.9, 30.0 and 27.8.
7
2
42; A. K. Patri, I. J. Majoros and J. R. Baker, Curr. Opin. Chem. Biol.,
002, 6, 466; S.-E. Stiriba, H. Frey and R. Haag, Angew. Chem., Int.
39
Ed., 2002, 41, 1329; A. T. Florence and N. Hussain, Adv. Drug Delivery
Rev., 2001, 50, S69; M. Liu and J. M. J. Fr e´ chet, Pharm. Sci. Technol.
Today, 1999, 2, 393; L. G. Schultz and S. C. Zimmerman, Pharm. News,
1999, 6, 25; R. Gandhi, A. J. Khopade and N. K. Jain, Indian Drugs,
1997, 34, 593.
NMR titration experiments . The NMR titration experiments
◦
(
300 MHz, 24 C) were performed in CDCl
3
that was previously
distilled from calcium hydride and stored on molecular sieves
˚
(
4 A). The dendrimer concentration in the prepared solutions was
3
4
For reviews on supramolecular chemistry and dendrimers see: P. J.
Gittins and L. J. Twyman, Supramol. Chem., 2003, 15, 5; M. W. P. L.
Baars and E. W. Meijer, Top. Curr. Chem., 2000, 210, 131; F. W. Zeng
and S. C. Zimmerman, Chem. Rev., 1997, 97, 1681.
ca. 5 mM and contained up to 5 equivalents of guest, except for the
titration with propionic acid in which the dendrimer concentration
was 14 mM and solutions containing up to 10 equivalents of
acid were measured. The association constants and complexation
induced shifts were obtained by non-linear least-squares fitting
V. J. Pugh, Q.-S. Hu, X. Zuo, F. D. Lewis and L. Pu, J. Org. Chem.,
2
6
001, 66, 6136; L.-Z. Gong, Q.-S. Hu and L. Pu, J. Org. Chem., 2001,
6, 2358.
44
using the GraFit 4.0 software package. The uncertainties are
the standard deviations determined by the error analysis of the
5 A. W. van der Made, P. W. N. M. van Leeuwen, J. C. de Wilde and
R. A. C. Brandes, Adv. Mater., 1993, 5, 466.
6
7
C. Schlenk and H. Frey, Monatsh. Chem., 1999, 130, 3.
A. W. van der Made and P. W. N. M. van Leeuwen, J. Chem. Soc.,
Chem. Commun., 1992, 1400.
program.
The binding constants K
ꢀ
1
and K
2
of host G3 with both
enantiomers of guest N-CBZ-glutamic acid 1-methyl ester (5) in
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◦
CDCl
3
(T = 24 C) were determined by varying the guest concen-
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constant at approximately 3.4 mM. The downfield shifts of the
ꢀ
G3 aromatic, Ala-CH and C(O)NHCH
2
proton resonances were
followed. The association constants were calculated from the data
45
using a non-linear least-squares fitting program. The best fits
were obtained assuming a 1:2 host–guest binding stoichiometry.
The titration experiments were performed in duplo.
2
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Job plot analysis . Two stock solutions of 9.34 mM L-5 and
ꢀ
9
.07 mM G3 in CDCl
3
were prepared. Nine solutions with varying
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ꢀ
ꢀꢀ
36 Similar observations have been made for N,N ,N -1,3,5-tris((S)-3,7-
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−
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◦
43 Specific optical rotation measured for N-CBZ-L-5: [a]D = + 7.9 (c 1.0
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This journal is © The Royal Society of Chemistry 2006
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