Structural diversity of α-amino acid based layer-block dendrons and their layer-block sequence-dependent gelation properties

Article abstract of DOI:10.1002/chem.200500174

A library of G1-G3 α-amino acid based layer-block dendrons 1-6 containing different amino acid residues in the different concentric layers was prepared by solution-phase peptide synthesis. The structures of these dendrons were characterized by ¹

Full text of DOI:10.1002/chem.200500174

FULL PAPER
Chem. Eur. J. 2005, 11, 5817 – 5831
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5817

DOI: 10.1002/chem.200500174
Structural Diversity of a-Amino AcidBasedLayer-Block Dendrons and
Their Layer-Block Sequence-Dependent Gelation Properties
[a]
Hak-Fun Chow* andJie Zhang
Abstract: A library of G1–G3 a-amino
acid based layer-block dendrons 1–6
containing different amino acid resi-
dues in the different concentric layers
was prepared by solution-phase peptide
synthesis. The structures of these den-
drons were characterized by 1H and
13C NMR spectroscopy and, except for
the G3 series of compounds, by mass
spectrometry. The purities of these
compounds were also determined by
size-exclusion chromatography. Owing
to the presence of a large number of
amide groups, these dendrons exhibit
unusually strong self-aggregating prop-
erties in bothpolar and nonpolar sol-
vents. Some of these dendrons are
found to be extremely good organoge-
lators towards aromatic solvents with
minimum gel concentrations approach-
ing 4 mgmLÀ1. Their gelation ability is
found to be highly dependent on the
nature of the amino acid compositions,
the amino acid layer-block sequence
within the dendritic architecture and
the nature of the focal-point function-
ality. IR spectroscopic analysis indi-
cates that gelation is induced by inter-
molecular hydrogen bonds. Circular di-
chroism studies suggest the formation
of hierarchical chiral structures in the
gel state, although the existence of
chiral morphologies could not be ob-
served by scanning electron microsco-
py.
Keywords: aggregation
·
amino
acids · dendrimers · gels · protein
models
Introduction
et al. recently reported that the esterolysis reactivity of a li-
brary of layer-block or segment-block peptide-based den-
dritic catalysts was dependent on their amino acid composi-
tion.[1f–i] Smith also disclosed that the two-component gela-
tion property of lysine-containing peptide-based dendrimers
with aliphatic diamines was dependent on the dendrimer
generation.[2] Although no structural diversity could be real-
ized with this series of compounds, as lysine was the only
amino acid component used, the study nonetheless revealed
that the number of lysine repeating units, and hence the
amino acid composition, of suchpeptide-based dendrimers
was an important determinant of the gelation properties. We
earlier disclosed the synthesis of b-alanine based dendrimers
and reported their self-aggregation properties in polar or-
ganic solvents.[5] However, owing to their poor solubility, we
were unable to study their properties in nonpolar solvents.
Here we report the synthesis of a new library of G1–G3 a-
amino acid based layer-block dendrons 1–6 by replacing the
b-alanine moieties withalanine, phenylalanine, or valine res-
idues. We show here that the a-amino acid side chains have
an important influence on the properties of these dendrons
and that they form dendritic physical gels in nonpolar aro-
matic solvents. Moreover, their gelation properties are also
determined by their layer-block sequence[6] and their amino
acid composition. This finding further supports the observa-
There has been an increasing interest in the use of natural
a-amino acids as components in the construction of peptide-
based[1,2] or amino acid based dendrimers[3] owing to their
structural resemblance to proteins and enzymes. Suchden-
drimers are also potentially useful molecules in catalysis and
biomedical applications because of their perceived biocom-
patibility.[4] One particular appealing attribute of this re-
searchis that dendrimers withextremely broad structural di-
versities can be generated by varying the a-amino acids
used in their construction. Yet another equally important
aspect lies in the establishment of whether the properties of
suchamino acid derived dendrimers can be controlled by
the constituent amino acid residues residing within the den-
dritic structure. This critical issue is closely related to the
doctrine that the amino acid sequence determines the prop-
erties of protein and enzyme molecules. Indeed, Reymond
[a] Prof. H.-F. Chow, Dr. J. Zhang
Department of Chemistry and Materials Science and Technology
ResearchCenter
Institute of Science and Technology
The Chinese University of Hong Kong
Shatin, NT, SAR (Hong Kong)
Fax : (+852)260-35-057
E-mail: hfchow@cuhk.edu.hk
5818
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 5817 – 5831

Amino Acid Based Dendrons
FULL PAPER
were then removed in the pres-
ence of HCl to give the di-
ammonium salts (ClÀ H3N+-
aa1)2-CO2Et (9) in quantitative
yields. Alternatively, the focal
point ethyl ester group was re-
moved by alkaline hydrolysis to
furnishteh various acid den-
drons G1-(aa1)2-CO2H (2) in
76–99% yields. The G1 acid
dendrons containing aa1 amino
acid residues were then coupled
to another diammonium salt
(ClÀ H3N+-aa2)2-CO2Et to give
the G2 ester dendrons G2-
(aa1)4(aa2)2-CO2Et (3) having a
layer-block sequence of aa1aa2
in the presence of HOBt, DCC,
and 4-methylmorpholine in 69–
93% yields. Six different G2
ester dendrons were thus pre-
pared and then subjected to al-
kaline hydrolysis to give the
corresponding G2 acid den-
drons 4 in 84–92% yield. For
the syntheses of the G3 ester
dendrons 5, the more reactive
1-[3-(dimethylamino)propyl]-3-
ethylcarbodiimide methiodide
(EDCI) was used instead of
DCC as the coupling reagent
and the product yields were
slightly inferior (38–62%). Fi-
nally, the G3 acid dendrons 6
were obtained by alkaline hy-
tion that the amino acid side chains not only confer the
structural diversity, but also play a very important role in
determining the physico-chemical properties of this interest-
ing class of biomimetic dendrimers.
drolysis from the G3 ester dendrons 5.
Characterization
NMR spectroscopy: The structures of all compounds were
1
characterized by H NMR spectroscopy. The presence of a
pseudo-C2 symmetry axis in these molecules greatly simpli-
1
Results andDiscussion
fied their spectral peak assignments. The H NMR spectra
of the different dendrons of the same generation are very
similar because they all possess the same dendrimer back-
bone and branching skeleton. The only notable differences
were the signals due to the side groups belonging to the dif-
Synthesis: The syntheses of the Boc-N-protected a-amino
acid dendrons 1–6 were similar to those of the b-alanine
dendrons reported earlier by us.[5] Only nonpolar amino
acids (l-alanine=A; l-phenylalanine=F; l-valine=V)
were chosen in the present study. They were connected by
amide linkages to a 3,5-diaminobenzoic acid branching unit
using liquid-phase peptide coupling methods by a conver-
gent synthesis methodology. The G1–G3 layer-block den-
drons 1–6 of all possible layer sequences were prepared.
Hence, reaction of BocNH-aa1-CO2H (7) withethyl 3,5-di-
aminobenzoate (8) in the presence of dicyclohexylcarbodi-
imide (DCC) and 1-hydroxybenzotriazole (HOBt) in THF
afforded the various ester dendrons G1-(aa1)2-CO2Et[7] 1 in
82–90% yields (Scheme 1). The Boc groups in compounds 1
1
ferent amino acid residues. For example, the H NMR spec-
tra of the three G1-(aa1)2-CO2Et dendrons all gave a sharp
singlet (d~1.3 ppm) due to the tert-butyl protons, a triplet
(d~1.3 ppm) and a quartet (d~4.3 ppm) due to the ethyl
ester protons, two singlets (d~7.9 and ~8.2 ppm) for aro-
matic protons of the branching aromatic unit, an NH dou-
blet for the carbamate (d~7.2 ppm), and a broad singlet (d~
10.2 ppm) for the anilide NH (Figure 1). On the other hand,
the chemical identities of the different G1-(aa1)2-CO2Et den-
drons could be confirmed by the “fingerprint” peaks due to
the different amino acid side chains. Hence, G1-A2-CO2Et
Chem. Eur. J. 2005, 11, 5817 – 5831
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5819

H.-F. Chow and J. Zhang
showed up as a doublet (d=
0.89 ppm) and a multiplet (d=
1.90–2.05 ppm). The presence
1
of H signals due to the minor
carbamate rotamers, as in the
case of the b-alanine dendrim-
ers,[5] was also found.
For the various G2-(aa1)4(aa2)2-
CO2Et dendrons, the positions
and patterns of the resonance
peaks pertaining to the aa1
amino acid side chain protons
located on the outer layer were
nearly unchanged when com-
pared to those of the corre-
sponding G1-(aa1)2-CO2Et den-
drons having the same amino
acid residue. On the other
hand, the resonance positions
for protons in the inner layer
aa2 amino acid side chains were
shifted downfield as compared
Scheme 1. Reagents and conditions: a) HOBt, DCC, THF, À108C to 258C, 11 h; b) HCl, EtOH, 25 8C, ~10 h;
c) KOH (2.0m), MeOH, H2O, 25 8C, ~10 h; d) HOBt, DCC, 4-methylmorpholine, DMF, À108C to 258C, 50 h;
e) KOH (2.0m), MeOH, THF, H2O, 25 8C, ~10 h; f) HOBt, EDCI, 4-methylmorpholine, DMF, À108C to
258C, 62 h.
withtohse of teh G1-(aa
2)2-
CO2Et dendrons. As an exam-
ple, the relevant proton reso-
nance signals of the two den-
drons having F residues in the
outer
layer—G2-F4A2-CO2Et
and G2-F4V2-CO2Et and the two dendrons having F in the
inner layer—G2-A4F2-CO2Et and G2-V4F2-CO2Et were
tabulated and compared with those of the G1-F2-CO2Et
dendron (Table 1). A closer examination of the data re-
vealed that the chemical shift values of the benzylic protons
Table 1. 1H NMR (300 MHz, [D6]DMSO) chemical shift values (d) of
proton signals relating to the F residues when placed in different layers
inside the dendrons.
G1-F2-
CO2Et
G2-F4A2- G2-F4V2- G2-A4F2- G2-V4F2-
CO2Et CO2Et CO2Et CO2Et
NCHCH2Ph2.75–3.05 2.68–3.08 2.72–3.07 3.07–3.21 3.05–3.21
NCHCH2Ph4.25–4.38 4.16–4.39 4.21–4.40 4.78–4.88 4.77–4.88
and the a protons of the F residues were shifted downfield
by d~0.2 and ~0.5 ppm, respectively, when the F residues
were moved from the outer to the inner layer. This is due to
a difference of the linker group connecting to the a-amino
residues. For those groups located in the outer layer, the
amino ends of the F residues are connected to a carbamate
functionality, while for those situated in the inner layer the
amino moieties are linked to the aromatic branching unit by
an amide bond. Suchan apparent upfield shift of 1H reso-
nance positions, when the amino acid residue is located on
the outer layer, can be used as a convenient tool to identify
the nature of the amino acid located on the outer layer of
the G2 and G3 layer-block dendrons.
Figure 1. 1H NMR (300 MHz) spectra of G1-(aa1)2-CO2Et: a) aa1 V (R=
iPr), b) aa1 =F (R=Bn), and c) aa1 A (R=Me) in [D6]DMSO.
could be distinguished from the other ester dendrons by the
presence of a doublet (d=1.25 ppm) from the side chain
methyl groups. For G1-F2-CO2Et, the side chain benzyl
groups appeared as three separate signals (d=2.75–2.90,
1
2.90–3.05, and 7.17–7.35 ppm) in its H NMR spectrum. Fi-
nally, the isopropyl signals in compound G1-V2-CO2Et
5820
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 5817 – 5831

Amino Acid Based Dendrons
FULL PAPER
The 13C NMR spectra of these dendrons also share the
same spectral characteristics as those of the H NMR spec-
Size-exclusion chromatography: The purities of the target
dendrons were further determined by size-exclusion chro-
matography (SEC). All ester dendrons, irrespective of den-
drimer generation, produced a symmetrical peak witha
narrow polydispersity (ꢀ1.03) in the SEC chromatogram in
DMF. No peaks due to the presence of defective dendrons
were detected. Surprisingly, the SEC chromatograms of all
acid dendrons were broad and unsymmetrical in DMF, sug-
gesting the presence of aggregates (Figure 3). However,
upon addition of 5% acetic acid to the eluting solvent, the
SEC peaks became sharper and symmetrical. The positions
of the peaks were shifted to longer retention times that
were nearly identical to that of their corresponding dendritic
1
tra. The chemical shift values of the carbon nuclei arising
from the dendritic backbone and the aromatic branching
unit are nearly the same. Hence, the primary and tertiary
carbon atoms of tert-butyl groups resonate at d=29 and
79 ppm, respectively. The peaks for the ethyl ester group ap-
peared at d=15 and 61 ppm, while the four aromatic carbon
signals of branching units were found around d=115–
140 ppm. Three carbonyl 13C signals appeared in the most
downfield area of the spectra. The carbonyl 13C signal at d~
156 ppm corresponded to the carbamate C=O group, while
the signal at d~166 ppm was assigned to the C=O ester
moiety. The third signal, located at d~172 ppm, originated
from the anilide C=O group. Similarly, the chemical identi-
ties of the amino acid residues could be differentiated, as in
1
the case of H NMR spectroscopic analysis, by the “finger-
print” peaks from the different side chain functionalities.
Mass spectrometry: The structures of the G1 and G2 den-
drons were also characterized by FAB-or L-SIMS mass
spectrometry. For the G1 series, molecular ions appeared in
forms of M+, [M+Na]+, or [M+K]+. For the G2 dendrons,
a molecular ion peak corresponding to [M+Na]+ and/or
[M+K]+ is always present, as well as a series of fragmenta-
tion ion peaks due to the sequential cleavage of up to four
Boc groups. For example, in addition to the molecular ion
peak signals at m/z 1657.8 [M+Na]+ and 1674.4 [M+K]+,
four fragment ion peaks at m/z 1535.9, 1436.4, 1335.7 and
1236.4, corresponding to [MÀBoc]+, [MÀ2Boc]+,
[MÀ3Boc]+ and [MÀ4Boc]+, respectively, were also found
in the mass spectrum of G2-F4V2CO2Et (Figure 2). Unfortu-
nately, we were unable to obtain satisfactory mass spectral
data for the G3 series of dendrons.
Figure 3. SEC chromatograms of G2-A4V2-CO2H in different solvent sys-
tems (flow rate: 1 mLminÀ1; temperature: 408C; columns: Waters Styra-
gel HR1 and HR3 in serial). The negative absorption peaks are due to
signals of water and acetic acid.
Figure 2. FAB mass spectrum of G2-F4V2-CO2Et.
Chem. Eur. J. 2005, 11, 5817 – 5831
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5821

H.-F. Chow and J. Zhang
ester precursors, indicating the breaking down of the aggre-
gates in a stronger hydrogen bonding solvent. Furthermore,
a linear relationship can be established between the SEC re-
tention time and the logarithm of the theoretical molecular
weight of the dendrons (Figure 4). Hence, dendrons of the
ent chiral components. For example, the molar rotations of
G1-A2-CO2R (R=Et or H) and G1-V2-CO2R dendrons are
negative, while those of the G1-F2-CO2R are positive. As a
result, the signs of the molar rotations of G2-A4V2-CO2R
and G2-V4A2-CO2R dendrons, which can be considered to
consist of G1-A2-CO2R and G1-V2-CO2R dendrons, are also
negative. However, the sign of molar rotations for G2 den-
drons consisting of a combination of A and F, or F and V
residues are difficult to predict, because the chiroptical ef-
fects of A and F, or F and V, are counteracting eachother,
but not in an exact or quantitative manner. Thus, G2-F4V2-
CO2R, a dendron that can roughly be considered as consist-
ing of two (+)-G1-F2-CO2R and one (À)-G1-V2-CO2R frag-
ments, has a negative molar rotation value. On the other
hand, G2-F4A2-CO2R has a positive molar rotation, even
though the molar rotation of G1-A2-CO2R is more negative
than that of G1-V2-CO2R. Obviously this simple dissection
of higher generation dendrons into smaller lower generation
dendritic fragments is an over-simplified analysis, because
the N-termini of the outer layer amino acids are linked to
Boc moieties while those of the inner layer amino acids are
connected to the 3,5-diaminobenzoic acid branching unit. It
has been noted that a slight change in the chemical environ-
ment of chiral units could lead to dramatically different chi-
roptical properties.[8] It is therefore not surprising to see that
an exact quantitative relationship cannot be formulated by
using sucha simplified structural dissection approach. Nev-
ertheless, a qualitative statement claiming that the molar ro-
tation of these dendrons is the simple sum of the rotations
of its constituted chiral units, as in the case of sterically non-
congested chiral dendrimers,[9] is possibly valid.
Figure 4. A plot of SEC retention time versus log(MW) of the G1–G3
dendrons (solvent: 5% HOAc/DMF).
same generation are found in close proximity in the figure.
As a result, three separate clusters were found in the plot,
with the G3 cluster located near the top left corner and the
G1 cluster situated at the bottom right corner. This finding
also suggests that dendrons of the same generation all pos-
sess similar hydrodynamic radii, irrespective of the amino
acid composition and the focal-point functional group.
Self-aggregation properties: In contrast to the poor solubili-
ty properties of the b-alanine dendrons reported earlier,[5]
these a-amino acid dendrons, owing to the presence of the
nonpolar alkyl amino acid side chains, are reasonably solu-
ble in aromatic and chlorinated solvents. As a result of this
change of amino acid composition, the a-amino acid den-
drons exhibit aggregation properties that were not revealed
previously as in the case of the b-alanine dendrimers. Most
of the a-amino acid dendrons prepared here were found to
have a tendency to form self-organized species in the solid
and solution states. For example, X-ray crystallographic
analysis of a G1-V2-CO2Et crystal (from ethyl acetate)
shows that the compound crystallizes as a dimer of approxi-
mate C2 symmetry (Figure 5). Eachmolecule in the dimer
embraces the other with its two longer, pincer-like arms,
such that the pair of aromatic rings are mutually nearly par-
allel and arranged in a staggered manner (dihedral angle be-
tween ring planes=8.18, distance between ring centers=
3.553 Š). The molecular association in the dimer is further
consolidated by four intermolecular hydrogen bonds of the
Optical polarimetry: The chiroptical data of the dendrons
were measured in 5% HOAc in 1,2-dichloroethane to avoid
complications due to aggregation (Table 2). One notable
feature is that the sign of the specific rotation does not
change from the dendritic esters to their corresponding car-
boxylic acids. This suggests that the nature of the focal-point
functionality has little influence on the chiral conformation.
Another point of interest is that the molar rotation of the
higher generation dendrons can be roughly estimated from
summation of the molar rotations of all the smaller constitu-
Table 2. Chiroptical data of G1 and G2 dendrons[a]
[b]
Dendron
[a]D
[M][c]
Dendron
[a]D
[M]
G1-A2-CO2Et
G1-F2-CO2Et
À66.9 À350
G1-A2-CO2H
+15.2 +103 G1-F2-CO2H
À60.7 À300
+8.8 +57
G1-V2-CO2Et
À30.5 À177
À52.6 À751
À74.8 À996
G1-V2-CO2H
G2-A4F2-CO2H
G2-A4V2-CO2H
À56.9 À313
À73.5 À958
À58.9 À768
+141.7 +2199
À48.4 À778
À1.8 À25
G2-A4F2-CO2Et
G2-A4V2-CO2Et
G2-F4A2-CO2Et
G2-F4V2-CO2Et
G2-V4A2-CO2Et
G2-V4F2-CO2Et
+26.1 +412 G2-F4A2-CO2H
À
type N H···O=C (N1···O7’ 2.947, N3···O4’ 2.977, N1’···O7
À0.6 À10
G2-F4V2-CO2H
G2-V4A2-CO2H
2.968, N3’···O4 2.996 Š).
À19.6 À272
The formation of dimeric species from G1-V2-CO2Et can
+13.3 +204 G2-V4F2-CO2H
+45.1 +682
1
also be revealed from a H NMR investigation. In CDCl3 so-
[a] In 1,2-dichloroethane/HOAc =95/5 (v/v) solutions at 258C. [b] Specif-
ic rotation (10À1 degcm2 gÀ1). [c] Molar rotation (10 degcm2 molÀ1).
lution, the chemical shift value of the NH anilide protons
5822
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 5817 – 5831

Amino Acid Based Dendrons
FULL PAPER
Figure 6. Concentration dependent 1H NMR (300 MHz) chemical shift of
the NHAr protons in G1-V2-CO2Et in CDCl3.
Figure 5. Structure of G1-V2-CO2Et showing the dimeric nature in the
solid state, as obtained by X-ray crystallography. Hydrogen atoms and
atoms from ethyl acetate are omitted for clarity.
polar hydrocarbon solvents or alcohols, and only weak gels
were formed in chlorinated solvents. On the other hand, ge-
lation was noted in a wide range of aromatic solvents
(Figure 7). The focal-point carboxylic acid or ethyl ester
functionality also played an important role in gel formation.
Hence, the lower generation G1 and G2 acid dendrons have
a stronger tendency than the ester dendrons to form very
stable transparent gels (mgc<2–100 mgmLÀ1), while for the
G3 series the ester dendrons are the better gelators. Most
interestingly, the nature of the amino acid side chains in the
various layers also exhibited an intriguing effect on the gela-
tion efficiency. Hence, among the three G1 acid dendrons,
only G1-F2-CO2H is capable of producing strong transparent
gels (mgc=5 mgmLÀ1) (Table 3). On the other hand, the
corresponding G1-F2-CO2Et ester dendron is a poor organo-
gelator and is highly soluble in aromatic solvents. To our
surprise, the strongest organogelator amongst the six G2
was shown to be dependent on the sample concentration
(Figure 6). The data could be fitted into a dimerization
model reported by Hunter[10] and the dimerization constant
was estimated to be 350Æ50mÀ1. Interestingly, the presence
of the dimeric (m/z 1156.7) and trimeric species (m/z
1736.1) could also be detected in the L-SIMS mass spectrum
of G1-V2-CO2Et.
Gelation properties: Minimum gelation concentration (mgc):
The self-assembling properties of the a-amino acid based
dendrons were further exemplified by their tendency to
form physical gels[2,11] in a solvent and layer-block sequence-
dependent manner. Gel formation was not observed in non-
Figure 7. Photographic images of amino acid based dendritic gels (concentration=10 mgmLÀ1). From left to right: 1) aqueous KMnO4 solution; 2) G1-
F2-CO2H in benzene; 3) G1-F2-CO2H in nitrobenzene; 4) G1-F2-CO2H in toluene; 5) G1-F2-CO2H in o-xylene; 6) G1-F2-CO2H in p-xylene; 7) G1-F2-
CO2H in m-xylene; 8) G1-F2-CO2H in CH2Cl2; 9) G3-A8V4F2-CO2Et in nitrobenzene; 10) G2-V4A2-CO2H in toluene; 11) G2-V4A2-CO2H in benzene.
Chem. Eur. J. 2005, 11, 5817 – 5831
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5823

H.-F. Chow and J. Zhang
Table 3. Minimum gelation concentrations of G1 dendrons in various or-
aromatic solvents (Table 5). Of the 12 possible G3 dendrons,
only G3-A8V4F2-CO2Et produced strong transparent gels
(mgc=6 mgmLÀ1) in nitrobenzene, while the corresponding
acid dendron G3-A8V4F2-CO2H was an inferior organogela-
tor. Hence, both the focal-point functional group and the
amino acid side chains in the various dendritic layers played
a pivotal role in determining the gelation process.
ganic solvents at 258C.[a]
G1-A2- G1-F2- G1-V2- G1-A2- G1-F2- G1-V2-
CO2Et CO2Et CO2Et CO2H CO2H CO2H
hexane
I
I
I
I
I
I
diethyl ether
THF
dichloromethane
P
S
S
I
S
S
P
S
S
I
S
I
I
S
OG
I
P
I
(10)
chloroform
ethyl acetate
acetone
acetonitrile
methanol
ethanol
S
S
S
C
S
S
S
PG
S
S
S
C
S
S
C
S
S
C
S
C
S
S
S
TG
(100)
TG
(80)
TG
(80)
TG
(80)
TG
(80)
TG
(90)
TG
(80)
PG
I
S
S
P
S
S
S
TG
(100)
PG
S
S
S
P
S
S
S
I
I
Gelation mechanism: The gelation process is mostly likely
induced by bothhydrogen-bonding and aromatic p–p stack-
ing interactions, since it is observed mainly in aromatic sol-
vents. Furthermore, the electron-deficient nitrobenzene was
the most effective aromatic solvent for gel formation. This
solvent was expected to interact more strongly withthe elec-
tron-rich3,5-diaminobenzamide brancinhg moiety. We
therefore studied the gelation mechanism by IR spectrosco-
py. Our initial attempt was to compare the IR spectral
changes between the solution and gel states of G1-F2-CO2H
in p-xylene. However, this compound rapidly formed gels in
the sample cell and we were unable to obtain a clear, homo-
geneous solution in p-xylene, even at very low organogelator
concentration (<0.2 mgmLÀ1). On the other hand, the FT-
IR signals were too weak to be observed at muchlower con-
centration, therefore the solution IR was recorded in CHCl3
for comparison. Peak assignments of N–H and C=O absorp-
tions were based on the IR data obtained from model com-
pounds BocNH-phenylalanine benzyl ester (BocNH-F-
CO2Bn) and G1-F2-CO2Bn, bothof whichformed clear solu-
tions in CHCl3 and in p-xylene. The IR spectrum of a nong-
elled sample of G1-F2-CO2H (10 mgmLÀ1) in CHCl3 exhibit-
PG
P
PG
PG
P
1-propanol
benzene
CG (3)
I
toluene
PG
S
S
S
S
S
S
S
S
TG (3)
CG (4)
CG (4)
CG (4)
PG
I
o-xylene
p-xylene
m-xylene
anisole
OG
(60)
PG
TG
(30)
TG
(100)
TG
(100)
TG
(70)
TG
(100)
CG
(40)
S
I
I
PG
PG
PG
I
PG
chlorobenzene
CG
(10)
TG
(20)
OG
(70)
S
o-dichloro-
benzene
nitrobenzene
OG
(100)
S
TG
(90)
CG (2) PG
[a] CG: clear transparent gel; PG: partial gelation; TG: translucent gel;
OG: opaque gel; S: soluble (>100 mgmLÀ1); I: insoluble upon heating;
C: crystallization; P: precipitation. The value given in parentheses is the
mgc in mgmLÀ1 to achieve gelation at 258C.
À
À
ed typical carbamate N H, anilide N H, acid/carbamate C=
O and anilide C=O stretchings at 3436, 3322, 1710 and
1685 cmÀ1, respectively (Figure 8). These signals were red-
shifted by 100, 70, 19 and 24 cmÀ1, respectively, in the p-
xylene gels (10 mgmLÀ1), revealing the presence of intermo-
lecular hydrogen bonds in the gelled sample.
dendrons is G2-V4A2-CO2H (mgc~4–50 mgmLÀ1)—a com-
pound that is deprived of F residues (Table 4). On the other
hand, the G2 dendron with the ’reverse’ layer-block struc-
ture G2-A4V2-CO2H turned out to be a less-efficient gelator,
and mainly formed translucent or opaque gels. The G3 den-
drons, in contrast to their lower generation analogues, pro-
duced mainly translucent or weakly opaque gels withmost
To investigate the chiral structure of the gel, circular di-
chroism (CD) spectra of G1-F2-CO2H (10 mgmLÀ1) in p-
xylene were recorded at different temperatures (Figure 9).
Prior to gelation, the solution sample showed only weak CD
signals. After gelation, a large CD band from the aromatic
chromophore was observed at
310 nm, the intensity of which
Table 4. Minimum gelation concentrations of G2 dendrons in various aromatic solvents at 258C.[a]
decreased gradually within-
creasing temperature. These re-
sults strongly indicate the for-
mation of hierarchical chiral ag-
gregates in the gelled state.
Scanning electron microscopic
(SEM) studies of a freeze-dried
gel sample of G1-F2-CO2H
Toluene
o-Xylene
Anisole
Nitrobenzene
o-Dichlorobenzene
G2-A4F2-CO2Et
G2-A4V2-CO2Et
G2-F4A2-CO2Et
G2-F4V2-CO2Et
G2-V4A2-CO2Et
G2-V4F2-CO2Et
G2-A4F2-CO2H
G2-A4V2-CO2H
G2-F4A2-CO2H
G2-F4V2-CO2H
G2-V4A2-CO2H
G2-V4F2-CO2H
OG (40)
OG (100)
S
OG (90)
PG
OG (70)
PG
S
TG (70)
PG
PG
OG (40)
TG (100)
OG (100)
OG (50)
CG (20)
TG (100)
CG (20)
CG (50)
S
TG (30)
PG
TG (100)
CG (60)
S
TG (50)
S
CG (40)
OG (50)
CG (30)
PG
CG (30)
CG (50)
PG
CG (30)
PG
S
OG (70)
S
CG (100)
TG (50)
TG (30)
PG
PG
S
OG (40)
OG (100)
TG (100)
OG (50)
CG (4)
TG (100)
TG (100)
OG (50)
CG (100)
CG (100)
CG (30)
PG
(10 mgmLÀ1)
in
p-xylene
showed the presence of fibrous
structures withdiameters rang-
ing from 50 to 100 nm (Figure
10).However, the existence of a
chiral morphology could not be
TG (30)
CG (30)
PG
[a] CG: clear transparent gel; PG: partial gelation; TG: translucent gel; OG: opaque gel; S: soluble (>
100 mgmLÀ1). The value given in parentheses is the mgc in mgmLÀ1 to achieve gelation at 258C.
5824
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 5817 – 5831

Amino Acid Based Dendrons
FULL PAPER
Table 5. Minimum gelation concentrations of G3 dendrons in various aromatic solvents at 258C.[a]
the degree of branching also
determines the aggregation pro-
cess. Unfortunately, we were
unable to obtain satisfactory
dried gel samples of the G3
dendrons for SEM investiga-
tions. Thin transparent films
were always formed and hence
the microscopic morphology of
the samples must have been
modified during sample prepa-
ration.
Toluene
o-Xylene
Anisole
Nitrobenzene
o-Dichlorobenzene
G3-A8F4V2-CO2Et
G3-A8V4F2-CO2Et
G3-F8A4V2-CO2Et
G3-F8V4A2-CO2Et
G3-V8A4F2-CO2Et
G3-V8F4A2-CO2Et
G3-A8F4V2-CO2H
G3-A8V4F2-CO2H
G3-F8A4V2-CO2H
G3-F8V4A2-CO2H
G3-V8A4F2-CO2H
G3-V8F4A2-CO2H
OG (50)
OG (50)
OG (100)
OG (20)
TG (20)
OG (40)
OG (60)
PG
OG (50)
OG (60)
OG (100)
OG (30)
TG (50)
OG (30)
OG (50)
PG
PG
TG (50)
S
PG
PG
TG (100)
CG (6)
S
TG (40)
PG
TG (100)
TG (70)
TG (20)
TG (60)
TG (50)
TG (30)
OG (100)
S
PG
TG (50)
TG (100)
TG (100)
TG (30)
S
CG (30)
TG (40)
TG (50)
PG
TG (90)
TG (60)
S
PG
TG (50)
TG (100)
OG (50)
TG (100)
PG
OG (50)
PG
PG
TG (100)
TG (100)
TG (100)
OG (60)
[a] CG: clear transparent gel; PG: partial gelation; TG: translucent gel; OG: opaque gel; S: soluble
(>100 mgmLÀ1). The value given in parentheses is the mgc in mgmLÀ1 to achieve gelation at 258C.
Figure 8. FT-IR spectra of G1-F2-CO2H (10 mgmLÀ1) in CHCl3 solution
(top two spectra) and in p-xylene gel (bottom two spectra). The peak la-
beled withan asterisk (*) is due to the presence of p-xylene.
Figure 10. SEM images of freeze-dried gel samples of (top) G1-F2-CO2H
from p-xylene (10 mgmLÀ1) and of (bottom) G2-V4A2-CO2H from tolu-
ene (10 mgmLÀ1).
Conclusion
Figure 9. Stacked CD spectra of G1-F2-CO2H in p-xylene gels
(10 mgmLÀ1) at different temperatures and in a non-gelled p-xylene solu-
tion.
We report here the synthesis of a new library of a-amino
acid based layer-block dendrons based on three nonpolar
amino acid residues. Suchdendrons are capable of forming
very strong, transparent physical gels (mgc down to
2 mgmLÀ1) witharomatic solvents throughintricate interac-
tions between the aromatic, amino and carbonyl functionali-
ties. It is believed that the solubility properties and structur-
al rigidities of the nonpolar amino acid side chains as well as
those of the focal-point functionality play an important role
in the gelation process. Only dendrons with the optimal
observed. These fibers were likely to be supramolecular
bundles formed from the intertwining of smaller chains re-
sulting from the intermolecular hydrogen bonding of indi-
vidual dendrons. On the other hand, the SEM image of the
G2-V4A2-CO2H (10 mgmLÀ1) dried gel sample in toluene
showed the presence of dense structures with no clear, well-
defined microscale architecture. These findings suggest that
Chem. Eur. J. 2005, 11, 5817 – 5831
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5825

H.-F. Chow and J. Zhang
1
tention time: 17.68 min. H NMR: d=1.25 (d, J=7.1 Hz, 6H), 1.31 (t, J=
7.1 Hz, 3H), 1.38 (s, 18H), 4.05–4.16 (m, 2H), 4.31 (q, J=7.0 Hz, 2H),
7.10 (d, J=7.0 Hz, 2H), 7.95 (s, 2H), 8.24 (s, 1H), 10.17 ppm (s, 2H);
13C NMR: d=15.1, 18.8, 29.2, 51.4, 61.8, 79.0, 115.1, 115.6, 131.5, 140.6,
156.1, 166.4, 173.2 ppm; MS (FAB): m/z (%): 545 ([M+Na]+, 21); ele-
mental analysis calcd (%) for C25H38N4O8: C 57.46, H 7.33, N 10.72;
found: C 57.35, H 7.47, N 10.83.
amino acid composition and the appropriate focal-point
functional group can prevent dissolution into or crystalliza-
tion from the solvent medium and exhibit such good gela-
tion properties. In other words, their gelation ability is
highly dependent on the amino acid layer-block sequence of
the dendrons, even though we are unable to clearly define
the structure–gelation relationship at the present moment.
Such a-amino acid based dendritic gels are potentially
useful molecules for biocompatible drug-delivery materials.
We envisage that the introduction of other amino acid resi-
dues of different polarity and hydrogen-bonding capabilities
will further enrich the structural diversity, physico-chemical
and biological properties of suchamino acid based dendritic
molecules, the results of which will be reported in the near
future.
G1-F2-CO2Et: Starting from BocNH-F-CO2H (11.68 g, 44.0 mmol), ethyl
3,5-diaminobenzoate (3.60 g, 20.0 mmol), HOBt (5.94 g, 44.0 mmol), and
DCC (9.06 g, 44.0 mmol), compound G1-F2-CO2Et was obtained as a
white crystalline solid (11.33 g, 84%) after flash chromatography (eluent:
EtOAc/hexane=1/2). M.p. 158–1598C. [a]2D0 =+15.2 (c=0.66). SEC re-
tention time: 17.67 min. 1H NMR: d=1.26–1.37 (m, 3H), 1.32 (s, 18H),
2.75–2.90 (m, 2H), 2.90–3.05 (m, 2H), 4.25–4.38 (m, 4H), 7.17–7.35 (m,
12H), 7.93 (s, 2H), 8.27 (s, 1H), 10.32 ppm (s, 2H); 13C NMR: d=15.2,
29.1, 38.2, 57.7, 61.9, 79.1, 115.2, 115.7, 127.3, 129.0, 130.2, 131.5, 138.9,
140.5, 156.4, 166.4, 172.1 ppm; MS (FAB): m/z (%): 675 ([M+H]+, 1); el-
emental analysis calcd (%) for C37H46N4O8: C 65.86, H 6.87, N 8.30;
found: C 65.84, H 6.88, N 8.27.
G1-V2-CO2Et: Starting from BocNH-V-CO2H (9.55 g, 44.0 mmol), ethyl
3,5-diaminobenzoate (3.60 g, 20.0 mmol), HOBt (5.94 g, 44.0 mmol), and
DCC (9.06 g, 44.0 mmol), compound G1-V2-CO2Et was obtained as a
white crystalline solid (9.48 g, 82%) after flash chromatography (eluent:
EtOAc/hexane=2/5). M.p. 149–1508C. [a]2D0 =À30.5 (c=0.82). SEC re-
tention time: 18.03 min. 1H NMR: d=0.89 (d, J=6.5 Hz, 12H), 1,32 (t,
J=7.1 Hz, 3H), 1.38 (s, 18H), 1.90–2.05 (m, 2H), 3.90 (t, J=7.8 Hz, 2H),
4.31 (q, J=7.0 Hz, 2H), 6.94 (d, J=8.3 Hz, 2H), 7.95 (s, 2H), 8.26 (s,
1H), 10.22 ppm (s, 2H); 13C NMR: d=15.2, 19.5, 20.2, 29.2, 31.2, 61.7,
61.9, 79.0, 115.1, 115.7, 131.6, 140.4, 156.6, 166.4, 172.1 ppm; MS (FAB):
m/z (%): 578 (M+, 16); HRMS (L-SIMS): calcd for M+: 578.3308;
found: 578.3302; elemental analysis calcd (%) for C29H46N4O8·H2O: C
58.37, H 8.11, N 9.39; found: C 58.21, H 8.05, N 9.39.[12]
General procedure for the synthesis of (ClÀ H3N+-aa1)2-CO2Et: G1-
(aa1)2-CO2Et was stirred in a HCl solution in ethanol (2.1m) at 258C. The
reaction was monitored by TLC until completion. The solvent was then
evaporated in vacuo and the residue poured into a large amount of dieth-
yl ether. The precipitate formed was collected by filtration under dry ni-
trogen, and washed with diethyl ether to give the desired product.
(ClÀ H3N+-A)2-CO2Et: Starting from G1-A2-CO2Et (5.22 g, 10.0 mmol)
and a HCl solution in ethanol (60 mL, 2.1m), the title compound was ob-
tained as a white solid (3.86 g, 98%). Tm 2598C. [a]2D0 =À3.7 (c=0.37,
MeOH); 1H NMR: d=1.31 (t, J=7.1 Hz, 3H), 1.48 (d, J=6.9 Hz, 6H),
4.11 (q, J=6.8 Hz, 2H), 4.31 (q, J=7.0 Hz, 2H), 8.07 (d, J=1.9 Hz, 2H),
8.23 (t, J=1.7 Hz, 1H), 8.45 (br. s, 6H), 11.15 ppm (s, 2H); 13C NMR:
d=15.1, 18.1, 49.9, 62.0, 115.5, 116.4, 131.8, 140.0, 166.1, 169.6 ppm; MS
(FAB): m/z (%): 323 ([MÀ2HCl+H]+, 37); HRMS (FAB): calcd for
[MÀ2HCl+H]+: 323.1713; found: 323.1692.
Experimental Section
THF was distilled from sodium benzophenone ketyl prior to use. DMF
was stirred with calcium hydride overnight and distilled in vacuo. Ma-
cherey Nagel 60M (230–400 mesh) silica gel was used for flash chroma-
tography. N-Boc-protected l-amino acids (BocNH-aa1-CO2H) and other
chemical reagents were used as received from Aldrich. All NMR spectra
were recorded in [D6]DMSO (dried over molecular sieve 4 Š) on a
Brüker DPX spectrometer at 300 MHz (1H) and 75.5 MHz (13C) at 258C
unless otherwise indicated. The residual proton or carbon signals of
[D6]DMSO (dH =2.50 ppm; dC =40.5 ppm) were used as internal referen-
ces. All chemical shifts are reported in ppm (d) and coupling constants in
Hz. Positive-ion L-SIMS and FAB spectra were carried out on a Bruker
APEX 47E FTMS spectrometer, a Hewlett Packard 5989B or a Thermo
Finnigan MAT 95XL mass spectrometer. Melting points were measured
on an Electrothermal IA9100 Digital Melting Point Apparatus and were
uncorrected. Melting temperatures (Tm) were collected on a Perkin-
Elmer DCS6 differential scanning calorimeter and are referred to as the
temperature at the onset of the transition. Optical rotations were taken
on a Perkin Elmer 341 Polarimeter at 589 nm and at 208C, in a solvent
mixture of 1,2-dichloroethane/HOAc (v/v 95/5). Size-exclusion chroma-
tography (SEC) analyses were performed on Waters Styragel columns
(HR 1 and HR 3 in serial) at 408C in 5% HOAc/DMF as eluent (flow
rate=1.0 mLminÀ1) using a Waters HPLC 515 pump equipped witha
Waters 486 tunable UV absorbance detector. Molecular weights obtained
from SEC measurements were based on a calibration curve derived from
polystyrene standards. Elemental analyses were performed either at the
Shanghai Institute of Organic Chemistry, Academic Sinica, China or at
MEDAC LTD, Brunel Science Center, Cooperꢁs Hill Lane, Englefield
Green, Egham, Surrey TW20 0JZ, UK.
(ClÀ H3N+-F)2-CO2Et: Starting from G1-F2-CO2Et (6.74 g, 10.0 mmol)
and a HCl solution in ethanol (80 mL, 2.1m), the target compound was
obtained as a white solid (5.42 g, 99%). Tm 2808C. [a]2D0 =+111.9 (c=
0.34, MeOH). 1H NMR: d=1.31 (t, J=7.1 Hz, 3H), 3.11–3.27 (m, 4H),
4.26–4.40 (m, 4H), 7.19–7.38 (m, 10H), 8.00 (d, J=1.8 Hz, 2H), 8.09 (t,
J=1.7 Hz, 1H), 8.56 (br. s, 6H) 11.20 ppm (s, 2H); 13C NMR: d=15.1,
37.8, 55.1, 62.0, 115.8, 116.7, 128.1, 129.5, 130.5, 131.7, 135.8, 139.7, 166.1,
168.0 ppm; MS (FAB): m/z (%): 475 ([MÀ2HCl+H]+, 100); HRMS (L-
SIMS): calcd for [MÀ2HCl+H]+: 475.2338; found: 475.2332.
General procedure for the synthesis of G1-(aa1)2-CO2Et: Dicyclohexyl
carbodiimide (DCC) (2.2 equiv) was added to
a stirred mixture of
BocNH-aa1-CO2H (2.2 equiv), ethyl 3,5-diaminobenzoate (1.0 equiv), and
1-hydroxybenzotriazole (HOBt) (2.2 equiv) in dry THF under a nitrogen
atmosphere at À108C. The mixture was kept at À108C for 1 hand then
at 258C for 10 h. The insoluble dicyclohexyl urea (DCU) produced was
removed by filtration and the solvent evaporated in vacuo. The residue
was dissolved in EtOAc (300 mL) and washed successively with saturated
NaHCO3 solution (100 mL), 10% citric acid solution (2”75 mL), saturat-
ed NaHCO3 solution (2”75 mL), and water (2”75 mL). The organic
layer was dried (MgSO4), filtered and evaporated in vacuo to give the
target compound that was purified by flash chromatography on silica gel.
(ClÀ H3N+-V)2-CO2Et: Starting from G1V2-CO2Et (5.78 g, 10.0 mmol)
and a HCl solution in ethanol (50 mL, 2.1m), the title compound was ob-
tained as a white solid (4.34 g, 98%). Tm 2688C. [a]2D0 =+47.2 (c=0.60,
MeOH). 1H NMR: d=0.99 (d, J=2.5 Hz, 6H), 1.01 (d, J=2.5 Hz, 6H),
1.32 (t, J=7.1 Hz, 3H), 2.14–2.29 (m, 2H), 3.89 (d, J=5.9 Hz, 2H), 4.32
(q, J=7.0 Hz, 2H), 8.08 (d, J=1.8 Hz, 2H), 8.27 (t, J=1.8 Hz, 1H), 8.40
(br. s, 6H), 11.14 ppm (s, 2H); 13C NMR: d=15.1, 18.9, 19.4, 30.9, 58.9,
62.0, 115.6, 116.5, 131.8, 139.8, 166.1, 168.3 ppm; MS (FAB): m/z (%):
379 ([MÀ2HCl+H]+, 34); HRMS (L-SIMS): calcd for [MÀ2HCl+H]+:
379.2338; found: 379.2337.
G1-A2-CO2Et: Starting from BocNH-A-CO2H (8.32 g, 44.0 mmol), ethyl
3,5-diaminobenzoate (3.60 g, 20.0 mmol), HOBt (5.94 g, 44.0 mmol) and
DCC (9.06 g, 44.0 mmol), compound G1-A2-CO2Et was obtained as a
white crystalline solid (9.41 g, 90%) after flash chromatography (eluent:
EtOAc/hexane=2/3). M.p. 147–1498C. [a]2D0 =À66.9 (c=0.68). SEC re-
General procedure for the synthesis of G1-(aa1)2-CO2H: An aqueous so-
lution of KOH (2.0m) was added to a stirred solution of G1-(aa1)2-CO2Et
5826
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 5817 – 5831

Amino Acid Based Dendrons
FULL PAPER
in MeOH at 258C. The reaction mixture was monitored by TLC until
completion. The solvent was evaporated in vacuo and the residue poured
into a large amount of water. The precipitate formed was collected by fil-
tration and washed with water to give the target product.
90%) after flash chromatography (eluent: CHCl3/MeOH 35/1). Tm
1818C. [a]2D0 =À74.8 (c 0.88). SEC retention time: 16.04 min. 1H NMR:
d=0.97 (d, J=6.5 Hz, 6H), 0.99 (d, J=6.4 Hz, 6H), 1.25 (d, J=7.1 Hz,
12H), 1.30 (t, J=7.2 Hz, 3H), 1.37 (s, 36H), 2.12–2.24 (m, 2H), 4.07–4.16
(m, 4H), 4.31 (q, J=7.1 Hz, 2H), 4.40 (t, J=8.2 Hz, 2H), 7.08 (d, J=
7.2 Hz, 4H), 7.68 (s, 4H), 8.00 (s, 2H), 8.18 (s, 2H), 8.31 (s, 1H), 8.36 (d,
J=7.5 Hz, 2H), 10.07 (s, 4H), 10.40 ppm (s, 2H); 13C NMR: d=15.1,
18.9, 19.8, 20.2, 29.1, 31.1, 51.4, 60.9, 61.8, 79.0, 113.7, 114.3, 115.2, 115.8,
131.6, 136.6, 140.2, 140.3, 156.1, 166.3, 168.0, 171.5, 173.0 ppm; MS
(FAB): m/z (%): 1353.4 ([M+Na)+, 16); HRMS (FAB): calcd for
[M+Na]+: 1353.6701; found: 1353.6671; elemental analysis calcd (%) for
C65H94N12O18: C 58.63, H 7.12, N 12.62; found: C 58.43, H 7.11, N 12.42.
G1-A2-CO2H: Starting from G1-A2-CO2Et (10.44 g, 20.0 mmol) in
MeOH (150 mL) and aqueous KOH solution (40.0 mL, 2.0m), the title
compound was obtained as a white solid (7.51 g, 76%). Tm 1508C. [a]D20
=
1
À60.7 (c=0.14). SEC retention time: 17.31 min. H NMR (CO2H not ob-
served): d=1.25 (d, J=6.9 Hz, 6H), 1.38 (s, 18H), 3.95–4.18 (m, 2H),
7.11 (d, J=6.9 Hz, 2H), 7.91 (s, 2H), 8.18 (s, 1H), 10.12 ppm (s, 2H);
13C NMR: d=18.8, 29.2, 51.4, 79.0, 114.8, 115.9, 132.4, 140.5, 156.1, 168.0,
173.1 ppm; MS (FAB): m/z (%): 494 ([M]+, 32); HRMS (L-SIMS): calcd
for M+: 494.2369; found: 494.2406; elemental analysis calcd (%) for
C23H34N4O8·H2O: C 53.90, H 7.08, N 10.93; found: C 53.21, H 6.79, N
10.82.
G2-F4A2-CO2Et: Starting from G1-F2-CO2H (10.44 g, 16.2 mmol),
(ClÀ H3N+-A)2-CO2Et (2.90 g, 7.4 mmol), 4-methylmorpholine (1.48 g,
14.7 mmol), HOBt (2.18 g, 16.2 mmol), and DCC (3.33 g, 16.2 mmol) in
DMF (65 mL), the target compound was obtained as a white solid
(10.8 g, 93%) after flash chromatography (eluent: CHCl3/MeOH 50/1).
Tm 1738C. [a]2D0 =+26.1 (c=0.61). SEC retention time: 16.00 min.
1H NMR: d=1.29–1.39 (m, 3H), 1.32 (s, 36H), 1.43 (d, J=6.9 Hz, 6H),
2.68–2.90 (m, 4H), 2.90–3.08 (m, 4H), 4.16–4.39 (m, 6H), 4.51–4.65 (m,
2H), 7.10–7.38 (m, 24H), 7.73 (s, 4H), 8.00 (s, 2H), 8.19 (s, 2H), 8.33 (s,
1H), 8.64 (d, J=6.0 Hz, 2H), 10.25 (s, 4H), 10.34 ppm (s, 2H);
13C NMR: d=15.1, 18.6, 29.1, 38.3, 50.9, 57.6, 61.8, 79.0, 113.9, 114.6,
115.2, 115.7, 127.2, 129.0, 130.2, 131.5, 136.5, 138.9, 140.1, 140.6, 156.3,
166.4, 167.6, 172.0, 172.6 ppm; MS (FAB): m/z (%): 1601.9 ([M+Na]+,
13); HRMS (FAB): calcd for [M+Na]+: 1601.7327; found: 1601.7351; ele-
mental analysis calcd (%) for C85H102N12O18·H2O: C 63.90, H 6.56, N
10.52; found: C 63.56, H 6.47, N 10.41.
G1-F2-CO2H: Starting from G1-F2-CO2Et (13.48 g, 20.0 mmol) in MeOH
(240 mL) and aqueous KOH solution (40.0 mL, 2.0m), the title com-
pound was obtained as a white solid (12.8 g, 99%). Tm 1608C. [a]D20
=
+8.8 (c=0.19). SEC retention time: 17.37 min. 1H NMR (CO2H not ob-
served): d=1.32 (s, 18H), 2.73–2.91 (m, 2H), 2.91–3.05 (m, 2H), 4.15–
4.35 (m, 2H), 7.08–7.39 (m, 12H), 7.90 (s, 2H), 8.19 (s, 1H), 10.23 ppm
(s, 2H); 13C NMR: d=29.2, 38.4, 57.8, 79.2, 114.6, 116.2, 127.4, 129.1,
130.3, 139.0, 140.3, 156.5, 168.2, 172.1 ppm; MS (FAB): m/z (%): 646
([M]+, 100); HRMS (L-SIMS): calcd for [M+H]+: 647.3073; found:
647.3083; elemental analysis calcd (%) for C35H42N4O8·3H2O: C 59.99, H
6.90, N 7.99; found: C 60.38, H 6.50, N 7.81.
G1-V2-CO2H: Starting from G1-V2-CO2Et (11.56 g, 20.0 mmol) in
MeOH (150 mL) and aqueous KOH solution (40.0 mL, 2.0m), the title
compound was obtained as a white solid (10.20 g, 93%). Tm 1528C.
[a]2D0 =À56.9 (c=0.063). SEC retention time: 17.61 min. 1H NMR (CO2H
not observed): d=0.89 (d, J=6.5 Hz, 12H), 1.38 (s, 18H), 1.81–2.08 (m,
2H), 3.90 (t, J=7.9 Hz, 2H), 6.92 (d, J=8.3 Hz, 2H), 7.93 (s, 2H), 8.19
(s, 1H), 10.17 ppm (s, 2H); 13C NMR: d=19.5, 20.2, 29.2, 31.2, 61.7, 79.0,
114.9, 116.0, 132.5, 140.3, 156.6, 168.0, 172.0 ppm; MS (FAB): m/z (%):
589 ([M+K]+, 3); HRMS (L-SIMS): calcd for M+: 550.2995; found:
550.3022.
General procedure for the synthesis of G2-(aa1)4(aa2)2-CO2Et: DCC
(2.2 equiv) was added to a stirred mixture of G1-(aa1)2-CO2H (2.2 equiv),
(ClÀ H3N+-aa2)2-CO2Et (1 equiv), 4-methylmorpholine (2 equiv),and
HOBt (2.2 equiv) in DMF under a nitrogen atmosphere at À108C. The
mixture was kept at À108C for 2 hand then at 25 8C for 48 h. The insolu-
ble DCU produced was removed by filtration and the solvent evaporated
in vacuo. The residue was dissolved in CHCl3, and washed successively
G2-F4V2-CO2Et: Starting from G1-F2-CO2H (4.64 g, 7.2 mmol),
(ClÀ H3N+-V)2-CO2Et (1.47 g, 3.3 mmol), 4-methylmorpholine (0.66 g,
6.5 mmol), HOBt (0.97 g, 7.2 mmol), and DCC (1.48 g, 7.2 mmol) in
DMF (35 mL), the title compound was obtained as a white solid (5.29 g,
84%) after flashchromatography (eluent: CHCl 3/MeOH 80/1 gradient to
60/1). Tm 1828C. [a]2D0 =À0.6 (c=0.49). SEC retention time: 16.05 min.
1H NMR: d=0.99 (d, J=6.7 Hz, 6H), 1.01 (d, J=6.6 Hz, 6H), 1.26–1.38
(m, 3H), 1.32 (s, 36H), 2.10–2.28 (m, 2H), 2.72–2.91 (m, 4H), 2.91–3.07
(m, 4H), 4.21–4.47 (m, 8H), 7.12–7.37 (m, 24H), 7.71 (s, 4H), 8.02 (s,
2H), 8.20 (s, 2H), 8.34 (s, 1H), 8.41 (d, J=7.7 Hz, 2H), 10.24 (s, 4H),
10.43 ppm (s, 2H); 13C NMR: d=15.1, 19.9, 20.2, 29.1, 31.2, 38.3, 57.6,
60.9, 61.9, 79.0, 113.8, 114.5, 115.2, 115.8, 127.2, 129.0, 130.2, 131.6, 136.7,
138.9, 140.1, 140.4, 156.3, 166.4, 168.0, 171.5, 172.0 ppm; MS (FAB): m/z
(%): 1657.8 ([M+Na]+, 7); HRMS (FAB): calcd for [M+Na]+:
1657.7953; found: 1657.8028.
withsaturated NaHCO solution, 10% citric acid solution, saturated
G2-V4A2-CO2Et: Starting from G1-V2-CO2H (3.63 g, 6.6 mmol),
(ClÀ H3N+-A)2-CO2Et (1.19 g, 3.0 mmol), 4-methylmorpholine (0.61 g,
6.0 mmol), HOBt (0.89 g, 6.6 mmol), and DCC (1.36 g, 6.6 mmol) in
DMF (40 mL), the target compound was obtained as a white solid
(3.63 g, 87%) after flash chromatography (eluent: CHCl3/MeOH 45/1).
Tm 1858C. [a]2D0 =À19.6 (c=0.44). SEC retention time: 16.28 min.
1H NMR: d=0.90 (d, J=6.4 Hz, 24H), 1.31 (t, J=7.1 Hz, 3H), 1.38 (s,
36H), 1.42 (d, J=7.3 Hz, 6H), 1.88–2.11 (m, 4H), 3.93 (t, J=7.9 Hz,
4H), 4.31 (q, J=7.1 Hz, 2H), 4.52–4.61 (m, 2H), 6.88 (d, J=8.4 Hz, 4H),
7.72 (s, 4H), 7.97 (s, 2H), 8.17 (s, 2H), 8.31 (s, 1H), 8.61 (d, J=6.3 Hz,
2H), 10.11 (s, 4H), 10.32 ppm (s, 2H); 13C NMR: d=15.1, 18.6, 19.4,
20.2, 29.1, 31.2, 50.9, 61.6, 61.8, 79.0, 113.9, 114.6, 115.3, 115.7, 131.5,
136.5, 139.9, 140.6, 156.5, 166.4, 167.6, 171.9, 172.6 ppm; MS (FAB): m/z
(%): 1409.4 ([M+Na]+, 25); HRMS (FAB): calcd for [M+Na]+:
1409.7327; found: 1409.7407; elemental analysis calcd (%) for
C69H102N12O18·2H2O: C 58.21, H 7.50, N 11.81; found: C 58.36, H 7.33, N
11.77.
3
NaHCO3 solution, and water. The organic layer was dried (MgSO4), fil-
tered and evaporated in vacuo to give the target compound that was pu-
rified by flashchromatography on silica gel.
G2-A4F2-CO2Et: Starting from G1-A2-CO2H (5.26 g, 10.7 mmol), (ClÀ
H3N+-F)2-CO2Et (2.65 g, 4.8 mmol), 4-methylmorpholine (0.98 g,
9.7 mmol), HOBt (1.44 g, 10.7 mmol), and DCC (2.19 g, 10.7 mmol) in
DMF (50 mL), the title compound was obtained as a white solid (6.37 g,
92%) after flashchromatography (eluent: CHCl 3/MeOH 60/1 gradient to
30/1). Tm 1828C. [a]2D0 =À52.6 (c=0.33). SEC retention time: 15.88 min.
1H NMR: d=1.26 (d, J=7.0 Hz, 12H), 1.33 (t, J=7.1 Hz, 3H), 1.38 (s,
36H), 3.07–3.21 (m, 4H), 4.05–4.22 (m, 4H), 4.32 (q, J=7.1 Hz, 2H),
4.78–4.88 (m, 2H), 7.08 (d, J=7.0 Hz, 4H), 7.15–7.49 (m, 10H), 7.66 (s,
4H), 7.97 (s, 2H), 8.11 (s, 2H), 8.29 (s, 1H), 8.67 (d, J=7.3 Hz, 2H),
10.05 (s, 4H), 10.43 ppm (s, 2H); 13C NMR: d=15.1, 18.9, 29.1, 38.0, 51.3,
56.7, 61.8, 79.0, 113.9, 114.4, 115.4, 115.9, 127.3, 129.1, 130.1, 131.5, 136.4,
138.8, 140.1, 140.4, 156.1, 166.3, 167.7, 171.4, 173.0 ppm; MS (FAB): m/z
(%): 1449.6 ([M+Na]+, 9); HRMS (FAB): calcd for [M+Na]+:
1449.6701; found: 1449.6664; elemental analysis calcd (%) for
C73H94N12O18·2H2O: C 59.91, H 6.75, N 11.48; found: C 59.67, H 6.69, N
11.18.
G2-V4F2-CO2Et: Starting from G1-V2-CO2H (3.63 g, 6.6 mmol),
(ClÀ H3N+-F)2-CO2Et (1.64 g, 3.0 mmol), 4-methylmorpholine (0.61 g,
6.6 mmol), HOBt (0.89 g, 6.6 mmol), and DCC (1.36 g, 6.6 mmol) in
DMF (35 mL), the title compound was obtained as a white solid (3.18 g,
69%) after flashchromatography (eluent: CHCl 3/MeOH 80/1 gradient to
60/1). Tm 1918C. [a]2D0 =+13.3 (c=0.40). SEC retention time: 16.19 min.
1H NMR: d=0.90 (d, J=6.1 Hz, 24H), 1.38 (s, 36H), 1.38 (m, 3H), 1.90–
2.08 (m, 4H), 3.05–3.21 (m, 4H), 3.93 (t, J=7.4 Hz, 4H), 4.32 (q, J=
G2-A4V2-CO2Et: Starting from G1-A2-CO2H (6.52 g, 13.2 mmol), (ClÀ
H3N+-V)2-CO2Et (2.71 g, 6.0 mmol), 4-methylmorpholine (1.21 g,
12.0 mmol), HOBt (1.78 g, 13.2 mmol), and DCC (2.72 g, 13.2 mmol) in
DMF (50 mL), the target product was obtained as a white solid (7.18 g,
Chem. Eur. J. 2005, 11, 5817 – 5831
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5827

H.-F. Chow and J. Zhang
6.7 Hz, 2H), 4.77–4.88 (m, 2H), 6.90 (d, J=8.2 Hz, 4H), 7.14–7.42 (m,
10H), 7.68 (s, 4H), 7.97 (s, 2H), 8.12 (s, 2H), 8.31 (s, 1H), 8.69 (d, J=
7.0 Hz, 2H), 10.10 (s, 4H), 10.44 ppm (s, 2H); 13C NMR: d=15.1, 19.4,
20.2, 29.1, 31.3, 38.1, 56.7, 61.5, 61.8, 79.0, 114.0, 114.6, 115.4, 115.9, 127.3,
129.1, 130.2, 131.5, 136.5, 138.8, 139.9, 140.4, 156.5, 166.4, 167.7, 171.4,
171.9 ppm; MS (FAB): m/z (%): 1561.8 ([M+Na]+, 10); HRMS (FAB):
calcd for [M+Na]+: 1561.7953; found: 1561.7960; elemental analysis
calcd (%) for C81H110N12O18·2H2O: C 61.74, H 7.29, N 10.67; found: C
61.98, H 7.25, N 10.60.
compound was obtained as a white solid (1.84 g, 91%). Tm 1868C. [a]D20
=
À1.8 (c=0.39). SEC retention time: 15.99 min. 1H NMR (CO2H not ob-
served): d=0.89 (d, J=6.5 Hz, 24H), 1.38 (s, 36H) 1.42 (m, 6H), 1.92–
2.05 (m, 4H), 3.93 (t, J=7.9 Hz, 4H), 4.53–4.62 (m, 2H), 6.88 (d, J=
8.5 Hz, 4H), 7.73 (s, 4H), 7.90 (s, 2H), 8.19 (s, 3H), 8.57 (d, J=6.1 Hz,
2H), 10.13 (s, 4H), 10.16 ppm (s, 2H); 13C NMR: d=18.8, 19.4, 20.1,
29.1, 31.2, 50.8, 61.5, 79.0, 113.8, 114.5, 116.5, 136.5, 139.7, 139.9, 156.4,
167.5, 171.8, 172.2 ppm; MS (FAB): m/z (%): 1381.5 ([M+Na]+, 5);
HRMS (FAB): calcd for [M+Na]+: 1381.7014; found: 1381.7062.
General procedure for the synthesis of G2-(aa1)4(aa2)2-CO2H: An aque-
ous KOH solution (2.0m) was added to a solution of G2-(aa1)4(aa2)2-
CO2Et in MeOH or in a 1/1 mixture of MeOH and THF. The reaction
mixture was stirred at 258C until completion of reaction as monitored by
TLC. The solvent was evaporated in vacuo and the residue poured into
water. The precipitate formed was collected by filtration and washed
withwater.
G2-V4F2-CO2H: Starting from G2-V4F2-CO2Et (4.64 g, 3.02 mmol) in a
1/1 mixture of THF/MeOH (40 mL) and aqueous KOH solution (8.0 mL,
2.0m), the title compound was obtained as a white solid (4.01 g, 88%).
Tm 1748C. [a]2D0 =+45.1 (c=0.41). SEC retention time: 16.08 min.
1H NMR (CO2H not observed): d=0.90 (d, J=6.6 Hz, 24H), 1.38 (s,
36H), 1.90–2.08 (m, 4H), 3.06–3.23 (m, 4H), 3.93 (t, J=8.0 Hz, 4H), 4.83
(q, J=8.3 Hz, 2H), 6.90 (d, J=8.4 Hz, 4H), 7.15–7.41 (m, 10H), 7.68 (s,
4H), 7.95 (s, 2H), 8.12 (s, 2H), 8.24 (s, 1H), 8.70 (d, J=7.4 Hz, 2H),
10.10 (s, 4H), 10.39 ppm (s, 2H); 13C NMR: d=19.5, 20.3, 29.2, 31.3, 38.2,
56.8, 61.6, 79.1, 114.1, 114.7, 115.2, 116.3, 127.4, 129.2, 130.3, 136.6, 139.0,
140.0, 140.3, 156.6, 167.8, 171.4, 172.0 ppm; MS (FAB): m/z (%): 1533.7
([M+Na]+, 7); HRMS (FAB): calcd for [M+Na]+: 1533.7640; found:
1533.7603.
General procedure for the synthesis of G3-(aa1)8(aa2)4(aa3)2-CO2Et:
EDCI (2.2 equiv) was added to a stirred mixture of G2-(aa1)4(aa2)2-
CO2H (2.2 equivalent), (ClÀ H3N+-aa3)2-CO2Et (1 equiv), 4-methylmor-
pholine (2 equiv), and HOBt (2.2 equiv) in DMF under nitrogen at
À108C. The mixture was kept at À108C for 2 hand then at 25 8C for
60 h. The insoluble precipitate produced was removed by filtration and
the solvent evaporated in vacuo. The residue was dissolved in CHCl3,
and washed successively with saturated NaHCO3 solution, 10% citric
acid solution, saturated NaHCO3 solution, and water. The organic layer
was dried (MgSO4), filtered, and evaporated in vacuo to give the target
compound that was purified by flash chromatography on silica gel.
G2-A4F2-CO2H: Starting from G2-A4F2-CO2Et (2.85 g, 2.0 mmol) in
MeOH (40 mL) and aqueous KOH solution (6.0 mL, 2.0m), the title
compound was obtained as a white solid (2.57 g, 92%). Tm 1768C. [a]D20
=
1
À73.5 (c=0.41). SEC retention time: 15.85 min. H NMR (CO2H not ob-
served): d=1.26 (d, J=7.0 Hz, 12H), 1.38 (s, 36H), 3.06–3.16 (m, 4H),
4.05–4.16 (m, 4H), 4.76–4.88 (m, 2H), 7.09 (d, J=7.1 Hz, 4H), 7.15–7.41
(m, 10H), 7.66 (s, 4H), 7.95 (s, 2H), 8.12 (s, 2H), 8.23 (s, 1H), 8.40 (d,
J=7.7 Hz, 2H), 10.05 (s, 4H), 10.38 ppm (s, 2H); 13C NMR: d=18.9,
29.1, 38.1, 51.3, 56.7, 78.9, 113.9, 114.4, 115.0, 116.2, 127.3, 129.1, 130.1,
136.4, 138.8, 140.1, 140.2, 156.1, 167.7, 171.3, 173.0 ppm; MS (FAB): m/z
(%): 1421.3 ([M+Na]+, 8); HRMS (FAB): calcd for [M+Na]+:
1421.6388; found: 1421.6438.
G2-A4V2-CO2H: Starting from G2-A4V2-CO2Et (4.00 g, 3.0 mmol) in
MeOH (55 mL) and aqueous KOH solution (9.0 mL, 2.0m), the target
compound was obtained as a white solid (3.47 g, 89%). Tm 1808C. [a]D20
=
1
À58.9 (c=0.42). SEC retention time: 15.83 min. H NMR (CO2H not ob-
served): d=0.97 (d, J=6.2 Hz, 6H), 0.99 (t, J=6.1 Hz, 6H), 1.25 (d, J=
7.0 Hz, 12H), 1.37 (s, 36H), 2.13–2.24 (m, 2H), 3.95–4.19 (m, 4H), 4.40
(t, J=8.1 Hz, 2H), 7.08 (d, J=7.1 Hz, 4H), 7.68 (s, 4H), 7.97 (s, 2H),
8.18 (s, 2H), 8.25 (s, 1H), 8.36 (d, J=7.5 Hz, 2H), 10.08 (s, 4H),
10.35 ppm (s, 2H); 13C NMR: d=18.9, 19.9, 20.2, 29.2, 31.2, 51.4, 60.9,
79.0, 113.7, 114.4, 115.0, 116.2, 132.8, 136.6, 140.2, 156.1, 168.0, 171.4,
173.0 ppm; MS (FAB): m/z (%): 1325.5 ([M+Na]+, 7); HRMS (FAB):
calcd for [M+Na]+: 1325.6388; found: 1325.6381.
G3-A8F4V2-CO2Et: Starting from G2-A4F2-CO2H (1.25 g, 0.89 mmol),
(ClÀ H3N+-V)2-CO2Et (0.17 g, 0.37 mmol), 4-methylmorpholine (0.075 g,
0.75 mmol), HOBt (0.12 g, 0.89 mmol), and EDCI (0.27 g, 0.89 mmol) in
DMF (10 mL), the product was obtained as a white solid (0.71 g, 61%)
after flash chromatography (eluent: CHCl3/MeOH=60/1 gradient to 40/
1). Tm 1868C. [a]2D0 =À121.4 (c=0.36). SEC retention time: 14.61 min.
1H NMR: d=0.98 (d, J=7.6 Hz, 6H), 1.00 (d, J=7.2 Hz, 6H), 1.25 (d,
J=6.8 HZ, 24H), 1.29–1.38 (m, 3H), 1.37 (s, 72H), 2.11–2.30 (m, 2H),
3.02–3.22 (m, 8H), 3.95–4.18 (m, 8H), 4.28 (q, J=7.0 Hz, 2H), 4.38 (t,
J=7.4 Hz, 2H), 4.78–4.92 (m, 4H), 7.08 (d, J=6.8 Hz, 8H), 7.39–7.18 (m,
20H), 7.66 (s, 8H), 7.76 (s, 4H), 8.04 (s, 2H), 8.16 (s, 4H), 8.24 (s, 3H),
8.41 (br. s, 2H), 8.67 (br. s, 4H), 10.05 (s, 8H), 10.39 ppm (s, 6H);
13C NMR: d=15.1, 18.9, 20.0, 20.2, 29.2, 31.2, 38.1, 51.4, 56.7, 61.0, 61.8,
79.0, 113.9, 114.4, 114.7, 115.2, 115.9, 127.3, 129.1, 130.2, 131.6, 136.5,
136.7, 138.9, 140.1, 140.4, 156.1, 166.4, 167.7, 168.0, 171.4, 171.5,
173.0 ppm.
G2-F4A2-CO2H: Starting from G2-F4A2-CO2Et (4.00 g, 2.5 mmol) in a 1/1
mixture of THF/MeOH (40 mL) and aqueous KOH solution (5.1 mL,
2.0m), the target compound was obtained as a white solid (3.29 g, 84%).
Tm 1738C. [a]2D0 =+141.7 (c=0.34). SEC retention time: 15.89 min.
1H NMR (CO2H not observed): d=1.31 (s, 36H), 1.43 (d, J=6.7 Hz,
6H), 2.71–2.93 (m, 4H), 2.93–3.08 (m, 4H), 4.16–4.39 (m, 4H), 4.58–4.67
(m, 2H), 7.12–7.37 (m, 24H), 7.74 (s, 4H), 7.91 (s, 2H), 8.20 (s, 2H), 8.23
(s, 1H), 8.60 (d, J=5.6 Hz, 2H), 10.21 (s, 2H), 10.26 ppm (s, 4H);
13C NMR: d=18.8, 29.1, 38.3, 50.9, 57.6, 79.0, 113.8, 114.1, 114.6, 116.4,
127.2, 129.0, 130.2, 136.5, 138.9, 140.0, 140.1, 156.3, 167.5, 172.0,
172.3 ppm; MS (FAB): m/z (%): 1574.1 ([M+Na]+, 2); HRMS (FAB):
calcd for [M+Na]+: 1573.7014; found: 1573.6979; elemental analysis
calcd (%) for C83H98N12O18·3H2O: C 62.08, H 6.53, N 10.47; found: C
62.24, H 6.27, N 10.38.
G3-A8V4F2-CO2Et: Starting from G2-A4V2-CO2H (2.50 g, 1.92 mmol),
(ClÀ H3N+-F)2-CO2Et (0.48 g, 1.15 mmol), 4-methylmorpholine (0.18 g,
1.15 mmol), HOBt (0.26 g, 1.92 mmol), and EDCI (0.57 g, 1.92 mmol) in
DMF (24 mL), the target compound was obtained as a white solid
(1.25 g, 47%) after flash chromatography (eluent: CHCl3/MeOH 60/1).
Tm 1838C. [a]2D0 =À35.3 (c=0.48). SEC retention time: 14.68 min.
1H NMR: d=0.97 (d, J=5.6 Hz, 12H), 0.99 (d, J=5.6 Hz, 12H), 1.25 (d,
J=6.9 Hz, 24H), 1.27–1.31 (m, 3H), 1.36 (s, 72H), 2.13–2.25 (m, 4H),
3.05–3.21 (m, 4H), 3.92–4.18 (m, 8H), 4.33 (q, J=7.0 Hz, 2H), 4.43 (t,
J=7.7 Hz, 4H), 4.78–4.95 (m, 2H), 7.07 (d, J=6.9 Hz, 8H), 7.14–7.38 (m,
10H), 7.69 (s, 8H), 7.73 (s, 4H), 7.99 (s, 2H), 8.18 (s, 7H), 8.34 (br. s,
4H), 8.71 (d, J=6.2 Hz, 2H), 10.07 (s, 8H), 10.30 (s, 4H), 10.41 ppm (s,
2H); 13C NMR: d=15.1, 18.9, 19.9, 20.2, 29.2, 31.2, 38.1, 51.4, 56.7, 61.0,
61.8, 79.0, 113.7, 114.35, 114.79, 115.3, 115.9, 127.3, 129.1, 130.1, 131.5,
136.5, 136.6, 138.8, 139.9, 140.2, 140.4, 156.1, 166.4, 167.7, 168.0, 171.4,
173.0 ppm; elemental analysis calcd (%) for C153H206N28O38·6H2O: C
58.27, H 6.97, N 12.44; found: C 58.35, H 6.73, N 12.19.
G2-F4V2-CO2H: Starting from G2-F4V2-CO2Et (3.78 g, 2.3 mmol) in a 1/1
mixture of THF/MeOH (70 mL) and aqueous KOH solution (4.6 mL,
2.0m), the target compound was obtained as a white solid (3.39 g, 91%).
Tm 1658C. [a]2D0 =À48.4 (c=0.56). SEC retention time: 15.88 min.
1H NMR (CO2H not observed): d=0.99 (d, J=6.1 Hz, 6H), 1.01 (d, J=
5.9 Hz, 6H), 1.31 (s, 36H), 2.15–2.26 (m, 2H), 2.74–2.91 (m, 4H), 2.91–
3.05 (m, 4H), 4.19–4.48 (m, 6H), 7.12–7.38 (24H, m), 7.72 (s, 4H), 7.99
(s, 2H), 8.22 (s, 2H), 8.26 (s, 1H), 8.40 (d, J=6.9 Hz, 2H), 10.26 (s, 4H),
10.35 ppm (s, 2H); 13C NMR: d=19.5, 19.8, 28.7, 30.8, 37.9, 57.2, 60.5,
78.6, 113.3, 114.1, 115.9, 126.8, 128.6, 129.7, 136.2, 138.5, 139.5, 139.6,
155.9, 167.5, 170.9, 171.6 ppm; MS (FAB): m/z (%): 1629.9 ([M+Na]+,
5); HRMS (FAB): calcd for [M+Na]+: 1629.7640; found: 1629.7673.
G2-V4A2-CO2H: Starting from G2-V4A2-CO2Et (2.07 g, 1.5 mmol) in
MeOH (20 mL) and aqueous KOH solution (3.0 mL, 2.0m), the target
G3-F8A4V2-CO2Et: Starting form G2-F4A2-CO2H (2.50 g, 1.61 mmol),
(ClÀ H3N+-V)2-CO2Et (0.30 g, 0.67 mmol), 4-methylmorpholine (0.14 g,
5828
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 5817 – 5831

Amino Acid Based Dendrons
FULL PAPER
1.34 mmol), HOBt (0.22 g, 1.61 mmol), and EDCI (0.48 g, 1.61 mmol) in
DMF (25 mL), the title compound was obtained as a white solid (0.93 g,
40%) after flashchromatography (eluent: CHCl 3/MeOH 60/1 gradient to
50/1). Tm 1908C. [a]2D0 =À81.9 (c=0.37). SEC retention time: 14.63 min.
1H NMR: d=0.96 (d, J=6.9 Hz, 6H), 0.99 (d, J=6.8 Hz, 6H), 1.22–1.30
(m, 3H), 1.30 (s, 72H), 1.43 (d, J=6.8 Hz, 12H), 2.10–2.25 (m, 2H),
2.72–2.88 (m, 8H), 2.88–3.05 (m, 8H), 4.18–4.49 (m, 12H), 4.58–4.69 (m,
4H), 7.10–7.36 (m, 48H), 7.72 (s, 8H), 7.75 (s, 4H), 8.04 (s, 2H), 8.19 (s,
4H), 8.22 (s, 1H), 8.27 (s, 2H), 8.41 (d, J=7.3 Hz, 2H), 8.62 (br. s, 4H),
10.23 (s, 8H), 10.26 (s, 4H), 10.40 ppm (s, 2H); 13C NMR: d=15.1, 18.7,
20.0, 20.2, 29.1, 31.2, 38.3, 50.8, 57.6, 61.0, 61.8, 79.0, 113.8, 114.6, 115.1,
115.8, 127.2, 129.0, 130.2, 131.6, 136.5, 136.6, 138.9, 140.0, 140.2, 140.3,
156.3, 166.3, 167.6, 168.0, 171.5, 172.0, 172.5 ppm; elemental analysis
calcd (%) for C185H222N28O38·5H2O: C 62.84, H 6.61, N 11.09; found: C
62.58, H 6.40, N 10.89.
water. The precipitate formed was collected by filtration and washed
withwater.
G3-A8F4V2-CO2H: Starting from G3-A8F4V2-CO2Et (0.47 g, 0.15 mmol)
in a 2/1 mixture of THF/MeOH (20 mL) and aqueous KOH solution
(2.0 mL, 2.0m), the product was obtained as a white solid (0.34 g, 72%).
Tm 1828C. [a]2D0 =À89.6 (c=0.21). SEC retention time: 14.70 min.
1H NMR (CO2H not observed): d=0.98 (d, J=6.5 Hz, 6H), 1.00 (d, J=
6.3 Hz, 6H), 1.25 (d, J=6.7 Hz, 24H), 1.37 (s, 72H), 2.08–2.25 (m, 2H),
3.00–3.20 (m, 8H), 3.91–4.21 (m, 8H), 4.33–4.48 (m, 2H), 4.78–4.95 (m,
4H), 7.08 (d, J=6.4 Hz, 8H), 7.38–7.17 (m, 20H), 7.66 (s, 8H), 7.75 (s,
4H), 8.00 (s, 2H), 8.12 (s, 4H), 8.18 (s, 1H), 8.24 (s, 2H), 8.42 (br. s, 2H),
8.68 (br. s, 4H), 10.06 (s, 8H), 10.33 (s, 2H), 10.39 ppm (s, 4H);
13C NMR: d=18.9, 20.0, 20.2, 29.2, 31.2, 38.1, 51.4, 56.7, 61.0, 79.0, 113.9,
114.5, 114.7, 116.4, 127.3, 129.1, 130.2, 136.5, 136.7, 138.9, 140.1, 156.1,
167.7, 168.0, 171.4, 173.0 ppm.
G3-A8V4F2-CO2H: Starting from G3-A8V4F2-CO2Et (1.00 g, 0.38 mmol)
in a 1/1 mixture of THF/MeOH (30 mL) and aqueous KOH solution
(4.0 mL, 2.0m), the target compound was obtained as a white solid
(0.78 g, 79%). Tm 1788C. [a]2D0 =À39.5 (c=0.68). SEC retention time:
14.67 min. 1H NMR (CO2H not observed): d=0.98 (d, J=5.7 Hz, 12H),
1.00 (d, J=3.9 Hz, 12H), 1.25 (d, J=6.9 Hz, 24H), 1.36 (s, 72H), 2.09–
2.28 (m, 4H), 3.02–3.20 (m, 4H), 3.90–4.19 (m, 8H), 4.43 (t, J=7.5 Hz,
4H), 4.78–4.88 (m, 2H), 7.08 (d, J=6.9 Hz, 8H), 7.12–7.41 (m, 10H),
7.69 (s, 8H), 7.72 (s, 4H), 7.98 (s, 2H), 8.19 (s, 7H), 8.35 (d, J=5.9 Hz,
4H), 8.72 (d, J=6.0 Hz, 2H), 10.08 (s, 8H), 10.30 (s, 4H), 10.37 ppm (s,
2H); 13C NMR: d=18.9, 19.9, 20.2, 29.2, 31.2, 38.1, 51.4, 56.8, 60.9, 79.0,
113.7, 114.4, 114.8, 116.3, 127.3, 129.1, 130.1, 136.55, 136.64, 138.8, 139.8,
140.2, 156.1, 167.7, 168.0, 171.4, 173.0 ppm; elemental analysis calcd (%)
for C151H202N28O38·5H2O: C 58.36, H 6.88, N 12.62; found: C 58.61, H
6.76, N 12.55.
G3-F8V4A2-CO2Et: Starting form G2-F4V2-CO2H (2.09 g, 1.30 mmol),
(ClÀ H3N+-A)2-CO2Et (0.20 g, 0.50 mmol), 4-methylmorpholine (0.10 g,
1.00 mmol), HOBt (0.18 g, 1.30 mmol), and EDCI (0.39 g, 1.30 mmol) in
DMF (20 mL), the target compound was obtained as a white solid
(0.67 g, 38%) after flash chromatography (eluent: CHCl3/MeOH 80/1
gradient to 60/1). Tm 1868C. [a]D20 =+23.4 (c=0.51). SEC retention time:
14.68 min. 1H NMR: d=0.95–1.08 (m, 24H), 1.22–1.32 (m, 3H), 1.30 (s,
72H), 1.41 (d, J=6.6 Hz, 6H), 2.14–2.27 (m, 4H), 2.76–2.90 (m, 8H),
2.90–3.04 (m, 8H), 4.18–4.40 (10H, m), 4.40–4.49 (m, 4H), 4.49–4.68 (m,
2H), 7.12–7.37 (48H, m), 7.71 (s, 8H), 7.79 (s, 4H), 8.02 (s, 2H), 8.20 (s,
4H), 8.24 (s, 3H), 8.39 (4H, br. s), 8.64 (2H, br. s), 10.25 (s, 8H), 10.32
(s, 2H), 10.34 ppm (s, 4H); 13C NMR: d=15.1, 18.7, 19.9, 20.2, 29.1, 31.2,
38.3, 50.9, 57.6, 60.9, 61.8, 79.0, 113.7, 114.1, 114.5, 114.8, 115.7, 127.2,
129.0, 130.2, 131.5, 136.6, 136.7, 138.9, 139.9, 140.1, 140.6, 156.3, 166.4,
167.6, 167.9, 171.4, 172.0, 172.6 ppm; elemental analysis calcd (%) for
G3-F8A4V2-CO2H: Starting from G3-F8A4V2-CO2Et (0.64 g, 0.19 mmol)
in a 1/1 mixture of THF/MeOH (20 mL) and aqueous KOH solution
(2.0 mL, 2.0m), the target product was obtained as a white solid (0.55 g,
87%). Tm 1858C. [a]2D0 =À69.1 (c=0.35). SEC retention time: 14.74 min.
1H NMR (CO2H not observed): d=0.98 (d, J=5.9 Hz, 12H) 1.31 (s,
72H), 1.44 (d, J=6.5 Hz, 12H), 2.13–2.22 (m, 2H), 2.75–2.91 (m, 8H),
2.91–3.09 (m, 8H), 4.19–4.40 (m, 8H), 4.40–4.48 (m, 2H), 4.58–4.71 (m,
4H), 7.16–7.37 (m, 48H), 7.78 (s, 8H), 7.79 (s, 4H), 7.89 (s, 2H), 8.23 (s,
7H), 8.36 (br. s, 2H), 8.65 (br. s, 4H), 10.05 (s, 2H), 10.29 (s, 4H),
10.36 ppm (s, 8H); 13C NMR: d=18.9, 19.9, 20.3, 29.1, 31.4, 38.3, 50.7,
57.7, 61.1, 79.0, 113.9, 114.7, 117.2, 127.2, 129.0, 130.2, 136.4, 136.7, 138.9,
140.1, 140.2, 156.3, 167.5, 167.8, 170.9, 172.0, 172.4 ppm.
C
10.52.
189H230N28O38·7H2O: C 62.57, H 6.78, N 10.81; found: C 62.33, H 6.52, N
G3-V8A4F2-CO2Et: Starting from G2-V4A2-CO2H (2.50 g, 1.84 mmol),
(ClÀ H3N+-F)2-CO2Et (0.42 g, 0.77 mmol), 4-methylmorpholine (0.15 g,
1.53 mmol), HOBt (0.25 g, 1.84 mmol), and EDCI (0.55 g, 1.84 mmol) in
DMF (20 mL), the product was obtained as a white solid (1.50 g, 62%)
after flash chromatography (eluent: CHCl3/MeOH 100/1 gradient to 40/
1). Tm 1968C. [a]2D0 =À104.5 (c=0.36). SEC retention time: 14.93 min.
1H NMR: d=0.89 (d, J=6.2 Hz, 48H), 1.29–1.38 (m, 3H), 1.37 (s, 72H),
1.42 (m, 12H), 1.89–2.08 (m, 8H), 3.03–3.22 (m, 4H), 3.92 (t, J=7.6 Hz,
8H), 4.31 (q, J=7.0 Hz, 2H), 4.54–4.70 (m, 4H), 4.78–4.88 (m, 2H), 6.88
(d, J=8.3 Hz, 8H), 7.16–7.38 (m, 10H), 7.70 (s, 4H), 7.72 (s, 8H), 8.00 (s,
2H), 8.17 (s, 4H), 8.21 (s, 3H), 8.60 (d, J=5.3 Hz, 4H), 8.69 (d, J=
6.2 Hz, 2H), 10.11 (s, 8H), 10.22 (s, 4H), 10.42 ppm (s, 2H); 13C NMR:
d=15.1, 18.7, 19.4, 20.2, 29.1, 31.3, 38.1, 50.8, 56.7, 61.6, 61.8, 79.0, 113.8,
114.2, 114.6, 115.3, 115.9, 127.3, 129.1, 130.1, 131.5, 136.4, 136.6, 138.8,
139.9, 140.1, 140.4, 156.5, 166.4, 167.6, 167.7, 171.4, 171.9, 172.5 ppm.
G3-F8V4A2-CO2H: Starting from G3-F8V4A2-CO2Et (1.00 g, 0.29 mmol)
in a 3/1 mixture of THF/MeOH (20 mL) and aqueous KOH solution
(3.0 mL, 2.0m), the title compound was obtained as a white solid (0.78 g,
79%). Tm 1878C. [a]2D0 =+34.0 (c=0.47). SEC retention time: 14.73 min.
1H NMR (CO2H not observed): d=0.89–0.99 (m, 24H), 1.30 (s, 72H),
1.41 (d, J=6.8 Hz, 6H), 2.13–2.28 (m, 4H), 2.75–2.92 (m, 8H), 2.92–3.09
(m, 8H), 4.18–4.36 (m, 8H), 4.36–4.49 (m, 4H), 4.49–4.59 (m, 2H), 7.11–
7.36 (m, 48H), 7.71 (s, 8H), 7.78 (s, 4H), 8.00 (s, 2H), 8.20 (s, 4H), 8.25
(s, 3H), 8.37 (br. s, 4H), 8.63 (d, J=5.5 Hz, 2H), 10.30 (s, 10H),
10.34 ppm (s, 4H); 13C NMR: d=18.7, 19.9, 20.2, 29.1, 31.2, 38.3, 50.9,
57.6, 60.9, 79.1, 113.8, 114.1, 114.5, 114.8, 116.1, 127.3, 129.0, 130.2, 136.7,
138.9, 139.9, 140.1, 140.4, 156.4, 167.7, 167.9, 171.4, 172.0, 172.6 ppm; ele-
mental analysis calcd (%) for C187H226N28O38·7H2O: C 62.39, H 6.72, N
10.89; found: C 62.23, H 6.43, N 10.85.
G3-V8F4A2-CO2Et: Starting from G2-V4F2-CO2H (4.01 g, 2.66 mmol),
(ClÀ H3N+-A)2-CO2Et (0.44 g, 1.11 mmol), 4-methylmorpholine (0.22 g,
2.22 mmol), HOBt (0.36 g, 2.66 mmol), and EDCI (0.79 g, 2.66 mmol) in
DMF (80 mL), the product was obtained as a white solid (1.95 g, 53%)
after flash chromatography (eluent: CHCl3/MeOH 80/1 gradient to 40/1).
Tm 1938C. [a]2D0 =À17.5 (c=0.32). SEC retention time: 14.91 min.
1H NMR: d=0.89 (d, J=6.5 Hz, 48H), 1.27–1.39 (m, 3H), 1.37 (s, 72H),
1.42 (d, J=6.6 Hz, 6H), 1.87–2.08 (m, 8H), 3.04–3.20 (m, 8H), 3.92 (t,
J=7.7 Hz, 8H), 4.30 (q, J=7.1 Hz, 2H), 4.51–4.66 (m, 2H), 4.80–4.88 (m,
4H), 6.89 (d, J=8.4 Hz, 8H), 7.13–7.42 (m, 20H), 7.67 (s, 8H), 7.76 (s,
4H), 8.02 (s, 2H), 8.11 (s, 4H), 8.22 (s, 3H), 8.65–8.68 (m, 6H), 10.10 (s,
8H), 10.31 (s, 4H), 10.38 ppm (s, 2H); 13C NMR: d=15.1, 18.7, 19.4,
20.2, 29.1, 31.2, 38.1, 50.9, 56.7, 61.6, 61.8, 79.0, 114.0, 114.6, 114.8, 115.7,
127.3, 129.1, 130.2, 131.5, 136.5, 138.9, 139.9, 140.6, 156.5, 166.4, 167.6,
167.7, 171.3, 171.9, 172.6 ppm.
G3-V8A4F2-CO2H: Starting from G3-V8A4F2-CO2Et (1.21 g, 0.38 mmol)
in a 1/1 mixture of THF/MeOH (15 mL) and aqueous KOH solution
(0.6 mL, 2.0m), the title compound was obtained as a white solid (1.01 g,
84%). Tm 1868C. [a]2D0 =À66.1 (c=0.42). SEC retention time: 14.83 min.
1H NMR (CO2H not observed): d=0.89 (d, J=6.4 Hz, 48H), 1.37 (s,
72H), 1.42 (d, J=7.0 Hz, 12H), 1.83–2.05 (m, 8H), 2.98–3.19 (m, 4H),
3.92 (t, J=7.9 Hz, 8H), 4.51–4.68 (m, 4H), 4.78–4.89 (m, 2H), 6.90 (d,
J=8.4 Hz, 8H), 7.10–7.38 (m, 10H), 7.71 (s, 4H), 7.74 (s, 8H), 7.93 (s,
2H), 8.19 (s, 7H), 8.50- 8.75 (m, 6H), 10.12 (s, 2H), 10.16 (s, 8H),
10.23 ppm (s, 4H); 13C NMR: d=18.8, 19.4, 20.2, 29.1, 31.2, 38.2, 50.8,
56.8, 61.6, 79.0, 113.9, 114.6, 127.3, 129.1, 130.1, 136.5, 138.9, 139.9, 140.1,
156.5, 167.5, 171.1, 171.9, 172.4 ppm.
General procedure for the synthesis of G3-(aa1)8(aa2)4(aa3)2-CO2H: An
aqueous KOH solution (2.0m) was added to a solution of G3-(aa1)8(aa2)4-
(aa3)2-CO2Et in a mixture of MeOH and THF. The reaction mixture was
stirred at 258C until the reaction went to completion as monitored by
TLC. The solvent was evaporated in vacuo and the residue poured into
Chem. Eur. J. 2005, 11, 5817 – 5831
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5829

H.-F. Chow and J. Zhang
G3-V8F4A2-CO2H: Starting from G3-V8F4A2-CO2Et (0.30 g, 0.091 mmol)
in a 1/1 mixture of THF/MeOH (10 mL) and aqueous KOH solution
(1.0 mL, 2.0m), the title product was obtained as a white solid (0.21 g,
71%). Tm 1868C. [a]2D0 =À13.1 (c=0.35). SEC retention time: 14.84 min.
1H NMR (CO2H not observed): d=0.89 (d, J=6.4 Hz, 48H) 1.20–1.45
(m, 6H), 1.37 (s, 72H), 1.85–2.02 (m, 8H), 3.01–3.19 (m, 8H), 3.92 (t, J=
7.5 Hz, 8H), 4.48–4.63 (m, 2H), 4.81–4.96 (m, 4H), 6.89 (d, J=8.2 Hz,
8H), 7.13–7.42 (m, 20H), 7.68 (s, 8H), 7.76 (s, 4H), 7.99 (s, 2H), 8.11 (s,
4H), 8.18 (s, 1H), 8.24 (s, 2H), 8.55–8.76 (m, 6H), 10.09 (s, 8H), 10.27 (s,
2H), 10.38 ppm (s, 4H); 13C NMR: d=18.7, 19.4, 20.1, 29.1, 31.2, 38.1,
50.9, 56.7, 61.5, 79.0, 114.0, 114.6, 114.8, 116.1, 127.3, 129.1, 130.2, 136.5,
138.9, 139.9, 140.0, 140.4, 156.5, 167.6, 167.7, 168.0, 171.3, 171.9,
172.5 ppm; elemental analysis calcd (%) for C171H226N28O38·4H2O: C
61.24, H 7.03, N 11.69; found: C 61.19, H 7.00, N 11.53.
FT-IR experiments: A hot solution of the organogelator G1-F2-CO2H
(1% w/v) was prepared in the solvent or solvent mixture of interest and
then transferred into a cell. The infrared spectrum was recorded on a
Nicolet 420 FT-IR spectrophotometer after the sample was cooled to
room temperature and equilibrated for 5 minutes. The spectrum of solid
G1-F2-CO2H was recorded as KBr pellet.
CD spectroscopy: CD spectra were recorded on a JASCO J-715 spectro-
polarimeter connected to a NESLAB RTE-211 temperature controller.
A weighed, hot solution of the gelator G1-F2-CO2H (1%, w/v) was pre-
pared in p-xylene and then transferred into a quartz cell (0.1 cm path
length) to allow gel formation. The temperature of the cell was detected
by a thermometer attached to the chamber supporting the quartz cell. At
eachtemperature, the sample was equilibrated for 30 minutes before
scanning. As the sol–gel transition temperature of G1-F2-CO2H in p-
xylene is beyond the highest temperature obtainable (~628C) by the tem-
perature controller, scanning was started immediately after the hot solu-
tion in p-xylene was put into the chamber in order to measure the CD
spectrum of the solution state. After the spectrum was recorded, the
sample was checked again to make sure it was still in the solution state.
Gelation test: A weighed sample of gelator was mixed with a solvent
(1 mL) in a septum-capped vial and heated. If the compound was unable
to dissolve, it was noted as insoluble (I). If a clear solution was obtained,
it was then cooled down to room temperature and left for 12 h. The ag-
gregation state was then assessed. If no flow was observed when inverting
the vial, a stable gel was formed and classified as transparent gel (CG),
translucent gel (TG) or opaque gel (OG) according to its transparency. If
part of the mixture formed a gel but flow was still observed, the phenom-
enon was recorded as partial gelation (PG). If crystallization or precipita-
tion occurred, C and P were noted respectively, and if the clear solution
was retained, it was marked as soluble (S). The mgc of the organogelator
was determined by measuring the minimum amount of gelator required
for the formation of a stable gel.
Electron microscopy: A gel was prepared as described above and frozen
in liquid nitrogen. The freezed sample was dried in a Labconco Freeze
Dryer under vacuum at À508C for 24 h. The xerogel thus obtained was
subjected to electron microscopic examination. A Leo 1450 VP scanning
electron microscope was used for taking the SEM micrographs. A small
slice of the xerogel was transferred on to a stub and was then sputtered
coated withgold. The sample was examined withan accelerating voltage
of 20 kV.
1H NMR dilution studies: 1H NMR spectra were recorded at 293 K on a
Brüker DPX spectrometer at 300 MHz using freshly prepared solutions.
CDCl3 was distilled from CaH2 and kept over 4 Š molecular sieves prior
to use. The molecular sieves employed were freshly activated. Relatively
concentrated NMR samples of G1-V2-CO2Et (c ꢁ 100 mm) in CDCl3
were prepared in volumetric flasks. Moderately concentrated samples
(10 mm=c < 100 mm) were obtained by serial dilution of a 100 mm stock
solution withCDCl 3. Very diluted samples (c < 10 mm) were prepared
from serial dilution of a 10 mm stock solution.
Acknowledgements
This work described in this paper was fully supported by a grant from the
ResearchGrants Council, HKSAR (Project No. CUHK4273/00P). We
thank Prof. T. C. W. Mak and Dr. C. K. Lam for helpful discussions.
X-ray diffraction study of G1-V2-CO2Et: A crystal suitable for X-ray dif-
fraction was obtained by recrystallization from ethyl acetate solution.
The diffraction experiment was carried out on a Bruker SMART 1 K
CCD diffractometer with a graphite-monochromated MoKa radiation at
293(2) K, w scan mode withincrement of 0.3 8. Preliminary unit cell pa-
rameters were obtained from 45 frames. Final unit cell parameters were
obtained by global refinements of reflections obtained from integration
of all the frame data. The collected frames were integrated using the pre-
liminary cell-orientation matrix. The SMART software was used for col-
lecting frames of data, indexing reflections, and determination of lattice
constants; SAINT-PLUS was used for integration of intensity of reflec-
tions and scaling;[13a] SADABS for absorption correction;[13b] and all the
structures were solved by direct methods and refined by full-matrix least
squares against F2 of all data, using SHELXTL software.[13c] Non-hydro-
gen atoms were refined in anisotropic, and hydrogen atoms in isotropic
approximation. The CO2Et group in one of the monomers exhibits orien-
tational disorder. The site occupancy factors for these two orientations
were found to be 0.5228 and 0.4772 respectively. The disordered atoms
O1’, O2’, C8’, O1’’, O2’’ and C8’’ are refined isotropically. The site occu-
pancy factor for the poorly resolved ethyl acetate solvent molecule was
suitably assigned as 1/2. Hydrogen atoms are omitted for the disordered
CO2Et group and the poorly resolved ethyl acetate solvent molecule.
[1] a) R. G. Denkewalter, J. Kolc, W. J. Lukasavage, U. S. Pat. 4410688,
1981; b) J. P. Tam, Proc. Natl. Acad. Sci. USA 1988, 85, 5409–5413;
c) B. Kayser, J. Altman, W. Beck, Chem. Eur. J. 1999, 5, 754–758;
d) Y. Kim, F. Zeng, S. C. Zimmerman, Chem. Eur. J. 1999, 5, 2133–
2138; e) J. Kress, A. Rosner, A. Hirsch, Chem. Eur. J. 2000, 6, 247–
257; f) A. Esposito, E. Delort, D. Lagnoux, F. Djojo, J.-L. Reymond,
Angew. Chem. 2003, 115, 1419–1421; Angew. Chem. Int. Ed. 2003,
42, 1381–1383; g) D. Lagnoux, E. Delort, C. Douat-Casassus, A. Es-
posito, J.-L. Reymond, Chem. Eur. J. 2004, 10, 1215–1226; h) A.
Clouet, T. Darbre, J.-L. Reymond, Adv. Synth. Catal. 2004, 346,
1195–1204; i) A. Clouet, T. Darbre, J.-L. Reymond, Angew. Chem.
2004, 116, 4712–4715; Angew. Chem. Int. Ed. 2004, 43, 4612–4615.
[2] a) K. S. Partridge, D. K. Smith, G. M. Dykes, P. T. McGrail, Chem.
Commun. 2001, 319–320; b) A. R. Hirst, D. K. Smith, M. C. Feiters,
H. P. M. Geurts, A. C. Wright, J. Am. Chem. Soc. 2003, 125, 9010–
9011; c) C. S. Love, A. R. Hirst, V. Chechik, D. K. Smith, I. Ash-
worth, C. Brennan, Langmuir 2004, 20, 6580–6585; d) A. R. Hirst,
D. K. Smith, M. C. Feiters, H. P. M. Geurts, Langmuir 2004, 20,
7070–7077.
[3] a) S. J. E. Mulders, A. J. Brouwer, R. M. J. Liskamp, Tetrahedron
Lett. 1997, 38, 3085–3088; b) D. PrØvôtØ, S. Le Roy-Gourvennec,
A.-M. Caminade, S. Masson, J.-P. Majoral, Synthesis 1997, 1199–
1207; c) A. J. Brouwer, S. J. E. Mulders, R. M. J. Liskamp, Eur. J.
Org. Chem. 2001, 1903–1915.
Crystallographic data for 2 G1-V2-CO2Et·1/2(CH3CO2C2H5): C60H96N8O17
(Mw =1201.45 gmolÀ1), monoclinic, space group P21, a=10.836(1), b=
23.831(2), c=15.154(1) Š, b=107.764(2)8, V=3726.7(5) Š3, Z=2, 1calcd
=
[4] For a review on biodendrimers, see: M. W. Grinstaff, Chem. Eur. J.
2002, 8, 2838–2846.
1.071 gcmÀ3
, , T=293 K, 2qmax =56.588, wR2=
m(MoKa)=0.078 mmÀ1
0.2523 (21364 reflections collected, 12470 unique), R1=0.0976 [I>2s(I)],
GOF=0.951. CCDC-263412 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_
request/cif.
[5] T. K.-K. Mong; A. Niu; H.-F. Chow; C. Wu; L. Li; R. Chen, Chem.
Eur. J. 2001, 7, 686- 699.
[6] The term “layer-block sequence” here refers to the order of disposi-
tion of the amino acid layers from the surface toward the interior of
the dendron.
5830
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 5817 – 5831

Amino Acid Based Dendrons
FULL PAPER
[7] The notation Gn-(aa1)(2n)··(aan)2-CO2R is used to represent the struc-
ture of the dendrons, where n denotes the dendron generation, aa1,
···, aan refer to the nature of the amino acid layers from the surface
toward the focal point of the dendrons, respectively. The protective
groups on the N-termini are tert-butyloxycarbonyl (Boc) groups.
[8] a) D. M. Junge, D. V. McGrath, Tetrahedron Lett. 1998, 39, 1701–
1704; b) J. R. McElhanon, D. V. McGrath, J. Am. Chem. Soc. 1998,
120, 1647–1656; c) P. K. Murer, J. M. Lapierre, G. Greiveldinger, D.
Seebach, Helv. Chim. Acta 1997, 80, 1648–1681.
[9] a) H.-F. Chow, L. F. Fok, C. C. Mak, Tetrahedron Lett. 1994, 35,
3547–3550; b) H.-F. Chow, C. C. Mak, J. Chem. Soc. Perkin Trans. 1
1994, 2223–2228; c) C. C. Mak, H.-F. Chow, Chem. Commun. 1996,
1185–1186; d) H.-F. Chow, C. C. Mak, J. Chem. Soc. Perkin Trans. 1
1997, 91–95; e) H.-F. Chow, C. C. Mak, Pure Appl. Chem. 1997, 69,
483–488; f) H.-F. Chow, C.-W. Wan, Helv. Chim. Acta 2002, 85,
3444–3454.
[10] The dimerization constant was obtained from curve fitting of the ex-
perimental 1H NMR data (r2 =0.9944) using a user-defined function
regression program in TableCurve 2D v5.0 (purchased from AISN
Software Inc.). The user-defined function is based on the dimeriza-
tion model described by Hunter, see A. P. Bisson, F. J. Carver, D. S.
Eggleston, R. C. Haltiwanger, C. A. Hunter, D. L. Livingstone, J. F.
McCabe, C. Rotger, A. E. Rowan, J. Am. Chem. Soc. 2000, 122,
8856–8868. However, it is conceivable that some higher oligomers
may also exist in CHCl3 solution.
[11] For examples of dendritic gels, see a) G. R. Newkome, C. N. Moore-
field, G. R. Baker, R. K. Behera, G. H. Escamillia, M. J. Saunders,
Angew. Chem. 1992, 104, 901; Angew. Chem. Int. Ed. Engl. 1992, 31,
917–919; b) G. R. Newkome, G. R. Baker, S. Arai, M. J. Saunders,
P. S. Russo, K. J. Theriot, C. N. Moorefield, L. E. Rogers, J. E.
Miller, T. R. Lieux, M. E. Murray, B. Phillips, L. Pascal, J. Am.
Chem. Soc. 1990, 112, 8458–8465; c) W.-D. Jang; D.-L. Jiang; T.
Aida, J. Am. Chem. Soc. 2000, 122, 3232–3233; d) C. Marmillon, F.
Gauffre, T. Gulik-Krzywicki, C. Loup, A.-M. Caminade, J.-P. Majo-
ral, J.-P. Vors, E. Rump, Angew. Chem. 2001, 113, 2696–2699;
Angew. Chem. Int. Ed. 2001, 40, 2626–2629; e) W.-D. Jang, T. Aida,
Macromolecules 2003, 36, 8461–8469.
[12] Similar to the b-alanine dendrimers reported earlier by us, the a-
amino acid dendrons are hygroscopic and contain water of recrystal-
lization in the solid state.
[13] a) SMART and SAINT for Windows NTꢂ Software Reference Man-
uals, Version 5.0, Brüker Analytical X-Ray Systems, Inc., Madison,
Wisconsin, USA, 1997; b) SHELXL Reference Manual, Version 5.1,
Brüker Analytical X-Ray Systems, Inc., Madison, Wisconsin, USA,
1997; c) G. M. Sheldrick, SADABS - V2.01, Brüker/Siemens area
detector absorption and other corrections, University of Gçttingen,
Germany, 2000.
Received: February 17, 2005
Published online: July 20, 2005
Chem. Eur. J. 2005, 11, 5817 – 5831
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5831