The chirality of dendrimer-based supramolecular complexes

Article abstract of DOI:10.1039/b413724h

Boc-protected L-phenylalanine has been connected to a spacer-armed ureido-acetic acid derivative, which can form multiple supramolecular complexes with urea-adamantyl modified poly(propylene imine) dendrimers in chloroform. Complexes of this guest with se

Full text of DOI:10.1039/b413724h

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A R T I C L E
The chirality of dendrimer-based supramolecular complexes
Maarten A. C. Broeren, Bas F. M. de Waal, Joost L. J. van Dongen, Marcel H. P. van Genderen
and E. W. Meijer*
Laboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology,
P.O. Box 513, 5600, MB Eindhoven, The Netherlands
Received 8th September 2004, Accepted 1st November 2004
First published as an Advance Article on the web 9th December 2004
Boc-protected L-phenylalanine has been connected to a spacer-armed ureido–acetic acid derivative, which can form
multiple supramolecular complexes with urea–adamantyl modified poly(propylene imine) dendrimers in chloroform.
Complexes of this guest with several generations of urea–adamantyl dendrimers were prepared. The dendrimer–guest
complexes were characterized in detail by 1H-NMR, 1H–1H-NOESY spectroscopy and mass spectrometry to prove
their formation. Optical rotation experiments performed on different generations of dendrimer–guest complexes
showed a constant positive value. These observations indicate that, though guest molecules decrease the flexibility at
the periphery of the dendrimer upon binding, the amino acid at the terminus of the guest molecule retains its high
local conformational freedom. This is in agreement with values found for covalently modified spacer-armed
dendrimers.
group possesses a strongly conformation-dependent optical
rotation, the presence of many different conformations in the
shell results in averaging of the optical rotation. In addition,
Introduction
The chirality of dendritic macromolecules has been a topic of
interest since the first report by Denkewalter et al. in 1981.1
dendrimers with amide–acetal end groups, which do not possess
Chiral units can be built in dendrimers at different positions,
a conformation-dependent optical rotation, exhibited the same
e.g. the core, the branching points or the periphery, resulting in
optical rotation for all generations.4 This issue was further
different architectures that have been the subject of numerous
investigated by introduction of a C-12 alkyl spacer between
studies.2–5 In our group, we modified the periphery of a fifth
generation poly(propylene imine) dendrimer with N-tert-Boc-
L-phenylalanine, resulting in the so-called “dendritic box”. It
the N-tert-Boc-L-phenylalanine unit and the dendrimer surface.4
The alkyl spacer played a crucial role in the specific optical
rotation obtained for dendrimers 3a and 3e (Fig. 1), revealing
was found that the periphery forms a dense shell and that small
20
a constant value of approximately [a] = +4. This is in sharp
contrast to the values found for the Ddendritic box analogues
and supports the idea that the conformational freedom of
the N-tert-Boc-L-phenylalanine unit is reflected in the optical
rotation.
molecules can be encapsulated inside the dendrimer.6 This dense-
shell behaviour was reflected in the chiroptical properties of the
dendritic box. The specific optical rotation of DAB–dendr–(NH-
tert-Boc-L-Phe)x, 2a–2e (Fig. 1), vanishes to zero on going from
the first generation with 4 end groups ([a]2D0 = −11, c = 1, CHCl3)7
More recently, new dendritic architectures have been obtained
by a supramolecular approach in which modification of the
dendrimer periphery is based on non-covalent interactions such
as electrostatic interactions, hydrogen bonding or hydrophobic
interactions.8–12
20
D
to the fifth generation with 64 end groups ([a] = −0.1, c = 1,
CHCl3).4
For other bulky Boc-protected amino acids, a similar effect
was observed. Though never completely understood, the van-
ishing optical rotation was explained by the rigid character
of the shell which does not enable all end groups to adopt
their most favourable conformation. Since this particular end
In our group, we designed a methodology in which poly(pro-
pylene imine) dendrimers are modified with urea–adamantyl
end groups covalently attached to the dendrimer (host) which
can be used as a scaffold to reversibly bind ureido–acetic acid
building blocks (guests, Scheme 1) due to electrostatic and
hydrogen-bonding interactions.13–18 We are now interested in
investigating the conformational freedom of end groups that
are non-covalently attached to dendrimers more thoroughly. T1-
Relaxation measurements already gave some indication that the
local mobility of the dangling end of guest molecules remains
unperturbed.13 On the other hand, T1-relaxation measurements
also showed that at the dendrimer periphery the mobility
decreases. In this article N-tert-Boc-L-phenylalanine has been
used as a chiral probe to investigate the conformational freedom
of the dangling ends of guest molecules. Therefore, an N-
tert-Boc-L-phenylalanine containing guest molecule has been
synthesized. Complexes of this guest with several generations
1
of urea–adamantyl dendrimers have been prepared. H-NMR
measurements, 1H–1H-NOESY experiments and mass spec-
trometry have been performed to prove that the guest molecules
are bound to the dendrimer. The chiroptical properties of the
host–guest complex of different dendrimer generations have
been studied in chloroform and have been compared to the
chiroptical properties of both the dendritic box and spacer
armed dendrimers 3a and 3e.
Fig. 1 Optical rotation values of spacer armed dendrimers 3a and 3e
in comparison to the values for the dendritic box (2a–2e).
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 1 – 2 8 5
2 8 1
©

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By addition of amine 4 to isocyanate 5, pure ester 6 could be
obtained after column chromatography. Catalytic hydrogena-
tion using Pd/C as a catalyst resulted in acid 7. All compounds
could be obtained in good yields and were characterized by
1H-NMR, 13C-NMR, ATR-IR spectroscopy and MALDI-TOF
mass spectrometry. The dendrimers were prepared according
to previously published work.13 Pincer molecule 1f is obtained
when bis(propylamine)methylamine is reacted with two equiv-
alents of 1-adamantyl isocyanate and can be used as a model
compound for dendritic hosts 1a–1e (Scheme 3). Guest molecule
7 is barely soluble in chloroform. However, upon addition of
4, 8 and 32 equivalents of guest 7 to second, third and fifth-
generation dendrimer respectively, a clear solution is obtained.
The resulting complexes are stable and can be characterised with
mass spectrometry and 1H-NMR. Using electrospray ionisation
mass spectrometry, it is possible to transfer the complexes from
solution to the gas phase,14 and this has been done for dendrimer
1c with approximately six equivalents of 7. As can be seen in
Fig. 2, apart from dendrimer 1c other peaks are visible that have
a mass difference equal to the mass of 7. These peaks are the
dendrimer with one to eight guest molecules bound to it. Most
likely, the distribution is different in solution as some guest
molecules will dissociate upon transfer to the gas phase. The
electrospray measurements do show, however, that the complex
is formed and that individual complexes can be observed.
Scheme 1 Schematic representation of the dendritic host–guest system.
Results and discussion
Guest 7 (Scheme 2) was synthesized starting from N-tert-
Boc-L-phenylalanine-N-hydroxysuccinimide ester and 1,6-hexa-
nediamine. By using a large excess of 1,6-hexanediamine, the
mono-functionalized amine is formed as the main product.
The purified amine 4 was converted to ester 6 via isocyanate
5. This isocyanate is formed in a two-step procedure starting
from p-toluenesulfonyl glycine benzyl ester. First the salt was
washed with a NaOH solution to liberate the free amine and
subsequently the amine was converted in situ to isocyanate 5
using di-tert-butyl-tricarbonate.19
Scheme 3 Synthesis of pincer molecule 1f. A) 1-adamantyl isocyanate,
CH2Cl2, 2 h.
Scheme 2 A) CH2Cl2, 12 h; B) 2.4 M NaOH (aq.), CH2Cl2; C) CH2Cl2, di-t-butyltricarbonate, 0.5 h; D) CH2Cl2, 2 h; E) Pd/C catalyst (10%),
tert-butanol : H2O 1 : 1 (v/v), 4 h.
2 8 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 1 – 2 8 5

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Fig. 2 The mass-spectrum of dendrimer 1c with six equivalents of
7. Apart from the “naked” dendrimer, several peaks at higher mass
are present that correspond to the dendrimer with one to eight guest
molecules bound to it.
1H-NMR measurements of the complexes revealed a down-
field shift of both the urea protons of the dendrimer (signals a
and b) and the methylene protons adjacent to the tertiary amine
of the outermost shell (signal f) in all cases, as depicted for the
1e·732 complex in Fig. 3.
Fig. 4 1H–1H-NOESY spectrum of 1e·732 in CDCl3 recorded at 25
0.5 ◦C. The NOE effects between the methylene protons of the guest (d)
and the periphery of the fifth generation urea adamantyl dendrimer (a,
e) are indicated.
T1-Relaxation measurements in chloroform for methylene
protons f give values of 0.84 s for pure 1e and 1.05 s for 1e·732,
which is in agreement with earlier measurements.13 This is an
indication that the periphery of the dendrimer becomes more
rigid upon complexation of the guest. Of course, we would like
to compare T1 values of the dangling ends of the guest upon
binding to 1e. Unfortunately, for chiral proton c this proved
to be very difficult due to the low intensity. The signal of the
Boc-group overlaps with the dendrimer, making it unsuitable
for reliable T1-measurements. However, the optical rotation can
be monitored easily and gives information about the mobility
of the dangling end. It can be compared to values found for the
covalently modified dendrimers, as well as with free guest 6.
Optical rotation measurements were performed in chloroform
to investigate the chiroptical properties of the complexes formed.
In all cases the concentration of 7 was kept constant at 10 mg
mL−1 (c = 1), so that the number of chiral groups was constant
in all samples. The different generations of dendrimer or pincer
were added in such an amount that a stoichiometry of one guest
per two end groups was present. This means that theoretically all
the guest molecules can bind to the peripheral tertiary amines
of the host. The results are depicted in Fig. 5. Compound 6
was taken as a reference (chosen because of the poor solubility
20
Fig. 3 1H-NMR spectra of dendrimer 1e and the complex 1e·732. The
of 7 in chloroform) and gives a value of [a] = 5
1. This
D
changes upon complexation are indicated with arrows.
value is also found for all of the different host–guest complexes.
This is comparable to spacer-armed dendrimers 3a and 3e and
This is indicative of hydrogen bonding between the urea
groups of guest and host and protonation of the tertiary amines
of the dendrimer. Due to the poor solubility of guest 7 in chlo-
roform, it was dissolved in deuterated 1,1,2,2-tetrachloroethane
1
and a H-NMR spectrum was obtained at a high temperature
(120 ◦C). This spectrum was used to assign signals c and d
of the 1e·732 complex. 1H–1H-NOESY measurements of the
1e·732 complex have been performed in CDCl3 to investigate
the location of the guest molecules.20 The spectrum depicted in
Fig. 4 shows NOE interactions between the ureido–acetic acid
part of 7 and the methylene protons next to the tertirary amines
of dendrimer 1e.
1
As a reference experiment, a H–1H-NOESY spectrum was
obtained of 1e and 32 equivalents of 6 in CDCl3. In this case
no NOE interactions were found between these compounds.
All other cross-peaks in the spectrum can be assigned to
intramolecular NOE-effects of the dendrimer or guest.
Fig. 5 Optical rotation measurements show a constant value for the
complexes of different generations of the urea–adamantyl dendrimer
with guest 7, which can be compared to the results obtained for the
spacer-armed dendrimers described in Fig. 1.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 1 – 2 8 5
2 8 3

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can be explained, as the amount of chiral groups present is
approximately equal in all cases.21
in the positive ion mode by application of 5 kV on the needle.
The source block temperature was maintained at 60 ◦C and
the desolvation gas was heated to 60 ◦C. The complex analysed
with mass spectrometry was prepared by adding four equivalents
of guest 7 to third generation urea–adamantyl dendrimer in a
concentration of approximately 1 mg mL−1 of total complex in
chloroform. To 400 lL of this solution was added 100 lL of
a solution of 1% acetic acid in chloroform. This mixture was
immediately injected into the mass spectrometer.
The results show a different behaviour than measurements
performed on the dendritic box, in which the optical rotation
decreased from [a]2D0 = −11 to −0.1 in going from the first to the
fifth generation dendrimer (Fig. 1), but are in agreement with
the spacer-armed dendrimers 3a and 3e. These results indicate
that the local conformational freedom of the N-tert-Boc-L-
phenylalanine part of the guest molecules remains constant upon
complexation and is comparable to the molecular motion of
molecules covalently attached to dendrimers via a spacer.
Optical rotation experiments were performed on a Pleuger
Optical Activity polarimeter and a Jasco DIP-370 digital
polarimeter and are expressed as 10−1 deg cm2 g−1. All samples
had a concentration of 10 mg mL−1 of guest molecule. The
1
NMR relaxation time experiments and the 2D NMR H–1H-
Conclusions
NOESY experiments were carried out on a Varian Unity Inova
500 spectrometer operating at 500.618 MHz and equipped
with a 5 mm 500 SW/PFG probe from Varian. Spectra were
referenced to TMS and were obtained at 25 ◦C. Prior to fourier-
transformation, the f1 and f2 data points were processed with a
squared shifted sinebell weighing function (for f1: sb = −0.13
and sbs = −0.13; for f2, sb1 = −0.065 and sbs1 = −0.065). A
mixing time of 0.1 s was used. Spin–lattice relaxation time (T1)
In conclusion, we have been able to synthesize an N-tert-
1
Boc-L-phenylalanine containing guest molecule. H-NMR has
revealed that this molecule is able to form a complex in chlo-
roform with poly(propylene imine) dendrimers functionalized
with urea adamantyl end groups. 1H–1H-NOESY spectroscopy
and mass spectrometry further confirmed the existence of
the supramolecular structures. T1-Measurements have shown
that the dendrimer periphery becomes more rigid when guest
molecules bind to the dendrimer due to complexation, but
optical rotation measurements on the complexes of different
generations revealed a constant value. These results indicate that
while the dendrimer periphery rigidifies upon complexation with
guest molecules, the conformational freedom at the dangling
ends of guest molecules non-covalently attached to dendrimers
does not change significantly upon complexation. We have to
take into account that the supramolecular complex is a dynamic
system. This means that guest molecules constantly associate
and dissociate from the dendrimer. Ureido–acetic acid guest
molecules that have a good solubility in chloroform have an
association constant of around 102–103 M−1.22 However, we
expect the association constant for 7 to be higher, as the solubility
of this guest in chloroform is limited and the dendrimer actually
helps to keep the guest solubilized. This most likely gives rise
to a higher association constant. Nevertheless, the dynamics
can influence the conformational freedom of the dangling end
groups. In addition to this, the chiral centre is connected to
the ureido–acetic acid binding site of the guest via a C-6
spacer, which also allows for more possibilities of reorganisation.
However, no change at all is observed in the specific optical
rotation, which is in sharp contrast with the dendritic box
dendrimers. This indicates that the mobility must be significantly
different from the covalently modified dendritic box analogues.
1
measurements were conducted using a standard H inversion
recovery experiment supplied by Varian.
Nꢀ(6-Aminohexyl)-N-tert-Boc-L-phenylalaninamide (4). To
a solution of 60 g (51 mmol) of 1,6-hexanediamine in 120 mL
of dichloromethane was added dropwise a solution of 3.62 g
(10 mmol) N-tert-Boc-L-phenylalanine-N-hydroxy-succinimide
ester in 200 mL of dichloromethane over 2 hours. Upon addition
of the ester a white precipitate started to form. After stirring
overnight the reaction mixture was transferred to a separatory
funnel and washed with water (6 × 300 mL) and a saturated
NaCl solution (1 × 100 mL). During this procedure the formed
precipitate disappeared. The organic phase was dried over
Na2SO4 and evaporated in vacuo. Column chromatography
(50 g SiO2) starting with CHCl3 : MeOH, 95 : 5 (v/v) as an
eluent was used to remove the doubly functionalized species
from the residue, and subsequently the eluent was changed
to CHCl3 : MeOH : N(Et)3, 90 : 5 : 5 v/v to remove the
mono-functionalized species from the column. Evaporation
of the solvent in vacuo gave pure amine 4 as a yellow oil
(2.5 g, 69%). ATR-IR: m (cm−1) = 3301.0, 2977.8, 2931.0,
2857.7, 1651.5, 1525.9, 1497.1, 1455.3, 1391.4, 1365.9, 1247.2,
1166.0, 1047.0, 1021.4, 748.7, 698.4. 1H-NMR (DMSO-d6):
d = 1.05–1.4 (m, 17 H, (CH3)3C (9H) + CH2(CH2)4CH2
(8H)), 2.55 (t, 2H, J = 7, H2NCH2), 2.7 (dd, 1H, JH
ꢀ
=
=
–
H
Ha
9.9, JH
ꢀ
ꢀꢀ = 13.6, PhCHꢀHꢀꢀC*), 2.85 (dd, 1H, JH
ꢀ
ꢀꢀ
–H
–
13.6, JHꢀꢀ
4.05 (pseudo dt, 1H, JHa
5.1, C*H), 6.8 (d, 1H, JHa
5H, PhH), 7.8 (br t, 1H, JNH
= 5.1, PhCHꢀHꢀꢀC*), 3.0 (m, 2H, CH2NHC(O)),
–Ha
= 8.8, JHa
NH
ꢀ
= 9.9, JHa ꢀꢀ =
–
–
NH
–H
–
H
Experimental
= 8.8, C*HNHC(O)), 7.2 (m,
General experimental
= 5.5, CH2NHC(O)). 13C-
–CH
NMR (CDCl3): d = 26.42, 26.56 2(H2NCH2CH2(CH2)2), 28.29
(C(CH3)3), 29.27, 33.48 (H2NCH2CH2(CH2)2CH2CH2), 38.84
(CH2NHC(O)), 39.33 (ArCCH2), 42.03 (H2NCH2), 56.06 (C*),
80.0 (C(CH3)3), 126.87, 128.61, 129.34 (PhCH), 136.95 (PhCipso ),
155.70 (NHC(O)OC(CH3)3), 171.03 (NHC(O)C*). MALDI-
TOF MS: Mr calc. for [M + H]+: 364.25, found 364.17; Mr
calc. for [M + Na]+: 386.24 found 386.16.
All solvents used were provided by Biosolve and of p.a.
quality. N-tert-Boc-L-phenylalanine-N-hydroxysuccinimide es-
ter (Sigma), p-toluenesulfonyl glycine benzyl ester (Fluka) and
1,6-hexanediamine (Janssen Chimica) were used as received.
Standard 1H-NMR, 13C-NMR and 1H–1H-NOESY spectra
were recorded at 25 ◦C on a Varian Gemini 300 or Varian
Mercury 400 MHz spectrometer. Chemical shifts are given
in ppm (d) relative to tetramethylsilane (0 ppm). IR spectra
were obtained using a Perkin Elmer Spectrum One ATR-FT-
IR machine. MALDI-TOF MS spectra were measured on
a Perspective DE Voyager spectrometer utilising an a-cyano-
4-hydroxycinnamic acid matrix. The ESI mass spectrum of
the dendrimer complex was recorded with a Q-Tof Ultima
GLOBAL mass spectrometer (Micromass, Manchester, UK)
equipped with a Z-spray source. The sample (10 lL) was injected
in the Flow Injection Analysis (FIA) mode. The HPLC-grade
chloroform was pumped with a Shimadzu LC-10ADvp at a
flow rate of 30 lL min−1. Electrospray ionization was achieved
Nꢀ(6(Benzyloxycarbonylmethyl-1,3-ureido)hexyl)-N-tert-Boc-
L-phenylalaninamide (6). A solution of 1.44 g (14.8 mmol)
of p-toluenesulfonyl glycine benzyl ester in 150 mL of
dichloromethane was washed with 75 mL of a NaOH solution
(2.4 M) and water (2 × 75 mL). Drying of the organic layer
with Na2SO4 and evaporation of the solvent gave glycine
benzyl ester as a slightly yellow oil (0.6 g, 85%). 1H-NMR
(CDCl3): d = 7.35 (s, 5H, PhH), 5.16 (s, 2H, PhCH2), 3.46 (s,
2H, CH2NH2), 1.42 (br, s, 2H, NH2). Of this amine 0.446 g
(2.7 mmol) in 2 mL of distilled dichloromethane was added to a
solution of 0.708 g (2.7 mmol) di-t-butyl-tricarbonate in 3 mL
2 8 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 1 – 2 8 5

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of distilled dichloromethane. IR spectroscopy showed a large
peak at 2252.3 cm−1, indicating that the amine was converted to
isocyanate 5. After stirring for half an hour a solution of 1.0 g
(2.8 mmol) of amine 4 in 3 mL of distilled dichloromethane was
added. IR spectroscopy revealed a complete disappearance of
the isocyanate peak after two hours. The reaction mixture was
subjected to column chromatography (SiO2, CHCl3 : MeOH,
95 : 5 v/v) and precipitation in hexane ◦to obtain pure 6 as a
(C(O)OH), 173.39 (NHC(O)C*). MALDI-TOF MS: Mr calc.
for [M + Na]+ 487.25, found 487.09.
References
1 R. G. Denkewalter, J. Kolc and W. J. Lukasavage, US Pat., 4, 289,
872, Sept. 15, 1981.
2 D. Seebach, J. M. Lapierre, K. Skobridis and G. Greiveldinger,
Angew. Chem., Int. Ed. Engl., 1994, 106, 457–458.
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4 H. W. I. Peerlings and E. W. Meijer, Chem. Eur. J., 1997, 3, 1563–
1570. In this publication the values for DAB(PA-LPhe)x should be
negative instead of positive.
20
white solid (1.27 g, 85%). Mp: 107–109 C. [a] = 5 (c = 1 in
D
CHCl3). Calc. for C30H42N4O6: C, 64.96; H, 7.63; N, 10.10%,
found C, 64.82; H, 7.55; N, 10.14%. ATR-IR: m (cm−1) =
3317.3, 2931.1, 2858.3, 1732.7, 1687.1, 1645.9, 1562.5, 1521. 9,
1455.4, 1439.0, 1390.9, 1365.3, 1290.7, 1232.2, 1200.8, 1168.0,
1024.7, 734.2, 697.0. 1H-NMR (DMSO-d6): d = 1.18–1.45
(br m, 8H, CH2(CH2)4CH2), 1.38 (s, 9H, (CH3)3C), 2.7 (dd,
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1H, JH
ꢀ
ꢀꢀ = 13.6, JH
ꢀ
= 9.9, PhCHꢀHꢀꢀC*), 2.9 (dd, 1H,
–
–
Ha
=H5.0, JH
ꢀ
ꢀꢀ = 13.6, PhCHꢀHꢀꢀC*), 2.95–3.1 (m, 4H,
20
7 The specific optical rotation was originally defined as [a]D = 100.
JHꢀꢀ
–Ha
–H
a/(c.l), in which a is the observed optical rotation in degrees, c
the concentration in grams per 100 milliliter solution and l the
(CH2(CH2)4CH2), 3.8 (d, 2H, JCH2
4.1 (pseudo dt, 1H, JHa
C*H), 5.1 (s, 2H, PhCH2O), 6.15 (m, 2H, NHCONH), 6.8
(d, 1H, JHa
= 6.2, NHCH2C(O)),
ꢀ
H
–
NH
= 8.5, JHa ꢀꢀ = 5.0, JHa
= 9.9,
–
NH
–
H
–
20
length of the tube in decimeters. The notation [a]D is used to
indicate the temperature (20 ◦C) and the wavelength of the light
= 8.5, NHC*), 7.18–7.38 (m, 10H, PhH),
–NH
(D line of a sodium lamp: k = 599.6 nm). Nowadays the following
7.8 (br t, 1H, C*C(O)NH). 13C NMR (CDCl3): d = 25.86,
25.91 (CH2CH2(CH2)2CH2CH2), 28.06 (CH3)3C), 28.84,
29.75 (CH2CH2(CH2)2CH2CH2), 38.84 (CH2(CH2)4CH2),
39.54 (PhCH2C*), 41.93 (CH2C(O)O), 55.85 (C*), 66.48
(CH2-benzyl), 79.40 (C(CH3)3), 126.42, 127.93, 128.08, 128.12,
128.30, 129.10 (ArCH), 135.21, 136.86 (PhCipso -benzyl +
PhCipso CH2C*), 155.56 (NHC(O)O), 158.72 (NHC(O)NH),
171.40 (C(O)O), 171.93 (NHC(O)). MALDI-TOF MS: Mr.
calc. for [M + Na]+ 577.30, found 577.07.
20
equation is used in textbooks, which is slightly different: [a]D
=
a/(c.l). In this case the concentration is given in grams per milliliter
solution, resulting in the same value for the specific optical rotation.
Throughout this article the old convention is used, so c = 1 refers to
a concentration in grams per 100 milliliters.
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Chem. Soc., 2001, 123, 8453–8458.
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Meijer, ChemBioChem, 2002, 3, 433–439.
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and P. L. Rinaldi, Macromolecules, 2004, 37, 8313–8318.
21 10 mg of 6 results in 0.01/554.69 = 1.80 × 10−5 moles of L-
phenylalanine units. 10 mg of 3a results in (0.01/2038.88) × 4 =
1.96 × 10−5 moles of L-phenylalanine units. 10 mg of 3e results in
(0.01/34725.58) × 64 = 1.84 × 10−5 moles of L-phenylalanine units.
The amount of chiral units that determine the optical rotation are
approximately the same.
Nꢀ(6(Carboxymethyl-1,3-ureido)hexyl)-N-tert-Boc-L-phenyl-
alaninamide (7). To a 1 : 1 v/v mixture of t-butanol and
water (50 mL) was added 1.00 g (0.15 mmol) of ester 2 and
40 mg of Pd/C catalyst (load: 10%). Subsequently, N2 gas was
bubbled through the solution for 15 minutes. The flask was put
in a Parr-apparatus, and was shaken for 3 hours under a H2
atmosphere (pressure: 50 Psi). Subsequently the suspension was
filtered to remove the catalyst and the solvent was evaporated
in vacuo, to give acid 7 as a white sticky foam (0.75 g, 89%).
Mp: 71–73 ◦C. Calc. for C23H36N4O6: C, 59.47; H, 7.81; N,
12.06%, found C, 59.73; H, 7.94; N, 11.68%. ATR-IR: m
(cm−1) = 3312.3, 2978.7, 2932.9, 2859.8, 1646.6, 1563.3, 1498.3,
1455.3, 1440.3, 1392.6, 1366.7, 1264.9, 1248.0, 1165.4, 699.6.
1H NMR (DMSO-d6): d = 1.18–1.40 (br, 8H, CH2(CH2)4CH2),
1.29 (s, 9H, (CH3)3C), 2.7 (dd, 1H, JH
ꢀ
= 9.0, JH
ꢀ
ꢀꢀ
H
=
–
–
13.6, PhCHꢀHꢀꢀC*), 2.9 (dd, 1H, JH
ꢀ
ꢀꢀ =H1a3.6, JHꢀꢀ
= 5.0,
–H
–
Ha
PhCHꢀHꢀꢀC*), 2.95–3.1 (m, 4H, (CH2(CH2)4CH2), 3.63 (d, 2H,
JCH2
8.8, JHa
= 5.9, NHCH2C(O)), 4.1 (pseudo dt, 1H, JHa
=
–
NH
–
NH
ꢀ
= 9.0, JHa ꢀꢀ = 5.0, C*H), 6.0, 6.1 (t, 2H, JNH
NH
=
–
H
–H
–CH2
5.8, NHCONH), 6.8 (d, 1H, JHa
= 8.8, NHC*), 7.23 (m,
–
5H, PhH), 7.84 (t, 1H, C*HNHC(O)). 13C-NMR (DMSO-d6):
d = 26.34 (CH2CH2(CH2)2CH2CH2), 28.36 (C(CH3)3, 29.22,
30.22 (NHC(O)NHCH2CH2 + CH2CH2NHC(O)C*), 38.01
(CH2NHC(O)C*), 42.96 (CH2C(O)OH), 56.01 (C*H), 78.15
(C(CH3)3), 126.37, 128.20, 129.40 (PhCH), 138.37 (PhCipso ),
155.36 (NHC(O)O(CH3)3), 158.23 (NHC(O)NH), 171.51
22 These results will be published elsewhere.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 1 – 2 8 5
2 8 5