L-Phe-D-Oxd: A privileged scaffold for the formation of supramolecular materials

Article abstract of DOI:10.1002/ejoc.201001643

Some compounds containing the L-Phe-D-Oxd [L-Phe = L-phenylalanine; D-Oxd = (4R,5S)-4-carboxy-5-methyl oxazolidin-2-one] moiety have been prepared and their properties as supramolecular material have been determined. Some derivatives of the dipeptide L-Ph

Full text of DOI:10.1002/ejoc.201001643

FULL PAPER
DOI: 10.1002/ejoc.201001643
L
-Phe-D
-Oxd: A Privileged Scaffold for the Formation of Supramolecular
Materials
Nicola Castellucci,[a] Gaetano Angelici,[b] Giuseppe Falini,[a] Magda Monari,[a] and
Claudia Tomasini*[a]
Keywords: Supramolecular chemistry / Peptides / Fibrous materials / Proline / Scanning probe microscopy
Some compounds containing the
L
-Phe-
D
-Oxd [
L
-Phe =
L
-
line) moiety to check if the presence of the Oxd moiety was
essential for the existence of those materials. In contrast to
phenylalanine; -Oxd = (4R,5S)-4-carboxy-5-methyl oxazol-
D
idin-2-one] moiety have been prepared and their properties
as supramolecular material have been determined. Some de-
the D-Oxd-containing compounds, no material was ever
formed with any of the
come suggests that the
D
-Pro-containing molecules. This out-
rivatives of the dipeptide
L-Phe-
L-Phe (which usually forms
L
-Phe- -Oxd moiety may be defined
D
nanotubes) and some long-chain derivatives that behave as
low-molecular-weight gelators have been prepared. We have
also replaced the D-Oxd moiety with a D-Pro (D-Pro = D-pro-
as a “privileged scaffold” for the formation of supramolecular
materials and it can be introduced into more complex struc-
tures to induce some selected properties in the solid state.
Introduction
A number of strategies have been envisaged recently to
design and build molecular materials based on self-assemb-
ling peptides and their derivatives.[1]
In our recent interest in this field, we have demonstrated
that the protected pseudo-peptide Boc-l-Phe-d-Oxd-OBn
[Boc = tert-butoxycarbonyl; l-Phe = l-phenylalanine; d-
Oxd = (4R,5S)-5-methyl-2-oxooxazolidin-4-carboxylic acid]
(Figure 1) forms a fibre-like material by self-organization
because it spontaneously forms infinite linear chains, in
which the parallel dipeptide units are connected only by
single hydrogen bonds.[2] This effect is due to the oxazol-
idin-2-one ring (d-Oxd), which has a nitrogen atom con-
nected to an endocyclic carbonyl, so that, on formation of
the imide bond, the exo- and endocyclic carbonyl groups lie
anti to one another, thus adopting a trans rigid conforma-
tion. The presence of stacking interactions is also important
for the formation of the materials.
To understand the importance of the l-Phe-d-Oxd scaf-
fold to build new architectures and, in particular, the role
of the d-Oxd group, we decided to explore how it behaved
when it was included in more complex structures and if the
term “privileged scaffold” could be used to define it. This
term was first proposed by Evans et al. to describe selected
Figure 1. Di- and tripeptides analyzed in this work. Bn = benzyl.
structural types that bind to multiple, unrelated classes of
protein receptors as high-affinity ligands.[3] These privileged
structures are typically rigid, polycyclic heteroatomic sys-
tems capable of orienting a variety of substituent patterns
in a well-defined three-dimensional space.[4]
We selected two examples for the formation of supra-
molecular materials: the tendency of derivatives of the di-
peptide l-Phe-l-Phe to form nanotubes[5] and the forma-
tion of gels by the use of low-molecular-weight gelators
(LMWGs).[6] We also replaced the d-Oxd moiety with a d-
Pro (d-Pro = d-proline) moiety to check if the presence of
the Oxd moiety was essential for the properties of the sup-
ramolecular material.
Thus, we prepared the tripeptide Boc-l-Phe-l-Phe-d-
Oxd-OBn (1b) and its analogue Boc-l-Phe-l-Phe-d-Pro-
OBn (1d) to determine their properties in the solid state.
Then, we prepared some long-chain derivatives of 1a–
d to determine the properties of these new compounds as
LMWGs, since an intermolecular interaction of suitable
strength was required for the formation of a gel. It is known
that three factors can favour the formation of a gel: 1) the
presence of hydrogen bonding and π–π stacking interac-
[a] Dipartimento di Chimica “G. Ciamician“ – Alma Mater
Studiorum Università di Bologna,
via Selmi 2, 40126 Bologna, Italy
Fax: +39-051-2099456
E-mail: claudia.tomasini@unibo.it
[b] Department of Chemistry, University of Basel,
St. Johanns-Ring 19, 4056 Basel, Switzerland
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001643.
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l-Phe-d-Oxd: A Privileged Scaffold
tions, which are the principle interactions involved in gel [N2H2N···O6Ј 2.204 Å, N2···O6Ј 3.005(4) Å, N2–
aggregation; 2) the tendency of the molecule head to orga- H2N···O6Ј 163°, symmetry code (I): x–1,y,z; N3H3N···O7ЈЈ
nize into a network; this influences the probability of gel 2.137 Å, N3···O7ЈЈ 2.941 Å, N3–H3N···O7ЈЈ 168°, sym-
formation; and 3) the presence of medium-sized aliphatic metry code (II): x + 1,y,z] to two neighbours, thus generat-
chains (4–8 methylene units) connected to a polar head.[7]
ing an infinite parallel β-sheet structure running along the
crystallographic a axis. Interestingly, this arrangement is
similar to that observed in Boc-l-Phe-d-Oxd-OBn, in which
one unit is connected to the adjacent ones through single
NH···OC hydrogen bonds and other related compounds.[10]
Results and Discussion
To determine the role of the d-Oxd unit in the dipeptide
1a, we prepared three new di- and tripeptides (1b, 1c and
1d; Figure 1) that differ from 1a by the addition of a l-Phe
unit (1b) or by the replacement of the d-Oxd moiety with
one l-Phe unit (1c) and with two l-Phe units (1d). These
three compounds have been obtained by means of normal
peptide synthesis in solution (see the Experimental Section).
By comparing the 1H NMR spectra of 1a–d, we immedi-
ately noticed that compounds 1a and 1b exist in solution as
a single conformer, whereas 1c and 1d were always a mix-
ture of conformers, as shown by 13C NMR spectra (see the
Supporting Information). This effect is typical of Pro-con-
taining peptides because the peptide bond is in a trans–cis
mixture, usually preferring the trans conformation.[8] This
equilibrium is missing from the pseudo-peptides containing
the Oxd moiety, since in this case the peptide bond is always
forced in the trans conformation owing to the effect of the
exocyclic carbonyl.[9] Several macroscopic effects depend on
this rigid conformation: the two pseudo-peptides 1a and 1b
are crystalline compounds that tend to aggregate into fibre-
like materials. While 1a has been already extensive de-
scribed,[2a] we report herein optical microscopy (OM) and
SEM images of 1b (Figure 2).
Figure 3. a) X-ray molecular structure and b) crystal packing of
1b.
Table 1. Selected backbone torsional angles [°] for 1b.
l-Phe1
l-Phe2
Oxd
C31–N3–C23–C22
N3–C23–C22–N2
C22–N2–C14–C13
N2–C14–C13–N1
C13–N1–C9–C8
N1–C9–C8–O1
φ1
–127.3(3)
109.5(3)
–126.4(3)
147.9(3)
56.2(4)
ψ1
φ2
ψ2
φ3
ψ3
32.4(4)
Figure 2. a) OM and b) SEM images of 1b.
It is possible to observe how 1b precipitates to form elon-
On the contrary, compounds 1c and 1d do not show any
gated crystals (up to a few millimeters) locally iso-oriented. propensity to form fibre-like materials because they hardly
Each single crystal (about 20 mm thick) has a well-defined become solids (1c is a liquid[11]). The powder X-ray diffrac-
crystalline habit and shows faces that are probably parallel tion of 1d shows that it is an amorphous solid (see the Sup-
to the crystallographic a axis. The pseudo-hexagonal cross- porting Information).
section is also shown.
To check the propensity of the derivatives of these four
The conformational analysis of 1b in the solid state was compounds to behave as LMWGs, after several attempts
further elucidated by a single-crystal X-ray diffraction we synthesized 2a–d and 3a–d, which were eight derivatives
study.
of a dicarboxylic, medium-sized aliphatic acid [azelaic acid
The molecular conformation of 1b is shown in part a of = HOOC-(CH2)7-COOH] that fulfil this requirement. Inter-
Figure 3 and relevant torsion angles are reported in Table 1. estingly, no derivative of monocarboxylic acids, such as
The backbone torsion angles for the two l-Phe units corre- hexonoic or undecanoic acids, form any kind of gel.
spond approximately to those in peptide β strands, as pre-
Compounds 2a–d and 3a–d may be defined as synthetic
viously reported for Boc-l-Phe-d-Oxd-OBn.[2a] In the crys- bolaamphiphiles.[12] In general, these compounds reproduce
tal packing of 1b (Figure 3, b) each molecule is connected the unusual architecture of monolayered membranes found
through four intermolecular NH···OC hydrogen bonds in archaebacteria.
Eur. J. Org. Chem. 2011, 3082–3088
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N. Castellucci, G. Angelici, G. Falini, M. Monari, C. Tomasini
FULL PAPER
Scheme 1. Preparation of compounds 2a–d and 3a–d.
Compounds 1a–d were deprotected with trifluoroacetic Table 2. Gelation properties of compounds 2a–d and 3a–d in se-
lected solvents (concentration: 10 mm).
acid (TFA) in dichloromethane to obtain the corresponding
trifluoroacetate salt in quantitative yield; this was coupled
with azelaic acid, using O-benzotriazole-N,N,NЈ,NЈ-tetra-
methyluronium hexafluorophosphate (HBTU) and triethyl-
amine as coupling agents (Scheme 1). Compounds 2a–d
were obtained pure after flash chromatography in high
yields. Then, they were all deprotected by hydrogenolysis to
give the free carboxy termini 3a–d in quantitative yield.
Then, the propensity of all of these compounds to form
gels was determined. The general method adopted to form
gels was to place one compound (2a–d or 3a–d) in a small
test tube (8 mm in diameter) and dissolve it in pure solvent
(distilled water was used) or in a solvent mixture (see
Entry Solvent
Compd. After sonication[a] After 2 h[a]
1
CH2Cl2/AcOEt 1:1
2a
2a
2a
2b
2b
2b
2c
2c
2c
2d
2d
2d
3a
3a
3a
3b
3b
3b
3c
3c
3c
3d
3d
3d
SP
S
SP
SP
S
SP
S
S
S
S
S
S
SP
SP
G
S
S
SP
S
S
S
S
SP
S
G
PG
PG
G
S
G
S
S
S
S
S
S
SP
PG
G
S
S
G
S
S
S
S
SP
S
2
CH2Cl2
3
AcOEt
4
5
CH2Cl2/AcOEt 1:1
CH2Cl2
6
AcOEt
7
8
CH2Cl2/AcOEt 1:1
CH2Cl2
9
AcOEt
10
11
12
13
CH2Cl2/AcOEt 1:1
CH2Cl2
AcOEt
MeOH
Table 2) to obtain a 10 mm solution. Because ultrasound 14
H2O
15
16
MeOH/H2O 1:1
MeOH
influences the aggregation properties of the molecules in the
solvents,[13] the tube was sonicated for 20 min at room tem-
17
H2O
perature, then it was left to stand for 2 h before gel forma-
18
MeOH/H2O 1:1
MeOH
H2O
MeOH/H2O 1:1
MeOH
H2O
tion was monitored. When a mixture of solvents was used,
the solvent that the gelling compound was more soluble in
was introduced first (i.e., dichloromethane was introduced
first in entries 1, 4, 7 and 10 and methanol was first in
entries 15, 18, 21 and 24 in Table 2).
19
20
21
22
23
24
MeOH/H2O 1:1
The most common diagnostic test of gelation is tube in-
version. In this test, a sample tube containing the mixture
of compound and solvent was inverted to ascertain if the
sample would flow under its own weight. A gel was as-
sumed to be a sample that had a yield stress that prevented
it from flowing down the tube. A solution was taken to be
a sample that flowed down the tube. When a partial gel is
formed, the compound sticks to the bottom of the test tube,
while a little solvent (Ͻ 20%) flows down.
[a] SP = suspension; G = gel; PG = partial gel; S = solution.
Compounds 2a, 2b, 3a and 3b form gels (Table 2, entries
1, 4, 6, 15 and 18) or partial gels (Table 2, entries 2 and 14),
whereas the Pro-containing molecules 2c, 2d, 3c and 3d Figure 4. a) Photograph of 2a in a 1:1 mixture of dichloromethane
and ethyl acetate (10 mm solution); b) OM image of the same sam-
ple; scale bar: 500 μm.
never form gels.
To check the structural properties of the gels formed, we
carried out our studies only on the gel reported in entry 1
as an example of this class of compounds (Figure 4).
Then, the sample was left to dry in air to form the xero- ure 5). The spectra of both the precipitated sample and the
gel and was completely dry after 24 h at 20 °C. We recorded xerogel showed the presence of a signal at about 3310 cm–1,
an FTIR spectrum (1% in dry KBr) and compared it with typical of C=O···H–N hydrogen bonds, whereas the 3 mm
the spectra of 2a in dilute solution (3 mm in dichlorometh- solution had a signal at 3430 cm–1, which was attributed to
ane) and as a precipitated material (1% in dry KBr) (Fig- the presence of a free NH group.[14]
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Eur. J. Org. Chem. 2011, 3082–3088

l-Phe-d-Oxd: A Privileged Scaffold
multilayer structures within the self-assemblies. This obser-
vation agrees with that observed for 2-glucosamide-based
bolaamphiphiles.[16]
Conclusions
We have shown several examples of pseudo-peptides con-
taining d-Oxd moieties and compared them with similar
compounds, in which d-Oxd was replaced with d-Pro. With
all of the d-Pro-containing molecules, no fibre-like material
or gel was ever formed. Furthermore, the presence of two
Phe moieties connected to one another did not affect the
properties of the material, since molecules containing one
or two Phe residues showed the same behaviour in the solid.
This outcome is opposite to that obtained with other l-Phe-
l-Phe derivatives, thus showing that l-Phe-d-Oxd is very
strong and leads to the formation of solids with well-de-
fined properties. Thus, l-Phe-d-Oxd fulfils the requirements
of a privileged scaffold for the formation of supramolecular
Figure 5. FTIR absorption spectra in the N–H (left) and C=O
(right) stretching regions for 2a: a) 3 mm solution in pure CH2Cl2; materials containing pseudo-proline moieties and it can be
b) solid as 1% mixture with dry KBr; and c) xerogel as a 1% mix-
ture with dry KBr.
introduced into more complex structures to induce some
selected properties in the solid state.
Further investigations, using SEM, gave a better idea of
the morphology of the xerogel (Figure 6): it forms long fila-
ments highly interconnected and branched with a diameter
Synthesis: The melting points of the compounds were determined
of about 0.5 μm. They have a strong tendency to aggregate,
in open capillaries and are uncorrected. High-quality infrared spec-
Experimental Section
forming a network of meshed and bundled architectural as-
semblies (Figure 6, a). These observations fit with the OM
images and the FTIR spectral analyses. The gel appears
opaque, suggesting the existence of extended molecular as-
semblies in the wet gel.[15] Moreover, the FTIR spectrum
indicates that this molecule may assemble into an organized
form by hydrogen-bonding interactions as soon as a limit
concentration that favours the formation of β sheets is
reached.
tra (64 scans) were obtained at 2 cm–1 resolution using a 1 mm
NaCl solution cell and a Nicolet 210 FTIR spectrometer. All spec-
tra were obtained of 3 mm solutions in dry CH2Cl2 at 297 K or as
a 1% solid mixture with dry KBr. All compounds were dried in
vacuo and all of the sample preparations were performed in a nitro-
gen atmosphere. Routine NMR spectra were recorded with a Var-
ian Mercury 400 spectrometer at 400 MHz and with a Varian Inova
300 at 300 MHz (1H NMR) and at 100 or 75 MHz (13C NMR).
The measurements were carried out in CD3OD and in [D6]DMSO.
The proton signals were assigned by gCOSY spectra. Chemical
shifts are reported in δ values relative to the solvent (CD3OD or
[D6]DMSO) peak.
Boc-L-Phe-L-Phe-D-Oxd-OBn (1b): A solution of Boc-l-Phe-d-
Oxd-OBn[2a] (2 mmol, 0.96 g) and TFA (36 mmol, 2.78 mL) in dry
dichloromethane (20 mL) was stirred at room temperature for 4 h,
then the volatile compounds were removed under reduced pressure
and the corresponding amine salt was obtained in quantitative
yield without the need for further purification.
Figure 6. SEM picture (a) and XRD patterns (b) of the xerogel
prepared from 2a. In (a) the inset shows a high magnification of
the wide view. The diffraction peaks have been indexed according
to a tetragonal unit cell (a = 1.97 nm, c = 2.67 nm).
A solution of Boc-l-Phe-OH (1.38 g, 0.52 mmol) and HBTU
(0.4 g, 1.04 mmol) in dry acetonitrile (22 mL) was stirred under a
nitrogen atmosphere for 10 min at room temperature. Then, a mix-
ture of the previously obtained amine salt (1.04 mmol) and Et3N
(3.2 mmol, 0.47 mL) in dry acetonitrile (15 mL) was added drop-
wise at room temperature. The solution was stirred for 40 min un-
der a nitrogen atmosphere, then acetonitrile was removed under
reduced pressure and replaced with ethyl acetate. The mixture was
washed with brine, 1 n aqueous HCl (3ϫ30 mL), and with 5%
(w/v) aqueous NaHCO3 (1ϫ30 mL), dried with sodium sulfate and
concentrated in vacuo. The pure product was obtained after silica
gel chromatography [CH2Cl2 100% Ǟ CH2Cl2/ethyl acetate (80:20)
as eluent] in 78% (0.98 g) overall yield; m.p. 68 °C. [α]2D0 = +34 (c
A further clue to the presence of an ordered assembly of
molecules in the xerogels is given by XRD analysis (Fig-
ure 6, b). The XRD pattern of the xerogel of 2a shows many
sharp diffraction peaks and a broad band at around 2θ =
20°, which suggests the coexistence of amorphous and high
crystalline phases. The diffraction peaks have been indexed
according to a tetragonal unit cell (a = 1.97 nm, c =
2.67 nm). These unit cell parameters agree with long-range
ordering and suggest that 2a may form crystalline = 1.0, CH Cl ). IR (CH Cl , 3 mm): ν = 3415, 1798, 1753, 1713,
˜
2
2
2
2
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N. Castellucci, G. Angelici, G. Falini, M. Monari, C. Tomasini
FULL PAPER
1688 cm–1. IR (1% in dry KBr): ν = 3327, 3307, 1794, 1746, 1714,
C51H56N4O12 (916.4): calcd. C 66.80, H 6.16, N 6.11; found C
66.75, H 6.19, N 6.07.
˜
1
1686, 1658 cm–1. H NMR (CDCl3, 400 MHz): δ = 1.52–1.56 (m,
12 H, Me + tBu), 2.87–3.05 (m, 4 H, 2ϫ CHN-CH2-Ph), 3.11 (dd,
J = 5.2, 12.4 Hz, 1 H, CHN-CH2-Ph), 4.20–4.35 (m, 2 H, CHN-
Oxd + CHN-CH2-Ph), 4.45–4.52 (m, 1 H, CHO-Oxd), 4.95 (br. s,
1 H, NH-Boc), 5.2, 2 H, J = 111 (AB system, 6 Hz, CH2OBn),
5.80–6.03 (m, 1 H, NH-Boc), 6.42 (br. s, 1 H, NH-Phe), 7.05–7.36
(m, 15 H, 3ϫ Phe) ppm. 13C NMR (CDCl3, 100 MHz): δ = 20.4,
21.3, 28.5, 38.5, 38.6, 53.1, 55.8, 60.7, 62.0, 68.3, 70.7, 73.9, 126.7,
127.5, 128.6, 128.8, 128.9, 129.0, 129.6, 135.6, 167.5, 170.4, 170.6
ppm. C35H39N3O8 (629.3): calcd. C 67.76, H 6.24, N 6.67; found
C 67.79, H 6.21, N 6.68.
CH2(C3H6CO-
L-Phe-L-Phe-D-Oxd-OBn)2 (2b): The synthetic pro-
cedure was the same as that of 2a, starting from 1a; yield 57%;
m.p. 175 °C. [α]2D0 = +19 (c = 0.9, CHCl ). IR (CH Cl , 3 mm): ν =
˜
3
2
2
3440, 3358, 3309, 1773, 1748, 1716, 1655 cm–1. IR (1% in dry KBr):
ν = 3297, 1644, 1795, 1740, 1710 cm–1. 1H NMR (CDCl3,
˜
400 MHz): δ = 1.16–1.21 [m, 10 H, CH2(CH2)5CH2], 1.48 (d, J =
6.4 Hz, 6 H, 2ϫ CH3Oxd), 2.10–2.18 [m, 4 H, CH2(CH2)5CH2],
2.52–3.04 (m, 8 H, 4ϫ CHN-CH2-Ph), 3.93 (d, J = 4.8 Hz, 1 H,
CHN-Oxd), 4.40 (m, 1 H, CHO-Oxd), 4.46 (m, 1 H, CHN-Oxd),
4.67 (m, 1 H, CHO-Oxd), 5.15 (m, 4 H, 2ϫ CH2OBn), 5.32 (br. s,
2 H, 2ϫ NH), 5.92 (br. s, 1 H, NH), 7.08–7.36 (m, 30 H, 6ϫ Phe)
ppm. 13C NMR (CDCl3, 100 MHz, mixture of conformers): δ =
21.0, 21.2, 24.6, 25.3, 25.4, 28.6, 28.8, 29.6, 30.9, 33.9, 36.2, 36.3,
37.8, 38.0, 38.3, 38.6, 52.9, 53.0, 54.0, 54.2, 61.7, 61.8, 67.3, 68.0,
73.7, 126.9, 128.2, 128.5, 128.7, 129.4, 130.0, 134.6, 135.3, 136.3,
136.4, 150.3, 151.2, 167.3, 170.4, 170.5, 170.7, 170.8, 171.3, 171.8,
177.6, 177.7, 177.8 ppm. C69H74N6O14 (1210.5): calcd. C 68.41, H
6.16, N 6.94; found C 68.38, H 6.18, N 6.94.
Boc-L-Phe-D
-Pro-OBn (1c): For the synthetic details, see ref.[7]
Boc-
L
-Phe-
L
-Phe- -Pro-OBn (1d): The synthetic procedure was the
D
same as that of 1b, starting from 1c; yield 79%; m.p. 55 °C. [α]2D0
=
+35 (c = 1.0, CHCl ). IR (CH Cl , 3 mm): ν = 3418, 1742, 1711,
˜
3
2
2
1673, 1645 cm–1. IR (1% in dry KBr): ν = 3419, 3285, 1747, 1712,
˜
1633 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 1.41 (s, 9 H, tBu),
1.77–1.95 (m, 4 H, NCH2CH2CH2CH-CO), 2.80–3.18 (m, 6 H,
NCH2CH2CH2CH-CO + 2ϫ CH-CH2-Ph), 4.31–4.43 (m, 2 H, 2ϫ
CH-CH2-Ph), 4.83–5.00 (m, 2 H, NCH2CH2CH2CH-CO + NH),
6.72 and 6.96 (d, J = 8 Hz, 1 H, NH, mixture of conformers), 7.18–
7.38 (m, 15 H, 3ϫ Ph) ppm. 13C NMR (CDCl3, 100 MHz, mixture
of conformers): δ = 22.4 and 24.3 , 26.9 and 28.3, 28.9 and 31.0,
37.5 and 38.3, 39.7, 46.6 and 46.8, 51.9 and 52.4, 55.4, 58.8 and
59.5, 66.7 and 67.3, 79.9, 126.7, 126.8, 127.0, 128.1, 128.2, 128.4,
128.5, 128.7, 129.2, 129.5, 135.2 and 135.6, 136.2 and 136.6, 155.2,
169.5, 170.5, 171.4, 172.0 ppm. C35H41N3O6 (599.3): calcd. C
70.10, H 6.89, N 7.01; found C 70.05, H 6.85, N 6.99.
BnO-D-Pro-L-Phe-CO-(CH2)7-CO-L-Phe-D-Pro-OBn (2c): The
synthetic procedure was the same as that of 2a, starting from 1c;
yield 83%; m.p. 63 °C. [α]2D0 = +76 (c = 1.0, CHCl3). IR (CH2Cl2,
3 mm): ν = 3419, 3304, 1746, 1717 cm–1. IR (1% in dry KBr): ν =
˜
˜
3404, 1736, 1629 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 1.07–1.19
[m, 10 H, CH2(CH2)5CH2], 1.31–1.53 (m,
8
H, 2ϫ
NCH2CH2CH2CH), 1.60–1.80 [m, 4 H, CH2(CH2)5CH2], 1.94–2.04
(m, 4 H, 2ϫ NCH2CH2CH2CH), 2.71–2.98 (m, 4 H, 2ϫ CHN-
CH2Ph), 4.21 (dd, J = 3.6, 8.4 Hz, 2 H, 2ϫ NCH2CH2CH2CH),
4.78–4.88 (m, 2 H, CHN-CH2Ph), 4.91–4.98 (m, 1 H, CHN-
CH2Ph), 4.99–5.04 (m, 4 H, 2ϫ OCH2Ph), 6.53 (d, J = 8.0 Hz, 1
H, NH), 7.02–7.22 (m, 20 H, 4ϫ Phe) ppm. 13C NMR (CDCl3,
100 MHz, mixture of conformers): δ = 24.2, 24.9, 25.0, 25.1, 25.2,
28.5, 28.6, 28.8, 30.9, 36.0, 38.5, 39.4, 46.8, 52.1, 58.7, 66.6, 67.2,
126.9, 127.8, 128.1, 128.1, 128.3, 128.4, 128.5, 129.0, 129.3, 135.4,
136.2, 136.9, 151.6, 170.2, 170.3, 171.5, 172.5, 172.6 ppm.
C51H60N4O8 (856.4): calcd. C 71.47, H 7.06, N 6.54; found C 71.44,
H 7.10, N 6.52.
CH2(C3H6CO-L-Phe-D-Oxd-OBn)2 (2a): A solution of Boc-l-Phe-
d-Oxd-OBn (2 mmol, 0.96 g) and TFA (36 mmol, 2.78 mL) in dry
dichloromethane (20 mL) was stirred at room temperature for 4 h,
then the volatile compounds were removed under reduced pressure
and the corresponding amine salt was obtained pure in quantitative
yield without further purification.
A solution of azelaic acid (0.98 g, 0.52 mmol) and HBTU (0.4 g,
1.04 mmol) in dry acetonitrile (22 mL) was stirred under nitrogen
atmosphere for 10 min at room temperature. Then, a mixture of the
previously obtained amine salt (1.04 mmol) and Et3N (3.2 mmol,
0.47 mL) in dry acetonitrile (15 mL) was added dropwise at room
temperature. The solution was stirred for 40 min under a nitrogen
atmosphere then acetonitrile was removed under reduced pressure
and replaced with ethyl acetate. The mixture was washed with
brine, 1 n aqueous HCl (3ϫ30 mL), and 5% (w/v) aqueous
NaHCO3 (1ϫ30 mL), dried with sodium sulfate and concentrated
in vacuo. The pure product was obtained after silica gel chromatog-
raphy [CH2Cl2 100%ǞCH2Cl2/ethyl acetate (80:20) as eluent] in
64% (1.17 g) overall yield; m.p. 207 °C. [α]2D0 = 45.0 (c = 0.1,
BnO-
D-Pro-(L-Phe)2-CO-(CH2)7-CO-(L-Phe)2-
D-Pro-OBn
(2d):
The synthetic procedure was the same as that of 2a, starting from
1d; yield 82%; m.p. 59 °C. [α]2D0 = +40 (c = 1.0, CHCl3). IR
(CH Cl , 3 mm): ν = 3412, 3293, 1749, 1643 cm–1. 1H NMR
˜
2
2
(CDCl3, 400 MHz): δ = 1.17–1.50 [m, 10 H, CH2(CH2)5CH2], 1.80–
1.89 (m, 8 H, 2ϫ NCH2CH2CH2CH), 2.05 [m, 4 H, CH2-
(CH2)5CH2], 2.81–3.03 (m, 4 H, 2ϫ CHN-CH2Ph), 3.39–3.53 (m,
4 H, 2ϫ NCH2CH2CH2CH), 4.33 (dd, J = 3.6, 7.6 Hz, 2 H,
NCH2CH2CH2CH), 4.62 (q, J = 6.8 Hz, 1 H, NCH-CH2Ph), 4.81
(dt, J = 6.0, 9.2 Hz, 1 H, 2ϫ CHN-CH2Ph), 5.08 (AB, J = 12.4 Hz,
2 H, OCH2Ph), 6.04 (d, J = 7.2 Hz, 2 H, NH), 6.57 (d, J = 7.6 Hz,
2 H, NH), 7.06–7.30 (m, 30 H, 6ϫ Phe) ppm. 13C NMR (CDCl3,
100 MHz, mixture of conformers): δ = 24.3, 25.3, 28.8, 28.9, 36.3,
38.2, 39.5, 46.8, 52.4, 53.8, 58.8, 66.7, 126.9, 127.0, 128.0, 128.3,
128.4, 128.5, 129.2, 129.4, 129.5, 135.6, 136.1, 136.3, 169.3, 170.3,
171.4, 172.8 ppm. C69H78N6O10 (1150.6): calcd. C 71.98, H 6.83,
N 7.30; found C 72.01, H 6.80, N 7.28.
CHCl ). IR (CH Cl , 3 mm): ν = 3428, 1789, 1754, 1707, 1672
˜
3
2
2
cm–1. IR (1% in dry KBr): ν = 3309, 1793, 1765, 1736, 1708, 1650
˜
cm–1. H NMR ([D6]DMSO, 300 MHz): δ = 0.95–1.18 [m, 10 H,
1
CH2(CH2)5CH2], 1.20–1.40 [m, 4 H, CH2(CH2)5CH2], 1.50 (d, J =
6.3 Hz, 6 H, OCHCH3), 2.00 (m, 4 H, CH2CO), 2.70 (dd, J = 10.8,
13.5 Hz, 2 H, CHN-CHH-Ph), 3.10–3.20 (dd, J = 3.3, 13.5 Hz, 2
H, CHN-CHH-Ph), 4.65 (d, J = 4.2 Hz, 2 H, CHN), 4.80–4.90 (m, CH2(C3H6CO-L-Phe-D-Oxd-OH)2 (3a): Compound 2a (1 mmol,
2 H, OCH), 5.18 (d, J = 12.3 Hz, 2 H, OCHHPh), 5.25 (d, J = 0.92 g) was dissolved in MeOH (35 mL) under nitrogen. Pd/C
12.6 Hz, 2 H, OCHHPh), 5.8 (m, 2 H, CHN-CH2Ph), 7.20–7.40 (50 mg, 10% w/w) was added under nitrogen. Vacuum was created
(m, 20 H, 4ϫ Ph), 8.25 (d, J = 8.7 Hz, 2 H, NH) ppm. 13C NMR
inside the flask by using the vacuum line. The flask was then filled
([D6]DMSO, 75 MHz): δ = 14.8, 15.3, 21.1, 25.9, 29.0, 35.7, 37.7, with hydrogen by using a balloon (1 atm). The solution was stirred
38.5, 51.0, 53.1, 55.4, 62.0, 67.7, 74.3, 127.2, 128.6, 128.8, 128.9,
129.2, 129.8, 136.0, 138.0, 152.5, 168.6, 172.7, 173.2 ppm.
for 2 h under a hydrogen atmosphere. The pure product was ob-
tained in quantitative yield (0.73 g) after the solution was filtered
3086
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3082–3088

l-Phe-d-Oxd: A Privileged Scaffold
through a Celite pad using ethyl acetate and concentrated in vacuo;
m.p. 201 °C. [α]2D0 = –36.0 (c = 1.2, MeOH). 1H NMR (CD3OD,
400 MHz): δ = 1.06–1.47 [m, 10 H, CH2(CH2)5CH2], 1.58 (d, J =
Microscopy: The gel and xerogel of 2a were systematically observed
by OM and SEM. The OM images were collected by using a Leica
optical microscope equipped with a CCD camera. SEM images
6.4 Hz, 6 H, OCHCH3), 2.03–2.15 [m, 4 H, CH2(CH2)5CH2], 2.91 were obtained from samples on glass cover slips after being coated
(dd, J = 9.6, 13.6 Hz, 2 H, CHN-CHHPh), 3.14 (dd, J = 5.2, with gold and observed by using a Philips XL20 scanning electron
13.6 Hz, 2 H, CHN-CHHPh), 4.00 (d, J = 5.6 Hz, 2 H, CHN- microscope. The images were recorded by using a CCD digital cam-
CHHPh), 4.62–4.87 (m, 2 H, OCH), 5.80 (m, 2 H, CHN-CH2Ph), era.
7.20–7.40 (m, 20 H, 4ϫ Ph) ppm. 13C NMR (CD3OD, 100 MHz):
Single-Crystal X-ray Diffraction for 1b: The X-ray intensity data
δ = 19.8, 25.3, 28.3, 28.5, 35.2, 37.6, 52.7, 61.7, 74.4, 126.5, 128.0,
for 1b were measured on a Bruker SMART Apex II CCD area
129.1, 136.6, 151.1, 153.3, 169.7, 172.7, 174.4 ppm. C37H44N4O12
detector diffractometer. Cell dimensions and the orientation matrix
(736.3): calcd. C 60.32, H 6.02, N 7.60; found C 60.36, H 6.04, N
were initially determined from a least-squares refinement on reflec-
tions measured in three sets of 20 exposures, collected in three dif-
7.55.
ferent ω regions and eventually refined against all data. A full
sphere of reciprocal space was scanned by 0.3° ω steps. The soft-
ware SMART[8] was used for collecting frames of data, indexing
reflections and determining of lattice parameters. The collected
frames were then processed for integration by the SAINT pro-
gram[9] and an empirical absorption correction was applied by
using SADABS.[11] The structure was solved by direct methods
(SIR 97)[10] and subsequent Fourier syntheses and refined by full-
matrix least-squares on F2 (SHELXTL)[11] by using anisotropic
thermal parameters for all non-hydrogen atoms. All hydrogen
atoms, except the amidic protons and methine hydrogen atoms,
were added in calculated positions, included in the final stage of
refinement with isotropic thermal parameters, U(H) = 1.2 Ueq(C)
[U(H) = 1.5 Ueq(C-Me)], and allowed to ride on their carrier car-
bons. The absolute structure configuration was not determined
from X-ray data, but was known from the synthetic route. Crystal
data and details of the data collection for 1b are reported in Table
S1 in the Supporting Information.
CH2(C3H6CO-L-Phe-L-Phe-D-Oxd-OH)2 (3b): The synthetic pro-
cedure was the same as that of 3a, starting from 2b; yield 92%;
m.p. 52 °C. [α]2D0 = +2 (c = 0.49, MeOH). 1H NMR (CD3OD,
400 MHz): δ = 1.14–1.25 [m, 10 H, CH2(CH2)5CH2], 1.43–1.57 (m,
6 H, 2ϫ CH3Oxd), 2.12–2.25 [m, 4 H, CH2(CH2)5CH2], 2.71–2.88
(m, 8 H, 4ϫ CHN-CH2-Ph), 3.06–3.25 (m, 2 H, 2ϫ CHN-CH2-
Ph), 4.29–4.65 (m, 4 H, 2ϫ CHO-Oxd + 2ϫ CHN-Oxd), 5.50–
5.62 (m, 2 H, 2ϫ CHN-CH2-Ph), 6.98–7.33 (m, 20 H, 6ϫ Phe)
ppm. 13C NMR (CD3OD, 100 MHz): δ = 14.0, 19.8, 24.6, 25.3,
28.6, 33.5, 35.3, 37.0, 37.3, 37.4, 52.9, 53.4, 54.0, 65.5, 74.6, 126.2,
126.3, 126.5, 128.0, 128.5, 128.9, 129.2, 129.8, 136.3, 137.0, 137.1,
171.6, 171.8, 173.4, 174.5, 174.7, 176.2 ppm. C55H62N6O14 (1030.4):
calcd. C 64.07, H 6.06, N 8.15; found C 64.03, H 6.05, N 8.17.
HO-D-Pro-L-Phe-CO-(CH2)7-CO-L-Phe-D-Pro-OH (3c): The syn-
thetic procedure was the same as that of 3a, starting from 2c; yield
96%; m.p. 103 °C. [α]2D0 = +30 (c = 1.04, MeOH). IR (1% in dry
KBr): ν = 3408, 3291, 1733, 1630 cm–1. 1H NMR (CDCl3,
˜
400 MHz): δ = 0.92–1.39 [m, 10 H, CH2(CH2)5CH2], 1.80–1.89 (m,
8 H, 2ϫ NCH2CH2CH2CH), 2.05 [m, 4 H, CH2(CH2)5CH2], 2.80–
3.40 (m, 12 H, 2ϫ NCH2CH2CH2CH-CO + 4ϫ CH-CH2Ph),
3.40–3.78 (m, 4 H, 2ϫ CH-CH2Ph), 4.83–5.00 (m, 2 H, 2ϫ
NCH2CH2CH2CH-CO), 7.18–7.38 (m, 10 H, 2ϫ Ph) ppm. 13C
NMR (CD3OD, 50 MHz, mixture of conformers): δ = 23.6, 25.4,
26.0, 26.7, 29.8, 30.1, 32.1, 34.9, 36.4, 36.6, 37.9, 38.8, 39.4, 53.6,
54.2, 60.4, 61.1, 127.7, 128.0, 129.4, 129.5, 130.3, 130.5, 138.1,
138.9, 172.0, 173.3, 175.2, 175.6, 176.1 ppm. C37H48N4O8 (676.3):
calcd. C 65.66, H 7.15, N 8.28; found C 65.70, H 7.18, N 8.31.
XRD Analysis: XRD patterns were collected by using a PanAnalyt-
ical X’Pert Pro system equipped with an X’Celerator detector pow-
der diffractometer using CuKα radiation generated at 40 kV and
40 mA. The instrument was configured with 1/32° divergence and
1/32° antiscattering slits. A standard quartz sample holder 1 mm
deep, 20 mm high and 15 mm wide was used. The diffraction pat-
terns were collected within the 2θ range from 2.5 to 40° with a step
size (Δ2θ) of 0.02° and a counting time of 1200 s. The diffraction
pattern was analysed by means of the software X’Pert High Score
Plus.
HO-D-Pro-(L-Phe)2-CO-(CH2)7-CO-(L-Phe)2-D-Pro-OH (3d): The
CCDC-803709 contains the supplementary crystallographic data
for 1b. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
synthetic procedure was the same as that of 3a, starting from 2d;
yield 97%; m.p. 98 °C. [α]2D0 = +5 (c = 1.1, MeOH). IR (1% in dry
1
KBr): ν = 3493, 3407, 3282, 1734, 1630 cm–1. H NMR (CD OD,
˜
3
400 MHz): δ = 0.97–1.48 [m, 10 H, CH2(CH2)5CH2], 1.60–1.88 (m,
8 H, 2ϫ NCH2CH2CH2CH), 2.05 [m, 4 H, CH2(CH2)5CH2], 2.82–
2.95 (m, 8 H, 4ϫ NHCH-CH2Ph), 3.36–3.53 (m, 2 H, 2ϫ
NCH2CH2CH2CH), 4.48–4.70 (m, 4 H, 4ϫ CHN-CH2Ph), 6.93–
7.30 (m, 20 H, 4ϫ Ph) ppm. 13C NMR (CD3OD, 100 MHz, mix-
ture of conformers): δ = 22.1, 24.0, 25.3, 28.4, 28.6, 28.6, 28.7, 30.7,
35.4, 36.7, 37.5, 38.0, 52.4, 52.6, 54.1, 59.0, 126.2, 126.3, 126.6,
127.9, 128.0, 128.1, 128.9, 128.9, 129.1, 136.5, 136.9, 137.1, 137.3,
170.0, 171.2, 171.7, 171.8173.6, 174.3, 174.5 ppm. C55H66N6O10
(971.1): calcd. C 68.02, H 6.85, N 8.65; found C 68.00, H 6.87, N
8.70.
Supporting Information (see footnote on the first page of this arti-
cle): 13C NMR spectra of compounds 1c and 1d, XRD patterns of
Boc-l-Phe-l-Phe-d-Pro-OBn (1d), and crystal data and structure
refinement for 1b.
Acknowledgments
C. T. is grateful to the Ministero dell’Università e della Ricerca
Scientifica (MIUR) (PRIN 2008), the Università di Bologna (funds
for selected topics) and to Fondazione del Monte di Bologna e di
Ravenna for financial support. G. F. thanks the Consorzio Inter-
Universitario di Ricerca della Chimica dei Metalli nei Sistemi Bio-
logici for financial support.
Conditions for Gel Formation: Compounds 2a–d or 3a–d (5 μmol)
and the solvent reported in Table 1 (500 μL) were placed in a test
tube (8 mm wide). The mixture was sonicated for 20 min until the
solid was totally dissolved and then it was left stand for 2 h for gel
formation.
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room temperature.
Eur. J. Org. Chem. 2011, 3082–3088
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: December 7, 2010
Published Online: April 20, 2011
3088
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3082–3088