Gemini amphiphilic pseudopeptides: Synthesis and preliminary study of their self-assembling properties

Article abstract of DOI:10.1016/j.tetlet.2010.07.146

The synthesis of a family of Gemini Amphiphilic Pseudopeptide (GAP) molecules by a reductive amination reaction has been carried out. The process is highly modular and can be efficiently performed with different pseudopeptidic diamines as well as aliphatic and aromatic aldehydes. Preliminary studies showed the abilities of the GAPs to self-assemble into supramolecular nanostructures.

Full text of DOI:10.1016/j.tetlet.2010.07.146

Tetrahedron Letters 51 (2010) 5861–5867
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Gemini amphiphilic pseudopeptides: synthesis and preliminary study
of their self-assembling properties
Jenifer Rubio a, Ignacio Alfonso b, , Miriam Bru a, M. Isabel Burguete a, Santiago V. Luis a,
⇑
⇑
a Departamento de Química Inorgánica y Orgánica, Universidad Jaume I, Avd. Sos Baynat s/n, Castellón, Spain
b Departamento de Química Biológica y Modelización Molecular, Instituto de Química Avanzada de Cataluña, CSIC, Jordi Girona 18-26, Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a family of Gemini Amphiphilic Pseudopeptide (GAP) molecules by a reductive amina-
tion reaction has been carried out. The process is highly modular and can be efficiently performed with
different pseudopeptidic diamines as well as aliphatic and aromatic aldehydes. Preliminary studies
showed the abilities of the GAPs to self-assemble into supramolecular nanostructures.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 9 June 2010
Revised 21 July 2010
Accepted 26 July 2010
Available online 6 September 2010
Dedicated to the memory of Professor J. M.
Concellón
Keywords:
Supramolecular chemistry
Amphiphiles
Self-assembly
Pseudopeptides
Nanostructures
The study of self-assembled organic nanostructures is an
emerging field in supramolecular chemistry and can be considered
as a bottom-up approach to nanoscience.1 Among all the possible
building blocks, those based on peptide-like structures are espe-
cially attractive due to their modular synthesis, good biocompati-
bility and large variety of possible non-covalent interactions.2
However, understanding and controlling the final nanostructures
is still a challenging work. Regarding that, some elegant examples
have been recently reported, using different stimuli to modulate
the size and shape of the supramolecular nanostructures.3 Follow-
ing our work in the field of supramolecular nanostructures based
on pseudopeptidic compounds,4 we envisioned to prepare simple
molecules able to display differential self-assembling properties
in different environments. Within this field, simple Gemini Amphi-
philic Pseudopeptide (GAP) molecules are good candidates due to
their structural properties, which can modulate their self-
assembling behaviour in different media. We designed a family
of C2 symmetrical gemini bis(amidoamines) (1) formed by two
amino acid units connected by an aliphatic flexible spacer and
bearing two hydrophobic tails (Fig. 1). With this design, the final
systems would have two hydrophobic tails, as well as a polar
pseudopeptidic core bearing H-bonding donors and acceptors. This
would allow the modulation of their self-assembling properties in
environments of different polarity.
Considering the basic design of the GAPs, we proposed a retro-
synthetic analysis using simple bis(amidoamines) 2 and 3 previ-
ously synthesized by our research group (Fig. 1).5 Our initial
approach was based on the alkylation of the precursor diamines
(2–3) with alkyl halides (R0CH2X) in the presence of a base.5,6 We
tried different reaction conditions, varying the leaving group, sol-
vent, base and temperature. In all the cases we obtained a compli-
cated mixture of compounds, showing polyalkylation of the amino
nitrogens. Moreover, the isolation of the desired products was
additionally complicated by the formation of foamy crudes of reac-
tion during the work-up procedures. Considering these results we
envisioned to use a reductive amination reaction (Scheme 1) as a
SPACER
O
O
O
O
H
H
R'
N
N
R'
H2N
NH2
N
N
N
N
n
n
H
H
H
H
R
R
R
R
1
TAIL
TAIL
2a-c (R=iPr)
3a-c (R=Bn)
a, b, c (n=2, 3, 4)
⇑
Corresponding authors. Tel.: +34 934006100x1381; fax: +34 932045904 (I.A.);
tel.: +34 964728239; fax: +34 964728214 (S.V.L.).
AMINO ACIDS
E-mail addresses: ignacio.alfonso@iqac.csic.es (I. Alfonso), luiss@qio.uji.es (S.V.
Luis).
Figure 1. Design of the GAP molecules.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.146

5862
J. Rubio et al. / Tetrahedron Letters 51 (2010) 5861–5867
Table 2
O
O
Self-assembled nanostructures observed in the SEM micrographs of samples grown
from different solvents
H2N
NH2
+
R'CHO
N
N
n
H
H
R
R
Entry
Compound
CHCl3 (width in
lm)
MeOH (width in lm)
4a (R'=C6H4OC10H21
4b (R'=C7H15
)
2a-c (R=iPr)
3a-c (R=Bn)
a, b, c (n=2, 3, 4)
)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
‘Worm’ fibrils (ꢁ0.2)
Not observed
Not observed
Not observed
Not observed
Not observed
Tubes (ꢁ0.2–0.4)
Tapes (ꢁ10)
Not homogeneousa
Not observed
Fibres (ꢁ0.10–0.2)
1) solvent
2) reducing agent
Not observed
‘Worm’ fibrils (ꢁ0.1)
Not observed
Fibres (ꢁ1–2)
O
H
O
H
Tapes (ꢁ5)
R'
R'
N
N
R'
Not observed
Fibres (ꢁ1–3)
N
H
N
H
n
a
R
R
The SEM micrographs showed the formation of some fibres, although they do
1a-i
not appear uniformly on the whole surface.
+
O
O
H
N
NH2
N
H
N
H
n
selective method for the monoalkylation of the two primary amine
nitrogens.6,7 First, we used bis(amidoamine) 2a and aldehyde 4a as
a model system (Table 1, entries 1–5). Surprisingly, the conven-
tional reaction conditions for this process (formation of the imine
R
R
5a-i
Scheme 1.
Table 1
Syntheses of GAPs by reductive amination reaction
Entry
Diamine (n, R)
Aldehyde (R0)
Solvent
Reducing agent
Yield 1a (%)
Yield 5a (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
2a (2, iPr)
2a (2, iPr)
2a (2, iPr)
2a (2, iPr)
2a (2, iPr)
2b (3, iPr)
2c (4, iPr)
3a (2, Bn)
3b (3, Bn)
3c (4, Bn)
2a (2, iPr)
2b (3, iPr)
2c (4, iPr)
4a (C6H4OC10H21
4a (C6H4OC10H21
4a (C6H4OC10H21
4a (C6H4OC10H21
4a (C6H4OC10H21
4a (C6H4OC10H21
4a (C6H4OC10H21
4a (C6H4OC10H21
4a (C6H4OC10H21
4a (C6H4OC10H21
)
MeOH
CH2Cl2
CH3CN
CH3CN
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
NaBH4
NaBH4
NaBH4
BH3ꢀPy
BH3ꢀPy
BH3ꢀPy
BH3ꢀPy
BH3ꢀPy
BH3ꢀPy
BH3ꢀPy
BH3ꢀPy
BH3ꢀPy
BH3ꢀPy
8 (1a)
17 (5a)
33 (5a)
33 (5a)
12 (5a)
5 (5a)
)
)
)
)
)
)
)
)
)
22 (1a)
45 (1a)
27 (1a)
63 (1a)
68 (1b)
66 (1c)
66 (1d)
61 (1e)
74 (1f)
26 (1g)
21 (1h)
32 (1i)
15 (5b)
19 (5c)
21 (5d)
19 (5e)
23 (5f)
b
4b (C7H15
4b (C7H15
4b (C7H15
)
)
)
—
—
—
b
b
a
Isolated yields.
Not observed.
b
Figure 2. SEM micrographs of (A and B) 1g and (C and D) 1h compounds grown from chloroform solutions. Two different magnifications are shown with the corresponding
scale bars for every picture.

J. Rubio et al. / Tetrahedron Letters 51 (2010) 5861–5867
5863
in methanol and subsequent reduction with NaBH4) rendered poor
yield, and a mixture of the intended dialkylated (1) and the unde-
sired monoalkylated (5) products (Table 1, entry 1). The use of less
polar (entry 2) or non-protic polar solvents (entry 3) slightly in-
creased the overall yield but still with low selectivity towards
the dialkylated product. The observed low yields were not due to
the low solubility of NaBH4 in non-protic solvents as confirmed
by the results obtained with borane pyridine complex (BH3ꢀPy)
as the reducing agent (entry 4).8
Since the reaction comprises a one-pot two-steps process, we
decided to study the formation of the imine intermediate in differ-
ent solvents by NMR. The 1H NMR spectra (500 MHz, 303 K) of 2a
with a slight excess of 4a after equilibration (24 h) rendered a pro-
portion of the corresponding mono- and diimine of 50:50 (in
CD3OD) or 20:80 (in CD3CN). However, when performing the same
condensation in a less polar solvent like chloroform, the mixture
showed a quantitative conversion to the diimine. Thus, the forma-
tion of the desired intermediate seems to be favoured by non-polar
solvents. We decided to use these conditions for the reaction, by
shifting to BH3ꢀPy as reducing agent, due to the very poor solubility
of NaBH4 in CHCl3. Satisfyingly, using this combination of solvent
and reductant (entry 5), we obtained very good yield and selectiv-
ity, after the work-up and the chromatographic purification pro-
cesses.9 The reaction can be carried out from bis(amidoamines)
having spacers with different lengths (entries 6 and 7), and both
aliphatic (entries 5–7) and aromatic side chains (entries 8–10) with
good yields and reasonable selectivity. However, when doing the
reaction with aliphatic aldehydes (entries 11–13) the yields were
lower. Since we did not observe starting materials or the corre-
sponding monoalkylated derivatives, we ascribed the lower yields
to problems in the purification process, because compounds 1g–i
showed a high trend to self-aggregate (see below) and thus,
Figure 3. SEM micrographs of (A and B) 1g, (C and D) 1h and (E and F) 1i compounds grown from methanol solutions. Two different magnifications are shown with the
corresponding scale bars for every picture.

5864
J. Rubio et al. / Tetrahedron Letters 51 (2010) 5861–5867
lower solubility in organic solvents (both polar and non-polar).
Despite the moderate isolated yields observed with these com-
pounds, the complete selectivity towards the dialkylated products
made the reaction a useful synthetic applicability.
atives are more efficient that the Phe derivatives, which can be ex-
plained by the shielding effect of intermolecular interactions with
aromatic side chains, previously observed for structurally related
compounds.10 With regards to the length of the spacer, no obvious
trends were observed.
As previously commented, the GAPs bearing exclusive aliphatic
tails showed a higher tendency to aggregate (entries 7–9). Ultra-
structure analysis from chloroform solutions showed that 1g self-
assembled in hollow tubes (Fig. 2a and b) while 1h aggregated in
large straight tapes (Fig. 2c and d). Since 1g and 1h only differ in
one methylene of the aliphatic spacer, the observed differences
can be ascribed to distinct relative disposition of the H-bonding
groups in both compounds, which could dictate the geometry of
the established intermolecular interactions.
Preliminary study of the self-assembling behaviour of the syn-
thesized GAPs has also been carried out. The morphology of the ob-
tained self-assembled nanostructures was initially studied by
scanning electron microscopy (SEM). Since the compounds are
amphiphilic, we assayed different environments from non-polar
(chloroform) to polar (MeOH) medium. Samples for SEM were pre-
pared by dissolving the corresponding compound in a given sol-
vent (ꢁ1–3 mg/mL), placing the solution directly onto the sample
holder and slowly evaporating at room temperature. A summary
of the results obtained for the compounds 1a–i is shown in Table 2.
Different nanostructures were observed, such as worm-like fibrils
(entries 1 and 5), hollow tubes (entry 7), fibres (entries 3, 7 and
9) or tapes (entry 8). As a general trend, the self-assembling is
more effective in MeOH than in chloroform. Besides, the Val deriv-
Studies performed from a polar medium (MeOH) with the same
compounds (Fig. 3) showed the formation of fibres for 1g and 1i,
while tapes for 1h. These data suggest that, in the case of the GAPs
with exclusive aliphatic tails, the self-aggregation process is
Figure 4. SEM micrographs of 1c grown from (A) chloroform and (B and C) methanol and (D) 2:1 methanol/water solutions. (E and F) Unstained TEM micrographs of samples
like in (B). Scale bars are shown for every picture.

J. Rubio et al. / Tetrahedron Letters 51 (2010) 5861–5867
5865
efficient in different environments. Besides, the shape of the nano-
structures suggested the establishment of the intermolecular inter-
actions along a preferred direction.
relatively rigid conformation in chloroform. However, when
acquiring the 1H NMR spectrum in methanol, the signals corre-
sponding to the protons from the pseudopeptidic moiety (a, b, c
Interestingly, the Val derivatives with the butylenic spacer
showed differential self-aggregation abilities in solvents of differ-
ent polarity (see entries 3 and 9 in Table 2). Thus, for instance,
the SEM study of samples of 1c grown from chloroform showed
the lack of self-assembled nanostructures (Fig. 4a), while the same
compound from methanol showed nanometre-sized fibres
(Fig. 4b). The width of the fibres were in the range of 100–
200 nm and they were grouped in bunches of several micrometres
(Fig. 4c). The morphology and size of the fibres of 1c did not sub-
stantially change by using 2:1 methanol/water as the solvent
(Fig. 4d), although we observed a more efficient and homogenous
coverage of the surface. These results suggest that the hydrophobic
interactions between the tails in 1c were playing an important role
in the self-assembling process. Additionally, TEM analysis of un-
stained samples (Fig. 4e–f) confirmed the formation of fibrous
nanostructures. The different behaviour of some of these GAPs in
solvents of different polarity is especially interesting for the future
preparation of a second generation of self-assembling pseudopep-
tides able to respond to external stimuli.
and A) moved up-field, while those from the hydrophobic tails
did not significantly change. More importantly, the methylenes
in A position lost their chemical non-equivalence, appearing as a
broad triplet. These observations were consistent with the break-
ing of the intramolecularly H-bonded pseudopeptidic structure,
leading to an unfolded conformation in solution. Thus, in non-polar
medium, the molecule tends to fold into a turn/hairpin conforma-
tion while in MeOH, the interactions with the solvent would pro-
duce an unfolding of the pseudopeptidic moiety to an extended
flexible conformation. With the aim of connecting this soluble
structure with the self-assembling process, the formation of the
nano-fibres of 1c was studied by ATR FT-IR spectroscopy. Thus,
we followed the evolution of representative bands during the con-
centration of the sample by slow evaporation of the solvent di-
rectly on the ATR sample holder (Fig. 6). Accordingly, we
monitored the amide A (N–H stretching at 3100–3500 cmꢂ1), the
amide I (C@O stretching at 1600–1700 cmꢂ1) and the aliphatic re-
gion (CH stretching at 2800–3000 cmꢂ1). In methanolic solution,
all the bands were relatively broad, suggesting the presence of a
mixture of different conformations in solution. The slow evapora-
tion of the solvent produced a gradual sharpening of the bands,
which implies a conformational ordering of the molecules. The fi-
nal values in the dried fibres were 3300 cmꢂ1 (amide A),
In order to get deeper structural information of 1c in solution,
we studied its 1H NMR spectra both in polar and in non-polar sol-
vent, below the critical concentration for the aggregation (Fig. 5).
The chemical shift (>7.00 ppm) and temperature dependence
(
D
dNH/
gested the presence of partially H-bonded amide groups. The high
chemical shift values of protons at and b positions are also in line
with this proposal. Besides, the methylene vicinal to the amide
D
T = ꢂ3.5 ppb/K) of amide NH protons signal in CDCl3 sug-
1636 cmꢂ1 (amide I), 2921 cmꢂ1 mass C–H) and 2853 cmꢂ1
( (msym
C–H), showing the formation of strongly H-bound b-stacks11 of
the pseudopeptidic core and a crystal-liquid phase12 for the ali-
phatic tails. These spectroscopic evidences highlighted the impor-
tance of both polar (H-bonding) and non-polar interactions in the
self-assembling process.
a
group (A in Fig. 5) showed chemical non-equivalence
[Dd
0
(HA/A ) = 0.052 ppm at 294 K] which was decreased upon heating
0
[
D
d (HA/A ) = 0.038 ppm at 323 K]. All these observations supported
In summary, herein we report on the synthesis of new GAPs by
a reductive amination reaction. Preliminary studies suggest that
that the pseudopeptidic moiety is intramolecularly H-bonded in a
5
7
9
11
13
3
O
2
O
4
6
8
10
12
γ
H
N
A
α
1
N
H
B
2
β
13
γ
γ
7-12
4
3
B
A
α
5
1
1’
6
β
7-12
13
γ
4
2
3
B
5
1 1’
α
6
NH
A
β
7.5
7.1
4.0
3.6
3.2
2.8
1.8
1.4
1.0
Figure 5. 1H NMR spectra of 1c (500 MHz, 303 K) in CDCl3 (lower trace) and CD3OD (upper trace).

5866
J. Rubio et al. / Tetrahedron Letters 51 (2010) 5861–5867
Figure 6. Evolution (1–3) of the ATR FT-IR spectra of 1c form MeOH solutions to dried fibres obtained upon slow evaporation. Selected bands are shown for (A) amide A, (B)
amide I and (C) C–H stretching regions.
the formation of self-assembled nanostructures can be accom-
plished by a delicate tune of the polar and non-polar intermolecu-
lar interactions, in some cases allowing the control of the process
by changing the polarity of the medium. Besides, we have found
that some structural features are needed for the modulation of
the self-assembling properties. The Val derivative with a relatively
flexible spacer and bearing two hydrophobic tails does not self-
assemble in non-polar solvent but self-assemble in fibres from a
polar medium. This fact pointed these systems as good candidates
for further development of stimulus responsive self-assembling
nanostructures. Studies on the effect of these and other structural
variables are undergoing in our laboratories.
References and notes
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Acknowledgements
This work was supported by the Spanish Ministry of Science
and Innovation (CTQ2009-14366-C02). J.R. thanks MICINN for per-
sonal financial support (FPU fellowship). We also thank Bogdan
Duma for his helpful assistance.
Supplementary data
5. Becerril, J.; Bolte, M.; Burguete, M. I.; Galindo, F.; García-España, E.; Luis, S. V.;
Miravet, J. F. J. Am. Chem. Soc. 2003, 125, 6677–6686.
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Rubio, J. J. Am. Chem. Soc. 2008, 130, 6137–6144.
Supplementary data (experimental and synthetic procedures,
full spectroscopic characterization of 1a–i and 5a–f, as well as
additional SEM micrographs) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2010.07.146.

J. Rubio et al. / Tetrahedron Letters 51 (2010) 5861–5867
5867
8. Campbell, F.; Kilner, C. A.; Wilson, A. J. Tetrahedron Lett. 2010, 51, 1361–1362.
9. General procedure for the reductive amination reaction, exemplified for the
preparation of 1a: Pseudopeptidic bis(amidoamine) 2a (96.5 mg, 0.374 mmol)
was dissolved in 4 mL of CHCl3 and the solution was placed inside a flask under
2H); 13C-NMR (125 MHz, CDCl3) d 14.3, 18.0, 19.8, 22.9, 26.3, 29.5, 29.8, 29.9,
31.5, 32.1, 39.6, 53.1, 68.0, 68.3, 114.8, 129.5, 131.7, 158.7, 174.7; HRMS (ESI-
TOF)+ calcd for C46H78N4O4 (M + H)+: 751.6101; found 751.6102. Anal. calcd for
C
46H78N4O4ꢀH2O: C, 71.93; H, 11.17; N, 6.70. Found: C, 71.83; H, 10.98; N, 6.90.
nitrogen atmosphere. 4-Decyloxybenzaldehyde 4a (213.0
lL, 202.3 mg,
Compound 5a: 5% yield; mp 78–82 °C; ½a D25
ꢃ
ꢂ2.5 (c 0.01, CHCl3); IR (ATR) 3299,
0.748 mmol) was dissolved in 3 mL of CHCl3, this solution was added over
the solution of 2a and then, 1 mL of CHCl3 were added until a final volume of
8 mL (0.05 M final concentration each). The mixture was stirred overnight, then
2958, 2852, 1631, 1553, 1513, 1467, 1244 cmꢂ1 1H NMR (500 MHz, CDCl3) d
;
0.81 (d, 6H, J = 6.7 Hz), 0.87 (m, 3H), 0.95 (d, 6H, J = 6.0 Hz), 1.30 (m, 12H), 1.43
(m, 2H), 1.65 (m, 2H), 1.76 (td, 1H, J = 6.6, 13.0 Hz), 2.08 (m, 1H), 2.25 (m, 1H),
2.96 (s, 1H), 3.19 (s, 1H), 3.40 (t, 4H, J = 12.5 Hz), 3.55 (d, 1H, J = 12.8 Hz), 3.69
(d, 1H, J = 11.4 Hz), 3.93 (t, 2H, J = 6.5 Hz), 6.84 (m, 2H), 7.19 (m, 2H), 7.61 (s,
2H), 7.69 (s, 2H); 13C NMR (75 MHz, CDCl3) d 14.3, 16.4, 18.1, 19.7, 22.9, 26.3,
29.5, 29.6, 29.8, 31.0, 31.4, 32.1, 39.3, 39.8, 52.9, 60.4, 67.9, 68.3, 114.8, 129.6,
131.4, 158.8, 174.7, 175.1; HRMS (ESI-TOF)+ calcd for C29H52N4O3 (M+H)+:
505.4118; found 505.4114. Anal. calcd for C29H52N4O3: C, 69.01; H, 10.38; N,
11.10. Found: C, 68.85; H, 10.70; N, 11.43.
a large excess of PyꢀBH3 complex, 95% (395.6
lL, 363.9 mg, 4.01 mmol) was
carefully added at 35 °C, and the mixture was allowed to react for 24 h before
being hydrolyzed (concd HCl, to acidity) and evaporated to dryness. The
residue obtained was dissolved in water, basified with 1 N NaOH, and extracted
with CHCl3. The combined organic layers were dried (MgSO4) and evaporated
in vacuum. The product was purified by flash chromatography on silica gel
using CH2Cl2 as eluent, increasing slowly the polarity with MeOH and several
drops of aqueous ammonia yielding 1a (firstly eluted) and 5a (secondly eluted).
10. (a) Alfonso, I.; Bolte, M.; Bru, M.; Burguete, M. I.; Luis, S. V.; Vicent, C. Org.
Biomol. Chem. 2010, 8, 1329–1339; (b) Alfonso, I.; Burguete, M. I.; Galindo, F.;
Luis, S. V.; Vigara, L. J. Org. Chem. 2007, 72, 7947–7956; (c) Alfonso, I.; Burguete,
M. I.; Luis, S. V. J. Org. Chem. 2006, 71, 2242–2250.
11. Kim, S. H.; Hartgerink, D.; Ghadiri, M. R. J. Am. Chem. Soc. 1998, 120, 4417–4424.
12. Hull, M. C.; Cambrea, L. R.; Hovis, J. S. Anal. Chem. 2005, 77, 6096–6099.
Compound 1a: 63% yield; mp 95–104 °C; ½a D25
ꢂ27.0 (c 0.01, CHCl3); IR (ATR)
ꢃ
3303, 2921, 2851, 1641, 1555, 1513 cmꢂ1 1H NMR (500 MHz, CDCl3) d 0.79 (m,
;
18H), 0.86 (m, 24H), 1.23 (m, 4H), 1.38 (s, 2H), 1.48 (m, 4H), 1.7 (m, 2H), 2.01
(m, 2H), 2.87 (m, 4H), 3.35 (dd, 2H, J = 5.2, 8.1 Hz), 3.45 (dd, 2H, J = 5.4, 8.2 Hz),
3.61 (t, 4H, J = 6.6 Hz), 6.77 (d, 4H, J = 6.7 Hz), 7.10 (d, 4H, J = 7.1 Hz), 7.53 (s,