Novel peptidomimetic macrocycles showing exciplex fluorescence

Article abstract of DOI:10.1016/j.tet.2007.06.087

The synthesis of five new chiral macrocyclic peptidomimetic naphthalenophanes, together with two open-chain derivatives, is described. The cyclization step is accomplished in good yields without the use of high dilution or template techniques. The new compounds have been photophysically studied by means of steady-state fluorescence spectroscopy. It has been found that the smaller the ring size, the higher the emission quantum yield from the excited charge-transfer state (CTS, exciplex) and the lower the fluorescence from the locally excited state (LES). The occurrence of exciplex fluorescence is noteworthy as the electron-donating groups are secondary amine moieties, which do not normally form emissive exciplexes.

Full text of DOI:10.1016/j.tet.2007.06.087

Tetrahedron 63 (2007) 9493–9501
Novel peptidomimetic macrocycles showing exciplex fluorescence
*
M. Isabel Burguete, Francisco Galindo, M. Angeles Izquierdo,
*
Santiago V. Luis and Laura Vigara
Departamento de Quꢀımica Inorgaꢀnica y Orgaꢀnica, Unidad Asociada de Materiales Orgaꢀnicos Avanzados (UAMOA),
Universitat Jaume I—CSIC, Avda. Sos Baynat, s/n, E-12071 Castelloꢀn, Spain
Received 3 April 2007; revised 22 June 2007; accepted 26 June 2007
Available online 4 July 2007
Abstract—The synthesis of five new chiral macrocyclic peptidomimetic naphthalenophanes, together with two open-chain derivatives, is
described. The cyclization step is accomplished in good yields without the use of high dilution or template techniques. The new compounds
have been photophysically studied by means of steady-state fluorescence spectroscopy. It has been found that the smaller the ring size, the
higher the emission quantum yield from the excited charge-transfer state (CTS, exciplex) and the lower the fluorescence from the locally
excited state (LES). The occurrence of exciplex fluorescence is noteworthy as the electron-donating groups are secondary amine moieties,
which do not normally form emissive exciplexes.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
of the parent naphthyl subunit, due to the formation, upon
excitation, of an emissive intramolecular excited-state
charge-transfer complex (exciplex) between a secondary
amine (electron donor) and the aromatic moiety (electron
acceptor).15 The fluorescence quantum yield of such an
emissive exciplex was determined to be 0.038 in dichloro-
methane, which is surprisingly high for an arene-secondary
amine exciplex. Normally, primary and secondary amines do
not form fluorescent exciplexes at room temperature but
deactivate through the proton-transfer pathway.16 It was
hypothesized that this anomalous value was due to the rigid-
ity of the macrocycle, which provided the special conditions
for the occurrence of such phenomenon.15 As a consequence
of this previous report a series of questions are raised: (a) Is
the macrocycle necessary for the formation of an emissive
exciplex?; (b) Given a macrocycle with N members, will
the Nꢀ1 be more fluorescent than the N, and the N+1 less
emissive?; (c) To what extent are the lateral chains pending
from the ring important?, are they neutral elements not
involved in the formation–decay of the exciplex or play
a role in the fine tuning of the energetics of ground and
excited states? For the formation of an emissive exciplex a
delicate balance between numerous factors must be attained,
many of which are based on speculation, as is recognized in
the literature.17–21 In order to answer the above questions,
while minimizing the speculative aspects, measurements
of molecules similar to but slightly modified versions of
1b were required.
Macrocyclic molecules have attracted great attention with
consideration of their interesting properties as ligands able
to form complexes with cations, anions and neutral mole-
cules.1 They have found applications in diverse areas like
medicinal,2 analytical3 or supramolecular chemistry.4
Among macrocycles, those containing amines or amides
(poly-aza or poly-amido macrocycles, respectively) must
be synthesized according to specific procedures that are
different to those required for the poly-oxa macrocyclic
compounds.5 Since the initial reports on macrocyclic poly-
amines by Stetter and Roos6 a great number of strategies
have been developed for the synthesis of this class of com-
pounds, including high dilution conditions, templation and
use of conformationally preorganized macrocycle precur-
sors.5,7,8 Recently we have developed a new methodology
for the synthesis of poly-(amino-amido) macrocycles.9
This methodology has been successfully employed to syn-
thesize families of chiral compounds for: molecular probes
for cellular studies;10 minimalistic peptidomimetic organo-
gelators;11 a fluorescent sensor for amino acid derivatives;12
selective receptors for Ag(I);13 and molecular rotors.14
Among the molecules synthesized using this protocol a fluo-
rescent macrocycle containing a 1,4-dimethylnaphthalene
fluorophore, two L-valine subunits, and a three-methylene
spacer (1b in Chart 1) was described.11b,12,15 The emission
spectrum of 1b in dichloromethane was remarkably red-
shifted (ca. 50 nm) with respect to the expected fluorescence
This work describes the synthesis and chemical character-
ization of seven new chiral compounds (five macrocyclic,
1a, 1c, 2a–c, and two open-chain derivatives, 3 and 4; see
* Corresponding authors. Tel.: +34 964 72 8239; fax: +34 964 72 8214;
e-mail addresses: francisco.galindo@uji.es; luiss@uji.es
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.087

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M. I. Burguete et al. / Tetrahedron 63 (2007) 9493–9501
Chart 1.
Chart 1) having a naphthyl chromophore and one or two
amino-amide moieties (derived from L-valine or from
L-phenylalanine). The macrocyclic compounds have been
obtained using the previously mentioned methodology9 in
moderate-good yields. The fluorescence quantum yields in
dichloromethane have been determined and discussed.
With this synthetic/photochemical study a double objective
was attained: on the one hand the family of photoactive
macrocycles developed in our group8,10,11b,12,15 has been
expanded with five new members and, on the other hand, it
provides some insight into the relationships between structure
and the photophysical properties of poly-azacyclophanes.22
(5, from valine or phenylalanine) were transformed into the
activated N-hydroxysuccinimide esters (6) and then coupled
with the corresponding 1,n-alkanediamine (7a–c). After
removal of the protecting groups from 8a–c and 9a–c, the
open-chain peptidomimetic compounds 10a–c and 11a–c
were obtained in an overall 60–80% yield.9 The macrocyc-
lization step was accomplished by reacting 10a–c and
11a–c with 1,4-bis(bromomethyl)naphthalene (12) in anhy-
drous acetonitrile, using potassium carbonate as base, and
tetrabutylammonium bromide as phase transfer catalyst.
The crude reaction products were purified by column chro-
matography to afford the pure macrocycles. The open-chain
derivatives were synthesized analogously to 1a–c and 2a–c
by using n-propylamine (13) instead of a 1,n-dialkylamine
(for 3 and 4) and 1-(chloromethyl)naphthalene (16) instead
of 1,4-bis(bromomethyl)naphthalene (for 4) (Scheme 2).
2. Results and discussion
2.1. Synthesis
The yield for the cyclization step of 1a–c and 2a–c is in the
range 20–41%, which can be considered as moderately-
good. The difference with the previously reported para and
meta-phenylene derivatives (45–69% cyclization yield) could
The synthesis of macrocycles 1a–c and 2a–c is outlined in
Scheme 1. Product 1b has been previously reported.11b,12,15
The commercially available N-Cbz protected L-amino acids
Scheme 1. Synthesis of 1a–c and 2a–c. Conditions: (i) DCC, N-hydroxysuccinimide, THF, 0–5 ꢁC; (ii) DME, 40–50 ꢁC; (iii) HBr/AcOH, rt; and (iv) CH3CN,
K2CO3 reflux.

M. I. Burguete et al. / Tetrahedron 63 (2007) 9493–9501
9495
Scheme 2. Synthesis of 3 and 4. Conditions: (i) THF, reflux; (ii) HBr/AcOH, rt; and (iii) CH3CN, reflux.
be related to the different volumes of the aromatic spacer
(naphthyl vs phenyl).23 If compared with other non-templated
macrocyclization reactions yielding cyclic amino-amides
the overall synthesis of 1a–c and 2a–c is advantageous since
very high dilution conditions need not be employed (typi-
cally 10 mM was used for these reactions whereas for other
systems concentrations ofw1 mM or lower are normally re-
ported24). In fact, macrocycles are obtained as white solids at
a quasi-gram scale (typically 300–700 mg was synthesized
for every compound). These good yields can be explained,
as previously analyzed in detail,9 considering intramolecular
H-bonds and solvophobic effects inducing a favorable
(folded) conformation of the reactants in acetonitrile.
will provide more information of the upper excited states.
More remarkable is the absence of any charge-transfer
(CT) absorption band at long wavelengths in any of the spec-
tra, since all these (with the exception of 4) match the
absorption of 1,4-dimethylnaphthalene (not shown). This
would indicate that population of the state responsible for
the exciplex emission15 cannot be done directly but only
by means of excitation of the upper singlet states. Regarding
the macrocycles derived from L-phenylalanine (2a–c), simi-
lar spectra were obtained from these compounds (max. at
289–290 nm) (Fig. 2), again with no significant CT absorp-
tion band. The different patterns observed in valine deriva-
tives (gradual shifting) versus phenylalanine derivatives
(almost identical position of the maxima) suggest a differing
influence of the lateral chain in the conformational stability
of both series of compounds.
2.2. Photophysical studies
The electronic absorption spectra of naphthalenophanes
(1a–c) and open-chain derivatives 3 and 4 in dichlorome-
thane are depicted in Figure 1. As it can be seen, the smallest
macrocycle 1a displays a broader and red-shifted (291 nm)
absorption profile as compared to the open-chain derivative
3 (288 nm); whereas the largest macrocycle 1c matches the
absorption of 3 (288 nm). The macrocycle 1b shows an ab-
sorption, which is intermediate (290 nm) between 1a and 1c.
The absorption of 4 is blue-shifted, presumably due to the
different substitution in the aromatic chromophore. The dif-
ferences observed between these macrocycles are indicative
of the influence of the ring size on the electronic properties
of their ground states, although fluorescence spectroscopy
The corrected fluorescence spectra of 1a–c, 3, and 4 in
dichloromethane, upon excitation at 300 nm, are shown in
Figure 3. Although the absorption spectra of these com-
pounds did not afford substantial information (Fig. 1), inter-
pretation of the emission spectra gives some clues to address
the questions posed earlier. In first instance, fluorescence
emission from 1a (391 nm) and 1b (389 nm) are almost
identical and can be attributed to an excited charge-transfer
state (CTS, exciplex) as previously noted.15 Only a minimal
difference can be seen: the profile of 1a emission is practi-
cally a perfect Gaussian curve whereas that of 1b displays
some irregularity in the 320–350 nm region. In that
Figure 1. Absorption spectra of compounds 1a–c, 3, and 4 in dichloro-
methane (concentration: 1.3ꢂ10ꢀ4 M).
Figure 2. Absorption spectra of compounds 2a–c in dichloromethane (con-
centration: 1.3ꢂ10ꢀ4 M).

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M. I. Burguete et al. / Tetrahedron 63 (2007) 9493–9501
Figure 3. Corrected fluorescence spectra of compounds 1a–c, 3, and 4 in
dichloromethane.
Figure 4. Corrected fluorescence spectra of compounds 2a–c in dichloro-
methane.
wavelength region, it was shown that the emission arises
from the locally excited state (LES), or S1, of the 1,4-di-
methylnaphthalene moiety. This residual fluorescence from
LES (<0.001)15 in 1b is absent in 1a. When the macrocycle
is one unit larger (1c) the fluorescence from the CTS falls to
one half of 1a or 1b and an appreciable emission from the
LES is observed. Comparing to the non-cyclic derivative
3, which could be formally considered as a macrocycle
with n¼N, the same tendency is followed, i.e., a decrease
of the CTS emission and an increase of the LES fluores-
cence. Finally, the monoamine 4 only displays very weak
emission from the LES. The absence of CTS emission
from 4 is in accordance with the paradigm about exciplexes
in arene-secondary amine systems, i.e., fluorescence from
LES of arene-secondary amine systems can be partially
quenched but does not lead to any exciplex emission at
room temperature. However, spectra of 1a–c and 3 suggest
a redefinition of such a statement. These results confirm
experimentally that emissive exciplexes from secondary
amines are not impossible at room temperature, and, most
importantly, they can be finely tuned by adjusting the ring
size of the macrocycle. Even non-cyclic compounds like 3,
while having two electron-donor groups, can display exci-
plex emission.
Comparing both series of peptidomimetic cyclophanes, 1a–c
vs 2a–c, it can be seen how the differences depend on the
ring size. For the smallest cycles, 1a and 2a, there is a reason-
able coincidence of shape and position of CTS fluorescence
spectra (Fig. 5), with 2a slightly blue-shifted compared to
1a. Additionally, the LES emission, absent in 1a, is incipi-
ently emerging in 2a. This small difference is amplified in
the medium-sized molecules, becoming apparent for the
comparison between 1b and 2b (Fig. 6), and more clearly
for 1c and 2c (Fig. 7). Thus, not only the ring size is impor-
tant to account for the emission of the CTS but also the ap-
pended chains. A question that remains to be elucidated is
the role of the intramolecular H-bonding pattern (between
amines and/or amides) in solution, as the strong influence
of this pattern on the stability of different conformers for
analogous macrocycles has been previously demon-
strated.14,26 However, this analysis would only give a partial
view of the picture (H-bonding of the amine lone-pairs, geo-
metrical orientation, and orbital overlapping, for instance)
The group of naphthalenophanes derived from L-phenylala-
nine shows a similar tendency in qualitative terms: the
smaller the ring size, the higher the fluorescence intensity
from the CTS, as can be seen in Figure 4. Noteworthy,
both exciplex emission and emission from the LES are
weak in the case of the largest macrocycle 2c. This would
mean that, on the one hand, the emissive CTS is either not
forming as efficiently as for 2a or its radiationless decay is
more efficient, and, on the other hand, the photoinduced
electron-transfer (PET) mechanism is operating to quench
the emission from the LES,25 probably to yield directly the
solvent separated radical anion (naphthyl moiety) and radi-
cal cation (amine) pair. In this case solvation of the radical
ions would be limited by the covalent link between donor
and acceptor, which would make back-electron transfer
(BET) very fast.
Figure 5. Corrected fluorescence spectra of compounds 1a and 2a in
dichloromethane.

M. I. Burguete et al. / Tetrahedron 63 (2007) 9493–9501
9497
In order to know the relative contributions of LES and CTS
to the total emission, deconvolution of curves into pure LES
and pure CTS was done. In this way, the percentage of pho-
tons coming from both emitting states can be determined
(Table 1). On the other hand, since the fluorescence quantum
yield of 1b has been previously measured and since all the
emissions were taken in isoabsorptive conditions, the total
emission quantum yields (LES+CTS) were determined by
calculating the areas under the curves and comparing to
that of the reference (1b) (Table 1). Hence, with %LES
and fem (total) the emission quantum yield from such a state
(fem (LES)), and analogously from the charge-transfer state
(fem (CTS)) can be calculated.
The higher values of fem (CTS) are those corresponding to
macrocycles 1a (0.037), 1b (0.038), and 2a (0.031), decreas-
ing considerably for medium and large macrocycles (0.019–
0.009). For the open-chain 3 the value of 0.005 (29% of the
total fluorescence), although low, points to the possibility
of the following occurring: (a) temporary intramolecular
H-bonding between both amide groups leading to a stable
conformation (pseudo-cyclic) favorable for the deactivation
of the CTS via fluorescence; or (b) triplex emission, which
would require both amines to be concurrently oriented to-
ward the aromatic ring, as described for some anthracenic
systems.27 A plot of fem (CTS) and fem (total) vs size of the
macrocyclic compound (N) is shown in Figure 8. As it can be
seen, decreasing the size of the macrocycle increases the
fluorescence (total and from the exciplex) butw0.040 seems
to be a limit, at least for these families of cyclophanes. Fi-
nally, the emission from LES is always much less important
than that expected from an unquenched naphthalene. In fact,
when 1b is fully protonated with HCl, and hence is PET
hampered, emission from LES reaches 0.130, as shown
previously.15
Figure 6. Corrected fluorescence spectra of compounds 1b and 2b in
dichloromethane.
3. Conclusion
The aim of this work was the description of the synthesis of
some new peptidomimetic naphthalenophanes in order to:
(a) add new chiral cyclophanes to the known pool of photo-
active macrocycles, which could be used in the future as chi-
ral receptors for species of biological interest (amino acids),
as reported for 1b;12 and (b) to confirm that the anomalous
emission of 1b is not a unique case. To fully understand
the ultimate reason for the differences between macrocycles,
the results presented here will be complemented with future
additional photophysical measurements (time resolved
Figure 7. Corrected fluorescence spectra of compounds 1c and 2c in
dichloromethane.
since it would not provide information about deactivation
pathways of the excited states (for instance intersystem
crossing (ISC) or back-electron transfer (BET) from the
CTS).
Table 1. Photophysical parameters of compounds 1a–c, 2a–c, 3, and 4: maxima absorption and emission wavelength for the LES and CTS in dichloromethane;
total and partial (LES or CTS) fluorescence quantum yields (excitation at 300 nm)
Entry
Compound
labs/nm
lem
(LES)/nm
lem
(CTS)/nm
% LES
% CTS
fem
(total)
fem
(LES)
fem
(CTS)
1
2
3
4
5
6
7
8
1a
1b
1c
2a
2b
2c
3
291
290
288
290
290
289
288
282
—
—
342
—
341
341
341
337
391
389
379
383
0
<2
47
18
52
66
71
100
100
>98
53
82
48
34
29
0
0.037
0.038
0.023
0.038
0.039
0.027
0.018
0.009
—
0.037
0.038
0.012
0.031
0.019
0.009
0.005
—
<0.001
0.011
0.007
0.020
0.018
0.013
0.009
382
380 (sh)
380 (sh)
—
4

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M. I. Burguete et al. / Tetrahedron 63 (2007) 9493–9501
450 W xenon lamp. Emission spectra were obtained from
air equilibrated dichloromethane samples (ca. 1.3ꢂ10ꢀ4 M),
exciting at 300 nm (280 nm for 4), in right angle mode
and using 1ꢂ1 cm [3 mL] quartz cells. The curves were pro-
cessed with the appropriate correction files. Excitation spec-
tra were also recorded in order to assure that no impurities
were responsible for the emission at longer wavelengths, i.e.,
the emitting LES and CTS are coming from the same singlet
excited state. All measurements were done at 295 K other-
wise stated.
4.2. Syntheses
4.2.1. General. The synthesis of the macrocyclic naphthal-
enophanes 1a–c and 2a–c was performed by the general
method previously described.9 The six open-chain peptido-
mimetic precursors 10a–c and 11a–c (Cbz-L-Val and Cbz-
L-Phe combined with 1,n-alkanediamines [n¼2, 3, and 4])
were obtained in multigram scale and their spectral proper-
ties matched those described.9 Reaction of such precursors
with 1,4-bis(bromomethyl)naphthalene (12) is described in
detail for macrocycle 1a. For the remaining macrocycles
an identical procedure was employed. For the open-chain
compounds 3 and 4 the synthesis was accomplished by
means of n-propylamine instead of 1,n-alkanediamine.
Figure 8. Fluorescence quantum yields of compounds 1a–c, 2a–c, and 3 in
dichloromethane. N Represents the total number of atoms in the ring of
cyclophanes 1a–c and 2a–c. Open-chain derivative has been introduced out
of scale (or N¼N). (a) fem (CTS) for valine derivatives; (b) fem (CTS) for
phenylalanine derivatives; (c) fem (total) for valine derivatives; and (d) fem
(total) for phenylalanine derivatives.
4.2.1.1. Synthesis of compound 1a. Compound 10a
(0.750 g, 2.90 mmol), anhydrous K2CO3 (4.00 g, 29.00
mmol), tetrabutylammonium bromide (0.46 g, 1.45 mmol),
and 1,4-bis(bromomethyl)naphthalene (0.91 g, 2.90 mmol)
were placed in a flask containing dry CH3CN (300 mL)
and the mixture was refluxed for 12 h under a nitrogen
atmosphere. The reaction was filtered (hot) and the solvent
evaporated under reduced pressure. The crude product was
dissolved in CHCl3 (50 mL) and extracted with aqueous
NaOH 0.01 M (50 mL, 3ꢂ). The organic phase was dried
over anhydrous MgSO4 and the solvent was evaporated un-
der reduced pressure. The product was purified by silica
flash chromatography using MeOH/CH2Cl2 (1:40) as the
eluent to give 238 mg of 1a as a white solid. Yield 20%;
fluorescence or laser flash photolysis) since multiple pro-
cesses affect not only the ground state (intramolecular
hydrogen bonding) but also the excited states (complete
charge separation to give the separated radical/ion pair,
charge recombination (BET), ISC to a triplet exciplex, dissi-
pation of energy as radiationless decay to S0, or even proton
transfer from the secondary amine to give a radical pair).
Work is in progress to obtain a more complete picture of
the energetics and dynamics of these and other macrocycles.
4. Experimental section
1
mp¼202–203 ꢁC. [a]D20 +89.9 (c 0.01, CH2Cl2); H NMR
4.1. Materials and methods
(500 MHz, CDCl3) d 0.73 (d, 6H, J¼7.0 Hz), 0.97 (d, 3H,
J¼7.0 Hz), 1.01 (3H, J¼7.0 Hz), 2.13 (m, 1H), 2.27 (m,
2H), 2.37 (m, 1H), 2.93 (d, 1H, J¼4.0 Hz), 2.97 (m, 2H),
3.02 (d, 1H, J¼4.0 Hz), 3.58 (d, 1H, J¼13.5 Hz), 4.20 (d,
1H, J¼14.0 Hz), 4.30 (d, 1H, J¼14.0 Hz), 4.91 (d, 1H,
J¼13.5 Hz), 7.23 (d, 1H, J¼7.0 Hz), 7.31 (d, 1H,
J¼7.0 Hz), 7.50 (m, 1H), 7.52 (m, 1H), 8.13 (m, 1H), 8.17
(m, 1H). 13C NMR (125 MHz, CDCl3) d 17.0, 17.3, 20.0,
31.6, 39.0, 39.1, 50.5, 53.9, 68.7, 70.2, 124.4, 126.5,
127.5, 131.7, 132.8, 135.0, 138.4, 174.4, 175.5; FTIR
(KBr) 3263, 2965, 1638, 1528 cmꢀ1; UV–vis (CH2Cl2)
(lmax, 3) 291 nm, 6512 Mꢀ1 cmꢀ1; ESIMS m/z¼411.7
(M+H+), 433.6 (M+Na+), 449.6 (M+K+); HRMSEI+ m/z
calcd for C24H34N4O2 (M+) 410.268177, found 410.268105.
All commercially available reagents (Aldrich or Fluka) were
used without further purification. 1,4-Bis(bromomethyl)-
naphthalene was prepared as previously described.28 Sol-
vents for reactions were distilled over an adequate drying
agent. Dichloromethane for fluorescence measurements
was distilled over CaH2 prior to use.
NMR spectra were recorded on a Varian INOVA 500 spec-
trometer (500 MHz for 1H and 125 MHz for 13C). Chemical
shifts are reported in parts per million using residual undeu-
terated solvent peaks as internal standards. Mass spectra
(ESI) were recorded on a Micromass Quattro LC spectrom-
eter equipped with an electrospray ionization source and
a triple-quadrupole analyzer. High resolution mass spectra
(HRMS) were recorded in a VG Autospect (electron impact
mode, EI+) at the Universitat de Valeꢁncia. Infrared spectra
were recorded in a Perkin–Elmer 2000 FTIR spectrometer.
UV–vis absorption spectra were recorded in a Hewlett-
Packard 8453 apparatus. Steady-state fluorescence spectra
were acquired in a Spex Fluorolog 3–11 equipped with a
4.2.1.2. Synthesis of 1b. Yield 690 mg, 40%. Spectro-
scopic data coincided with those previously reported.11b
4.2.1.3. Synthesis of 1c. Yield 210 mg, 41%; white solid;
1
mp¼241–243 ꢁC. [a]D20 +88.7 (c 0.01, CH2Cl2); H NMR
(500 MHz, CDCl3) d 0.37 (m, 2H), 0.56 (m, 2H), 0.90 (d,
6H, J¼6.8 Hz), 1.12 (d, 6H, J¼7.0 Hz), 1.90 (s, 2H), 2.28

M. I. Burguete et al. / Tetrahedron 63 (2007) 9493–9501
9499
(m, 2H), 3.20 (m, 2H), 3.80 (d, 2H, J¼14.8 Hz), 4.70 (d, 2H,
J¼14.7 Hz), 6.84 (br s, 2H), 7.41 (s, 2H), 7.56 (m, 2H), 8.11
(m, 2H); 13C NMR (125 MHz, CDCl3) d 17.6, 20.1, 26.0,
31.3, 38.4, 52.0, 70.1, 124.7, 125.4, 126.4, 132.0, 136.3,
173.6; FTIR (KBr) 3373, 2958, 1671, 1509 cmꢀ1; UV–vis
(CH2Cl2) (lmax, 3) 288 nm, 7715 Mꢀ1 cmꢀ1; ESIMS m/z¼
461.6 (M+Na+); HRMSEI+ m/z calcd for C26H38N4O2
(M+) 438.299477, found 438.299698.
water and dried in vacuum for 20 h at 65 ꢁC. Yield of 14:
3.98 g, 95%; mp¼155–156 ꢁC; 1H NMR (500 MHz, d6-
DMSO) d 0.84 (m, 9H), 1.39 (m, 2H), 1.92 (m, 1H), 2.97
(m, 1H), 3.06 (m, 1H), 3.79 (t, 1H, J¼8.0 Hz), 5.02 (s,
2H), 7.18 (d, 1H, J¼ 8.9 Hz), 7.32 (m, 4H), 7.87 (s, 1H);
13C NMR (125 MHz, d6-DMSO) d 11.2, 18.1, 19.1, 22.1,
30.1, 40.1, 60.2, 65.2, 127.5, 127.6, 128.2, 137.0, 155.9,
170.8; FTIR (KBr) 3300, 2962, 1686, 1642 cmꢀ1; ESIMS
m/z¼315.3 (M+Na+), 331.2 (M+K+).
4.2.1.4. Synthesis of 2a. Yield 280 mg, 20%; mp¼110–
113 ꢁC. [a]D20 +77.9 (c 0.01, CH2Cl2); 1H NMR (500 MHz,
CDCl3) d 2.11 (m, 2H), 2.18 (br s, 2H), 2.36 (m, 1H), 2.57
(m, 1H), 2.67 (m, 1H), 3.04 (m, 2H), 3.28 (m, 2H), 3.38
(m, 1H), 3.40 (d, 1H, J¼14.0 Hz), 3.57 (dd, 1H, J¼10.5,
4.0 Hz), 4.03 (d, 1H, J¼14.5 Hz), 4.12 (d, 1H, J¼
14.5 Hz), 4.71 (d, 1H, J¼14.0 Hz), 6.07 (br s, 1H), 6.15
(br s, 1H), 7.27–7.39 (m, 12H), 7.56 (m, 2H), 8.10 (d, 1H,
J¼9 Hz), 8.17 (d, 1H, J¼9.0 Hz); 13C NMR (125 MHz,
CDCl3) d 38.8, 39.1, 39.9, 40.2, 49.7, 53.3, 64.8, 66.2,
124.1, 124.3, 126.3, 126.4, 126.9, 127.0, 127.4, 127.5,
128.8, 128.9, 129.0, 129.1, 131.4, 132.5, 134.4, 137.7,
137.8, 138.4, 174.3, 174.9; FTIR (KBr) 3369, 3050, 1654,
4.2.1.8. Synthesis of 15. Product 14 (2.20 g, 7.52 mmol)
was added to 15 mL of HBr/AcOH (33%) and the mixture
was stirred at room temperature until CO2 evolution ceased.
To the resulting mixture 50 mL of distilled water was added
and then extracted with chloroform (50 mL, 3ꢂ). Solid
NaOH was then added up to a pH value of 12 and the result-
ing solution was saturated with NaCl and extracted with di-
chloromethane (50 mL, 3ꢂ). The organic phase was dried
over MgSO4 and evaporated under vacuum to obtain the de-
sired product 15 (oil). Yield 1.07 g, 90%; 1H NMR
(500 MHz, CDCl3) d 0.77 (d, 3H, J¼6.5 Hz), 0.87 (t, 3H,
J¼8.5 Hz), 0.92 (d, 3H, J¼7.5 Hz), 1.34 (br s, 2H), 1.47
(m, 2H), 2.22 (m, 1H), 3.16 (m, 3H), 7.28 (br s, 1H); 13C
NMR (125 MHz, CDCl3) d 11.4, 16.1, 19.7, 23.0, 30.9,
40.7, 60.3, 174.3; FTIR (NaCl) 3304, 2962, 1649,
1528 cmꢀ1; ESIMS m/z¼181.2 (M+Na+), 192.2 (M+K+).
1517 cmꢀ1
;
UV–vis (CH2Cl2) (lmax
;
,
3) 290 nm,
7278 Mꢀ1 cmꢀ1
ESIMS m/z¼507.4 (M+H+), 529.4
(M+Na+); HRMSEI+ m/z calcd for C32H34N4O2 (M+)
506.268177, found 506.268860.
4.2.1.5. Synthesis of 2b. Yield 509 mg, 35%; mp¼74–
4.2.1.9. Synthesis of 3. Analogously to the synthesis of
cyclophanes, coupling between 15 and 1,4-bis(bromome-
thyl)naphthalene (12) gave 3 (white solid). Yield 730 mg,
1
79 ꢁC. [a]D20 ꢀ11.8 (c 0.01, CH2Cl2); H NMR (500 MHz,
CDCl3, 328 K) d 2.24 (m, 2H), 2.53 (m, 2H), 2.65 (m,
4H), 2.77 (m, 2H), 3.22 (dd, 2H, J¼14.1, 4.4 Hz), 3.56 (br
s, 2H), 3.80 (br s, 2H), 4.41 (m, 2H), 6.40 (br s, 2H), 7.21
(t, 2H, J¼7.0 Hz), 7.25 (d, 4H, J¼7.0 Hz), 7.26 (s, 2H),
7.30 (t, 4H, J¼7.0 Hz), 7.35 (m, 2H), 8.00 (br s, 2H); 13C
NMR (125 MHz, CDCl3) d 27.6, 29.4, 35.9, 39.0, 65.1,
124.3, 125.8, 126.5, 128.4, 129.1, 132.4, 138.1, 175.0;
FTIR (KBr) 3339, 2935, 1651, 1520 cmꢀ1; UV–vis
(CH2Cl2) (lmax, 3) 290 nm, 7496 Mꢀ1 cmꢀ1; ESIMS m/z¼
521.6 (M+H+), 543.6 (M+Na+); HRMSEI+ m/z calcd for
C33H36N4O2 (M+) 520.283827, found 520.281919.
1
47%; mp¼158–160 ꢁC. [a]D20 ꢀ9.9 (c 0.01, CH2Cl2); H
NMR (500 MHz, CDCl3) d 0.86–0.88 (m, 12H), 0.97 (d,
6H, J¼6.9 Hz), 1.41 (m, 4H), 1.66 (br s, 2H), 2.15 (m,
2H), 3.05 (m, 4H), 3.18 (m, 2H), 4.16 (s, 4H), 7.16 (m,
2H), 7.38 (s, 2H), 7.57 (m, 2H), 8.14 (m, 2H); 13C NMR
(125 MHz, CDCl3) d 11.5, 17.7, 19.7, 22.9, 31.4, 40.6,
51.6, 68.5, 124.3, 126.1, 126.2, 132.1, 135.3, 173.4; FTIR
(KBr) 3308, 2961, 1641, 1556 cmꢀ1; UV–vis (CH2Cl2)
(lmax, 3) 288 nm, 7644 Mꢀ1 cmꢀ1; ESIMS m/z¼469.4
(M+H+), 491.3 (M+Na+); HRMSEI+ m/z calcd for
C28H43N4O2 ((Mꢀ1)+) 467.338602, found 467.338524.
4.2.1.6. Synthesis of 2c. Yield 365 mg, 32%; mp¼71–
1
75 ꢁC. [a]D20 ꢀ11.9 (c 0.01, CH2Cl2); H NMR (500 MHz,
4.2.1.10. Synthesis of 4. Analogously to the synthesis of
cyclophanes, coupling between 15 and 1-(chloromethyl)-
naphthalene (16) gave 4 (white solid). Yield 184 mg, 55%;
mp¼80–81 ꢁC; 1H NMR (500 MHz, CDCl3) d 0.87 (d, 3H,
J¼7.0 Hz), 0.88 (t, 3H, J¼6.0 Hz), 0.96 (d, 3H,
J¼7.0 Hz), 1.42 (m, 2H), 2.19 (m, 1H), 3.10 (m, 2H), 3.19
(m, 1H), 4.20 (s, 2H), 7.24 (br s, 1H), 7.44 (m, 1H), 7.51
(m, 1H), 7.55 (m, 1H), 7.81 (m, 2H), 7.88 (d, 1H,
J¼8.0 Hz), 8.08 (d, 1H, J¼8.0 Hz); 13C NMR (125 MHz,
CDCl3) d 11.4, 17.8, 19.5, 22.9, 31.2, 40.6, 51.4, 68.4,
123.2, 125.5, 125.8, 126.4, 128.3, 129.0, 131.6, 133.9,
170.0; FTIR (KBr) 3290, 2960, 1637, 1555 cmꢀ1; UV–vis
(CH2Cl2) (lmax, 3) 282 nm, 6449 Mꢀ1 cmꢀ1; ESIMS m/z¼
299.3 (M+H+), 321.3 (M+Na+); HRMSEI+ m/z calcd for
C19H26N2O (M+) 298.204514, found 298.203308.
CDCl3) d 0.41 (m, 2H), 0.61 (m, 2H), 1.97 (br s, 2H), 2.28
(m, 2H), 2.64 (d, 1H, J¼10.5 Hz), 2.67 (d, 1H,
J¼10.5 Hz), 3.24 (dd, 2H, J¼14.1, 10.5 Hz), 3.39 (dd, 2H,
J¼14.0, 3.5 Hz), 3.60 (dd, 2H, J¼14.0, 3.5 Hz), 3.65 (d,
2H, J¼15.0 Hz), 4.46 (d, 2H, J¼15.0 Hz), 6.82 (br s, 2H),
7.29–7.46 (m, 12H), 7.53 (m, 2H), 7.95 (m, 2H); 13C
NMR (125 MHz, CDCl3) d 26.0, 29.8, 38.6, 40.0, 51.2,
53.6, 65.8, 124.1, 126.5, 127.4, 129.2, 129.3, 131.8, 137.8,
177.2; FTIR (KBr) 3349, 2927, 1651, 1656 cmꢀ1; UV–vis
(CH2Cl2) (lmax, 3) 289 nm, 7307 Mꢀ1 cmꢀ1; ESIMS m/z¼
535.6 (M+H+), 557.6 (M+Na+); HRMSEI+ m/z calcd for
C34H38N4O2 (M+) 534.299477, found 534.298988.
4.2.1.7. Synthesis of 14. The N-hydroxysuccinimide es-
ter of N-Cbz-L-valine (5.00 g, 14.35 mmol) was dissolved
in anhydrous THF (40 mL) cooled in an ice bath. n-Propyl-
amine (1.20 mL, 14.35 mmol) dissolved in dry THF
(10 mL) was added in several stages. The reaction mixture
was refluxed for 4 h and then the solvent was evaporated
at reduced pressure. The white solid was washed with cold
Acknowledgements
ꢀ
Financial support from the Spanish Ministerio de Educacion
y Ciencia (MEC, projects CTQ2006-15672-C05-02/BQU

9500
M. I. Burguete et al. / Tetrahedron 63 (2007) 9493–9501
ꢀ
8. (a) Burguete, M. I.; Escuder, B.; Garcıa-Espan˜a, E.; Luis, S. V.;
Miravet, J. F. Tetrahedron 2002, 58, 2839–2846; (b) Burguete,
M. I.; Escuder, B.; Luis, S. V.; Miravet, J. F.; Querol, M.
Tetrahedron Lett. 1998, 39, 3799–3802; (c) Altava, B.;
Burguete, M. I.; Escuder, B.; Luis, S. V. Tetrahedron 1997,
and CTQ2006-26251-E/BQU [Programa Explora]), Gener-
ꢀ
alitat Valenciana (project GV/2007/277), from Fundacio
Caixa Castello—UJI (project P1$1B2004-38) and FEDER
ꢀ
is acknowledged. F.G. thanks the financial support from
ꢀ
MEC (Ramon y Cajal Program). L.V. thanks financial sup-
port from MEC (FPU).
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53, 2629–2640; (d) Burguete, M. I.; Escuder, B.; Garcıa-
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