Bis(diamido)-bridged basket resorcin[4]arenes as enantioselective receptors for amino acids and amines

Article abstract of DOI:10.1002/ejoc.200700829

On the research avenue opened by the rigidified double-spanned resorcin[4]arene 1, we have synthesized both enantiomers of the two chiral basket resorcin[4]arenes 3 and 4, each containing two 1,2-diaminocyclohexane and 1,2-diphenylethylenediamine bridges, respectively. In the new compounds, the aromatic rims assume the expected flattened cone arrangement, whereas two different conformations, tentatively designated as "open wings" and "folded wings", were attributed to the bridge substituents according to molecular modeling studies. In MSⁿ (ESI) experiments, the proton-bonded diastereomeric [4·H·A]⁺ complexes with amino acidic guests (A) exhibited a pronounced selectivity towards the enantiomers of tyrosine methyl ester (tyr^OMe) and amphetamine (amph), whereas the chirality of tryptophan (trp) was ineffective. Moreover, a kinetic study on the base-induced displacement of the guest revealed that the L-tyr ^OMe (and L-amph) enantiomer is faster displaced from the heterochiral [4·H·L-tyr^OMe]⁺ (or [ent- 4·H·L-amph]⁺) complex than from the homochiral [ent-4·H·L-tyr^OMe]⁺ (or [4·H· L-amph]⁺) one. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700829

FULL PAPER
DOI: 10.1002/ejoc.200700829
Bis(diamido)-Bridged Basket Resorcin[4]arenes as Enantioselective Receptors
for Amino Acids and Amines
Bruno Botta,*[a] Ilaria D’Acquarica,[a] Laura Nevola,[a] Fabiola Sacco,[a]
Zara Valbuena Lopez,[a] Giovanni Zappia,[b] Caterina Fraschetti,[a] Maurizio Speranza,*[a]
Andrea Tafi,[c] Fabiana Caporuscio,[a] Matthias C. Letzel,[d] and Jochen Mattay[d]
Keywords: Macrocycles / Chirality / Resorcinarenes / Host–guest systems
On the research avenue opened by the rigidified double-
spanned resorcin[4]arene 1, we have synthesized both
enantiomers of the two chiral basket resorcin[4]arenes 3 and
4, each containing two 1,2-diaminocyclohexane and 1,2-di-
phenylethylenediamine bridges, respectively. In the new
compounds, the aromatic rims assume the expected flattened
cone arrangement, whereas two different conformations, ten-
tatively designated as “open wings” and “folded wings”,
were attributed to the bridge substituents according to mo-
lecular modeling studies. In MSn (ESI) experiments, the pro-
ton-bonded diastereomeric [4·H·A]+ complexes with amino
acidic guests (A) exhibited a pronounced selectivity towards
the enantiomers of tyrosine methyl ester (tyrOMe) and am-
phetamine (amph), whereas the chirality of tryptophan (trp)
was ineffective. Moreover, a kinetic study on the base-in-
duced displacement of the guest revealed that the
(and -amph) enantiomer is faster displaced from the hetero-
chiral [4·H·
-tyrOMe + (or [ent-4·H·L-amph]+) complex than
L
-tyrOMe
L
L
]
from the homochiral [ent-4·H·L ]
-tyrOMe + (or [4·H·L-amph]+)
one.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
Several chiral calixarenes have been synthesized,[6,7] but
just a few of them have shown good chiral recognition
properties. Recently, chiral calix[4]arenes bearing optically
pure aminol groups[8a] and a 1,2-diphenyl-1,2-oxyamino
residue[8b] at the lower rim showed exceptional chiral re-
cognition properties for carboxylic acids. Lower rim bis-
(urea) calix[4]arene-based receptors have just been de-
scribed with remarkable enantioselective binding ability for
N-acetylphenylalaninate and N-acetylalaninate anions.[8c]
We have shown that ethereal BF3 catalyzes the tetrameri-
zation of (E)-2,4-dimethoxycinnamic acid derivatives to the
corresponding resorcin[4]arene octamethyl ethers,[9] which
are macrocycles with a cavity-shaped flexible architecture.
With the aim to build rigidified hosts and to compare their
recognition ability with that of the parent more-flexible
macrocycle, we prepared preorganized double-spanned res-
The knowledge of the geometrical positioning and of the
manner of interaction of a biomolecule in a receptor cavity
is the key for understanding the origin of the amazing selec-
tivity and efficiency of enzyme catalysis.[1a,1b] Biomolecules
are often chiral and many biochemical processes show pref-
erence for one enantiomer over the other. Chiral recogni-
tion, one of the most sophisticated functions of enzymes,
motivated chemists to design hosts to be used for enantiose-
lective reactions.[1c,1d] Among various molecular platforms
that can be proposed for the construction of such receptors,
macrocycles of multiple aromatic units have widely been
used. Calixarenes,[2] cavitands[3] such as resorcinarenes,[4]
and cyclophanes[5] have largely been studied over the last
two decades.
[a] Dipartimento di Studi di Chimica e Tecnologia delle Sostanze orcin[4]arenes, such as 1 (Figure 1), by the insertion of two
polymethylene bridges,[10] resembling a basket. Following
Biologicamente Attive, Università “La Sapienza”,
P.le Aldo Moro 5, 00185 Roma, Italy
this research, here we report the synthesis of chiral basket
resorcin[4]arenes 3 and 4 (Figure 1) starting from the com-
mon ethyl tetraester resorcin[4]arene precursor 2, already
described.[9a] Molecular modeling (MM) conformational
studies of the new compounds and preliminary molecular
recognition studies by electrospray ionization mass spec-
trometry [MS (ESI)] in the gas phase of compound 4 were
also performed.
E-mail: bruno.botta@uniroma1.it
[b] Istituto di Chimica Farmaceutica, Università degli Studi di Ur-
bino “Carlo Bo”,
P.za del Rinascimento 6, 61029 Urbino, Italy
[c] Dipartimento Farmaco Chimico Tecnologico, Università di Si-
ena,
Via Aldo Moro, 53100 Siena, Italy
[d] Department of Chemistry, Bielefeld University,
P. O. Box 100131, 33501 Bielefeld, Germany
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Results and Discussion
Synthesis and NMR Spectroscopic Analysis
Resorcin[4]arene octamethyl ether tetraester 2 (cone con-
formation), obtained as described previously,[9a] was hy-
drolyzed by treatment with NaOH (2  in ethanol solution),
and the corresponding tetraacid 2a was quantitatively con-
verted into the tetrachloride derivative 2b by reaction with
thionyl chloride (Scheme 1). Treatment of highly diluted dry
THF solutions of 2b with diisopropylethylamine (DIPEA)
and
then with
(1R,2R)-(–)-1,2-diaminocyclohexane
(DACH) under an atmosphere of nitrogen afforded com-
pound 3 (Scheme 2, 35% yield relative to 2b). The same
synthetic procedure with (1S,2S)-(+)-1,2-diaminocyclohex-
ane gave ent-3 (36% yield, with opposite [α]D and coinci-
dent NMR/MS spectroscopic data).
Scheme 1. Reagents and conditions: (i) 2  NaOH, EtOH, reflux,
4 h, glacial AcOH; (ii) thionyl chloride, dry benzene, reflux, 4 h.
To check the general applicability of the synthetic pro-
cedure, tetrachloride derivative 2b was treated with
(1R,2R)-(+)-1,2-diphenylethylenediamine (DPEDA) under
Figure 1. Chemical structures of a basket resorcin[4]arene with two
polymethylene bridges (1)[10] and of chiral basket resorcin[4]arenes
3 and 4.
1
Table 1. 13C and H NMR data for chiral basket resorcin[4]arenes 3 and 4.
Position/Type
Chiral basket resorcin[4]arenes 3[a]
Chiral basket resorcin[4]arenes 4[b]
δ{1H} [ppm], mult. (J [Hz])
δ{13C} [ppm] δ{1H} [ppm], mult. (J [Hz]) δ{13C} [ppm]
C=O
174.65; 172.53
156.58; 157.48
156.24; 155.05
126.77
–
–
174.72; 171.65
157.34; 156.62
155.98; 154.88
126.42
–
–
4,16; 6,18
10,22; 12,24
25,27
5.96, s
6.92, s
–
6.00, s
7.07, s
–
26,28
126.38
126.24
1,13; 3,15;
5,17; 9,21
11,23
125.43; 124.53
121.72; 121.59
97.85
125.15; 124.30
121.40ϫ2
97.81
6.13, s
6.22, s
7,19
94.82
57.23
51.48
56.21ϫ2
55.93; 55.55
41.85
6.49, s
94.51
60.27
58.09
55.93ϫ2
55.80; 55.34
41.69
6.46, s
CH–N (b)
CH–N (a)
OCH3
2.99, tdd (11, 6.5, 4)
3.86, m (Σ 34.5)
3.94, s; 3.90, s
3.52, s; 3.24, s
3.27, dd (14, 5)
2.22, dd (14, 12.5)
2.94, dd (17, 4)
2.69, dd (17, 13.5)
5.03, dd (12.5, 5)
4.60, dd (13.5, 4)
6.82, d (6, 5)
4.90, dd (11, 7.5)
5.43, dd (11, 8)
3.86, s; 3.85, s
3.57, s; 3.29, s
3.24, dd (14, 5.5)
2.39, dd (14.5, 12.5)
3.00, dd (17, 4)
2.83, dd (17, 13)
5.09, dd (12.5, 5)
4.66, dd (13, 4)
7.62, d (7, 5)
H–C–H (b)
H–C–H (a)
40.30
40.09
8,20 (b)
2,14 (a)
N–H (a)
N–H (b)
33.69ϫ2
33.49
33.27
–
–
–
–
5.49, d (8, 5)
–
5.97, d (8, 2)
[a] Other signals for 3: C4(H8): δ = 32.71, 31.73, 25.38, 24.34 (CH2) ppm; (C4)H8: δ = 1.58 (m, 4 H), 1.24 (m, 4 H) ppm. [b] Other signals
for 4: δ = C6(H5): 140.05, 137.40 (C-1Ј); 128.79ϫ2, 128.08ϫ4, 127.57ϫ2 (C-2Ј, C-3Ј, C-5Ј, C-6Ј); 128.20, 127.11 (C-4Ј); (C6)H5: 7.20–
7.01 (m, 5 H) ppm.
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Bis(diamido)-Bridged Basket Resorcin[4]arenes
Table 2. DIF NOE experiments on chiral basket resorcin[4]arenes 3 and 4.
Chiral basket resorcin[4]arenes 3
Chiral basket resorcin[4]arenes 4
Irradiated
proton
Enhancement
Irradiated
proton
Enhancement
NH (a)
CH (a)
NH (b)
HB-CH (a)
HB-CH (b)
HA-CH (b)
CHN (a)
CH (b)
6.82
4.60
5.49
2.69
2.22
3.27
–
3.86 CHN (b); 2.22 CH2 (b)
5.49 NH (b); 2.94 HA-CH (a)
3.86 CHN (b); 4.60 CH (a); 6.92 Hi (26,28)
2.94 HA-CH (a); 6.92 Hi Ͼ 5.96 Hi; 4.60 CH (a) 2.39
3.27 HA-CH (b); 6.92 Hi Ͼ 6.82 NH (b)
2.22 HA-CH (b); 5.03 CH (b)
–
–
–
7.62
4.66
–
7.07 Hi (26,28); 5.43 CHN (a) Ͼ 4.90 CHN (b)
5.97 NH (b)
–
7.62 NH (a); 7.07 Hi (26,28); 3.24 HA-CH (a)
–
–
7.07 Hi (26,28); 7.62 NH (a); 4.90 CHN (b)
3.57 OMe Ͼ 3.85 OMe
3.57 OMe; 3.29 OMe
–
–
5.43
5.09
6.22
–
–
He (11,23)
Molecular Modeling
Computational studies, performed by means of the
MacroModel/Maestro software package[11] equipped with
Amber* force field[12] confirmed the experimental findings
and allowed evaluation of both the shape and rigidity of
the two basket resorcin[4]arenes 3 and 4. Three types of
molecular simulations were carried out during the calcula-
tions: interactive structure building with partial point-
charge calculations, geometry optimization, and conforma-
tional searching.
Scheme 2. Reagents and conditions: (i) DIPEA, dry THF, 1,2-
DACH, reflux, 3 h; (ii) DIPEA, dry THF, 1,2-DPEDA, reflux, 3 h.
A refined 3D structure, obtained from previous stud-
ies,[9a] was utilized as an input geometry for the resorcin[4]-
arene nucleus, whereas the two pairs of joint chains (wings)
of each compound were manually built in Maestro by the
BUILD tool. To deal with the structural complexity of 3
and 4 (both possessing 14 rotatable bonds), statistical meth-
ods of conformational search and molecular dynamics
(MD) simulations at 300 K were employed. Access to the
conformations of both compounds populated in chloro-
form solution was gained by using two Monte Carlo statis-
tical analysis methodologies: the MCMM (Monte Carlo
multiple minimum search)[13] and the MCMM/LMCS (a
mixed-mode procedure, combining MCMM with the low
mode conformational search),[14] together with the constant
temperature stochastic dynamics (SD).[15] The combination
of the two Monte Carlo protocols with the SD simulations
was aimed at ensuring a complete and reasonably homo-
geneous sampling of the whole potential-energy hypersur-
face of the systems by taking into account dynamic and
entropic effects. Indeed, the time evolution of the molecular
motions of 3 and 4 was expected to provide a dynamic pic-
ture of the two compounds. Moreover, as energy minimiza-
tions in molecular mechanics give steric energies corre-
sponding to enthalpies at 0 K, constant-temperature SD
simulations are more appropriate to obtain average enthalp-
ies at 300 K for large and flexible systems.
the same experimental conditions to give chiral basket res-
orcinarene 4 (Scheme 2, 31% yield relative to 2b).
Analogously, ent-4 (29% yield) with opposite [α]D and
identical NMR/MS spectroscopic data to that of 4 was pre-
pared from 2b and (1S,2S)-(–)-1,2-diphenylethylenediamine.
1
At a first sight, the H and 13C NMR spectra of 3 and 4
(see Table 1) exhibit a close similarity to those of 1.[10]
These compounds are characterized by a flattened cone dis-
tribution of the aromatic rings and bridged side chains
(from C2 to C8 and C14 to C20) surrounding the two vis a
vis aromatic rings (B and D). Because of the presence of
the two chiral centers and the restricted rotation of the
methylene protons, the a and b sides of the bridge are not
symmetrical with respect to the B/D aromatic rings. The
chemical shifts of the Hi and He protons are not influenced
by this disposition: for instance, H-25 and H-27 are super-
imposable after a 180° rotation of the molecule around a
C2 axis, that is to say, C-25 and C-27 are like enantiomeric
carbon atoms. This is not valid for the methoxy groups and
the pairs of equivalent OMe protons on C4/C16, C6/18,
C10/C22, and C12/C24, which give four (6 H) signals.
DIF NOE experiments (Table 2) revealed that the NH
(a) proton of the methylene unit lies to the b side, which
suggests that the low-field value of the signal is caused by
H-bonding with the C=O (b) carbonyl group (notice also
the 13C NMR different resonances of the carbonyl groups).
Conversely, irradiation of the signal for the NH (b) proton
revealed the proximity of the Hi (26,28) and CH (a) protons
Structure and Conformations of Basket Resorcin[4]arene 3
and confirmed a distorted arrangement of the double chain
The Monte Carlo conformational search revealed a quite
1
wings. The NH signals appear slightly high-field in the H narrow spectrum for 3; six minima (low-energy conformers)
NMR spectrum of 4, probably because of a different influ- within 20.0 kJmol–1 above the global minimum were found.
ence of the flattened aromatic (A/C) rings.
The conformations populated at 300 K, according to a
Eur. J. Org. Chem. 2007, 5995–6002
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B. Botta, M. Speranza et al.
FULL PAPER
Figure 2. Lowest energy conformers of basket resorcin[4]arene 3 from MCMM and MCMM/LCMS calculations. Left to right 3a, 3b,
and 3c (in order of increasing energy).
Boltzmann distribution, were filtered to afford three fami- matched perfectly, and the 3a conformation can be consid-
lies of conformers. The lowest-energy member of each fam- ered as the most likely 3D structure of 3 in chloroform.
ily (hereafter named respectively 3a, 3b, and 3c) is depicted
Structure and Conformations of Basket Resorcin[4]arene 4
in Figure 2 from left to right in order of increasing energy.
All the geometries show a slight distortion of the resorcin-
The conformational search of 4 revealed a conforma-
[4]arene nucleus, which is probably due to the chirality and tional spectrum broader than 3, and 34 low-energy con-
to the resulting asymmetric orientation of the joint chains. formers within 20.0 kJmol–1 above the global minimum
In all cases, both cyclohexane rings adopt the energetically were found, which highlighted a larger flexibility of this
favored chair geometry, whereas one hydrogen bond is molecule. Again, three families of conformers were col-
formed within each wing between the carbonyl group of lected after filtration. The lowest-energy member of each
one side chain and the NH functionality of the other one family (hereafter named 4a, 4b, and 4c) is depicted in Fig-
(vide supra). In 3a (steric energy = –273.4 kJmol–1), the ure 3 from left to right in order of increasing energy. The
four aromatic rings lie in a flattened cone conformation as three geometries of 4 showed similar features to those of 3,
in nonchiral baskets such as 1;[10] both the joint chains are such as the slight distortion of the resorcin[4]arene nucleus
extended outwards in an arrangement tentatively desig- and the H-bonding interactions, whereas the phenyl pen-
nated as “open wings”. In contrast, in 3c (steric energy = dants assume a roughly parallel equatorial orientation two
–256.1 kJmol–1) both the substituents point downwards in by two. Analogous to geometries 3a–c, 4a (steric energy =
a “folded wings” conformation. Finally, in the mixed con- –240.5 kJmol–1), 4b (steric energy = –233.1 kJmol–1), and
formation of 3b (steric energy = –264.7 kJmol–1) one wing 4c (steric energy = –232.6 kJmol–1) were designated as
is outwards and the other downwards (“mixed wings”).
“open wings”, “mixed wings”, and “folded wings” confor-
SD simulations performed at 300 K and starting from mations, respectively. In conclusion, the Monte Carlo se-
the three minima 3a, 3b, and 3c allowed the identification arch at 0 K depicted a conformational scenario for 4 that is
of the most populated conformation of 3 in solution by comparable to 3. SD simulations for both 4b and 4c gave
comparison of their average enthalpies. Geometries 3a, 3b, steadily constant enthalpy values roughly equal to
and 3c showed enthalpy values roughly equal to 168, 177, 271 kJmol–1 at 300 K and did not show interconversion
and 184 kJmol–1, respectively. As a result, the lowest en- during the runs. In contrast, in the case of 4a, the initial
thalpy SD geometry and the Monte Carlo global minimum enthalpy value of ca. 268 kJmol–1 decreased by a few
Figure 3. Lowest energy conformers of basket resorcin[4]arene 4 from MCMM and MCMM/LCMS calculations. Left to right 4a, 4b,
and 4c (in order of increasing energy).
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Bis(diamido)-Bridged Basket Resorcin[4]arenes
kJmol–1 during the simulation. Notably, the enthalpy
In the 15-eV CID spectra of the proton-bonded dia-
change was accompanied by the irreversible conversion of stereomeric [4·H·trp]+ complexes (m/z = 1389), no signifi-
4a into a conformation of the 4c family through a change cant effects of the configuration of the amino acidic guest
in the orientation of the flattened cone that brought the aro- was observed (Figure S1, Supporting Information). In con-
matic A/C rings face to face. The distance between two trast, resorcin[4]arene 4 exhibited an appreciable selectivity
dummy atoms, each one corresponding to the center of the towards the enantiomers of tyrOMe (Figure S2, Supporting
bond connecting the two phenyl-substituted carbon atoms Information) and amph (Figure S3, Supporting Infor-
of each wing, was estimated during the SD run to testify mation). In particular, the 15-eV CID spectra of the dia-
the occurrence of such an event. Figure 4 gives signs of the stereomeric [4·H·tyrOMe +
irreversible conversion of 4a into 4c after about 1200 ps acterized by a [4·H]+/[4·H·trp]+ abundance ratio that
(300 frames), which culminates into the matching between strongly decreased from the heterochiral [4·H·-tyrOMe +
the lowest enthalpy SD geometry in solution of 4 and the complex (2.26) to the homochiral [4·H·-tyrOMe +
one
] adducts (m/z = 1380) were char-
]
]
Monte Carlo minimum 4c. The low steric energy difference (0.72). In contrast, the 15-eV CID spectra of the dia-
between the Monte Carlo minima 4a and 4c (less than stereomeric [4·H·amph]+ complexes (m/z = 1320) exhibited
3.0 kcalmol–1 at 0 K), and the irreversible conversion of the a [4·H]+/[4·H·amph]+ ratio that slightly increased on going
former input structure into the latter during the SD run at from the heterochiral [4·H·-amph]+ (0.36) to the homochi-
300 K supports the 4c geometry as the most likely 3D struc- ral [4·H·-amph]+ adduct (0.75). These findings lend sup-
ture of 4 in chloroform.
port to the view that the homochiral [4·H·-tyrOMe]+ com-
plex is significantly more stable than its heterochiral coun-
terpart. The reverse is true for the [4·H·amph]+ dia-
stereomers, whereas the [4·H·trp]+ ones are essentially de-
generate.
To verify whether the relative stabilities of the dia-
stereomeric [4·H·tyrOMe + and [4·H·amph]+ complexes are
]
mirrored by their kinetic enantioselectivity, we carried out
a detailed kinetic study on their base-induced displacement
reaction [Equation (1)], which took place in the cell of an
electrospray ionization fourier-transform ion cyclotron res-
onance mass spectrometer [FTICR (ESI)] filled with the
enantiomers of 2-aminobutane (B) kept at a constant par-
tial pressure (PB).
Figure 4. Distance between two dummy atoms corresponding to
the center of the bond connecting the two phenyl-substituted car-
bon atoms of each wing estimated during the SD run for 4a.
[M·H·A]+ + B Ǟ A + [M·H·B]+
(1)
Figures 6 and 7 summarize the relevant kinetic plots,
where I is the intensity of the [M·H·A]+ complex (M = 4 or
ent-4; A = -tyrOMe and -amph, respectively) at the delay
time t and I0 is the sum of the intensities of the [M·H·A]+
and [M·H·B]+ adducts. The pseudo-first-order rate con-
stants kЈ of Equation (1) were obtained from the slopes of
the kinetic curves of Figures 6 and 7. The values of the
corresponding second-order rate constants, k = kЈ/[B], are
listed in Table 3 together with the relevant reaction effi-
ciencies (eff) calculated from the ratio between k and the
collision rate constant (kcoll).[17] The enantioselectivity is de-
fined by ρ = khomo/khetero, when referred to the configura-
tion of the M/A pair, or by ξ = kR/kS, when referred to the
configuration of the amine B. The ρϽ1 values indicate that
the amine B displaces the guest -tyrOMe (or -amph) faster
from the heterochiral [4·H·-tyrOMe]+ (or [ent-4·H·-amph]+)
Mass Spectrometry
Some insights into the molecular recognition of basket
resorcin[4]arene 4 towards representative chiral molecules
were gathered in the gas phase by MS (ESI) experiments.[16]
For this purpose, the proton-bonded diastereomeric [4·H·A]+
complexes [A = tyrosine methyl ester (tyrOMe), tryptophan
(trp), or amphetamine (amph); see Figure 5] were generated
in the source of an ion-trap mass spectrometer, and their
collision-induced decomposition (CID) spectra were investi-
gated. A common feature of the CID fragmentation spectra
is the exclusive observation of the [4·H]+ fragment at any
collision energy employed (10–25 eV, lab frame), which in-
dicates that the gas-phase basicity of host 4 largely exceeds
that of all the A guests used.
complex than from the homochiral [ent-4·H·-tyrOMe +
] (or
[4·H·-amph]+) one. The reverse is true for values ρϾ1. A
ξϽ1 value indicates that the displacement of the A guest is
faster with the (S)-amine (BS) than with the (R)-amine (BR).
The reverse is true with ξϾ1.
The results of Table 3, in particular the ρ and ξ terms
diverging from unity, indicate that the kinetics of the gas-
phase displacement is found to depend on the nature and
the configuration of the guest A and the configuration of
Figure 5. Chemical structures of chiral guests A.
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B. Botta, M. Speranza et al.
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Table 3. Exchange rate constants (kϫ10–10 cm3 molecule–1 s–1).
Host
Guest
(R)-(–)-2-butylamine
(S)-(+)-2-butylamine
k
eff
ρ = khomo/khetero
0.93Ϯ0.03
k
eff
ρ = khomo/khetero ξ = kR/kS
4
-tyrOMe
-tyrOMe
-amph
-amph
1.20Ϯ0.01
1.12Ϯ0.02
1.34Ϯ0.05
1.06Ϯ0.02
0.10
0.09
0.11
0.09
1.35Ϯ0.03
1.06Ϯ0.02
1.07Ϯ0.03
1.17Ϯ0.04
0.11
0.09
0.09
0.10
0.78Ϯ0.04
0.89Ϯ0.03
1.06Ϯ0.04
1.25Ϯ0.09
0.91Ϯ0.05
ent-4
4
1.26Ϯ0.09
0.91Ϯ0.06
ent-4
Figure 6. (a) Kinetic plots for the gas-phase reaction between (R)-
(–)-2-butylamine (PB = 4.6ϫ10–8 mbar) and [4·H·-tyrOMe +
(open
circles) or [ent-4·H·-tyrOMe +
(full circles); (b) kinetic plot for the
gas-phase reaction between (S)-(+)-2-butylamine (PB
4.6ϫ10–8 mbar) and [4·H·-tyrOMe +
(open circles) or [ent-4·H·-
tyrOMe +
(full circles).
Figure 7. (a) Kinetic plots for the gas-phase reaction between (R)-
(–)-2-butylamine (PB = 7.2ϫ10–8 mbar) and [ent-4·H·-amph]+
(open circles) or [4·H·-amph]+ (full circles); (b) kinetic plot for the
]
]
=
gas-phase reaction between (S)-(+)-2-butylamine (PB
=
4.7ϫ10–8 mbar) and [ent-4·H·-amph]+ (open circles) or [4·H·-
]
]
amph]+ (full circles).
Conclusions
the B amine. Thus, the diastereomeric [4·H·tyrOMe +
plexes invariably exhibit ρϽ1 values, which is in qualitative
] com-
If the previously synthesized basket resorcin[4]arene 1 is
agreement with the stability trend of the diastereomeric taken as a model, the resorcin[4]arene precursor 2b was ri-
[4·H·tyrOMe +
]
complexes (homoϾhetero). In contrast, the gidified by the introduction of two bridges built by reaction
diastereomeric [4·H·amph]+ complexes do not follow an of the acid chloride functionalities of two adjacent substitu-
univocal trend, as they display ρϾ1 factors in the reaction ents with trans-1,2-diaminocyclohexane or 1,2-diphenyl-
with BR and ρϽ1 factors in that with BS. This opposite ethylendiamine. The ent forms of the synthetic resorcin-
enantioselectivity is reflected in the corresponding ξ terms, arenes with satisfactory [α]D values were also prepared. The
which exhibit a ξϽ1 value with the heterochiral complex investigation by MM on the possible conformation pro-
and a ξϾ1 value with the homochiral one. This picture duced a series of low-energy conformers, where the aro-
confirms the view that the enantioselectivity of Equation (1) matic rings are arranged in a flattened cone form, as sug-
with [4·H·amph]+ is essentially kinetic. It is governed by gested by the distribution pattern of the signals in the NMR
the effects of the resorcin[4]arene frame upon the transition spectra. H-bonding between the carbonyl group and the op-
structures involved in the displacement reaction, whereas posite NH drives the two bridges to different asymmetric
the relative stability of the diastereomeric [4·H·amph]+ frameworks, which were designated as “open”, “mixed”,
complexes plays only a minor role.
and “folded wings”. Notably, the two different “open” and
6000
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5995–6002

Bis(diamido)-Bridged Basket Resorcin[4]arenes
ent-3: Treatment of 2b with (1S,2S)-(+)-1,2-diaminocyclohexane
under the same conditions as those used for the preparation of 3
afforded ent-3 (0.021 g, 36%) as a vitreous solid. [α]2D0 = +2.54 (c
“folded wings” orientations were attributed by calculations
to 3 and 4, respectively. Examination of the CID spectra
of the proton-bonded diastereomeric [M·H·A]+ complexes
between 4 and a number of chiral guests A led to the con-
clusion that the host had a pronounced selectivity towards
the enantiomers of some guests (tyrOMe, amph), but was
unaffected by the chirality of others (trp). The homochiral
1
= 0.15, CHCl3). H and 13C NMR signals and MS (ESI) data are
coincident with those reported for 3.
Basket Bis(diamidodiphenylethylene) Resorcin[4]arene (4): DIPEA
(0.062 mL, 0.36 mmol) was added to a solution of 2b (0.054 g,
0.06 mmol) in dry THF (5 mL), and the mixture was stirred at
room temperature for about 20 min. A solution of (1R,2R)-(+)-1,2-
diphenylethylenediamine (0.038 g, 0.18 mmol) in dry THF (5 mL)
was then added dropwise over 1.5 h. The mixture was stirred and
heated at reflux for 3 h. Standard workup and purification (silica
gel; CHCl3/MeOH, 99.5:0.5) gave compound 4 (0.022 g, 31%) as a
complex [4·H·-tyrOMe +
] was more stable than its hetero-
chiral counterpart, but the opposite was true for the
[4·H·amph]+ complexes. In spite of their similar thermo-
dynamic stabilities, a detailed kinetic study of the their
base-induced replacement reactions revealed that the
[M·H·A]+ complexes undergo an enantioselective loss of the
guest governed by the effects of the chiral conformation of
the resorcinarene architecture
1
vitreous solid. [α]2D0 = –59.9 (c = 0.22, CHCl3). H and 13C NMR
signals as in Table 1. MS (ESI+): m/z = 1208.4 [M + Na]+.
C72H72N4O12 (1185.38): calcd. C 72.95, H 6.12, N 4.73; found C
72.73, H 6.10, N 4.71.
ent-4: Treatment of 2b with (1S,2S)-(–)-1,2-diphenylethylenedi-
amine under the same conditions as those used for the preparation
of 4 afforded ent-4 (0.021 g, 29%) as a vitreous solid. [α]2D0 = +59.9
Experimental Section
1
General Remarks: H and 13C NMR spectra were recorded at 400
1
(c = 0.12, CHCl3). H and 13C NMR signals and MS (ESI) data
and 75 MHz, respectively (TMS = 0 ppm as internal standard in
CDCl3 solutions). Mass spectra (MS) were obtained with a
Thermo Finnegan LCQ Deca XP-Plus ion-trap mass spectrometer
equipped with an electrospray ionization (ESI) source. Conditions
as follows: source voltage = +5.0 kV, sheath gas = 25 AU (Arbi-
trary Units), auxiliary gas = 10 AU, capillary voltage = +40.0 V,
capillary temperature = 200 °C, tube lens offset = +15 V. The
FTICR experiments were performed with an APEX III (7 T Mag-
net) FTICR mass spectrometer equipped with an Apollo ESI
source (Bruker Daltonik GmbH, Bremen). Optical rotations were
measured with a Jasco P-1030 polarimeter.
are coincident with those reported for 4.
Mass Spectrometric Experiments: The - and  enantiomers of
guests A [A = tryptophan (trp), tyrosine (tyr), and amphetamine
(amph)] were purchased from Aldrich Co. and used without further
purification. The same source provided (R)-(–)-2-butylamine (BR)
and (S)-(+)-2-butylamine (BS), which were purified in a vacuum
manifold with several freeze–thaw cycles. A simple and safe pro-
cedure was used to prepare the pure enantiomers of tyrOMe: acetyl
chloride (5 mL) was added dropwise to cooled dry methanol
(50 mL; T = 0 °C) containing - or -tyrosine (1.7 mmol). The mix-
ture was heated at reflux for about 2 h and then evaporated to
dryness.
The proton-bound diastereomeric complexes [M·H·A]+ were gener-
ated by electron-spraying hydroalcoholic solutions of 4 (1ϫ10–5 ;
H2O/CH3OH, 1:3) containing a fivefold excess of the single
enantiomers of guests A. Abundant signals corresponding to the
natural isotopomers of the proton-bound complex [M·H·A]+ were
monitored and isolated from the accompanying ions. The single
complexes were then individually subjected to collision-induced
dissociation (CID) by using He (10–5 Torr) as target gas.
For the FTICR experiments, stock solutions (1ϫ10–5 ; H2O/
CH3OH, 1:3) of either 4 or ent-4 containing a fivefold excess of -
tyrOMe or -amph were electrosprayed through a heated capillary
(T = 130 °C) into the external source of the FTICR mass spectrom-
eter, and the resulting positive ions were transported into the ana-
lyzer cell. Abundant signals corresponding to the natural isotopo-
mers of the proton-bound complex [M·H·A]+ were monitored and
isolated by broad-band ejection of the accompanying ions. When
a background pressure of 4.6–7.3ϫ10–8 mbar of the chiral amine
B was introduced into the FTICR cell, the exchange reaction
[Equation (1)] exclusively took place. The appearance of the ex-
changed product [M·H·B]+ was monitored as a function of time.
All the exchange reactions represented by Equation (1) obey
pseudo-first-order kinetics (corr. coeff. r2 Ͼ 0.990). This indicates
that the [M·H·A]+ complexes were thermalized in their reactions
with B. The corresponding second-order rate constants k were cal-
culated from the ratio between the slope of the first-order plots and
the B pressure. Their values, compared with the relevant collision
rate constants (kcoll), estimated according to Su’s trajectory calcula-
tion method,[17] provides directly the efficiency of the reaction (eff
= k/kcoll).
Resorcin[4]arene Tetraacid 2a: Compound 2 (1.6 g, 1.7 mmol), syn-
thesized as described previously,[9a] was dissolved in EtOH (10 mL),
and 2  NaOH (1.2 g, 30 mmol) was added (5 mL). The reaction
mixture was stirred for 4 h at reflux. EtOH was removed in vacuo,
and the aqueous solution was acidified with glacial acetic acid. The
precipitate was filtered, rinsed several times with water, and dried
to give 2a in a quantitative yield. 1H NMR (400 MHz, CDCl3,
298 K): δ = 9.57 (br. s, 1 H, COOH), 6.52 (s, 4 H, Hi), 6.30 (s, 4
H, He), 4.95 (t, J = 7.0 Hz, 4 H, CH), 3.63 (s, 24 H, OMe), 2.78 (d,
J = 7.0 Hz, 8 H, CH2) ppm. 13C NMR (75 MHz, CDCl3, 298 K): δ
= 175.86 (COOH), 156.03 (C-O), 125.88 (CHi), 123.99 (C-C), 96.28
(CHe), 55.89 (OMe), 36.25 (CH2), 33.01 (CH) ppm.
Resorcin[4]arene Tetrachloride (2b): SOCl2 (2.4 mL, 33 mmol) was
added under an atmosphere of nitrogen to a solution of 2a (0.15 g,
0.18 mmol) in dry benzene (15 mL). The reaction mixture was
heated at reflux whilst stirring for 4 h and allowed to stand at room
temperature overnight. Final evaporation in vacuo under an atmo-
sphere of nitrogen gave 2b as a solid in a quantitative yield.
Basket Bis(diamidocyclohexane) Resorcin[4]arene 3: Diisopropyl-
ethylamine (DIPEA; 0.062 mL, 0.36 mmol) was added to a solution
of 2b (0.054 g, 0.06 mmol) in dry THF (5 mL), and the mixture
was stirred at room temperature for about 20 min. A solution of
(1R,2R)-(–)-1,2-diaminocyclohexane (0.020 g, 0.18 mmol) in dry
THF (5 mL) was then added dropwise over 1.5 h. The mixture was
stirred and heated at reflux for 3 h. Standard workup and purifica-
tion (silica gel; CHCl3/MeOH, 97:3) afforded 3 (0.021 g, 35%) as
a vitreous solid. [α]2D0 = –2.45 (c = 0.20, CHCl3). 1H and 13C NMR
signals as in Table 1. MS (ESI+): m/z = 1012.2 [M + Na]+.
C56H68N4O12 (989.17): calcd. C 68.00, H 6.93, N 5.66; found C
68.20, H 6.95, N 5.68.
Eur. J. Org. Chem. 2007, 5995–6002
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6001

B. Botta, M. Speranza et al.
FULL PAPER
[7] a) S. Shinkai, T. Arimura, H. Satoh, O. Manabe, J. Chem. Soc.
Chem. Commun. 1987, 1495–1496; b) T. Grady, S. J. Harris,
M. R. Smyth, D. Diamond, P. Hailey, Anal. Chem. 1996, 68,
3775–3782; c) X. Hu, A. S. C. Chan, X. Han, J. He, J. Cheng,
Tetrahedron Lett. 1999, 40, 7115–7118; d) T. Nagasaki, H. Fuji-
shima, S. Shinkai, Chem. Lett. 1994, 989–992; e) H. Hioki, T.
Yamada, C. Fujioka, M. Kodama, Tetrahedron Lett. 1999, 40,
6821–6825; f) L. J. Prins, K. A. Jolliffe, R. Hulst, P. Timmer-
man, D. N. Reinhoudt, J. Am. Chem. Soc. 2000, 122, 3617–
3627; g) L. J. Prins, F. De Jong, P. Timmerman, D. N. Rein-
houdt, Nature 2000, 409, 181–183; h) Y. He, Y. Xiao, L. Meng,
Z. Zeng, X. Wu, C.-T. Wu, Tetrahedron Lett. 2002, 43, 6249–
6253; i) K. Ito, M. Noike, A. Kida, Y. Ohba, J. Org. Chem.
2002, 67, 7519–7522; j) W. Guo, J. Wang, C. Wang, J. He, X.
He, J. Cheng, Tetrahedron Lett. 2002, 43, 5665–5667.
[8] a) Y. S. Zheng, C. Zhang, Org. Lett. 2004, 6, 1189–1192; b) X.-
X. Liu, Y.-S. Zheng, Tetrahedron Lett. 2006, 47, 6357–6360; c)
A. V. Yakovenko, V. I. Boyko, V. I. Kalchenko, L. Baldini, A.
Casnati, F. Sansone, R. Ungaro, J. Org. Chem. 2007, 72, 3223–
3231.
[9] a) B. Botta, M. C. Di Giovanni, G. Delle Monache, M. C.
De Rosa, E. Gács-Baitz, M. Botta, F. Corelli, A. Tafi, A. San-
tini, E. Benedetti, C. Pedone, D. Misiti, J. Org. Chem. 1994,
59, 1532–1541; b) B. Botta, G. Delle Monache, G. Zappia, D.
Misiti, M. C. Baratto, R. Pogni, E. Gács-Baitz, M. Botta, F.
Corelli, F. Manetti, A. Tafi, J. Org. Chem. 2002, 67, 1178–1183.
[10] B. Botta, G. Delle Monache, M. C. De Rosa, C. Seri, E. Bened-
etti, R. Iacovino, M. Botta, F. Corelli, V. Masignani, A. Tafi,
E. Gács-Baitz, A. Santini, D. Misiti, J. Org. Chem. 1997, 62,
1788–1794.
Supporting Information (see footnote on the first page of this arti-
cle): CID spectra of the proton-bonded diastereomeric [4·H·A]+
complexes [A = tyrosine methyl ester (tyrOMe), tryptophan (trp), or
amphetamine (amph)].
Acknowledgments
Financial support by the Università “La Sapienza”, Roma, Italy
(Funds for selected research topics 2005–2007), FIRST (grant
RBIP067F9E), FIRB 2003, and FIRB (grant RBPR05NWWC_
006) is acknowledged.
[1] a) H.-J. Schneider, Angew. Chem. Int. Ed. Engl. 1991, 30, 1417–
1436; b) A. J. Kirby, Angew. Chem. Int. Ed. Engl. 1996, 35,
706–724; c) A. P. Davis, R. S. Wareham, Angew. Chem. Int. Ed.
1999, 38, 2978–2996; d) W. B. Motherwell, M. J. Bingham, Y.
Six, Tetrahedron 2001, 57, 4663–4686.
[2] a) C. D. Gutsche, Monographs in Supramolecular Chemistry:
Calixarenes (Ed.: J. F. Stoddart), Royal Society of Chemistry,
Cambridge, 1989; b) J. Vicens, V. Böhmer (Eds.), Calixarenes:
A Versatile Class of Macrocyclic Compounds, Kluwer, Dord-
recht, 1991 and references cited therein; c) V. Böhmer, Angew.
Chem. Int. Ed. Engl. 1995, 34, 713–745; d) C. D. Gutsche,
Aldrichimica Acta 1995, 28, 3–9; e) Z. Asfari, V. Böhmer, J.
Harrowfield, J. Vicens (Eds.), Calixarenes 2001, Kluwer, Dord-
recht, 2001.
[3] a) D. J. Cram, J. M. Cram, Monographs in Supramolecular
Chemistry: Container Molecules and Their Guests (Ed. J. F.
Stoddart), Royal Society of Chemistry, Cambridge, 1994; b) F.
Hof, S. L. Craig, C. Nuckolls, J. Rebek Jr, Angew. Chem. Int.
Engl. Ed. 2002, 41, 1488–1508; c) R. Warmuth, J. Yoon, Acc.
Chem. Res. 2001, 34, 95–105; d) I. Higler, P. Timmerman, D. N.
Reinhoudt, Eur. J. Org. Chem. 1998, 2689–2702.
[4] a) D. M. Rudkevich, J. Rebek Jr, Eur. J. Org. Chem. 1999,
1991–2005; b) A. Jasat, J. C. Sherman, Chem. Rev. 1999, 99,
931–968.
[11] L. L. C. Schrodinger, New York, USA, http://www.schroding-
er.com.
[12] a) S. J. Weiner, P. A. Kollman, D. A. Case, U. Chandra Singh,
C. Ghio, G. Alagona, S. Profeta Jr., P. Weiner, J. Am. Chem.
Soc. 1984, 106, 765–784; b) S. J. Weiner, P. A. Kollman, D. T.
Nguyen, D. A. Case, J. Comput. Chem. 1986, 7, 230–252; c)
D. Q. McDonald, W. C. Still, Tetrahedron Lett. 1992, 33, 7743–
7746.
[13] G. Chang, W. C. Guida, W. C. Still, J. Am. Chem. Soc. 1989,
[5] F. Diedrich, Monographs in Supramolecular Chemistry: Cy-
clophanes (Ed. J. F. Stoddart), Royal Society of Chemistry,
Cambridge, 1994.
111, 4379–4386.
[14] I. Kolossvàry, W. C. Guida, J. Comput. Chem. 1999, 20, 1671–
1684.
[6] a) W. Verboom, P. J. Bodewes, G. V. Essen, P. Timmerman,
G. J. Hummer, S. Harkeman, D. N. Reinhoudt, Tetrahedron
1995, 51, 499–512; b) P. A. Reddy, C. D. Gutsche, J. Org. Chem.
1993, 58, 3245–3251; c) Z.-C. Ho, M.-C. Ku, C.-M. Shu, L.-G.
Lin, Tetrahedron 1996, 52, 13189–13200; d) F. Arnaud-Neu, G.
Ferguson, S. Fuangswasdi, A. Notti, S. Pappalardo, M. F. Par-
isi, A. Petringa, J. Org. Chem. 1998, 63, 7770–7779; e) G. Fer-
guson, J. F. Gallagher, A. J. Lough, A. Notti, S. Pappalardo,
M. F. Parisi, J. Org. Chem. 1999, 64, 5876–5885; f) K. Iwamoto,
H. Shimizu, K. Araki, S. Hinkai, J. Am. Chem. Soc. 1993, 115,
3997–4006; g) S. Pappalardo, M. F. Parisi, Tetrahedron Lett.
1996, 37, 1493–1496; h) J. K. Browne, M. A. McKervey, M.
Pitarch, J. A. Russell, J. S. Millership, Tetrahedron Lett. 1998,
39, 1787–1790; i) C.-M. Shu, W.-S. Chung, S.-H. Wu, L.-G.
Lin, J. Org. Chem. 1999, 64, 2673–2679; j) Y.-D. Cao, J. Luo,
Q.-Y. Zheng, C.-F. Chen, M.-X. Wang, Z.-T. Huang, J. Org.
Chem. 2004, 69, 206–208; k) Y. Kubo, S. Maeda, T. Sumio, M.
Kubo, Nature 1996, 382, 522–524; l) C. Lynam, K. Jennings,
K. Nolan, P. Kane, M. A. McKervey, D. Diamond, Anal.
Chem. 2002, 74, 59–66.
[15] W. F. Gunsteren, H. J. C. Berendsen, Mol. Simul. 1988, 1, 173–
185.
[16] a) B. Botta, M. Botta, A. Filippi, A. Tafi, G. Delle Monache,
M. Speranza, J. Am. Chem. Soc. 2002, 124, 7658–7659; b) A.
Tafi, B. Botta, M. Botta, G. Delle Monache, A. Filippi, M.
Speranza, Chem. Eur. J. 2004, 10, 4126–4135; c) B. Botta, D.
Subissati, A. Tafi, G. Delle Monache, A. Filippi, M. Speranza,
Angew. Chem. Int. Ed. 2004, 43, 4767–4770; d) B. Botta, F.
Caporuscio, I. DЈAcquarica, G. Delle Monache, D. Subissati,
A. Tafi, M. Botta, A. Filippi, M. Speranza, Chem. Eur. J. 2006,
12, 8096–8105; e) B. Botta, F. Caporuscio, D. Subissati, A. Tafi,
M. Botta, A. Filippi, M. Speranza, Angew. Chem. Int. Ed.
2006, 45, 2717–2720.
[17] T. Su, J. Chem. Phys. 1988, 88, 4102–4103.
Received: September 5, 2007
Published Online: November 12, 2007
6002
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