Chiral lactic acid and ethyl lactate p-tert-butylcalix[4]arene derivatives

Article abstract of DOI:10.1039/a702794j

Ethyl (S)-(-)-O-tosyllactate reacted with p-tert-butylcalix[4]arene in K₂CO₃-acetone with inversion of configuration on the asymmetric centre, and only the bis-substitution product on the distal oxygens was obtained. Further attempts to react the bis(lactate)p-tert-butylcalix[4]arene derivative with BrCH₂CO₂CH₃ under the same conditions failed. X-Ray analysis of the lactate derivative shows two independent molecules in the unit cell; one CH₃ of the ethyl radical is immersed in the cavity of the other molecule Both adopt a slightly distorted cone conformation. NMR analysis shows that carbons and hydrogens of the methylene bridges and meta positions are diastereotopic. Ester hydrolysis was carried out without racemization, and the diastereotopic behaviour of the lactic acid derivative was maintained.

Full text of DOI:10.1039/a702794j

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Chiral lactic acid and ethyl lactate p-tert-butylcalix[4]arene
derivatives
Márcio Lazzarotto,* Francine F. Nachtigall, Ivo Vencato and Faruk Nome*
Departamento de Química, Universidade Federal de Santa Catarina, 88049-970, Florianópolis,
SC, Brasil
Ethyl (S)-(؊)-O-tosyllactate reacted with p-tert-butylcalix[4]arene in K2CO3–acetone with inversion
of configuration on the asymmetric centre, and only the bis-substitution product on the distal oxygens
was obtained. Further attempts to react the bis(lactate) p-tert-butylcalix[4]arene derivative with
BrCH2CO2CH3 under the same conditions failed. X-Ray analysis of the lactate derivative shows two
independent molecules in the unit cell; one CH3 of the ethyl radical is immersed in the cavity of the other
molecule. Both adopt a slightly distorted cone conformation. NMR analysis shows that carbons and
hydrogens of the methylene bridges and meta positions are diastereotopic. Ester hydrolysis was carried
out without racemization, and the diastereotopic behaviour of the lactic acid derivative was maintained.
Introduction
Calixarenes are versatile macrocycles, which, when properly
OTs
functionalized, have their conformational mobility restricted,
+
C
H
allowing the obtention of host molecules with functional
groups in well-defined positions. Thus, especially in the cone
conformation, they can be used as a basic skeleton1 in the prep-
aration of synthetic receptors that possess sites with convergent
functional groups for binding of ions or neutral molecules.
The exhaustive alkylation of calix[4]arenes with alkyl bromo-
acetates furnishes products used as selective ionophores for
sodium ions.2 Furthermore, ketone,3 amide and sulfonamide4
correlates have been synthesized, displaying interesting proper-
ties as hosts to alkaline and alkaline earth as well as transition
metals, which have been attributed to the convergent location
of electron-rich atoms. On the other hand, there are no
examples of asymmetric calixarenes obtained by an analogous
procedure.
EtO2C
CH3
4
OH
K2CO3 acetone
–OH–EtOH
Heq
Heq
Two synthetic pathways for the preparation of chiral calix-
arenes are possible. The first is a stepwise synthesis yielding
inherently chiral calixarenes, which was used by Shinkai et al.5
to prepare the first resolved chiral calixarene. Other asymmetric
calixarenes with different groups have been synthesized,6,7 with-
out resolution. The second method is the introduction of
a chiral residue into the calixarene structure through function-
alization at the lower8,9 or upper rim.10 The only example of a
chiral calixarene that is capable of acting as a chiral receptor,
prepared by this method, was a calix[4]crown ether developed
by Pappalardo and Parisi.11
In this work, we report the reaction of ethyl (S)-(Ϫ)-O-
tosyllactate with p-tert-butylcalix[4]arene, which yields a chiral
bis(ethyl lactate) p-tert-butylcalix[4]arene derivative. The chiral
lactate moieties impose asymmetry upon the calixarene struc-
ture, as is established via 1H and 13C NMR experiments.
2
2
O
C
Hax OH
O
Hax OH
CO2Et
C
H
H3C
CO2H
H3C
H
2
1
Scheme 1
tetrasubstituted product,13 the bis-substituted product being
obtained only by the use of 2 equiv. of BrCH2CO2Et.14 The
complete substitution of 1 at the remaining phenolic oxygens
was attempted with the less bulky BrCH2CO2Me, but failed to
occur under the same conditions (K2CO3–acetone).
The infrared analysis of 1 shows a broad absorption at 3390
cmϪ1, revealing intramolecular hydrogen bonding. This correl-
ates with a ‘cone’ conformation, where the remaining phenolic
hydrogens are at a suitable distance from the vicinal oxygens.
The hydrolysis of the lactate ester 1 in EtOH–OHϪ yields the
lactic acid 2 without racemization.
Results and discussion
The reaction of p-tert-butylcalix[4]arene with ethyl (S)-(Ϫ)-O-
tosyllactate in potassium carbonate–acetone resulted in bis-
substitution on the distal phenolic oxygens (compound 1, in
Scheme 1). The degree of alkylation did not increase, even in
the presence of 10 equiv. of the tosyllactate. The reaction pro-
ceeds via an SN2 mechanism, with inversion of the asymmetric
centre, and the formation of a diastereoisomeric pair was not
observed via NMR spectroscopy.12
NMR Data
1
The H NMR spectra (Fig. 1) exhibited two singlets, at δ 1.30
and 0.93 for 1 and δ 1.31 and 1.02 for 2, corresponding to the
tert-butyl groups linked to the unsubstituted and substituted
rings with the lactate (1) and lactic acid moieties (2), respect-
ively. The hydrogens and carbons of the calix structure, outside
the axis defined by the phenolic oxygen and the carbon linked
to the tert-butyl groups, are diastereotopic and distinct by
NMR analysis due to the presence of the chiral moiety. For
Under identical conditions, the reaction of p-tert-butyl-
calix[4]arene with ethyl bromoacetate furnishes exclusively the
J. Chem. Soc., Perkin Trans. 2, 1998
995

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Table 1 Chemical shifts of bis-substituted calixarenes
R
δax
δeq
∆δ = δax Ϫ δeq
1 CH(CH3)CO2Et
2 CH(CH3)CO2H
3a CH2CO2Eta
3c CH2CO2Ha
4.35; 4.45
4.05; 4.23
4.48
4.23
4.21
4.43
4.17
4.24
3.32; 3.33
3.42; 3.47
3.25
3.38
3.31
3.23
3.41
3.42
1.03; 1.12
0.63; 0.76
1.23
0.85
0.90
1.20
0.76
0.82
3b CH2COMea
a
3d CH2CONEt2
a
3e CH2CONH2
3f CH2CN
a Values extracted from ref. 14.
Fig. 2 13C NMR spectrum (aromatic carbons) of 1 in CDCl3
aromatic hydrogens of 1 are more shielded than 2, while the
aromatic carbons linked to the phenolic oxygens and the signals
due to the lactic moiety are less shielded. We believe that
the lactic acid moieties of 2 are more closed than the lactate
moieties of 1. This makes the substituted rings of 1 more paral-
lel, communicating a major distinction for the equatorial and
axial hydrogens. In fact, for a series of bis-substituted calix-
arene derivatives 3, the groups where ∆δ = δeq Ϫ δax is smaller
are those whose substituents are also smaller, as seen in Table 1.
Fig. 1 1H NMR spectrum of 1 in CDCl3
example, the methylene hydrogens of 1 give four doublets; the
signals corresponding to the equatorial hydrogens are centred
at δ 3.30 and 3.29, and the axial hydrogens are centred at δ 4.46
and 4.38. The meta hydrogens of the aromatic rings give four
doublets (J = 2 Hz). Surprisingly, the difference between the
signals of the aromatic hydrogens without the ethyl lactate
moiety (δ 7.01 and 7.09) is higher than that of the substituted
rings (δ 6.72 and 6.78). It is noteworthy that the methylenic
hydrogens of the CH2CH3 group, which may rotate freely, are
not split by the asymmetric centre, so the rigidity of the calix
cavity is important to the splitting of signals.
This diastereotopic behaviour remains after the hydrolysis of
the ester. The difference in chemical shift between the axial
hydrogens of compound 1 is ca. 0.1 ppm and increases to ca.
0.18 ppm in compound 2. The splitting of the equatorial hydro-
gens is smaller and increases from 0.01 ppm (lactate calix 1) to
0.05 ppm (lactic calix 2) upon hydrolysis of the lactate moiety.
Our data indicate that the compounds are in the cone con-
formation in solution, since ∆δ (∆δ = δeq Ϫ δax) is ca. 0.9 0.2
ppm for a system in the cone conformation and zero for a sys-
tem in the 1,3 alternate conformation. The value ∆δ decreases
drastically from 1.03–1.12 for compound 1 to 0.63–0.76 for 2
(see Table 1). The signal of the axial methylenic hydrogen of
compound 2, which is lower than those reported for similar
compounds (Table 1), may be due to the proximity of the lactic
acid moiety.
2
OR
OH
3
X-Ray structural analysis of compound 1
The cone conformation predicted from IR and NMR data
agrees with the X-ray analysis of 1 (Fig. 3). The crystallo-
graphic cell contains two independent molecules, which caused
difficulties in the treatment of the data, but there are no
important differences between the geometrical parameters of
molecule A and molecule B.
An ethoxy group of molecule B is immersed in the cavity of
molecule A, and the methyl group lies midway from the centre
of the aromatic rings. Least-square planes show that the aro-
matic rings are planar, and their planes intercept the plane
formed by the four methylenes with angles of 111.0, 125.6,
116.0 and 126.5Њ for molecule A and 114.5, 123.8, 116.1 and
125.7Њ for molecule B, revealing that molecules A and B adopt a
cone shape with little distortion. The substituted rings present
the smaller angles for both molecules.
This reported behaviour is typical of diastereotopic systems
and demonstrates that the introduction of the chiral lactate
group induces the asymmetric phenomena observed.
The aromatic carbons of 1 and 2 consistently generate 12
peaks (Fig. 2). This fact indicates that the ortho and meta
carbons from the same rings are different from one another.
The DEPT analysis of 1 and 2 reveals that the four most intense
aromatic peaks belong to carbons linked to hydrogens, as
expected. The methylenic carbons of 2 split into two signals
very near δ 32.4 and 32.6, while with 1 this splitting was not
observed.
The lactate moieties spread away from one another, and the
carbonyls are oriented outwards from the cavity, pointing
towards opposite sides. The two α-methyls also point towards
opposite sides, and apparently block the remaining phenolic
oxygens, confirming their low reactivity to further reactions.
1
The H and 13C NMR signals of the tert-butyl groups and
996
J. Chem. Soc., Perkin Trans. 2, 1998

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three times with 20 ml of CH2Cl2, the organic phase was
washed with 1  HCl and brine, and dried over MgSO4. The
solvent was evaporated and the residue was recrystallized from
ethanol–water giving 1.05 g of colourless crystals. Yield: 78%;
mp 151 ЊC; 1H NMR δ 7.09 (d, Ar-H, 2 H, J 2), 7.01 (d, Ar-H, 2
H, J 2), 6.78 (d, Ar-H, 2 H, J 2), 6.72 (d, Ar-H, 2 H, J 2), 4.60
(q, CH, 2 H, J 6.8), 4.46 (d, ArCH2Ar, 2 H, J 13.8), 4.38 (d,
ArCH2Ar, 2 H, J 12.8), 4.41 (q, CH2, J 7.14 H), 3.30 (d,
ArCH2Ar, 2 H, J 13.8), 3.29 (d, ArCH2Ar, 2 H, J 12.8), 1.76 (d,
6 H, CH3, J 6.6), 1.30 [s, 18 H, C(CH3)3], 1.28 (t, 6 H, J 7.1,
CH3), 0.93 [s, 18 H, C(CH3)3]; 13C NMR δ 172.3, 151.3, 149.7,
147.4, 141.9, 133.5, 132.7, 129.0, 128.0, 126.7, 125.9, 125.8,
125.6, 80.6, 61.9, 34.5, 32.9, 32.4, 31.6, 18.6, 14.7; νmax(KBr)/
cmϪ1 3300 (O᎐H), 2960 (C᎐H), 1750 (C᎐O) (Calc. for C H O :
᎐
54 72
8
C, 76.38; H, 8.55. Found: C, 76.43; H, 8.05%); [α]D ϩ40 (c 5,
CHCl3).
Fig. 3 An ORTEP view of molecule A of compound 1 showing the
atomic numbering. For clarity, all the atoms are shown as small spheres
of arbitrary size.
5,11,17,23-Tetra-tert-butyl-25,27-bis[(R)-(؉)-1-carboxy-
ethoxy]-26,28-dihydroxycalix[4]arene 2
To a suspension of 1 (138 mg, 0.16 mmol) in 5 ml of ethanol was
added two drops 1  NaOH. The mixture was stirred at room
temperature for 12 h and then acidified to pH 1. The precipitate
formed was filtered and recrystallized from ethanol–water,
giving 100 mg of colourless crystals. Yield: 77%; mp 250 ЊC
(decomp.); 1H NMR δ 7.10 (d, Ar-H, 2 H, J 2), 7.05 (d, Ar-H, 2
H, J 2), 6.96 (d, Ar-H, 2 H, J 2), 6.89 (d, Ar-H, 2 H, J 2), 4.70
(q, CH, J 6.8, 2 H), 4.23 (d, ArCH2Ar, 2 H, J 13.7), 4.05 (d,
ArCH2Ar, 2 H, J 13.2), 3.47 (d, ArCH2Ar, 2 H, J 13.7), 3.42
(d, ArCH2Ar, 2 H, J 13.2), 1.70 (d, CH3, 6 H, J 6.7), 1.31 [s,
C(CH3)3, 18 H], 1.02 [s, C(CH3)3, 18 H]; 13C NMR δ 172.5,
149.3, 148.2, 147.3, 143.1, 132.6, 132.3, 127.3, 127.1, 126.9,
125.7, 125.6, 125.4, 80.8, 34.1, 33.9, 32.6, 32.4, 31.6, 30.9, 17.1;
The X-ray analysis shows the absence of a rigid pre-
organised cavity formed by the O᎐C᎐C᎐O moieties in the solid
᎐
state, to which the complexation ability of the tetrasubstituted
ethoxycarbonylmethylcalix[4]arenes may be attributed.
Each molecule exhibits two intramolecular O᎐H ؒ ؒ ؒ O hydro-
gen bonds between the phenolic oxygen and ethereal oxy-
gen atoms, as may be deduced by the distances of the
vicinal oxygens [O31 ؒ ؒ ؒ O11 = 2.76(2), O51 ؒ ؒ ؒ O71 = 2.62(2),
O31Ј ؒ ؒ ؒ O11Ј = 2.81(2), O51Ј ؒ ؒ ؒ O71Ј = 2.70(2) Å].
The X-ray data are in accordance with the cone conform-
ations deduced from the NMR data, allowing us to understand
the low reactivity of the remaining phenolic hydroxy groups of
1. The effect of the asymmetric centre on the methylene and
aromatic sites occurs through space, due to the low mobility of
the structure.
νmax(KBr)/cmϪ1 1730 (C᎐O) (Calc. for C H O ϩ H O: C,
᎐
50 64
8
2
74.03; H, 8.21. Found: C, 74.20; H, 8.08%); [α]D Ϫ27 (c 5,
CHCl3).
Crystallographic data for 1
Conclusion
C54H72O8, M = 849.17, triclinic, a = 11.484(3), b = 12.865(2),
c = 18.656(6) Å, α = 76.21(2), β = 84.40(3), γ = 74.02(2)Њ, V =
2572.1(9) Å3 (by least-squares refinement on diffractometer
angles for 23 automatically centred reflections, λ = 0.710 73 Å),
space group P1, Z = 2, Dc = 1.096 kg mϪ3, µ(Mo-Kα) = 0.673
cmϪ1, F(000) = 920. A transparent crystal of approximate
dimensions 0.30 × 0.45 × 0.65 mm was used for data collection.
Data were measured at room temperature on a CAD4 auto-
matic four-circle diffractometer in the range 2.2–24Њ. 8423
reflections were collected of which 6872 were unique and 4326
were observed with I у 3σ(I). Data were corrected for Lorentz
and polarization effects but not for absorption. The struc-
ture was solved by direct methods16 and refined using the
MOLEN17 program package. In the final least-squares cycles,
only the non-hydrogen atoms of the phenyl rings were refined
anisotropically due to the small number of observed reflections,
in comparison to the large number of parameters to be refined
(two independent molecules in the asymmetric unit). H atoms
were included at calculated positions with fixed distance of 0.95
Å, and Biso = 4.0 Å2, except for OH groups. A weighting scheme
The preparation of chiral bis[(R)-ethyl lactate] and bis[(R)-
lactic acid] p-tert-butylcalix[4]arene derivatives in good yields
has been achieved. The chiral moieties communicate asym-
metry to all elements of the calixarene structure, which adopts a
slightly distorted cone conformation. The reported method
allows the introduction of chiral moieties on the lower rim of
calixarenes.
To the best of our knowledge, the asymmetric phenomena
observed in the NMR spectra, where the hydrogens and
carbons of the calix structure are diastereotopic and distinct,
has not been reported for p-tert-butylcalix[4]arene derivatives.
Thus, compounds 1 and 2 represent the first examples of this
type of behaviour.
Experimental
Mps were obtained on a double plate melting-point apparatus
and are uncorrected, infrared spectra on an FT-IR Bomem
device as KBr discs. 1H NMR spectra were obtained on a
Bruker 200 spectrometer, using CDCl3 solutions with tetra-
methylsilane as internal reference. Coupling constants (J) are
given in Hz. Acetone was dried over K2CO3. Ethyl (S)-(Ϫ)-O-
tosyllactate was synthesized according to a process described in
the literature.15
w
Ϫ1 = [σ2(F) ϩ (0.02F)2 ϩ 1] was used. The thermal parameters
are generally large, which are characteristic of calixarene
crystals.18–20 For these reasons the final R converged at 0.11,
Rw = 0.12 and S = 1.297 for 854 refined parameters, the final
difference Fourier map showing features from 0.48 to Ϫ0.35 e
ÅϪ3
.
5,11,17,23-Tetra-tert-butyl-25,27-bis[(R)-(؉)-1-ethoxycarbonyl-
ethoxy]-26,28-dihydroxycalix[4]arene 1
p-tert-Butylcalix[4]arene (1.0 g, 1.54 mmol), ethyl (S)-(Ϫ)-O-
tosyllactate (3.0 g, 11.1 mmol) and K2CO3 (1.0 g, 7.14 mmol)
were suspended in 20 ml of acetone under N2. The mixture was
heated under reflux for 24 h. The solvent was evaporated and
water was added to the residue. This mixture was extracted
Full crystallographic details, excluding structure factor
tables, have been deposited at the Cambridge Crystallographic
Data Centre (CCDC). For details of the deposition scheme,
see ‘Instructions for Authors’, J. Chem. Soc., Perkin Trans. 2,
available via the RSC Web pages (http://www.rsc.org/authors).
Any request to the CCDC for this material should quote the full
literature citation and the reference number 188/120.
J. Chem. Soc., Perkin Trans. 2, 1998
997

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10 T. Nagasaki, T. Yusuke and S. Shinkai, Recl. Trav. Chem. Pays-Bas.,
Acknowledgements
1993, 112, 407.
We thank PADCT, CNPq, PRONEX and CAPES for support
of this work.
11 S. Pappalardo and M. F. Parisi, Tetrahedron Lett., 1996, 37, 1493.
12 In a recent work, we observed the formation of two diastereo-
isomers in the reaction of p-tert-butylcalix[4]arene and phthaloyl--
alanine, duplicating the 1H NMR signals of the methylene and
aromatic hydrogens.
13 K. Iwamoto and S. Shinkai, J. Org. Chem., 1992, 57, 7066.
14 E. M. Collins, M. A. McKervey, E. Madigan, M. B. Moran,
M. Owens, G. Ferguson and S. J. Harris, J. Chem. Soc., Perkin Trans.
1, 1991, 3137.
15 D. Johnston and K. N. Slessor, Can. J. Chem., 1979, 57, 233.
16 B. Burla, M. Camalli, A. Altomare, G. Cascarano, C. Giocavazzo
and A. Guagliardi, XIV European Crystallographic Meeting,
Enschede, The Netherlands, 1992.
17 C. K. Fair, MOLEN, An Interactive Structure Solution Procedure,
Enraf-Nonius, Delft, The Netherlands, 1990.
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J. Chem. Soc., Perkin Trans. 2, 1998