A xanthone-based neutral receptor for zwitterionic amino acids

Article abstract of DOI:10.1016/S0040-4039(03)01795-7

Combination of a xanthone and crown ether provides a receptor that extracts phenylalanine from water. Strong anisotropic shifts were observed for the guest aromatic ring in the complex. The ninhydrin test was used to assess the amount of other amino acids extracted by this receptor.

Full text of DOI:10.1016/S0040-4039(03)01795-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6983–6985
A xanthone-based neutral receptor for zwitterionic amino acids
Jose´ V. Herna´ndez, Francisco M. Mun˜iz, Ana I. Oliva, Luis Simo´n, Emilio Pe´rez and
Joaqu´ın R. Mora´n*
Departamento de Qu´ımica Orga´nica, Plaza de los Caidos 1-5, Universidad de Salamanca, E-37008 Salamanca, Spain
Received 28 May 2003; revised 11 July 2003; accepted 24 July 2003
Abstract—Combination of a xanthone and crown ether provides a receptor that extracts phenylalanine from water. Strong
anisotropic shifts were observed for the guest aromatic ring in the complex. The ninhydrin test was used to assess the amount of
other amino acids extracted by this receptor.
© 2003 Elsevier Ltd. All rights reserved.
Molecular recognition of carboxylic acids,1 and espe-
cially a amino acids,2 is of current interest due to the
great biological and technical importance of these
molecules. Successful extraction of amino acids from
water to apolar solvents has been achieved with
charged receptors.3 However, neutral systems4 may
have advantages, since the geometry and properties of
neutral complexes are easier to predict because they do
not need a counterion. Xanthones5 and chromenones6
have been shown to be useful for the development of
carboxylate hosts. Modelling studies suggest that recep-
tor 1 may be suitable for amino acid association, since
it combines a crown ether for the ammonium group
with strong xanthone based hydrogen bonds for the
carboxylate (Fig. 1).
Scheme 1 shows the synthesis of this compound.
Addition of the amino acids to the receptor in a
biphasic system of CDCl3/ D2O led to significant shifts
1
in the H NMR of the receptor signals, which suggests
associate formation. However, owing to the complex
spectra, identification of the amino acid signals in the
spectrum was, in general, not easy. An exception was
phenylalanine; the aromatic ring of this guest was
strongly shielded in the complex, and therefore easy to
identify. ortho Protons appeared at 6.86 ppm, meta at
6.33 ppm, and para at 6.26 ppm, probably because they
lay in the xanthone shielding cone (Fig. 1). Semiempiri-
cal geometry optimisations were carried out at the
restricted Hartree–Fock (RHF) level using the PM3
semiempirical SCF-MO method, including molecular
mechanics correction for HCON linkages (keyword
PM3MM), as implemented in the Gaussian 98W pro-
gram.7 These modelling studies reveal that the phenyl
ring of the guest lays over the xanthone and that
stacking effects are probable (Fig. 2).
1
Integration of the H NMR signals showed 70% extrac-
tion of this amino acid. Since NMR was not a suitable
tool for assessing the extent to which other amino acid
association was taking place, the classic ninhydrin8 test
was used. The results, summarised in Table 1, showed
that aromatic amino acid such as phenylalanine and
tryptophan are the best substrates. The stacking effect
is a good explanation for this preference, since other
lipophilic amino acids such as leucine or valine were
poorly extracted. The exception was glycine, which
owing to its small size seems to fit the cleft especially
well. Other more hydrophilic amino acids (serine,
asparagine, tyrosine) could not be extracted with this
system.
Figure 1. Proposed structure for the associate of receptor 1
and L-phenylalanine.
* Corresponding author. Tel: +34-9-2329-4481; fax: +34-9-2329-4574;
e-mail: romoran@usal.es
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01795-7

6984
J. V. Herna´ndez et al. / Tetrahedron Letters 44 (2003) 6983–6985
Scheme 1. Preparation of receptor 1. Reagents and conditions: (a) MeOH, SOCl2, 92%; (b) 4-t-butylnitrophenolate potassium salt,
DMF, 96%; (c) Fe, MeOH/AcOH, 96%; (d) HBr, reflux, 95%; (e) P2O5/MeSO3H, 86%; (f) SOCl2; (g) NEt2, 75%; (h) COCl2; (i)
t-octylamine, 96%; (j) SnCl2, MeOH, 98%; (k) acryloyl chloride, THF, 72%; (l) 1-aza-18-crown-ether-6, THF, 80%.
Figure 2. Modelling study of receptor 1 and L-phenylalanine. The diethyl carboxamide and the t-octyl group are omitted for
simplicity.
Table 1. Results of the extraction of saturated water solutions of several amino acids (0.2 ml) at 20°C with receptor 1 (4 mg)
in chloroform solution (2 ml)
Receptor 2
Glycine
98%
Alanine
25%
Phenylalanine
74%
Tryptophan
49%
Phenylglycine
8%
Valine
4%
Leucine
7%
Extraction

J. V. Herna´ndez et al. / Tetrahedron Letters 44 (2003) 6983–6985
6985
We hope that further developments on this structure
may provide highly selective amino acid extraction
systems.
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Acknowledgements
We thank Anna Lithgow for the 400 MHz NMR
spectra; Ce´sar Raposo for the mass spectra. We also
thank the ‘Direccio´n General de Investigacio´n Cien-
t´ıfica y Te´cnica’ (DGICYT Grant PB 98-0275) and JCL
(SA 63/00B) for their support of this work. The MEC
is acknowledged for three fellowships (F.M.M., L.S.,
A.I.O.).
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