A trans-tetrahydrobenzoxanthene receptor for the resolution of racemic mixtures of sulfonylamino acids Ana I. Oliva, a Luis Simón, a Francisco M. Muñiz, a Francisca Sanz b and Joaquín R. Morán* a a Departament of Organic Chemistry, University of Salamanca, Plaza de los Caídos, 1-5, 37008, Salamanca, Spain. E-mail: romoran@usal.es; Fax: 0034923294574; Tel: 0034923294481 b General X-Ray Diffraction Service, University of Salamanca, Plaza de los Caídos, 1-5, 37008, Salamanca, Spain. E-mail: sdrayosx@usal.es; Tel: 0034923291590 Received (in Cambridge, UK) 9th October 2003, Accepted 22nd December 2003 First published as an Advance Article on the web 22nd January 2004 An enantioselective cleft-type receptor for sulfonylamino acids has been prepared and its use for the resolution of the amino acid racemic mixture is shown. Enantioselective amino acid recognition is of current interest 1 and the resolution of large amounts of amino acid racemic mixtures, making use of supramolecular properties, is a very attractive possibility. 2 trans-Benzoxanthene receptors have been successful in the association of carboxylic acids. 3 Despite the fact that receptor 1 (Scheme 1) is a chiral compound, no enantioselective discrimina- tion was found when acids with asymmetric a carbons were tested. Taking into account the previously reported geometry for the associates of receptor 1 and carboxylic acids, we expected that if a sulfonyl amino acid is used as the guest its conformation could be fixed due to the formation of a strong H-bond in receptor 2, in which the carboxyl group is substituted by an aminopyridine group (Fig. 1). The preparation of receptor 2 is straightforward from receptor 1 and the lithium salt of 2-aminopyridine (Scheme 1).† The chiral recognition properties of receptor 2 were tested in CDCl 3 using competitive 1 H NMR titrations. Competitive experi- ments were carried out with the racemic receptors and enantiomer- ically pure amino acid derivatives, adding small portions of the guest to the receptor solution in CDCl 3 . 4 The formation of the diastereomeric complexes led to a splitting of the 1 H NMR host 2 signals. A plot of the movement of the chemical shift of a single proton of one diastereomeric complex against the chemical shift of the other provides a curve characteristic for each chiral recognition. The use of a home-made curve-fitting program provided the enantioselectivities. The results are shown in Table 1 and from them the importance of the acidity of the guest NH can be seen. Sulfonyl amino acids provided the best recognitions, with chiral recognitions up to 20 in the case of the dansyl derivative. Due to their high acidity, other amino acid triflates were also tested. Table 2 shows leucine to be the best substrate, while the large aromatic ring of phenylglycine probably undergoes steric hindrance, leading to low enantioselectivities. While these results seem to be in agreement with the proposed structure for the complexes of receptor 2, this could not be confirmed with the NMR experiments. Therefore, an X-ray diffraction study was undertaken. Slow evaporation of a solution of the racemic receptor 2 with racemic leucine triflate in chloroform– undecane yielded suitable cristals of the complex for X-ray analysis.‡ The structure of the complex is shown in Fig. 2 and it does not match our expectations or the structure of previous benzoxazole–tetrahydrobenzoxanthene associates. 3 The preference of the carboxylic acid for the pyridine nitrogen can be explained in terms of the higher basicity of this atom compared to the benzoxazole (pyridines are usually 10 000 times more basic than the oxazole with similar structure 5 ). This is supported by the shorter H- bond distance of the carboxylic acid in this complex (COOH…N 2.53 Å) as compared to that previously observed, in which the oxazole acts as the H-bond acceptor (COOH…N 2.66 Å). 3 Another Scheme 1 Synthesis of receptor 2. Fig. 1 Receptor 2 and the proposed complex with an amino acid triflate. Table 1 K ass Ratios between the enantiomers of receptor 2 and some amino acid derivatives in CDCl 3 at 20 °C Dansyl-L-leucine 20.0 Triflate-L-leucine 15.0 N-Phenyl-L-leucine 8.5 Mesylate-L-leucine 7.7 Carbamoyl-L-lactic acid 3.6 L-Mandelic acid 1.7 L-Lactic acid 1.2 Table 2 K ass Ratios between the enantiomers of receptor 2 and some amino acid triflates in CDCl 3 at 20 °C Triflate-L-leucine 15.0 Triflate-L-phenylalanine 13.0 Triflate-L-valine 11.0 Triflate-L-alanine 3.4 Triflate-L-phenylglycine 2.9 Fig. 2 Schematic representation of the complex between receptor 2 and the leucine triflate. This journal is © The Royal Society of Chemistry 2004 DOI: 10.1039/b312560b 426 Chem. Commun., 2004, 426–427