Noncovalent Interactions DOI: 10.1002/ange.200903281 Quantification of a CH–p Interaction Responsible for Chiral Discrimination and Evaluation of Its Contribution to Enantioselectivity** Romen Carrillo, Matías López-Rodríguez, VictorS. Martín, and Tomµs Martín* Dedicated to Professor Julius Rebek, Jr. on the occasion of his 65th birthday The CH–p interaction, in which the CH group is aliphatic, is one of the weakest known interactions. However, this interaction is very important, [1] as it contributes significantly to the overall stability of protein structures, [2] the selective recognition and binding affinity between proteins and ligands, [3] the conformational preference of DNA, [4] the stereoselectivity of organic reactions, [5] and molecular recog- nition. [6] Therefore, the measurement of its strength and scope is very important. Such CH–p interactions have been inves- tigated qualitatively through protein mutation studies, [7] IR [8] and NMR [9] spectroscopy, X-ray crystallographic analysis, [10] and by computational methods. [11] However, the quantifica- tion of such a weak interaction is usually not easy and thus there are only a few reports of studies in this area. [12] Remarkable contributions to this field are Wilcoxs torsion balance, [13] the carbohydrate–p interaction within a b-hairpin- peptide [14] and dangling-ended DNA [15] model systems, and cyclohexylphenyl recognition in the center of a DNA duplex. [16] It is even more difficult to evaluate the contribution of a single noncovalent interaction that is involved in a specific biological or chemical event, particularly for the weak interactions. Therefore, the development of simple molecular models in order to assess the contribution of a CH–p interaction in chiral recognition processes is extremely important. Herein, we show the key role of a CH–p interaction in a remarkably high chiral discrimination dis- played by a new synthetic receptor. Furthermore, we use this new receptor as a useful model for the quantification of the interaction and for an unprecedented evaluation of its contribution to the whole chiral recognition process. During our search for new chiral cation receptors using the cis-2-oxymethyl-3-oxy-tetrahydropyran unit as a key motif, [17] we found that receptor 1 [18] displayed high associa- tion constants with ammonium salts of a-amino acid methyl esters (Scheme 1). [19] The association constants were distinc- tively higher with the d enantiomers of the amino acids, and chiral discrimination was conserved using either different solvents or different anions (Table 1 and Table S1 in the Supporting Information). Particularly high enantioselectivity was shown for those amino acids that bear aromatic side chains. Tryptophan (Trp), which has the most effective donor aromatic side chain, displays the highest association constant for the d enantiomer and the best chiral discrimination, which reached values of up to K D /K L = 33.78  0.90 (DDG 0 = (8.72  0.07) kJ mol 1 ) for Trp-OMeNO 3 in CD 3 CN (Table S1 in the Supporting Information). These data suggest that the aro- matic side chain is likely to be involved in the origin of the enantioselectivity. [20] To gain insight into the causes of this remarkably high chiral recognition, a detailed NMR-based study of the geometry of the complexes in solution was carried out. Complexation-induced chemical shifts (CISs) derived from 1 H NMR titration of the receptor 1 with both enantiomers of alanine (Ala), leucine (Leu), phenylalanine (Phe), and tryptophan picrate (Pic) salts [21] in CD 3 CN were analyzed, and a great deal of information about their binding was obtained (Figure 1). The signals for protons in positions 3, 6 (equatorial), 7, 11, and 12 are shifted markedly downfield Scheme 1. Chemical structures of receptors 1, 1F, and the ammonium salts of a-amino acid methyl esters. [*] Dr. T. Martín Instituto de Productos Naturales y Agrobiología, CSIC Francisco Sµnchez, 3, 38206 La Laguna, Tenerife (Spain) Fax: (+ 34) 922-260-135 E-mail: tmartin@ipna.csic.es Dr. R. Carrillo, Prof. Dr. M. López-Rodríguez, Prof. Dr. V. S. Martín, Dr. T. Martín Instituto Universitario de Bio-Orgµnica “Antonio Gonzµlez” Universidad de La Laguna Francisco Sµnchez, 2, 38206 La Laguna, Tenerife (Spain) [**] The authors thank Dr. K. Hirose and Dr. J. M. Sanderson for providing the titration isotherm curve fitting program, Dr. Eze- quiel Q. Morales for TOC graphic design, and Dr. David Tejedor and Dr. Fernando García-Tellado for helpful discussions. This research was supported by the Spanish MEC (CTQ2005-09074-C02-01 and 02), the MICINN-FEDER (CTQ2008-03334/BQU and CTQ2008- 06806-C02-01/BQU), FICIC, the MSC ISCIII (RETICS RD06/0020/ 1046). R.C. thanks the Spanish MEC for an FPU fellowship. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.200903281. Angewandte Chemie 7943 Angew. Chem. 2009, 121, 7943 –7948  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim