Chiral Molecular Recognition in a Tripeptide Benzylviologen Cyclophane Host Julia A. Gavin, Maurie E. Garcia, † Alan J. Benesi, and Thomas E. Mallouk* Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802 Received February 24, 1998 A cationic chiral cyclophane was synthesized and studied as a host for chiral and racemic π-donor molecules. The cyclophane host has a rigid binding cavity flanked by (S)-(valine-leucine-alanine) and N,N′-dibenzyl-4,4′-bipyridinium subunits, which allow for hydrogen-bonding and π-stacking interactions with included aromatic guest molecules. 1 H NMR binding titrations were performed with several different pharmaceutically interesting guest molecules including -blockers, NSAIDs, and amino acids and amino acid derivatives. The host-guest complexation constants were generally small for neutral and cationic guests (0-39 M -1 at 20 °C in water/acetone mixtures). However, a (R)/(S) enantioselectivity ratio of 13 ( 5 was found for DOPA, a strongly π-donating cationic guest. Two-dimensional NOESY 1 H NMR spectra confirm that (R)-DOPA binds inside the cavity of the host and that there is no measurable interaction of the cavity with (S)-DOPA under the same conditions. Introduction Cyclophanes, which are cyclic molecules containing aromatic groups in the ring, have interesting molecular recognition properties. 1 Because they are macrocycles, these hosts have built into them a measure of preorga- nization that enhances their affinity for guest molecules of the appropriate size and shape. 2 The hydrophobicity and π-stacking interactions of their aromatic groups also contribute to host-guest affinity, which can be very high. For these reasons, they have been widely studied as synthetic receptors 3 and as components of supramolecu- lar assemblies. 4 Chiral cyclophanes are of particular interest as the active components of stationary phases for chiral separa- tions. Cram and co-workers prepared the first cyclo- phane of this type, a crown ether incorporating a chiral binaphthol unit. 5 This host was later tethered to chro- matographic silica to produce a commercially available stationary phase that has been used for the analysis of chiral hydrogen bond donors, including amines, amino alcohols, amino acids, and amino esters. 6 More recently, Armstrong et al. 7 have immobilized several antibiotic macrocycles onto silica and have used these materials in the analysis of a wide variety of enantiomeric and diastereomeric guests. Recent work in our laboratory has shown that the intercalation of chiral cationic host molecules into R-zirconium phosphate, a lamellar cation exchanger, provides a useful medium for batchwise resolution of racemic mixtures. 8 The scale of this process is more than an order of magnitude higher than it is with conventional “brush”-type chiral stationary phases, but expansion and contraction of the solid and concomitant host preorganization effects have precluded its use in chromatographic applications. Replacing the linear chiral host that was used in those experiments with a cyclo- phane-type host containing a rigid, preorganized binding cavity could solve the problem of host preorganization and motivates the study reported in this paper. Several groups 9-11 have now incorporated chiral amino acids into cyclophane hosts. There are three significant advantages to this approach. First, the synthesis is modular and employs well-established peptide coupling methods. Second, each amide bond potentially provides two hydrogen-bonding contacts to the guest, in close proximity to an asymmetric carbon atom. Third, because there is a large inventory of natural and unnatural amino acids from which to choose, a very large number of structurally similar host molecules can be prepared. For hosts containing more than one amino acid, the synthesis can be done in combinatorial fashion, and so in principle one can make and test a diverse library of host molecules. † Current address: Department of Chemistry, Texas A&M Univerisi- ty, College Station, TX 77843. (1) For recent examples and reviews, see: (a) Wilcox, C. S.; Glagov- ich, N. M.; Webb, T. H. ACS Symp. Ser. 1994, 568, 282-90. (b) Webb, T. H.; Wilcox, C. S. Chem Soc. Rev. 1993, 22, 383-395. (c) Diederich, F.; Cyclophanes; The Royal Society of Chemistry: Cambridge, U.K. 1991. (d) Torneiro, M.; Still, W. C. J. Am. Chem. Soc. 1995, 117, 5887. (e) Helgeson, R. C.; Knobler, C. B.; Cram, D. J. J. Am. Chem. Soc. 1997, 119, 3229. (2) Cram, D. J. Angew. Chem., Int. Ed. Engl. 1988, 27, 1009. (3) Murakami, Y.; Hayashida, O. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 1140. (4) Fyfe, M. C. T.; Stoddart, J. F. Acc. Chem. Res. 1997, 30, 393. (5) (a) Kyba, E. P.; Gokel, G. W.; De Jong, F.; Koga, K.; Sousa, L. R.; Siegel, M. G.; Kaplan, L.; Sogah, G. D. Y.; Cram, D. J. J. Org. Chem. 1977, 42, 4173. (b) Cram, D. J.; Helgeson, R. C.; Peacock, S. C.; Kaplan, L. J.; Domeier, L. A.; Moreau, P.; Koga, K.; Mayer, J. M.; Chao, Y.; Siegel, M. G.; Hoffman, D. H.; Sogah, G. D. Y. J. Org. Chem. 1978, 43, 1930. (c) Lingenfelter, D. S.; Helgeson, R. C.; Cram, D. J. J. Org. Chem. 1981, 46, 393. (6) (a) Shinbo, T.; Yamaguchi, T.; Nishimura, K.; Suguira, M. J. Chromatogr. 1987, 405, 145. (b) Applications Guide for Chiral Column Selection, 2nd ed.; Chiral Technologies Inc.: Exton, PA 1993. (7) (a) Armstrong, D. W.; Tang, Y.; Chen, S.; Zhou, Y.; Bagwill, C.; Chen, J.-R. Anal. Chem. 1994, 66, 1473. 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