Molecular recognition by novel cage-type azaparacyclophanes bearing chiral binding sites in aqueous media

Novel cage-type cyclophanes which are constructed with two rigid macrocyclic skeletons, tetraaza[6.1.6.1 Iparacyclophane and tetraaza[3.3.3.3]paracyclophane, and four chiral bridging components were prepared. An asymmetric character of the internal cavity was clarified by means of circular dichroism (CD) spectroscopy and a computer-aided molecular modeling study based on molecular mechanics and dynamics (BIOGRAF, Dreiding-l and Dreiding-ll) conformational search. In aqueous media, the present hosts strongly bound anionic and nonionic hydrophobic guests to form inclusion complexes in 1 :I stoichiometry and the CD phenomena were induced in an incorporated achiral guest molecule through its stereochemical interaction with the chiral host cavity. In addition, the present hosts exhibited discriminative recognition toward steroid hormones in D20/CD30D (3:l v/v) as effected by hydrophobic and x--x interactions. The chirality-based discrimination of estrogens was attributed to their different modes of hydrogen bonding with the hosts. INTRODUCTION Currently, there is growing interest in molecular recognition by cyclophanes in order to mimic specific functions of naturally occurring supramolecular hosts, such as enzymes and receptors (ref. 1). The overall guest-binding ability of a host molecule in aqueous media is highly dependent on the hydrophobic character of the host cavity, and enhanced as the hydrophobicity increases since noncovalent host-guest interactions become more effective in well-desolvated and hydrophobic microenvironments. Although moderate guest recognition has been exercised by various cyclophanes composed of a single macrocyclic skeleton, more specific molecular recognition can be achieved by modified cyclophane hosts capable of providing a three-dimensionally extended internal cavity. On these grounds, we have recently developed Kyuphane (1) composed of six faces, each being constructed with a 2,11,20,29-tetraaza[3.3.3.3]paracyclophane ring, as a cage-type host (ref. 2). Host 1 is soluble in acidic aqueous media below pH 4, and exhibits the following unique functions with regard to molecular recognition: (1) 1 demonstrates a pH-dependent guest-binding ability due to change in the specific microenvironmental polarity of its three dimensional cavity upon variable protonation of the nitrogen atoms. (2) 1 shows sizeand shapesensitive molecular discrimination originating from the rigid geometry of the hydrophobic cavity and the specific protonation geometry. (3) The proton NMR signals of guest molecules, such as naphthalene2,6-disulfonate, 8-anilinonaphthalene-1-sulfonate and 6-p-toluidinonaphtalene-2-sulfonate, completely disappear upon complexation with 1. Meanwhile, binding sites of naturally occurring enzymes and receptors are constructed with various optically active amino acid residues so that these supramolecules show outstanding chiral recognition toward substrates and other external substances. In this context, the next strategy is to get further insights into the chirality-based molecular recognition behavior of cage-type cyclophanes toward various guests in aqueous media. From such a viewpoint, we prepared novel cage-type peptide cyclophanes bearing chiral binding sites provided by Land D-valine residues [(+)-2 and (-)-2, respectively] (ref. 3). Both (+)-2 and (-)-2 are soluble in acidic aqueous media and behave as polycationic hosts. In order to obtain water-soluble hosts in aqueous media over a wide pH range, we modified (+)-2 and (-)-2 by introducing a pyridinium moiety into each bridging component to afford cationic cage-type peptide cyclophanes [(+)-3 and (-)-31 (refs. 4, 5). Non-cage cyclophanes were also synthesized by introducing the identical Land D-amino acid residues into a rigid tetraaza[6.1.6.l]paracyclophane skeleton [(+)-4 and (-)-4, respectively] as references in order to characterize the specific molecular recognition feature of the cage molecules.