BIS(ALKYLGUANIDINIUM) RECEPTORS FOR PHOSPHODIESTERS - EFFECT OF COUNTERIONS, SOLVENT MIXTURES, AND CAVITY FLEXIBILITY ON COMPLEXATION

Four bis(guanidinium) receptors have been synthesized in which the guanidinium groups are spatially preorganized by an octahydroacridine (meso-3 and d,l-3) or hexahydrodicyclopenta[b,e]pyridine (meso-4 and d,l-4) spacer to complement a phosphodiester. These structures are designed to mimic the active site of staphylococcal nuclease and, thereby form four hydrogen bonds to a bound phosphodiester with little reorganization of the host structures. The syntheses involve two parts: construction of the spacer and formation of the aminoimidazoline groups via an intramolecular cyclization between an amine and a thiouronium salt. Binding constants between the receptors and dibenzyl phosphate range from 4.0 X 10(3) to 10 M-1 in highly competitive solvent systems such as aqueous DMSO. Each receptor forms both a 1:1 and 2:1 phosphate to host complex. The methods for determining K1 and K2 are discussed in detail and involve both P-31 and H-1 NMR titration experiments followed by a linear treatment of the data. Binding in pure DMSO is worth 3-4 kcal/mol, but the addition of water significantly decreases the degree of complexation. When the guanidinium counterions are tetraphenylboron, the meso forms of the hosts are the best receptors due to preorganization of the guanidinium groups on the same face of the spacer. When the counterions are chloride, the d,l forms can be the best receptors due to a specific ion effect where a chloride is involved in the host-guest complex. Addition of chloride salts increases binding, possibly due to a chaotropic ''salting-out' phenomenon. The structures of the host-guest complexes of meso-4 with dibenzyl phosphate and phenyl phosphate have been determined by X-ray analysis. The structures demonstrate the chloride-counter ion assistance and confirm the four hydrogen bonds between the host and the guest. Near-identical structures to the crystal structures are calculated by molecular mechanics for the complex formed between dimethyl phosphate and meso-3 and meso-4. meso-3 has been found to act as an RNA hydrolysis catalyst and is the first step toward the optimization of a functional RNA-cleaving artificial enzyme.