Designed Water-Soluble Macrocyclic Esterases: From Nonproductive to Productive Binding

Article abstract of DOI:10.1021/jo00247a017

The synthesis and esterase properties of three water-soluble macrobicylic hosts, designed as α-chymotryspin mimics, are described.For supramolecular complexation in aqueous solution, host 1 possesses an apolar tetraoxa<6.1.6.1>paracyclophane binding cavity, while hosts 2 and 4 have a larger tetraoxa<8.1.8.1>paracyclophane binding site.A phenolic nucleophile is located atop the cavity of 1 and 2, while an alcoholic hydroxyl group is attached to 4.The multistep synthesis of hosts 1, 2, and 4 involves two macrocyclization reactions.A Williamson ether cyclization gives the tetraoxaparacyclophanes, and an amide cyclization attaches the nucleophiles to the binding sites.¹H NMR host-guest complexation analysis demonstrates that both 1 and 2 form complexes of high stsbility with naphthalene guests in aqueous solution.In aqueous phosphate buffer at pH 8, host 2, with its partially ionized phenolic residue, is acylated much faster by complexed 4-nitro-1-naphthyl acetate (26) than host 4, which possesses the nonionized alcoholic hydroxyl group.The acylation of 2 by the complexed ester 26 is much faster than the hydrolysis of the ester in the presence of 1, a host with the same phenolic nucleophile but with a smaller binding site.The difference in esterase activity between 1 and 2 is explained in terms of productive versus nonproductive binding.The acylation of 2 by complexed ester 26 follows saturation kinetics whereas the hydrolysis of 26 in the presence of 1 obeys second-order kinetics.Host 2 shows a modest catalytic turnover in the hydrolysis of 26 in aqueous phosphate buffer at pH 8.The nature of catalysis provided by 2 is discussed.