The recognition, complexation, and transport of cations across cell and organelle membranes are phenomena which mediate numerous cellular events. Ionophores are compounds which form lipid-soluble complexes with cations and enhance the transport of these ions across low polarity barriers such as organic solvents and biological membranes. They exhibit profound biological activity by their ability to perturb transmembrane ion gradients and electrical potentials. The purpose of this proposed research program is to develop methodologies for the preparation of highly substituted and chiral crown ethers 1 and 2 (where R1 through R6 can be varied, in a deliberate and unambiguous way, to include methyl, hydroxymethyl (and alkylated derivatives of this), and carboyxl) as ionophores toward alkali- and alkaline earth cations. An examination of Corey-Pauling-Koltum (CPK) molecular models indicate that crowns 1 and 2 should be conformationally more rigid than less substituted ones, and the binding site (the ether oxygens lining the crown ring cavity) would be more preorganized in the uncomplexed state, relative to less substituted crowns. They should thus be better binders of these cations. Unsubstituted crowns have no cavity in the uncomplexed state, filling in their molecular voids by turning one or more methylene units towards the center. The substituents in 1 and 2 would give not only a degree of structural preorganization, but also include functional groups (such as ether, hydroxyl, and carboxyl) which can provide additional binding sites to the cation. Highly substituted crowns are a largely unexplored middle ground between the conformationally very flexible crowns (bearing no or few substituents), and other increasingly structured and rigid cavitands: hemispherands, spherands, and carcerands. The synthetic methodologies, which involve the reductive cleavage of C-0 bonds in bis(cyclic acetals) as a key step in the synthesis of the substituted dietherdiols which are precursors to crown ethers 1 and 2, would also allow for the preparation of acyclic ionophores such as 3, and of species 4, a model for transmembrane ion channels. The proposed studies will provide information which will help answer the following questions: 1) Do the substituents impart sufficient conformational rigidity to provide a significant amount of preorganization to the uncomplexed crown, allowing them to be better binders of the cations?; 2) Can we control, by variation of identity and stereochemistry of substituents R1-R6, the selectivities which these ionophores exhibit towards cations of different effective size and charge type? The availability of a general synthetic approach to highly substituted, and chiral, crown ethers is significant in that these could find applications such as: models for molecular receptors: as enzyme mimics and analogs; and, where the substituents R1 - R6 include one or more carboxyl groups, as the basis for new cardiovascular drugs.
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