Cyclic Hydropyran Oligolides as Preorganized Ligand Arrays: Cumulative Effects of Structural Elements on Shape and Cation Binding

摘要

Substituted hydropyrans are important structural elements in numerous natural ionophores. Synthetic methods developed in our laboratories provide access to hydropyrans varying widely in substitution and stereochemistry. In order to exploit this diversity, a program to design, synthesize, and study cyclic oligolides of hydropyran modules has begun. These unnatural ionophores differ in substitution type, relative stereochemistry, or ring size. This paper focuses on the structural features that define the shape and binding efficacy of the 18-membered triolides 1-8 (Figure 1). Preorganization, binding-site convergence and complementarity, and cumulative noncovalent interactions are important in the design of effective host molecules. Several types of local conformational control elements (A-E, Figure 2) were expected to contribute to the overall shape and degree of rigidity of 1-8 (Figure 1) by restricting rotation about every σ-bond of the macrocycle periphery. In A, the C1-C2-O3-C6-C7 region is spatially oriented because of the cis-2,6-diequatorial hydropyran substitution. The pronounced preference for the syn (Z) ester conformation (B) confers rigidity about the C1-O2 bonds. Secondary carbinol esters are known to exist preferentially in conformations wherein the carbinyl hydrogen is close to the plane of the ester carbonyl (C), in this case restricting O2-C7 rotation. The gauche (or synclinal) preference in vicinal dialkoxyethanes is shown in D, suggesting an increment of conformational preference about the C7-C6 bonds. Finally, although less predictable than the preceding effects, it was anticipated that the α-alkoxy ester residue comprising the C1-C2 bonds (E) would reflect electronic and/ or steric effects in a conformational bias.