Synthesis and study of C3-symmetric hydropyran cyclooligolides with oriented aryl and alcohol appendages at 10 Å spacing

Modular syntheses of C-3-symmetric macrocycles with pendant aryl and hydroxymethyl groups are described. These functional groups, amenable to further elaboration, were installed early in each synthesis and carried through an iterative sequence of module coupling and macrolactonization. Association constants for macrolides la-c with alkali metal cation guests were determined, and sandwich-type complexes with Ba2+ were confirmed for these macrocycles based on H-1 NMR studies, including Job plots. X-ray crystallographic data for macrolides la and Ic were obtained and are discussed in detail. These data provide support that the macrolides are structurally well-defined and preorganized for binding the potassium cation. Preparation of the tris(bromoacetylated) macrotriolide 43 exemplifies a functionalized platform suitable for elaboration with peptide or carbohydrate residues.