Optically active cyclophane receptors for mono- and disaccharides: The role of bidentate ionic hydrogen bonding in carbohydrate recognition

Article abstract of DOI:10.1002/1522-2675(20010815)84:8<2243::AID-HLCA2243>3.0.CO;2-G

A new family of optically active cyclophane receptors for the complexation of mono- and disaccharides in competitive protic solvent mixtures is described. Macrocycles (-)-(R,R,R,R)-1-4 feature preorganized binding cavities formed by four 1,1′-binaphthalene-2,2′-diyl phosphate moieties bridged in the 3,3′-positions by acetylenic or phenylacetylenic spacers. The four phosphodiester groups converge towards the binding cavity and provide efficient bidentate ionic H-bond acceptor sites (Fig. 2). Benzyloxy groups in the 7,7′-positions of the 1,1′-binaphthalene moieties ensure solubility of the nanometer-sized receptors and prevent undesirable aggregation. The construction of the macrocyclic framework of the four cyclophanes takes advantage of Pd⁰-catalyzed aryl-acetylene cross-coupling by the Sonogashira protocol, and oxidative acetylenic homo-coupling methodology (Schemes 2 and 8-10). Several cleft-type receptors featuring one 1,1′-binaphthalene-2,2′-diyl phosphate moiety were also prepared (Schemes 1, 6, and 7). An undesired side reaction encountered during the synthesis of the target compounds was the formation of naptho[b]furan rings from 3-ethynylnaphthalene-2-ol derivatives, proceeding via 5-endo-dig cyclization (Schemes 3-5). Computer-assisted molecular modeling indicated that the macrocycles prefer nonplanar puckered, cyclobutane-type conformations (Figs. 7 and 8). According to these calculations, receptor (-)-(R,R,R,R)-1 has, on average, a square binding site, which is complementary in size to one monosaccharide. The three other cyclophanes (-)-(R,R,R,R)-2-4 feature, on average, wider rectangular cavities, providing a good fit to one disaccharide, while being too large for the complexation of one monosaccharide. This substrate selectivity was fully confirmed in ¹H-NMR binding titrations. The chiroptical properties of the cyclophanes and their nonmacrocyclic precursors were investigated by circular dichroism (CD) spectroscopy. The CD spectra of the acyclic precursors showed a large dependence from the number of 1,1′-binaphthalene moieties (Fig. 9), and those of the cyclophanes were remarkably influenced by the nature of the functional groups lining the macrocyclic cavity (Fig. 11). Profound differences were also observed between the CD spectra of linear and macrocyclic tetrakis(1,1′-binaphthalene) scaffolds, which feature very different molecular shapes (Fig. 10). In ¹H-NMR binding titrations with mono- and disaccharides (Fig. 13), concentration ranges were chosen to favor 1:1 host - guest binding. This stoichiometry was experimentally established by the curve-fitting analysis of the titration data and by Job plots. The titration data demonstrate conclusively that the strength of carbohydrate recognition is enhanced with an increasing number of bidentate ionic host - guest H-bonds (Table 1) in the complex formed. As a result of the formation of these highly stable H-bonds, carbohydrate complexation in competitive protic solvent mixtures becomes more favorable. Thus, cleft-type receptors (-)-(R)-7 and (-)-(R)-38 with one phosphodiester moiety form weak 1:1 complexes only in CD₃CN. In contrast, macrocycle (-)-(R,R,R,R)-1 with four phosphodiester groups undergoes stable inclusion complexation with monosaccharides in CD₃CN containing 2% CD₃OD. With their larger number of H-bonding sites, disaccharide substrates bind even more strongly to the four phosphodiester groups lining the cavity of (-)-(R,R,R,R)-2 and complexation becomes efficient in CD₃CN containing 12% CD₃OD. Finally, the introduction of two additional methyl ester residues further enhances the receptor capacity of(-)-(R,R,R,R)-3, and efficient disaccharide complexation occurs already in CD₃CN containing 20% CD₃OD.