Optically Active Cyclophane Receptors for Mono- and Disaccharides: The Role of Bidentate Ionic Hydrogen Bonding in Carbohydrate Recognition

Abstract

A new family of optically active cyclophane receptors for the complexation of mono-and disaccharides in competitive protic solvent mixtures is described. Macrocycles (À)-(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 Pd 0 -catalyzed arylÐacetylene 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 (À)-(R,R,R,R)-1 has, on average, a square binding site, which is complementary in size to one monosaccharide. The three other cyclophanes (À)-(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 1 H-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 1 H-NMR binding titrations with mono-and disaccharides (Fig. 13), concentration ranges were chosen to favor 1 : 1 hostÀguest 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 hostÀguest 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 (À)-(R)-7 and (À...

Shape‐Persistent Macrocycles Based on Acetylenic Scaffolding

“…The smaller SPM 65 was capable of selective carbohydrate recognition with several glucopyranosides, with modest enantioselectivity observed in some cases. Later generations of SPMs built on this same concept incorporated larger carbon scaffolds and modified receptor sites such as phosphate ester 67 shown below, a molecule that bonded selectively to disaccharides[69][70][71][72].Kawase, Oda, and coworkers have synthesized a unique series of belt-shaped paraphenylacetylene macrocycles 68-71 (Scheme 6.18A) and studied their hostguest supramolecular chemistry. The precursor polyenes 72-75 were synthesized using a modified McMurry reaction, and a subsequent bromination/dehydrobromination sequence with t-BuOK gave the desired SPMs 68-71.…”

Phase transfer of monosaccharides through noncovalent interactions: Selective extraction of glucose by a lipophilic cage receptor

“…C arbohydrate recognition is an active area of supramolecular chemistry, motivated by the biological importance of saccharides and also by the unusual challenge represented by these complex substrates (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). On the one hand, carbohydrates must be recognized and processed during metabolism, whereas saccharide motifs are known to mediate cell-cell recognition, the infection of cells by pathogens, and many aspects of the immune response (14)(15)(16)(17).…”

“…On the other, carbohydrates possess structures that are fairly large, irregular, and multivalent, while being quite similar to clusters of water molecules. Even in nonpolar solvents, selective carbohydrate receptors require extended, sophisticated architectures (1,(3)(4)(5)(6). In the presence of liquid water, the problem becomes yet more difficult.…”

Chiral Carbon‐rich Macrocycles and Cyclophanes

“…The complexation of these receptors with two disaccharides was investigated by 1 H NMR spectroscopy and showed that the incorporation of the methyl carboxylate groups in 142 increased the association relative to the unfunctionalized derivative 141. A subsequent publication reported on the detailed binding affinities of square cyclophane 140 and tetrameric 141-143 [55] with mono-and disaccharide guests. In general, their findings showed that the smaller and more size complementary cyclophane 140 preferentially bound monosaccharide guests.…”