Molecular Recognition of Pyranosides by a Family of Trimeric, 1,1′-Binaphthalene-Derived Cyclophane Receptors

Abstract

The synthesis and carbohydrate-recognition properties of a new family of optically active cyclophane receptors, 1 – 3, in which three 1,1′-binaphthalene-2,2′-diol spacers are interconnected by three buta-1,3-diynediyl linkers, are described. The macrocycles all contain highly preorganized cavities lined with six convergent OH groups for H-bonding and complementary in size and shape to monosaccharides. Compounds 1 – 3 differ by the functionality attached to the major groove of the 1,1′-binaphthalene-2,2′-diol spacers. The major grooves of the spacers in 2 are unsubstituted, whereas those in 1 bear benzyloxy (BnO) groups in the 7,7′-positions and those in 3 2-phenylethyl groups in the 6,6′-positions. The preparation of the more planar, D3-symmetrical receptors (R,R,R)-1 (Schemes 1 and 2), (S,S,S)-1 (Scheme 4), (S,S,S)-2 (Scheme 5), and (S,S,S)-3 (Scheme 8) involved as key step the Glaser-Hay cyclotrimerization of the corresponding OH-protected 3,3′-diethynyl-1,1′-binaphthalene-2,2′-diol precursors, which yielded tetrameric and pentameric macrocycles in addition to the desired trimeric compounds. The synthesis of the less planar, C2-symmetrical receptors (R,R,S)-2 (Scheme 6) and (S,S,R)-3 (Scheme 9) proceeded via two Glaser-Hay coupling steps. First, two monomeric precursors of identical configuration were oxidatively coupled to give a dimeric intermediate which was then subjected to macrocyclization with a third monomeric 1,1′-binaphthalene precursor of opposite configuration. The 3,3′-dialkynylation of the OH-protected 1,1′-binaphthalene-2,2′-diol precursors for the macrocyclizations was either performed by Stille (Scheme 1) or by Sonogashira (Schemes 4, 5, and 8) cross-coupling reactions. The flat D3-symmetrical receptors (R,R,R)-1 and (S,S,S)-1 formed 1 : 1 cavity inclusion complexes with octyl 1-O-pyranosides in CDCl3 (300 K) with moderate stability (ΔG0 ca. −3 kcal mol−1) as well as moderate diastereo- (Δ(ΔG0) up to 0.7 kcal mol−1) and enantioselectivity (Δ(ΔG0)=0.4 kcal mol−1) (Table 1). Stoichiometric 1 : 1 complexation by (S,S,S)-2 and (S,S,S)-3 could not be investigated by 1H-NMR binding titrations, due to very strong signal broadening. This broadening of the 1H-NMR resonances is presumably indicative of higher-order associations, in which the planar macrocycles sandwich the carbohydrate guests. The less planar C2-symmetrical receptor (S,S,R)-3 formed stable 1 : 1 complexes with binding free enthalpies of up to ΔG0=−5.0 kcal mol−1 (Table 2). With diastereoselectivities up to Δ(ΔG0)=1.3 kcal mol−1 and enantioselectivities of Δ(ΔG0)=0.9 kcal mol−1, (S,S,R)-3 is among the most selective artificial carbohydrate receptors known.