Molecular Clefts Derived from 9,9′‐spirobi[9H‐fluorene] for enantioselective complexation of pyranosides and dicarboxylic acids

Abstract

The molecular clefts (R)‐ and (S)‐3, incorporating 9,9′‐spirobi[9H‐fluorene] as a spacer and two N‐(5,7‐dimethyl‐1,8‐naphthyridin‐2‐yl)carboxamide (CONH(naphthy)) units as H‐bonding sites were prepared via the bis(succinimid‐N‐yl esters) of (R)‐and (S)‐9,9′‐spirobi[9H‐fluorene]‐2,2′‐dicarboxylic acid (5). Derivative 6, with one CONH(naphthy) unit and one succinimid‐N‐yl ester residue allowed easy access to spirobifluorene clefts with two different H‐bonding sites, as exemplified by the synthesis of 4. Binding studies with (R)‐ and (S)‐3 and optically active dicarboxylic acids in CDCl₃ exhibited differences in free energy of the formed diastereoisomeric complexes (Δ(ΔGº)) between 0.5 and 1.6 kcal mol⁻¹ (T 300 K). Similar enantioselectivities were observed with the spirobifluorene clefts (R)‐ and (S)‐1, bearing two N‐(6‐methylpyridin‐2‐yl)carboxamide (CONH(py)) H‐bonding sites. The thermodynamic quantities ΔHº and ΔSº for the recognition processes with (R)‐ and (S)‐1 were determined by variable‐temperature ¹H‐NMR titrations and compared to those with (R)‐ and (S)‐2, which have two CONH(py) moieties attached to the 6,6′‐positions of a conformationally more flexible 1,1′‐binaphthyl cleft. All association processes showed high enthalpic driving forces which are partially compensated by unfavorable changes in entropy. Pyranosides bind to the optically active clefts 1 and 3 in CDCl₃ with −ΔGº = 3.0–4.3 kcal mol⁻¹. Diastereoisomeric selectivities up to 1.2 kcal mol⁻¹ and enantioselectivities up to 0.4 kcal mol⁻¹ were observed. Cleft 4 and N‐(5,7‐dimethyl‐1,8‐naphthyridin‐2‐yl)acetamide (25) complexed pyranosides 22–24 as effectively as 3 indicating that only one CONH(naphthy) site in 3 associates strongly with the sugar derivatives. Based on the X‐ray crystal structure of 3, a computer model for the complex between (S)‐3 and pyranoside 22 was constructed. Molecular‐dynamics (MD) simulations showed that differential geometrical constraints are at the origin of the high enantioselectivity in the complexation of dicarboxylic acid (S)‐7 by (R)‐ and (S)‐1 and (R)‐ and (S)‐3.