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

The molecular clefts ( R )‐ and ( S )‐ 3 , incorporating 9,9′‐spirobi[9 H ‐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[9 H ‐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 CDCl 3 exhibited differences in free energy of the formed diastereoisomeric complexes (Δ(Δ G º)) 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 Δ H º and Δ S º for the recognition processes with ( R )‐ and ( S )‐ 1 were determined by variable‐temperature 1 H‐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 CDCl 3 with −Δ G º = 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 .