MOLECULAR CLEFTS DERIVED FROM 9,9'-SPIROBI[9H-FLUORENE] FOR ENANTIOSELECTIVE COMPLEXATION OF PYRANOSIDES AND DICARBOXYLIC-ACIDS

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 (Delta (Delta G degrees)) 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)) II-bonding sites. The thermodynamic quantities Delta H degrees and Delta S degrees for the recognition processes with (R)- and (S)-1 were determined by variable-temperature H-1-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 -Delta G degrees = 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)ac (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.