Molecular Clefts Derived from 9,9'-Spirobi for Enantioselective Complexation of Pyranosides and Dicarboxylic Acids

Article abstract of DOI:10.1002/hlca.19950780209

The molecular elefts (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 elefts 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(ΔG⁰)) 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 ΔH⁰ and ΔS⁰ 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 CDCl3 with -ΔG⁰ = 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-)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 pyranosiide 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.