CHIRAL RECOGNITION OF CINCHONA ALKALOIDS AT THE MINOR AND MAJOR GROOVES OF 1,1'-BINAPHTHYL RECEPTORS

A variety of chiral 1,1'-binaphthyl derivatives with one or two hydroxyl groups at either the 2,2'-(minor groove) or the 7,7'-positions (major groove) were prepared for enantioselective recognition of the cinchona alkaloids quinine and quinidine. The study was initiated when it was found that (+/-)-7,7'-bis(benzyloxy)-2,2'-dihydroxy-1,1'-binaphthyl ((+/-)-1a) was readily resolved through simple clathrate formation with quinine and quinidine. Optical resolution of (+/-)-1a was also achieved by fractional crystallization of its cyclic phosphate ester with quinidine. The absolute configuration of the optically pure binaphthyl derivatives was established by transformation of (-)-1a into a binaphthyl derivative of known absolute configuration (R) through reactions of defined stereochemistry. The X-ray crystal structure analysis of the (S)-(+)-1a.quinidine complex showed that ion pairing is the major interaction between the two components. Complexation of quinine and quinidine at both major and minor grooves of the 1,1'-binaphthyl derivatives occurred in CDCl3 with a significant degree of chiral recognition, and differences in stability between diastereomeric complexes were as large as Delta(Delta G degrees) approximate to 1 kcal mol(-1) (293 K). Quinine is consistently better bound by the (R)-receptors whereas quinidine always prefers the (S)-enantiomers. The structures of the complexes, which are stabilized by hydrogen-bonding and aromatic-aromatic interactions, were analyzed on the basis of the complexation-induced changes in H-1 NMR chemical shifts of the binding partners at saturation binding Delta delta(sat), H-1{H-1} nuclear Overhauser effects (NOEs), and molecular modeling.