SYNTHESIS AND ABSOLUTE-CONFIGURATION OF THE STEREOISOMERS OF [2-(1-DIETHYLAMINOPROPYL)] 1-HYDROXY-1,1'-BICYCLOHEXYL-2-CARBOXYLATE, A MUSCARINIC ANTAGONIST

The compound [2-(1-diethylaminopropyl)] 1-hydroxy-1,1'-bicyclohexyl-2- carboxylate 1 is a muscarinic antagonist characterized by the presence of three chiral atoms and eight possible stereoisomers. The binding a ffinities to the five cloned m(1)-m(5) muscarinic receptors of the ste reoisomers of 1 were previously investigated and proved to be related to the chirality of the molecules. The eight isomers are prepared thro ugh the synthesis of their racemates followed by chemical resolution a s (+) and (-) tartrate or (+) and (-) dibenzoyltartrate salts. The iso mers with cis-configuration of OH and COOH substituents of the cyclohe xane are also obtained by coupling optically active (1S, 2S) or (1R,2R )-1-hydroxy-[1,1'-bicyclohexyl]-2-carboxylic acid with (S)- or (R)-1-d iethylamino-2-propanol. Chiral GC and HPLC methods are used to determi ne their optical purity. The absolute configurations of the four cis-a nd four trans-isomers are established by stereospecific synthesis and X-ray crystallographic data. (C) 1997 Wiley-Liss, Inc.