Quinuclidine chemistry. 3. .beta.-cis-2-(4'-Chlorobenzhydryl)-3-quinuclidinol, a new central nervous system stimulant. Importance of the benzhydryl configuration

Abstract

The 1,4 addition of p-chlorophenylmagnesium bromide to 2-benzylidene-3-quinuclidinone gave 2-(4-chlorobenzhydryl)-3-quinuclidinone as two diastereoisomers. Selective reduction of this ketone with aluminum isopropoxide gave the two cis-2-(4-chlorobenzhydryl)-3-quinuclidinols, which differ only in the configuration of the benzhydryl group, designated alpha and beta in order of their elution on chromatography. Reduction with NaBH4 gave a mixture of four isomeric alcohols, of which the two cis isomers were selectively oxidized. The two trans-2-(4-chlorobenzhydryl)-3-quinuclidinols were chromatographically separated and desingated alpha and beta in order of elution. Only the beta-cis and beta-trans alcohols showed CNS stimulant properties. The beta-cis isomer was shown to be related both qualitatively and quantitatively more to methylphenidate (Ritalin) than to d-amphetamine.