Ethyl 3-oxocyclohexanecarboxylate (I) was protected as the ethylene ketal (II) and its ethyl ester group was subsequently hydrolyzed to carboxylic acid (III). After activation of acid (III) as the mixed anhydride (IV) with isobutyl chloroformate, coupling with 4-phenyl-1,2,3,6-tetrahydropyridine (V) gave amide (VI). Reduction of amide (VI) to the corresponding amine (VII) was accomplished by treatment with LiAlH4 in the presence of AlCl3. Addition of phenylmagnesium bromide to the ketone (VIII), obtained by acidic hydrolysis of ketal (VII), provided the tertiary alcohol (IX). Dehydration of alcohol (IX) by means of trifluoroacetic acid gave rise to a mixture of isomeric cyclohexene derivatives (X) and (XI), which were separated by column chromatography. The racemic 3-cyclohexenyl isomer (XI) was then resolved via formation of the salts with (R)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate to furnish the title (R)-(+)-enantiomer.

A further procedure employed the chiral keto acid (XXII) as the key intermediate. The cyclohexenone carboxylic acid (XXI) was synthesized via aldol condensation between 3-benzoylacrylic acid (XIX) and ethyl acetoacetate (XX), followed by cyclization and decarboxylation under Robinson annulation reaction conditions. Resolution of (XXI) to furnish the desired (S)-enantiomer (XXII) was accomplished either via formation of the diastereomeric salts with cinchonidine or, alternatively, by esterification of (XXI) with n-butanol --yielding the isomeric mixture (XXIII)--, followed by enantioselective hydrolysis of the (S)-butyl ester from in the presence of alpha-chymotrypsin. Coupling of keto acid (XXII) with tetrahydropyridine (V) provided keto amide (XXIV). The keto group of (XXIV) was then reduced with NaBH4 to form a diastereomeric mixture of allylic alcohols (XXV), which were further reduced employing NaBH3CN in the presence of ZnCl2 to furnish the target (R)-cyclohexenecarboxamide (XXVI). The amide function of (XXVI) was finally reduced to the title amine by means of LiAlH4 in methyl tert-butyl ether.

Racemic amide (VI) was also prepared by a closely related procedure. Coupling of keto acid (XII) with tetrahydropyridine (V) using DCC gave keto amide (XIII), which was then protected as the ethylene ketal (VI) upon treatment with 2-methoxy-1,3-dioxolane (XIV) in the presence of methanesulfonic acid.

The analogous asymmetric synthesis starting from the (R)-enantiomer of 3-oxocyclohexanecarboxylic acid (XV) was also reported. The chiral (R)-keto acid (XV), prepared by resolution of the racemic acid (XII) with brucine, was coupled with tetrahydropyridine (V) to give keto amide (XVI). Protection as the ethylene ketal (XVII), followed by amide reduction and acidic ketal hydrolysis, furnished the (R)-amino ketone (XVIII). This was converted into the title compound by addition of phenylmagnesium bromide, followed by acidic dehydration and separation of isomers as in Scheme 19758501a.

Swern oxidation of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (I) with oxalyl chloride in DMSO/dichloromethane gives the corresponding piperidone (II), which is submitted to a Grignard reaction with [U-14C]phenylmagnesium bromide (III) in THF to yield 4-hydroxy-4-phenylpiperidine-1-carboxylic acid tert-butyl ester (IV). The reaction of (IV) with BF3/Et2O in dichloromethane affords labeled 4-phenyl-1,2,3,6-tetrahydropyridine (V), which is condensed with 3-phenyl-3-cyclohexene-1(R)-carboxylic acid (VI) by means of HOBT, DCC and TEA in ethyl acetate to provide the labeled 1-(3-phenyl-3-cyclohexen-1(R)-yl)-1-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)methanone (VII). Finally, this compound is reduced with LiAlH4 and AlCl3 in THF to obtain the target tetrahydropyridine derivative.