A) Synthesis of intermediate (VII): The hexanophenone (I), prepared by Freidel-Crafts acylation of anisole with hexanoyl chloride, was condensed with lithioacetonitrile to generate the carbinol (II), which was then dehydrated using trifluoroacetic acid in dichloromethane to produce the unsaturated nitrile (III) predominantly as its (E)-isomer (E/Z ratio > 12:1). Reduction of the newly formed alpha,beta-unsaturated nitrile with diisobutylaluminum hydride furnished the (E)-octenal (IV), which was then treated with the stabilized ylid (carbomethoxymethylene)triphenylphosphorane to yield the dienoic acid ester (V). While use of a polar reaction medium such as methanol or ethanol in this Wittig reaction resulted in mixtures of isomers with an E/Z ratio as high as 3:2 around the newly introduced double bond, formation of the (Z)-isomer could be minimized (< 7%) through the use of an aprotic reaction solvent, e.g., dichloromethane or benzene. In preparation for its conversion to the target carboxamide, the (E,E)-decadienoic acid ester was saponified and the resulting acid (VI) condensed with p-nitrophenol in the presence of dicyclohexylcarbodiimide to yield the highly reactive p-nitrophenyl ester (VII).

B) Synthesis of intermediate (XIV): Palladium-catalyzed coupling of 1-pentyn-4-ol (VIII) with 3-bromopyridine (IX) afforded the pyridinealkynol (X), which was then subjected to sequential hydrogenation and Swern oxidation followed by reductive amination of the intermediate ketone (XI) with sodium cyanoborohyride to afford the racemic amine (XII). Resolution was achieved through fractional crystallization of the corresponding diastereoisomeric (R)-mandelamides that had been obtained by acylation of the racemic amine with (R)-mandelic acid in DMF in the presence of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide. Acid-catalyzed hydrolysis of the diastereoisomerically pure (R,R)-mandelamide (XII) provided the resolved (R)-alpha-methyl-3-pyridinebutanamine (XIV). C) Synthesis of Ro-24-0238: Stereochemical assignment was based on a single crystal X-ray analysis of the intermediate mandelamide. Reaction of the chiral amine with the activated ester of (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid gave Ro 24-0238. Stereochemical assignment was based on a single crystal X-ray analysis of the intermediate mandelamide. Reaction of the chiral amine with the activated ester of (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid gave Ro 24-0238.

A) Synthesis of intermediate (VII): The hexanophenone (I), prepared by Freidel-Crafts acylation of anisole with hexanoyl chloride, was condensed with lithioacetonitrile to generate the carbinol (II), which was then dehydrated using trifluoroacetic acid in dichloromethane to produce the unsaturated nitrile (III) predominantly as its (E)-isomer (E/Z ratio > 12:1). Reduction of the newly formed alpha,beta-unsaturated nitrile with diisobutylaluminum hydride furnished the (E)-octenal (IV), which was then treated with the stabilized ylid (carbomethoxymethylene)triphenylphosphorane to yield the dienoic acid ester (V). While use of a polar reaction medium such as methanol or ethanol in this Wittig reaction resulted in mixtures of isomers with an E/Z ratio as high as 3:2 around the newly introduced double bond, formation of the (Z)-isomer could be minimized (< 7%) through the use of an aprotic reaction solvent, e.g., dichloromethane or benzene. In preparation for its conversion to the target carboxamide, the (E,E)-decadienoic acid ester was saponified and the resulting acid (VI) condensed with p-nitrophenol in the presence of dicyclohexylcarbodiimide to yield the highly reactive p-nitrophenyl ester (VII).

B) Synthesis of intermediate (XIV): Palladium-catalyzed coupling of 1-pentyn-4-ol (VIII) with 3-bromopyridine (IX) afforded the pyridinealkynol (X), which was then subjected to sequential hydrogenation and Swern oxidation followed by reductive amination of the intermediate ketone (XI) with sodium cyanoborohyride to afford the racemic amine (XII). Resolution was achieved through fractional crystallization of the corresponding diastereoisomeric (R)-mandelamides that had been obtained by acylation of the racemic amine with (R)-mandelic acid in DMF in the presence of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide. Acid-catalyzed hydrolysis of the diastereoisomerically pure (R,R)-mandelamide (XII) provided the resolved (R)-alpha-methyl-3-pyridinebutanamine (XIV). C) Synthesis of Ro-24-0238: Stereochemical assignment was based on a single crystal X-ray analysis of the intermediate mandelamide. Reaction of the chiral amine with the activated ester of (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid gave Ro 24-0238. Stereochemical assignment was based on a single crystal X-ray analysis of the intermediate mandelamide. Reaction of the chiral amine with the activated ester of (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid gave Ro 24-0238.