合成路线1

Condensation of piperonal (I) with nitromethane in the presence of NaOH provided nitrostyrene (II) (1-3). Ketoester (IV) was prepared by treatment of n-heptanoic acid (III) with 1,1'-carbonyldiimidazole and further condensation with ethyl magnesium malonate (1). Subsequent conjugate addition of (II) to ketoester (IV) using DBU provided adduct (V). Reduction of the nitro group of (V), with concomitant ring closure formed the cyclic imine (VI), which was reduced with NaBH3CN to yield the pyrrolidine (VII) as a diastereomeric mixture. The crude mixture was isomerized to a mixture of only cis,trans and trans,trans pyrrolidines (VIII) by base-catalyzed equilibration with NaOEt. N-Alkylation of the pyrrolidines (VIII) with N,N-dibutyl bromoacetamide (IX) furnished (X). Basic hydrolysis of the ester group of (X) with either NaOH or LiOH gave rise to the target trans,trans pyrrolidine-3-carboxylic acid. The undesired cis,trans isomeric ester (XI) was not hydrolyzed under these conditions, allowing its removal from the product by means of differential extraction.