Acylation of L-proline t-butyl ester (I) with 3,5-dichlorobenzenesulfonyl chloride (II) affords sulfonamide (III). The tert-butyl ester group of (III) is then cleaved by treatment with aqueous trifluoroacetic acid, yielding carboxylic acid (IV). Coupling of sulfonyl proline (IV) with the racemic 3-endo-amino-bicyclo[2.2.1]heptane-2-endo-carboxylate (V) leads to a mixture of four diastereoisomeric amides, resulting from carboxylate group epimerization. This mixture can be separated into two pairs of diastereoisomers (VI) and (VII) by flash chromatography. The desired diastereoisomeric mixture of esters (VII) is then hydrolyzed under alkaline conditions to furnish the title carboxylic acid along with its epimer (VIII).
In an alternative procedure, Diels-Alder condensation between methyl (E)-3-nitroacrylate (I) and cyclopentadiene (II) produces a mixture of bicyclic adducts (III) and (IV) in a 6:1 ratio. After chromatographic isolation of the major isomer (III), catalytic hydrogenation of its olefin double bond in the presence of PtO2 yields nitro ester (V). Subsequent nitro group reduction in (V) by transfer hydrogenation with ammonium formate and Pd/C produces the racemic amino ester (VI). Coupling of racemic (VI) with carboxylic acid (VII) leads to a mixture of diastereoisomeric amides (VIII) and (IX). Finally, after alkaline hydrolysis of its methyl ester function, the target carboxylic acid isomer is isolated by flash chromatography.