Addition of the organozinc reagent (II) to the cyclic anhydride (I) produced keto acid (III). After activation of the carboxyl group of (III) with carbonyl diimidazole, condensation with the lithium enolate of tert-butyl acetate furnished keto ester (IV). This was subsequently cyclized to the cyclopentapyridine system (V) upon treatment with silica in CHCl3. Addition of 2,2-difluoro-1,3-benzodioxol-5-ylmagnesium bromide (VI) to the keto group of (V) gave carbinol (VII). After hydroxyl group acetylation, hydrogenation of the olefin and simultaneous hydrogenolysis of the O-benzyl groups of (VII) over Pd/C yielded (VIII). Further epimerization of the carboxylate group of (VIII) in the presence of potassium tert-butoxide afforded isomer (IX). After conversion of (IX) to the aryl triflate (X), palladium-catalyzed coupling of (X) with allylic alcohol (XI) produced (XII).
Resolution of (XII) by chiral HPLC and then acetylation of the hydroxyl group gave the chiral acetate (XIII). The pyridine ring of (XIII) was converted to the corresponding N-oxide (XIV) by means of meta-chloroperbenzoic acid. Subsequent displacement of the N-oxide of (XIV) with N-isopropyl-benzimidoyl chloride (XV) introduced the N-benzoyl-N-isopropylamino group into the pyridine to afford (XVI). After tert-butyl ester cleavage with trifluoroacetic acid, yielding (XVIII), basic hydrolysis of the benzamido group provided the title compound.