合成路线1

Knoevenagel condensation of 4-fluorobenzaldehyde (I) with ethyl cyanoacetate (A) gave adduct (II). Subsequent conjugate addition of NaCN to (II), followed by alkylation with ethyl 3-chloropropionate (B) furnished the dicyano diester (III). Acid hydrolysis of (III), with concomitant decarboxylation, afforded tricarboxylic acid (IV), which was further esterified with methanolic HCl to give ester (V). Dieckmann cyclization of (V) using NaOMe, and then hydrolysis and decarboxylation gave rise to the racemic trans ketoacid (VI). Esterification of (VI), and reduction of the resulting keto ester (VII) with NaBH4 produced a mixture of diastereomeric alcohols. The desired trans,trans-isomer (VIII) was then isolated by column chromatography. Ester hydrolysis of (VIII) and re-solution as the corresponding salt with (R)-alpha-methylbenzylamine furnished the (-)-hydroxy acid (IX) that was esterified to (X) with methanolic HCl.