m-Fluorocinnamic acid (I) is coupled to (S)-4-benzyloxazolidin-2-one (II), via the corresponding mixed anhydride with pivaloyl chloride, to furnish the N-cinnamoyl oxazolidinone (III). Cycloaddition of (III) with N-methoxymethyl-N-trimethylsilylmethyl benzylamine (IV) in the presence of trifluoroacetic acid produces a mixture of the diastereoisomeric pyrrolidines (V) and (VI), separable by column chromatography. The desired isomer (V) is then reduced by means of LiAlH4 to the primary alcohol (VII), which is further protected by silylation with t-butyldimethylsilyl chloride. The resultant silyl ether (VIII) is then subjected to benzyl group cleavage under transfer hydrogenation conditions, producing pyrrolidine (IX) (1).

Diazotization of L-cyclopropylalanine (X) with NaNO2/H2SO4 gives rise to the chiral hydroxy acid (XI). Subsequent treatment of hydroxyacid (XI) with p-methoxybenzyl chloride (XII) in the presence of Et3N furnishes the corresponding p-methoxybenzyl ester (XIII). Hydroxy ester (XIII) is then converted to triflate (XIV), which is further condensed with pyrrolidine (IX) to yield amino ester (XV). Desilylation of (XV) with tetrabutylammonium fluoride affords alcohol (XVI). This is then subjected to Swern oxidation to provide aldehyde (XVII) (1).

4-(Hydroxymethyl)piperidine (XVIII) is protected as the N-Boc derivative (XIX) with Boc2O in CH2Cl2. Conversion of alcohol (XIX) into the corresponding mesylate, followed by treatment with NaI in acetone, furnishes the alkyl iodide (XX). Quaternization of triphenylphosphine with iodide (XX) in refluxing acetonitrile gives rise to the phosphonium salt (XXI).

Addition of 4-fluorophenylmagnesium bromide (XXII) to dimethyl oxalate (XXIII) leads to methyl 4-fluorobenzoylformate (XXIV). Subsequent fluorination of (XXIV) employing diethylaminosulfur trifluoride affords the gem-difluoro ester (XXV). Reduction of ester (XXV) with NaBH4 in cold MeOH gives rise to the aldehyde hemiacetal (XXVI). Then, Wittig condensation of hemiacetal (XXVI) with the ylide generated from phosphonium salt (XXI) provides olefin (XXVII). This is partly reduced to the saturated compound (XXVIII) by treatment with in situ generated diimide, and completely reduced to (XXVIII) by catalytic hydrogenation over iridium black. Cleavage of the N-Boc protecting group of (XXVIII) to furnish piperidine (XXIX) is accomplished by means of iodotrimethylsilane in CHCl3.

Reductive condensation between piperidine (XXIX) and aldehyde (XVII) in the presence of NaBH(OAc)3 leads to adduct (XXXVIII). The p-methoxybenzyl ester group of (XXXVIII) is then removed by hydrogenolysis over Pearlman's catalyst to provide the title carboxylic acid.

The intermediate piperidine (XXIX) has been prepared by an alternative procedure. N-Boc-3-(4-Piperidinyl)propionic acid (XXX) is converted to the mixed anhydride (XXXI), which is further reacted with N,O-dimethylhydroxylamine producing the Weinreb amide (XXXII). Condensation of (XXXII) with 4-fluorophenylmagnesium bromide (XXII) leads to ketone (XXXIII). Acidic cleavage of the N-Boc group of (XXXIII), followed by treatment of the resultant piperidine (XXXIV) with benzyl chloroformate leads to the Cbz-protected analogue (XXXV). Difluorination of ketone (XXXV) is carried out by the method of Katzenellenbogen, consisting of formation of dithioketal (XXXVI), which is then reacted with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) in the presence of HF-pyridine to afford the gem-difluoro compound (XXXVII), accompanied by an unseparable by-product. A new protecting group switch is required in order to achieve complete purification of (XXXVII), which is thus converted into the N-Boc derivative (XXVIII). Acidic cleavage of (XXVIII) as above leads to the piperidine (XXIX).