合成路线1

The reaction of 2-phenylbutyric acid (I) with LDA gives the enolate (II), which is condensed with ethyl 4-iodobenzoate (III) to yield the not isolated intermediate (IV), which decarboxylates to afford 1-(4-iodophenyl)-2-phenyl-1-butanone (V). The Grignard reaction of the ketone (V) with 4-[2-(1-pyrroliidnyl)ethyl]phenylmagnesium bromide (VI) (obtained from the corresponding bromobenzene (VII) and Mg in THF) affords the tertiary alcohol (VIII), which is esterified with pivaloyl chloride (IX) and KHMDS to provide the pivalate (X). Finally, this compound is treated with hexamethyldisylazane at 165 C to provide the target ethylene.

合成路线2

Bromination of tetralone (I) in the presence of AlCl3 provided (II), which was coupled with (trimethylsilyl)acetylene (III) using PdCl2(PPh3)2 and CuI as the catalysts yielding (IV). Removal of the protecting trimethylsilyl group from (IV) with K2CO3 in MeOH gave the arylacetylene (V), which was subjected to a second Pd-catalyzed coupling reaction with ethyl 4-iodobenzoate (VI) to furnish diarylacetylene (VII). Ketone group of (VII) was then reduced with NaBH4 to provide racemic alcohol (VIII), which was separated into the enantiomers employing chiral HPLC. Alternatively, enantioselective reduction using several chiral reducing agents furnished the enantiomerically enriched alcohols. The desired (R)-alcohol was condensed with dihydropyran in the presence of a catalytic amount of p-toluenesulfonic acid to yield a diastereomeric mixture of tetrahydropyranyl ethers (IX). After isolation by means of normal phase-HPLC, the (R,R)-isomer was finally hydrolyzed with LiOH to the target carboxylic acid.

合成路线3

Addition of 3-methyl-2-butenoic acid (II) to 4-methoxythiophenol (I) in the presence of piperidine at 105 C afforded adduct (III). After conversion of (III) to the corresponding acid chloride (IV) with oxalyl chloride, Friedel-Crafts cyclization using SnCl4 produced thiochromanone (V). Cleavage of the methyl ether of (V) by means of BBr3 gave phenol (VI), which was converted to triflate (VII) with trifluoromethanesulfonic anhydride in pyridine. Coupling of (VII) with trimethylsilyl acetylene (VIII) using a palladium catalyst provided (IX). Subsequent desilylation of (IX) with K2CO3 in MeOH, followed by palladium-catalyzed coupling of the resulting alkyne with ethyl 4-iodobenzoate (X) afforded the diaryl acetylene (XI). Introduction of the 4-aryl group in (XI) was achieved by conversion of (XI) to vinyl triflate (XIII) upon treatment of the sodium enolate with the bis-triflimide reagent (XII), and further condensation with 4-ethyl-phenylzinc chloride (XIV) yielding (XV). Finally, basic hydrolysis of the ethyl ester (XV) furnished the target carboxylic acid.

合成路线4

Iodination of 3-methylcyclohexenone (I) using iodine and azidotrimethylsilane produced the iodo ketone (II) (1). Palladium-catalyzed coupling of iodide (II) with 2-(tributylstannyl)ethenyltrimethylsilane (III), prepared from (trimethylsilyl)acetylene and tributyltin hydride, furnished the silylethenyl cyclohexenone (IV), which was further treated with iodine to yield vinyl iodide (V) (1,2). Ethyl 4-ethynylbenzoate (VIII) was prepared by reaction of ethyl 4-iodobenzoate (VI) with (trimethylsilyl)acetylene (VII) in the presence of palladium catalyst (1). Heck reaction between acetylene (VIII) and vinyl iodide (V) provided adduct (IX). Conjugate addition of the in situ generated lithium dimethylcuprate to the unsaturated ketone (IX) gave the 3,3-dimethyl cyclohexanone (X). Treatment of (X) with triflic anhydride and a hindered base produced the desired vinyl triflate (XI) along with its vinyl regioisomer, which were separated by preparative chromatography. Reaction of triflate (XI) with 4-tolylzinc bromide (XIII), prepared from 4-iodotoluene (XII), yielded the phenylcyclohexene derivative (XIV). The ethyl ester group of (XIV) was finally hydrolyzed to the corresponding carboxylic acid using NaOH.

合成路线5