The alkylation of 4-hydroxy-3-iodo-5-methoxybenzaldehyde (I) with propyl bromide (II) by means of K2CO3 in hot DMF gives the propyl ether (III), which is condensed with 3-(dimethylamino)-1-(3,4,5-trimethoxyphenyl)-1-propanone (IV) (obtained by reaction of 3,4,5-trimethoxyacetophenone (V) with dimethylamine and formaldehyde), yielding the asymmetric butanedione (VI). The reaction of (VI) with dimethyl disulfide by means of Cu at 160 C affords the methylsulfanyl compound (VII), which is oxidized with MCPBA in dichloromethane to provide the sulfone derivative (VIII). The reduction of the butanedione (VIII) with NaBH4 in hot ethanol gives the (RS,RS)-diol (IX), which is finally cyclized by means of TFA in chloroform.

Synthesis of intermediate 1,4-bis(3,4,5-trimethoxyphenyl)butane-1,4-dione (V). This compound can be obtained by three related methods: 1. The Grignard reaction of 3,4,5-trimethoxybenzaldehyde (I) with vinylmagnesium bromide (II), followed by oxidation with MnO2, gives 1-(3,4,5-trimethoxyphenyl)-2-propen-1-one (III), which is then condensed with aldehyde (I) by means of the thiazolium salt (IV) to yield the target intermediate (V). 2. The condensation of 3,4,5-trimethoxyacetophenone (VI) with methylamine and formaldehyde gives 3-(dimethylamino)-1-(3,4,5-trimethoxyphenyl)-1-propanone (VII), which is treated with methyl iodide at 80 C to afford the previously reported propenone intermediate (III). 3.The direct dimerization of acetophenone (VI) by means of LDA and CuCl2 also gives the target intermediate (V). Synthesis of the target compound: The reduction of the butanedione intermediate (V) with LiAlH4 or NaBH4 gives (RS,RS)-1,4-bis(3,4,5-trimethoxyphenyl)butane-2,3-diol (IX), which is dehydrated to the target tetrahydrofuran by means of TFA, PdCl2/Cu(NO3)2 or MsCl/pyridine. Alternatively, the reduction of butanedione (V) can be performed stepwise, first with LiAlH(O-tBu)3 to give the intermediate hydroxyketone (VIII), which is reduced to the diol (IX). The isolation of the intermediate hydroxyketone (VIII) allows the separation of enantiomers offering the possibility of obtaining chiral forms of the target tetrahydrofuran.

The reaction of 3,4,5-trimethoxyacetophenone (I) with diethylamine and formaldehyde gives 3-(dimethylamino)-1-(3,4,5-trimethoxyphenyl)-1-propanone (II), which is treated with methyl iodide at 80 C to yield 1-(3,4,5-trimethoxyphenyl)-2-propen-1-one (III). The condensation of (III) with 3-methoxy-5-(methylsulfonyl)-4-propoxybenzaldehyde (IV) by means of TEA and the thiazolium derivative (V) affords the asymmetric butane-1,4-dione (VI), which is reduced with LiAlH4 or NaBH4 to provide the (RS,RS)-butane-1,4-diol (VIII). Finally, this compound is dehydrated to the target tetrahydrofuran by means of TFA, PdCl2/Cu(NO3)2 or MsCl/pyridine.

The selective monoreduction of the already known (see scheme 14265002a) 1-[3-methoxy-5-(methylsulfonyl)-4-propoxyphenyl]-4-(3,4,5-trimethoxyphenyl)butane-1,4-dione (I) with LiAlH(O-t-Bu)3 in THF gives the hydroxybutanone (II) as a racemic mixture that is separated by esterification with (-)-(R)-mandelic acid, separation of diastereomers and hydrolysis with KOH in ethanol yielding (S)-(III) and (R)-(IV) as pure enantiomers. The reduction of both (S)-(III) and (R)-(IV) with NaBH4 in hot ethanol gives (S)-(V) and (R)-(VI) diols that are cyclized by means of TFA in chloroform to afford trans-(S,S)- and trans-(R,R)-target compounds. Both compounds are impurified with about 25% of the corresponding cis-isomer that is separated by chromatography.

A new synthesis for L-659989 has been reported: The alkylation of 4-hydroxy-3-iodo-5-methoxybenzaldehyde (I) with propyl bromide in hot DMF gives 3-iodo-5-methoxy-4-propoxybenzaldehyde (II), which is condensed with tert-butyl acrylate (III) by means of NaCN in DMF to yield 3-(3-iodo-5-methoxy-4-propoxybenzoyl)propionic acid tert-butyl ester (IV). The stereoselective reduction of (IV) with chlorodiisopinocampheylborane (V) in THF affords 4(S)-hydroxy-4-(3-iodo-5-methoxy-4-propoxyphenyl)butyric acid tert-butyl ester (VI), which is hydrolyzed with KOH in methanol-water to the corresponding free acid (VII). The cyclization of (VII) with pyridinium p-toluenesulfonate in toluene gives 5(S)-(3-iodo-5-methoxy-4-propoxyphenyl)tetrahydrofuran-2-one (VIII), which is treated with dimethyl disulfide and copper in refluxing pyridine to yield 5(S)-[3-methoxy-5-(methylthio)-4-propoxyphenyl]tetrahydrofuran-2-one (IX). The oxidation of (IX) with magnesium monoperoxyphthalate in acetonitrile-water affords the corresponding sulfone (X), which is reduced with diisobutylaluminum hydride in toluene giving 5(S)-[3-methoxy-5-(methylsulfonyl)-4-propoxyphenyl]tetrahydrofuran-2-ol (XI). Finally, this compound is treated first with bromotrimethylsilane and then with 3,4,5-trimethoxyphenylmagnesium bromide, yielding the final product with a trans/cis ratio of 15/1 and a yield of 55%.