合成路线1

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%.