合成路线1

Selective cleavage of the 2,3 methyl ether functionalities of 2,3,4-trimethoxybenzaldehyde (I) employing boron trichloride furnished diol (II), which was subsequently converted to the bis-silylated derivative (III). The phosphonium bromide (V), prepared from 3,4,5-trimethoxybenzyl bromide (IV) and triphenyl phosphine, was then subjected to a Wittig reaction with aldehyde (III) to provide the corresponding olefin (VIa-b) as a mixture of E/Z isomers. After chromatographic isolation of the desired Z-isomer, the silyl protecting groups were removed by treatment with either potassium fluoride in DMF or tetrabutylammonium fluoride in THF to furnish combretastatin A-1 (VII). Further condensation of diphenol (VII) with dibenzyl phosphite in the presence of DIEA and DMAP in CCl4 produced the 2',3'-O-di(bis-benzylphosphoryl)combretastatin A-1 (VIII). Alternatively, (VII) was reacted with dibenzyl N,N-diisopropylphosphoramidite to yield the bis-phosphite (IX), which was further oxidized to the corresponding phosphate (VIII) with m-chloroperbenzoic acid. Cleavage of the benzyl phosphate esters of (VIII) was achieved by treatment with in situ-generated iodotrimethylsilane, and the resulting phosphoric acid was converted to the tetrasodium salt by means of methanolic sodium methoxide.