Reaction of 3,4,5-trimethoxybenzyl alcohol (I) with LiBr/Me3SiCl gives the benzylic bromide (II), which is further condensed with triphenylphosphine to provide the phosphonium salt (III). Wittig reaction of (III) with 4-methoxy-3-(thexyldimethylsilyloxy)benzaldehyde (thexyl is the acronym of 1,1,2-trimethylpropyl) derivative (IV) produces the cis-stilbene (V). Subsequent desilylation of (V) by means of tetrabutylammonium fluoride leads to combretastatin A4 (VI) (1). Phosphitylation of the phenolic hydroxyl group of (VI) with di-tert-butyl N,N-diethylphosphoramidite in the presence of tetrazol provides phosphite ester (VII), which is oxidized by means of m-CPBA to yield phosphate (VIII). The tert-butyl phosphate ester groups of (VIII) are finally cleaved employing trifluoroacetic acid to furnish the desired combretastatin A4 phosphate (1-3).
In an alternative method, 3-hydroxy-4-methoxybenzaldehyde (I) is converted to the corresponding imine (II) with butylamine and p-toluenesulfonic acid. Phosphitylation of (II), followed by oxidation with m-CPBA leads to the aldehyde phosphate (III). This is then subjected to Wittig reaction with 3,4,5-trimethoxybenzyl triphenylphosphonium bromide (IV) to produce the stilbene derivative (V). Finally, acidic cleavage of the tert-butyl ester groups of (V) yields combretastatin phosphate.
Reaction of 3,4,5-trimethoxybenzyl alcohol (I) with LiBr/Me3SiCl gives the benzylic bromide (II), which is further condensed with triphenylphosphine to provide the phosphonium salt (III). Wittig reaction of (III) with 4-methoxy-3-(thexyldimethylsilyloxy)benzaldehyde (thexyl is the acronym of 1,1,2-trimethylpropyl) derivative (IV) produces the cis-stilbene (V). Subsequent desilylation of (V) by means of tetrabutylammonium fluoride leads to combretastatin A4.
Similarly, combretastatin A4 (I) is phosphorylated employing bis (2,2,2-trichloroethyl) phosphorochloridate (II) to afford phosphate (III). Reductive cleavage of the trichloroethyl ester groups of (III) by means of Zn/AcOH, followed by passage through a cation exchange resin furnishes the target sodium phosphate salt.
A related phosphorylation of combretastatin A4 (I) is carried out by coupling with dibenzyl phosphite (A) in the presence of CCl4 and DMAP to furnish phosphate (II). The benzyl phosphate esters of (II) are removed by treatment with NaI/Me3SiCl to afford combretastatin A4 phosphate (III), which is finally converted to the corresponding disodium salt with sodium methoxide in MeOH (2-4). Alternatively, phosphitylation of combretastatin A4 (I) with bis(trimethylsilylethoxy) N,N-diisopropyl phosphoramidite (B), followed by oxidation with m-CPBA affords phosphate (IV). The silylethoxy ester groups of (IV) are then removed with tetrabutylammonium fluoride to yield combretastatin A4 phosphate (III) (2,3).