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.

The CH2Cl2/MeOH extracts of Combretum caffrum stem wood were fractionated using a solvent partition sequence, followed by gel filtration and column chromatography to provide a mixture of three substituted stilbenes: combretastatin A-4 (I), combretastatin A-5 (II) and combretastatin A-6 (III). Further separation of these compounds was achieved via derivatization with tert-butyldimethylsilyl chloride and separation of the respective silyl ethers (IV), (V) and (VI) by preparative TLC. The least polar component (IV) was then desilylated by treatment with tetrabutylammonium fluoride to yield pure combretastatin A-4 (I)

The O-silyl stilbene precursor (IV) was also synthesized by the Wittig reaction either between 3,4,5-trimethoxybenzaldehyde (VII) and the phosphonium salt (VIII) or between phosphonium bromide (IX) and 3-(tert-butyldimethylsilyloxy)-4-methoxybenzaldehyde (X), to furnish in both cases a mixture of the target Z-stilbene (IV) and its E-isomer (XI), which were separated by flash chromatography

Isovanillin (I) was protected as the silyl ether (II) and subsequently reduced to the benzyl alcohol (III). After conversion of (III) to bromide (IV), its reaction with triphenylphosphine gave phosphonium bromide (V). The ylide resulting from deprotonation of (V) with n-butyllithium was then condensed with 3,4,5-trimethoxybenzaldehyde (VI) to afford the required E-stilbene (VII) along with the corresponding Z-isomer, which were separated by column chromatography. Asymmetric Sharpless dihydroxylation of (VII) by means of AD mix-alpha provided the (1S,2S)-diol (VIII). Finally, desilylation of (VIII) using tetrabutylammonium fluoride afforded the target phenol.

In a different synthetic strategy, the required dibromostyrene (XIV) was prepared in low yield by Wittig-like condensation of 3-hydroxy-4-methoxybenzaldehyde (XII) with carbon tetrabromide in the presence of PPh-3. In an improved process, the phenolic hydroxyl of (XII) was first protected as the silyl ether (X), which was then condensed with CBr4/PPh3 to give (XIII). Subsequent desilylation of (XIII) with tetrabutylammonium fluoride provided (XIV). Stereoselective debromination of the dibromostyrene (XIV) with tributyltin hydride and tetrakis(triphenylphosphine)palladium(0) led to the Z-bromostyrene (XV). This was finally subjected to a palladium-catalyzed Suzuki coupling with 3,4,5-trimethoxybenzeneboronic acid (XVI) to furnish the title Z-olefin as the major isomer

A further synthetic strategy was based on the Perkin condensation between 3,4,5-trimethoxyphenylacetic acid (XVII) and 3-hydroxy-4-methoxybenzaldehyde (XII). Decarboxylation of the resultant phenylcinnamic acid (XVIII) by heating with copper powder in quinoline furnished the desired stilbene, accompanied by only minor amounts of the corresponding E-isomer