SYNTHESIS OF ISOHARRINGTONINE AND SEPARATION OF THE ISOMERS

Isoharringtonine, one of the four cephalotaxine esters exhibiting antitumor activity yeas synthesized by using cephalotaxine as the starting material. Cephalotaxine ester of 5-methyl-2-oxo-hexanoic acid was treated with activated zinc dust and methyl a-benzyloxy-a-bromoacetate instead of bromoacetic acid esters commonly used in the Reformatsky reaction to give a mixture of four stereoisomers with 51% yield. TLC scanning combined with HPLC revealed that the mixture contained approximately equal amounts of four isomers. However, it could only be separated into two parts (8 a) and (8b) by chromatotron. No further separation could be achieved by column chromatograph, TLC or chromatotron. Parts (8a) and(Sb) were hydrogenated separately with 10% Pd/C to furnish the dihydroxy products (9 a) and (9 b) in 30% and 72% yield, respectively. They were separated by chromatotron to (9a₁), (9a₂) and (9b₁), (9b₂) which showed identical MS, and almost superimposed IR but with different NMR spectra. The melting point and spectrometric data of (9b₁) are identical with those of natural isoharringtonine. The configurations of the C_2' and C_3' of the rest three isomers were postulated based upon their NMR spectra.