异三尖杉酯碱的合成及其异构体的分离

本文报道对实验动物肿瘤有抑制作用的异三尖杉酯碱的合成。以天然的三尖杉碱为原料,经过三尖杉碱-5-甲基-2-氧己酸酯与α-苄氧溴乙酸酯和活化锌进行Reformatsky反应,产品为苄氧异三尖杉酯碱及其三个立体异构体的混合物(8),收率51%。所含四个异构体的量相近。经旋转薄层层析分离为(8 a)和(8 b)两部分。分别以10%钯炭氢解生成(9 a)和(9 b),氢解产物再分别分离为(9 a₁),(9 a₂)和(9 b₁),(9 b₂)。(9 b₁)的物理常数和各种光谱均与天然异三尖杉酯碱一致。根据核磁共振光谱推测了其它三个立体异构体的绝对构型。

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 (9a_1), (9a_2) and (9b_1), (9b_2) which showed identical MS, and almost superimposed IR but with different NMR spectra. The melting point and spectrometric data of (9b_1) 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.