Total Synthesis Of Antineoplastic Agent CA-4 And Attempted Synthesis Of Its Water Soluble Prodrug

Total synthesis of CA-4 (Combretastatin A-4) and attempted synthesis of itswater soluble prodrug was described in the dissertation. CA-4 was abstracted fromCombretum caffrum, an African bush willow by Pettit in 1987. As a new potentanticancer agent, CA-4 can inhibit the growth of many tumors and a broader marketwas prospected, but its low solubility in water and saline sets a limit to its use inclinical research and cancer therapy. It is necessary to synthesize a new prodrug ofCA-4, which may not only improves its solubility in water, but also keeps itsanticancer activity. To achieve this aim, 3,4,5-trimethoxybenzyltriphenylphosphoniumbromide was synthesized from 3,4,5-trimethoxybenzaldehyde. Then 4-methoxy-3-[(tert-butyldimethylsilyl)oxy] -benzaldehyde was prepared by the silylation of4-methoxy-3-hydroxybenzaldehyde. After that, 3'-[(tert-butyldimethylsilyl)oxy]-Combretastatin A-4 was prepared by the reaction of the aldehyde and thephosphonium bromide under the action of n-butyl lithium. Through the desilylationprocedure, Combretastatin A-4 was prepared, which reacted upon1-chloro-4,5-benzo-2,6-dioxaphosphorinanone-(3)-1-oxide to produce 1-(Combreta-statin A-4)-4,5-benzo-2,6-dioxaphosphorinanone-(3)-1-oxide. According to 1H NMRspectrum, the water soluble prodrug of Combretastatin A-4 contaminated withimpurities was believed prepared by the hydrolysis of 1-(CombretastatinA-4)-4,5-benzo-2,6-dioxaphosphorinanone-(3)-1-oxide in water solution of NaOH.We are purifying the product.