The Study On Synthesis Of Paclitaxel Side Chain Via Multi-component Reaction And Paclitaxel Analogues

Taxol?paclitaxel,trade name Taxol^??is a diterpenoid natural product with anticancer activity extracted from the bark of Pacific Linden.Paclitaxel and its semi-synthetic analogue docetaxel are one of the most effective anti-cancer drugs so far,which currently used for the treatment of breast cancer,non-small cell lung cancer,ovarian cancer,head and neck cancer,soft tissue cancer,leukemia and gastrointestinal cancer.Paclitaxel is mainly found in the bark of the rare plant yew,but its natural content is just about 0.069%.The separation and extraction method not only fails to meet the market demand,but also causes great damage to the yew.In addition,the chemical structure of paclitaxel is complex,which makes it very difficult to achieve through total chemical synthesis.Therefore,the current mainstream method for the production of paclitaxel is a semi-synthesis method using 10-deacetylbaccatin??10-DAB?as a raw material.This thesis is divided into two parts.The first part is the synthesis of paclitaxel side chain.First,on the basis of the research on the multi-component reaction of our group,we optimized the hydroxy ylide involved multi-component reaction.Water was used as starting material instead of alcohol,and the?-hydroxy-?-amino acid ester skeleton was constructed in one step through a four-component reaction under the catalysis of Cu?OTf?₂.Then the taxol oxazolidine-type side chain was efficiently synthesized after another four steps.The second part is the semi-synthesis and anticancer activity test of novel taxol derivatives.Combined with the results of the first part of the methodological research,18 paclitaxel derivatives were synthesized in this paper.In the test of anti-tumor activity,several novel compounds with excellent activity were discovered.In this dissertation,combining the methodology and application of multi-component reaction,a highly efficient method for synthesizing paclitaxel side chain derivatives was developed,which was applied into the semi-synthesis of paclitaxel analogues.This research provided a new approach to the study of structure-activity relationship and had potential application value.