Study On The Synthesis Of Phenanthroindolizidine

ObjectiveCancer is threatening human health severely. The number of people who died of cancer ranks second, only after that of cardiovascular and cerebrovascular diseases worldwide. Nowadays, chemotherapy is still one of the most important methods of curing cancer. Modern anti-cancer medical research focuses on finding lead compounds with high efficiency, low toxicity and high specificity.Phenanthroindolizidine alkaloids have drew great attention of pharmacists due to their dramatic anti-cancer activity. Based on the results of recent studies, the targets of Phenanthroindolizidine alkaloids are different from those of traditional anti-cancer drugs, which are likely to be developed into new anti-cancer drugs with high efficiency and low toxicity. In recent years, reports of synthesis of this kind of alkaloids are mainly about the synthesis and activities of Phenanthroindolizidine alkaloids of which 2,3,6 and 7 positions are substituted with hydroxyl and methoxyl functional groups. Studies on structure-activity relationship show that phenanthrene ring is necessary for the activities, the positions and types of substituents on the aromatic skeleton have great impacts on the activities, and pharmacokinetic characters of 14-hydroxyl substituted derivatives will be better.As part of the studies on the anti-turner activities and the structure-activity relationship of this kind of alkaloids, this paper mainly investigates the synthetic method of 14-hydroxyl substituted phenanthoindolizidine alkaloids, which will provide material basis for the future studies on the impacts on the activities caused by changing 14-hydroxyl and other substituents. In this paper, we discussed the synthetic method of 14-hydroxyl substituted phenanthoindolizidine alkaloids, with 14-hydroxytylophorine as the target compound. Methodα-phenyl cinnamic acid was obtained though Perkin condensation started from 3,4-dimethoxy benzaldehyde and 3,4-dimethoxy phenylacetic acid. Phenanthrene acid derivatives were synthesized by oxidation coupling reaction with metal ions as catalyst. The key intermediate was acquired through LAH reduction, Swern oxidation, and the reductive amination with L-proline methyl ester. The target compound was obtained through PPA-catalyzed ring closing and LAH reduction.ResultBased on the synthetic methods of former papers, we thoroughly studied the synthetic process of 14-hydroxyl substituted Phenanthroindolizidine alkaloids, designed simple and feasible methods to adapt the needs of massive production of derivatives and studies of structure-activity relationship.Total synthesis of 14-hydroxytylophorine is designed and completed, which will provide experimental basis for the future studies on the derivatives of these alkaloids.ConclusionMethods in this study were simple and feasible. Skeleton of this kind of alkaloids was obtaind. oxidation coupling reaction, reductive amination and Friedel-Crafts acylation etc. were disgussed in this paper.