Au-catalyzed Annulation And Its Application In Synthesis Of Cephalotaxine And Cephalezomine H

Cephalotaxus alkaloids,isolated from Cephalotaxaceae,constitute an important kind of bioactive natural products.Cephalotaxine,the parent member of many Cephalotaxus alkaloids,processes a unique benzazepine-bearing pentacyclic ABCDE-ring skeleton.Naturally occurring esters of Cephalotaxine(harringtonine and homoharringtonine)have been found to be highly effective for the treatment of acute human leukemia.The unique structure and the therapeutic potential of this group of alkaloids have stimulated much synthetic interest since its isolation in 1960 s.Although several elegant total syntheses of Cephalotaxus alkaloids have been reported,it is still significant to explore a new strategy to achieved the synthesis of this group of alkaloids.This dissertation mainly aims at the synthetic study of Cephalotaxine and Cephalezomine H along with the related methodologies,in which a new strategy featuring Au-catalyzed [2+3] annulation was applied to the effective construction of the azaspiro[4.4]nonane.The following three parts are mainly included in this dissertation:Part 1: The classification and distribution of Cephalotaxus were described,and the isolation,structure and bioactivity of Cephalotaxus alkaloids were also presented.With the retrospective analysis for the previous literature reports on the Cephalotaxine,some representative achievements were summarized on the basis of different strategies.In addition,the isolation,structure,bioactivity and total synthesis of Cephalezomine H were presented.According to our retrosynthetic analysis,a transition metal catalyzed annulation of enamide with propargyl ester as the key step was designed for the synthesis of bioactive Cephalotaxus alkaloids.Part 2: Investigations on the key annulation reaction were conducted in details.First,some representative transition metal catalyzed reactions of propargyl esters were summarized;Second,standard conditions of the annulation were optimized by using model substrates,and the detailed investigations on the functional groups and the scope of substrates were also conducted;Finally,according to the results obtained above,the plausible reaction mechanism was proposed.Part 3: According to the key annulation reaction we developed,the first generation of synthetic strategy based on the intramolecular [2+3] annulation was carried out,but it was proved to be infeasible.The second generation of synthetic strategy base on the intermolecular [2+3] annulation was then put forword;and then the Witkop photocyclization was used to construct the benzazepine,the total synthesis of(?)-Cephalotaxine and(?)-Cephalezomine H was accomplished successfully.