Synthesis Of Alkaloid Alkaloid Leucophyllidine

Leucophyllidine is an indole alkaloid that has recently been isolated from the plant Leuconotis griffithii.As a potential anti-tumor and anti-inflammatory drug,it exhibits significant vitro cytotoxicity to drug-sensitive and vincristine-resistant KB cells and can also reduce i NOS protein expression in LPS-stimulated cells.And this compound has a novel structure,two skeletons and four c hiral centers and it is a dimer of the compound Eburnamine and the natural product Eucophylline.But its natural abundance is very low,and its total synthesis has not been achieved.So,its total synthesis research will be very important.In this paper,a powerful precursor compound 3-ethyl-3-allylpiperidone was designed with the aim of total synthesis of natural product Leucophyllidine.It can not only synthesize two kinds of skeletons of two alkaloids,Leucophyllidine,but also can be widely used in the synthesis of natural products of many other frameworks.This article is divided into the following three sections:In the first part of this paper,an overview of research progress about the background of the indole alkaloid,Leucophyllidine,was summarized,including including its separation,structure,biological activity and possible biogenetic pathways.Herein,The progress of total synthesis of Leucophyllidine is described in detail,focused on Landsis' s way in 2015 and Pandey's way in 2017.The second part is the research content of this dissertation,which is divided into the following three aspects:(1)Ethyl malonic acid was used as the starting material.After a 7-step reaction,the pair of 3-ethyl-3-allylpiperidone was synthesized with a total yield of 14.9% and an enantiomeric excess of 96.1%.Among the key steps,palladium-catalyzed allyl alkylation reactions were used to construct chiral quaternary carbon centers with high yield and high enantioselectivity.The synthesis method has the advantages of easy availability of raw materials,simple steps,stable yield,and high enantioselectivity.(2)The synthesis of Eucophylline,the lower fragment of Leucophyllidine,was studied.3-ethyl-3-allylpiperidone was used as a raw material to synthesize important intermediates with a total yield of 12.1% and only six steps of reaction,and then synthesized(±)-Eucophylline after five steps according to reports of Landasis group.The advantage of this synthesis method is an optically active intermediate which can complete the total synthesis of(+)-Eucophylline.(3)We still used 3-ethyl-3-allylpiperidone as the raw material,synthesized the triterpene compound with quinone nucleus,which is the important intermediate of Eburnamine.This method is even simple,only including three steps of reaction,but the total yield reached 23.1%.We tried to construct a tetracyclic compound and initially obtain the product.The advantage of this synthesis method is that the route is very short.This paper explored and enriched the total synthesis of the natural product Leucophyllidine.At the same time,we synthesized a chiral precursor compound,3-ethyl-3-allylpiperidone which can simplify the synthetic route of natural products.