Studies On Novel Approach Toward Total Synthesis Of Norketoyobyrine

Norketoyobyrine is an indolequinazine alkaloid isolated from the Nauclea latifolia plant,which contains an indole AB ring and a dihydropyridopyridone CD ring,that is similar with yohimbine.The difference is that the E ring of Norketoyobyrine is benzene and has no substituent groups.Norketoyobyrine has potential medicinal value in the treatment and prevention of non-alcoholic fatty liver disease and cardiovascular disease.However,it is far from being able to achieve medicinal purposes only by extracting from plants.Based on the total synthesis of harringtonine and berberine,a novel isoquinoline cyclization reaction developed by our group was used to construct skeleton,and bring forward a new method for the total synthesis of Norketoyobyrine.In this design route,we make it through commercial materials and mild reaction conditions,which is hoped to provide valuable help in the total synthesis of Nauclea indole alkaloids and derivatives.In the first chapter of this article,we briefly summarized the origin,classification,active ingredients and Biosynthetic pathway of the Nauclea indole alkaloids to which Norketoyobyrine belongs in.Based on the order of obtaining ring construction,the research progress of total synthesis of Norketoyobyrine in recent years was systematically summarized;while taking the key reactions as the classification criteria,we reviewed the representative total synthesis of Nauclefine and Yohimbine which containing similar pentacyclic structures with Norketoyobyrine.Second chapter of this article,we expounds the Norketoyobyrine’s new strategy and new method of total synthesis.First of all,in the basis of the topic,we given an Introduction of the basic concepts of classical Reissert reaction,and emphasised the total synthesis of Berberine analogue、Pterosaurus alkaloids and Triceutaxine precursor compound through new reaction.In the next place,we speculated the inverse synthesis route of Norketoyobyrine,based on the novel isoquinoline cyclization reaction.Finally,it is given a systematic discussion on the total synthesis of Norketoyobyrine with a total yield of 16%,based on the novel isoquinoline cyclization reaction,reduction reaction,hydrolysis reaction and decarbonylation reaction.Third chapter of this article,the preparation of N-Me-Norketoyobyrine derivatives was reported by the same synthetic strategy,which provides more directions for structural modification and substrate expansion of alkaloids containing pentacyclic structures of indolequinazine.After adjusting the reaction sequence,a new β-Karoline alkalinoid lactone derivatives was obtained,which provides an efficient method for the synthesis of such derivatives,and a new research direction for the conversion pathway of indole alkaloids from the Nauclea indole alkaloids to β-Carboline alkaloids.The structure of the new β-Karoline alkalinoid lactone derivatives was characterized by single crystal X-Ray diffraction,while discussed the possible reaction mechanism.