Study On The Synthesis Route Of Lycorine Alkaloids

This paper mainly focuses on the synthesis of 2-25 compounds by intramolecular Schmidt rearrangement reaction of ω-alkyl azide carboxylic acid compound 2-26,and the key intermediate lactam 2-25 was explored for the synthesis route of lycorine alkaloids.The paper mainly covers the following two main aspects:1.A brief review on the synthetic value and synthesis of lycorine alkaloids;The Schmidt rearrangement reaction with imide cation being as the key intermediate was used as the key strategy to synthesize compound 2-25 with the core skeleton of lycorine alkaloids,The synthesis ofα-lycorane was completed with compounds 2-25,and the exploration of synthetic routes for the synthesis of lycorine alkaloids in the highly oxidized state was carried out.The first chapter focuses on the medicinal value of lycorine alkaloids and the progress of synthetic research.Lycorine alkaloids have important physiological activities such as anti-tumor,inducing apoptosis of white blood cells,and have inhibitory effects on various viruses.Due to their enormous medicinal value,many research groups have been continuously researching the synthesis of lycorine alkaloids for many years.The main skeleton of lycorine alkaloids is the pyrrole fused phenanthridine ring,which is a multi-ring structure containing A ring,B ring,C ring,and D ring.The key to the synthesis of lycorine alkaloids is how to form the ring systems.The classic cyclization methods include the Diels-Alder cyclization,photo cyclization,Bischler Napieralski cyclization,palladium catalyzed C-C coupling cyclization,Pictet Spengler cyclization,free radical cyclization,asymmetric synthesis,and other methods.Many research groups have used different ring forming methods to synthesize one or more of the rings as a key strategy in the total synthesis of lycorine alkaloids.The second chapter mainly focuses on the synthesis of α-lycorane and the exploration of the synthesis of highly oxidized lycorine alkaloids,the key step is the Schmidt rearrangement reaction ofω-azidocarboxylic acid compounds.Our research group has reported the Schmidt rearrangement reaction through the isocyanate cations as the key intermediate for total synthesis of α-lycorane.However,when the attempt for synthesis of lycorine was from lactam 2-20 was tried,the C=C double bond on the C ring of would be migrated or oxidized,either no reaction occurs or the C ring proceeded aromatization,which made it impossible to continue the research.In addition,in the α-lycorane synthetic route,depropargyl reaction of compound 2-18 resulted in moderate yield,and if the reaction was amplified,the yield encountered further decrease,affecting the synthesis efficiency of α-lycorane.In order to continue exploring the synthesis route on the lycorine alkaloids and solve the problem of low yield of depropargylation reaction,we designed and employed a new synthetic route for preparing the compound 2-25.The synthesis work used the Diels-Alder reaction as the key reaction,where the carbonyl group was transferred to another side for producing lactone 2-31,and then ring-opening and bromination of the lactone,azidation and saponification were carried out,and the ω-azido carboxylic acid 2-25 was addressed,and the lycorine core skeleton 2-25 was obtained from the intramolecular Schmidt rearrangement reaction.Then we completed the synthesis of α-lycorane through the hydrogenation reaction and carbonyl reduction of compound 2-25.The new synthetic route avoided the poor depropargyl reaction,and the overall synthetic efficiency of α-lycorane was improved.Further,dihydroxylation reaction of compound 2-25 failed,where no positive results were obtained.Finally,allylic oxidation of the lactam 2-25 gave the alcohol 2-42,which should be useful for further synthesis on the highly oxidized lycorine alkaloids in the future.