Total Syntheses Of Eight Stemona Alkaloids Including Bisdehydroneostemonine,Bisdehydrostemoninine A And Stemoninine A

As a traditional medicinal herb,“Baibu”(Stemonaceae plant)is widely used in China,Japan,and some Southeast Asian countries.The main active ingredients of Stemonaceae are Stemona alkaloids,and so far,over 200 structures of Stemona alkaloids have been isolated and identified.There are various types of Stemona alkaloids,but most of them contain a common 5/7 azaheterocyclic core structure.Therefore,the construction of a 5/7 bicyclic skeleton of Stemona alkaloids is of great significance for the divergent synthesis of natural products of this family,among which the construction of a seven membered ring is a difficult but important point in the total synthesis of Stemona alkaloids.Based on this,we have conducted a comprehensive and systematic summary of the previous reports on the total synthesis of Stemona alkaloids,focusing on the construction of the seven membered ring of Stemona alkaloids.After systematically summarizing the previous research reports,we conducted a study on the total synthesis of Stemoamide type Stemona alkaloids.Comparing the structure of these alkaloids,we found that they all have a common 5/7/5 tricyclic skeleton,and can be divided into stemoamide type and ethyl-stemoamide type according to the substituents at the C10 position.Previous research was limited to the synthesis of stemoamide with methyl substituted at C10 position.In order to divergently obtain stemoamide and 10-ethyl-stemoamide,and then synthesize a series of natural products derived from these two compounds,we designed a strategy with Prins cyclization reaction as the key step to construct the 5/7 bicyclic skeleton.Then the third five-membered ring was constructed through ruthenium catalyzed CO insertion reactions and intramolecular HWE reactions,respectively,and the methyl/ethyl substituents at C10 position were introduced.Based on this,the pyrrole construction method developed by our research group was empolyed to transform the γ-lactam ring to pyrrole ring.Followed by nucleophilic addition to the ester group,deprotection,and oxidation,the synthesis of natural product bisdehydroneostemonine was achieved.And Vilsmeier Haack reaction was used to introduce formyl groups onto the pyrrole ring,then a lactone ring was constructed using Grignard reaction,deprotection,and oxidation/lactonization,achieving the synthesis of natural products bisdehydrostemonine and bisdehydroprotostemonine.On the other hand,starting from the ethyl-stemoamide,we synthesized the natural product bisdehydroneostemoninine through several steps of pyrrole ring formation,nucleophilic addition,deprotection,and oxidative internal esterification.On this basis,we used Friedel-Craft acylation reaction to achieve the efficient introduction of its substituted side chain at the C3 position in one step.Then,through methyl ester hydrolysis,we completed the complete synthesis of bisdehydrostemoninine A,and used the same intermediate to reduce ketone carbonyl group to synthesize bisdehydrostemoninine.In addition,using a similar method to the synthesis of bisdehydrostemoninine,we also completed the complete synthesis of the natural product stemoninine A.Thus,we had finished the divergent total synthesis of eight Stemona alkaloids,among which bisdehydrosterone A,bisdehydrosteroninine A and stemonine A were synthesized for the first time.