1,3-dipolar Cycloaddition For The Construction Of C5-Unsubstituted Pyrrolidines:The Development Of Methodology And Applications In Total Synthesis

Natural products,also known as secondary metabolites,have been utilized to regulate functions of enzymes and expressions of genes,which could influence the process of life.Bioactive natural products have drawn much attention from synthetic and medicinal chemists,due to their diverse architectures and good prospects for biomedical applications.Alkaloids,an important class of natural products containing unique functional units,have exhibited various bioactivities.Total synthesis of alkaloids drived by novel methodologies has always been a core research area in our lab.By dissecting the structures of certain kind of alkaloids,we aim to find the similarities in their structures and discover some unresolved synthetic problems.Then we might develop some effective methodologies or strategies to realize the concise total syntheses of these alkaloids.In this doctoral dissertation,we have reported a novel two-step strategy to construct C5-unsubstituted pyrrolidines,which have been applied in the synthetic studies towards several pyrrolidine-containing alkaloids.A traceless[3+2]-cycloaddition reaction to build functionalized C5-unsubstituted pyrrolidines has been illustrated in this thesis:a-iminonitriles act as the equivalent of unstable ylides,which retain the high stereoselectivity and reaction activity of stable ylides,and the cycloadducts could be easily converted to the same cycloaddition targets of unstable ylides through one-step reductive decyanation.This strategy has a couple of advantages,such as broad substrate scope,mild reaction conditions,high diastereoselectivity and scalability.Furthermore,we have expanded the substrate scope of the[3+2]-cycloaddition of a-iminonitriles and the aliphatic a-iminonitriles are also feasible with this strategy.Meanwhile,we have developed a novel chain reductive decyanation reaction for the access to various derivatives of β-proline,in which sodium borohydride acts as a basic initiator.Based on extensive mechanistic experiments,a plausible mechanism of the decyanation reaction is proposed.A practical strategy for the synthesis of multisubstituted β-prolinols has also been developed,featuring a[3+2]-cycloaddition of a-iminonitriles and a programmed reduction mediated by a combination of borane and lithium aluminum hydride.β-Prolinols are also shown to be valuable building blocks for polyheterocycles and pyrrolidine-containing natural products.Moreover,the traceless[3+2]cycloaddition strategy has been applied in the synthetic studies towards pyrrolidine-containing natural products,such as isoretronecanol,martinellic acid,and actinophyllic acid.A five-step total synthesis of isoretronecanol,the construction of the tricyclic skeleton of martinellic acid and the tetracyclic skeleton of actinophyllic acid have been realized based on this strategy.