Studies On Asymmetric Synthesis Of γ-butyrolactam Derivatives

γ-Butyrolactam(pyrrolidone)is one kind of nitrogen-containing heterocyclic compounds,and also constitutes a basic structural element prevalent in a large family of natural products,most of which exhibit distinct biological activities and have become increasingly important for medical research.For this reason,the development of synthetic methods to build such "privileged" molecules is of great importance.So far,a series of methodologies,like ring-closure reactions,cycloadditions,emerged as classic pathways for this target.However,those strategies are employed only for racemic synthesis,and examples on enantioselective synthesis are seldom reported.If we take under consideration that chiral is one of the fundamental properties of naturally existed compounds,enantiomers might show completely different or even opposite biological activity.Therefore,catalytic asymmetric reaction constructing various functionalized enantiopure γ-butyrolactams has become focus of our research.This dissertation focuses mainly on the new methodologies for the asymmetric synthesis of γ-butyrolactam derivatives.In our work,we have realized asymmetric additions participated by unsaturated y-butyrolactam,trimethylsilyl cyanide and oxazolone,which are either.new reaction patterns or novel catalytic systems.By using these new methods,a variety of chiral γ-butyrolactam derivatives or their synthetic precursors were efficiently constructed.This dissertation includes five chapters.The first chapter reviewed the research developments in chemical synthetic methodologies of γ-butyrolactam derivatives and the enantioselective synthesis of those molecules from unsaturated γ-butyrolactam.In chapter 2,we firstly disclosed the asymmetric Aldol addition/isomerization reaction,asymmetric vinylogous 1,6-addition and Michael addition of unsaturatedγ-butyrolactam for the synthesis of various substituted y-butyrolactam derivatives.Those methods not only expand the reaction site of nucleophilic addition from γ-toα-position in un saturated γ-butyrolactam substrate,but also broaden its asymmetric addition scope at γ-position.At the same time,we present a simple strategy to construct the alkyl ester derivatives.In chapter 3,we focus our study on the discovery and development of novel chiral phenol magnesium catalyzed asymmetric conjugated cyanation.In this catalytic system,both α,β-unsaturated ketones and amides obtained high levels of stereochemistry control.This strategy provides an efficient way for the synthesis of the β-substituted y-butyrolactam derivatives.Magnesium catalyst was recently developed as a straightforward way for pharmaceutical compounds synthesis,which was low-cost,non-toxic and environmentally friendly compare to the transition metals.It also stands for a practical prospect in the field of chemical catalysis.In chapter 4,A highly efficient enantioselective Michael addition between oxazolones and α,β-unsaturated trichloromethyl ketones has been developed,a series of very useful synthetic precursors of multi-substituted y-butyrolactam derivatives were prepared,which could be easily transformed into our desired compounds via ring isomerization.The last chapter is about the brief summary of our work and the prospect in this research field.