Studies On The [5+1] Annultation Of Polysubstituted Divinyl Ketones With Ethyl Isocyanoacetate

Six-membered cyclic compounds, as one of the most common ring-systems, are the important topics in organic synthesis and total synthesis of natural products. Their synthetic methodology has focused much attention of chemists, in which [5+1] annulation is a novel strategy attracting a growing body of research. We have been dealing with functionalized ketene dithioacetals for several years and had succeeded in the preparation of six-membered aromatic and heterocyclic compounds based on [5C+1C], [5C+1N] and [5C+1S] annulation. Further exploration for such a useful [5+1] annulation on versatile reaction system is still of great importance and will promote intensive study on [5+1] annulation.This thesis is devoted to expand the utility of [5+1] annulation to divinyl ketones with isocyanoacetate as the one carbon nucleophiles.β,β-disubstituted divinyl ketones are selected as the five-carbon synthon based on our previous research work, a series of poly-substituted cyclohexanones are synthesized through highly efficient one-pot [5+1] annulation. An in-depth research on [5+1] annulation for the construction of six-membered cyclic compounds is developed.This thesis is divided into five chapters.In Chapter one, the progresses on the cyclization of divinyl ketones, especially the Nazarov reaction and [5C+1X] annulation, and the isocyanide chemistry are reviewed. Based on chapter one and combined with our group's research work, the thesis proposal is presented in chapter two:the construction of biologically active six-membered cyclic compounds based on the [5+1] annulation ofβ,β-disubstituted divinyl ketones and isocyanoacetate.Chapter three involves the synthesis of symmetric substituted and asymmetric substituted divinyl ketones via conventional methods, based on the summarized synthetic methodology for various divinyl ketones. These syntheses lay a good foundation for the further research work.Chapter four emphatically describes the efficient [5+1] annulation of the easily available divinyl ketones and isocyanoacetate under the catalysis of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in which a series of poly-substituted cyclohexanones are obtained in high yields. A possible mechanism of this reaction is proposed and the products of poly-substituted cyclohexanones are further hydrolized under acidic conditions, affording N-formyl amino acid esters which have the potential biological activities. Furthermore, some pyrroline derivatives are also obtained via the [3+2] cycloaddition from the same divinyl ketones and isocyanide under varied reaction conditions. All of the reactions described above are highly efficient under mild reaction conditions. Thus, a novel [5+1] annulation strategy is developed, which enriches and expands the application for such a type of reactions.Chapter five discloses the reduction of the synthesized poly-substituted cyclohexanones described above in the presence of suitable reducing agent, giving bridgedδ-lactones. In comparative studies on the generation of bridgedδ-lactones, isocyanoacetate has the similar reactivity with other substrates such as ethyl cyanacetate. The crystal structure of the bridgedδ-lactone is further analyzed based on the X-ray crystallography.The benefits of the [5+1] annulation for divinyl ketones and isocyanoacetate in this thesis are summarized as below (1) high efficiency under mild reaction conditions; (2) a novel synthetic strategy for the synthesis of cyclohexyl isocyanide is developed with isocyano group remained, providing a broad space for further research. (3) the application scope for [5+1] annulation is expanded and enriched.