The Asymmetric Strategies For The Synthesis Of Bioactive Spirooxindole Scaffolds

With the development of chemical genomics, small organic molecules has become one of the important tools of life activities study. The spirooxindole unit constitutes a core structural element prevalent in a large family of natural products and medicinally relevant compounds exhibiting important biological activities, and has been apllied in medicinal chemistry and chemical biology research. Thus, the synthesis, biological and pharmaceutical evaluations of spirooxindoles have attracted significant attentions from oganic chemists, medicinal chemists and biologists.This dissertation focuses on the study of the biology-oriented synthetic methodology of spirooxindole scaffolds. We have developed a series of organocatalytic asymmetric 1,3-dipolar cycloadditions and cascade reactions for the construction of optically pure spirooxindoles library, which may benefits drug discovery and chemical biology.The dissertation includes six chapters. The first chapter reviews the recent developments on organocatalytic asymmetric methods for spirooxindoles. In Chapter 2, we have developed an unprecedented organocatalytic enantioselective 1,3-dipolar cycloaddition reaction between azlactones and methyleneindolinones that proceeds in high yields with good diastereoselectivities and good to excellent enantioselectivities.To the best our knowledge, no organocatalytic enantioselective 1,3-dipolar cycloaddition reaction of azlactones that takes advantage of the nucleophilic C4 and electrophilic C2 atoms has been reported previously. In the third chapter, we have developed a chiral bis-phosphoric acid bearing triple axial chirality and applied it in the asymmetric 1,3-DC of methyleneindolinones and N,N'-cyclic azomethine imines for the construction of enantiomerically pure spiro[pyrazolidin-3,3'-oxindoles] for the first time. The activation mode proposed by us according to experimental and calculation results may open unprecedented opportunities for phosphoric acid catalyzed asymmetric reactions. In Chapter 4, we have developed two organocatalytic cascade strategies, involving Michael-Alkylation and Michael-Michael cascades, for the enantioselective construction of densely functionalized spirocyclopentane bioxindoles with the control of multi contiguous stereocenters. In the fifth chapter, we have developed a highly efficient "organo-metal" synergistic catalysis strategy for the synthesis of spirocyclopentene oxindole derivatives. The integration of the two distinct catalytic cycles in one process facilitates the rapid and controlled production of valuable chiral spirocyclopentene oxindoles in moderate-to-high yields with good diastereoselectivities and excellent enantioselectivities. Importantly, the process is significantly characterized by greatly improved reactivity and selectivity by using synergistic catalysis strategy. The sixth, also the last chapter, is a brief summery and outlook of our work and related research.