Catalytic Asymmetric Construction Of Indole-Annulated Medium-Sized-Ring Skeletons Via Cycloaddition Reactions

Chiral indole-annulated medium-sized rings,as the dominant skeleton of drug molecules and natural products,have become one of the research hotspots in drug innovation and organic synthesis.This thesis mainly focuses on novel catalytic asymmetric cycloaddition reactions involving three types of active intermediates of azomethine ylides,trimethylenemethanes and isobenzofulvenes,providing a simple and efficient way for the highly stereoselective construction of chiral indole-annulated medium-sized-ring skeletons,including the following three aspects of research work:1.Asymmetric construction of indole annulated tropanes via[3+3]cycloaddition reactionBased on the strategy of copper catalysis and BF3·Et2O as activator,the asymmetric[3+3]cycloaddition of cyclic azomethine ylides with electron-deficient 2-indolyl ethylenes was developed,providing the indole annulated tropanes in good yields with excellent stereoselectivies.This process provides new opportunities for the asymmetric synthesis of structural diversified indole annulated tropanes.2.Asymmetric construction of indole annulated cycloheptanes via[4+3]cycloaddition reaction8-Cl-tetrahydroquinoline-derived phosphoramidite ligand was designed,synthesized and applied to pallidum catalyzed[4+3]cycloaddition of trimethylenemethanes with electrondeficient indole-dienes,affording indole annulated cycloheptanes in excellent yields with exclusive regioselectivities and excellent stereoselectivies.This process provides new methods for the asymmetric construction of biologically important indole annulated cycloheptanes.3.Asymmetric construction of indole annulated bicyclo[4.2.1]nonanes via[8+4]cycloaddition reactionThe chiral secondary amine catalyzed asymmetric[8+4]cycloaddition of indene-2carbaldehydes with electron-deficient indole-dienes was developed for the first time,delivering the indole annulated bicyclo[4.2.1]nonanes in good yields with moderate diastereoselectivities and good enantioselectivies.This process lays a solid synthetic foundation for the further application of such skeletons in medicinal chemistry.