Phosphine-catalyzed Asymmetric Synthesis Of Chiral Nitrogen-Containing Hetereocycles

Nitrogen-containing heterocyclic compound is a class of organic synthesis intermediates existing widely in natural products,pharmaceutical molecules and alkaloids.Nitrogen-containing heterocyclic compounds have a wide range of applications in the fields of organic chemistry,medicinal chemistry and biochemistry.However,asymmetric synthesis of nitrogen-containing heterocyclic compounds in divergent manners remains a great challenge.In particular,nucleophilic phosphine catalysis has emerged as one of the most powerful and straightforward synthetic strategies for the generation of heterocyclic structural motifs.In this thesis,we reported the asymmetric phosphine-catalyzed y-addition reaction and[4+2]annulation with allenoates for the construction of chiral nitrogen-containing heterocyclic compounds in good yields with excellent regio-,and enantioselectivity.In the first chapter,we briefly introduced the characteristics of phosphine-catalyzed reactions,and summarized the recent research progress of phosphine-catalyzed asymmetric reactions with allenoates.In the second chapter,the progress of constructing chiral pyrazole and imidazole compounds has been disclosed.Over the past decade,the enantioselective phosphine-catalyzed y-addition reaction has emerged as an important transformation.Many nucleophiles,such as oxygen,carbon,sulfur and nitrogen,were added to allenoates in a very straightforward manner.However,a brief survey of the literature reveals that the direct phosphine-catalyzed asymmetric N-?-additions of nitrogen heterocycles are very rare.Herein,we envisaged that the methodology via asymmetric y-addition reaction of pyrazole and imidazole derivatives to allenoates will provide the corresponding chiral nitrogen-containing heterocyclic compounds.By using a phosphine catalyst,we developed the first highly regio-and enantioselective addition of pyrazoles and imidazoles to allenoates in an atom-economic manner.The reaction tolerates a broad range of substituted pyrazoles and imidazoles,bearing various functional groups,to deliver y-heterocycle-butenoates in good to excellent yields along with high regio-and enantioselectivities.Furthermore,we have demonstrated possible opportunities for derivatization of the corresponding y-addition products,including the incorporation into small-molecule pharmaceutical such as JAK inhibitor and muscarinic receptor M3 antagonist.In the third chapter,a synthetic method to construct chiral hydrocarbozoles molecules was developed based on[4+2]annulation.Considerable research efforts have been devoted to the development of new methods for the phosphine-catalyzed enantioselective annulations.One particularly versatile and reactive species is the phosphine-mediated 1,4-dipole generated upon addition of the phosphine catalyst to an allenoate substrate,thus providing a concise approach for accessing enantioselective[4+2]annulations.By utilizing 3-nitroindole and allenoates as starting materials,we developed simple and efficient synthetic routes to highly enriched hydrocarbozoles through chiral phosphine-catalyzed[4+2]annulation.This phosphine-catalyzed enantioselective[4+2]annulation procedure involving tandem dearomatization and aromatization steps proceeds under mild conditions.This reaction displays a broad substrate scope with respect to the substituents.Additionally,the corresponding dihydrocarbozole could be efficient transformed to an analgesic agent containing polycyclic indole frameworks.In summary,we have developed a series of powerful and efficient methods to construct chiral nitrogen-containing heterocyclic compounds in this dissertation,and have proved the application value of these reactions via the scale-up reaction and derivatization.