The Diversity-oriented Synthesis Of Chiral Spiro Oxindole Skeletons

The specificity of biological activities found in natural compounds is generally in connection with the characteristic structural complexity and well-defined stereo-architecture. In this context, much attention has been paid to the asymmetric synthetic strategies for assembling challenging scaffolds widespreadly rooted in natural compounds. The spiro oxindole scadles is a privileged scaffold that is featured in a myriad of bioactive naturally occuring alkaloids and medicinally relevant compounds. This unique structural array along with the interesting biological activity and vast pharmaceutical potential makes the asymmetric assembly of this family of molecules an attractive but challenging task. Therefore, structure-based design has been developed to access potent analogues containing these priviledged skeletons in biology- and diversity-oriented synthesis. Albeit the outstanding progress in this field, the construction of highly functionalized polycyclic skeletons, particularly those containing multiple spiro-quaternary stereocenters, poses a great synthetic problem.Herein, we focused on the development of new methodology to synthesis a series of chiral spiro oxindole skeletons. The dissertation includes three parts. Firstly, we described the first highly enantioselective organocatalytic aza-hetero-Diels-Alder reaction of cyclic 3-alkylidene oxindoles and N-tosyl-2-methylenebut-3-enoates for the construction of functionalized azaspiro oxindole skeletons via a dual HOMO dienophiles and LUMO dienes controlling pathway. We also presented the first asymmetric vinylogous Michael addition/cyclization cascade reaction of α,α-dicyanoalkenes and 3-alkylidene oxindoles to construct diversely structured spiro-oxindole skeletons with excellent yields and stereoselectivities. Lastly, a tertiary amine thiourea mediated 1,3-dipolar cycloaddition has been successfully developed, providing a series of spirotricyclic skeletons with over four contiguous stereocenters, two of which are spiro-quaternary carbon centers. A series of infrequent spiro [γ-butyrolactone-pyrrolidin-3,3’-oxindole] tricyclic skeletons was provided with high enantiopurity and significant opportunities for structural diversification.Simple precursors were used under mild conditions to construct the oxindole derivatives with extraordinary levels of efficiency and stereocontrol. The new methodology provides facile access to a range of multisubstituted polycyclic compounds derivatives, and should be useful in medicinal chemistry and diversity-oriented syntheses of this intriguing class of skeletons.