Asymmetric Strategy For The Construction Of Spiropyrazolone

Pyrazolone skeletons constitute an important class of molecular architecture that are frequently found in natural products,pharmaceutical agents and ligands for asymmetric catalysis.In particular,spiropyrazolones have been demonstrated to be a promising pharmacophore by recent studies.Hence,the construction of spiropyrazolone has attracted intense interest from synthetic chemists.In the past years,several strategies for the construction of spiropyrazolones,especially those featuring all-carbon spirocenters at C-4position,have been developed.In addition,access to spiropyrazolones with an oxygen-attached spirocenter was also documented.However,as far as we know,the construction of spirocyclic structures containing nitrogen atom at the C-4 position of the pyrazolone unit was rarely reported.All of the reported strategies were usually limited to very narrow substrate range or low enantioselectivity.In order to expand the chemical space and structural diversity of spiropyrazolone entities for medicinal research,we recentlyintroduced a new,ambiphilic pyrazolone building block,i.e.4-isothiocyanato pyrazolones,which proved to be a competent synthon toward enantio-enriched spiropyrazolones.Herein,we report the construction of spirocyclic4-aminopyrazolone adducts via asymmetric cyclization of 4-isothiocyanato pyrazolones and ethyl ?-benzoylacrylate catalyzed by the quinine-derived squaramide.The reaction undergoes the Michael/cyclization cascade process to obtain the pyrazolone spiro product with excellent yield(up to 91%)and enantioselectivity(up to 95% ee).After optimizing reaction conditions such as substituents,catalysts,solvents,temperature and reaction feed ratio,19 different spiro[pyrazolone-pyrrolidinethione] skeletons were obtained with high yield and enantioselectivity under optimal reaction conditions.One pot synthesized spiro[pyrazolone-pyrrolidinethione] cores bearing three contiguous stereogenic centers.The reaction can be carried out under mild conditions,and the working-up is efficient and atomic economic,it conforms the concept of green chemistry.