Study On Chiral Phosphoric Acid Catalyzed [4+1] Annulation Of Heterocyclic Diazo Compounds With Para-quinone Methides To Access Chiral Spiro-dihydrobenzofurans

Objective: To develop a greener,more direct and efficient enantioselective strategy to realize the synthesis of structurally diverse chiral spiro-benzodihydrofuran compounds,and provide a new route for the asymmetric construction of chiral spiro-benzodihydrofuran compounds,as well as further effectively enrich the structure types of spiro-dihydrobenzofuran derivatives and lay a material foundation for pharmaceutical chemistry research in related fields.Methods: At the first,a highly stereoselective asymmetric [4 + 1] cycloaddition reaction system was constructed by screening chiral phosphoric acid catalysts,solvent,temperature,and other influencing factors by using the heterocyclic diazo compounds and para-Quinone Methides(p-QMs)as starting materials.Then a series of chiral spiro-dihydrobenzofuran derivatives were synthesized through a substrate investigation of the substituted heterocyclic diazo compounds and p-QMs,In the following,the synthetic application of this methodology was further explored through a large scale-up experiment and the product derivatization.In addition,the structure of the synthesized chiral products was characterized by NMR,HRMS,IR,and the X-ray single-crystal analysis,and the reaction process was verified according to the structure characterization results and the design control experiments.Results:(1)25 examples of chiral spiro[dihydrobenzofuran-2,3'-oxindole]derivatives(up to 90% yield,>20:1 dr,95% ee),and 4 examples of chiral spiro[2,4'-oxisoquinoline] derivatives(up to 61% yield,6:1 dr,67% ee)were synthesized.(2)On the basis of the synthetic model product 3h,tenfold scale-up experiment was performed,and the product 3h was obtained in 73% yield with 93% ee and >20:1 dr.The yield and stereoselectivity were not decreased comparing with the model reaction.(3)Other three chiral spiro[dihydrobenzofuran-2,3'-oxindoles] with more diverse structures derived from 3h were obtained via the palladium-catalyzed Suzuki C-C/C-B cross-coupling reactions and the retro-Friedel-Crafts reaction.(4)The absolute configuration of the products was assigned by an X-ray single-crystal analysis of the derivative 6.(5)The crucial role of the ortho hydroxyl group in the reaction was verified and the possible transition state of the reaction was also proposed on the basis of the absolute configuration of the products and control experiments.Conclusion: In this subject,a metal-free and organocatalyzed asymmetric [4 + 1]cyclization of the heterocyclic diazo compounds as a direct nucleophile with p-QMs has been developed,which provide a greener and more direct new strategy for the stereoselective synthesis of chiral structurally diverse spiro-dihydrobenzofuran derivatives.