Synthesis Of Sulfur Ylides And Chiral Phosphoric Acids And Their Application In Construction Of Spirocompounds

Spirocyclic scaffolds are important structures in natural world,many of them have been reported to possess various biological activities.Due to their high medicinal value,the synthesis of spirocompounds has became an important research field in organic chemistry.In this thesis,sulfur ylides and BINOL chiral phosphoric acids were utilized to construct spirocyclopropanes and N-hetero spirocompounds.The study in this thesis gave a comprehensive reference for the further research of spirocompounds.The first chapter of this thesis gave a full review of cyclopropyl fragment,including the physicochemical properties,pharmaceutical potential,utilization in constructing other structures and major synthetic methods of cyclopanation.Due to its unique bonding and characteristic ring strain,cyclopropane ring is often used to increase the drug's stability and prolong the drug metabolism time in vivo,they can also be used to increase drug's lipophilicty.Till now,many cyclopropyl drugs have been advanced into clinical utilization,for example,the anticancer drug Lenvatinib and anti-HCV drug Boceprevir and Ledipasvir et al.Based on the structural feature,the reaction activity of cyclopane is very much alike that of an olefinic double bond.At the presence of active catalysts,the cyclopropane derivative is able to transform into 1,3-zwitterion via ring opening and therefore is able to attack electrophiles or accept the attack of nucleophiles.The main methods for synthesizing cyclopropane derivative is Simmons-Smith cyclopropanation,transition-metal-catalyzed cyclopropanation and Michael-initiated ring closure.The second part of this thesis focused on an efficient synthetic method for spirocyclopropanes using a highly active reaction between sulfur ylides and cyclic enones.The reaction is carried out under catalyst-free conditions and is able to afford multifunctional spirocyclopropanes in good yield(up to 99%)and promising diastereoselectivity(up to >20:1dr).The asymmetric version of this method was realized by using an easily available chiral sulfur ylide,affording products with moderate to good stereoselectivity.In the third chapter of this thesis,the preparation of a highly applicable BINOL chiral phosphoric acid was optimized,and a test experiment was performed.Through the optimization of the preparation process of chiral BINOL phosphoric acid,an efficient and simple synthetic route was obtained.Using the prepared BINOL phosphoric acid as catalyst,a[2+3] annulation between electron deficient cyclic enone and azlactone was developed.N-hetero spirocompound can be obtained in high yield and high stereoselectivity.