Chiral Br(?)nsted Base Catalyzes Synthesis Of Polycyclic Thiazole Derivatives

As people pay more and more attention to the safety of medication,the safety of chiral drugs has become one of the major issues facing the pharmaceutical industry in the world.Asymmetric catalytic synthesis has been used in the synthesis of single optical isomers by scientific researchers from all over the world for its high efficiency,economy and simplicity.Br(?)nsted bases often start proton cycles by accepting protons and are often used in various synthetic chemistry.Thiazoles are widely used as medicinal frameworks and synthetic modules in the field of medicinal chemistry and synthesis,Benzothiazolopyrimidine skeletons,which are many natural products and active pharmaceutical molecules with physiological activities The core structural unit,and this kind of skeleton compounds can also be widely used as Lewis bases in the field of asymmetric catalysis.Therefore,with the commercialization of many pharmaceutical products containing thiazole ring compounds,further development of chiral thiazole compounds has its special scientific value.This subject uses cinchona base-derived chiral Br(?)nsted base to activate α-haloaldehyde(F,Cl,Br),and via enol activation mode to occur with α,β-unsaturated imine substrates [4 +2] Cyclization reaction to synthesize a series of basic skeleton compounds with benzothiazolopyrimidine ring.The reaction conditions are mild,and the corresponding products can be obtained in high yield(up to 99%),high enantioselectivity(up to 99% ee),and high diastereoselectivity(19: 1 dr).Substrate adaptability.It is worth noting that this is the first time we have reported the use of enol activation mode to synthesize compounds with aza hemiacetals and halogen-containing quaternary carbon centers.An F atom has been introduced at the center of the quaternary carbon,which increases the fat solubility of the compound and improves drug absorption.In order to further prove the practicability of the method of this subject,we modified the skeleton the synthesized products.First,the pyrimidine ring can be opened with triethylsilyl hydrogen.The azahemacetal hydroxyl group were substituted by a DAST fluoro reagent and a dichlorosulfoxide reagent.In addition,the halogen at the center of the quaternary carbon is replaced by a sodium azide reagent,and then the azahemacetal hydroxyl group can be oxidized by a TPAP reagent.Finally,the oxidized product can be used to replace the quaternary carbon halogen with a nucleophilic substitution reagent,the quaternary carbon halogen can be eliminated in a dimethyl sulfoxide solvent,and the amide structure can be reduced by using a lithium aluminum tetrahydrogen reagent.