Studies On The Syntheses Of Spirocyclic Oxindoles And Quinine-boronic Acids

Pharmacophore-containing compounds play an extremely important role in medicinal chemistry and natural product molecules.Due to the limited application of single-pharmacophore compounds,the status of multi-pharmacophore hybrid compounds in the field of new drug development and chemical pharmacy is constantly improving.Therefore,the development of fast and efficient synthetic methods for multi-pharmacophore hybrid compounds is of great significance for new drug development and chemical biology research.Spirocyclic-oxindole is an important drug-active backbone structure,which exists in many biologically active natural products and marketed drug molecules.Since spirocyclic indole oxide and its derivatives play an important role in the research and development of drugs,a method for efficiently obtaining spirocyclic indole oxide compounds with complex and diverse structures is developed,especially at the same time.The synthetic method of hybridizing multiple pharmacophore into one molecule is of great significance and value to the development of organic chemistry and medicinal chemistry.In this paper,the 1,3-dipolar cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines and maleimide was realized under the condition of phase transfer catalysis.A spirocyclic compound with four pharmacophore groups,pyrrolidine,indole oxide,maleimide and trifluoromethyl.The optimal reaction conditions were determined by screening catalysts,bases,solvents and stoichiometric ratios of reactants.Under optimal conditions,a large number of substrate expansions were carried out to synthesize complex and diverse spiroheterocyclic compounds,and the product yield was up to 96%,at the same time,the diastereoselectivity of most cycloaddition reactions is excellent(>99:1 dr).In addition,the product was also derivatized by palladium-catalyzed Suzuki-Miyaura cross-coupling reaction,and a series of derivatives with more abundant structures were obtained with a yield of up to 47%.When studying the mechanism of phase transfer catalyzed 1,3-dipolar cycloaddition reaction,it was found that the real catalyst for the reaction may be THAC generated in situ by THAB and Cs₂CO₃ through the replacement reaction.The series of multi-pharmacophore hybrid compounds synthesized in this study may become candidate compounds for new drug development,and the phase transfer catalytic synthesis method developed at the same time has the advantages of rapidity and high yield,and is also expected to enter the new drug development toolbox of medicinal chemists.After completing the above research topics on phase transfer catalysis and synthesis,we also carried out a new topic in the field of oxidative coupling methodology.Quinine is a classic natural product derived from the bark of the African cinchona tree and currently plays a pivotal role in medicinal chemistry and organocatalysis.Therefore,it is of great significance to carry out structural modification around the quinine skeleton through efficient organic synthesis.In this paper,the structural modification of boronation at the C6position of the hydroquinoline ring by Miyaura oxidative coupling reaction was investigated.Using quinine as the starting material,O-silyl hydroquinine trifluoromethanesulfonate was synthesized through four-step reaction of palladium-catalyzed hydrogenation,demethyl ether protection,sulfonic acid esterification and silyl ether protection.The target product,O-silyl-6-hydroquinineboronic acid,was successfully synthesized by Miyaura reaction using the sulfonic acid ester and bispinacol diboron as raw materials.The effects of catalysts,ligands,inorganic bases,solvents and stoichiometric ratios of reactants on the reaction were investigated,and the optimal reaction conditions were determined,and the product yield of up to 84%.The relative configuration of the compound was determined by X-ray single crystal diffraction.In addition,the influence of the protective group on the hydroxyl group of hydroquinine on the coupling reaction was also discussed.Based on the unparalleled chemical structure expansion of arylboronic acid molecules,this O-silyl-6-hydroquinine boronic acid may have potential applications in the fields of drug development and organocatalysis.