Studies On One-Pot Double Asymmetric Cascade Reaction By Employing Chiral Phosphate Catalyst

Bioactive chiral compounds such as natural products and pharmaceuticals are quite abundant in nature,so how to obtain and purify chiral molecules through efficient enantioselective ways is of particularly great significance.The development of asymmetric synthesis and catalysis is one of the frontier fields where has been constantly exploring and researching in industry and the chemical academic field.The discovery of new and efficient catalysts in asymmetric catalytic methodology is also the direction of organic chemists.In the past decades,although many methods have been found to be suitable for asymmetric synthesis,organoatalysis has been widely used in chiral methods compared with conventional metal catalysis,which uses small chiral organic molecules as ligands to control the stereoselectivity of the reaction process.It is environmental friendliness,affordable price,easy to prepare and post-treatment,and less toxic by-products,etc.It is worth mentioning that chiral phosphoric acid catalysis has become a splendid breakthrough and great branch in chiral synthesis.BINOL derivatives and VAPOL derivatives with high catalytic activity and enantioselectivity have also been proved to be excellent catalysts for numerous organic transformations.In addition,the chiral metal phosphate forms were neutralized by phosphoric acid and alkoxide metal salts,which work as Lewis acid coordinating with reaction substrates.This outstanding strategy introduces a fresh catalytic activity and reduces the dependence on the structure of substrates,and the application scope and substrate adaptability of phosphoric acid were broadened.In recent years,a mushrooming number of asymmetric multicomponent reactions（AMCRs）has become an increasingly fashionable trend in industry and academic research due to their strong atomic economy and product diversity.At the same time,the co-catalysis of chiral phosphoric acid and transition metal in the field of chiral asymmetric synthesis has also attracted wide attention.Based on our previous reports,herein,a new concept Double Asymmetric Cascade Reaction or DACR is proposed,which is defined as the versatile enantioselective products with different structures can be afforded by two or more reactants in a single vessel,catalyzed by only one chiral catalyst.However,different catalytic reactions have different reaction conditions,reaction mechanisms and transition states,which means the realization of this idea has great challenges that can be considered obviously more difficult to control in terms of selectivity and stereoselectivity.The focus of our writing is on the chiral metal phosphate catalyst which activate the nucleophile and electrophile by coordination to form two reaction intermediates,and realizes the controlling enantioselectivity in one pot.It is pleasantly surprised,matching two previous enantiocontrolled independently reactions in our laboratory,we have established a case of highly enantioselective control DACR in this thesis,including among 3-aryl substituted oxindoles,N-Boc-imines and chlorophthalimide as the model reactants,the highly yield and enantioselective chlorination products and aminal products can be obtained by the catalysis of chiral vaulted biphenanthrol VAPOL（PA1）calcium phosphate complex Ca[PA1]₂.This case introduced that chlorophthalimide can be divided into two parts,one can be used as electrophile for chlorination of 3-aryl substituted oxindoles with high yield and enantioselectivity,another remained part can be conducted as nucleophile to realize the enantiocontroled amilation for amides to imines.Over a variety of optimized conditions were screened,a highly catalytic Double Asymmetric Cascade Reaction has been described.A large range of substituents both on the oxindole arene ring and imine arene ring can be tolerant in this catalytic system through one pot with high efficiency and selectivity,which realized an atom-economical green chemistry.This method utilizes a commercially available source of chlorine,a series of simple and easy-to-synthesize oxindoles and Boc-imines,and a catalytic amount of chiral VAPOL calcium phosphate to explore the range of substrates for this highly enantioselective reaction.To the best of our knowledge,this induction is the first firm case to accomplish this cascade transformation under the mild conditions,the yield and enantioselectivity of chlorination and aminsl products are as high as 99%yield/99%ee and 91%yield/95%ee at room temperature,respectively.The versatility of catalytic concept with high atom and step economy opens the window for exploring the systematic study of catalytic cascade reactions in the future.