Efficient Construction Of Active Natural Product Core Framework Chiral Chromanone-2-Carboxylic Acid And Its Derivatives

Chiral 2-substituted chromanones are widely existed in traditional Chinese medicines and natural products such as Guttiferae,Asclepiadaceae,Compositae,Rutaceae and bacteria and fungi such as Stereaceae Pilat,and have rich pharmacological activities such as anti-tumor,antioxidant,anti-inflammatory,anti-diabetic,neuroprotective,antibacterial.Under the guidance of the concept of modernization of traditional Chinese medicine,the modification and optimization of the active ingredient skeleton of traditional Chinese medicine and natural products have become an important direction for new drug development.The synthesis,modification and optimization of the chiral 2-substituted chromanone,which constitute as the core skeleton of many active natural products,have become a hot topic in the development of innovative drugs.Although many methods for synthesizing chiral 2-substituted chromanones have been developed,the following problems still exist:1.Many synthetic methods suffer from a narrow scope of application and high cost and is difficult to be used for the construction of complex natural products;2.Most of the existing methods focus on the synthesis of chiral 2-substituted chromanones substituted with alkyl or aryl groups,which are difficult to be further derived,and thus be limited for their subsequent structural modification and optimization.Therefore,in order to meet the needs of innovative natural product-like drug development,it is of great value to develop a synthetic method for the efficient construction of easily derivatized chiral 2-chromanone skeletons.The introduction of a carboxyl group at the 2-position of the chromanone skeleton can greatly improve the derivatization of such skeletons,thereby facilitating the clustered and diversified construction of a library of chromanone compounds with novel structures and rich types,which may not only lay a solid foundation for new drug development,but also provide effective methods for the synthesis of structurally-complex natural products.In view of this,based on the previous work of our research on the asymmetric catalytic hydrogenation of unsaturated carboxylic acids and the synthesis of natural product-like chiral compounds,we developed herein a highly efficient catalytic hydrogenation of chromone-2-carboxylic acids to obtain the chromanone-2-carboxylic acid skeletons.The following work was mainly carried out:1.A total of 25 aryl-substituted chromone-2-carboxylic acids and thiochromone-2-carboxylic acids were synthesized,and their structures were confirmed by ¹H NMR,¹³C NMR and HRMS;2.The conditions of the catalytic hydrogenation reaction were thoroughly screened and an optimized condition was achieved,under which a total of 22 chromanone-2 containing different aryl substituents were obtained with chemical yields of 87-97%and stereoselectivities of 83-99%ee.Besides,3 thiochromanone-2-carboxylic acid compounds with 62-82%chemical yield and90-94%ee stereoselectivity were also synthesized.The catalyst system features in readily available and low-cost catalyst,high catalytic efficiency（the minimum amount of catalyst can reach 0.01 mol%）and good substrate generality.In addition,in order to better apply this catalytic system to the synthesis of chiral chromanone compounds and their analogs,we have conducted a preliminary discussion on the catalytic reaction mechanism,which provides a theoretical basis for the follow-up progress of the subject;3.By decarbonylation,selective reduction of carboxyl and carbonyl groups as well as preparation of new chromanone bridged compounds,we also preliminarily investigated the modifiability of the constructed chromanone-2-carboxylic acid skeleton and demonstrated the application potential of the developed method in the efficient construction and structural modification of chiral chromanone compounds.The work of this thesis provides an efficient method for the synthesis of natural product-like active chromanone compounds,and lays a solid foundation for the study of the pharmacological activities and mechanisms of these compounds.The work of this thesis provides an efficient method for the synthesis of chromanone compounds,which are active components of traditional Chinese medicine and natural products,and aims to lay a good material foundation for the study of the pharmacological activities and mechanisms of such compounds,in order to provide a basis for the research and development of innovative chromanone-like drugs.