The Application Of Directed C(sp~3)-H Activation Reactions By Palladium Catalysis In Natural Products Structure Modification

As the secondary metabolites of animals,plants,microorganisms and marine organisms,most natural products play key roles in their physiological homeostasis,self-defense and propagation.Structures of naturally active products,characterized by diversity,individuality and novelty,have been important sources for drug innovation.The natural active substances are good lead compounds,but unlikely meet the demands for druggability,and need structural modification and optimization.At present,the studies about structural modification or optimization of natural products through chemical synthesis focus on more active chemical position in substituents or side chains,while pay less attention to unactivated C（sp³）-H bonds with large in the natural product structure.The unactivated C（sp³）-H bonds are the most abundant covalent bond in organic molecules,one-step conversion of these bonds to the desired functional group shortens synthetic pathways,saving reagents,solvents,and labor.So it has a very important significance to regard the C-H bond as a transformable functional group.At present,C-H bond functionalization has been widely used as a very useful tool in the synthesis of natural products,drug molecules and materials.However,the study on its application to modification and transformation of natural product structure is still rare.In this work,the palladium-catalysed unactivated C（sp³）-H bond activation reactions by 8-aminoquinoline directing are applied to the structural modification of natural small molecules.As the key step,this reactions selectively activate the carbonylβ-position unactivated C（sp³）-H bond of the heterocyclic imino acids and organic acids,and directly carry out the cyclization or arylation reaction,thus successfully synthesizing the diazabicyclicβ-lactam compounds having a plurality of chiral centers,drug molecules（-）-preclamol and part of natural product derivatives.The results of these studies include the following aspects:In the first chapter,we adopts the synthetic route of which the main step is palladium-catalyzed unactivated C（sp³）-H bond activation and intramolecular amination by 8-aminoquinoline directing,to modify the structure of the heterocyclic imino acid derivatives and enantioselectively synthesize a series of 5/4,6/4 ring system diazabicyclicβ-lactam compounds.The determination of the e.e.value of the key intermediates proved that the palladium-catalyzed unactivated C（sp³）-H bond activation and intramolecular amination has high enantioselectivity.The formation of the chiral center of the target product is induced by the chiral center of the derivative and the bidentate ligand regulation.And the absolute configuration of the target diazabicyclicβ-lactam compound was determined by X-ray diffraction data analysis.The data of X-ray diffraction further demonstrate that the chiral centers of the heterocyclic imino acids are well maintained.In the second chapter,we use L-pipecolinic acid as the starting material,using palladium-catalyzed unactivated C（sp³）-H arylation and radical decarboxylation reaction as the key steps of the synthesis route,（-）-preclamol was synthesized in a total yield of 18.6%in 10 steps.The determination of the e.e.value of the key intermediates proved that the palladium-catalyzed C（sp³）-H arylation and the radical decarboxylation reaction have high enantioselectivity.The formation of the chiral center of the target product is induced by the chiral center of the derivative and the bidentate ligand regulation.The X-ray single crystal diffraction analysis of the palladium complex shows that the electron-donating substituent on the nitrogen atom of the L-pipecolinic acid derivative has an inhibitory effect on the C（sp³）-H arylation.The absolute configuration of palladium-complex also confirmed the mechanism of the palladium-catalyzed unactivated C（sp³）-H arylation reaction.In the third chapter,the structure of the natural organic acids was modified by palladium-catalyzed unactivated C（sp³）-H activation reactions using 8-aminoquinoline as the directing group,thus realizing theβ-lactam derivatization andβ-arylation.In order to increase the utilization value of the above method,the directing group and the protecting group of the lithocholic acid derivatives are removed.In addition,in the structure modification of the natural organic acid,the substrate type that can not occur the palladium-catalyzed unactivated C（sp³）-H bond activation and intramolecular amination reaction is summarized.This provides a basis for the selection of substrate for natural product structure modification.Innovation:（1）Different from the traditional strategy of structural modification in which more lively chemical position in substituents or side chains is modified.Under the direction of 8-aminoquinoline and palladium acetate catalysis,the structural modification of the heterocyclic imino acids and organic acids in the present study is the unactivated C（sp³）-H bond at the carbonylβposition.These synthetic routes provide new ideas and methods for the structural modification of natural products.（2）Compared with the literature method,our method get the chiral diazabicyclicβ-lactam compounds environmentally friendly,and has the characteristics of simple,efficient,economic.This will provide new routes for the development of C-type beta-lactamase inhibitors and for the total synthesis of saframycin subfamily alkaloids,and the synthesized derivatives will provide the material basis for the screening of new C-typeβ-lactamase inhibitors.（3）The synthesis of（-）-preclamol used in this study avoids the use of expensive reagents such as platinum,and reagents sensitive to the air and moisture such as grignard reagents.The conditions are mild and it is easy to operate.In addition,the route also has high enantioselectivity,which can not only effectively avoid the chiral separation process of cumbersome and relatively low yield,but also avoid the use of expensive and complex chiral ligand or auxiliary,showing a certain degree of economy.The route will also provide a new synthetic route for the development of the selective D₂-like dopamine autoreceptor agonist（-）-preclamol and its derivatives.（4）In this work,the natural organic acids were modified to obtain a series of organic acidβ-lactam derivatives and aryl derivatives.The method will lay the foundation for the further introduction of other functional groups.At the same time,considering the excellent antibacterial activity exhibited by organic acids and their derivatives,the organic acid derivatives synthesized by this method will also provide a material basis for further activity testing.