Enantioselective Synthesis Of Chromanones With Multiple Chiral Centers Via Organocatalytic Tandem Reactions

The chromanone skeleton is the core structure of many natural products and a variety of biologically active molecules,which has a wide range of physiological activities.The chromanone skeleton is an important building block in the drug discovery and synthesis of active lead compounds.Therefore,the diversified synthetic research of chromanone derivatives will help promote the development of such compounds in pharmaceutical research.A variety of chiral catalytic systems have been reported to efficiently construct optically active chromanone derivatives.However,the reported methods are mainly focused on the funcnalizlation of chromone or chromene as the material,and the construction of a chromanone derivative containing only a single(or two)chiral center.The construction of a chromanone containing three(or more)multi-chiral centers still poses great challenges.The chiral prolinol silyl ether catalyst has the advantages of stable,being simple,easy to synthesis,and highly efficient in the asymmetric catalytic reaction.It has been widely used in a variety of asymmetric reactions,including asymmetric Michael addition reaction,Mannich reaction,and Domino reaction,cycloadditions reaction,etc.On the other hand,1,3-dicarbonyl compounds such as β-ketoesters or malonate derivatives have been used in asymmetric catalytic reactions due to their high reactivity,and further application of functionalized 1,3-dicarbonyl compounds such as1,3-diketone derivatives in asymmetric tandem reactions may provide a potential method for the efficient construction of multi-chiral chromanone derivatives.The first part of this thesis is asymmetric synthesis of lactone-fused tricyclic chromanones through reaction of 1-(2-hydroxyaryl)-1,3-diketones and α,β-unsaturated aldhides in the presence of chiral prolinol silyl ether catalyst.The chiral prolinol silyl ether catalyst actvited the α,β-unsaturated aldhide to form imine cation intermediates.Then,the Michael addition/ketalization and hemiacetalization tandem reaction is performed between this intermediate and 1-(2-hydroxyaryl)-1,3-diketones nuclephile,followed by the oxdation reaction in the presence of DMP(Des Martin)reagent to provide tricyclic chromanone derivatives with three adjacent chiral centers in high diastereoselectivity,enantioselectivity and good yield.The reaction system has wide substrate scope.A series of α,β-unsaturated alkenals and alkyl-substituted1-(2-hydroxyaryl)-1,3-dione compounds can smoothly participate in the reaction and obtain the chromanone derivatives with the yield up to 96%,>19:1 diastereoselectivity and >99% enantioselectivity.Further diversification of products has been achieved.In addition,more complex chromanone derivatives containing biologically active building blocks such as glucose and estrone also have been successfully synthesized.The second part of this thesis is inspired by the work of the first part,trying to develop a tandem reaction involving the fluorinated nucleophile2-fluoro-1-(2-hydroxyaryl)-1,3-dione compound to construct chromanone derivative with the multi-chiral centers which includes a carbon-fluorine chiral center.The results have shown that when 3-alkenyl or 3-aryl substituted 2-fluoro1-(2-hydroxyaryl)-1,3-dione compounds were used,chiral prolinol silyl ethers can efficiently catalyze the reaction with α,β-unsaturated aldehyde via Michael addition/ketalization/hemiacetalization tandem reaction,and further acylation reaction,to provide the fluorinated chromanone derivatives with adjacent multi-chiral centers in high yields and excellent stereoselectivities.The raction system can also be applied to the synthesis of biologically active compounds such as sorbic acid,naproxen and estrone derivatives with satisfactory results.