Catalytic Asymmetric Oxidative C-H Functionalization And Redox Deracemization Of Heterocycles

Heterocycles that contain a chiral center at ?-position of the heteroatom,for example chiral ?-substituted tetrahydroisoquinolines,chiral ?-substituted quinolines and chiral ?-substituted isochromans are common structure motifs in numerous drug moleculars and natural products.As a consequence,more and more attention has been paid in the asymmetric synthesis of these structures.Traditional methods rely on chiral starting materials and multistep synthesis which are opposite to the concept of green chemistry.Asymmetric functionalization based on C-H activation is an active field in recent years and it has emerged as an effective method in complex molecular synthesis without prior installation of functional groups.However,current results are quite limited as substrates are mainly based on N-Aryl tetrahydroisoquinolines.The asymmetric C-H functionalization of other substrates,for example N-acyl tetrahydroisoquinoline.quinoline and isochroman,are still challenging.Based on our previous work and the intermediates found in experiments,we envision an "acetal pool" strategy might be the solution.Due to the low reactivity of the substrate and poor stability of the resulting acyliminium or oxocarbinium,the C-H oxidation is thermodynamically unfavorable.We envision that a protic additive that reacts quickly and thermodynamically favorably with acyliminium or oxocarbinium would drive the C-H oxidation to completion and retain the oxidation state in the form of acetal.A suitable acid would promote the conversion of acetal to acyliminium or oxocarbinium with a better counterion to stabilize the cation,and the coupling might be viable.In the second chapter,we realized the first catalytic asymmetric cross-dehydrogenative coupling of cyclic carbamates with terminal alkynes.The optimal condition is as follows:TEMPO BF4-as oxidant,EtOH and H2O as protic additives,Yb(OTf)3 as Lewis acid.KOH as base,CuBr and Pybox as catalyst.A wide range of structurally and electronically diverse carbamates and terminal alkynes are tolerated with high enantiocontrol and excellent functional group tolerance.N-Acyl acetals were identified as the real intermediates through preliminary control experiments.Employing readily removable carbamates as substrates rather than traditionally adopted N-aryl amines allows applications in complex molecule synthesis and therefore advances the C-H functionalization strategy to a synthetically useful level.In the third chapter,the first catalytic asymmetric alkylation of N-acyl quinoliniums with aldehydes is described.Direct C-H activation of dihydroquinoline failed because the low stability of N-acyl quinoliniums.A copper/amine synergistic catalytic system has been developed,allowing the coupling of functionalized aldehydes with a wide range of electronically varied N-acyl acetals in good yields with excellent enantiocontrol.The synergistic catalytic system was also effective for N-acyl dihydroisoquinoline acatal and ?-caboline acatal.demonstrating the general applicability of the protocol in the enantioselective alkylation of diverse cyclic N-acyl acetals.What follows in the forth chapter is the first redox deracemization of a series of cyclic benzyl ic ethers.including 6H-benzo[c]chromenes,isochromans.and 1H-isochr-omenes.The "acetal pool" strategy was adopted to harmonize the complete oxidation of secondary ethers with imidodiphosphoric acid catalyzed asymmetric transfer hydrogenation.The synthetic utility of the process was demonstrated by the effective deracemization of biologically active molecules of interest that are difficult to prepare by other methods.In conclusion.a-substituted tetrahydroisoquinolines.chiral a-substituted quinolines and chiral a-substituted isochromans are synthesized via direct C-H activation or acetal based on our "acetal pool" strategy.A broad range of structurally and electronically diverse tetrahydroisoquinolines,dihydroquinolines and isochromans were well tolerated with this process.The N-carbamoyl protecting group can be easily cleaved under mild conditions,whicn allows applications in complex molecule synthesis.Mechanistic studies indicated the real intermediates are acetals.The "acetal pool”strategy offers an useful solution to the direct C-H functionalization of substrates with low activity.