Study On The Catalytic Asymmetric Tandem Annulation Reactions Of Bielectrophilic Reagents

Oxygenated heterocycles are very important organic structural units,which abundant in numerous biologically active natural products and drugs,and they have important research value in biomedicine field.For this reason,how to efficiently construct such compounds has attracted more and more attention from chemists.Currently,the synthetic methods for developing such five and six-membered oxygenated heterocycles scaffolds predominantly focus on(3+2)and(4+2)cycloadditions,and most cycloaddition strategies which reaction conditions are severe rely on the transition metal or Lewis acid-catalyzed cyclization processes.To date,(4+1)and(5+1)cycloaddition methods have been far less investigated and there are fewer studies on compounds containing active methylene as substrates.Therefore,the development of(n+1)(n = 4,5)annulation strategies,especially catalytic asymmetric annulation to construct five-and six-membered chiral oxygenated heterocycles will have important research value.We mainly focuses on the synthesis method of such oxygenated heterocycles compounds,and the synthesis method of chiral spirooxindoles developed on the basis of this research,the following three aspects are studied in this thesis:Part one: We have designed and synthesized a series of bielectrophilic peroxides,which function as electrophilic oxygen and carbon reagents.A general(4+1)cyclization reaction of various carbonyl nucleophiles with bielectrophilic peroxides,which function as unique electrophilic oxygen synthons to construct C-O bond with umpolung strategy,for the synthesis of a broad range of 2,2-disubstituted tetrahydrofurans is achieved under operationally mild conditions.Moreover,by incorporating a chiral auxiliary group into the reaction substrates,the chiral tetrahydrofurans with high diastereoselectivities were access by this unprecedented asymmetric version of such reaction via chiral auxiliary-assisted cyclization which proved the feasibility of such asymmetric cycloaddition strategy and will provide a good starting point for our future research.Finally,the new method can be applied to the synthesis of core structure of posaconazole drug with gram-scale,which practicality was further demonstrated.Part two: Catalytic asymmetric annulation has been established as a powerful method for enantioselective synthesis of oxygenated heterocycles by one-step.Based on the research of part one,we envisage the construction of chiral oxygenated heterocycles through the method of asymmetric phase-transfer catalysis.We carried out a unified catalytic asymmetric(n+1)(n = 4,5)annulation reaction of oxindoles with bifunctional peroxides has been achieved in the presence of a cinchona alkaloid-derived chiral phase-transfer catalyst(PTC)giving rise to a wide range of chiral spirooxindole-tetrahydrofurans and-tetrahydropyrans with good yields and high enantioselectivities.This strategy,along with broad scope and mild conditions,provides a simple and distinct method for the synthesis of chiral five-and six-membered oxacycles.Next,to elucidate the catalytic mechanism of the reaction,DFT calculations were conducted to analyze the transition states of the reaction,these results can be performed to rationalize the origin of high enantioselectivity.This method provides a new way for the efficient synthesis of oxygenated heterocyclic compounds with important pharmaceutical value.Part three: Based on the catalytic asymmetric research of part two,we have designed and synthesized a series of dihalides substrates as bielectrophilic reagent,using oxindoles as the nucleophilic substrate,and carried out preliminary exploration of the reaction under the same phase transfer conditions.We developed a general phase-transfer-catalyzed asymmetric(n+1)(n = 4,5)annulation reaction along with unified and mild condition,featuring the direct coupling of simple oxindoles with alkyl dihalides has been developed to provide previously inaccessible cyclopentane-and cyclohexane-fused spirooxindole scaffolds with high yields and enantioselectivities.Along with a broad scope and mild conditions,the new protocol also enables a two-step and gram-scale synthesis of the core of drug ubrogepant,the practicality of the new reactions was further demonstrated.In summary,this thesis mainly introduces the method of(n+1)(n = 4,5)annulation to construct oxygenated heterocycles,moreover,under the condition of asymmetric phase transfer,the chiral oxygenated heterocycles and spirooxindoles are synthesized.Afterwards,we applied such an annulation method to the synthesis of the core of drug,confirming the practicality of our developed methods.