Studies On The Organocatalytic Asymmetric Intramolecular Aza-Michael Reaction

Asymmetric organocatalytic synthesis reaction is considered to be the third asymmetric catalytic method relative to transition-metal catalysis and enzyme catalysis reaction.Because of its stability,cheapness,operability,high selectivity and low toxicity,organocatalytic asymmetric reaction has become an important tool to construct molecular skeletons and has broad application in the respect of development in medicine,biology and materials science.Using chiral catalysts,organocatalytic asymmetric intramolecular aza-Michael reaction can form C-N bond with stereoselectivity and build nitrogen-containing heterocycles with chiral center,therefore it has an important value for organic synthesis.Highly enantioselective synthesis of three kinds of chiral nitrogen-containing heterocyclics using organocatalytic asymmetric intramolecular aza-Michael reaction was reported in the thesis and it can be divided into the four parts.In chapter 1,progress of the research on organocatalytic asymmetric aza-Michael reaction was summarized.Firstly,several kinds of organocatalysts and organocatalysis mechanisms were introduced;secondly,two types of intramolecular aza-Michael reaction including exo and endo type were summarized successively,a variety of chiral nitrogen-containing heterocycles were synthesized using different organocatalysis in respect to substrates in high yields and enantioselectivity.In chapter 2,the synthesis of chiral 3-substituted 1,2-oxazinanes using quinine-derived amine catalyst and PhCO2H as cocatalyst via organocatalytic 6-exo-trig intramolecular aza-Michael reaction in high yields and good enantioselectivity was reported.The products are important building blocks of some pharmaceutical moleculars and can be transformed to functionalized amino alcohols with important synthetic utility.The method is efficient and convenient for chemists to synthesize chiral 1,2-oxazinanes.In chapter 3,the synthesis of biologically active azaflavanones using organocatalytic 6-endo-trig aza-Michael reaction in high yields and excellent enantioselectivity was reported.Comparing the methods reported previously,quinine-derived trifunctional catalyst and PhCO2H as cocatalyst were used in the method,with simple substrates,broad scope and excellent enantioselectivity,the method features atom-economic and high efficiency.In chapter 4,the synthesis of 4-piperidones that are important building blocks of some pharmaceutical moleculars using organocatalytic 6-endo-trig aza-Michael reaction was studied.Through conditions screening such as catalysts,cocatalysts and solvents,the product was obtained in the yield of 36%and 90/10 er value.The chiral catalysts such as quinine-derived amines,quinine-derived thioureas,phosphoric acids were synthesized and were applied to optimize reaction conditions of the several transformations above.The substrates and products that had not been reported before were verified by NMR,IR and HRMS.