Synthesis Of Indoloquinolizidine By Oxidative Asymmetric Aza [4+2] Cycloaddition Reaction

Indole compounds are widely distributed in various heterocyclic compounds in nature and have significant biological activities and application functions.Introducing different modified groups into the structure of indole can produce a series of compounds with pharmacological effects.Some drug molecules,such as indirubin,vinblastine,melatonin,phenanthrolidine alkaloids and so on contain indole groups in their molecular skeleton.According to the research,these compounds have kinase inhibitory effect and play a very important role in lowering blood pressure,anti-cancer,anti-inflammatory and other aspects.Therefore,it is of great significance to study the synthesis of indole-containing skeleton compounds and their derivatives.Asymmetric catalytic synthesis is one of the most effective methods for the synthesis of chiral indoles,a large number of chiral products can be prepared by using a small amount of chiral catalysts.Catalytic asymmetric Diels-Alder reaction is one of the important methods to form new C-C bonds.Catalysts for catalytic asymmetric Diels-Alder mainly include two types of organic small molecule catalysts and metal complexes,which have been extensively studied in asymmetric reactions.Among organic small molecule catalysts,thiourea organic compounds are receiving more and more attention because of their easy preparation and easy formation of hydrogen bonds to activate reactants.However,due to the incompatibility of these chiral catalysts with the oxidation system,studies on asymmetric nitrogen oxide Diels-Alder reactions have so far been rarely reported.A highly enantioselective and non-enantioselective synthesis of six-membered nitrogen-containing compounds with indole-pyrazine structure from tetrahydro-β-caroline and α,β-unsaturated ketone under the synergistic catalysis of Ru(II)salt and chiral thiosemicarbazide catalyst was proposed.Here we explore the best reaction conditions by exploring the reaction conditions of solvents,acids,amine catalysts and oxidants.Finally,we found that using TBHP as the oxidant,good yield(73%)and high enantioselectivity(94% ee)were obtained in the presence of toluene as solvent and benzoic acid.In terms of substrate suitability,when the α,β-unsaturated ketone derivatives have substituent groups with different electronic properties on the aromatic ring,they all participate in the reaction smoothly,and have good reaction results,indicating that the reaction is better,the substrate is adapted to the highest range,and the highest is the phenyl substituted ketene,which yields 96% of ee.The reaction realizes one-pot oxidation of asymmetric aza Diels-Alder reaction,and the reaction raw material is easy to prepare,the amount of catalyst is low,and the generated optical product has important value.In addition,this paper provides a catalytic oxidation system to catalyze the asymmetric aza Diels-Alder reaction,which has broad application prospects.