Oxidative Kinetic Resolution Of α-substituted N-hydroxy Tetrahydroisoquinoline

Chiral nitroxides show good pharmaceutical value,and their asymmetric synthesis has attracted the attention of chemists.Existing nitroxides are usually commercially available as racemates,and exploring how to synthesize the chiral nitroxides efficiently,conveniently and greenly has become an important topic in drug synthesis research.On the other hand,as an important structural unit of various alkaloids and one of the most common frameworks in drug molecules,the asymmetric synthesis of tetrahydroisoquinoline(THIQ)is also very important.Combining the above practical needs,we designed and realized the oxidation kinetic resolution ofα-substituted N-hydroxy tetrahydroisoquinoline.The traditional asymmetric synthesis strategies of α-chiral N-hydroxy tetrahydroisoquinoline are mainly divided into two types.First,the optically pureα-substituted N-hydroxy tetrahydroisoquinoline are prepared from 3,4-dihydroisoquinoline nitrone by asymmetric nucleophilic addition of nitrones.This method has obvious disadvantages,such as narrow substrate range,requirement of equivalents of alkyl zinc additives and chiral auxiliary,many reaction by-products,and low enantioselectivity.Second,the preparation of chiral nitrogen oxides by asymmetric hydrogenation of carbon-nitrogen double bonds,such as enantioselective hydrosilation of nitrones,asymmetric hydrogenation of oximes,etc.,can achieve high enantioselectivity.In 2020,Nicolai Cramer published his research work on iridium-catalyzed asymmetric hydrogenation of oxime to generate hydroxylamine on Science,and for the first time efficiently catalyzed the synthesis of optically pure nitrogen oxides in a strongly acidic environment.However,the strategy of asymmetric hydrogenation of carbon-nitrogen double bonds is mostly used to prepare open-chain chiral hydroxylamine,and asymmetric hydrosilation of tetrahydroisoquinoline nitrone to tetrahydroisoquinoline hydroxylamine can only achieve 50-60%ee value.Oxidative kinetic resolution is an important method for asymmetric synthesis of drugs.This thesis mainly discussed the preparation of optically pure N-hydroxy tetrahydroisoquinoline by oxidative kinetic resolution strategy.The details are as follows:We first selected α-phenyl tetrahydroisoquinoline hydroxylamine as the initial substrate.By screening a variety of catalysts and oxidants,it was found that when the air was used as the oxidant and the iron complex was used as the catalyst,the substrate could be oxidized to α-phenyl 3,4-dihydroisoquinolinone,so we chose air as the reaction oxidizing agent.After further screening of the reaction system,we selected the iron catalyst of benzimidazole skeleton and the reaction conditions at room temperature.Under optimal conditions,94%enantiomeric excess of the initial substrate was achieved at a conversion of 58%,and the s value was 18.After determining the optimal reaction conditions,we extended the substrate range.When a substituent was introduced into the para position of the α-aryl group,the reaction was very compatible and excellent enantioselectivity was achieved,while when the substituent was introduced into the ortho or meta position,the enantioselectivity decreases significantly.In addition,the enantioselectivity of substrates with a small steric substituent is poor.According to this catalytic system,we synthesized a variety of chiral α-aryl tetrahydroisoquinoline hydroxylamines,and the obtained products could be derivatized to a variety of biologically active alkaloids,which enriches the synthetic methods of chiral isoquinoline alkaloids.In conclusion,we reported for the first time the synthesis of optically pure N-hydroxy tetrahydroisoquinolines catalyzed by cheap metal.Various substituted tetrahydroisoquinoline hydroxylamines with high enantioselectivity were synthesized under mild reaction conditions using air as oxidant and cheap metal iron as catalyst.Different from the previous asymmetric synthesis strategies,this method does not require any additives nor does it need harsh reaction conditions such as high pressure.It achieves high enantioselectivity under greener conditions,and creates a new method for asymmetric synthesis of hydroxylamine compounds by oxidation strategy.