Visible-light Induced Radical Addition And Dynamic Kinetic Resolution

Green chemistry aims to decrease or eliminate the generation of detrimental substances to the environment during the design,manufacture,and application of chemical compounds.One of the most important techniques available to green chemistry is photochemistry,which has been an active research field over the past decades.Under this circumstance,the utilization of abundant visible light as a source of energy for chemical change,or as a reaction reagent directly,can allow quite clean,mild,and sustainable reaction conditions,and is expected to alleviate the tremendous pressure caused by the energy crisis.In this thesis,an efficient one-pot two-step synthesis strategy of multifunctionalγ-lactones is achieved through the core ketyl radical intermediate by means of visible-light photocatalysis.Besides,an enzymatic transesterification adopted by us successfully realized the kinetic resolution（KR）of an aliphatic secondary amine.Subsequent visible-light catalyzed racemzation of an alternative of this secondary amine suggested a highly possible dynamic kinetic resolution（DKR）.Combining the abovementioned KR with the photocatalytic racemization,we have made some progress in the dynamic kinetic resolution of secondary amines.In the second chapter of this thesis,we mainly studied the reductive coupling reaction of various aromatic ketones or aldehydes withα,β-unsaturated alkenes.Under the irradiation of 450 nm blue light,the linerγ-hydroxyl esters were successfully synthesized with an iridium complex as the photoredox catalyst,acetophenone and 2-phenylethyl acrylate as the model substrates.Then,the optimal reaction conditions were finally determined after evaluating the factors influencing the reaction efficacy,such as the photocatalysts,the molar ratio and solvent of the reaction,the external reducing agents,and the reaction time.Besides,further studies have demonstrated that after the simply addition of an appropriate acid catalyst to the reaction,the linerγ-hydroxyl ester can be smoothly converted into a multi-substitutedγ-lactone compound with higher practical value and synthesis potential.The substrate scope of the reaction thoroughly showcased the wide applicability of this methodology,including excellent functional group compatibility and good reaction efficiency（yields up to 97%）.In terms of mechanism investigation,the existence of the core ketyl radical was first proved through the radical clock experiment and radical self-coupling experiment.Morever,after adding the radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy（TEMPO）,the reaction was completely inhibited,which indicates a free radical pathway and is consistent with the aforementioned results.Acid/base adding experiments showed that acidic additives can promote the reaction slightly,while basic additives impeded the reaction a lot,implying a proton-coupled electron transfer（PCET）induced ketyl radical formation.Finally,the deuteration experiment of Hantzsch ester certified that the generation ofγ-hydroxyl esters is closely related to Hantzsch ester radical species,excluding the direct hydrogen atom transfer（HAT）mechanism via Hantzsch ester radical cations to construct the C-H bond.In a word,we report a reductive coupling reaction between aromatic ketones and electron-deficient unsaturated compounds for the first time.The green,mild,and high-efficient merits of this reaction highlight its potential for future applications in organic synthesis.In the third chapter of this thesis,we paid much attention to the visible-light and enzyme catalyzed dynamic kinetic resolution of secondary amines.Chemoenzymatic reactions,which is more preferred in many industrial processes,provide appealing alternatives to equivalent asymmetric synthesis techniques as a result of their typical mild,green,controllable,and less hazardous reaction conditions.Kinetic resolutions of racemates can,by definition,yield no more than 50%of the desired product.To overcome this limitation,several approaches have been attempted,while dynamic kinetic resolution has received considerable attention in recent years.The key step of dynamic kinetic resolution is combining a kinetic resolution with a racemization process.In this way,the stereoisomers within a racemate are subjected to a fast dynamic equilibrium,and one of the enantiomer is selectively removed.We herein combined the visible-light catalyzed racemization with an enzyme catalyzed kinetic resolution,in order to realize the DKR of more challenging aliphatic secondary amines.First,we have realized the kinetic resolution of 1-methyl-1,2,3,4-tetrahydroisoquinoline by employing a lipase(Lipomod^TM34P from Candida sp.)as the biocatalyst.With the assistance of an activated carbonate acyl donor,we finally obtained a secondary amine in 36%yield with high enantiomeric excess（97%e.e.）,and the corresponding N-acylation product in 40%yield（97%e.e.）.Visible-light promoted racemization showed that chiral 1-phenyl-1,2,3,4-tetrahydroisoquinoline can racemize from 99%e.e.to 7%e.e.under the catalysis of thiol-mediated hydrogen atom transfer process.It is expected that this conclusion is also suitable to 1-methyl-1,2,3,4-tetrahydroisoquinoline and its derivatives,which means similar results would be achieved.Finally,we investigated the dynamic kinetic resolution of 1-methyl-1,2,3,4-tetrahydroisoquinoline though combining the enzyme catalyzed kinetic resolution with the photocatalytic racemization,which is still ongoing in our lab.Such a practical method undoubtedly has great application potential in the industrial production of enantiopure amines some day.