Rational Design Of 2-substituted DMAP-N-oxides As Acyl Transfer Catalysts: Dynamic Kinetic Resolution Of Azlactones With Alcohols

The development of chiral acyl transfer catalysts is one of the research hotspots of organic catalysis.Among them,chiral DMAP has attracted much attention as a classic acyl transfer catalyst.In 1996,the Vedejs’s and Fu’s groups have respectively pioneered the development of chiral DMAP,and applied those DMAP catalysts in asymmetric acyl transfer reactions.After that,chiral DMAP as acyl transfer catalysts have been greatly developed.However,for chiral DMAP as an acyl transfer catalyst,a problem that has plagued more than two decades is that the C-2 position of the pyridine ring is difficult to use.Due to the obvious steric hindrance between the stereocontrol group at C-2 position and N-acyl moiety,the chiral 2-substituted DMAP exhibited low activity and should be employed in a stoichiometric amount,resulting in the seldom utilization of C-2 position in the further design of chiral DMAP catalysts as acyl transfer catalysts.Thus,the C-3 and C-4 positions,which are adequately distant from the nucleophilic site,have been extensively studied,In order to reduce or even avoid steric hindrance influence of C-2 substituent toward catalytic activity,we present a novel concept that conversion of chiral 2-substituted DMAP into its DMAP-N-oxide will make C-2 substituent far away from the O-acyl moiety,thus enhancing the activity of catalyst and utilizing the C-2 position.Therefore,we will introduce a L-prolinamide at the C-2 position of the pyridine ring to design a chiral 2-substituted DMAP-N-oxide,and hope to achieve asymmetric acylation with the assistance of H-bond interaction.The catalyst has unique advantages whether it is obtained from cheap and easily available chiral source,simple in structure and easy to modify,or simple in synthesis steps.First,we synthesized a series of L-proline amides from L-proline,and further reacted with2-chloro-4-nitropyridine-N-oxide to obtain 2-substituted DMAP-N-oxide.After one-step amination,the desired chiral 2-substituted DMAP-N-oxide catalyst was obtained directly,which was applied in dynamic kinetic resolution of azlactone.We used 4-benzyl-2-（4-methoxyphenyl）azlactone as the template substrate,and screened the reaction conditions from catalysts,solvents,temperatures,additives,and various substrate concentrations.Finally,chiral 2,6-diisopropylaniline-derived 2-substituted DMAP-N-oxide was selected as the better catalyst,dichloromethane as the solvent,benzoic acid as the additive,and the reaction time as 8hours at room temperature.Under optimal conditions,a series ofα-amino acid derivatives were obtained with excellent enantioselectivities and high yields.In the scale-up experiment（1.12 g of azlactone）,excellent results（94%ee,93%yield）could still be generated.Furthermore,with CH₃OD as the reactant,α-deuterium labeled（4-methoxybenzoyl）-L-phenylalanine methyl ester was obtained in 98%yield,90%ee,and 93:7 D/H ratio.Compared with similar reactions,the catalyst of this structure type has better catalytic activity,and the use of methanol with smaller nucleophilic steric hindrance can also achieve good results.The use equivalent is also less than the similar reports.For the substituted isopropyl substrate,the catalytic system in the literature did not achieve good results.The catalytic system also showed good catalytic performance.After the reaction,it achieved a result of up to 92%ee and a yield of 84%.Finally,throuth control experiments and DFT calculations,the mechanism of the dynamic kinetic resolution of azlactones with Me OH has been proposed.This article describes in detail the design and synthesis of chiral 2-substituted DMAP-N-oxide and its application in the dynamic kinetic resolution of azlactone,which opens up the development of chiral2-substituted DMAP-nitrogen oxide door.