| Optically activeα-aryl-α-alkyl carboxylic acids and their derivatives,such as（S）-ibuprofen,（S）-naproxen,（S）-ketoprofen,（S）-fenaprofen,and（S）-flurbinprofen,are important biologically active molecules that are extensively used as nonsteroidal anti-inflammatory drugs.Therefore,development of efficient methodologies for their synthesis is highly desirable.In our study,chiral DMAP-N-oxides in DKR ofα-aryl-α-alkyl carboxylic esters were examined.When chiral DMAP-N-oxide catalyst derived from diphenylmethanamine was used as the catalyst,pentafluorophenol ester and diphenylmethanol as reactant,Et3N as base,and mixture solvent of Ph CF3/DCM at 0 oC for 72 h,desiredα-aryl-α-alkyl carboxylic ester was generated in 91%yield with 93%ee.Under optimized reaction conditions,the scope of pentafluorophenol esters was explored to construct chiralα-aryl-α-alkyl carboxylic esters in up to 93%yield and 99%ee.Based on the developed method,（S）-naproxen,（S）-ibuprofen ester,（S）-ketoprofen ester,（S）-fenaprofen ester,and（S）-flurbinprofen ester were obtained.To further evaluate the synthetic utility of the developed methodology in drug synthesis,we conducted gram-scale synthesis of（S）-naproxen ester.It should be noted that the reactivity and enantioselectivity of gram-scale synthesis was maintained compared with that on smaller scale.Further recrystallization gave（S）-naproxen ester as a pure enantiomer（>99%ee）.Catalyst was recovered by flash chromatography on silica gel.Recovered catalyst was employed in DKR reaction,in which the reactivity and enantioselectivity were also well kept.Mechanistic studies were conducted by control experiments,HRMS analysis,NMR detection,stereochemical experiments,racemization study,competitive experiments,linearity relationship determination,kinetic order analysis,and DFT computational study.In the presence of Et3N,there were two different racemization pathways,including the racemize in-situ via tautomerization of ketone and enol forms of pentafluorophenol ester and racemization of O-acylated pyridinium salt generated from pentafluorophenol ester and catalyst,in which the latter was more easily racemized than the former.Meanwhile,the nucleophilic attack of diphenylmethanol to O-acylated pyridinium cation may be the rate-determining step of the reaction.The obtained results suggested that in DMAP-N-oxides,the oxygen atom served as the nucleophilic site and N-H bond acted as H-bond donor,resulting in a synergistic effect.Compared with previous works using nitrogen or carbon as the nucleophilic sites,we found that chiral DMAP-N-oxides with oxygen as the nucleophilic site could also catalyze such reactions. |
