Enzymatic Resolution Of Arlyamines Via Amidation Reaction In Organic Media

Optically active arylamines bearing the stereogenic center at α-positon are important compounds because of their broad range of applications and their pharmacological properties. They have been used as chiral auxiliaries, resolving agents and building blocks for the preparation of natural and unnatural compounds. They prepared by chemical asymmetrical synthesis, resoluting with chiral agents and resoluting with lipases. We focused on the resolution of arylamines catalyzed by enzymes. The scheme is:Arylamines were synthesized from arylketones. Based upon the screening of acyl donors, enzymes and solvents with 1-phenylethylamine as a substrate, it was concluded that isopropenyl acetate was the most suitable acyl donor and a small amount of NaHSO₃ can reduce side reactions. Novozym 435 showed both the highest catalytic activity and the highest enantioselectivity. Toluene was the most suitable medium for the reaction. Effects of ester concentration, amine concentration , enzyme concentration, shaking rate and temperature on the reaction were examined systematically. The optimum ratio of amine and ester, amine concentration . enzyme concentration, shaking rate and temperature were 1:0.6, 200mmol/L, 4mg/ml, 200rpm, 30℃, respectively. Under the optimal conditions mentioned above, E value was 89. A product enantiomeric excess(ee_p) of 96% was achieved with conversion of 39% after 4 h of the reaction and a substrate enantiomeric excess(ee_s) of 98% was achived with conversion of 52.4% after 10h of the reaction. Then other arylamines were resoluted. The relationship of structure of substrates and the enantioselectivety was demonstrated. The enantioselectivity depends on the relative sizes of the substituents at the stereocenter, electronic effects and the steric repusions. Thekinetics was found to obey the Ping-Pong bi-bi mechanism and the simulatedvalues correspond to the experimental value quite well.