Asymmetric chemoenzymatic synthesis of N-acetyl-α-amino esters based on lipase-catalyzed kinetic resolutions through interesterification reactions

Several phenylalanine analogs have been synthesized through a four-step route starting from easily available ethyl acetamidocyanoacetate. In a first reaction, and making use of phase transfer catalysts, this compound reacted with several alkyl halides, being benzyltributylammonium chloride identified as the best one for the production of a series of quaternary amino acids in moderate to excellent yields (52-95%). Then, the corresponding N-acetyl-phenylalanine methyl and allyl ester derivatives were obtained through acidic hydrolysis, esterification, and N-acetylation. Rhizomucor miehei lipase was found as a versatile enzyme for the resolution of these amino esters, finding the best results through interesterification reactions with butyl butyrate in acetonitrile. A great influence in the stereoselectivity was found depending on the chemical structure of the compound, achieving for the non- or para-substituted in the phenyl ring excellent stereoselectivities, being moderate for the meta-nitro derivative, while the ortho-nitro amino ester did not react. (c) 2014 Elsevier Ltd. All rights reserved.