Carica papaya Lipase Catalysed Resolution of β‐Amino Esters for the Highly Enantioselective Synthesis of (S)‐Dapoxetine

Abstract

AbstractAn efficient synthesis of the (S)‐3‐amino‐3‐phenylpropanoic acid enantiomer has been achieved by Carica papaya lipase (CPL) catalysed enantioselective alcoholysis of the corresponding racemic N‐protected 2,2,2‐trifluoroethyl esters in an organic solvent. A high enantioselectivity (E > 200) was achieved by two strategies that involved engineering of the substrates and optimization of the reaction conditions. Based on the resolution of a series of amino acids, it was found that the structure of the substrate has a profound effect on the CPL‐catalysed resolution. The enantioselectivity and reaction rate were significantly enhanced by switching the conventional methyl ester to an activated trifluoroethyl ester. When considering steric effects, the substituted phenyl and amino groups should not both be large for the CPL‐catalysed resolution. The mechanism of the CPL‐catalysed enantioselective alcoholoysis of the amino acids is discussed to delineate the substrate requirements for CPL‐catalysed resolution. Finally, the reaction was scaled up, and the products were separated and obtained in good yields (≥ 80 %). The (S)‐3‐amino‐3‐phenylpropanoic acid obtained was used as a key chiral intermediate in the synthesis of (S)‐dapoxetine with very high enantiomeric excess (> 99 %).