Stereoselective Chemoenzymatic Preparation of β‐Amino Esters: Molecular Modelling Considerations in Lipase‐Mediated Processes and Application to the Synthesis of (S)‐Dapoxetine

Abstract

A wide range of optically active 3-amino-3-arylpropanoic acid derivatives have been prepared by means of a stereoselective chemoenzymatic route. The key step is the kinetic resolution of the corresponding b-amino esters. Although the enzymatic acylations of the amino group with ethyl methoxy-A C H T U N G T R E N N U N G acetate showed synthetically useful enantioselectivities, the hydrolyses of the ester group catalyzed by lipase from Pseudomonas cepacia have been identified as the optimal processes concerning both activity and enantioselectivity. The enantiopreference of this lipase in these reactions has been explained, at the molecular level, by using a fragment-based approach in which the most favoured binding site for a phenyl ring and the most stable conformation of the 3-aminopropanoate core nicely match the (S)-configuration of the major products. The conversion and enantioselectivity values of the enzymatic reactions have been compared in order to understand the influence of the different substitution patterns present in the phenyl ring. This chemoenzymatic route has been successfully applied to the preparation of a valuable intermediate in the synthesis of (S)-dapoxetine, which has been chemically synthesised in excellent optical purity.

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

“…Nowadays, the asymmetric synthesis of (S)-dapoxetine has been intensively investigated because the (S) and (R) isomers usually display very different pharmacological or physiological properties. [6,9] However, the enantioselectivities Scheme 1. [8] Lipase is considered as an ideal tool for the preparation of enantiomerically pure compounds and has been widely exploited for the resolution of racemic mixtures in the preparation of pharmaceuticals.…”

Efficient Synthesis of New Fluorinated β-Amino Acid Enantiomers through Lipase-Catalyzed Hydrolysis

“…They can be applied on an industrial scale [ 15 , 16 ]. Lipase-catalyzed methods for the resolution of both cyclic [ 17 ] and acyclic [ 18 ] β-amino carboxylic esters through hydrolysis are known in the literature. Various enzymatic procedures have been developed by our research group for the preparation of biologically active β-aryl-substituted, β-heteroaryl-substituted, and β-arylalkyl-substituted β-amino acid enantiomers through enantioselective ( E > 200) hydrolysis of the corresponding β-amino carboxylic esters both in H 2 O or in an organic solvent catalyzed by lipase ( Pseudomonas cepacia ) PS[ 19 , 20 , 21 ].…”

β-Phenylalanine Ester Synthesis from Stable β-Keto Ester Substrate Using Engineered ω-Transaminases

“…A prominent example of β-amino acids in pharmaceuticals is β-phenylalanine ( 1 ), or rather α-hydroxy-β-phenylalanine, present in the natural substance paclitaxel (Taxol), which is a prominent anti-cancer agent [ 11 ]. Moreover, esters of 1 are interesting for the synthesis of nitrogen-containing heterocyclic compounds, e.g., for the synthesis of β-lactams, aminophenylpropanoic acid-terminated polyoxyethylene esters, nicotinamide derivatives for the treatment of respiratory and allergic diseases, ( S )-dapoxetine (reaction with LiAlH 4 ), and for the synthesis of putative anti-amnesiant agents [ 12 , 13 , 14 , 15 , 16 , 17 ].…”