Asymmetric Amination of α‐Chiral Aliphatic Aldehydes via Dynamic Kinetic Resolution to Access Stereocomplementary Brivaracetam and Pregabalin Precursors

Abstract

Over the last decades biocatalysis has emerged as an indispensable and versatile tool for the asymmetric synthesis of active pharmaceutical ingredients (APIs). In this context, especially transaminases (TAs) have been successfully used for the preparation of numerous a-chiral, optically pure amines, serving as important building blocks for APIs. Here we elaborate on the development of transaminases recognizing the a-chiral centre adjacent to an aldehyde moiety with aliphatic residues, opening up concepts for novel synthetic routes to the antiepileptic drugs Brivaracetam and Pregabalin. The transformation proceeded via dynamic kinetic resolution (DKR) based on the bio-induced racemisation of the aldehyde enantiomers, enabling the amination of the racemic substrates with quantitative conversions. Medium, substrate as well as enzyme engineering gave access to both (R)-and (S)-enantiomers of the amine precursors of the stereocomplementary drugs in high optical purity, representing a short route to mentioned APIs.

The Impact of Recent Developments in Technologies which Enable the Increased Use of Biocatalysts

“…The use of a mutated lipase from Thermomyces lanuginosus has also been reported in the resolution of 66 , giving increased activity against 69 . Recently, the use of transaminases has been applied to the resolution of pregabalin 67 and brivaracetam 70 intermediate α ‐chiral aldehydes (Scheme C ) . The aldehydes racemize under the biotransformation conditions, specifically in the presence of the amine donor isopropylamine 31 , furnishing an effective DKR by taking advantage of the inherent equilibrium under the reaction conditions.…”

Definitive Screening Design Optimization of Chemoenzymatic Process for (R)‐3‐(Carbamoylmethyl)‐5‐methylhexanoicacid: A Key Intermediate of Pregabalin

“…On scale these reactions carry a significant burden for safe operations, but can be used if no other options are available. Furthermore, a myriad of methodologies, namely asymmetric amination, [6] cyanation, [7] organocatalysis, [8,9] Mi-chael addition reactions on nitroalkanes, [10][11][12][13] ring closer metathesis approach, [14] exo-ring radical cyclization [15] and sequential flow system with heterogeneous catalyst [16] have developed to produce 1.…”

A Photo-Enzymatic Cascade to Transform Racemic Alcohols into Enantiomerically Pure Amines

“…These additional stages prolong the synthesis time and significantly decrease the atom efficiency of the reaction. To aid these shortcomings, biocatalytic approaches have been extensively studied [29][30][31][32]. Pyridoxal-5-phosphate (PLP)-dependent ω-transaminases (ω-TAs) provide an elegant way to convert a carbonyl group to an amine moiety at the expense of a sacrificial amine donor [31,33].…”

“…Pyridoxal-5-phosphate (PLP)-dependent ω-transaminases (ω-TAs) provide an elegant way to convert a carbonyl group to an amine moiety at the expense of a sacrificial amine donor [31,33]. ω-TAs have been increasingly applied in industrial chemical synthesis, in particular for the manufacturing of active pharmaceutical ingredients (APIs) [29,34,35]. Other main applications deal with the production of surfactants [36], amino acids [37], and plastic fiber monomers [36,38,39].…”