Expanding dynamic kinetic protocols: transaminase-catalyzed synthesis of α-substituted β-amino ester derivatives

Abstract

Several α-alkylated β-amino esters have been obtained via DKR processes employing a kit of transaminases and isopropylamine as amino donor in aqueous medium at mild conditions. Thus, while acyclic α-alkyl-β-keto esters afforded excellent conversions and enantioselectivities, although usually 10 low diastereoselectivities, with more constrained cyclic β-keto esters high to excellent inductions were obtained.The development of enzymatic strategies that enable access to 100% theoretical yield of stereoisomerically enriched compounds starting from easily available racemic or prochiral derivatives, 15 has recently attracted many efforts due to the simpler isolation and purification techniques required. 1 In this sense, recent advances achieved in dynamic systems to get access to enantio-or diastereomerically pure compounds have been described. Thus, performing a kinetic resolution on a substrate which simulta-20 neously can undergo racemization has led to efficient dynamic kinetic resolutions (DKRs). 2 While this methodology has extensively been employed with hydrolases (usually in combination with a metal-based racemization) 3 and oxidoreductases (often combined with a racemization in basic conditions), 4 for other 25 enzymes it has been scarcely exploited.For instance, with ω-transaminases (ω-TAs, EC 2.6.1.x), 5 one of the most promising biocatalysts applied to the synthesis of chiral amines, it is remarkable that only one example described by Kroutil and co-workers can be recognized as a dynamic ki-30 netic resolution. 6 In this contribution, the authors proposed the DKR of an α-chiral aldehyde through spontaneous racemization combined with the use of an ω-TA to afford, after ring closure, 4-phenylpyrrolidin-2-one with 92% isolated yield and 68% ee. 35Scheme 1 General overview for the synthesis of enantioenriched α-alkylated β-amino esters through ω-TA-catalyzed dynamic amination.Due to our previous experience with the synthesis of several α-alkylated β-keto esters, 4a,d and since these substrates can racemize at neutral pH, it was decided to study the DKR of these com-40 pounds through ω-TA-catalyzed amination to obtain the corresponding α-substituted β-amino esters (Scheme 1). These compounds have a great relevance since they are present in biologically active peptides, 7 and are also valuable for the preparation of peptidomimetics, 8 substituted β-lactams 9 and β-amino 45 acids. 10 The selective synthesis of these unprotected synthons is challenging, 11 and no general strategy comprising the direct asymmetric reductive amination of the α-substituted β-keto ester precursors has been described until now. 12 50 Scheme 2 Synthesis of racemic aliphatic α-substituted β-amino ester derivatives through enamine formation-reduction protocol.Thus, it was planned the synthesis of racemic β-keto esters 1b-k and the corresponding mixture of syn and anti diastereoisomers of the α-substituted β-amino esters 2b-k and 3b-k (Scheme 2), to 55 optimize the analytical methods to measure the enzymatic conversions and the enantio-a...

Efficient synthesis of α-alkyl-β-amino amides by transaminase-mediated dynamic kinetic resolutions

“…Furthermore, an increase in the pH up to 10 led to better dr, especially when ATA-025 was the TA of choice (entries 11 and 12). Finally, encouraged by previous studies where excellent diastereomeric ratios were attained by using a cyclic β-keto ester as starting material, 23 the biotransamination of cyclic βketo amide 2h was envisaged through this DKR strategy (Table 2 and Sections 4.8 and 6.8 in the ESI). In this case, only (R)-TAs seemed to be effective biocatalysts, leading ATA-415 to the best results (entries 13 and 14).…”

“…In one of our groups a DKR protocol was designed for the synthesis of a wide panel of diastereo-and enantioenriched α-alkyl-β-amino esters starting from the corresponding racemic β-keto esters employing TAs. 23 In general, high conversion and ee values were found, however, moderate dr values (<60%) were observed. Following this study and due to the lack of biocatalytic methodologies to synthesize β 2,3 -amino amides, we decided to develop a TA-mediated protocol to produce different diastereo-and enantioenriched αalkyl-β-amino amides through DKR transformations.…”

Transaminases and their Applications

“…Another approach has recently been described by Cuetos et al for the dynamic kinetic resolution of α-substituted β-amino esters [77]. Several ω-transaminases and acyclic alkyl-β-keto esters were tested, leading to high conversion rates and high ee and de values.…”

Dynamic Kinetic Resolution of 2‐Phenylpropanal Derivatives to Yield β‐Chiral Primary Amines via Bioamination

“…For the amination of α‐chiral ketones only very low chiral recognition of the α‐chiral centre has been reported not exceeding in general 60% ee ;2a for only one designated substrate a de of 98% was reported using commercial enzymes.…”