Biocatalytic Transamination for the Asymmetric Synthesis of Pyridylalkylamines. Structural and Activity Features in the Reactivity of Transaminases

Abstract

ABSTRACT. A set of transaminases has been investigated for the biocatalytic amination of 1-(4-chloropyridin-2-yl)alkan-1-ones. The influence of the chain length of the n-1-alkanone at the C-2 position of the pyridine has been studied in the reaction with different (R)-and (S)-selective transaminases. Thus, enantiopure amines were isolated with high purity starting from a wide selection of prochiral ketones. On the one hand excellent yields (97->99% conversion, up to 93% isolated yield) and stereoselectivity values (>99% ee for both amine enantiomers) were found for n-1-alkanone linear short chain substituents such as ethanone or propanone. On the other hand, more hindered substrates were accepted only when using evolved enzymes such as an evolved variant of (R)-Arthrobacter (ArRmut11-TA). An initial common structural feature was the presence of a chlorine atom on the C-4 position of the pyridine core, which was found to increase the reactivity of the starting ketone, giving extra versatility for the introduction of other chemical functionalities towards more complex and applicable organic molecules. In order to gain a deeper understanding about the substrate specificity of different transaminases, additional structural features were considered by variation of the acetyl group position on the pyridine ring and the use of related acetophenone derivatives.

Stereoselective Synthesis of 1‐Arylpropan‐2‐amines from Allylbenzenes through a Wacker‐Tsuji Oxidation‐Biotransamination Sequential Process

“…required for shifting the equilibrium towards high conversions into the amine 8 a encouraged us to perform energy calculations in order to have a deeper understanding of the enzymatic processes (Table S18). For that reason, Gibbs free energies of the ketone/amine pairs were calculated at the M06‐2X/6‐311++G(3df,2p) level, to compare the predicted ΔG of the global amination reactions of 1‐phenylpropan‐2‐one ( 2 a ) and a reference substrate such as acetophenone with isopropylamine. The thermochemical study reflects that the equilibrium shift of the (bio)transamination of 2 a is highly favoured (ΔG=−12.0 kJ/mol), while the formation of α‐methylbenzylamine is unfavourable (ΔG=+5.4 kJ/mol), explaining in this manner the large excess of isopropylamine required for the biotransamination of acetophenone in comparison with 1‐phenylpropan‐2‐one ( 2 a ).…”

Development of Biotransamination Reactions towards the 3,4-Dihydro-2H-1,5-benzoxathiepin-3-amine Enantiomers

“…These settings include the use of a large excess of isopropylamine as amine donor (1 M), pyridoxal 5'-phosphate (PLP, 1 mM) as cofactor, a 100 mM phosphate buffer pH 7.5 with acetonitrile (5% v/v) as cosolvent to favour the ketone solubility, at 30 °C and 250 rpm for 20 h (Scheme 2). Three different types of enzymes were Due to the amine transaminases catalytic mechanism, which involves two pairs of ketones and amines in equilibrium, the reductive amination of the substrate must be thermodynamically favoured in order to obtain high yields of the desired product [45,46]. In order to displace the equilibrium towards amine formation, the removal of the generated co-products by coupling different multienzyme networks is often required [20], but also worth noting is the use of sacrificial substrates, which normally range from the use of a large excess of a commercially available amine donor, typically isopropylamine [47], to "smart cosubstrates", mainly diamines, in a stoichiometric amount that are able to drive equilibrium by spontaneous cyclisation or aromatisation reactions [31,[48][49][50].…”

Recent Advances in ω-Transaminase-Mediated Biocatalysis for the Enantioselective Synthesis of Chiral Amines

“…Other than an industrially applied procedure for antidiabetic Sitagliptin, the recent successful examples of amine synthesis by ω-TA-mediated catalysis include pyridyl alkylamines [46], (R)-ramatroban precursor [47] and serinol [48]. Moreover, substituted aminotetralins, potential agents used to treat Parkinson's disease and cardiovascular disorders, have also been successfully synthesized using an engineered ω-TA from Arthrobacter citreus [ω-TAAc] [49] and a novel (S)-selective ω-TA from Pseudomonas fluorescens KNK08-18 [50].…”