Biocatalysis is gaining increasing attention in the academic and industrial sector due to the possibility of developing highly stereoselective transformations in a sustainable manner. The creation of stereogenic centers in organic synthesis is not trivial and multiple approaches have been disclosed based on 2 organometallic and organocatalytic methods with the use of day by day more complex catalysts to induce asymmetry in selected transformations. The intrinsic chirality of enzymes makes them powerful tools for the development of stereoselective transformations, catalysing a wide range of chemical reactions due to the high abundance and diversity of enzymes in nature. In addition, the enormous advances in rational design and molecular biology methods have opened up the possibility to create more robust and versatile biocatalysts, which have improved the initial activities displayed by wild-type enzymes. Therefore, their applicability has been widely increased in terms of reaction conditions, substrate specificity, activity and selectivity among others. All these properties have attracted the industrial sector, which has taken advantage of the enzyme selectivities in multiple scenarios. Herein, the focus has been put in recent developments of stereoselective transformations for the synthesis of valuable building blocks towards the production of pharmaceuticals and biologically active natural products.
The synthesis of chiral amines is of central importance to pharmaceutical chemistry, and the inclusion of fluorine atoms in drug molecules can both increase potency and slow metabolism. Optically enriched β-fluoroamines can be obtained by the kinetic resolution of racemic amines using amine transaminases (ATAs), but yields are limited to 50 %, and also secondary amines are not accessible. In order to overcome these limitations, we have applied NADPH-dependent reductive aminase enzymes (RedAms) from fungal species to the reductive amination of α-fluoroacetophenones with ammonia, methylamine and allylamine as donors, to yield β-fluoro primary or secondary amines with > 90 % conversion and between 85 and 99 % ee. In addition, the effect of the progressive introduction of fluorine atoms to the α-position of the acetophenone substrate reveals the effect of mono-, di-and tri-fluorination on the proportion of amine and alcohol in product mixtures, shedding light on the promiscuous ability of imine reductase (IRED)-type dehydrogenases to reduce fluorinated acetophenones to alcohols. Chiral amines are significant functional groups that feature prominently in many pharmaceuticals. There are many asymmetric methods for their synthesis that use transition metal catalysis coupled to chiral ligands, [1,2] but considerations of selectivity, sustainability and green chemistry have dictated that biocatalytic methods have achieved prominence in recent years. [3][4][5] The synthesis of fluoroamines represents a special case of chiral amine synthesis, as the addition of the fluorine atom can improve the efficiency of bioactive molecules through increased potency or slower metabolism. [6,7] β-Fluoroamines are very interesting derivatives as they can be excellent pyridoxal 5'-phosphate (PLP)-dependent enzyme inhibitors. [8] They can be synthesized simply through the ring opening of N-tosyl aziridines with TBAF, [9] but their asymmetric synthesis is rare, and complicated if chirality at both the amine and fluorinebearing carbons is under consideration. In a recent example, Vara and Johnston used Brønsted base catalysts, such as (MeO) 2 PBAM · HNTf, for the enantioselective synthesis of Bocprotected β-amino-α-fluoro-nitroalkanes from α-fluoro arylnitromethane and aldimine precursors. [10] Other examples using organocatalytic catalysts have been provided by Lindsley and co-workers, [11,12] who performed the enantioselective fluorination of N-sulfinyl aldimines, followed by nucleophilic addition using a Grignard reagent, providing the final compounds in high dr (> 20 : 1).More recently, we showed that amine transaminases (ATAs) can be applied to the 100 mg scale asymmetric synthesis of βfluoroamines, with up to 99 % ee., through the kinetic resolution of racemic substrates. [13] A series of racemic β-fluoro arylethylamines including 1 b and 2 b (Scheme 1) was converted by both (S)-and (R)-selective ATAs to give the corresponding enantiopure β-fluoroamines, in addition to acetophenones 3 a and 4 a, co-products that arise through the enanti...
Abstract:The applicability of deep eutectic solvents has been demonstrated for the first time in promiscuous lipase-catalysed aldol reactions. The model reaction between 4-nitrobenzaldehyde and acetone was examined in depth, an excellent compatibility being found between porcine pancreas lipase and choline chloride: glycerol mixtures for the formation of the aldol product in high yields. The system was compatible with a series of aromatic aldehydes and ketones including acetone, cyclopentanone and cyclohexanone. In some cases the corresponding ,β-unsaturated carbonyl compounds were found as minor products. Control experiments demonstrate that the enzymatic preparation was also responsible of the collateral dehydration reaction once the aldol product is formed.
Abstract:A one-pot chemoenzymatic method has been described for the synthesis of -butyrolactones starting from the corresponding ketones through a Baeyer-Villiger reaction.The approach is based on a lipase-catalyzed perhydrolysis for the formation of peracetic acid, which is the responsible for the ketone oxidation. Optimization studies have been performed in the oxidation of cyclobutanone, finding Candida antarctica lipase type B, ethyl acetate and urea-hydrogen peroxide complex as the best system. The relative ratio of these reagents has also been analyzed in depth. This synthetic approach has been successfully extended to a family of 3-substituted cyclobutanones in high substrate concentration, yielding the corresponding lactones with excellent isolated yields and purities, under mild reaction conditions and after a simple extraction protocol.
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