A chemoenzymatic route to (1R,2S)‐metaraminol is described, combining gold(I)‐catalysed alkyne hydration and stereoselective biotransamination in a sequential one‐pot fashion. Strategic phenol protection enables compatibility across lipase‐catalysed resolutions or laccase‐mediated oxidations combined with carbonyl bioreduction, providing access to enantiopure propargylic alcohols to later explore the hydration‐biotransamination strategy. Best results were found when the phenolic group was protected, including methoxy, benzyloxy or a silyl ether functionality. Gold‐catalysed hydration was more efficient when considering propargylic acetates instead of alcohols, leading to enantiopure hydroxy esters that were next subjected to enzymatic experiments. Evaluating (S)‐selective transaminases enabled the development of highly stereoselective biotransamination experiments using Chromobacterium violaceum transaminase overexpressed in E. coli and commercial ATA‐251 to synthesise suitable enantiopure metaraminol precursors (67‐97% conversion). Finally, the gold‐transaminase one‐pot cascade was performed in a sequential manner, attaining the synthesis of metaraminol after benzyl deprotection under palladium‐catalysed hydrogenolysis conditions.

Chiral fluorhydrins are important intermediates in asymmetric organic synthesis, serving as crucial building blocks in medicinal chemistry and related areas for the preparation of specialized fluorinated materials and biologically active molecules. In this study, the bioreduction of a series of alpha-halogenated ketones has been studied using the ketoreductase KRED1 from Pichia glucozyma, heterologously overexpressed in Escherichia coli. Both a lyophilized whole-cell preparation and the purified recombinant enzyme were used as catalysts, finding better chemoselectivities with the purified enzyme, likely due to the absence of interfering endogenous activities present in the whole-cell system. The influence of reaction parameters was analyzed and optimized, obtaining a series of (R)-fluorohydrins, in general, with very high conversions and excellent stereoselectivities (62%-> 99% yield and 70%-> 99% ee). Remarkably, the enzyme accepted mono- and dihalogenated substrates at the alpha-position to the carbonyl group, but also other motifs such as (hetero)aromatic and aliphatic substituents.

A novel synthesis of 1,4- and 1,5-diketones based on a gold( i )-catalyzed hydration reaction is herein described. Application to chemoenzymatic cascades is also shown under mild conditions.

Hydration reactions consist of the introduction of a molecule of water into a chemical compound. This process is a particularly useful method to allow, for instance, the conversion of alkynes into carbonyls, which are strategic intermediates in the synthesis of a plethora of compounds. Herein we demonstrate that L-cysteine can catalyse the hydration of activated alkynes in a very effective and fully regioselective manner to access β-ketosulfones, amides and esters in aqueous conditions. The mild reaction conditions facilitated the integration with enzyme catalysis to access chiral β-hydroxy sulfones from the corresponding alkynes in a one-pot cascade process in good yields and excellent enantiomeric excess. These findings pave the way towards establishing a general method for metal-free, cost-effective, and more sustainable alkyne hydration processes

The asymmetric mixed carboligation of aldehydes catalyzed by thiamine diphosphate (ThDP)-dependent enzymes provides a sensitive system for monitoring changes in activity, chemo-, and enantioselectivity. While previous studies have shown that organic cosolvents influence these parameters, we now demonstrate that similar effects occur upon addition of water-miscible ionic liquids (ILs). In this study, six ThDP-dependent enzymes were analyzed in the presence of 14 ILs under comparable conditions to assess their influence on enzymatic carboligation reactions yielding 2-hydroxy ketones. ILs exerted a moderate to strong influence on activity and, more notably, altered enantioselectivity. (R)-selective reactions were generally stable upon IL addition, while (S)-selective reactions frequently showed reduced selectivity or even inversion to the (R)-enantiomer. The most significant change was observed for the ApPDC_E469G variant of pyruvate decarboxylase from Acetobacter pasteurianus, where the enantiomeric excess shifted from 86 % (S) to 60 % (R) in the presence of 9 % (w/v) Ammoeng 102. Control experiments indicated that this shift was primarily due to the Ammoeng cation rather than the anion. To explore the molecular basis of this phenomenon, all-atom molecular dynamics (MD) simulations were performed on wild-type ApPDC and the E469G variant in Ammoeng 101 and Ammoeng 102. The simulations revealed that hydrophobic and hydrophilic regions of the Ammoeng cations interact with the (S)-selective binding pocket, thereby favoring formation of the (R)-product. These results highlight the potential of solvent engineering for modulating enzyme selectivity and demonstrate that MD simulations can capture functionally relevant enzyme-solvent interactions at the atomic level.

Enantiopure β-chlorohydrins are valuable intermediates in organic synthesis, acting as chiral building blocks for obtaining biologically active compounds. This work presents a one-pot two-step linear sequence for the efficient deracemization of β-chlorohydrins by combining a photocatalytic alcohol oxidation with a stereoselective carbonyl bioreduction using alcohol dehydrogenases. Despite the thermodynamic challenges of the oxidation step for this family of substrates, three efficient photochemical conditions under white light irradiation are found using catalytic 2,4,6-triphenylpyrylium tetrafluoroborate or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in this case in stoichiometric or by in situ regeneration of the catalyst. In addition, its sunlight-driven applicability and its implementation in flow chemistry are demonstrated. After testing the scope of these methodologies, 2-chloro-1-arylethanols are found as suitable substrates. For those β-halohydrins oxidized with complete conversion, the deracemization strategy is successfully achieved, yielding 12 enantiopure (R)- and (S)-β-halohydrins. Furthermore, 2-chloro-1-phenylethanol enantiomers are subjected to an additional chemical cyclization under basic conditions, providing both (R)- and (S)-styrene oxide in a three-step one-pot process and without loss of the optical activity.

Merging different strategies in one‐pot processes is attracting considerable attention due to their straightforward and sustainable potential for synthesizing novel organic compounds. In particular, the exquisite selectivity displayed by enzymes and the possibility of coupling biotransformations with metal‐, photo and electrocatalytic processes open new avenues for stereoselective synthesis. Herein, the preparation of chiral (hetero)aryl‐3,3‐dihalopro‐2‐en‐1‐ols is described for the first time. To achieve this, a photochemical and biocatalytic one‐pot sequence is developed, employing visible light irradiation and stereoselective alcohol dehydrogenases (ADHs) for the transformation of commercially available alkynes into optically active compounds in an aqueous medium. The one‐pot, two‐step sequential approach involves a photocatalyst‐free reaction between terminal and internal alkynes with polyhalomethanes, leading to gem‐dihaloenones, which are subsequently reduced using ADHs. After optimizing the individual steps and identifying suitable conditions for combining both processes, the use of complementary ADHs enables the synthesis of a novel family of optically active allylic alcohols with high stereoselectivity. Their chemical derivatization is further explored, allowing the stereoselective synthesis of a chiral propargylic alcohol from the corresponding γ,γ‐dihalo‐β‐enol.

The direct synthesis of alkenes from alkynes usually requires the use of transition‐metal catalysts. Unfortunately, efficient biocatalytic alternatives for this transformation have yet to be discovered. Herein, the selective bioreduction of electron‐deficient alkynes to alkenes catalysed by ene‐reductases (EREDs) is described. Alkynes bearing ketone, aldehyde, ester, and nitrile moieties have been effectively reduced with excellent conversions and stereoselectivities, observing clear trends for the E/Z ratios depending on the nature of the electron‐withdrawing group. In the case of cyanoalkynes, (Z)‐alkenes were obtained as the major product, and the reaction scope was expanded to a wide variety of aromatic substrates (up to >99% conversion, and Z/E stereoselectivities of up to >99/1). Other alkynes containing aldehyde, ketone, or ester functionalities also proved to be excellent substrates, and interestingly gave the corresponding (E)‐alkenes. Preparative biotransformations were performed on a 0.4 mmol scale, producing the desired (Z)‐cyanoalkenes with good to excellent isolated yields (63‐97%). This novel reactivity has been rationalised through molecular docking by predicting the binding poses of key molecules in the ERED‐pu‐0006 active site.

The combination of a gold(I) N‐heterocyclic carbene complex and an ene‐reductase (ERED) has made possible the synthesis of enantiopure β,β‐disubstituted ketones in a one‐pot concurrent approach. The protocol consists of the Meyer‐Schuster rearrangement of racemic propargylic tertiary alcohols using [1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene]‐[bis(trifluoromethanesulfonyl)‐imide]gold(I) (IPrAuNTf2), followed by asymmetric alkene reduction of the α,β‐unsaturated ketone intermediate using the Zymomonas mobilis ERED (NCR‐ERED). The chemoenzymatic cascade was optimised with a model substrate, where E/Z‐isomers both generated the (R)‐ketone, which was rationalised using in silico molecular docking experiments. The cascade was then applied towards the production of a series of (R)‐4‐substituted‐alkan‐2‐ones in enantiopure form in a straightforward manner.

A novel thiol-free MCR for the mild synthesis of enantioenriched β-acetoxy sulfides using enzymatically prepared chiral halohydrins, potassium thioacetate and electrophiles is described.

Oxidative alkene cleavage of a series of (hetero)aryl alkyl styrenes in aqueous medium has been developed using either 9‐mesityl‐10‐methylacridinium perchlorate ([AcrMes]ClO 4 ) and sodium anthraquinone‐2‐sulfonate (SAS) as photosensitizers under blue LED irradiation. Reaction conditions were studied to find a suitable media for the development of a linear cascade after subsequent stereoselective reduction of the corresponding ketone intermediate. The use of cesium carbonate provided an adequate pH to the reaction medium for the alcohol dehydrogenase action. [AcrMes]ClO 4 was found to be the best photocatalyst, allowing the development of concurrent or sequential cascades depending on the ability of the photosensitizer to oxidize back the chiral alcohol to the ketone. Overall, the photobiocatalytic approach has allowed the synthesis of a wide number of alcohol compounds, the formation of ( S )‐ or ( R )‐enantiomers being attained with excellent stereoselectivity and moderate to good yields.

The combination of RLi‐mediated organic transformations (under air and at room temperature) with a subsequent stereoselective biocatalytic reaction is for the first time presented. Most of the previous asymmetric chemoenzymatic routes have been limited to the concomitant or sequential combination of transition metals/organocatalysts with enzymes. However, the use of polar organometallic reagents (RLi) in the design of these stereoselective hybrid protocols has been totally neglected, as far as we are concerned. Thus, in this work, the combination of organolithium chemistry and asymmetric biocatalysis is described for the first time in a one‐pot fashion. The chemoenzymatic approach converts a series of nitriles into chiral alcohols consisting of two steps, where the key item was the finding of suitable conditions to adapt the reactivities of organolithiums and alcohol dehydrogenases (ADHs) in the same recipient. The organolithium addition occurred with total chemoselectivity (no side reactions were observed) under neat conditions and room temperature leading to the corresponding imines, which were hydrolyzed using a buffer, and adjusting the pH for the subsequent ADH action. Commercial and made in house overexpressed ADHs allowed to produce chiral alcohols with excellent selectivities and good overall yields. The different behavior displayed for the reductive enzymes in the presence of diethyl ether clearly influenced in the decision to let the organolithium solvent evaporate under open‐air conditions before developing the bioreduction step. Our results demonstrate the importance of the fine orchestration of the reaction conditions for the development of efficient hybrid chemoenzymatic cascades without the need of intermediate isolation/purification steps or compartmentalization of the different synthetic systems.

Merging different catalytic strategies in one-pot is attracting considerable attention for the straightforward and sustainable synthesis of novel organic compounds. In particular, the exquisite selectivity displayed by enzymes and the possibility to couple biotransformations with metal-, photo and electrocatalytic processes opens new avenues for stereoselective synthesis. Herein, the preparation of chiral (hetero)aryl-3,3-halo-prop-2-en-1-ols has been described for the first time. To achieve this aim, a photochemical and biocatalytic one-pot sequence has been followed employing visible light irradiation and the action of stereoselective alcohol dehydrogenases (ADHs) for the transformation of commercial acetylenes into a series of optically active gamma,gamma-dihalo-beta-enols in aqueous medium. The one-pot two-step sequential approach consisted of the free-photocatalyst reaction between a series of terminal and internal alkynes with polyhalomethanes (CClBr3 or CBr4) leading to gem-dihaloenones, which were subsequently enzymatically reduced with ADHs. After optimisation of individual steps and finding conditions to perform both processes in one-pot, the use of complementary ADHs has allowed the synthesis of a novel family of optically active allylic alcohols with high stereodiscrimination, whose applicability has been demonstrated, for example, towards the synthesis of a chiral propargylic alcohol.

Hydration reactions consist of the introduction of a molecule of water into a chemical compound and are particularly useful to transform alkynes into carbonyls, which are strategic intermediates in the synthesis of a plethora of compounds. Herein we demonstrate that L–cysteine can catalyse the hydration of activated alkynes in a very effective and fully regioselective manner to access important building blocks in synthetic chemistry such as β-ketosulfones, amides and esters, in aqueous media. The mild reaction conditions facilitated the integration with enzyme catalysis to access chiral β-hydroxy sulfones from the corresponding alkynes in a one-pot cascade process in good yields and excellent enantiomeric ratios. These findings pave the way towards establishing a general method for metal-free, cost-effective, and more sustainable alkyne hydration processes.

Enone reduction by ene-reductase (ERED) has not been reported yet in bulk organic media probably due to expected challenges with the cofactor recycling using a second enzyme and the exchange of the NAD(P)-cofactor between the two enzymes. Herein, the combination of an ERED from Zymomonas mobilis (NCR-ERED) and Thermoanaerobacter ethanolicus alcohol dehydrogenase (TeSADH) has been found as an efficient biocatalytic redox system for the reduction of cyclohex-2-enone into cyclohexanol in bulk organic solvents. Both enzymes were successfully immobilised on three EziG supports, finding Coral as the most promising carrier for both of them. The highest enzymatic activities were found in hydrophobic solvents such as toluene and isooctane. It was observed that the control of water content and post-immobilisation treatments enabled retention of enzyme activity. Both enzymes were co-immobilised on the same bead together with NADP+, leading to the production of a self-sufficient catalytic system, although the external supplementation of the nicotinamide cofactor was necessary for an efficient enzyme reuse. In this case, no ERED activity loss was detected after two additional cycles, while the ADH experienced less than 20 % activity loss upon reuse. The immobilisation of ene-reductase from Zymomonas mobilis (NCR-ERED) and alcohol dehydrogenase from Thermoanaerobacter ethanolicus (TeSADH) onto EziG supports enabled the development of a self-sufficient catalytic system for cyclohex-2-enone bioreduction in bulk organic solvents. Controlling water content in enzyme formulation together with post-immobilisation treatments were key parameters, whereas, external addition of the nicotinamide cofactor was necessary for efficient of co-immobilised enzymes. image

The photocatalytic Meerwein arylation between aromatic diazonium salts and isopropenyl acetate under blue LED light irradiation in aqueous medium has been deeply investigated. Optimization of the reaction conditions in terms of substrate concentration, ester equivalents, cosolvent type and amount, reaction time and photocatalyst source, has allowed the access to a variety of 1-arylpropan-2-ones with yields up to 95% using 9-mesityl-10-methylacridinium perchlorate ([Acr-Mes]ClO4). Next, the design of a one-pot sequential photobiocatalytic linear approach was accomplished, by the combination of the Meerwein arylation with the bioreduction of the corresponding ketone intermediates. Thus, a total of 19 pairs of 1-arylpropan-2-ol enantiomers were obtained depending on the alcohol dehydrogenase stereopreference. Global yields up to 76% were attained with high to excellent stereoselectivity (90 to >99% ee). Also, it was possible to get access to both 1-phenylpropan-2-ol antipodes (51-53% yield) starting from aniline through a one-pot three-step sequential photobiocatalytic protocol.

The combination of gold(I) and enzyme catalysis has provided access to a series of nor(pseudo)ephedrine derivatives in a regio- and stereoselective manner. The approach involves developing IPrAuNTf2-catalyzed hydration of 1-phenylprop-2-yn-1-yl acetate or N-(1-phenylprop-2-yn-1-yl)acetamide, followed by (dynamic) asymmetric biotransamination or bioreduction of the corresponding keto ester or keto amide intermediates. Enzyme actions were completely selective towards the modification of the methyl ketones in a highly stereoselective manner, allowing the synthesis of enantio- and diastereomerically enriched products using either racemic or optically active starting materials. Thus, a series of amino alcohol, diol, and diamine derivatives were produced from propargyl esters or amides (57 to 86% isolated yield), the biocatalyst of choice determining the (stereo)selectivity of the overall cascade process (70-99% diastereomeric excess and > 98% enantiomeric excess), and providing access to nor(pseudo)ephedrine compounds in a straightforward manner.

Furan-based amines are highly valuable compounds which can be directly obtained via reductive amination from easily accessible furfural, 5-(hydroxymethyl)furfural (HMF) and 2,5-diformylfuran (DFF). Herein the biocatalytic amination of these carbonyl derivatives is disclosed using amine transaminases (ATAs) and isopropylamine (IPA) as amine donors. Among the different biocatalysts tested, the ones from Chromobacterium violaceum (Cv-TA), Arthrobacter citreus (ArS-TA), and variants from Arthrobacter sp. (ArRmut11-TA) and Vibrio fluvialis (Vf-mut-TA), afforded high levels of product formation (>80 %) at 100–200 mM aldehyde concentration. The transformations were studied in terms of enzyme and IPA loading. The pH influence was found as a key factor and attributed to the imine/aldehyde equilibrium that can arise from the high reactivity of the carbonyl substrates with a nucleophilic amine such as IPA.

The combination of metal-, photo-, enzyme-, and/or organocatalysis provides multiple synthetic solutions, especially when the creation of chiral centers is involved. Historically, enzymes and transition metal species have been exploited simultaneously through dynamic kinetic resolutions of racemates. However, more recently, linear cascades have appeared as elegant solutions for the preparation of valuable organic molecules combining multiple bioprocesses and metal-catalyzed transformations. Many advantages are derived from this symbiosis, although there are still bottlenecks to be addressed including the successful coexistence of both catalyst types, the need for compatible reaction media and mild conditions, or the minimization of cross-reactivities. Therefore, solutions are here also provided by means of catalyst coimmobilization, compartmentalization strategies, flow chemistry, etc. A comprehensive review is presented focusing on the period 2015 to early 2022, which has been divided into two main sections that comprise first the use of metals and enzymes as independent catalysts but working in an orchestral or sequential manner, and later their application as bionanohybrid materials through their coimmobilization in adequate supports. Each part has been classified into different subheadings, the first part based on the reaction catalyzed by the metal catalyst, while the development of nonasymmetric or stereoselective processes was considered for the bionanohybrid section.