L-Cysteine-Catalysed Hydration of Activated Alkynes.

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.

BioLindlar Catalyst: Ene-Reductase-Promoted Selective Bioreduction of Cyanoalkynes to Give (Z)-Cyanoalkenes.

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.

Thiol-free multicomponent synthesis of non-racemic β-acyloxy thioethers from biocatalytically obtained chiral halohydrins.

A novel multicomponent chemoenzymatic strategy for the preparation of enantioenriched β-acyloxy thioethers has been developed. This robust methodology employs mild bases, air atmosphere, room temperature and avoids the use of foul-smelling thiols. Instead, potassium thioacetate is employed as a universal sulfur source.

Spectrophotometric Assay for the Detection of 2,5-Diformylfuran and Its Validation through Laccase-Mediated Oxidation of 5-Hydroxymethylfurfural.

Modern biocatalysis requires fast, sensitive, and efficient high-throughput screening methods to screen enzyme libraries in order to seek out novel biocatalysts or enhanced variants for the production of chemicals. For instance, the synthesis of bio-based furan compounds like 2,5-diformylfuran (DFF) from 5-hydroxymethylfurfural (HMF) via aerobic oxidation is a crucial process in industrial chemistry. Laccases, known for their mild operating conditions, independence from cofactors, and versatility with various substrates, thanks to the use of chemical mediators, are appealing candidates for catalyzing HMF oxidation.

Biotransamination of Furan-Based Aldehydes with Isopropylamine: Enzyme Screening and pH Influence.

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.

Chemoselective Lipase-Catalyzed Synthesis of Amido Derivatives from 5-Hydroxymethylfurfurylamine.

The acylations of furfurylamine and 5-hydroxymethylfurfurylamine (HMFA) have been studied finding immobilized lipase B (CALB) as an ideal biocatalyst. CALB was used immobilized on two different supports (Novozyme 435 and EziG-CALB), with the polymer-coated controlled porosity glass carrier material from EnginZyme being an excellent carrier to yield an active and stable enzymatic preparation for the acylation of the primary amine group. The amount of the acyl donor in the reaction was a key factor to achieve the mono- and chemoselective N-protection of HMFA with large excess of ethyl acetate leading to the formation of the N,O-diacetylated product.

Laccases from Pleurotus ostreatus Applied to the Oxidation of Furfuryl Alcohol for the Synthesis of Key Compounds for Polymer Industry.

Laccases are oxidative enzymes with high synthetic potential. In this work, their value in biocatalysis is shown through the green and selective oxidation of furfuryl alcohol into furfural with the aid of mediators. The influence of different parameters, such as pH, enzyme/mediator composition, buffer type, cosolvent tolerance, and reaction times, is investigated.

Chemoenzymatic Cascades Combining Biocatalysis and Transition Metal Catalysis for Asymmetric Synthesis.

The combination of catalytic methods provides multiple advantages in organic synthesis, allowing access to diverse organic molecules in a straightforward manner. Merging metal and enzyme catalysis is currently receiving great attention due to the possibility to assemble metal catalysis in C-C coupling, olefin metathesis, hydration and other reactions with the exquisite stereospecificity displayed by enzymes. Thus, this minireview is organized based on the action of the metal species (Pd, Ru, Au, Ir, Fe…) in combination with different enzymes.

Expanding the Synthetic Toolbox through Metal-Enzyme Cascade Reactions.

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.

Combination of gold and redox enzyme catalysis to access valuable enantioenriched aliphatic β-chlorohydrins.

The synthesis of enantioenriched β-chlorohydrins is highly appealing due to their relevance as building-blocks in organic synthesis. However, the approximation to aliphatic derivatives is particularly challenging due to the difficulties to get access to the α-chloroketone precursors. Herein, we propose a straightforward and scalable approach combining in a concurrent manner gold(I) and redox enzyme catalysis through a hydration-bioreduction cascade.

Synthesis of Optically Active - and -Chlorohydrins through a Bienzymatic Reductive Cascade.

A bienzymatic cascade has been designed and optimized to obtain enantiopure chlorohydrins starting from the corresponding 1-aryl-2-chlorobut-2-en-1-ones. For the synthesis of these α-chloroenones, a two-step sequence was developed consisting of the allylation of the corresponding aldehyde with 3-dichloroprop-1-ene, followed by oxidation and further isomerization. The selective cooperative catalytic system involving ene-reductases (EREDs) and alcohol dehydrogenases (ADHs) afforded the desired optically active chlorohydrins under mild reaction conditions in excellent conversions (up to >99%) and selectivities (up to >99:1 diastereomeric ratio (dr), >99% enantiomeric excess ()).

Transaminases as suitable catalysts for the synthesis of enantiopure β,β-difluoroamines.

Transaminases have shown the ability to catalyze the amination of a series of aliphatic and (hetero)aromatic α,α-difluorinated ketones with high stereoselectivity, thus providing the corresponding β,β-difluoroamines in high isolated yields (55-82%) and excellent enantiomeric excess (>99%). It was also observed that these activated substrates could be quantitatively transformed by employing a small molar excess of the amine donor since this amination process was thermodynamically favored. Selected transformations could be scaled up to 500 mg, showing the robustness of this methodology.

Chemoenzymatic Oxosulfonylation-Bioreduction Sequence for the Stereoselective Synthesis of β-Hydroxy Sulfones.

A series of optically active β-hydroxy sulfones has been obtained through an oxosulfonylation-stereoselective reduction sequence in aqueous medium. Firstly, β-keto sulfones were synthesized from arylacetylenes and sodium sulfinates to subsequently develop the carbonyl reduction in a highly selective fashion using alcohol dehydrogenases as biocatalysts. Optimization of the chemical oxosulfonylation reaction was investigated, finding inexpensive iron(III) chloride hexahydrate (FeCl  ⋅ 6H O) as the catalyst of choice.

Alcohol Dehydrogenases and N-Heterocyclic Carbene Gold(I) Catalysts: Design of a Chemoenzymatic Cascade towards Optically Active β,β-Disubstituted Allylic Alcohols.

The combination of gold(I) and enzyme catalysis is used in a two-step approach, including Meyer-Schuster rearrangement of a series of readily available propargylic alcohols followed by stereoselective bioreduction of the corresponding allylic ketone intermediates, to provide optically pure β,β-disubstituted allylic alcohols. This cascade involves a gold N-heterocyclic carbene and an enzyme, demonstrating the compatibility of both catalyst types in aqueous medium under mild reaction conditions. The combination of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene][bis(trifluoromethanesulfonyl)-imide]gold(I) (IPrAuNTf ) and a selective alcohol dehydrogenase (ADH-A from Rhodococcus ruber, KRED-P1-A12 or KRED-P3-G09) led to the synthesis of a series of optically active (E)-4-arylpent-3-en-2-ols in good yields (65-86 %).

Sequential Two-Step Stereoselective Amination of Allylic Alcohols through the Combination of Laccases and Amine Transaminases.

A sequential two-step chemoenzymatic methodology for the stereoselective synthesis of (3E)-4-(het)arylbut-3-en-2-amines in a highly selective manner and under mild reaction conditions is described. The approach consists of oxidation of the corresponding racemic alcohol precursors by the use of a catalytic system made up of the laccase from Trametes versicolor and the oxy-radical TEMPO, followed by the asymmetric reductive bio-transamination of the corresponding ketone intermediates. Optimisation of the oxidation reaction, exhaustive amine transaminase screening for the bio-transaminations and the compatibility of the two enzymatic reactions were studied in depth in search of a design of a compatible sequential cascade.

The Versatile Applications of DES and Their Influence on Oxidoreductase-Mediated Transformations.

In the last decade, new types of solvents called deep eutectic solvents (DES) have been synthesized and commercialized. Among their main advantages, they can be eco-friendly and are easy to synthesize at different molar ratios depending on the desired solvent properties. This review aims to show the different uses of DES in some relevant biocatalytic redox reactions.

Novel chemoenzymatic oxidation of amines into oximes based on hydrolase-catalysed peracid formation.

The efficient transformation of benzylamines into the corresponding oximes has been described by means of a chemoenzymatic process. This strategy is based on a two-step sequence developed in one-pot at 30 °C and atmospheric pressure. First, the formation of a reactive peracid intermediate occurs by means of a lipase-catalysed perhydrolysis reaction, and then this peracid acts as a chemical oxidising agent of the amines.

Catalytic Promiscuity of Transaminases: Preparation of Enantioenriched β-Fluoroamines by Formal Tandem Hydrodefluorination/Deamination.

Transaminases are valuable enzymes for industrial biocatalysis and enable the preparation of optically pure amines. For these transformations they require either an amine donor (amination of ketones) or an amine acceptor (deamination of racemic amines). Herein transaminases are shown to react with aromatic β-fluoroamines, thus leading to simultaneous enantioselective dehalogenation and deamination to form the corresponding acetophenone derivatives in the absence of an amine acceptor.

Highly enantioselective synthesis of α-azido-β-hydroxy methyl ketones catalyzed by a cooperative proline-guanidinium salt system.

The combined activity of (S)-proline and an achiral tetraphenylborate TBD-derived guanidinium salt permits the aldol reaction between azidoacetone and aromatic, or heteroaromatic aldehydes. The α-azido-β-hydroxy methyl ketones obtained as products can be isolated in good yield, with high diastereo- and enantioselectivity.

Steric vs. electronic effects in the Lactobacillus brevis ADH-catalyzed bioreduction of ketones.

Lactobacillus brevis ADH (LBADH) is an alcohol dehydrogenase that is commonly employed to reduce alkyl or aryl ketones usually bearing a methyl, an ethyl or a chloromethyl as a small ketone substituent to the corresponding (R)-alcohols. Herein we have tested a series of 24 acetophenone derivatives differing in their size and electronic properties for their reduction employing LBADH. After plotting the relative activity against the measured substrate volumes we observed that apart from the substrate size other effects must be responsible for the activity obtained.

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

Several α-alkylated β-amino esters have been obtained via DKR processes employing a kit of transaminases and isopropylamine as an amino donor in aqueous medium under mild conditions. Thus, while acyclic α-alkyl-β-keto esters afforded excellent conversions and enantioselectivities, although usually low diastereoselectivities, using more constrained cyclic β-keto esters high to excellent inductions were obtained.

Synthesis of enantiopure fluorohydrins using alcohol dehydrogenases at high substrate concentrations.

The use of purified and overexpressed alcohol dehydrogenases to synthesize enantiopure fluorinated alcohols is shown. When the bioreductions were performed with ADH-A from Rhodococcus ruber overexpressed in E. coli, no external cofactor was necessary to obtain the enantiopure (R)-derivatives.

Coupling biocatalysis and click chemistry: one-pot two-step convergent synthesis of enantioenriched 1,2,3-triazole-derived diols.

A fully convergent one-pot two-step synthesis of different chiral 1,2,3-triazole-derived diols in high yields and excellent enantio- and diastereoselectivities has been achieved under very mild conditions in aqueous medium by combining a single alcohol dehydrogenase (ADH) with a Cu-catalysed 'click' reaction.

Mimicking nature: synthetic nicotinamide cofactors for C═C bioreduction using enoate reductases.

A series of synthetic nicotinamide cofactors were synthesized to replace natural nicotinamide cofactors and promote enoate reductase (ER) catalyzed reactions without compromising the activity or stereoselectivity of the bioreduction process. Conversions and enantioselectivities of >99% were obtained for C═C bioreductions, and the process was successfully upscaled. Furthermore, high chemoselectivity was observed when employing these nicotinamide cofactor mimics (mNADs) with crude extracts in ER-catalyzed reactions.

Expanding the regioselective enzymatic repertoire: oxidative mono-cleavage of dialkenes catalyzed by Trametes hirsuta.

The first report of a biocatalytic regioselective oxidative mono-cleavage of dialkenes was successfully achieved employing a cell-free enzyme preparation from Trametes hirsuta at the expense of molecular oxygen. Selected reactions were performed on a preparative scale affording high to excellent conversions and chemoselectivities.