A simple, solvent-free method for the synthesis of (thio)esters from simple acid chlorides at room temperature is reported. Simple FeCl₃ (5 mol%) enables facile, near complete conversion of equimolar starting materials in high selectivity. Recycling of the catalyst has been demonstrated.

In this contribution, we report chemoenzymatic bromodecarboxylation (Hunsdiecker-type) of α,ß-unsaturated carboxylic acids. The extraordinarily robust chloroperoxidase from Curvularia inaequalis (CiVCPO) generated hypobromite from H2O2 and bromide, which then spontaneously reacted with a broad range of unsaturated carboxylic acids and yielded the corresponding vinyl bromide products. Selectivity issues arising from the (here undesired) addition of water to the intermediate bromonium ion could be solved by reaction medium engineering. The vinyl bromides so obtained could be used as starting materials for a range of cross-coupling and pericyclic reactions.

Aromatic hydroxylation reactions catalyzed by heme-thiolate enzymes proceed via an epoxide intermediate. These aromatic epoxides could be valuable building blocks for organic synthesis giving access to a range of chiral trans-disubstituted cyclohexadiene synthons. Here, we show that naphthalene epoxides generated by fungal peroxygenases can be subjected to nucleophilic ring opening, yielding non-racemic trans-disubstituted cyclohexadiene derivates, which in turn can be used for further chemical transformations. This approach may represent a promising shortcut for the synthesis of natural products and APIs.

Invited for this month's cover is the group of Prof. Dr. Frank Hollmann at Delft University of Technology in the Netherlands. The Front Cover shows the vanadium-dependent haloperoxidase from the marine organism Curcuvaria inaequalis, which efficiently activates halides as hypohalites that can then initiate spontaneous halo-lactonization and halo-etherification reactions. The Communication itself is available at 10.1002/cssc.201902240.

The scale-up of chemoenzymatic bromolactonization to 100 g scale is presented, together with an identification of current limitations. The preparative-scale reaction also allowed for meaningful mass balances identifying current bottlenecks of the chemoenzymatic reaction.

En route to a bio-based chemical industry, the conversion of fatty acids into building blocks is of particular interest. Enzymatic routes, occurring under mild conditions and excelling by intrinsic selectivity, are particularly attractive. Here we report photoenzymatic cascade reactions to transform unsaturated fatty acids into enantiomerically pure secondary fatty alcohols. In a first step the C=C-double bond is stereoselectively hydrated using oleate hydratases from Lactobacillus reuteri or Stenotrophomonas maltophilia. Also, dihydroxylation mediated by the 5,8-diol synthase from Aspergillus nidulans is demonstrated. The second step comprises decarboxylation of the intermediate hydroxy acids by the photoactivated decarboxylase from Chlorella variabilis NC64A. A broad range of (poly)unsaturated fatty acids can be transformed into enantiomerically pure fatty alcohols in a simple one-pot approach.

An increasing number of biocatalytic oxidation reactions rely on H ₂ O ₂ as a clean oxidant. The poor robustness of most enzymes towards H ₂ O ₂ , however, necessitates more efficient systems for in situ H ₂ O ₂ generation. In analogy to the well-known formate dehydrogenase to promote NADH-dependent reactions, we here propose employing formate oxidase (FOx) to promote H ₂ O ₂ -dependent enzymatic oxidation reactions. Even under non-optimised conditions, high turnover numbers for coupled FOx/peroxygenase catalysis were achieved.

A chemoenzymatic method for the halocyclization of unsaturated alcohols and acids by using the robust V-dependent chloroperoxidase from Curvularia inaequalis (CiVCPO) as catalyst has been developed for the in situ generation of hypohalites. A broad range of halolactones and cyclic haloethers are formed with excellent performance of the biocatalyst.

The selective oxidation of trans-2-hexen-1-ol to the corresponding aldehyde using a recombinant aryl alcohol oxidase from Pleurotus eryngii (PeAAOx) is reported. Especially using the two liquid phase system to overcome solubility and product inhibition issues enabled to achieve more than 2.200.000 catalytic turnovers for the production enzyme as well as molar product concentrations, pointing towards an economic feasible reaction.

Deazaflavins are potentially useful redox mediators for the direct, nicotinamide-independent regeneration of oxidoreductases. Especially the O₂-stability of their reduced forms have attracted significant interest for the regeneration of monooxygenases. In this contribution we further investigate the photochemical properties of deazaflavins and investigate the scope and limitations of deazaflavin-based photoenzymatic reaction systems.

A photoenzymatic NADH regeneration system was established. The combination of deazariboflavin as a photocatalyst with putidaredoxin reductase enabled the selective reduction of NAD⁺ into the enzyme-active 1,4-NADH to promote an alcohol dehydrogenase catalysed stereospecific reduction reaction. The catalytic turnover of all the reaction components was demonstrated. Factors influencing the efficiency of the overall system were identified.

Propranolol is a widely used beta-blocker that is metabolized by human liver P450 monooxygenases into equipotent hydroxylated human drug metabolites (HDMs). It is paramount for the pharmaceutical industry to evaluate the toxicity and activity of these metabolites, but unfortunately, their synthesis has hitherto involved the use of severe conditions, with poor reaction yields and unwanted byproducts. Unspecific peroxygenases (UPOs) catalyze the selective oxyfunctionalization of C-H bonds, and they are of particular interest in synthetic organic chemistry. Here, we describe the engineering of UPO from Agrocybe aegerita for the efficient synthesis of 5′-hydroxypropranolol (5′-OHP). We employed a structure-guided evolution approach combined with computational analysis, with the aim of avoiding unwanted phenoxyl radical coupling without having to dope the reaction with radical scavengers. The evolved biocatalyst showed a catalytic efficiency enhanced by 2 orders of magnitude and 99% regioselectivity for the synthesis of 5′-OHP. When the UPO mutant was combined with an H₂O₂ in situ generation system using methanol as sacrificial electron donor, total turnover numbers of up to 264 000 were achieved, offering a cost-effective and readily scalable method to rapidly prepare 5′-OHP.

Alcohol dehydrogenases are well-established catalysts for various reduction reactions. However, the reduction of carboxylic acid derivatives has not yet been reported with these enzymes. In this contribution, we demonstrated that carboxylic acid thioesters could be readily reduced by a range of alcohol dehydrogenases, albeit at significantly reduced rates relative to those observed for corresponding ketones. A molecular explanation, especially for the lower turnover rates for thioesters relative to those obtained for ketones, is presented, as is a preliminary substrate scope.