Metal-chelating noncanonical amino acids (ncAAs) are uniquely functional building blocks for proteins, peptide catalysts, and small molecule sensors. However, catalytic asymmetric approaches to synthesizing these molecules are hindered by their functional group variability and intrinsic propensity to ligate metals. In particular, bipyridyl-L-alanine (BpyAla) is a highly sought ncAA, but its complex, inefficient syntheses have limited utility. Here, we develop a chemoenzymatic approach to efficiently construct BpyAla. Three enzymes that can be produced in high titer together react to convert Gly and an aldehyde into the corresponding -hydroxy ncAA, which is subsequently deoxygenated. We explore approaches to synthesizing biaryl aldehydes and show how the three-enzymatic cascade can access a range of -amino acids with bulky side chains, including a variety of metal-chelating amino acids. We show that newly accessible BpyAla analogues are compatible with existing amber suppression technology, which will enable future merging of traditional synthetic and biosynthetic approaches to tuning metal reactivity.

Billions of years of evolution have led to the selection of (hyper)thermophiles capable of flourishing at elevated temperatures. The corresponding native (hyper)thermophilic enzymes retain their tertiary and quaternary structures at near-boiling water temperatures and naturally retain catalytically competent conformational dynamics under these conditions. And yet, while hyper/thermophilic enzymes offer special opportunities in biocatalysis and in hybrid bio/chemocatalytic approaches to modern synthesis in both academia and industry, these enzymes remain underexplored in biocatalysis. Among the strategic advantages that can be leveraged in running biocatalytic transformations at higher temperatures are included more favorable kinetics, removal of volatile byproducts to drive reactions forward, improved substrate solubility and product separation, and accelerated stereodynamics for dynamic kinetic resolutions. These topics are discussed and illustrated with contemporary examples of note, in sections organized by stratagem. Finally, the reader is alerted in particular to archaeal enzymes that have proven useful in non-natural synthetic chemistry ventures, and at the same time is referred to a rich area of archaea whose genomes have been sequenced but whose enzymatic activities of interest have not yet been mined. Though hyperthermophilic archaea are among the most ancient of organisms, their enzymes may hold the key to many future innovations in biocatalytic chemistry - perhaps we really do need to go 'back to the future'.

Electrosynthesis represents a dynamic field in organic chemistry for the development of important and selective reactions. Among the most interesting electrosynthetic transformations is the non-directed arene C-H amination. Despite increasing reports, the quest for a non-directed electrochemical arene C-H amination capable of accommodating a wide range of arenes and amines with high site-selectivity remains ongoing. Non-directed electrochemical C-H amination presents a metal-free, mild approach for synthesizing complex aminated compounds of interest in pharmaceuticals and natural products. This concept aims to introduce the concept of non-directed electrochemical C-H amination and provide an overview of the recent advances in the field as well as the current limitations and potential directions.

To test the ability of geochemical surfaces in serpentinizing hydrothermal systems to catalyze reactions from which metabolism arose, we investigated H-dependent CO reduction toward metabolic intermediates over silica-supported Co-Fe catalysts. Supported catalysts converted CO to various products at 180 °C and 2.0 MPa. The liquid product phase included formate, acetate, and ethanol, while the gaseous product phase consisted of CH, CO, methanol, and C-C linear hydrocarbons. The 1/1 ratio CoFe alloy with the same composition as the natural mineral wairauite yielded the highest concentrations of formate (6.0 mM) and acetate (0.8 mM), which are key intermediates in the acetyl-coenzyme A (acetyl-CoA) pathway of CO fixation. While Co-rich catalysts were proficient at hydrogenation, yielding mostly CH, Fe-rich catalysts favored the formation of CO and methanol. Mechanistic studies indicated intermediate hydrogenation and C-C coupling activities of alloyed CoFe, in contrast to physical mixtures of both metals. Co in the active site of Co-Fe catalysts performed a similar reaction as tetrapyrrole-coordinated Co in the corrinoid iron-sulfur (CoFeS) methyl transferase in the acetyl-CoA pathway. In a temperature range characteristic for deeper regions of serpentinizing systems, oxygenate product formation was favored at lower, more biocompatible temperatures.

Vitamin B (VB) is a flexible and sustainable catalyst both in nature and the reaction flask, facilitating varied organic transformations of high value to both enzymatic processes and synthetic chemists. Key to this value is the breadth of reactivity it possesses, capable of both ionic, 2 electron chemistry, and radical, 1 electron chemistry. In particular, the ability to generate carbon-centered radical intermediates via photolysis of organocobalt intermediates formed from alkyl electrophiles opens the door to powerful new radical transformations challenging to achieve using classical photoredox or ligand-to-metal charge transfer (LMCT) catalysis. While this unique photocatalytic reactivity of VB has been increasingly leveraged in monocatalytic schemes, recent reports have demonstrated VB is able to function as the photocatalytic component in cooperative schemes, driving diverse reactivity including remote elimination of alkyl halides, regioselective epoxide arylation, and regioselective epoxide reduction. This concept briefly overviews the enabling photochemical properties of VB and recent applications in cooperative catalysis, providing a framework for the continued development of new cooperative catalyst systems using this powerful photoactive complex.

A series of thirteen 4-arylbut-3-ene-2-amines were prepared and subjected to photosensitization experiments to interrogate their photostationary state (PS) composition of geometrical olefin isomers (E and Z). The amine PS compositions were found to depend on arene structure and temperature, while being largely independent of nitrogen substitution, solvent, or presence of triplet-quenching oxygen. Photonic efficiency of isomerization (ζ) was found to depend on amine structure, solvent choice, and presence of quencher. With the proper choice of conditions, ζ was able to closely approach the theoretical maximum value of 0.5.

Capturing and converting CO through artificial photosynthesis using photoactive, porous materials is a promising approach for addressing increasing CO concentrations. Porphyrinic Zr-based metal-organic frameworks (MOFs) are of particular interest as they incorporate a photosensitizer in the porous structure. Herein, the initial step of the artificial photosynthesis is studied: CO sorption and activation in the presence of water. A combined vibrational and visible spectroscopic approach was used to monitor the adsorption of CO into PCN-222 and PCN-223 MOFs, and the photophysical changes of the porphyrinic linker as a function of water concentration. A shift in CO sorption site and bending of the porphyrin macrocycle in response to humidity was observed, and CO/HO competition experiments revealed that the exchange of CO with HO is pore-size dependent. Therefore, humidity and pore-size can be used to tune CO sorption, CO capacity, and light harvesting in porphyrinic MOFs, which are key factors for CO photoreduction.

Aza-substitution, the replacement of aromatic CH groups with nitrogen atoms, is an established medicinal chemistry strategy for increasing solubility, but current methods of accessing functionalized azaindoles are limited. In this work, indole-alkylating aromatic prenyltransferases (PTs) were explored as a strategy to directly functionalize azaindole-substituted analogs of natural products. For this, a series of aza-l-tryptophans (Aza-Trp) featuring -substitution of every aromatic CH position of the indole ring and their corresponding cyclic Aza-l-Trp-l-proline dipeptides (Aza-CyWP), were synthesized as substrate mimetics for the indole-alkylating PTs FgaPT2, CdpNPT, and FtmPT1. We then demonstrated most of these substrate analogs were accepted by a PT, and the regioselectivity of each prenylation was heavily influenced by the position of the -substitution. Remarkably, FgaPT2 was found to produce cationic -prenylpyridinium products, representing not only a new substrate class for indole PTs but also a previously unobserved prenylation mode. The discovery that nitrogenous indole bioisosteres can be accepted by PTs thus provides access to previously unavailable chemical space in the search for bioactive indolediketopiperazine analogs.

We present the use of Pd-complex-containing supported ionic liquid phases (SILPs) as a novel approach for continuous-flow allylic alkylation of -nucleophiles. This immobilization strategy gave simple access to air-tolerating catalyst frameworks, providing rapid and convenient access to various achiral and chiral -allylation products. Under optimized conditions, the flow-reaction could be maintained for 3.5 hours with constant product output; meanwhile, only a marginal 0.7 wt % of ionic liquid leaching and no detectable palladium-complex leaching could be observed.

Indole is a significant structural moiety and functionalization of the C-H bond in indole-containing molecules expands their chemical space, and modifies their properties and/or activities. Indole prenyltransferases (IPTs) catalyze the direct regiospecific installation of prenyl, C5 carbon units, on indole-derived compounds. IPTs have shown relaxed substrate flexibility enabling them to be used as tools for indole functionalization. However, the mechanism by which certain IPTs target a specific carbon position is not fully understood. Herein, we use structure-guided site-directed mutagenesis, in vitro enzymatic reactions, kinetics and structural-elucidation of analogs to verify the key catalytic residues that control the regiospecificity of all characterized regiospecific C6 IPTs. Our results also demonstrate that substitution of PriB_His312 to Tyr leads to the synthesis of analogs prenylated at different positions than C6. This work contributes to understanding of how certain IPTs can access a challenging position in indole-derived compounds.

Imine reductases (IREDs) are NADPH-dependent enzymes with significant biocatalytic potential for the synthesis of primary, secondary, and tertiary chiral amines. Their applications include the reduction of cyclic imines and the reductive amination of prochiral ketones. In this study, twenty-nine novel IREDs were revealed through genome mining. Imine reductase activities were screened at pH 7 and 9 and in presence of either NADPH or NADH; some IREDs showed good activities at both pHs and were able to accept both cofactors. IREDs with Asn and Glu at the key 187 residue showed preference for NADH. IREDs were also screened against a series of dihydroisoquinolines to synthesise tetrahydroisoquinolines (THIQs), bioactive alkaloids with a wide range of therapeutic properties. Selected IREDs showed high stereoselectivity, as well high THIQ yields (>90 %) when coupled to a glucose-6-phosphate dehydrogenase for NADPH cofactor recycling.

The mechanism and the reactive species involved in the oxidation of alkenes, and alcohols with HO, catalysed by an prepared mixture of a Mn salt, pyridine-2-carboxylic acid and a ketone is elucidated using substrate competition experiments, kinetic isotope effect (KIE) measurements, and atom tracking with O labelling. The data indicate that a single reactive species engages in the oxidation of both alkenes and alcohols. The primary KIE in the oxidation of benzyl alcohols is ca. 3.5 and shows the reactive species to be selective despite a zero order dependence on substrate concentration, and the high turnover frequencies (up to 30 s) observed. Selective O labelling identifies the origin of the oxygen atoms transferred to the substrate during oxidation, and is consistent with a highly reactive, ., [Mn(O)(OH)] or [Mn(O)], species rather than an alkylperoxy or hydroperoxy species.

Artificial redox catalysts are typically limited by unfavorable scaling relations of reaction intermediates leading to a significant overpotential in multi-electron redox reactions such as for example the oxygen reduction reaction (ORR). The multicopper oxidase laccase is able to catalyze the ORR in nature. In particular the high-potential variants show a remarkably low overpotential for the ORR and apparently do not suffer from such unfavorable scaling relations. Although laccases are intensively studied, it is presently unknown why the overpotential for ORR is so low and a clear description regarding the thermodynamics of the catalytic cycle and the underlying design principles is lacking. In order to understand the laccase catalyzed ORR from an electrochemical perspective, elucidation of the free energy scheme would be of high value. This article reviews the energetics of the proposed laccase catalyzed ORR mechanisms based on experimental and computational studies. However, there are still remaining challenges to overcome to elucidate the free energy scheme of laccase. Obtaining thermodynamic data on intermediates is hard or even impossible with analytical techniques. On the other hand, several computational studies have been performed with significantly different parameters and conditions, thus making a direct comparison difficult. For these reasons, a consensus on a clear free energy scheme is still lacking. We anticipate that ultimately conquering these challenges will result in a better understanding of laccase catalyzed ORR and will allow for the design of low overpotential redox catalysts.

Carbocycles are core skeletons in natural and synthetic organic compounds possessing a wide diversity of important biological activities. Herein, we report the development of an excited-state copper-catalyzed radical carbo-aroylation of unactivated alkenes to synthesize ketonylated tetralins, di- and tetrahydrophenanthrenes, and cyclopentane derivatives. The reaction is operationally simple and features mild reaction conditions that tolerate a broad range of functional groups. Preliminary mechanistic studies suggest a reaction pathway beginning with photoexcitation of [CuI-BINAP] and followed by a single electron transfer (SET), radical aroylation of unactivated alkenes, radical cyclization, and re-aromatization, affording the desired ketonylated carbocycles.

Tandem catalysis stands out as a major instrument towards the intensification of existing and future chemical processes. Initially formulated in the field of homogeneous catalysis, the concept relies on the single-pot integration of two (or more) catalysts showing high specificity for mechanistically decoupled reactions, while being operational and compatible under a single set of operation conditions. Isolated metal atoms stabilized on solid carriers in single-atom catalysts (SACs) hold the potential to reconcile the high reaction specificities of mononuclear sites in molecular catalysts with an intrinsic catalyst compartmentalization on inorganic matrices. Understandably, SACs have started to be considered as platforms in tandem catalysis. Tandem (electro)catalytic processes based on SACs have been showcased recently. While this sets excellent prospects for the expansion of this research subarea, challenges are faced, particularly as to the verification of the tandem nature of the processes.

Vanadium redox flow batteries (VRFBs) are appealing large-scale energy storage systems due to their unique properties of independent energy/power design. The VRFBs stack design is crucial for technology deployment in power applications. Besides the design, the stack suffers from high voltage losses caused by the electrodes. The introduction of active sites into the electrode to facilitate the reaction kinetic is crucial in boosting the power rate of the VRFBs. Here, an O-rich layer has been applied onto structured graphite felt (GF) by depositing WO to increase the oxygen species content. The oxygen species are the active site during the positive reaction (VO /VO) in VRFB. The increased electrocatalytic activity is demonstrated by the monoclinic ()-WO/GF electrode that minimizes the voltage losses, yielding excellent performance results in terms of power density output and limiting current density (556 mWcm@800 mAcm). The results confirm that the -WO/GF electrode is a promising electrode for high-power in VRFBs, overcoming the performance-limiting issues in a positive half-reaction.

Low-coordinate, open-shell 3d metal complexes have attracted great attention due to their critical role in several catalytic transformations but have been notoriously difficult to prepare and study due to their high lability. Here, we report the synthesis of a heteroleptic tri-coordinate amidoferrate that displays high catalytic activity in the regioselective hydrosilylation of alkenes.

The development of highly active and long-term stable electrocatalysts for the cathode of proton-exchange membrane fuel cells (PEMFC) is a paramount requirement for high performance and durable PEMFC stacks. In this regard, alloying Pt with rare earth metals (REM) has emerged as a promising approach. This short review summarizes and discusses the most relevant advances on Pt-REM alloy electrocatalysts, from bulk polycrystalline surfaces to carbon supported nanostructures, for the oxygen reduction reaction (ORR), and their implementation in PEMFCs, and is a starting point to establish the challenges in synthesis and design and properties goals for novel Pt-REM alloys.

In this work, we discuss the role of manganese oxide as a promoter in Cu catalysts supported on graphitic carbon during hydrogenation of CO and CO. MnO is a selectivity modifier in an H/CO feed and is a highly effective activity promoter in an H/CO feed. Interestingly, the presence of MnO suppresses the methanol formation from CO (TOF of 0.7 ⋅ 10 s at 533 K and 40 bar) and enhances the low-temperature reverse water-gas shift reaction (TOF of 5.7 ⋅ 10 s) with a selectivity to CO of 87 %. Using time-resolved XAS at high temperatures and pressures, we find significant absorption of CO to the MnO, which is reversed if CO is removed from the feed. This work reveals fundamental differences in the promoting effect of MnO and ZnO and contributes to a better understanding of the role of reducible oxide promoters in Cu-based hydrogenation catalysts.

The chemo- and stereoselective semi-hydrogenation of alkynes to alkenes is a fundamental transformation in synthetic chemistry, for which the use of precious 4d or 5d metal catalysts is well-established. In mankind's unwavering quest for sustainability, research focus has considerably veered towards the 3d metals. Given their high abundancy and availability as well as lower toxicity and noxiousness, they are undoubtedly attractive from both an economic and an environmental perspective. Herein, we wish to present noteworthy and groundbreaking examples for the use of 3d metal catalysts for diastereoselective alkyne semi-hydrogenation as we embark on a journey through the first-row transition metals.

Friedel-Crafts alkylation and acylation reactions are important methodologies in synthetic and industrial chemistry for the construction of aryl-alkyl and aryl-acyl linkages that are ubiquitous in bioactive molecules. Nature also exploits these reactions in many biosynthetic processes. Much work has been done to expand the synthetic application of these enzymes to unnatural substrates through directed evolution. The promise of such biocatalysts is their potential to supersede inefficient and toxic chemical approaches to these reactions, with mild operating conditions - the hallmark of enzymes. Complementary work has created many bio-hybrid Friedel-Crafts catalysts consisting of chemical catalysts anchored into biomolecular scaffolds, which display many of the same desirable characteristics. In this Review, we summarise these efforts, focussing on both mechanistic aspects and synthetic considerations, concluding with an overview of the frontiers of this field and routes towards more efficient and benign Friedel-Crafts reactions for the future of humankind.