LongLarf

A step‐ and redox‐economic route toward aminoallenes from simple alkynes and N‐fluorobenzenesulfonimide (NFSI) was established via selenium‐π‐acid catalysis. This unprecedented method significantly streamlines the assembly of heterosubstituted 1,3‐propadiene motifs and is characterized by a broad functional group tolerance.

Abstract

The facile synthesis of aminoallenes, accomplished by a selenium‐π‐acid‐catalyzed cross‐coupling of an N‐fluorinated sulfonimide with simple, non‐activated alkynes, is reported. Until now, aminoallenes were difficult to be accessed by customary means, inasmuch as pre‐activated and, in part, intricate starting materials were necessary for their synthesis. In sharp contrast, the current study shows that ordinary internal alkynes can serve as simple and readily available precursors for the construction of the aminoallene motif. The operating reaction conditions tolerate numerous functional groups such as esters, nitriles, (silyl)ethers, acetals, and halogen substituents, furnishing the target compounds in up to 86 % yield.

Taking control: Dihalogenation is one of the most typical electrophilic addition reactions to alkenes. Nevertheless, the development of reagent‐controlled asymmetric versions of this reaction has proven to be a formidable challenge and general methods are not yet available. This review summarizes the current state‐of‐the‐art for this reaction and discusses relevant mechanistic features for future catalyst development.

Abstract

The dihalogenation of alkenes is one of the classic reactions in organic chemistry and a prime example of an electrophilic addition reaction. The often observed anti‐selectivity in this addition reaction can be explained by the formation of a haliranium‐ion intermediate. Although dihalogenations have been studied for more than a century, the development of reagent‐controlled, enantioselective dihalogenation has proved to be very difficult. Only recently, significant progress has been achieved. In this review, an overview on current method development in enantioselective dihalogenation is provided and mechanistic aspects that render this transformation challenging are discussed.

Improving on nature: Synthetic bioisosteres of the natural product curcumin are designed, synthesized, and computationally evaluated by molecular dynamics and replica‐exchange molecular dynamics simulations for their interaction with amyloid‐β 42 aggregation. Biological evaluation shows that such compounds greatly exceed the anti‐neuroinflammatory and neuroprotective properties of their parent compounds.

Abstract

Many (poly‐)phenolic natural products, for example, curcumin and taxifolin, have been studied for their activity against specific hallmarks of neurodegeneration, such as amyloid‐β 42 (Aβ42) aggregation and neuroinflammation. Due to their drawbacks, arising from poor pharmacokinetics, rapid metabolism, and even instability in aqueous medium, the biological activity of azobenzene compounds carrying a pharmacophoric catechol group, which have been designed as bioisoteres of curcumin has been examined. Molecular simulations reveal the ability of these compounds to form a hydrophobic cluster with Aβ42, which adopts different folds, affecting the propensity to populate fibril‐like conformations. Furthermore, the curcumin bioisosteres exceeded the parent compound in activity against Aβ42 aggregation inhibition, glutamate‐induced intracellular oxidative stress in HT22 cells, and neuroinflammation in microglial BV‐2 cells. The most active compound prevented apoptosis of HT22 cells at a concentration of 2.5 μm (83 % cell survival), whereas curcumin only showed very low protection at 10 μm (21 % cell survival).

Existing methods for the chlorination of C(sp³)−H bonds occur with low site‐selectivity and tolerance for functional groups. We report a highly selective chlorination of C(sp³)−H bonds suitable for the late‐stage functionalization of natural products and active pharmaceutical ingredients by a reaction design that separates the components abstracting the H‐atom (an azidoiodinane) and transferring the chlorine atom (a copper(II) chloride complex).

Abstract

C(sp³)−Cl bonds are present in numerous biologically active small molecules, and an ideal route for their preparation is by the chlorination of a C(sp³)−H bond. However, most current methods for the chlorination of C(sp³)−H bonds are insufficiently site selective and tolerant of functional groups to be applicable to the late‐stage functionalization of complex molecules. We report a method for the highly selective chlorination of tertiary and benzylic C(sp³)−H bonds to produce the corresponding chlorides, generally in high yields. The reaction occurs with a mixture of an azidoiodinane, which generates a selective H‐atom abstractor under mild conditions, and a readily‐accessible and inexpensive copper(II) chloride complex, which efficiently transfers a chlorine atom. The reaction's exceptional functional group tolerance is demonstrated by the chlorination of >30 diversely functionalized substrates and the late‐stage chlorination of a dozen derivatives of natural products and active pharmaceutical ingredients.

The electrophotocatalytic C−H heterofunctionalization of arenes with high chemoselectivity under both batch and flow conditions is demonstrated.

Abstract

The electrophotocatalytic heterofunctionalization of arenes is described. Using 2,3‐dichloro‐5,6‐dicyanoquinone (DDQ) under a mild electrochemical potential with visible‐light irradiation, arenes undergo oxidant‐free hydroxylation, alkoxylation, and amination with high chemoselectivity. In addition to batch reactions, an electrophotocatalytic recirculating flow process is demonstrated, enabling the conversion of benzene to phenol on a gram scale.

The fix is in: This Review examines progress made in developing (de)carboxylases for application in organic synthesis for CO₂ fixing reactions. It highlights the synthetic scope of promising (de)carboxylase enzymes and the numerous strategies devised to increase enzymatic carboxylation yield, including application of (de)carboxylases in synthetic cascades.

Abstract

In recent years, (de)carboxylases that catalyze reversible (de)carboxylation have been targeted for application as carboxylation catalysts. This has led to the development of proof‐of‐concept (bio)synthetic CO₂ fixation routes for chemical production. However, further progress towards industrial application has been hampered by the thermodynamic constraint that accompanies fixing CO₂ to organic molecules. In this Review, biocatalytic carboxylation methods are discussed with emphases on the diverse strategies devised to alleviate the inherent thermodynamic constraints and their application in synthetic CO₂‐fixation cascades.

Organic transformations using electric current as a sustainable activator are a rapidly developing interdisciplinary field. However, different scientific backgrounds have led to a loss of important information being reported. Several pitfalls and misunderstandings regarding important parameters exist, which can cause challenges in reproducibility, even though electrical current is able to dial-in various reactivities.

Abstract

The use of electric current as a traceless activator and reagent is experiencing a renaissance. This sustainable synthetic method is evolving into a hot topic in contemporary organic chemistry. Since researchers with various scientific backgrounds are entering this interdisciplinary field, different parameters and methods are reported to describe the experiments. The variation in the reported parameters can lead to problems with the reproducibility of the reported electroorganic syntheses. As an example, parameters such as current density or electrode distance are in some cases more significant than often anticipated. This Minireview provides guidelines on reporting electrosynthetic data and dispels myths about this technique, thereby streamlining the experimental parameters to facilitate reproducibility.

Nature Chemistry, Published online: 01 March 2021; doi:10.1038/s41557-021-00639-9

Nature Communications, Published online: 02 March 2021; doi:10.1038/s41467-021-21633-2

Artificial metalloenzymes were created by supramolecular assembly in the cytoplasm of E. coli cells. The cells were then applied to the enantioselective biocatalysis of a Friedel–Crafts alkylation of indoles (see picture) and a Diels–Alder reaction. Directed evolution of the artificial metalloenzymes inside the cells provided improved variants for both whole‐cell biocatalytic reactions.

Abstract

We report the supramolecular assembly of artificial metalloenzymes (ArMs), based on the Lactococcal multidrug resistance regulator (LmrR) and an exogeneous copper(II)–phenanthroline complex, in the cytoplasm of E. coli cells. A combination of catalysis, cell‐fractionation, and inhibitor experiments, supplemented with in‐cell solid‐state NMR spectroscopy, confirmed the in‐cell assembly. The ArM‐containing whole cells were active in the catalysis of the enantioselective Friedel–Crafts alkylation of indoles and the Diels–Alder reaction of azachalcone with cyclopentadiene. Directed evolution resulted in two different improved mutants for both reactions, LmrR_A92E_M8D and LmrR_A92E_V15A, respectively. The whole‐cell ArM system required no engineering of the microbial host, the protein scaffold, or the cofactor to achieve ArM assembly and catalysis. We consider this a key step towards integrating abiological catalysis with biosynthesis to generate a hybrid metabolism.

The zinc‐catalyzed selective reduction of isocyanates via hydroboration is reported for the first time. Amide bond formation by the chemoselective reduction of isocyanates and hydrodeoxygenation of isocyanates to secondary methyl amine have been described.

Abstract

Herein, a remarkable conjugated bis‐guanidinate (CBG) supported zinc hydride, [{LZnH}₂; L={(ArHN)(ArN)−C=N−C=(NAr)(NHAr); Ar=2,6‐Et₂‐C₆H₃}] (I) catalyzed partial reduction of heteroallenes via hydroboration is reported. A large number of aryl and alkyl isocyanates, including electron‐donating and withdrawing groups, undergo reduction to obtain selectively N‐boryl formamide, bis(boryl) hemiaminal and N‐boryl methyl amine products. The compound I effectively catalyzes the chemoselective reduction of various isocyanates, in which the construction of the amide bond occurs. Isocyanates undergo a deoxygenation hydroboration reaction, in which the C=O bond cleaves, leading to N‐boryl methyl amines. Several functionalities such as nitro, cyano, halide, and alkene groups are well‐tolerated. Furthermore, a series of kinetic, control experiments and structurally characterized intermediates suggest that the zinc hydride species are responsible for all reduction steps and breaking the C=O bond.