LongLarf

Nature, Published online: 01 June 2022; doi:10.1038/s41586-022-04456-z

Synthesis
DOI: 10.1055/a-1792-6579

Nitroarenes are readily available compounds that are commonly utilized in reductive processes to form C–NAr bonds via reactive nitrogen intermediates. Recent advances in the development of reductive reactions of nitroarenes using organomagnesium, organozinc, and single-electron transfer reagents are discussed within this short review. 1 Introduction2 Organomagnesium-Mediated Reductive Reactions of Nitroarenes3 Organozinc- and Zinc-Mediated Reductive Reactions of Nitroarenes4 Iodine-Catalyzed Redox Cyclizations of Nitroarenes5 Titanium(III)-Mediated Reductive Cyclizations6 Sulfur-Mediated Reductive Reactions of Nitroarenes7 Alkoxide-Mediated Reductive Reactions of Nitroarenes8 4,4′-Bipyridine-Mediated Reductive Reactions of Nitroarenes9 Visible-Light-Driven Reductive Amination Reactions10 Electrochemical Reductive Reactions11 Conclusion
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
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Three acidic catecholamine metabolites, including 3,4-dihydroxymandelic acid (DHMA), 3-methoxy-4-hydroxymandetic acid (VMA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were investigated by PNRSS. DHMA, which contains an α-hydroxycarboxylate moiety (red shade, marked as 1) and an adjacent cis-hydroxyl groups on the benzene ring (blue shade, marked as 2), reports two binding modes (PBA-1 and PBA-2) simultaneously resolvable by PNRSS, demonstrating a high resolution of PNRSS. A custom machine learning algorithm was also developed to achieve automatic event classification.

Abstract

Acidic catecholamine metabolites, which could serve as diagnostic markers for many diseases, demonstrate an importance of accurate sensing. However, they share a highly similar chemical structure, which is a challenge in the design of sensing strategies. A nanopore may be engineered to sense these metabolites in a single molecule manner. To achieve this, a recently developed programmable nano-reactor for stochastic sensing (PNRSS) technique adapted with a phenylboronic acid (PBA) adaptor was applied. Three acidic catecholamine metabolites, including 3,4-dihydroxyphenylacetic acid (DOPAC), 3,4-dihydroxymandelic acid (DHMA) and 3-methoxy-4-hydroxymandetic acid (VMA) were investigated by PNRSS. Specifically, DHMA, which contains an α-hydroxycarboxylate moiety and an adjacent cis-hydroxyl groups on its benzene ring, reports two binding modes simultaneously resolvable by PNRSS. Assisted with the high resolution of PNRSS, direct regulation of these two binding modes by pH can also be observed. A custom machine learning algorithm was also developed to achieve automatic event classification.

Delicious deprotonations: The scrumptiously tantalising diphenylberyllium Brønsted-base bratwurst can be combined with an enticing selection of Brønsted-acid sauces to result in the formation of dreamy beryllium compounds, such as an XRD-confirmed homoleptic beryllium alkoxide and an NHC-stabilised beryllium Grignard. More information can be found in the Research Article by M. R. Buchner and co-workers (DOI: 10.1002/chem.202200851).

A bioinspired clickable selenylation reaction of indole has been developed by using benzoselenazole as selenylation reagent under nonmetallic B(C₆F₅)₃ catalysis. The practical application of the reaction has been well demonstrated in on-DNA and on-microplate parallel synthesis of indole-selenides.

Abstract

Click chemistry is a concept wherein modular synthesis is used for rapid functional discovery. To this end, continuous discovery of clickable chemical transformations is the pillar to support the development of this field. This report details the development of a clickable C3-H selenylation of indole that is suitable for on-plate parallel and DNA-encoded library (SeDEL) synthesis via bioinspired LUMO activation strategy. This reaction is modular, robust and highly site-selective, and it features a simple and mild reaction system (catalyzed by nonmetallic B(C₆F₅)₃ at room temperature), high yields and excellent functional group compatibility. Using this method, a library of 1350 indole-selenides was parallel synthesized in an efficient and practical manner, enabling the rapid identification of 3 ai as a promising compound with nanomolar antiproliferative activity in cancer cells via in situ phenotypic screening. These results indicate the great potential of this new clickable selenylation reaction in high-throughput medicinal chemistry and chemical biology.

A new catalyst platform for C(sp³)−H bond functionalization has been discovered. “Sandwich” diimine-copper(I) complexes catalyze reactions of alkane, ether, and amine C−H bonds with a large panel of diazo compounds. Additionally, the first metal-catalyzed C(sp³)−H methylation by CH₂N₂ is disclosed. The electrophilicity and extreme steric bulk of these catalysts are likely reasons for their efficiency.

Abstract

We report here “sandwich” diimine-copper(I) catalysts for C(sp³)−H bond functionalization. Reactions of alkanes and ethers with trimethylsilyldiazomethane, ethyl diazoacetate, and trifluoromethyl-diazomethane have been demonstrated. We also report C(sp³)−H bond methylation, benzylation, and diphenylmethylation by diazomethane, aryldiazomethanes, and diphenyldiazomethane. These reactions are rare examples of base-metal catalyzed, intermolecular C(sp³)−H functionalizations by employing unactivated diazo compounds. Electrophilicity and unique steric environment of “sandwich”-copper catalysts are likely reasons for their catalytic efficiency.

Nature Catalysis, Published online: 16 May 2022; doi:10.1038/s41929-022-00779-2

Publication date: 12 May 2022

Source: Chem, Volume 8, Issue 5

Author(s): Bijin Li, Mazen Elsaid, Haibo Ge

Synthesis
DOI: 10.1055/a-1806-4513

The Ni-catalysed hydrogenolysis and cross-coupling of aryl ethers has emerged as a powerful synthetic tool to transform inert phenol-derived electrophiles into functionalised aromatic molecules. This has attracted significant interest due to its potential to convert the lignin fraction of biomass into chemical feedstocks, or to enable orthogonal reactivity and late-stage synthetic modification. Although the scope of nucleophiles employed, and hence the C–C and C–heteroatom bonds that can be forged, has expanded significantly since Wenkert’s seminal work in 1979, mechanistic understanding on how these reactions operate is still uncertain since the comparatively inert Caryl–O bond of aryl ethers challenge the involvement of classical mechanisms involving direct oxidative addition to Ni(0). In this review, we document the different mechanisms that have been proposed in the Ni-catalysed hydrogenolysis and cross-coupling of aryl ethers. These include: (i) direct oxidative addition; (ii) Lewis acid assisted C–O bond cleavage; (iii) anionic nickelates, and; (iv) Ni(I) intermediates. Experimental and theoretical investigations by numerous research groups have generated a pool of knowledge that will undoubtedly facilitate future discoveries in the development of novel Ni-catalysed transformations of aryl ethers.1 Introduction2 Direct Oxidative Addition3 Hydrogenolysis of Aryl Ethers4 Lewis Acid Assisted C–O Bond Cleavage5 Anionic Nickelates6 Ni(I) Intermediates7 The ‘Naphthalene Problem’8 Conclusions and Outlook
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
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Oxalyl thioesters are cell metabolites endowed with remarkably powerful acyl transfer abilities. The bioinspired design of stable and activatable oxalyl thioester surrogates and their application for the modification of peptides and proteins is reported. Formation of a stable oxalamide crosslink proceeds at rates ≈30 M⁻¹ s⁻¹, in the nanomolar concentration range, in purified media or in protein extracts of cell lysates.

Abstract

We show that latent oxalyl thioester surrogates are a powerful means to modify peptides and proteins in highly dilute conditions in purified aqueous media or in mixtures as complex as cell lysates. Designed to be shelf-stable reagents, they can be activated on demand to enable ligation reactions with peptide concentrations as low as a few hundred nM at rates approaching 30 M⁻¹ s⁻¹.

Directed evolution rendered P450_BSβ capable of β-hydroxylating unactivated C−H bonds in aliphatic carboxylic acids with broad substrate scope and excellent chemo-, regio-, and enantioselectivity. The crystal structure of the evolved variant rationalizes the improved reactivity and selectivity. This study demonstrates the potential of exploring biocatalysts to fulfill reactions that are otherwise elusive with chemical strategies.

Abstract

Catalytic selective hydroxylation of unactivated aliphatic (sp³) C−H bonds without a directing group represents a formidable task for synthetic chemists. Through directed evolution of P450_BSβ hydroxylase, we realize oxyfunctionalization of unactivated C−H bonds in a broad spectrum of aliphatic carboxylic acids with varied chain lengths, functional groups and (hetero-)aromatic moieties in a highly chemo-, regio- and enantioselective fashion (>30 examples, Cβ/Cα>20 : 1, >99 % ee). The X-ray structure of the evolved variant, P450_BSβ-L78I/Q85H/G290I, in complex with palmitic acid well rationalizes the experimentally observed regio- and enantioselectivity, and also reveals a reduced catalytic pocket volume that accounts for the increased reactivity with smaller substrates. This work showcases the potential of employing a biocatalyst to enable a chemical transformation that is particularly challenging by chemical methods.

Alcohol dehydrogenases (ADHs) have become important catalysts for stereoselective oxidation and reduction reactions of alcohols, aldehydes and ketones. The aim of this contribution is to provide the reader with a timely update on the state-of-the-art of ADH-catalysis. Mechanistic basics are presented together with practical information about the use of ADHs. Current concepts of ADH engineering and ADH reactions are critically discussed. Finally, this contribution highlights some prominent examples and future-pointing concepts.

Isothermal titration calorimetry (ITC) is a popular chemical analysis technique that can be used to measure macromolecular interactions and chemical and physical processes. ITC involves the measurement of heat flow to and from a measurement cell after each injection during a titration experiment. ITC has been useful to measure the thermodynamics of macromolecular interactions such as protein-ligand or protein-protein binding affinity and also chemical processes such as enzyme catalyzed reactions. The use of ITC in biocatalysis has a number of advantages as ITC enables the measurement of enzyme kinetic parameters in a direct manner and, in principle, can be used for most enzymes and substrates. ITC approaches have been developed to measure reversible and irreversible enzyme inhibition, the effects of molecular crowding on enzyme activity, the activity of immobilized enzymes and the conversion of complex polymeric substrates. A disadvantage is that in order to obtain accurate kinetic parameters special care has to be taken in proper experimental design and data interpretation, which unfortunately is not always the case in reported studies. Furthermore, special caution is necessary when ITC experiments are performed that include solvents, reducing agents and may have side reactions. An important bottleneck in the use of calorimetry to measure enzyme activity is the relatively low throughput, which may be solved in the future by sensitive chip based microfluidic enzyme calorimetric devices.