LongLarf

Nature Chemistry, Published online: 05 May 2022; doi:10.1038/s41557-022-00931-2

Enzymes, either purified or as whole-cell biocatalysts, can be concatenated into catalytic cascades and used to produce pharmaceutically relevant molecules. This Review discusses the advantages and requirements of multistep enzyme cascades and also highlights how they can be harnessed to achieve highly sustainable and cost-efficient syntheses.

As teaching, meetings, and conferences move to virtual settings during the global COVID-19 pandemic, students, and early-career professionals are deprived of mentorship opportunities. This suggests that the mentorship platforms need to be adapted to bring a positive change and this Viewpoint Article shares insights from the perspective of Transformative Education and Mentoring Talks programs.

Abstract

During the global crisis triggered by the COVID-19 pandemic, university programs, meetings, and conferences have moved to virtual settings, with consequent erosion of mentorship opportunities for students and early-career professionals. This calls for mentorship platforms that are adapted to the new landscape in order to bring about a positive change. Our Viewpoint Article shares the perspective of the Transformative Education program and Mentorship Talks initiative at the American University of Beirut in Lebanon, with the aim of providing insights that could stimulate other mentorship platforms.

We report and demonstrate the practical utility of an N-chloropeptide strategy for the rapid construction of ΔAA-containing peptides. The quinuclidine (ABCO)-catalyzed N-chlorination of peptide bonds and the subsequent β-elimination of N-chloroamide efficiently provides ΔAA-containing peptides in high yield. The strategy enables the late-stage installation of ΔAA motifs into already-constructed oligopeptides, including a macrocyclic peptide.

Abstract

Conventional methods for the construction of dehydroamino acids (ΔAAs), which are a unique class of non-proteinogenic amino acids, require the pre-installation of special amino acids. Herein, we report and demonstrate the practical utility of an N-chloropeptide strategy for the rapid construction of ΔAA-containing peptides. The electrophilic N-chlorination of peptide bonds is drastically accelerated by a catalytic amount of quinuclidine (ABCO), and the subsequent β-elimination of N-chloroamide efficiently provides ΔAA-containing peptides in high yield. The strategy enables, for the first time, the construction of a wide variety of ΔAA residues in peptides without any pre-functionalized side chains and facilitates the late-stage installation of ΔAA motifs into already-constructed oligopeptides, including a medicinally important macrocyclic peptide.

Sortase A was found to mediate the efficient and irreversible ligation of a protein/peptide containing a C-terminal thioester with another protein/peptide bearing an N-terminal Gly, with broad tolerance for a wide variety of LPxT-derived sequences. The thioester-assisted SrtA-mediated ligation strategy enabled the expedient preparation of proteins bearing various N- or C-terminal labels and post-translationally modified proteins.

Abstract

Sortase A (SrtA)-mediated ligation, a popular method for protein labeling and semi-synthesis, is limited by its reversibility and dependence on the LPxTG motif, where “x” is any amino acid. Here, we report that SrtA can mediate the efficient and irreversible ligation of a protein/peptide containing a C-terminal thioester with another protein/peptide bearing an N-terminal Gly, with broad tolerance for a wide variety of LPxT-derived sequences. This strategy, the thioester-assisted SrtA-mediated ligation, enabled the expedient preparation of proteins bearing various N- or C-terminal labels, including post-translationally modified proteins such as the Ser139-phosphorylated histone H2AX and Lys9-methylated histone H3, with less dependence on the LPxTG motif. Our study validates the chemical modification of substrates as an effective means of augmenting the synthetic capability of existing enzymatic methods.

This Minireview summarizes the different strategies used in the design and engineering of novel enzymes that accommodate iminium catalysis. The advantages and challenges of developing enzymes for this catalysis mode are discussed. Recent developments in iminium biocatalysis showcase the tremendous power of combining chemomimetic biocatalyst design and directed evolution to create useful biocatalysts for new-to-nature transformations.

Abstract

The application of biocatalysis in conquering challenging synthesis requires the constant input of new enzymes. Developing novel biocatalysts by absorbing catalysis modes from synthetic chemistry has yielded fruitful new-to-nature enzymes. Organocatalysis was originally bio-inspired and has become the third pillar of asymmetric catalysis. Transferring organocatalytic reactions back to enzyme platforms is a promising approach for biocatalyst creation. Herein, we summarize recent developments in the design of novel biocatalysts that adopt iminium catalysis, a fundamental branch in organocatalysis. By repurposing existing enzymes or constructing artificial enzymes, various biocatalysts for iminium catalysis have been created and optimized via protein engineering to promote valuable abiological transformations. Recent advances in iminium biocatalysis illustrate the power of combining chemomimetic biocatalyst design and directed evolution to generate useful new-to-nature enzymes.

Publication date: 12 May 2022

Source: Chem, Volume 8, Issue 5

Author(s): Wen-Xin Lv, Hang Chen, Xinglong Zhang, Chang Chin Ho, Yingguo Liu, Shuquan Wu, Haiqi Wang, Zhichao Jin, Yonggui Robin Chi

Synlett
DOI: 10.1055/s-0040-1719920

By using cheap and innocuous sodium chlorite, a series of tertiary amines have been oxidized to the corresponding lactams with good selectivity and high yield. In this method, neither transition-metal catalyst nor oxidant was used. In the oxidation step, the pH of the sodium chlorite was precisely adjusted to pH around 6 using CO2, such pH is a compromise between oxidative properties, chemical stability, and unwanted precipitation. In addition, buffer salts are not necessary, which allows this oxidation reaction to be performed under safe and environmentally benign conditions.
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

Despite their promising properties, hypervalent bromine(III) reagents remain underexplored due to their low stability and difficult preparation. A fresh approach involves chelation-stabilized bromine(III) species which are conveniently prepared by electro-oxidation of parent bromoarenes. The intrinsic Br(III) reactivity can be unlocked in the presence of acids. In this mechanistic study, electrochemical synthesis, redox properties, and chemical reactivity aspects of chelation-stabilized hypervalent bromine(III) species are disclosed.

Abstract

Hypervalent bromine(III) reagents possess a higher electrophilicity and a stronger oxidizing power compared to their iodine(III) counterparts. Despite the superior reactivity, bromine(III) reagents have a reputation of hard-to-control and difficult-to-synthesize compounds. This is partly due to their low stability, and partly because their synthesis typically relies on the use of the toxic and highly reactive BrF₃ as a precursor. Recently, we proposed chelation-stabilized hypervalent bromine(III) compounds as a possible solution to both problems. First, they can be conveniently prepared by electro-oxidation of the corresponding bromoarenes. Second, the chelation endows bromine(III) species with increased stability while retaining sufficient reactivity, comparable to that of iodine(III) counterparts. Finally, their intrinsic reactivity can be unlocked in the presence of acids. Herein, an in-depth mechanistic study of both the electrochemical generation and the reactivity of the bromine(III) compounds is disclosed, with implications for known applications and future developments in the field.

Publication date: 9 June 2022

Source: Chem, Volume 8, Issue 6

Author(s): Kazuhiro Aida, Marina Hirao, Aiko Funabashi, Natsuhiko Sugimura, Eisuke Ota, Junichiro Yamaguchi

Detection and quantitation of protein persulfides requires trapping with alkylating agents. Persulfide adducts derived from commonly used alkylating agents are unstable under biologically relevant conditions. The adducts convert to thioethers by losing sulfane sulfur to nucleophilic acceptors. Alkylating agents that form stable persulfide adducts and are suitable for persulfide trapping in biological samples are also reported.

Abstract

Protein persulfides (R-S-SH) have emerged as a common post-translational modification. Detection and quantitation of protein persulfides requires trapping with alkylating agents. Here we show that alkylating agents differ dramatically in their ability to conserve the persulfide's sulfur–sulfur bond for subsequent detection by mass spectrometry. The two alkylating agents most commonly used in cell biology and biochemistry, N-ethylmaleimide and iodoacetamide, are found to be unsuitable for the purpose of conserving persulfides under biologically relevant conditions. The resulting persulfide adducts (R-S-S-Alk) rapidly convert into the corresponding thioethers (R-S-Alk) by donating sulfur to ambient nucleophilic acceptors. In contrast, certain other alkylating agents, in particular monobromobimane and N-t-butyl-iodoacetamide, generate stable alkylated persulfides. We propose that the nature of the alkylating agent determines the ability of the disulfide bond (R-S-S-Alk) to tautomerize into the thiosulfoxide (R-(S=S)-Alk), and/or the ability of nucleophiles to remove the sulfane sulfur atom from the thiosulfoxide.

An intriguing class of free Au-substituted phosphines (AuPhos) featuring an electronically and sterically tunable, extremely electron-rich phosphorus center has been described. These AuPhos are potent synthons for multi-nuclear transition metal complexes and have tremendous potential for transition metal catalysis.

Abstract

We report herein a facile and highly modular access to an intriguing class of free Au-substituted phosphines (AuPhos), namely (LAu) _n PR_3−n (L=singlet carbene ligand; R=H, aryl, alkyl, silyl) (n=1–3). The Tolman electronic parameter (TEP) values coupled with theoretical investigations showcase that Au-substitution can boost the electron-releasing ability of AuPhos, thus leading to an electronically and sterically tunable, extremely electron-rich phosphorus center. The high basicity of AuPhos is attributed to the d-p lone pair π-repulsion arising from interaction between Au substituents and the lone pair at P. A series of multi-nuclear transition metal complexes (i.e. Rh, Ir, Pd, Au, W, Mn) ligated by AuPhos are readily prepared via a straightforward process. Preliminary catalytic results reveal the facilitation of Pd-catalyzed C−N coupling reactions and Ir-catalyzed decarbonylation reactions via AuPhos. This work provides insights for future development of electron-rich ligands.

Nature Catalysis, Published online: 02 May 2022; doi:10.1038/s41929-022-00777-4

Engineering enzymes to perform new-to-nature reactions can address long-standing challenges in synthetic chemistry. Now a ketoreductase has been evolved to undergo a photoinduced single-electron-transfer pathway, thereby achieving an enantioselective Giese-type radical conjugate addition that yields α-chiral esters.

Bioconjugation deals with the chemical modification of proteins. For the establishment of antibody drug conjugates (ADCs) and other bioconjugates, many click-type reactions have been applied, providing novel drugs that have entered clinical phases and also the market over recent years. Recent developments to broaden the chemical toolbox to meet the challenge of selective, bioorthogonal modification of biomolecules are showcasing new ways to apply novel click chemistry in the bioconjugation context.

Abstract

Bioconjugation deals with the chemical modification of proteins. The reactions used exploit either the intrinsic chemical reactivity of the biomolecule or introduce functionalities that can then be subsequently reacted without interfering with other functional groups of the biological entity. Perfectly selective, high yielding chemical transformations are needed that can be run in aqueous environment under mild pH conditions. Requirements that have an obvious overlap with the definition of click chemistry. This review shows a selection of successfully applied click-type reactions in bioconjugation as well as some recent developments to broaden the chemical toolbox to meet the challenge of selective, bioorthogonal modification of biomolecules.

Synthesis
DOI: 10.1055/s-0040-1719919

A novel and practical method to synthesize trifluoromethyl tertiary alcohols has been developed. Under mild reaction conditions, the present reaction could be compatible with a wide range of functional groups. Moreover, the performance of gram-scale reaction and further transformations illustrated the good potential utility of the present chemistry. Furthermore, the radical process of this reaction has been proved by mechanistic studies.
[...]

Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

A manganese biopolymer-supported catalyst is reported for hydrogen/deuterium exchange in anilines, phenols, heterocycles, and electron-rich arenes. Notably, taking advantage of deuterium oxide as easy-to-handle isotope source, deuterated compounds are obtained in high yields in a practical manner.

Abstract

There is a constant need for deuterium-labelled products for multiple applications in life sciences and beyond. Here, a new class of heterogeneous catalysts is reported for practical deuterium incorporation in anilines, phenols, and heterocyclic substrates. The optimal material can be conveniently synthesised and allows for high deuterium incorporation using deuterium oxide as isotope source. This new catalyst has been fully characterised and successfully applied to the labelling of natural products as well as marketed drugs.

Reversible transamidation is described for different maleamic acids. Amide formation and exchange proceed to equilibrium at room temperature without external catalysts, and the equilibrium composition can be controlled using different stimuli. Thermodynamic and kinetic compositions can be accessed by amide libraries produced in this way. This new dynamic bond can be useful in dynamic combinatorial chemistry.

Abstract

Dynamic combinatorial chemistry is a method widely used for generating responsive libraries of compounds, with applications ranging from chemical biology to materials science. It relies on dynamic covalent bonds that are able to form in a reversible manner in mild conditions, and therefore requires the discovery of new types of these bonds in order to progress. Amides, due to their high stability, have been scarcely used in this field and typically require an external catalyst or harsh conditions for exchange. Compounds able to undergo uncatalysed transamidation at room temperature are still rare exceptions. In this work, we describe reversible amide formation and transamidation in a class of compounds known as maleamic acids. Due to the presence of a carboxylic acid in β-position, these compounds are in equilibrium with their anhydride and amine precursors in organic solvents at room temperature. First, we show that this equilibrium is responsive to external stimuli: by alternating the additions of a Brønsted acid and a base, we can switch between amide and anhydride several times without side-reactions. Next, we prove that this equilibrium provides a pathway for reversible transamidation without any added catalyst, leading to thermodynamic distributions of amides at room temperature. Lastly, we use different preparation conditions and concentrations of Brønsted acid to access different library distributions, easily controlling the transition between kinetic and thermodynamic regimes. Our results show that maleamic acids can undergo transamidation in mild conditions in a reversible and tunable way, establishing them as a new addition to the toolbox of dynamic combinatorial chemistry.

Nature, Published online: 27 April 2022; doi:10.1038/s41586-022-04599-z

Untreated, postconsumer-PET from 51 different thermoformed products can all be almost completely degraded by FAST-PETase in 1 week and PET can be resynthesized from the recovered monomers, demonstrating recycling at the industrial scale.

Nature, Published online: 27 April 2022; doi:10.1038/s41586-022-04516-4

A study demonstrates that nitrous oxide can act as the source of O in a catalytic conversion of aryl halides to phenols, releasing N2 as by-product.