LongLarf

Synthesis
DOI: 10.1055/a-2109-1642

The synthesis of complex polycycles starting from simple building blocks in just a few reaction steps is usually very challenging. Herein, we present the gold(I)-catalyzed synthesis of various polycycles via the dearomatization–allenene reaction of aryl propargyl ethers with different nucleophiles. Depending on the starting material, polycycles can be isolated in yields up to 94% and with an enantiomeric excess of 95%. Quantum chemical calculations show that for all starting materials a Claisen rearrangement to the allenene occurs in the first reaction sequence. The subsequent cyclization and reaction with a nucleophile leads to various polycycles with the formation of up to six new C–C bonds in only one reaction step. All reactions proceed with excellent dia­stereoselectivity, with an α-quaternary carbonyl carbon present in the products.
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

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Nature Catalysis, Published online: 20 July 2023; doi:10.1038/s41929-023-00986-5

Controlling the stereoselectivity in free-radical-mediated reactions is challenging. Now, a metalloredox biocatalysis strategy is reported that uses engineered cytochrome P450 enzymes for the unnatural asymmetric radical cyclization of α-haloesters to arenes.

Bivalent ligands can engage homodimeric protein targets with high affinity due to avidity effects. This study shows that compounds conjugated to a masked formyl acetamide can be coupled efficiently and conveniently through trifluoroacetic acid (TFA)-catalyzed pyridone formation. In most cases, the product is produced in nearly quantitative yield and in excellent purity. The reaction is tolerant of a wide range of functional groups.

Abstract

Many proteins exist as oligomers (homodimers, homotrimers, etc.). A proven strategy for the development of high affinity ligands for such targets is to link together two modest affinity ligands that allows the formation of a 2 : 2 (or higher-order) protein-ligand complex. We report here the discovery of a convenient, “click-like” reaction for the homodimerization of protein ligands that is efficient, operationally simple to carry out, and tolerant of many functional groups. This chemistry reduces the synthetic burden inherent in the creation of homodimeric ligands since only a single precursor is required. The utility of this strategy is demonstrated by the synthesis of homodimeric inhibitors, including PROTACs.

Nature Chemical Biology, Published online: 13 July 2023; doi:10.1038/s41589-023-01387-2

Tian et al. developed a bacterial orthogonal DNA replication system by harnessing the temperate phage GIL16 DNA replication machinery, which provides a powerful tool for continuous evolution in prokaryotic cells.

Nature Reviews Chemistry, Published online: 11 July 2023; doi:10.1038/s41570-023-00517-7

Late-stage modification of peptides with photoactivatable groups often weakens their binding interaction with target proteins. Now, this challenge has been addressed using large libraries of cyclic peptides with photocrosslinkers incorporated prior to screening.

Abstract

With the aim of achieving bioorthogonal intracellular catalysis, a library of platinum(II) complexes was synthesized. Their non-toxicity to living cells was demonstrated and their catalytic activity was evaluated on a cyclization reaction leading to a highly fluorescent coumarin. None of the platinum complexes showed any catalytic activity for coumarin synthesis. Still, we demonstrated that the silver salt AgSbF₆ commonly used to ‘activate’ metal catalysts by removing a chloride is a very efficient catalyst for the studied intramolecular cyclization reaction.

Two-component peptide stapling is an appealing method for preparing enzymatically stable peptides with incorporated biologically relevant tags. An unprecedented approach, utilising the tryptophan-mediated multicomponent Petasis reaction (TMPR), facilitates the generation of stapled peptides and enables their late-stage functionalisation. A variety of examples are presented to highlight the advantages of the method.

Abstract

Peptide stapling is a robust strategy for generating enzymatically stable, macrocyclic peptides. The incorporation of biologically relevant tags (such as cell-penetrating motifs or fluorescent dyes) into peptides, while preserving their binding interactions and enhancing their stability, is highly sought after. Despite the unique opportunities offered by tryptophan‘s indole scaffold for targeted functionalisation, its utilisation in peptide stapling has been limited as compared to other amino acids. Herein, we present an approach for peptide stapling using the tryptophan-mediated Petasis reaction. This method enables the synthesis of both stapled and labelled peptides and is applicable to both solution and solid-phase synthesis. Importantly, the use of the Petasis reaction in combination with tryptophan facilitates the formation of stapled peptides in a straightforward, multicomponent fashion, while circumventing the formation of undesired by-products. Furthermore, this approach allows for efficient and diverse late-stage peptide modifications, thereby enabling rapid production of numerous conjugates for biological and medicinal applications.

Peptide-mimic phosphonium salt catalysts, a judicious combination of ion-pair elements with peptide scaffolds that bear multiple hydrogen-bonding donors, have captivated considerable attention for their unprecedented performance in a plethora of enantioselective transformations, in many cases enabling never-before-seen patterns of reactivity and selectivity. In this context, we provide a succinct overview of recent progress in this field.

Abstract

Chiral phosphonium salt catalysis, traditionally classified as a type of phase transfer catalysis, has proven to be a powerful strategy for the stereoselective preparation of diverse optically active molecules. However, there still remain numerous forbidding issues of reactivity and selectivity in such well-known organocatalysis system. Accordingly, the development of new and high-performance phosphonium salt catalysts with unique chiral backbones is highly desirable, yet challenging. This Minireview describes the prominent endeavours in the development of a new family of chiral peptide-mimic phosphonium salt catalysts with multiple hydrogen-bonding donors and their applications in a plethora of enantioselective synthesis during the past few years. Hopefully, this minireview will pave a way for further developing much more efficient and privileged chiral ligands/catalysts featuring exclusively catalytic ability in asymmetric synthesis.

Nature Catalysis, Published online: 13 July 2023; doi:10.1038/s41929-023-00979-4

The direct regioselective oxidation of internal alkenes to ketones poses an important synthetic challenge. Now, directed evolution of a cytochrome P450 enzyme affords a ketone synthase that can efficiently oxidize internal arylalkenes directly to ketones with high chemo- and regioselectivity.

Nature Catalysis, Published online: 22 June 2023; doi:10.1038/s41929-023-00959-8

Hydrogen carriers play an important role in the hydrogen economy. Now, methyl formate is proposed as a suitable chemical hydrogen source for a carbon-neutral hydrogen energy cycle, and faster catalytic hydrogen production rates are achieved compared with those from the widely investigated formic acid and methanol.

Nature, Published online: 26 June 2023; doi:10.1038/s41586-023-06347-3

Functional Group Translocation of Cyano Groups by Reversible C–H Sampling

Nature Reviews Chemistry, Published online: 21 June 2023; doi:10.1038/s41570-023-00505-x

The development of radical sulfurating reagents, which react with carbon-centred radicals to install a variety of organosulfur motifs in a highly selective manner, circumvents the need to preserve these often-vulnerable moieties through lengthy syntheses.

Nature Chemistry, Published online: 03 July 2023; doi:10.1038/s41557-023-01252-8

An enzymatic reaction installs endogenous β-amino acids in proteins with unique reactivity. Now it has been shows that this reaction can be used for site-specific modification with tetrazine dienophiles to introduce labels onto target proteins. Applications include generation of a radiolabel chelator-modified Her2-binding Affibody and intracellular, fluorescently labelled cell division protein FtsZ.

Biocatalysis is a powerful tool to achieve selective modifications on peptides with strong potential in the development of pharmaceuticals and in biological research. This review focuses on amino acid residue-specific enzymes with broad substrate tolerance as well as their nonnative substrates. These enzymes have enabled the modification of a wide range of peptides and proteins at late-stage.

Abstract

The late-stage functionalization of peptides and proteins holds significant promise for drug discovery and facilitates bioorthogonal chemistry. This selective functionalization leads to innovative advances in in vitro and in vivo biological research. However, it is a challenging endeavor to selectively target a certain amino acid or position in the presence of other residues containing reactive groups. Biocatalysis has emerged as a powerful tool for selective, efficient, and economical modifications of molecules. Enzymes that have the ability to modify multiple complex substrates or selectively install nonnative handles have wide applications. Herein, we highlight enzymes with broad substrate tolerance that have been demonstrated to modify a specific amino acid residue in simple or complex peptides and/or proteins at late-stage. The different substrates accepted by these enzymes are mentioned together with the reported downstream bioorthogonal reactions that have benefited from the enzymatic selective modifications.

Nature, Published online: 20 June 2023; doi:10.1038/d41586-023-01980-4

By modifying the blueprint of life, researchers are endowing proteins with chemistries they’ve never had before.