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  • Plant asparaginyl endopeptidases that function preferentially as transpeptidases naturally catalyse the head-to-tail cyclization of plant peptides. Using substrate mimicry and reaction optimization, their function has now been repurposed to catalyse intermolecular isopeptide bond formation on diverse peptide and protein substrates.

    • Fabian B. H. Rehm
    • Tristan J. Tyler
    • Thomas Durek
    ArticleOpen Access
  • Although functionalized cyclopropenes have found uses in many applications, their synthesis has been severely limited. Now, a hypervalent iodine reagent, in conjunction with gold catalysis, has been utilized to control their reactivity, allowing efficient formation of cyclopropenyl alkynes/alkenes.

    • Sayad Doobary
    • Berit Olofsson
    News & Views
  • The σ-type cyclopropenium cations (CPCs) are unstable species and currently underdeveloped. Now, an iodine(III)-based cyclopropenyl transfer reagent has been developed, which can generate electrophilic cyclopropenyl-gold(III) species as equivalents of σ-type CPCs. The synthetic potential has been demonstrated by the transfer of σ-type CPCs to terminal alkynes and vinylboronic acids.

    • Xiangdong Li
    • Matthew D. Wodrich
    • Jérôme Waser
    ArticleOpen Access
  • Electrophilic halogenation approaches often suffer from low reactivity and chemoselectivity when it comes to complex compounds. Now a class of halogenating reagents based on anomeric amides that can halogenate complex bioactive molecules with diverse functional groups and heterocycles has been developed. The higher reactivity of these anomeric amide reagents is attributed to the energy stored in the pyramidalized nitrogen.

    • Yu Wang
    • Cheng Bi
    • Phil S. Baran
  • Liquid droplets form in cells to concentrate specific biomolecules (while excluding others) in order to perform specific functions. The molecular mechanisms that determine whether different macromolecules undergo co-partitioning or exclusion has so far remained elusive. Now, two studies uncover key principles underlying this selectivity.

    • Michael Phillips
    • Kingshuk Ghosh
    News & Views
  • The synthesis of cationic all-metal aromatic systems without covalent functionalization remains an underexplored area in chemistry. Now a tetracationic [Bi4]4+ featuring all-metal σ-aromaticity has been stabilized through a supramolecular approach relying on dianionic calix[4]pyrrolato indiumbromide shells. This planar rhomboid represents the global minimum for 16 valence electron systems.

    • Ravi Yadav
    • Avijit Maiti
    • Lutz Greb
    ArticleOpen Access
  • Multi-payload antibody–drug conjugates (ADCs) are an emerging class of targeted therapeutics. Comprising a monoclonal antibody with multiple unique payloads attached, these constructs have the potential to produce synergistic anticancer effects with reduced therapeutic resistance. In this Review, methods for generating multi-payload ADCs are discussed, highlighting some key preclinical results.

    • Toby Journeaux
    • Gonçalo J. L. Bernardes
    Review Article
  • The chemistry of beryllium, one of the periodic table’s lightest elements, remains poorly understood. Now, a nucleophilic beryllium complex with a highly polarized Be–Be bond has been prepared—this compound could be seen as a mixed-oxidation state Be(0)/Be(II) complex. The Be–Be bond is cleaved upon reaction with an organic substrate.

    • Josef T. Boronski
    • Agamemnon E. Crumpton
    • Simon Aldridge
    ArticleOpen Access
  • Engineering new ligands that specifically target multiple G protein-coupled receptors with desired activity profiles requires time-consuming and expensive cycles of design-make-test-analyse work. Now it has been shown that limited experimental data can be used to train sophisticated machine learning models to accurately predict the activity of previously uncharacterized peptide ligand variants.

    • Anna M. Puszkarska
    • Bruck Taddese
    • Lucy J. Colwell
    ArticleOpen Access
  • Understanding how membrane-bound styrene oxide isomerase (SOI) catalyses the Meinwald rearrangement—a Lewis-acid-catalysed isomerization of an epoxide to a carbonyl compound—can be useful as SOI represents a green alternative to chemical synthesis. Here, the catalytic mechanism of SOI was determined using cryo-EM, EPR spectroscopy, mutagenesis, functional assays and docking experiments.

    • Basavraj Khanppnavar
    • Joel P. S. Choo
    • Xiaodan Li
    ArticleOpen Access
  • Calcium difluoride is a source of fluorochemicals, but the reactivity of Ca–F moieties is not well understood. Now a library of molecular Ca–F complexes featuring unique structural motifs has been synthesized, including via fluorochemical defluorination. Studies of mono- and dinuclear systems provided structure–activity relationships for E–F bond formation.

    • Job J. C. Struijs
    • Mathias A. Ellwanger
    • Simon Aldridge
    ArticleOpen Access
  • Dimetallocenes are a narrow class of compounds represented by the homobimetallic examples dizincocene and diberyllocene. Now a heterobimetallic dimetallocene featuring lithium and aluminium centres has been synthesized. The Al–Li bond is shown to cleave upon reaction with N-heterocyclic carbenes and heteroallenes.

    • Inga-Alexandra Bischoff
    • Sergi Danés
    • André Schäfer
    ArticleOpen Access
  • John Steele and Stephen Wallace discuss recent advances in the chemical and biotechnological synthesis of the prolific platform chemical adipic acid.

    • John F. C. Steele
    • Stephen Wallace
    In Your Element
  • Chiral sulfur pharmacophores are crucial in drug discovery, but the controlled synthesis of sulfinamides with stereogenic-at-sulfur(IV) centres is a long-standing challenge. Now a method for the catalytic asymmetric synthesis of sulfinamides and sulfinate esters has been developed that features the acyl transfer sulfinylation of diverse nucleophiles, including aromatic amines and alcohols, using chiral 4-arylpyridine N-oxides as catalysts.

    • Tao Wei
    • Han-Le Wang
    • Hai-Ming Guo
  • Fusicoccane diterpenoids are complex natural products with intricate tricyclic skeletons and intriguing biological activities. Now a chemoenzymatic strategy has been developed for modularly synthesizing a number of compounds from the family. This approach combines de novo skeletal construction and hybrid C–H oxidations, allowing the synthesis of ten different natural products.

    • Yanlong Jiang
    • Hans Renata
  • The number of known high-oxidation-state transuranic compounds remains limited, and these typically feature high coordination numbers and/or multiply-bonded donor atoms. Now, a tetrahedral, pentavalent neptunium complex supported by four monoanionic ligands has been isolated and characterized. This complex is stable in the solid state and undergoes a proton-coupled electron transfer reaction in solution.

    • Julie E. Niklas
    • Kaitlyn S. Otte
    • Henry S. La Pierre
  • Evolution separates complex modern enzymes from their hypothetical simpler early ancestors, which raises the question of how unevolved sequences can develop new functions. Here a library of non-natural protein sequences was subjected to ultrahigh-throughput screens in microfluidic droplets, leading to the isolation of a phosphodiesterase enzyme capable of hydrolysing the biological second messenger, cyclic AMP.

    • J. David Schnettler
    • Michael S. Wang
    • Michael H. Hecht
    ArticleOpen Access
  • Two-dimensional covalent organic frameworks (2D COFs) enable the construction of bespoke functional materials, but designing dynamic 2D COFs is challenging. Now it has been shown that perylene-diimide-based COFs can open and close their pores upon uptake or removal of guests, while fully retaining their crystalline long-range order. Moreover, the variable COF geometry enables stimuli-responsive optoelectronic properties.

    • Florian Auras
    • Laura Ascherl
    • Thomas Bein
  • A robust organometallic platform is developed for stoichiometric cross-couplings of common aryl and alkyl electrophiles under a single set of conditions. Inexpensive and persistent organonickel complexes are prepared by electrolysis and implemented in the diversification of drug-like molecules with high reliability from a diverse set of alkyl precursors.

    • Long P. Dinh
    • Hunter F. Starbuck
    • Christo S. Sevov