Research articles

A set of enantioprobes—photoreactive, clickable fragment pairs differing only in absolute stereochemistry—have been used to provide a robust and streamlined chemical proteomic map of small-molecule/protein interactions in human cells. More than 170 stereoselective fragment–protein interactions were discovered and shown to occur at functional sites on proteins from diverse classes.

Ring-opening metathesis polymerization of norbornene-based (macro)monomers produces macromolecules with diverse compositions and complex architectures that cannot be degraded easily. Now, it has been shown that a class of eight-membered cyclic bifunctional silyl ether-based monomers copolymerize efficiently with norbornene-based (macro)monomers, providing a range of copolymers with tunable degradability under mildly acidic aqueous conditions.

Tuning the selectivity for [2+2] photocycloadditions remains challenging. Now, triplet–triplet energy transfer from CdSe quantum dots enables the homo- and heterocouplings of 4-vinylbenzoic acid derivatives via [2+2] photocycloaddition. Preorganization of substrates on the quantum dots reverses intrinsic stereoelectronic preferences to yield cyclobutane products with unprecedented diastereo- and regioselectivity.

Asymmetric Sonogashira C(sp³)–C(sp) couplings provide complementary approaches to established C(sp³)–C(sp²/sp³) couplings for chiral C–C bond formation; however, relatively few reactions have been developed. Now, a versatile, enantioconvergent Sonogashira coupling via a radical intermediate has been developed. The approach uses a copper catalyst featuring a multidentate electron-rich cinchona alkaloid-derived ligand.

The oxidation of water remains the kinetic bottleneck of solar-to-fuel synthesis. Now, spectroelectrochemical evidence together with density functional theory calculations show that charge accumulation determines the reaction mechanism on metal–oxide photoanodes. These insights reveal features that are common to the mechanisms of water oxidation carried out by other inorganic and biological systems.

Generating stable single-atom catalysts is far from straightforward and can involve complicated preparation procedures. Now, mononuclear gold oxo-clusters formed in alkaline solutions through a facile one-pot synthesis are shown to catalyse the heterogeneous methanol self-coupling reaction to methyl formate and hydrogen. The intrinsic activity is the same for both supported and unsupported gold catalysts.

The isoelectronic series of alanes [R₃Al] and silylium cations [R₃Si]⁺ has now been extended with the synthesis and characterization of two phosphorandiylium dications ([R₃P]²⁺), which are trigonal planar Lewis superacids. The electrophilicity at the phosphorus atom is governed by the π-electron-donating ability of the attached N-heterocyclic imine substituents.

A flavin-dependent halogenase with a remarkable preference for iodination has now been discovered. The halogenase (VirX1) was discovered using a bioinformatics-based approach and comes from a cyanophage. Structural characterization and kinetic studies show that VirX1 possesses broad substrate tolerance, making it an attractive tool for synthesis.

The four-coordinate iron sites of typical iron–sulfur clusters rarely react with small molecules, implicating three-coordinate iron in many catalytic cycles. Now, a [4Fe-3S] cluster featuring three-coordinate iron sulfide that resembles the proposed substrate binding site has been synthesized. This cluster shows biomimetic reactivity with a low-spin electronic configuration.

Stereoselective functionalization of C(sp³)–H bonds could greatly simplify the construction of complex molecular scaffolds. Now, a series of enzyme catalysts derived from a cytochrome P450 have been developed using directed evolution. The catalysts enable the enantioselective amination of primary, secondary and tertiary C(sp³)–H bonds.

Phase-forming conversion chemistry, like that observed in Li–S and Li–O₂ batteries, shows great promise, but these systems suffer some drawbacks, such as practically low cathode areal capacities and electrolyte decomposition. Now, high-energy conversion battery chemistry—based on nitrate/nitrite redox where one of the products is soluble—has been enabled by using nanoparticulate Ni/NiO electrocatalysts.

The electronic structures of the metal cofactors of nitrogenase are key to biological nitrogen fixation; however, the [Fe₈S₇] P-cluster and FeMo cofactor have eluded detailed electronic characterization. Now, the electronic structure of the P-cluster of nitrogenase has been revealed at the many-electron level through exhaustive quantum wavefunction simulations.

Quantum teleportation moves the quantum state of a system between physical locations without losing its coherence, an essential criterion for emerging quantum information applications. Now, electron-spin-state teleportation in covalent organic electron donor–acceptor–stable radical molecules is demonstrated using entangled electron spins produced by photo-induced electron transfer.

Enacyloxin IIa is an antibiotic, assembled by a modular polyketide synthase, with promising activity against the Gram-negative bacterium Acinetobacter baumannii. Now, it has been shown that the enacyloxin IIa polyketide chain is released via transfer to a separately encoded carrier protein by a non-elongating ketosynthase domain, followed by condensation with 3,4-dihydroxycyclohexane carboxylic acid by a non-ribosomal peptide synthetase condensation domain.

Asymmetric autocatalysis—such as that observed experimentally in the Soai reaction—may have been responsible for the origin of biological homochirality. The magnitude of the energy imbalance required to induce directed symmetry breaking and asymmetric amplification in the Soai reaction has now been identified and compared to the parity violation energy difference.

Current photodynamic therapy photosensitizers require oxygen; however, tumours are often hypoxic. Now, an organoiridium complex with an unusually high redox potential, which is effective in normoxia and hypoxia, has been developed. The organoiridium complex kills cancer cells by an immunogenic apoptotic mechanism involving efficient photocatalytic oxidation of NADH to NAD radicals, and reduction of cytochrome c.

The antibiotic enacyloxin IIa is assembled by a modular polyketide synthase, and released from it by condensation of the enacyloxin acyl chain with 3,4-dihydroxycyclohexane carboxylic acid. A multipronged approach shows the structural basis for recognition between the peptidyl carrier protein domain that bears the acyl chain and the non-ribosomal peptide synthetase condensation domain that ligates it with the carboxylic acid.

Precolibactin 886 is a complex microbiome-derived metabolite implicated in colorectal cancer and produced by the clb gene cluster. A chemical synthesis and analysis of precolibactin 886 is reported which shows that its biosynthetic precursor degrades to other known clb metabolites. The data also provide insights into the structures and reactivity of advanced clb products.

The complete biosynthesis of the fungal indole alkaloid malbrancheamide, which culminates in an intramolecular [4+2] hetero-Diels–Alder cyclization to produce the bicyclo[2.2.2]diazaoctane scaffold, has now been discovered. Chemical synthesis and protein structural analysis were used to provide mechanistic insight into this enzyme-dependent diastereo- and enantioselective cycloaddition.

Difluorocarbene transfer is mostly limited to reactions that utilize its intrinsic electrophilicity. Now, a controllable palladium-catalysed difluorocarbene transfer reaction is reported that involves nucleophilic and electrophilic palladium difluorocarbene species. The selective reactions between arylboronic acids and the difluorocarbene precursor BrCF₂PO(OEt)₂ give four different products—difluoromethylated and tetrafluoroethylated arenes and their corresponding fluoroalkylated ketones.