Synthesis and enabling technologies

The metalloenzyme SznF catalyses the formation of an N–N bond in the biosynthesis of streptozotocin, providing insights into the enzymatic assembly of an N-nitroso group.

Analysis of two homologous groups of fungal pericyclases demonstrates how they can catalyse either an Alder-ene reaction—which has not previously been found in nature—or a hetero-Diels–Alder reaction.

A prebiotic synthesis of the purine DNA nucleosides (deoxyadenosine and deoxyinosine) in which the pyrimidine RNA nucleosides (cytidine and uridine) persist has implications for the coexistence of DNA and RNA at the dawn of life.

A manganese-catalysed oxidative C(sp³)–H methylation method allows a methyl group to be selectively installed into medicinally important heterocycles, providing a way to improve pharmaceuticals and better understand the ‘magic methyl effect’.

Nitrogen is ‘deleted’ from secondary amines using anomeric amide reagents, which react with the amine to form an isodiazene, after which nitrogen gas is released and the resulting carbon radicals combine to form a carbon–carbon bond.

Selective borylation of azines—nitrogen-containing aromatic heterocycles used in the synthesis of many pharmaceuticals—is made possible by forming a radical from an aminoborane using a photocatalyst.

The synthesis of aziridines—three-membered nitrogen-containing heterocycles—is achieved by a new method involving the electrochemical coupling of alkenes and amines, via a dicationic intermediate.

Inverting the order of nature’s two-phase biosynthesis of terpenes offers a strategy by which the synthesis of these compounds can be simplified. The key reaction is a palladium-catalysed polyenyne cycloisomerization that not only tolerates the presence of all of the oxygen functionalities but also is facilitated by them.

In an effort to extend the important hydroformylation reaction, a palladium-catalysed carboformylation reaction has now been developed in which two new carbon–carbon bonds are created across an alkyne. This modular reaction relies on a CO shuffling process and uses an acid chloride as a dual carbon and CO source.

Although azetidines represent highly desirable building blocks in drug discovery, methods for their efficient and straightforward synthesis remain underdeveloped. Now, it has been shown that highly functionalized azetidines can be prepared via an intermolecular [2+2] photocycloaddition reaction between cyclic oximes and alkenes, in a process enabled by a visible-light-mediated triplet energy transfer.

The synthesis of chiral amino alcohols from simple alcohol starting materials can be achieved through a catalytic, asymmetric radical relay. Multiple catalysts work in concert to harness a H-atom transfer mechanism to enable enantio- and regioselective C–H amination by transient N-centred radicals.

O-methyl nitronate is a rare functional group in natural products. Now, the biosynthetic pathway to O-methyl nitronate, which involves O-methylation of a peptidyl carrier protein (PCP)-tethered nitronate, has been revealed. In some bacteria, the same PCP-tethered nitronate is shown to be oxidized by nitronate monooxygenases to provide nitrite and a PCP-tethered glyoxylate.

A cell-free system for cannabinoid production uses only low-cost inputs with 12 enzymes and can operate either aerobically or anaerobically, in addition to reducing ATP requirements by use of an engineered system for malonate-CoA biosynthesis.

General methods to regioselectively introduce both amine and alcohol functionalities into alkene substrates to afford 1,2-aminoalcohols in a single step are lacking. Now, this has been addressed by a metal-free photosensitization strategy using oxime carbonate as a suitable bifunctional reagent.

Controlling the regioselectivity in the coupling of simple aromatics is challenging. Now, para–para selectivity is achieved during the aerobic dehydrogenative homocoupling of arenes through a shape-selective catalyst based on molecular palladium confined within the framework of zeolite materials.

Enantioselective oxidative cross-coupling of unactivated C(sp³)−H bonds and terminal alkynes is challenging. Here, the authors developed a copper/cinchona alkaloid catalyst for the asymmetric Sonogashira-type alkynylation of C(sp³)-H bonds via radical intermediates.

Cross-coupling processes without the use of transition metals are challenging to achieve. Here, the authors show a transition-metal-free cross-coupling utilizing aryl(heteroaryl) methyl sulfoxides and alcohols to afford alkyl aryl(heteroaryl) ethers and propose a nucleophilic addition mechanism based on experiments and theory.

Several Hasubanan alkaloids have been synthesized in the past decades, however a divergent approach to access the 3 subclasses of such natural products has not been reported yet. Here, the authors show the enantioselective total syntheses of four representative members via a unified strategy leading to the three topologically different classes of alkaloids.

α-Pyridones and α-pyrones are ubiquitous structural motifs found in natural products and components of biologically active small molecules. Here, the authors report an oxidant-free Rh-catalyzed electrochemical divergent vinylic C–H annulation of acrylamides with alkynes to α-pyridones and cyclic imidates.

Alkyne metathesis catalysts usually suffer from high moisture/air sensitivity, which limit their wide applicability. Here, the authors report efficient alkyne metathesis catalysts that can operate under open-air conditions with a broad functional group tolerance.

The biosynthesis of inorganic nanomaterials in microorganisms is an environmentally friendly alternative to chemical synthesis. This Review describes the engineering of microorganisms to rationally prepare nanomaterials for diverse applications.

Discovery and application of enzymes that catalyse new reactions is essential for broad implementation of biocatalysts in organic synthesis. This Review describes recent developments in biocatalytic carbon–carbon bond formation.

Silyl-substituted silicon–carbonyl complexes that are stable at room temperature have been prepared by exposure of highly reactive bis(silyl)silylenes to carbon monoxide. The compounds show structural features and reactivity that are reminiscent of their ubiquitous transition-metal–carbonyl counterparts, including π-backbonding and ligand liberation as well as substitution and functionalization reactions.

The vast majority of species capable of converting dinitrogen to ammonia rely on transition metals. Now, a boron compound has been shown to mediate the one-pot binding, cleavage and reduction of N₂ to ammonium salts under mild conditions through a complex cascade mechanism involving multiple reduction–protonation sequences.

A wide variety of organic and inorganic compounds show π-aromaticity, yet for all-metal systems it has remained restricted to compounds with three to five atoms. Now, the anionic cluster [Th@Bi₁₂]⁴⁻ has been shown to exhibit π-aromaticity, with a significant ring current despite relying on the delocalization of only two π-electrons.

Unlike ferrocene and its cationic counterpart ferrocenium, the ferrocene monoanion is an unusual species that has been observed through low-temperature electrochemical studies. Now, a family of isostructural 3d metallocenates has been isolated that consists of a manganocene, a cobaltocene and a high-spin ferrocene anion stabilized by cyclopentadienyl ligands bearing bulky aliphatic groups.

Metallocenes are attractive mechanophores because they are stable in the absence of force, yet reactive under tension. Now, covalently bridging the two cyclopentadienyl (Cp) ligands of ferrocenes embedded in a polymer has been shown to alter their mechanochemical reactivity, leading to a faster dissociation of the Fe–Cp bond, which occurs through a peeling mechanism rather than a shearing one.

It is difficult to investigate the chemical properties of superheavy elements, which are only available an atom at a time and rapidly decay. A co-precipitation method with samarium has now been developed that suggests rutherfordium would form hydroxide precipitates—but not ammine ones—if it were possible to perform these experiments on macroscopic quantities.

Although iron–sulfur cofactors are known to carry out biological nitrogen fixation, how these clusters bind dinitrogen remains poorly understood. Now, a dinitrogen complex of a synthetic iron–sulfur cluster has been characterized, and electronic cooperation in the cluster has been shown to result in strong N–N bond activation.

Obtaining mechanistic data after the rate-determining step of a chemical reaction is difficult but essential for its understanding. Now, a Ru(iv) side-on peroxo complex has been isolated following the rate-determining step of the water oxidation reaction (O–O bond formation) carried out using a Ru-based molecular catalyst.

The ammonia was synthesized under ambient conditions via a mechanochemical method, reaching a final concentration of 82.5 vol%.

Nitrous-oxide-mediated oxidation reactions can be effectively promoted by iron-containing zeolites, although structural information on the interaction between oxidant and metal centre is limited. Here, the authors report the characterization of the N₂O-ligated Fe(ii) active site in iron-exchanged zeolite beta.

Manganese-based hydrogenation catalysts are sensitive to high temperatures and may degrade under industrially relevant conditions. Here, the authors report a highly efficient manganese pincer pre-catalyst displaying high TOF values (up to 41 000 h⁻¹) and stability (TON up to 200 000) at loadings as low as 5-200 ppm.

Realizing ultra-high work functions (UHWFs) in hole-doped polymer semiconductors remains a challenge due to water-oxidation reactions. Here, the authors determine the role of water-anion complexes in limiting the work function and develop a design strategy for realizing UHWF polymers.

Heteroepitaxy is used to precisely control the growth of Mn₃O₄ shells on the faces of a Co₃O₄ nanocube crystal, producing uniform grain boundary defects and highly ordered multigrain nanostructures.

An anion and metal ion template is used to form woven polymer patches that are joined together by polymerization into a fully woven, two-dimensional, molecular patchwork.

A simple but flexible technique based on a capillary-force-driven rolling-up process produces high-order van der Waals superlattices that are hard to produce with existing fabrication techniques.

Two-dimensional MOFs can possess porosity and electrical conductivity but are difficult to grow as single crystals. Here, by balancing in-plane and out-of-plane interactions, single crystals of sizes up to 200 µm are grown, allowing in-plane transport measurements and atomic-resolution analysis.

Polycarbonates and polyesters with materials properties like those of high-density polyethylene can be recycled chemically by depolymerization to their constituent monomers, re-polymerization yielding material with uncompromised processing and materials properties.

The copolymerization of CO₂ with epoxides is an attractive approach for valorizing waste products and improving sustainability in polymer manufacturing. Now, a heterodinuclear Mg(ii)Co(ii) complex has been shown to act as a highly active and selective catalyst for this reaction at low CO₂ pressure. The synergy between the two metals was investigated using polymerization kinetics.

Layered COFs are attractive precursors for two-dimensional materials but they are difficult to cleave into mono- or few-layer sheets. Pseudorotaxane moieties have now been embedded into layered COFs to facilitate their cleavage into sheets of uniform thickness. Crown-ether macrocycles within the COF backbone bind to ionic viologen guests, leading to electrostatic repulsion between layers.

Fluorinated polyacetylene has typically proven to be inaccessible using traditional polymer synthesis, but there is much interest in its predicted properties. Now, a mechanochemical unzipping strategy has succeeded in the synthesis of a gold-coloured, semiconducting fluorinated polyacetylene with improved stability in air compared to polyacetylene.

Iron-catalysed [2+2] cycloaddition/oligomerization of neat butadiene affords (1,n′-divinyl)oligocyclobutane—a telechelic, crystalline material consisting of 1,3-enchained cyclobutyl units. This oligocyclobutane can be chemically recycled to pure butadiene using the same iron catalyst employed in its synthesis, demonstrating design principles for next-generation plastic materials that can be returned to pristine monomer.

Lustrous flexible thin films of semiconducting cyclic polyacetylene (c-PA) have been synthesized and characterized. Rapid and efficient tungsten-catalysed acetylene polymerization conditions produce temporarily soluble c-PA, enabling the in situ derivatization of this typically insoluble polymer. Compelling evidence for the cyclic topology—and its influence on the physical properties of the polymer—are presented.

Multi-element oxide catalysts can feature superior properties compared with their single-element analogues but obtaining such complex structures remains a challenge. Here, a method is reported to access single-phase denary nanoparticles as stable and efficient catalysts for the combustion of methane.

Constructing molecular cages from entangled molecules is a complex task requiring precise topological control. Here, the authors thread together six metal-peptide rings into a giant cubic molecular capsule with a defined cavity and 24 crossover points.

The controllable synthesis of organometallic polymers that can be used in ultrahigh information storage and anti-counterfeiting security has been an unsolved challenge. Here, the authors show sequence-controlled electrosynthesis of organometallic polymers with exquisite insertion of multiple and distinct monomers.

The introduction of shape anisotropy at the nanoscale is a potent way to access new properties and functionalities. This Review appraises different methods for the bottom-up synthesis of anisotropic nanoparticles, and highlights the unique properties and applications of these materials with otherwise inaccessible functionality.

The self-assembly of biomimetic peptides can mimic complex natural systems involving whole proteins. This Review describes how synthetic peptides afford tunable scaffolds for biomineralization, drug delivery and tissue growth.

Incorporating the mechanical bond into polymer architectures allows access to polymers with high-mobility elements, leading to unique material properties. This Review outlines the structure–property relationships of materials based on either polyrotaxanes (including slide-ring materials and daisy-chain polymers) or polycatenanes, and looks towards future applications and technologies.

An automated synthesis instrument comprising a series of continuous flow modules that are radially arranged around a central switching station can achieve both linear and convergent syntheses.

A mobile robot autonomously operates analytical instruments in a wet chemistry laboratory, performing a photocatalyst optimization task much faster than a human would be able to.

A synthetic route-planning algorithm, augmented with causal relationships that allow it to strategize over multiple steps, can design complex natural-product syntheses that are indistinguishable from those designed by human experts.

Bayesian optimization is applied in chemical synthesis towards the optimization of various organic reactions and is found to outperform scientists in both average optimization efficiency and consistency.

Automated synthesis technologies are often highly specialized, focusing only on a narrow set of reaction classes. Now, solid-phase peptide synthesis, iterative Suzuki–Miyaura cross-coupling and diazirine chemistry have all been automated using the same universal platform architecture. A convergent 12-step synthesis demonstrates the utility of the reported Chemputer system.

Organic chemical reactions can be divided into classes that allow chemists to use the knowledge they have about optimal conditions for specific reactions in the context of other reactions of similar type. Schwaller et al. present here an efficient method based on transformer neural networks that learns a chemical space in which reactions of a similar class are grouped together.

After a difficult start, medicinal chemists are now ready to embrace AI-based methods and concepts in drug discovery, explains Gisbert Schneider.

Translating discovery scale vial-based batch reactions to continuous flow scale-up conditions is limited by significant time and resource constraints. Here, the authors report a photochemical droplet microfluidic platform, which enables high throughput reaction discovery in flow to generate pharmaceutically relevant compound libraries.

Predictive computational approaches are fundamental to accelerating solid-state inorganic synthesis. This work demonstrates a computational tractable approach constructed from available thermochemistry data and based on a graph-based network model for predicting solid-state inorganic reaction pathways.

Although strategies for the automated assembly of compounds of pharmaceutical relevance is a growing field of research, the synthesis of small-molecule pharmacophores remains a predominantly manual process. Now, an automated six-step synthesis of prexasertib is achieved by multistep solid-phase chemistry in a continuous-flow fashion using a chemical recipe file that enables automated scaffold modification through both early and late-stage diversification.