Explore the vast range of titles available.

(+)-Perseanol is an isoryanodane diterpene that is isolated from the tropical shrub Persea indica 1 and has potent antifeedant and insecticidal properties. It is structurally related to (+)-ryanodine, which is a high-affinity ligand for and modulator of ryanodine receptors—ligand-gated ion channels that are critical for intracellular Ca 2+ signalling in most multicellular organisms 2 . Ryanodine itself modulates ryanodine-receptor-dependent Ca 2+ release in many organisms, including mammals; however, preliminary data indicate that ryanodane and isoryanodane congeners that lack the pyrrole-2-carboxylate ester—such as perseanol—may have selective activity in insects 3 . Here we report a chemical synthesis of (+)-perseanol, which proceeds in 16 steps from commercially available ( R )-pulegone. The synthesis involves a two-step annulation process that rapidly assembles the tetracyclic core from readily accessible cyclopentyl building blocks. This work demonstrates how convergent fragment coupling, when combined with strategic oxidation tactics, can enable the concise synthesis of complex and highly oxidized diterpene natural products. The chemical synthesis of (+)-perseanol, a diterpene with potent insecticidal properties, is reported.

(+)-Ryanodine and (+)-ryanodol are complex diterpenoids that modulate intracellular calcium-ion release at ryanodine receptors, ion channels critical for skeletal and cardiac muscle excitation-contraction coupling and synaptic transmission. Chemical derivatization of these diterpenoids has demonstrated that certain peripheral structural modifications can alter binding affinity and selectivity among ryanodine receptor isoforms. Here, we report a short chemical synthesis of (+)-ryanodol that proceeds in only 15 steps from the commercially available terpene (S)-pulegone.The efficiency of the synthesis derives from the use of a Pauson-Khand reaction to rapidly build the carbon framework and a SeO₂-mediated oxidation to install three oxygen atoms in a single step. This work highlights how strategic C-0 bond constructions can streamline the synthesis of polyhydroxylated terpenes by minimizing protecting group and redox adjustments.

The study and application of transition metal hydrides (TMHs) has been an active area of chemical research since the early 1960s 1 , for energy storage, through the reduction of protons to generate hydrogen 2 , 3 , and for organic synthesis, for the functionalization of unsaturated C–C, C–O and C–N bonds 4 , 5 . In the former instance, electrochemical means for driving such reactivity has been common place since the 1950s 6 but the use of stoichiometric exogenous organic- and metal-based reductants to harness the power of TMHs in synthetic chemistry remains the norm. In particular, cobalt-based TMHs have found widespread use for the derivatization of olefins and alkynes in complex molecule construction, often by a net hydrogen atom transfer (HAT) 7 . Here we show how an electrocatalytic approach inspired by decades of energy storage research can be made use of in the context of modern organic synthesis. This strategy not only offers benefits in terms of sustainability and efficiency but also enables enhanced chemoselectivity and distinct, tunable reactivity. Ten different reaction manifolds across dozens of substrates are exemplified, along with detailed mechanistic insights into this scalable electrochemical entry into Co–H generation that takes place through a low-valent intermediate. A perspective is given on how an electrocatalytic approach, inspired by decades of energy storage studies, can be used in the context of efficient cobalt-hydride generation with a variety of applications in modern organic synthesis.

Models can codify our understanding of chemical reactivity and serve a useful purpose in the development of new synthetic processes via, for example, evaluating hypothetical reaction conditions or in silico substrate tolerance. Perhaps the most determining factor is the composition of the training data and whether it is sufficient to train a model that can make accurate predictions over the full domain of interest. Here, we discuss the design of reaction datasets in ways that are conducive to data-driven modeling, emphasizing the idea that training set diversity and model generalizability rely on the choice of molecular or reaction representation. We additionally discuss the experimental constraints associated with generating common types of chemistry datasets and how these considerations should influence dataset design and model building.

The synthesis of conolidine, a scarce, naturally occurring compound, has enabled the first studies of its pharmacological properties to be carried out. Excitingly, conolidine is a painkiller that seems to have an unusual mechanism of action.

A concise chemical synthesis of pactamycin, a natural product that targets the ribosome, may allow the development of less toxic derivatives. [Also see Report by Malinowski et al. ] Natural products—small molecules isolated from plants, fungi, bacteria, and other microorganisms—continue to serve as an important source of chemical tools for the study of biological systems and disease pathology, as well as new drugs. One example is the natural product pactamycin, which has been instrumental in the investigation of ribosome structure and function ( 1 , 2 ). However, the structural complexity of this small molecule has historically rendered it—and by extension its unnatural analogs—synthetically inaccessible, hindering efforts at the development of pactamycin-derived therapeutics. On page 180 of this issue, Malinowski et al. ( 3 ) report a total chemical synthesis of pactamycin that elegantly addresses this challenge and opens a new chapter in the story of this natural product.

A variant of a classical reaction has been used to generate short-lived chemical species called arynes, allowing the one-step synthesis of structurally complex benzene derivatives from simple precursors. See Article p.208 A new approach to aryne syntheses Arynes are reactive intermediates derived from aromatic systems, which can be 'trapped' to give products that find use as chemical reagents and in pharmaceuticals, agrochemicals, dyes and polymers. This study explores a new synthetic strategy that combines de novo generation of benzynes — through a hexadehydro-Diels–Alder reaction — with their in situ elaboration into structurally complex benzenoid products. The reaction is metal-free and reagent-free, and the authors provide examples of how this approach allows new modes of intrinsic reactivity to be revealed.