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Training algorithms to computationally plan multistep organic syntheses has been a challenge for more than 50 years 1 – 7 . However, the field has progressed greatly since the development of early programs such as LHASA 1 , 7 , for which reaction choices at each step were made by human operators. Multiple software platforms 6 , 8 – 14 are now capable of completely autonomous planning. But these programs ‘think’ only one step at a time and have so far been limited to relatively simple targets, the syntheses of which could arguably be designed by human chemists within minutes, without the help of a computer. Furthermore, no algorithm has yet been able to design plausible routes to complex natural products, for which much more far-sighted, multistep planning is necessary 15 , 16 and closely related literature precedents cannot be relied on. Here we demonstrate that such computational synthesis planning is possible, provided that the program’s knowledge of organic chemistry and data-based artificial intelligence routines are augmented with causal relationships 17 , 18 , allowing it to ‘strategize’ over multiple synthetic steps. Using a Turing-like test administered to synthesis experts, we show that the routes designed by such a program are largely indistinguishable from those designed by humans. We also successfully validated three computer-designed syntheses of natural products in the laboratory. Taken together, these results indicate that expert-level automated synthetic planning is feasible, pending continued improvements to the reaction knowledge base and further code optimization. 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.

The artemisinin (ART)-based antimalarials have contributed significantly to reducing global malaria deaths over the past decade, but we still do not know how they kill parasites. To gain greater insight into the potential mechanisms of ART drug action, we developed a suite of ART activity-based protein profiling probes to identify parasite protein drug targets in situ. Probes were designed to retain biological activity and alkylate the molecular target(s) of Plasmodium falciparum 3D7 parasites in situ. Proteins tagged with the ART probe can then be isolated using click chemistry before identification by liquid chromatography–MS/MS. Using these probes, we define an ART proteome that shows alkylated targets in the glycolytic, hemoglobin degradation, antioxidant defense, and protein synthesis pathways, processes essential for parasite survival. This work reveals the pleiotropic nature of the biological functions targeted by this important class of antimalarial drugs.

Polyene cyclizations are among the most complex and challenging transformations in biology. In a single reaction step, multiple carbon–carbon bonds, ring systems and stereogenic centres are constituted from simple, acyclic precursors 1 – 3 . Simultaneously achieving this kind of precise control over product distribution and stereochemistry poses a formidable task for chemists. In particular, the polyene cyclization of (3 E ,7 E )-homofarnesol to the valuable naturally occurring ambergris odorant (−)-ambrox is recognized as a longstanding challenge in chemical synthesis 1 , 4 – 7 . Here we report a diastereoselective and enantioselective synthesis of (−)-ambrox and the sesquiterpene lactone natural product (+)-sclareolide by a catalytic asymmetric polyene cyclization by using a highly Brønsted-acidic and confined imidodiphosphorimidate catalyst in the presence of fluorinated alcohols. Several experiments, including deuterium-labelling studies, suggest that the reaction predominantly proceeds through a concerted pathway in line with the Stork–Eschenmoser hypothesis 8 – 10 . Mechanistic studies show the importance of the enzyme-like microenvironment of the imidodiphosphorimidate catalyst for attaining exceptionally high selectivities, previously thought to be achievable only in enzyme-catalysed polyene cyclizations. The catalytic asymmetric polyene cyclization of homofarnesol to ambrox is achieved using a highly Brønsted-acidic and confined imidodiphosphorimidate catalyst.

Chiral amines can be made by insertion of a carbene into an N–H bond using two-catalyst systems that combine a transition metal-based carbene-transfer catalyst and a chiral proton-transfer catalyst to enforce stereocontrol. Haem proteins can effect carbene N–H insertion, but asymmetric protonation in an active site replete with proton sources is challenging. Here we describe engineered cytochrome P450 enzymes that catalyse carbene N–H insertion to prepare biologically relevant α-amino lactones with high activity and enantioselectivity (up to 32,100 total turnovers, >99% yield and 98% e.e.). These enzymes serve as dual-function catalysts, inducing carbene transfer and promoting the subsequent proton transfer with excellent stereoselectivity in a single active site. Computational studies uncover the detailed mechanism of this new-to-nature enzymatic reaction and explain how active-site residues accelerate this transformation and provide stereocontrol.A haem protein that serves as a dual-function catalyst capable of inserting a carbene into a N–H bond to form α-amino lactones has been reported. The enzyme catalyses both carbene transfer and the subsequent proton transfer in a single active site. This transformation can proceed at the gram scale with high efficiency and enantioselective control.

In recent years, researchers have often encountered the significance of the aberrant metabolism of tumor cells in the pathogenesis of malignant neoplasms. This phenomenon, known as the Warburg effect, provides a number of advantages in the survival of neoplastic cells, and its application is considered a potential strategy in the search for antitumor agents. With the aim of developing a promising platform for designing antitumor therapeutics, we synthesized a library of conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones. To gain insight into the determinants of the biological activity of the prepared compounds, we showed that the conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones, which are cytotoxic agents, demonstrate selective activity toward a number of tumor cell lines with glycolysis-inhibiting ability. Moreover, the results of molecular and in silico screening allowed us to identify these compounds as potential inhibitors of the pyruvate kinase M2 oncoprotein, which is the rate-determining enzyme of glycolysis. Thus, the results of our work indicate that the synthesized conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones can be considered a promising platform for designing selective cytotoxic agents against the glycolysis process, which opens new possibilities for researchers involved in the search for antitumor therapeutics among compounds containing piperidone platforms.

Ring-closing metathesis is a widely used chemical transformation that can generate organic macrocycle compounds; here, an approach is described by which the E -stereoisomer of a macrocycle is generated selectively, exemplified by synthesizing the antibiotic recifeolide and the anti-cancer drug pacritinib. E -isomers preferred in olefin metathesis Olefin metathesis reactions are important in synthetic organic chemistry and were recognized with a Nobel Prize in 2005. Controlling which isomer ( E or Z ) is produced during the reaction can be vital, particularly at late stages in multistep syntheses, or when the product is sensitive to further reactions intended to convert to a single isomer. As Z -isomers are thermodynamically favoured, routes to form E -isomers directly are particularly valuable and, when this is applied to ring-closing reactions, the additional challenge of having equimolar amounts of each coupling partner by default means that typical reagent-excess strategies cannot be used. Now, Amir Hoveyda and colleagues report a catalyst system for direct and selective E -alkene formation in ring-closing metathesis reactions, exemplified by the synthesis of pacritinib and recifeiolide in E / Z ratios greater than 98/2. Macrocyclic compounds are central to the development of new drugs, but preparing them can be challenging because of the energy barrier that must be surmounted in order to bring together and fuse the two ends of an acyclic precursor such as an alkene (also known as an olefin) 1 . To this end, the catalytic process known as ring-closing metathesis (RCM) 2 , 3 , 4 has allowed access to countless biologically active macrocyclic organic molecules, even for large-scale production 5 . Stereoselectivity is often critical in such cases: the potency of a macrocyclic compound can depend on the stereochemistry of its alkene; alternatively, one isomer of the compound can be subjected to stereoselective modification (such as dihydroxylation 6 ). Kinetically controlled Z -selective RCM reactions have been reported 7 , 8 , 9 , 10 , but the only available metathesis approach for accessing macrocyclic E -olefins entails selective removal of the Z -component of a stereoisomeric mixture by ethenolysis 10 , sacrificing substantial quantities of material if E / Z ratios are near unity. Use of ethylene can also cause adventitious olefin isomerization—a particularly serious problem when the E -alkene is energetically less favoured. Here, we show that dienes containing an E- alkenyl–B(pinacolato) group, widely used in catalytic cross-coupling 11 , possess the requisite electronic and steric attributes to allow them to be converted stereoselectively to E -macrocyclic alkenes. The reaction is promoted by a molybdenum monoaryloxide pyrrolide complex and affords products at a yield of up to 73 per cent and an E / Z ratio greater than 98/2. We highlight the utility of the approach by preparing recifeiolide (a 12-membered-ring antibiotic) 12 , 13 and pacritinib (an 18-membered-ring enzyme inhibitor) 14 , 15 , the Z -isomer of which is less potent than the E -isomer 16 . Notably, the 18-membered-ring moiety of pacritinib—a potent anti-cancer agent that is in advanced clinical trials for treating lymphoma and myelofibrosis—was prepared by RCM carried out at a substrate concentration 20 times greater than when a ruthenium carbene was used.

Tricyclic and tetracyclic lactone derivatives of thieno[2,3-b]pyrazine or thieno[2,3-b]quinoline, and 2H-pyrones were prepared using different methodologies. Pd/Cu-catalyzed Sonogashira coupling using Et3N as a base, of methyl 7-bromothieno[2,3-b]pyrazine-6-carboxylate and (het)arylalkynes to yield the Sonogashira ester products, gave also the corresponding tricyclic lactones as minor products. However, the major products did not cyclize with TFA. Tricyclic lactones were then obtained by a tandem one-pot Sonogashira coupling and 6-endo-dig lactonization of 7-bromothieno[2,3-b]pyrazine-6-carboxylic acid with (het)arylalkynes, in good yields. Halogenated tricyclic lactones were synthesized by halocyclization using CuX and NXS. Tetracyclic lactones were synthesized through a Rh(III)-catalyzed formal [4+2] cycloaddition, between thieno[2,3-b]quinoline-2-carboxylic acid and internal alkynes, triggered by C-H activation, with the carboxylic group acting as a directing group. Using the SRB assay, the antitumor activity of both Sonogashira products and lactones was evaluated across five human cancer cell lines (CaCo-2, MCF-7, AGS, HeLa, NCI-H460). The best-performing compound was a Sonogashira product showing a GI50 < 10 µM in all tumor cell lines and low toxicity in PLP2 cells. Additionally, antiparasitic testing against Trypanosoma brucei and Leishmania infantum revealed some compounds with IC50 < 11 µM, though some level of cytotoxicity was observed in THP-1—derived macrophages.

A concise and efficient synthesis of the aggregation pheromone of Cryptolestes ferrugineus, Ferrulactone II, and its enantiomer has been developed. The synthetic route features CBS reduction, the zipper reaction, a copper(I)-catalyzed coupling, stereoselective partial hydrogenation, Yamaguchi esterification, and the Mitsunobu inversion reaction. The structures and absolute configurations of both enantiomers of the target pheromone were confirmed by NMR, HRMS, specific rotation, and ECD spectroscopy. This study provides a reliable supply of material for further biological evaluation.

Lactones play crucial roles in various fields, such as pharmaceuticals, food, and materials science, due to their unique structures and diverse biological activities. However, certain lactones are difficult to obtain in large quantities from natural sources, necessitating their synthesis to study their properties and potential. In this study, we investigated the photocatalytic conversion of D-fructose, a biomass-derived and naturally abundant sugar, using a TiO 2 photocatalyst under light irradiation in ambient conditions. The resulting products were identified using HPLC, LCMS, MALDI TOF MS, and 1 H NMR. The results confirmed the successful production of D-arabino-1,4-lactone as a key product, along with the formation of other valuable compounds, including rare sugars such as erythrose and glyceraldehyde. Analysis of the reaction mechanism revealed that D-arabino-1,4-lactone can be directly produced by the α scission (C 1 -C 2 position cleavage) of D-fructose. Furthermore, erythrose and glyceraldehyde, as rare sugars, can be produced from the decomposition of D-arabino-1,4-lactone, which means that D-arabino-1,4-lactone can be used as a source of rare sugars. Furthermore, to investigate the biological activity of D-arabino-1,4-lactone, it was administered to Bifidobacterium . The results showed that Bifidobacterium proliferated and produced more lactic acid than when cultured in a medium without D-arabino-1,4-lactone, suggesting that Bifidobacterium can utilize D-arabino-1,4-lactone.

Strigolactones (SLs) have potential to be used in sustainable agriculture to mitigate various stresses that plants have to deal with. The natural SLs, as well as the synthetic analogs, are difficult to obtain in sufficient amounts for practical applications. At the same time, fluorescent SLs would be useful for the mechanistic understanding of their effects based on bio-imaging or spectroscopic techniques. In this study, new fluorescent SL mimics containing a substituted 1,8-naphthalimide ring system connected through an ether link to a bioactive furan-2-one moiety were prepared. The structural, spectroscopic, and biological activity of the new SL mimics on phytopathogens were investigated and compared with previously synthetized fluorescent SL mimics. The chemical group at the C-6 position of the naphthalimide ring influences the fluorescence parameters. All SL mimics showed effects similar to GR24 on phytopathogens, indicating their suitability for practical applications. The pattern of the biological activity depended on the fungal species, SL mimic and concentration, and hyphal order. This dependence is probably related to the specificity of each fungal receptor–SL mimic interaction, which will have to be analyzed in-depth. Based on the biological properties and spectroscopic particularities, one SL mimic could be a good candidate for microscopic and spectroscopic investigations.