Carbonyls Out, Heteroatoms In

Carbonyl Swapping Converts Cyclic Ketones to Saturated Heterocycles

Z. Xue,^† Z. Lou,^† X. Lou, P. He, J. Wang & Y. Xu*

Nature 2026 (DOI: 10.1038/s41586-026-10508-5)

The authors report a modular approach to saturated heterocycles via formal carbonyl-to-heteroatom replacement of cyclic ketones, enabled by a bis(aroylperoxy) ketal intermediate. Electronically guided peroxy cleavage induces double C–C bond scission to generate alkyl dichlorides, which serve as versatile handles for N/O/S/Se/Te incorporation. The method shows broad scope and functional-group tolerance, supporting both accelerated target synthesis and late-stage diversification. Its utility is further demonstrated through ring construction– and ring functionalization–carbonyl replacement strategies, as well as a proof-of-concept formal CH₂-to-heteroatom conversion.

Enantioconvergent Vinylcyclopropane–Cyclopentene Rearrangement with Vessel-Controlled Chemodivergence

Z.-T. Jiang,^† B. Li,^† G. Chen,^† J. Chen, J.-L. Yuan, X. Wei* & Y. Xia*

Nat. Chem. 2026 (DOI: 10.1038/s41557-026-02132-7)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-s4fnb) 🔓

The authors report an enantioconvergent vinylcyclopropane–cyclopentene (VCP–CPent) rearrangement of vinyl gem-difluorocyclopropanes via a vinyl fluoroallyl rhodium intermediate. An intriguing vessel-controlled chemodivergence is observed, with gem-difluorocyclopentenes formed in plastic tubes and cyclopentenones in glass vials. The protocol delivers both products with high chemo- and enantioselectivity. Mechanistic studies elucidate the rearrangement pathway and origin of the vessel effect, while preliminary biological evaluation highlights gem-difluorocyclopentenes as potential cyclopentenone bioisosteres.

👉️ For related work, see the authors’ recent mechanistic study of Rh-catalyzed cycloadditions via dual C–C/C–F activation.

Angle-Strained Cycloalkyne-Mediated Carbonyl 1,2-Transposition

K. Ji, Y. Liao, S. Deng & Z. Wu*

Nat. Synth. 2026 (DOI: 10.1038/s44160-026-01059-8)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-79gqk) 🔓

The authors report a strain-release-driven strategy for one-pot carbonyl 1,2-transposition in cyclic ketones. The method exploits angle-strained cycloalkynes, generated in situ from cyclic ketones, that undergo regioselective 1,2-addition followed by hydrolysis to furnish carbonyl-migrated products. This approach enables rapid access to complex structures and natural product analogues via late-stage functionalization.

Taming Distonic Radical Cations for Precise γ-C–H Functionalization of Alkylamines

T. Kinoshita,^† K. Hirate,^† K. Hamawaki,^† S. Chiba,^† K. Terada, Y. Sakakibara* & K. Murakami*

Nat. Synth. 2026 (DOI: 10.1038/s44160-026-01042-3) 🔓

While remote functionalization of primary and secondary alkylamines is well established, analogous transformations of tertiary amines remain challenging, despite their prevalence in 60% of alkylamine-containing pharmaceuticals. This study employs α-ammonio radicals, a class of distonic radical cations, to enable γ-selective functionalization of tertiary amines. Halomethylammonium salts serve as the radical precursors, promoting selective γ-C–H activation via intramolecular radical transfer. The resulting γ-radicals undergo diverse transformations, including thioetherification, amination, alkylation, (hetero)arylation and alkenylation.

A Flexible and Affordable Self-Driving Laboratory for Automated Reaction Optimization

S. Pilon,^† E. Savino,^† O. M. Bayley,^† M. Vanzella, M. Claros, P. Siasiaridis, J. Liu, F. Lukas, M. Damian, V. Tseliou, N. Intini, A. Slattery, J. SanJosé-Orduna, T. den Hartog, R. A. H. Peters, A. F. G. Gargano, F. G. Mutti & T. Noël*

Nat. Synth. 2026 (DOI: 10.1038/s44160-026-01053-0) 🔓

The authors introduce RoboChem-Flex, a low-cost, modular self-driving laboratory platform designed to democratize autonomous chemical experimentation. The system integrates customizable in-house-built hardware with a flexible Python-based software framework for real-time device control and advanced Bayesian optimization, including multi-objective and transfer learning workflows. It supports both fully autonomous closed-loop and human-in-the-loop operation, facilitating integration with shared analytical equipment. The platform is validated across six case studies spanning photocatalysis, biocatalysis, thermal cross-couplings, and enantioselective catalysis, covering both single- and multi-objective optimization.

Visible-Light-Induced C–S Bond Cleavage Enables Alkyl Radical Generation from Redox-Inert Substrates

R. Yanagida, V. G. Alfonso,^‡ J. Ching,^‡ S. Murakami* & H. Ohmiya*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c01895)

The authors report a visible-light-driven platform for generating alkyl radicals from redox-inert substrates without external photocatalysts, enabled by photoexcitation of sulfur-containing intermediates formed via polar activation. Thioethers derived from simple alkenes undergo homolytic C–S bond cleavage under visible light, eliminating the need for photocatalysts or stoichiometric additives. The strategy extends to unactivated alkyl chlorides and epoxides, which are typically resistant to single-electron reduction under mild conditions. The resulting radicals participate in carbon–carbon bond formation, exemplified by metal-free alkenylation with styrenes.

Seven-Step Total Synthesis of Conidiogenone B Enabled by Radical Cyclizations

J. Bernard, Z. Zhang & M. Dai*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c02334) 🔓

The authors report a concise total synthesis of conidiogenone B, a cyclopiane diterpene with potent antibacterial activity against multidrug-resistant pathogens, featuring a congested 6/5/5/5 tetracyclic framework with four all-carbon quaternary centers. The strategy hinges on an MHAT-initiated reductive olefin–nitrile radical cyclization to construct the A ring and install vicinal quaternary centers. B-ring formation is achieved through either an intramolecular aldol condensation or a cyclopropane-based (3+2) approach, while an MHAT-based reductive olefin–enone cyclization enables D-ring construction. The natural product is delivered in 7 steps without protecting groups.

Catalyst-Free Photoinduced Deaminative Functionalization of Amino Acids and Glutarimide Precursors

T. G. Chong, J. R. Dorsheimer, Z. Zhu, T. C. Sherwood, C. L. Joe, E. R. Welin & T. Rovis*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c04839)

The authors report a general strategy for the synthesis of alkylated N-heterocycles from abundant primary amines via an electron donor–acceptor (EDA) complex. Blue-light irradiation generates a diradical intermediate that forms alkyl iodides in situ, which are then displaced by nucleophiles. This umpolung approach converts primary amines into electrophilic coupling partners, enabling efficient heteroarylation. Application to glutamate and glutamine derivatives provides streamlined access to glutarimide motifs relevant to cereblon E3-ligase modulators.

Ab Initio Molecular Dynamics Simulations for Organic Chemists—It is About Time!

M. M. Nielsen, C. C. Wagen, L. A. Gomes, D. J. Tantillo,* S. A. Lopez* & E. N. Jacobsen*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.5c20878) 🔓

Molecular dynamics (MD) simulations model chemical reactions as continuous changes in molecular structure over time instead of static minima and transition states. This perspective highlights the importance of such dynamics in reactions that deviate from a single minimum-energy pathway, where traditional transition state theory (TST) often fails. Key examples include short-lived intermediates, non-equilibrium solvation, momentum-controlled selectivity, post-transition state bifurcations, and hidden intermediates. In these cases, MD reveals the sequence of structural changes that governs a reaction outcome. Emerging machine learning-based MD approaches, particularly in photochemistry and solvent modelling, are also discussed. While MD does not replace TST, it provides a complementary, time-resolved framework essential for understanding complex reaction mechanisms. This perspective outlines the methodology to help organic chemists determine when MD simulations are most appropriately applied.

Enantioselective Total Syntheses of Grayanoid (−)-Mollfoliagein A and (−)-Rhodomollein XXV

S.-F. Du,^† Y.-P. Zhang,^† Q.-L. Wu & H. Zhang*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c03596)

The authors report the convergent total syntheses of (−)-mollfoliagein A and (−)-rhodomollein XXV, two highly oxygenated grayanoids featuring a challenging oxa-tricyclo[3.3.1.0^3.7 ]nonane motif. The 5/7/6/5/5 skeleton of mollfoliagein A is assembled in a single step from two fragments via a Stille carbonylative coupling/cascade sequence involving transannular oxa-Michael addition and vinylogous Knoevenagel condensation. Further key steps include C/D ring formation through reshaping of a bicyclo[3.3.0]octene to a bicyclo[3.2.1]octane framework, and PPTS-mediated conversion of (−)-mollfoliagein A to (−)-rhodomollein XXV.

Total Synthesis of Euphopia B and Discovery of a Selective Inhibitor of Potassium Efflux-Independent NLRP3 Inflammasome Activation

C. Xue,^† Z. Zhang,^† Z. Ding, G. Xie, R. Liu, F. Wang, J. Yu, T. Wang, F. Xue, H. Song, Q. Chen* & Y. Qin*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c02838)

The authors report the first asymmetric total synthesis of the jatrophane diterpenoid euphopia B, which contains ten contiguous stereocenters and multiple oxygenated functional groups. A robust and scalable route, featuring copper-catalyzed asymmetric hydroboration, Claisen rearrangement, and SmI₂-mediated cyclization, enables single-batch preparation on >100 mg scale. Bioactivity studies reveal that euphopia B selectively inhibits NLRP3 inflammasome activation induced by potassium efflux-independent activators, establishing it as a chemical probe for interrogating NLRP3 activation mechanisms.

Recent Advances in Transition-Metal-Catalyzed Cine-Coupling Reactions

M. Bai,* A. Qiao, F. Gou, C. Shi, B. Guo, Q. Wen, X. Huang, Z. Liu, X. Chen, J. Yuan & Z. Feng*

ACS Catal. 2025, ASAP (DOI: 10.1021/acscatal.6c01027) 🔓

The authors review recent advances in transition-metal-catalyzed cine-substitution reactions as a strategy for site-selective molecular editing. In contrast to traditional ipso-coupling, cine-coupling enables bond formation at positions adjacent to the leaving group, offering complementary regioselectivity and structural diversification. These transformations proceed via diverse mechanisms, including metal migration and radical pathways, but a general framework for controlling selectivity between ipso- and cine-coupling remains lacking. This review summarizes key reaction classes, mechanistic features, and synthetic applications, highlighting opportunities for reaction development, catalyst design, and improved control of cine-selectivity.

A Modular Approach to Functionalized Azetidines: Preparation of a Bioactive Ciprofloxacine Analogue

Y. Galushchak, Y. Shevchenko, A. Slobodianyk, R. Kotsiubchyk, T. Soós, S. Bondaruk, G. Al-Maali & P. K. Mykhailiuk*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15002028/v1) 🔓

Since its discovery in 1924, the Bruylants reaction between aminonitriles and organomagnesium reagents has become a widely used method for the synthesis of tertiary amines and has been applied to a broad range of ketone substrates. Notably, however, N-Boc azetidinone has remained an unexplored exception despite its importance to azetidine-containing pharmaceuticals. Here, the authors identify the origin of this limitation and develop conditions that enable its successful participation in the Bruylants reaction. This advancement provides access to previously inaccessible azetidine derivatives from a simple starting material and expands the scope of this classical transformation.

Visible-Light-Mediated Aryl Ketone Coupling with Vinyl Thianthrenium Salts Enables Formal Paternò-Büchi Reactions

S. A. Chamness, M. Liu,^‡ J. B. Erdei,^‡ T. M. A. Weise & C. S. Schindler*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv-2025-0kdn2/v2) 🔓

The authors report a visible-light-mediated ketone–alkene coupling strategy that achieves formal Paternò–Büchi reactivity via alkene radical anion formation from vinyl thianthrenium salts. This method enables access to 2-aryl, 2′-alkyl oxetanes that are typically inaccessible using conventional visible-light [2+2] cycloadditions. The transformation proceeds under mild conditions across a broad range of aromatic ketones and involves β-hydroxy thianthrenium intermediates that undergo cyclization to form 2,2′-disubstituted oxetanes.

Quadricyclanes: Saturated Bioisosteres for ortho-Substituted Arenes

X. Zhou, J. Dong,* B. Zhang, D. Yu, S. Yuan, H. Sun, Z. Chen & D. Xue*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15002037/v1) 🔓

The authors report 1,5-disubstituted carbocyclic quadricyclanes as a new class of saturated bioisosteres for ortho-disubstituted arenes. A visible-light-mediated, energy-transfer-catalyzed [2π+2π] photocycloaddition of 2,3-disubstituted norbornadienes was developed to access diverse quadricyclane derivatives, including drug-like analogues. Crystallographic analysis shows that these frameworks share similar geometric parameters of ortho-substituted phenyl rings. However, evaluation of a quadricyclane analogue of lomitapide revealed diminished aqueous solubility, increased lipophilicity, and reduced metabolic stability, highlighting potential limitations of this scaffold as a bioisosteric replacement.

High-Fidelity Transfer of Chiral Sulfoximine Radicals

R. Li,^† C. Liu,^† W. Li,^† M. V. Truong, S. W. Khoo, Y. Li, R. R. Merchant, B. S. Matsuura, H. Y. J. Fung, S. Chen* & T. Qin*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15001863/v1) 🔓

The authors report a family of chiral sulfonimidoyl radicals in which the radical center coincides with the stereogenic center, enabling stereoretentive radical transfer using bench-stable reagents. This strategy establishes a general platform for S(VI) chiral radical transfer, providing switchable and modular access to enantioenriched sulfoximines and sulfinamides while avoiding the need for strong oxidants and organometallic nucleophiles. The approach also achieves chemoselective sulfur-centered reactivity. Mechanistic and computational studies provide insight into the high stereochemical fidelity observed for these chiral sulfonimidoyl radical species.

Evolution, Accelerated

🧬 Evolution, Accelerated. After emerging in Africa ~200,000–300,000 years ago, Homo sapiens spread across the globe; however, for most of that time, evolution appears to have been relatively gradual. Now, a large ancient DNA study in Nature analysing ~15,000 genomes shows that the last 10,000 years—particularly following the rise of farming—saw widespread and ongoing natural selection across the human genome.

Farming was likely a major contributing factor: it reshaped diet, increased population size, and brought humans into closer contact with livestock and infectious disease. The study identifies around 479 regions of the genome showing consistent changes over time, many involved in immune function. For example, variants linked today to immune response—including those associated with tuberculosis susceptibility—shift in frequency in ways that match changing patterns of infectious disease. In some cases, variants thought to be protective rise during periods of high disease burden, before later slowing or reversing over the past ~2,000 years as environments and population structures changed.

Other signals reflect broad lifestyle shifts. Variants associated with higher body fat tend to decrease after the adoption of agriculture, consistent with changes in diet and more stable food supplies. In West Eurasia, variants linked to lighter skin pigmentation increase over time. Importantly, many signals do not move in a single direction but rise and fall over millennia, reflecting changing diets, movement between populations, and shifting disease pressures.

A second intensification of selection during the Bronze Age (~5,000 years ago) likely reflects further increases in population density associated with agricultural expansion, early urbanisation and technological change, which would have increased transmission of infectious disease and strengthened selection on immune genes.