Medium-sized bridged heterocycles are highly attractive structural motifs in bioactive natural products and medicinal chemistry. However, their broader exploration remains limited due to the lack of concise and modular synthetic strategies, as their synthesis is challenged by unfavorable enthalpic and entropic constraints. Herein, we report an energy transfer (EnT)-catalyzed intermolecular (5 + 4) dearomative cycloaddition of furans with vinyl cyclopropanes, providing direct access to (Z)-10-oxabicyclo[5.2.1]deca-3,8-diene scaffolds in a single step. Visible light triplet sensitization unlocks a distinct diene-type 1,4-biradical activation mode in furans. This triplet-state reactivity enables intermolecular higher-order (5 + 4) cycloadditions that remain inaccessible under conventional thermal activation. Mechanistic investigations support an energy transfer pathway and provide insights into the origin of the observed regioselectivity. The resulting partially unsaturated cycloadducts offer multiple synthetic handles for downstream functionalization, enabling rapid and modular incorporation of heterobicyclo[5.2.1]alkane motifs and highlighting their potential as versatile building blocks in synthetic chemistry.

Since Graph Neural Networks (GNNs) made a big impact on graph structured datasets, they are widely utilized in the field of chemistry. However, the reasons behind the prediction of GNNs are not always obvious, so they are considered as black-box models. In this paper, we introduce a graphical user interface (GUI) which can be used for explaining the predictions of GNNs. We aim to integrate our GUI into the user’s research directly to make the predictions of GNNs more understandable in both classification and regression tasks. Furthermore, we offer the option to use the built-in GNN models to train custom datasets directly. Additionally, the system incorporates several explainable artificial intelligence (XAI) techniques, and also allows users to assess the accuracy of explanation findings using various assessment metrics and thus to compare the explanation outcomes. Using the well-known datasets in the field, this tool can also be used for education purposes. The interface provides a comprehensive platform for examining and interpreting the predictions provided by the GNNs and merging several GNN models with XAI approaches. This will facilitate a deeper understanding and possibly lead to new discoveries in researchers’ respective domains in understanding the underlying elements that influence the model’s explainability. The code is made publicly available at https://github.com/ChemGraphExplainer/ChemGraphExplainer .

Bicyclo[1.1.0]butanes (BCBs) have recently garnered significant research interest as versatile precursors for synthesizing potential [n.1.1] bioisosteres and multi-functionalized cyclobutanes in a straightforward and atom-economical manner. Here, we report a solvent-dependent divergent cyclization of BCBs that provides highly diastereospecific decorated cyclobutanes and oxygen-containing bicyclo[3.1.1]heptanes (BCHeps), which serve as bioisosteres of meta-substituted arenes. Additionally, an unprecedented 1,2-difunctionalization reaction mode for BCBs was explored, thus expanding the chemical space of arene bioisosteres and highly functionalized cyclobutanes.

Zusammenfassung closo ‐Carborane sind ikosaedrische Kohlenstoff‐Bor‐Cluster mit einzigartigen Eigenschaften und vielfältigen Anwendungsmöglichkeiten. Besonders hervorzuheben ist ihre Rolle in der Wirkstoffentwicklung, wo sie als privilegierte Strukturmotive für die Bor‐Neutroneneinfangtherapie (BNCT) sowie als sehr hydrophobe Bioisostere für das Rotationsvolumen von Phenylringen dienen. In dieser Arbeit stellen wir die Synthese von N‐geschützten Carboranylanaloga von β‐Arylethylaminen – Strukturmotive, die häufig in biologisch aktiven Molekülen vorkommen – mittels eines einstufigen Verfahrens durch Difunktionalisierung von Alkenen vor. Entscheidend für unseren Erfolg waren die mechanistischen Besonderheiten der Energietransferkatalyse, die wir erstmals zur Erzeugung von closo ‐Carboranylradikalen eingesetzt haben. Nachgeschaltete Modifikationen führten zu einer Reihe von Analoga von Aminosäuren und bekannten N ‐Methyl‐ d ‐Aspartat‐Rezeptor (NMDAR)‐Antagonisten.

closo‐Carborane sind ikosaedrische Kohlenstoff‐Bor‐Cluster mit einzigartigen Eigenschaften und vielfältigen Anwendungsmöglichkeiten. Besonders hervorzuheben ist ihre Rolle in der Wirkstoffentwicklung, wo sie als privilegierte Strukturmotive für die Bor‐Neutroneneinfangtherapie (BNCT) sowie als sehr hydrophobe Bioisostere für das Rotationsvolumen von Phenylringen dienen. In dieser Arbeit stellen wir die Synthese von N‐geschützten Carboranylanaloga von β‐Arylethylaminen – Strukturmotive, die häufig in biologisch aktiven Molekülen vorkommen – mittels eines einstufigen Verfahrens durch Difunktionalisierung von Alkenen vor. Entscheidend für unseren Erfolg waren die mechanistischen Besonderheiten der Energietransferkatalyse, die wir erstmals zur Erzeugung von closo‐Carboranylradikalen eingesetzt haben. Nachgeschaltete Modifikationen führten zu einer Reihe von Analoga von Aminosäuren und bekannten N‐Methyl‐d‐Aspartat‐Rezeptor (NMDAR)‐Antagonisten.

Visible-light-mediated energy transfer (EnT) photocatalysis has emerged as a highly appealing strategy for converting planar (hetero)arenes into complex, medicinally relevant, three-dimensional (3D) architectures. Current methodologies for intermolecular dearomative photocycloadditions, however, are restricted to bicyclic (hetero)aromatic systems, while the more abundant monocyclic (hetero)arenes remain vastly underexplored. Accessing the triplet state of the ubiquitous monocyclic (hetero)arenes poses a formidable challenge due to their high triplet energy barriers. Herein, we report several EnT-catalyzed intermolecular dearomative cycloadditions of monocyclic heteroarenes with alkenes and bicyclo[1.1.0]butanes. To overcome the intrinsic limitations in triplet-state reactivity and accelerate reaction discovery, we introduced a data-driven three-layer screening strategy that integrates predictive data science tools for mapping excited-state properties with luminescence quenching and reaction-based screening. This synergistic three-layer screening strategy uncovers structure-reactivity relationships between substituted monocyclic heteroarenes and biradical acceptors, facilitating the accelerated discovery of new reactivity. Utilizing this data-driven approach, we developed the EnT-catalyzed intermolecular dearomative cycloaddition of thiophenes, oxazoles, and thiazoles with alkenes/bicyclo[1.1.0]butanes, providing access to unprecedented C(sp3)-rich 3D molecular scaffolds.

closo-Carboranes are icosahedral carbon-boron clusters with unique properties and broad applicability. They particularly stand out in the context of drug development as privileged structural motifs for boron neutron capture therapy (BNCT) and as highly hydrophobic bioisosteres for the rotational volume of phenyl rings. Herein, we unveil the synthesis of N-protected carboranyl analogs of β-arylethylamines-widely found structural motifs in biologically active molecules-via a one-step alkene difunctionalization approach. Key for our success were the enabling mechanistic characteristics of energy transfer catalysis which we have used for the first time to generate closo-carboranyl radicals. Downstream modifications gave a series of analogs of amino acids and known N-methyl-d-aspartate receptor (NMDAR) antagonists.

Heteroaromatic rings play a prominent role in medicinal chemistry, featuring in numerous biologically relevant molecules. However, unlike benzene ring the saturated and structurally rigid bioisosteric mimetics of heteroaromatic rings are rarely known, mainly due to the inherent challenges associated with the stability and synthesis of heteroatom-substituted C(sp3)-rich polycyclic hydrocarbons. We envisioned that the strategic and highly selective insertion of different heteroatomic units to bicyclo[1.1.0]butanes (BCBs) could offer an ideal platform to access diverse heterobicyclo[n.1.1]alkanes. Herein, by circumventing the intrinsic challenges associated with the reaction of BCBs with heteroatomic radicals, we report a photoredox-catalyzed highly regio- and chemoselective insertion of amidyl radicals to BCBs, which provided direct access to 2-oxa-4-azabicyclo[3.1.1]hept-3-enes. Detailed experimental and computational studies have been carried out to underpin the mechanistic paradigm of this reaction. The newly synthesized heterobicyclic motifs are structurally rigid and exhibit well-defined exit vectors, the two important molecular properties in medicinal chemistry. Moreover, various downstream transformations were carried out with these compounds, highlighting their utility as versatile building blocks in synthetic chemistry.

With over 10,000 new reaction protocols arising every year, only a handful of these procedures transition from academia to application. A major reason for this gap stems from the lack of comprehensive knowledge about a reaction's scope, i.e., to which substrates the protocol can or cannot be applied. Even though chemists invest substantial effort to assess the scope of new protocols, the resulting scope tables involve significant biases, reducing their expressiveness. Herein we report a standardized substrate selection strategy designed to mitigate these biases and evaluate the applicability, as well as the limits, of any chemical reaction. Unsupervised learning is utilized to map the chemical space of industrially relevant molecules. Subsequently, potential substrate candidates are projected onto this universal map, enabling the selection of a structurally diverse set of substrates with optimal relevance and coverage. By testing our methodology on different chemical reactions, we were able to demonstrate its effectiveness in finding general reactivity trends by using a few highly representative examples. The developed methodology empowers chemists to showcase the unbiased applicability of novel methodologies, facilitating their practical applications. We hope that this work will trigger interdisciplinary discussions about biases in synthetic chemistry, leading to improved data quality.

Due to the magnitude of chemical space, the discovery of novel substrates in energy transfer (EnT) catalysis remains a daunting task. Experimental and computational strategies to identify compounds that successfully undergo EnT-mediated reactions are limited by their time and cost efficiency. To accelerate the discovery process in EnT catalysis, we herein present the EnTdecker platform, which facilitates the large-scale virtual screening of potential substrates using machine-learning (ML) based predictions of their excited state properties. To achieve this, a data set is created containing more than 34,000 molecules aiming to cover a vast fraction of synthetically relevant compound space for EnT catalysis. Using this data predictive models are trained, and their aptitude for an in-lab application is demonstrated by rediscovering successful substrates from literature as well as experimental validation through luminescence-based screening. By reducing the computational effort needed to obtain excited state properties, the EnTdecker platform represents a tool to efficiently guide substrate selection and increase the experimental success rate for EnT catalysis. Moreover, through an easy-to-use web application, EnTdecker is made publicly accessible under entdecker.uni-muenster.de.

The incorporation of three-dimensional structures into drug molecules has demonstrated significant improvements in clinical success. Late-stage saturation of drug molecules provides a direct pathway for this transformation. However, achieving selective and controllable reduction of aromatic rings remains challenging, particularly when multiple aromatic rings coexist. Herein, we present the switchable and chemoselective hydrogenation of benzene and pyridine rings. The utility of the protocol has been comprehensively investigated in diversified substrates with the assistance of a fragment-screening technique. This approach provides convenient access to a diverse array of cyclohexane and piperidine compounds, prevalent in various bioactive molecules and drugs. Furthermore, it discloses promising avenues for applications in the late-stage switchable saturation of drugs, facilitating an increase in the fraction of sp(3)-carbons which holds the potential to enhance the medicinal properties of drugs.

In pursuit of potent pharmaceutical candidates and to further improve their chemical traits, small ring systems can serve as a potential starting point. Small ring units have the additional merit of loaded strain at their core, making them suitable reactants as they can capitalize on this intrinsic driving force. With the introduction of cyclobutenone as a strained precursor to ketene, the photocycloaddition with another strained unit, bicyclo[1.1.0]butane (BCB), enables the reactivity of both π-units in the transient ketene. This double strain-release driven [2π+2σ]-photocycloaddition promotes the synthesis of diverse heterobicyclo[2.1.1]hexane units, a pharmaceutically relevant bioisostere. The effective reactivity under catalyst-free conditions with a high functional group tolerance defines its synthetic utility. Experimental mechanistic studies and density functional theory (DFT) calculations suggest that the [2π+2σ]-photocycloaddition takes place via a triplet mechanism.

Replacing planar aromatic rings in drug molecules with C(sp3)-rich isosteric mimetics, such as bicyclo[n.1.1]alkanes, can significantly alter their physicochemical and pharmacokinetic properties, often leading to higher clinical success rates. However, unlike a benzene ring, the structurally rigid C(sp3)-rich isosteric mimetics of heteroaromatic rings are rare. Heterobicyclo[n.1.1]alkanes are promising in this regard, but the lack of modular synthetic methods has currently hindered their exploration. We envisioned that the strategic and selective insertion of different heteroatomic units to bicyclo[1.1.0]butanes could offer a highly modular platform to access diverse heterobicyclo[n.1.1]alkanes. Herein we report a photoredox-catalysed highly regioselective and chemoselective insertion of amidyl radicals to bicyclo[1.1.0]butanes, providing direct access to 2-oxa-4-azabicyclo[3.1.1]hept-3-enes. The exit vector analysis shows a geometric resemblance of these C(sp3)-rich heterobicyclic motifs with pyridine and pyrimidine derivatives, suggesting their potential as isosteric mimetics of such medicinally important heterocycles. Additionally, various downstream transformations demonstrate their utility as versatile building blocks in synthetic chemistry. Heteroatom-substituted C(sp3)-rich polycyclic hydrocarbon rings, isosteric to heterocyclic rings, are not common due to the challenging synthesis. Now a photoredox-catalysed strategy to insert amidyl radicals into bicyclo[1.1.0]butanes is presented, providing direct access to 2-oxa-4-azabicyclo[3.1.1]hept-3-enes.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Sulfur(VI) fluoride exchange (SuFEx) gives rise to a plethora of high-valent sulfur linkages; however, the availability of (aliphatic) sulfonyl fluoride manifolds lag behind, owing to the limited sources of introducing the SO2F moiety via a classical two-electron approach. Recently, radical-based methodologies have emerged as a complementary strategy to increase the diversity of accessible click partners. In this work, synthesis of a bench-stable sulfamoyl fluoride reagent is presented, which may undergo sigma-bond homolysis upon visible-light-induced sensitization to form protected β-amino sulfonyl fluorides from alkene feedstocks. Notably, this offers an appealing strategy to access various building blocks for peptido sulfonyl fluorides, relevant in a medicinal chemistry context, as well as an intriguing entry to β-ammonium sulfonates and β-sultams, from alkenes. Densely functionalized 1,3-sultones were obtained by employing allyl alcohols as substrates. Surprisingly, allyl chloride-derived β-imino sulfonyl fluoride underwent S-O bond formation and ring closure to yield rigid cyclopropyl β-imino sulfonate ester under SuFEx conditions. Furthermore, by engaging a thiol-based hydrogen atom donor in the reaction, the reactivity of the same reagent can be tuned toward the direct synthesis of aliphatic sulfonyl fluorides. Mechanistic experiments indicate an energy transfer (EnT)-mediated process. The transient sulfonyl fluoride radical adds to the alkene and product formation occurs upon either radical-radical coupling or hydrogen atom transfer (HAT), respectively.