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The 57th SCS Conference on Stereochemistry, better known as the Bürgenstock Conference, brought together a diverse range of chemistry expertise in Brunnen, Switzerland., (© 2024 Wiley-VCH GmbH.)

The synthesis of enantioenriched α-substituted 1,3-dicarbonyls remains a contemporary challenge in synthesis due to their tendency to undergo racemization via keto-enol tautomerization. Herein, we report a method to access enantioenriched β-ketoamides by a chiral sulfinimine-mediated [3,3]-sigmatropic sulfonium rearrangement. The transformation displays good chirality transfer, as well as excellent chemoselectivity and functional group tolerance. Diastereoselective reduction of the ketone moiety, also achievable in one-pot fashion, affords enantioenriched β-hydroxyamides., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The dehydro-Diels-Alder (DDA) reaction is a powerful method for the construction of aromatic compounds. However, the enantioselective DDA reaction has been rarely developed, probably due to the competitive thermal reaction. Herein, we report a copper-catalyzed enantioselective DDA reaction through vinyl cation pathway. The reaction leads to the atom-economical synthesis of axially chiral phenyl and indolyl carbazoles in generally excellent yields with good to excellent atroposelectivities. This methodology represents the first example of non-noble metal-catalyzed enantioselective DDA reaction. Notably, new chiral ligand and organocatalyst derived from the constructed axially chiral carbazole are demonstrated to be useful in asymmetric catalysis., (© 2024 Wiley-VCH GmbH.)

The multi-substituted anilines are widely found in organic synthesis, medicinal chemistry and material science. The quest for robust and efficient methods to construct a diverse array of these compounds using readily accessible starting materials under simple reaction conditions is of utmost importance. Here, we report an unprecedented and efficient approach for the synthesis of 2,4-di and 2,4,6-trisubstituted anilines. With a simple molybdenum(VI) catalyst, a wide range of 2,4-di and 2,4,6-trisubstituted anilines were efficiently prepared in generally good to excellent yields from readily accessible ynones and allylic amines. The synthetic potential of this methodology was further underscored by its applications in several synthetic transformations, gram-scale reactions, and derivatization of bioactive molecules. Preliminary mechanistic studies suggested that this aniline formation might involve a cascade of aza-Michael addition, [1,6]-proton shift, cyclization, dehydration, 6π-electrocyclization, and aromatization. This novel strategy provided a robust, simple, and modular approach for the syntheses of various valuable di- or trisubstituted anilines, some of which were otherwise challenging to access., (© 2024 Wiley-VCH GmbH.)

Benzo[1,3,2]dithiazole-1,1,3-trioxides are bench-stable and easy-to-use reagents. In photoredox catalysis, they generate methyl and perdeuteromethyl radicals which can add to a variety of radical acceptors, including olefins, acrylamides, quinoxalinones, isocyanides, enol silanes, and N-Ts acrylamide. As byproduct, a salt is formed which can be regenerated to the original methylating agent. Flow chemistry provides an option for reaction scale-up further underscoring the synthetic usefulness of these methylation reagents. Mechanistic investigations suggest a single-electron transfer (SET) pathway induced by photoredox catalysis., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

An enantioconvergent palladium-catalyzed Negishi cross-coupling with racemic secondary organozinc reagents has been developed, enabling access to enantioenriched 1,1-diarylalkane motifs in high yields and enantioselectivities. Computational data indicates that the racemization of organozinc compounds most likely occurs through a bridged bimolecular mechanism., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Starting from N-acyl sulfonimidamides, mechanochemically generated rhodium nitrenoids undergo intramolecular N-O couplings to provide unprecedented 1,3,2,4-oxathiadiazole 3-oxides in good to excellent yields. The cyclization proceeds efficiently with a catalyst loading of only 0.5 mol % in the presence of phenyliodine(III) diacetate (PIDA) as oxidant. Neither an inert atmosphere nor additional heating is required in this solvent-free procedure. Under heat or blue light, the newly formed five-membered heterocycles function as nitrene precursors reacting with sulfoxides as exemplified by the imidation of dimethyl sulfoxide., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Two diterpene synthases from the bacterium Chitinophaga pinensis were characterised. The first enzyme mainly produced the rearranged diterpene palmatol, a compound known from octocorals, while the second enzyme made the new coral-type eunicellane chitinol. The mechanisms of both enzymes were deeply studied through isotopic labelling experiments, DFT calculations, and with a substrate analog containing a saturated double bond, resulting in the formation of derailment products that gave additional insights into the nature of the cyclisation cascade intermediates. The formation of coral-type diterpenes poses interesting questions on the functions of these compounds in organisms as different as bacteria and corals., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

This work reports synthesis of a germylene based donor-acceptor molecule and its thermal excitation to a triplet state by coordination with a Lewis acid. Products have been characterized by single crystal X-ray diffraction, EPR spectroscopy, and SQUID measurement, in conjunction with DFT calculation. The singlet-triplet energy gap of the donor-acceptor molecule is dramatically reduced from -18.8 to -7.2 kcal/mol by the coordination with B(C 6 F 5 ) 3 (BCF), which enables an intramolecular single electron transfer from one germylene moiety to another upon heating, forming an intramolecular radical ion pair with diradical character. The work provides an approach to the formation of thermally populated open-shell species of heavier main group elements., (© 2024 Wiley-VCH GmbH.)

Most of the reported work focus on the development of O-, N-, C- and S-glycosylation methods. However, no study explores P(III)-glycosylation reaction. Herein we describe a convenient protocol to realize P(III)-glycosylation process. A simple β-phosphino ester is adopted as P(III)-transfer reagent for this new type of glycosylation via a nucleophilic substitution and release strategy. Diverse phosphine units are introduced to the anomeric center of various sugars efficiently and with excellent stereoselectivity. The value of this method is showcased by the prepared P(III)-sugars as novel linkers in bioactive molecule conjugation, new chiral ligands in metal-catalyzed asymmetric allylic substitutions and organocatalysts. Preliminary mechanistic studies corroborated the designed P(III)-transfer process., (© 2024 Wiley‐VCH GmbH.)

While aromatic diazonium salts are important reagents in organic synthesis, 'Diazonium ions generated from ordinary aliphatic primary amines are usually useless for preparative purposes, since they lead to a mixture of products giving not only substitution by any nucleophile present, but also elimination and rearrangements if the substrate permits.'[1] In this work, we report that the statement is no longer valid, and it is now possible to control diazotization of aliphatic amines by utilizing isopentyl nitrite in HFIP. This transformation enabled electrophilic aromatic substitution with these highly abundant and commercially available alkyl reagents, as well as transforming them into building blocks typically employed in organic synthesis. The methodology opens an avenue for reactions involving aliphatic amines, even such demanding substrates as amino acids, as a source of carbocations thus expanding the degree of chemical space., (© 2024 Wiley‐VCH GmbH.)

Halogenases are spurring a growing interest in the fields of biosynthesis and biocatalysis. Although various halogenases have been identified in numerous natural product biosynthetic pathways, the mechanisms for multiple halogenations and site-selectivity remain largely unclear. In this study, we biochemically characterized FasV, a flavin-dependent halogenase (FDH) that catalyzes five successive chlorinations in the biosynthesis of the naphthacene-containing aromatic polyketide naphthacemycin. This multiple halogenation reaction was elucidated to occur in an orderly fashion, as evidenced by enzyme kinetics, time-course assays, and computational simulations. Crystallographic analyses and mutagenesis studies revealed previously unrecognized amino acid residues, including T53, L81, F93, and I212, that are crucial for controlling regioselectivity and substrate specificity. Based on this, a I212T mutant was generated to exclusively catalyze selective monohalogenation. We propose a novel dual-activation mechanism and demonstrate that the larger binding pocket of FasV makes it a valuable biocatalyst for other substrates with diverse structures. Therefore, this study provides new insight into multi-site polyhalogenases and highlights the potential for engineering FasV-like FDHs for biocatalytic applications., (© 2024 Wiley-VCH GmbH.)

Steroid hormones are C 18 -C 21 -sterane derivatives, featuring the typical 6-6-6-5 ring system. Here we report on a novel C 18 -steroid ring system named batrachane with a contracted A-ring resulting in a 5-6-6-5 ring arrangement. The isolation, structural elucidation, and total synthesis of three members of the novel batrachopolyene family occurring in the tropical frog genus Odontobatrachus is reported. The batrachopolyenes represent an entirely new collection of volatile steroidal natural products produced by anuran amphibians. Alongside the contracted A-ring, each member contains a Δ 16-17 double bond but differs in the central belt of the steroidal structure. To create these atypical structural features, syntheses featuring a combination of Breslow radical chain relay chlorination, Favorskii ring contraction, and Clemmensen reduction proved successful. The occurrence of such compounds in another distal anuran group, the Mantellinae, suggests a more widespread distribution of the batrachane-type compounds among frogs. The new structural steroid type raises questions concerning steroid biosynthesis and reception, as well as distribution in frogs in general and the structures of their hormones., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

With the rise of machine learning (ML), the modeling of chemical systems has reached a new era and has the potential to revolutionize how we understand and predict chemical reactions. Here, we probe the historic dependence on utilizing enantiomeric excess (ee) as a target variable and discuss the benefits of using relative Gibbs free activation energies (ΔΔG ≠ ), grounded firmly in transition-state theory, emphasizing practical benefits for chemists. This perspective is intended to discuss best practices that enhance modeling efforts especially for chemists with an experimental background in asymmetric catalysis that wish to explore modelling of their data. We outline the enhanced modeling performance using ΔΔG ≠ , escaping physical limitations, addressing temperature effects, managing non-linear error propagation, adjusting for data distributions and how to deal with unphysical predictions,in order to streamline modeling for the practical chemist and provide simple guidelines to strong statistical tools. For this endeavor, we gathered ten datasets from the literature covering very different reaction types. We evaluated the datasets using fingerprint-, descriptor-, and graph neural network-based models. Our results highlight the distinction in performance among varying model complexities with respect to the target representation, emphasizing practical benefits for chemists., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Deuterated and tritiated analogs of drugs are valuable compounds for pharmaceutical and medicinal chemistry. In this work, we present a novel hydrogen isotope exchange reaction of drugs using non-directed homogeneous Pd-catalysis. Aromatic C-H activation is achieved by a commercially available pyridine ligand. Using the most convenient and cheapest deuterium source, D 2 O, as the only solvent 39 pharmaceuticals were labelled with clean reaction profiles and high deuterium uptakes. Additionally, we describe the first application of non-directed homogeneous Pd-catalysis for H/T exchange on three different pharmaceuticals by using T 2 O as isotopic source, demonstrating the applicability to the synthesis of radiotracers., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Covalent organic frameworks (COFs) have been demonstrated as promising photocatalysts for hydrogen peroxide (H 2 O 2 ) production. However, the construction of COFs with new active sites, high photoactivity, and wide-range light absorption for efficient H 2 O 2 production remains challenging. Herein, we present the synthesis of a novel azobenzene-bridged 2D COF (COF-TPT-Azo) with excellent performance on photocatalytic H 2 O 2 production under alkaline conditions. Notably, although COF-TPT-Azo differs by only one atom (-N=N- vs. -C=N-) from its corresponding imine-linked counterpart (COF-TPT-TPA), COF-TPT-Azo exhibits a significantly narrower band gap, enhanced charge transport, and prompted photoactivity. Remarkably, when employed as a metal-free photocatalyst, COF-TPT-Azo achieves a high photocatalytic H 2 O 2 production rate up to 1498 μmol g -1  h -1 at pH = 11, which is 7.9 times higher than that of COF-TPT-TPA. Further density functional theory (DFT) calculations reveal that the -N=N- linkages are the active sites for photocatalysis. This work provides new prospects for developing high-performance COF-based photocatalysts., (© 2024 Wiley-VCH GmbH.)

Perfusion dynamics play a vital role in delivering essential nutrients and oxygen to tissues while removing metabolic waste products. Imaging techniques such as magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET) use contrast agents to visualize perfusion and clearance patterns; however, each technique has specific limitations. Hybrid PET/MRI combines the quantitative power and sensitivity of PET with the high functional and anatomical detail of MRI and holds great promise for precision in molecular imaging. However, the development of dual PET/MRI probes has been hampered by challenging synthesis and radiolabeling. Here, we present a novel PET/MRI probe, [ 18 F][Gd(FL 1 )], which exhibits excellent stability comparable to macrocyclic MRI contrast agents used in clinical practice. The unique molecular design of [ 18 F][Gd(FL 1 )] allows selective and expeditious radiolabeling of the gadolinium chelate in the final synthetic step. Leveraging the strengths of MRI and PET signals, the probe enables quantitative in vivo mapping of perfusion and excretion dynamics through an innovative voxel-based analysis. The diagnostic capabilities of [ 18 F][Gd(FL 1 )] were demonstrated in a pilot study on healthy mice, successfully detecting early cases of unilateral renal dysfunction, a condition that is typically challenging to diagnose. This study introduces a new approach for PET/MRI and emphasizes a streamlined probe design for practical synthesis and improved diagnostic accuracy., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Here we report the reaction of aryl thianthrenium salts that allows selective functionalization of the meta position of arenes. The combination of a site-selective thianthrenation with a Catellani reaction provides access to 3,5-dimethylated arenes. The developed reaction is complementary to the previously discovered reductive ipso-alkylation of aryl thianthrenium salts and extends the possibilities for late-stage methylation of arenes with a single aryl thianthrenium salt., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Axially chiral tetrasubstituted alkenes are of increasing value and interest in chemistry-related areas. However, their catalytic asymmetric synthesis remains elusive, owing to the high steric repulsion and relatively low conformational stability. Herein, we disclose the straightforward construction of atropisomeric tetrasubstituted alkenes by effective enantiocontrol in a reaction with vinyl cation intermediates. This copper-catalyzed enantioselective C(sp 2 )-H functionalization of sterically hindered (hetero)arenes with vinyl cations enables the efficient and atom-economical preparation of axially chiral acyclic tetrasubstituted styrenes and pyrrolyl ethylenes with high atroposelectivities. Importantly, this reaction represents the first example of the assembly of axially chiral alkenes via vinyl cations. Computational mechanistic studies reveal the reaction mechanism, origin of regioselectivity, Z/E selectivity and enantioselectivity. The synthetic utility has been demonstrated by diverse product derivatizations, chiral organocatalyst synthesis, as well as further applications in asymmetric catalysis., (© 2024 Wiley-VCH GmbH.)

There is a perpetual need for efficient and mild methods to integrate deuterium atoms into carbon frameworks through late-stage modifications. We have developed a simple and highly effective synthetic route for hydrogen isotope exchange (HIE) in aromatic compounds under ambient conditions. This method utilizes catalytic amounts of hexafluorophosphate (PF 6 - ) in deuterated 1,1,1,3,3,3-hexafluoroisopropanol (HFIP-d 1 O. Phenols, anilines, anisoles, and heterocyclic compounds were converted with high yields and excellent deuterium incorporations, which allows for the synthesis of a wide range of deuterated aromatic compounds. Spectroscopic and theoretical studies show that an interactive H-bonding network triggered by HFIP-d 2 O. Phenols, anilines, anisoles, and heterocyclic compounds were converted with high yields and excellent deuterium incorporations, which allows for the synthesis of a wide range of deuterated aromatic compounds. Spectroscopic and theoretical studies show that an interactive H-bonding network triggered by HFIP-d 1 activates the typically inert P-F bond in PF 6 - for D 2 then triggers HIE, offering a new way to deuterated building blocks, drugs, and natural-product derivatives with high deuterium incorporation via the activation of strong bonds.2 F 2 then triggers HIE, offering a new way to deuterated building blocks, drugs, and natural-product derivatives with high deuterium incorporation via the activation of strong bonds., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Organolithium reagents, known for their low cost, ready availability, and high reactivity, allow fast cross-coupling under ambient conditions. However, their direct cross-coupling with fluoroalkyl electrophiles remains a formidable challenge due to the easy formation of thermo-unstable fluoroalkyl lithium species during the reaction, which are prone to decomposition via rapid α/β-fluoride elimination. Here, we exploit heteroatom-stabilized allylic anions to harness the exceptional reactivity of organolithium reagents, enabling the compatibility of difluoroalkyl halides and facilitating versatile and precise fluorine functionality introduction under mild conditions. In this process, a nickel-catalyzed difluoroalkylation of β,γ-unsaturated α-amino nitrile derived lithium reagents (N-stabilized allyl lithium reagents) with various difluoroalkyl bromides has been developed, opening a new avenue to access fluorinated compounds through catalytic cross-coupling of organolithium reagents with fluoroalkyl electrophiles. This approach allows for the efficient and precise construction of secondary C(sp 3 )-CF 2 R bonds, previously challenging in transition-metal-catalyzed fluoroalkylation reactions due to β-hydride elimination. The rapid fluorine-editing of drugs demonstrates the synthetic versatility and utility of this protocol, showing the perspective in modern drug discovery., (© 2024 Wiley-VCH GmbH.)

Transition metal π-arene complexes enable the dearomatization of benzene rings to access diversified unsaturated carbocycles through multistep synthetic procedures involving sequential addition of nucleophiles and electrophiles. This work details a single-step dearomatization process by reaction of Ru(η 6 -arene) complexes with enolates derived from α-halo or α-(tosyloxy)esters to directly transform π-coordinated arenes to ring-expanded cycloheptatrienes., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The reducing power of iodide anion is an underexplored property that can be used for the cross-electrophile coupling of organic molecules. Herein we harness this trait for the preparation of tertiary amines through the combination of two simple reagents: an electrophilic-carbon precursor and an iminium iodide in a dual role - both as nitrogen-containing building block and as reducing agent. The underlying mechanism of this new C-C bond-formation paradigm is explored through a combination of experiment and quantum chemical calculations., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Herein, a copper(I)-catalyzed asymmetric 1,4-hydroarsination of β-substituted α,β-unsaturated esters is achieved in moderate to excellent yields with high to excellent enantioselectivity, based on the proposed nucleophilic [Cu]-AsPh 2 species. As for α-substituted α,β-unsaturated esters, a 1,4-hydroarsination/enantioselective protonation event occurs smoothly in satisfying results. Furthermore, β-substituted α,β-unsaturated ketone, α,β-unsaturated amide, and α,β-unsaturated phosphine sulfide are well applied in the present catalytic system. Finally, some control experiments show that HAsPh 2 is activated through coordination with the copper(I) catalyst and HAsPh 2 exhibits inferior soft Lewis basicity to HPPh 2 in the presence of a copper(I)-bisphosphine complex., (© 2024 Wiley-VCH GmbH.)

Borazine and its derivatives can be considered critical doping units for engineering hybrid C(sp2)-based molecules with tailored optoelectronic properties. Herein, we report the first synthesis of hexaarylborazines that, bearing ortho-substituted aryl moieties, extend three-dimensionally. Using a one-pot protocol, we first form an electrophilic chloroborazole and then react it with an aryl lithium (ArLi). By selecting the appropriate ortho-substituent, we can guide the ArLi to add to the BN-core in a specific way, ultimately controlling the stereochemical outcome of the three-substitution reaction. Rationalization of the stereochemical model through computational analysis allowed us to show that when aryl lithium nucleophiles bearing rigid long-range ortho-substituents are used, i.e., stiff substituents. The ortho-substituent shields its side of the electrophilic B3N3 core, biasing the incoming ArLi to add anti at each addition step, forming the final tri-aryl borazine exclusively as cc-isomer. Leveraging this stereoselective approach, prototypical multichromophoric borazine derivatives were prepared, and we showcased how the stereochemical arrangement of these chromophores distinctly influences their redox behavior. This methodology paves the way for previously inaccessible borazines to serve as privileged precursors to transcend the conventional bidimensionality associated with graphenoid systems and pioneer the construction of new forms of three-dimensional C(sp2)-based architectures., (© 2024 Wiley‐VCH GmbH.)

Fatty acid synthase (FAS) multienzymes are responsible for de novo fatty acid biosynthesis and crucial in primary metabolism. Despite extensive research, the molecular details of the FAS catalytic mechanisms are still poorly understood. For example, the β-ketoacyl synthase (KS) catalyzes the fatty acid elongating carbon-carbon-bond formation, which is the key catalytic step in biosynthesis, but factors that determine the speed and accuracy of his reaction are still unclear. Here, we report enzyme kinetics of the KS-mediated carbon-carbon bond formation, enabled by a continuous fluorometric activity assay. We observe that the KS is likely rate-limiting to the fatty acid biosynthesis, its kinetics are adapted to the length of the bound fatty acyl chain, and that the KS is also responsible for the fidelity of biosynthesis by preventing intermediates from undergoing KS-mediated elongation. To provide mechanistic insight into KS selectivity, we performed computational molecular dynamics (MD) simulations. We identify positive cooperativity of the KS dimer, which we suggest to affect the conformational variability of the multienzyme. Advancing our knowledge about the KS molecular mechanism will pave the ground for engineering FAS for biotechnology applications and the design of new therapeutics targeting the fatty acid metabolism., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Six-vertex closo-SB 5 Cl 5 (1) and ten-vertex closo-1-SB 9 Cl 9 (2) thiaboranes have been prepared, besides the already known 12-vertex closo-SB 11 Cl 11 (3), from the co-pyrolysis reaction of B 2 Cl 4 with S 2 Cl 2 at 280 °C in vacuo. The compounds are sublimable, off-white solids. Their elemental composition has been determined by high-resolution mass spectrometry. They were further characterized by one- and two-dimensional 11 B NMR spectroscopy and X-ray structure determination for 1 and 3. Ab initio/GIAO/NMR computations support octahedral, bicapped square-antiprismatic, and icosahedral geometries for 1, 2 and 3, respectively, as expected based on their closo-electron counts. 1 is the first isolated example of a neutral polyhedral closo-thiaborane with a cluster size smaller than ten vertices. The solid-state structure of 3 is one of the rare examples of a single-crystal X-ray structure determination of an icosahedral heteroborane reported. The corresponding crystal-packing forces show the different role of chalcogen bonding in these octahedral and icosahedral crystals. In addition, there is a mass-spectrometry evidence for the recurrent formation of further thiaborane homologs of closo-SB n Cl n with n=4, 6, 10, and supra-icosahedral 12., (© 2024 Wiley-VCH GmbH.)

C-H functionalization of purely aliphatic substrates is a challenging endeavor, as the absence of directing groups generally thwarts attempts at regiocontrol. This is particularly true for difunctionalization reactions, where the control of relative stereochemistry poses an additional obstacle. The Baddeley reaction of decalins, despite suffering from strong limitations with regard to yield and generality, stands as one of only few known transformations capable of regio- and stereocontrol in aliphatic C-H functionalization. Herein, we report a regio- and diastereoselective method for the double functionalization of decalins enabling access to a novel, unreported regioisomer in synthetically useful yields. This method was also successfully applied to a range of other alkane substrates, enabling a straightforward synthesis of keto alcohols from the simplest alkane building blocks., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The development of Michael addition reactions to conjugated cyclopropenes is a challenge in organic synthesis due to the fleeting and reactive nature of such strained Michael acceptor systems. Herein, the development of a photochemical approach towards such conjugated cyclopropenes is reported that serves as a strategic entry point to densely functionalized cyclopropanes in a diastereoselective fashion. The process involves the light-mediated generation of transient cyclopropenyl α,β-unsaturated esters from vinyl diazo esters, followed by an organic base catalyzed nucleophilic addition of N-heterocycles to directly access β-N-heterocyclic cyclopropanoic esters. With this synergistic approach, various trisubstituted cyclopropanes bearing N-heteroaryl and N-heterocyclic rings such as indole, pyrrole, benzimidazole, isatin, pyridinone, and quinolinone were accessed efficiently in good yield and decent to good diastereoselectivities. Further, β-indolyl cyclopropanoic acids have been synthesized and were successfully evaluated as FABP-4 inhibitors. Theoretical calculations have been performed to elucidate the mechanism, which was further supported by experimental findings., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The recent development of photoredox and energy transfer catalysis has led to a significant expansion of visible-light-driven chemical transformations. These methods have demonstrated exceptional efficiency in converting a wide range of substrates into radical intermediates and generating open-shell catalytic species. However, the simplification of catalytic systems and the direct generation of highly reactive radical organocatalysts through direct visible-light irradiation from stable precatalysts remains largely an unrealized goal. This challenge is mainly due to the limited availability of precatalysts that are responsive to visible light. Herein, we introduce a new class of bench-stable dicationic disulfuranes, which release highly reactive thiyl radicals upon blue-light excitation. Spectroscopic and computational studies reveal that this reactivity arises from a combination of structural features and intermolecular interactions. This family of molecules has been employed to catalyze radical cascades previously incompatible with photoredox conditions, enabling the efficient formation of 1,2-dioxolanes and 1,3-hydroxyketones in excellent yields and short reaction times., (© 2024 Wiley-VCH GmbH.)

Infrared (IR) transparent polymer materials prepared by inverse vulcanization, as a promising candidate to replace inorganic materials, are new materials for constructing key devices in IR optics. However, it is difficult to achieve a balance between infrared optical and thermal properties in polymers due to the intrinsic infrared absorption of organic materials. Herein, our strategy is to construct a high boiling point symmetrical molecular norbornadiene derivative cross-linking agent (DMMD) which can be inverse vulcanized with molten sulfur, and obtain Poly (S-r-DMMD) with different sulfur content by controlling the feed ratio of sulfur. With the rigid core and low IR activity in DMMD, the prepared polymers exhibit tunable thermal properties (T g : 98.3-119.8 °C) and high IR transmittance (medium-wave infrared region (MWIR): 42.9-52.6 %; long-wave infrared region (LWIR): 1.5-5.29 %). In addition, Poly (S-r-DMMD) can be used to prepare large-size free-standing Fresnel lenses for IR imaging by simple hot-pressing, which provides flexibility in the design and production of IR fine lenses. This study provides a novel strategy for balancing the thermal and optical properties of IR transparent polymer materials, while providing relevant references for balancing the IR optical and thermal properties of polymer materials., (© 2024 Wiley-VCH GmbH.)

Selective C-F bond activation through a radical pathway in the presence of multiple C-H bonds remains a formidable challenge, owing to the extraordinarily strong bond strength of the C-F bond. By the aid of density functional theory calculations, we disclose an innovative concerted electron-fluoride transfer mechanism, harnessing the unique reactivity of Lewis base-boryl radicals to selectively activate the resilient C-F bonds in fluoroalkanes. This enables the direct abstraction of a fluorine atom and subsequent generation of an alkyl radical, thus expanding the boundaries of halogen atom transfer reactions., (© 2024 Wiley-VCH GmbH.)

Methods enabling direct C-H alkylation of heterocycles are of fundamental importance in the late-stage modification of natural products, bioactive molecules, and medicinally relevant compounds. However, there is a scarcity of a general strategy for the direct C-H alkylation of a variety of heterocycles using commercially available alkyl surrogates. We report an operationally simple palladium-catalyzed direct C-H alkylation of heterocycles using alkyl halides under the visible light irradiation with good scalability and functional group tolerance. Our studies suggest that the photoinduced alkylation proceeds through a cascade of events comprising, site-selective alkyl radical addition, base-assisted deprotonation, and oxidation. A combination of experiments and computations was employed for the generalization of this strategy, which was successfully translated towards the modification of natural products and pharmaceuticals., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Excited states of radical anions derived from the photoreduction of stable organic molecules are suggested to serve as potent reductants. However, excited states of these species are too short-lived to allow bimolecular quenching processes. Recently, the singlet excited state of Meisenheimer complexes, which possess a long-lived excited state, was identified as the competent species for the reduction of challenging organic substrates (-2.63 V vs. SCE, saturated calomel electrode). To produce reasonably stable and simply accessible different Meisenheimer complexes, the addition of nBuLi to readily available aromatic heterocycles was investigated, and the photoreactivity of the generated species was studied. In this paper, we present the straightforward preparation of a family of powerful photoreductants (*E ox <-3 V vs. SCE in their excited states, determined by DFT and time-dependent TD-DFT calculations; DFT, density functional theory) that can induce dehalogenation of electron-rich aryl chlorides and to form C-C bond through radical cyclization. Photophysical analyses and computational studies in combination with experimental mechanistic investigations demonstrate the ability of the adduct to act as a strong electron donor under visible light irradiation., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Metal-free synthesis of heterocycles is highly sought after in the pharmaceutical industry and has garnered widespread attention due to eliminating the need to remove trace metal catalysts from the reaction. We report a radical 6-endo addition method for pyridine synthesis from cyclopropylamides and alkynes under metal-free conditions. Various terminal and substituted alkynes are inserted as C2 units into cyclopropylamides to synthesize versatile pyridines with 57 examples. Mechanistic investigations and computational studies indicate the unprecedented 6-endo-trig addition of vinyl radicals to the imine nitrogen atom rather than the conventional 5-exo-trig addition to the imine carbon atom, in which the hypervalent iodine(III) plays a critical role. This reaction easily scales up with excellent functional group compatibility and suits the late-stage pyridine installation on complex molecules., (© 2024 Wiley-VCH GmbH.)

Isomerisation reactions provide streamlined routes to organic compounds which are otherwise hard to directly synthesise. The most common forms are positional, geometrical or stereochemical isomerisations which involve the relocation of a double bond or a change in relative location of groups in space. In contrast, far fewer examples of structural (or constitutional) isomerisation exist where the connectivity between atoms is altered. The development of platforms capable of such rearrangement poses a unique set of challenges because chemical bonds must be selectively cleaved, and new ones formed without overall addition or removal of atoms. Here, we show that a dual catalytic system can enable the structural isomerisation of readily available allylic alcohols into more challenging-to-synthesise α-arylated ketones via a H-atom transfer initiated semi-pinacol rearrangement. Key to our strategy is the combination of a cobalt catalyst and photocatalyst under reductive, protic conditions which allows intermediates to propagate catalytic turnover. By providing an unusual disconnection to structural motifs which are difficult to access through direct arylation, we anticipate inspiring other advanced catalytic isomerisation strategies that will further retrosynthetic logic for complex molecule synthesis., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Metal migration strategy can offer BH functionalization of o-carboranes at different positions from where initial bond activation occurs to achieve bifunctionalized o-carboranes in one reaction. We report in this article an enantioselective 3,4-bifunctionalization of o-carboranes via asymmetric Pd migration with a high efficiency and up to 98 % ee. This asymmetric catalysis has a broad substrates scope, leading to the preparation of a class of chiral-at-cage o-carborane derivatives. The enantiocontrol model is suggested on the basis of density functional theory (DFT) results, where the chiral Trost ligand plays a crucial role in this enantioselective Pd migration from exo-alkenyl sp 2 C to the cage B(4) position of o-carborane., (© 2024 Wiley-VCH GmbH.)

The flexible acquisition of substrates from nutrient pools is critical for microbes to prevail in competitive environments. To acquire glucose from diverse glycoside and disaccharide substrates, many free-living and symbiotic bacteria have developed, alongside hydrolysis, a non-hydrolytic pathway comprised of four biochemical steps and conferred from a single glycoside utilization gene locus (GUL). Mechanistically, this pathway integrates within the framework of oxidation and reduction at the glucosyl/glucose C3, the eliminative cleavage of the glycosidic bond and the addition of water in two consecutive lyase-catalyzed reactions. Here, based on study of enzymes from the phytopathogen Agrobacterium tumefaciens, we reveal a conserved Mn 2+ metallocenter active site in both lyases and identify the structural requirements for specific catalysis to elimination of 3-keto-glucosides and water addition to the resulting 2-hydroxy-3-keto-glycal product, yielding 3-keto-glucose. Extending our search of GUL-encoded putative lyases to the human gut commensal Bacteroides thetaiotaomicron, we discover a Ca 2+ metallocenter active site in a putative glycoside hydrolase-like protein and demonstrate its catalytic function in the eliminative cleavage of 3-keto-glucosides of opposite (α) anomeric configuration as preferred by the A. tumefaciens enzyme (β). Structural and biochemical comparisons reveal the molecular-mechanistic origin of 3-keto-glucoside lyase stereo-complementarity. Our findings identify a basic set of GUL-encoded lyases for glucoside metabolism and assign physiological significance to GUL genetic diversity in the bacterial domain of life., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

We herein describe the first example of ligand-controlled, copper-catalyzed regiodivergent asymmetric difunctionalization of terminal alkynes through a cascade hydroboration and hydroallylation process. The catalytic system, consisting of (R)-DTBM-Segphos and CuBr, could efficiently achieve asymmetric 1,1-difunctionalization of aryl terminal alkynes, while ligand switching to (S,S)-Ph-BPE could result in asymmetric 1,2-difunctionalization exclusively. In addition, alkyl substituted terminal alkynes, especially industrially relevant acetylene and propyne, were also valid feedstocks for asymmetric 1,1-difunctionalization. This protocol is characterized by good functional group tolerance, a broad scope of substrates (>150 examples), and mild reaction conditions. We also showcase the value of this method in the late-stage functionalization of complicated bioactive molecules and simplifying the synthetic routes toward the key intermediacy of natural product (bruguierol A). Mechanistic studies combined with DFT calculations provide insight into the mechanism and origins of this ligand-controlled regio- and stereoselectivity., (© 2024 Wiley-VCH GmbH.)

Molecular-recognition events are highly relevant in biology and chemistry. In the present study, we investigated such processes in the solid state under mechanochemical conditions using the formation of racemic phases upon reacting enantiopure entities as example. As test systems, α-(trifluoromethyl)lactic acid (TFLA) and the amino acids serine and alanine were used. The effects of ball-milling and resonant acoustic mixing (RAM) on the formation of racemic phases were probed by using solid-state Nuclear Magnetic Resonance (NMR) spectroscopy. In a mixer mill, a highly efficient and fast racemic phase formation occurred for both TFLA and the two amino acids. RAM led to the racemic phase for TFLA also, and this process was facilitated upon employing pre-milled enantiopure entities. In contrast, under comparable conditions RAM did not result in the formation of racemic phases for serine and alanine., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Real-time monitoring of molecular transformations is crucial for advancements in biotechnology. In this study, we introduce a novel self-assembling 19 F-labeled nuclear magnetic resonance (NMR) probe that disassembles upon interaction with various nucleotides. This interaction not only activates the 19 F signals but also produces distinct signatures for each specific component, thereby enabling precise identification and quantification of molecules in evolving samples. We demonstrate the capability of this probe for real-time monitoring of adenosine triphosphate (ATP) hydrolysis and screening potential enzyme inhibitors. These applications highlight the probe's significant potential in enzyme analysis, drug development, and disease diagnostics., (© 2024 Wiley-VCH GmbH.)

Amide bioisoterism is a widely used strategy in drug development to fine-tune physicochemical, pharmacokinetic, and metabolic properties, eliminate toxicity and gain intellectual property rights in uncharted chemical space. Of these, oxetane-amines offer particularly exciting possibilities as bioisosteres, although they are less frequently investigated than warranted due to the lack of simple and widely applicable synthetic methods. Herein, we report a two-step, practical, modular, robust, and scalable method for the construction of oxetane-containing amide bioisosteres that relies on the readily available oxetan-3-one. This operationally simple procedure exploits the enhanced reactivity of the keto group of the commercially available oxetan-3-one to form amine-benzotriazole intermediates, which springloaded adducts are then reacted with various aliphatic and aromatic organometallic reagents under mild conditions to afford various amino-oxetanes in good to high yields. The simplicity and broad applicability of the method greatly facilitates the synthesis of derivatives that were previously difficult or impossible to produce. The usefulness of this method in the field medicinal chemistry was also demonstrated by eliminating the well-known metabolic problem of ketoconazole., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Bioactive dimeric (pre-)anthraquinones are ubiquitous in nature and are found in bacteria, fungi, insects, and plants. Their biosynthesis via oxidative phenol coupling (OPC) is catalyzed by cytochrome P450 enzymes, peroxidases, or laccases. While the biocatalysis of OPC in molds (Ascomycota) is well-known, the respective enzymes in mushroom-forming fungi (Basidiomycota) are unknown. Here, we report on the biosynthesis of the atropisomers phlegmacin A 1 and B 1 of the mushroom Cortinarius odorifer. The biosynthesis of these unsymmetrically 7,10'-homo-coupled dihydroanthracenones was heterologously reconstituted in the mold Aspergillus niger. Methylation of the parental monomer atrochrysone to its 6-O-methyl ether torosachrysone by the O-methyltransferase CoOMT1 precedes the regioselective homocoupling to phlegmacin, catalyzed by the enzyme CoUPO1 annotated as an "unspecific peroxygenase" (UPO). Our results reveal an unprecedented UPO reaction, thereby expanding the biocatalytic portfolio of oxidative phenol coupling beyond the commonly reported enzymes. The results show that Basidiomycota use peroxygenases to selectively couple aryls independently of and convergently to any other group of organisms, emphasizing the central role of OPC in natural processes., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The hydrostannylation of white phosphorus (P 4 ) allows this crucial industrial precursor to be easily transformed into useful P 1 products via direct, 'one pot' (or even catalytic) procedures. However, a thorough mechanistic understanding of this transformation has remained elusive, hindering attempts to use this rare example of successful, direct P 4 functionalization as a model for further reaction development. Here, we provide a deep and generalizable mechanistic picture for P 4 hydrostannylation by combining DFT calculations with in situ 31 P NMR reaction monitoring and kinetic trapping of previously unobservable reaction intermediates using bulky tin hydrides. The results offer important insights into both how this reaction proceeds and why it is successful and provide implicit guidelines for future research in the field of P 4 activation., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Despite impressive advances in the construction of enantioenriched silacarbocycles featuring silicon-stereogenic centers via a selection of well-defined sila-synthons, the development of a more convenient and economic method with readily available starting materials is significantly less explored and remains a considerable challenge. Herein, we report the first example of copper-catalyzed sequential hydrosilylation of readily accessible methylenecyclopropanes (MCPs) and primary silanes, affording an efficient and convenient route to a wide range of chiral silacyclopentanes bearing consecutive silicon- and carbon-stereogenic centers with excellent enantio- and diastereoselectivities (generally ≥98 % ee, >25 : 1 dr). Mechanistic studies reveal that these reactions combine copper-catalyzed intermolecular ring-opening hydrosilylation of aryl MCPs and intramolecular asymmetric hydrosilylation of the resultant Z/E mixture of homoallylic silanes., (© 2024 Wiley-VCH GmbH.)

Enantioselective synthesis of (spiro)cyclobutane derivatives poses significant challenges yet holds promising applications for both synthetic and medicinal chemistry. We report here a nickel-catalyzed asymmetric syn-hydrometalative 4-exo-trig cyclization of 1,4-alkynones to synthesize alkenyl cyclobutanols with a tetrasubstituted stereocenter. This strategy features a broad substrate scope, delivering a variety of trifluoromethyl-containing rigid (spiro)carbocycle skeletons in good yields with high enantioselectivities (up to 84 % yield and 98.5 : 1.5 er). The synthetic utility is demonstrated through stereospecific transformations into fused spiro molecules. Experimental and computational mechanistic studies indicate that the reaction is initiated by an active Ni-H species, with carbonyl-directed hydrometalation as the key for regioselective control. This catalytic method provides a general solution for regioselective hydrofunctionalization of alkynes and represents an efficient reaction pattern for assembling highly strained enantioenriched bioisosteres., (© 2024 Wiley-VCH GmbH.)

Axially chiral biaryl compounds are ubiquitous scaffolds in natural products, bioactive molecules, chiral ligands and catalysts, but biocatalytic methods for their asymmetric synthesis are limited. Herein, we report a highly efficient biocatalytic route for the atroposelective synthesis of biaryls by dynamic kinetic resolution (DKR). This DKR approach features a transient six-membered aza-acetal-bridge-promoted racemization followed by an imine reductase (IRED)-catalyzed stereoselective reduction to construct the axial chirality under ambient conditions. Directed evolution of an IRED from Streptomyces sp. GF3546 provided a variant (S-IRED-Ss-M11) capable of catalyzing the DKR process to access a variety of biaryl aminoalcohols in high yields and excellent enantioselectivities (up to 98 % yield and >99 : 1 enantiomeric ratio). Molecular dynamics simulation studies on the S-IRED-Ss-M11 variant revealed the origin of its improved activity and atroposelectivity. By exploiting the substrate promiscuity of IREDs and the power of directed evolution, our work further extends the biocatalysts' toolbox to construct challenging axially chiral molecules., (© 2024 Wiley-VCH GmbH.)

Metallo-supramolecular cages have garnered tremendous attention for their diverse yet molecular-level precision structures. However, the physical properties of these supramolecular ensembles, which are of potential significance in molecular electronics, remain largely unexplored. We herein constructed a series of octahedral metallo-cages and cage-fullerene complexes with notably enhanced structural stability. As such, we could systematically evaluate the electrical conductivity of these ensembles at both the single-molecule level and aggregated bulk state (as well-defined films). Our findings reveal that counteranions and fullerene guests play a pivotal role in determining the electrical conductivity of the aggregated state, while such effects are less significant for single-molecule conductance. Both the counteranions and fullerenes effectively tune the electronic structures and packing density of metallo-supramolecular assemblies, and facilitate efficient charge transfer between the cage hosts and fullerenes, resulting in a notable one order of magnitude increase in the electrical conductivity of the aggregated state., (© 2024 Wiley-VCH GmbH.)

Terpenes occupy a unique place among the secondary metabolites due to their broad utility and extraordinary structural diversity. Their synthesis via polyene cyclization, either biomimetic or enzymatic, represents the cutting edge of modern synthetic chemistry. However, these endeavors have been inherently tied to the availability of natural and non-natural acyclic polyene starting materials. Herein, we report an oxetane-based platform for the modular construction of oxygenated polyolefins with precise geometric control. This "tail-to head" iterative method leverages the site-selective cross-metathesis of terminal olefins to form an alkylidene oxetane moiety and the regioselective ring opening of alkenyl-oxetanes for chain elongation. In addition, the unique and peculiar propensity of alkylidene oxetane fragment in various reactions was also revealed and exploited for site-selective functionalization, cyclization, and as a protecting group in polyenes., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)