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The dehydrocoupling of terminal alkynes and hydrosilanes catalyzed by alkaline-earth complexes: calcium, strontium and, most prominently, barium, is reported. [Ba{N(SiMe₃)₂}₂.(thf)₂] (1) is a convenient precatalyst, affording conversions in the range 75–95+% and good chemoselectivity for substrates bearing aromatic substituents, e.g., with the benchmark phenylacetylene and phenyldimethylhydrosilane. Over 20 different combinations of substrates were coupled, typically over 12–24 h at 90 °C with a 5 mol-% loading of 1. Reaction rates increase upon descending group 2, according to Ca < Sr < Ba. Kinetic analysis performed for the coupling of our benchmark substrates catalyzed by 1 in pyridine-d₅ allows for the determination of the rate law r = k.[barium]¹.[PhMe₂SiH]¹, with ΔH^‡ = 12.7(1) kcal mol^–1 and ΔS^‡= –42.8(1) cal mol^–1K^–1 consistent with a kinetically affordable, albeit relatively slow, reaction. DFT calculations conducted on the system 1/pyridine indicate the mono-solvated [Ba{N(SiMe₃)₂}₂.pyridine] to be the prevailing catalyst, with a rate-determining step consisting of the protonolysis between a [Ba]-hydride intermediate and floating HN(SiMe₃)₂. Compared to Ca and Sr, the greater efficiency of Ba precatalysts stems from the greater ability of barium to lose precoordinated pyridine and, thus, to generate the catalytically competent mono-solvated species.

The Front Cover portrays a phosphinine-borane adduct that promotes a new mode of C─N σ─bond activation reaction that finally results in the P-functionalization of the aromatic phosphorus heterocycle. More information can be found in the Research Article by Z. Benkő, C. Müller and co-workers (DOI: 10.1002/ceur.202500280) Artwork by Linus Lohs, Samantha Frank and Christian Müller.

We present a method for the rapid assembly of highly substituted 1,4-benzodiazepin-2-ones by the addition of unsymmetrical imides to arynes, the subsequent deprotection of a protected amino functionality followed by immediate ring closure. An optimized procedure for the synthesis of diversely substituted unsymmetrical imides was developed, granting access to a large pallet of benzodiazepine precursors. This allows for the application of this protocol in a modular fashion, which is demonstrated for both the unsymmetrical imides and the benzodiazepines. Ultimately, we thereby reveal rapid access to a large variety of densely functionalized benzodiazepine cores.

The Cover Feature depicts the interaction of linearly and circularly polarized light with a series of oligoamide foldamers bearing different lateral electron-donating groups. Using advanced quantum chemistry methods, this work provides the first computational chemistry investigation of their linear and nonlinear (chir)optical responses. More information can be found in the Research Article by B. Champagne and co-workers (DOI: 10.1002/ceur.202500404).

Cleavage by γ-secretase within the transmembrane domain (TMD) of amyloid precursor protein (APP) generates Aβ peptides that can accumulate in amyloid plaques in Alzheimer's disease pathogenesis. How γ-secretase selects its substrates has been an enigma as they do not have a consensus sequence. In our previous study, we discussed a dynamic signature that controls internal bending/kinking and orientation of the two halves of the TMD. The extent, however, had remained ambiguous due to limitations of NOE-based NMR structure determination. To solve this question, we measured residual dipolar couplings (RDCs) of APP-TMD, using a polyethylene glycol gel-based alignment medium with TFE/water mixtures. Using ¹H¹⁵N RDCs, we analyzed the conformations of APP-TMD and two mutants, G38L and G38P, which previously had differed significantly in bend and orientation and cleavage efficiency by γ-secretase. By fitting snapshots from a molecular dynamics trajectory, we analyzed how well structures matched the measured RDC values. This indicated that G38L retained mainly its relatively straight conformation, whereas bent and—in the case of G38P—locally unfolded structures likewise contribute dynamically to the other two. The RDC selected structures thus reproduce the features of the NOE-derived structures, but show that all three TMDs retain some conformational adaptability.

High-entropy alloy (HEA) nanoparticles (NPs) have been subject to increasing interest as prospective catalyst materials. However, highly controllable synthesis methods for HEA NPs remain scarce. To address this issue, we present a systematic study of the synthesis parameter space in a simple colloidal synthesis approach where IrPdPtRuRh NPs were synthesised in triethylene glycol. We show that ultra-small (1–3 nm), single-phase HEA NPs can be synthesised through a hot-injection synthesis approach. In contrast, multiple phases are observed when a one-pot synthesis is carried out. We also show that the particle sizes and morphologies are affected by the choice of metal precursor counterion, and further investigate the dependence of metal reduction on the reaction temperature. Additionally, we present the synthesis of mixed noble/non-noble-metal IrPdPtRuNi and IrPdPtRuCo HEA NPs. By carrying out reduction kinetics experiments, we relate phase separation and compositional gradients of some of the synthesised samples to large differences in the reduction rates of the reacting metals. The individual metal reduction rates are found to vary depending on which other elements are present during particle formation. These results emphasise the importance of understanding the chemical landscape during reaction for the controlled synthesis of HEA NPs.

While biocatalysis has rapidly become a versatile tool in the synthetic chemist's toolbox, one of its main benefits, the broad cross-compatibility of enzymes, which could lead to cell biochemistry-like artificial metabolisms, is still underutilized in organic synthesis. Herein, we demonstrate the power of biocatalysis with an integrated single-pot operation for the total synthesis of the fungal tenuipesone spirolactones directly from the biorefinery side stream furfural. An assembly of six enzymes at the core of a route design covering five linear steps delivers the tenuipesones in overall yields up to 72% (i.e. 94% per individual step). Careful selection of specific enzyme combinations allows to produce either of the enantiomers in excellent optical purities, facilitating the reassignment of the metabolites’ absolute configurations. This one-pot process highlights the immense potential of complex multienzyme in vitro metabolisms and may inspire a much broader implementation of biocatalytic retrosynthesis to develop streamlined routes to other target scaffolds.

Gold nanoparticles (AuNPs) stabilized by N-heterocyclic carbenes (NHCs) represent robust alternatives to thiol-protected counterparts owing to the NHCs’ strong AuC bonds that provide enhanced stability. While NHC-capped AuNPs with a single type of carbene have been reported many times, strategies to introduce multiple NHC ligands on the same nanoparticle remain unexplored. Here, we investigate NHC-for-NHC ligand exchange on AuNPs stabilized either by benzimidazol-2-ylidene or by mesoionic triazolylidene scaffolds, employing an in situ generated free carbene route. Prior to ligand exchange, the formation and stability of the studied NHCs from the corresponding azolium salts were examined and characterized by NMR spectroscopy. In situ NMR studies of the exchange reaction showed no evidence of ligand substitution under argon, the conventional atmosphere for free NHC intermediates. Although no exchange was detected by NMR, X-ray photoelectron spectroscopy (XPS) analysis of the purified AuNPs revealed that ligand substitution had in fact occurred. Further investigation indicated that oxygen plays a key role in promoting the exchange, and that its involvement is also associated with oxidation of the gold core and the formation of NHC-Au(I) complexes. Taken together, our results highlight the complexity of NHC-for-NHC exchange on AuNPs by the free carbene route and point to the need for alternative strategies to achieve controlled ligand substitution.

Following previous work on helicene–porphyrin conjugates in which carbo[6]helicene are connected to zinc-porphyrin via phenyl-bis-ethynyl bridges (Por(Zn)-H[6]¹, series 1), and displaying clear exciton coupling (EC) chirality, novel carbo[6]helicenes derivatives substituted at their 2,15 positions by zinc-porphyrin units are prepared, either through a triple bond (Por(Zn)-H[6]², series 2), or through an alkynyl-phenyl bridge (Por(Zn)-H[6]³, series 3). Series 2 is also synthesized with free porphyrins or different metals [Ni(II) and Pd(II)]. Their photophysical and chiroptical properties (electronic circular dichroism and circularly polarized luminescence) are characterized, and it is examined how i) the distance between the porphyrin units and ii) the metal type impacted these properties. Experimental and theoretical analyses highlight strong responses originating from EC chirality in combination with the typical helicene-centered optical activity. The Por(Zn)-H[6]² system displaying strong absorption dissymmetry factors is then selected to experimentally examine the chiral-induced spin selectivity effect by magnetic conductive atomic force microscopy; a spin polarization of 50% is measured.

Functionalized benzosultam and sulfonamide derivatives represent privileged pharmacophores in medicinal chemistry. However, noncanonical amino acids (ncAAs) featuring benzosultam side chains remain underexplored for peptide therapeutics, despite significant advances in peptide drug development. Herein, we report the promiscuous activity of the PLP-dependent decarboxylative aldolase UstD in catalyzing β-Mannich reactions. An engineered variant, UstD2.0_S60A, was developed and applied to synthesize 23 enantioenriched ncAAs, achieving yields up to 96%, a total turnover number (TTN) of 7500, and excellent stereoselectivity (>95:5 dr, >99:1 er). The reaction is scalable to gram quantities for preparative applications. This study facilitates the future use of benzosultam-containing ncAAs in peptide chemistry and highlights the opportunity of engineering aldolases for non-natural Mannich reaction to access chiral amine products.