Thomas Weyhermüller

The rhodium-catalyzed asymmetric hydroformylation (AHF) of vinyl ethers provides a powerful synthetic step to yield chiral aldehydes as products or intermediates for industrially relevant fine chemicals. Out of the 40 chiral ligands tested, the phosphine-phosphorodiamidite (S,S,RP,S)-BettiPhos L7 and the phosphine-phosphoramidite ligand L6 performed best in this transformation, combining high activity, regio- and enantioselectivity. Branched 2-aryloxypropionaldehydes (16 examples) were obtained with b/l-ratios ranging from 3.1:1 to exclusive branched products, and with enantioselectivities between 79 and 94% ee. Interestingly, for these substrates, the selective decomposition of the linear aldehydes to the respective arenols and acrolein via β-hydride elimination was observed. Branched 2-alkyloxypropionaldehydes (3 examples) were obtained with fair b/l-ratios (1.7:1–2.6:1) and good to high enantioselectivities (85–95% ee). The utility of this transformation was demonstrated by synthesizing the commercial herbicide (R)-Mecoprop on a gram scale in 69% yield and 91% ee via hydroformylation of 4-chloro-2-methyl-1-(vinyloxy)benzene, followed by oxidation. The catalytic system could also be used under slightly modified reaction conditions for reductive asymmetric hydroformylation to produce in one-pot chiral 2-aryloxypropanols. The synthetic potential was further explored by applying the tandem asymmetric hydrohydrazonemethylation (AHHM) followed by reduction, yielding γ-chiral N′-substituted acetohydrazides as shown for 6 examples. Hydrogenolysis of the crude product mixtures results in the corresponding chiral primary amines, as demonstrated in the synthesis of 2-phenoxypropanamine from (vinyloxy)benzene with an overall yield of 74% and 94% ee on a gram scale. Moreover, another tandem reaction—specifically, the asymmetric hydrosulfiniminomethylation (AHSM)—enables access to halogen-containing chiral primary amines, as demonstrated by the synthesis of 2-(4-chlorophenoxy)propanamine in an overall yield of 53% and >99% ee.

We report an electrochemical platform for the direct decarboxylative coupling of structurally diverse carboxylic acids with para ‐quinones, enabling a single‐step approach to rapidly construct complex molecular architectures without pre‐functionalization, stoichiometric oxidants, or metal salts. Radical intermediates generated through direct anodic oxidation of carboxylic acids mediate efficient C(sp ³ )─C(sp ² ) decarboxylative cross‐coupling, thereby expanding the synthetic scope of electrochemical radical functionalization. The method demonstrates broad functional group tolerance across diverse carboxylic acids, with aromatic and aliphatic functionalization, and provides streamlined access to pharmaceutically relevant scaffolds, including antimalarial motifs and intermediates associated with east coast fever treatment. Additionally, the method was successfully scaled on a 2 g scale. In contrast to the majority of known procedures, this electrochemical approach preserves synthetically valuable halide substituents on the para ‐quinone core, including bromides, enabling further modification of the derived product. In addition, this protocol enables selective transfer of fully deuterated methyl groups from readily available acetic acid‐ d ₄ to pharmaceutically relevant target molecules while preserving the deuterium content, avoiding use of hazardous methylating reagents. As a representative application, the selectively deuterated antimalarial lead structure plasmidone‐ d ₃ was synthesized successfully in two electrochemical steps from commercially available starting materials. Mechanistic investigations support a proposed electrode surface‐mediated stepwise E ₁ C ₁ C ₂ E ₂ C ₃ pathway.

Electrochemically generated para -periodate enables a simple and scalable Witkop–Winterfeldt-type oxidation of indole derivatives, providing an alternative one-pot/one-step protocol to synthesize quinolones and pyrrolo[3,2- b ]quinolones.

β-Methyl-branched α-amino acids are important motifs in peptide therapeutics. However, only few methods on their synthesis have been reported to date. Herein we report an efficient, one-step synthesis of these β-Me-branched α-amino acids through the deoxygenative arylation of threonine, yielding a diverse scope of noncanonical α-amino acids with good functional group tolerance. Our method could also be extended to the deoxygenative arylation of 3-hydroxyproline, giving access to various therapeutically relevant arylated amino acids.

We established an electrochemical platform for the direct decarboxylative coupling of various carboxylic acids with para -quinones. This single-step approach rapidly constructs complex molecular architectures without pre-functionalization and offers a handle for accessing drug-like scaffolds. By generating radicals via direct anodic oxidation of carboxylic acids, this approach expands the synthetic toolbox for electrochemical sp ³ –sp ² decarboxylative couplings. The method demonstrates excellent functional group tolerance across diverse carboxylic acids, including both aromatic and aliphatic substrates. Furthermore, it enables synthesis of various antimalarial scaffolds and pharmaceutical precursors for east coast fever treatment. The method was successfully scaled up 16-fold, confirming its robustness. This electrochemical approach preserves halide moieties such as bromide on the para -quinone core and therefore allows further modification of the derived product, demonstrating the formation of a platform compound. The protocol further enables transfer of fully deuterated methyl groups from acetic acid- d ₄ to pharmaceutically relevant target molecules while preserving the deuterium content without the use of hazardous methyl group transfer agents. A selectively deuterated antimalarial lead structure was synthesized successfully in two electrochemical steps from readily available starting materials.

Despite the vast number of reports on benzimidazoles, 1,2-substituted N-amido benzimidazoles remain an underrepresented and scarcely accessible compound class with promising pharmacological relevance. We present a safe, reliable electrochemical protocol that provides easy access to those structures. The reaction exhibits broad functional group tolerance and affords the target compounds in ≤89% yields.

An electrochemical one-pot synthesis of enaminyl sulfonate esters was established, featuring a quasidivided cell under constant current conditions. The multicomponent reaction utilizes simple and readily available alkylamines and an easy-to-use stock solution of SO₂ and alcohols. Omission of additional supporting electrolyte through in-situ-generated monoalkylsulfite facilitates the downstream processing. A diverse scope with more than 28 examples and yields up to 85% as well as a 20-fold scale-up reaction prove the feasibility of this novel protocol.

An inner-sphere approach to aldehyde electrohydrogenation leads to a key nickeloxirane. Protonation of that intermediate yields the hydrogenation products, but electrocatalysis remains challenging.

The synergistic interaction between Mn and Fe centers is investigated via a comprehensive analysis of full 1s3p resonant inelastic X-ray scattering (RIXS) planes at both the Fe and Mn K-edges in a series of homo- and heterometallic molecular systems. Deconvolution of the experimental two-dimensional 1s3p RIXS maps provides insights into the modulation of metal-ligand covalency and variations in the metal multiplet structure induced by subtle electronic structural differences imposed by the presence of the second metal. These modulations in the electronic structure are key toward understanding the reactivity of biological systems with active sites that require heterometallic centers, including MnFe purple acid phosphatases and MnFe ribonucleotide reductases. Herein, we demonstrate the capabilities of 1s3p RIXS to provide information on the excited state energetics in both element- and spin-selective fashion. The contributing excited states are identified and isolated by their multiplicity and π- and σ-contributions, building a conceptual bridge between the electronic structures of metal centers and their reactivity. The ability of the presented 1s3p RIXS methodology to address fundamental questions in transition metal catalysis reactivity is highlighted.