Neil A. Strotman

Electrochemical synthesis can provide more sustainable routes to industrial chemicals^1,2,3. Electrosynthetic oxidations may often be performed ‘reagent-free’, generating hydrogen (H₂) derived from the substrate as the sole by-product at the counter electrode. Electrosynthetic reductions, however, require an external source of electrons. Sacrificial metal anodes are commonly used for small-scale applications⁴, but more sustainable options are needed at larger scale. Anodic water oxidation is an especially appealing option^1,5,6, but many reductions require anhydrous, air-free reaction conditions. In such cases, H₂ represents an ideal alternative, motivating the growing interest in the electrochemical hydrogen oxidation reaction (HOR) under non-aqueous conditions^{7,8,9,10,11,12}. Here we report a mediated H₂ anode that achieves indirect electrochemical oxidation of H₂ by pairing thermal catalytic hydrogenation of an anthraquinone mediator with electrochemical oxidation of the anthrahydroquinone. This quinone-mediated H₂ anode is used to support nickel-catalysed cross-electrophile coupling (XEC), a reaction class gaining widespread adoption in the pharmaceutical industry^13,14,15. Initial validation of this method in small-scale batch reactions is followed by adaptation to a recirculating flow reactor that enables hectogram-scale synthesis of a pharmaceutical intermediate. The mediated H₂ anode technology disclosed here offers a general strategy to support H₂-driven electrosynthetic reductions.

Electrochemical synthesis can provide more sustainable routes to industrial chemicals. Electrosynthetic oxidations often may be performed "reagent-free", generating H2 derived from the substrate as the sole byproduct at the counter electrode. Electrosynthetic reductions, however, require an external source of electrons. Sacrificial metal anodes are commonly used for small-scale applications, but more sustainable options are needed at large scale. Anodic water oxidation is an especially appealing option, but many reductions require anhydrous, air-free reaction conditions. This constraint motivates the growing interest in the electrochemical hydrogen oxidation reaction (HOR) under non-aqueous conditions. Here, we report a mediated H2 anode that achieves indirect electrochemical oxidation of H2 by pairing thermal catalytic hydrogenation of an anthraquinone mediator with electrochemical oxidation of the anthrahydroquinone. This quinone-mediated H2 anode is used to support nickel-catalyzed cross-electrophile coupling (XEC), a reaction class gaining widespread adoption within the pharmaceutical industry. Initial validation of this method in small-scale batch reactions is followed by adaptation to a recirculating flow reactor that enables hectogram-scale synthesis of a pharmaceutical intermediate. The mediated H2 anode technology disclosed here offers a general strategy to support H2-driven electrosynthetic reductions.

A catalyst selection method for the optimization of an asymmetric, vinylogous Mukaiyama aldol reaction is described. A large library of commercially available and synthetically accessible copper-bis(oxazoline) catalysts was constructed in silico. Conformer-dependent, grid-based descriptors were calculated for each catalyst, defining a chemical feature space suitable for machine learning. Selection of a diverse subset of catalyst space produced an initial training set of 26 novel bis(oxazoline) ligands which were synthesized and tested for stereoselectivity in the copper-catalyzed, vinylogous Mukaiyama aldol reaction for five substrate combinations. One ligand in the training set provided 88% average enantiomeric excess, exceeding the performance of catalysts identified through an initial optimization campaign. Supervised and semi-supervised catalyst selection methods, including quantitative structure-selectivity relationship modelling, nearest neighbors analysis, and a focused analogue clustering strategy, were employed to identify an additional 12 novel bis(oxazoline) ligands. The selected ligands outperformed the initial training set hit in four out of five product classes, and in some cases demonstrated excellent enantiocontrol exceeding 95% ee. The effectiveness of the unsupervised training set selection process is discussed, and the expediency of the nearest neighbor and focused analogue approaches are contrasted with the supervised quantitative structure-selectivity relationship modelling approach.

The development of a convergent route to the NLRP3 (nucleotide-binding domain and leucine-rich repeat-containing protein 3) agonist BMS-986299 is reported. The synthesis relies on a key Miyaura borylation and a tandem Suzuki-Miyaura coupling between an iodoimidazole and an o-aminochloroarene, followed by acid-mediated cyclization to afford the aminoquinoline core. The subsequent Boc cleavage and regioselective acylation afford the target compound. Two routes to the iodoimidazole intermediate are presented, along with the synthesis of the o-aminochloroarene via Negishi coupling. The convergent six-step route leads to an 80% reduction in process mass intensity compared to the linear enabling synthesis.

Adenosine triphosphate (ATP) provides the driving force necessary for critical biological functions in all living organisms. In synthetic biocatalytic reactions, this cofactor is recycled in situ using high-energy stoichiometric reagents, an approach that generates waste and poses challenges with enzyme stability. On the other hand, an electrochemical recycling system would use electrons as a convenient source of energy. We report a method that uses electricity to turn over enzymes for ATP generation in a simplified cellular respiration mimic. The method is simple, robust, and scalable, as well as broadly applicable to complex enzymatic processes including a four-enzyme biocatalytic cascade in the synthesis of the antiviral molnupiravir.

Hydrogen isotope exchange (HIE) represents one of the most attractive labeling methods to synthesize deuterium‐ and tritium‐labeled compounds. Catalytic HIE methods that enable site‐selective C−H bond activation and exchange labeling with gaseous isotopes D₂ and T₂ are of vital importance, in particular for high‐specific‐activity tritiation of pharmaceuticals. As part of our interest in exploring s‐block metals for catalytic transformations, we found CsN(SiMe₃)₂ to be an efficient catalyst for selective HIE of benzylic C−H bonds with D₂ gas. The reaction proceeds through a kinetic deprotonative equilibrium that establishes an exchange pathway between C−H bonds and D₂ gas. By virtue of multiple C−H bonds activation and high activity (isotope enrichment up to 99 %), the simple cesium amide catalyst provided a very powerful and practically convenient labeling protocol for synthesis of highly deuterated compounds and high‐specific‐activity tritiation of pharmaceuticals.