Chip Le

The advent of single-electron, nickel-mediated cross-coupling reactions has fundamentally transformed how carbon bonds can be forged and is now a mainstay of modern synthesis and medicinal chemistry. Nickel is a prevailing transition metal that facilitates these innovations, and yet despite its obvious competence, standardized practices regarding Ni/ligand preparation and administration, as separate entities or as a single precomplex or catalyst, have not been systematically established. This study investigates the synthesis, isolation, and efficacy of simple, ligated Ni(II) precatalysts (NiPCs) to expedite and standardize protocols for contemporary single-electron nickel-mediated cross-coupling reactions. We demonstrate the effectiveness of a library of isolated NiPCs in commonly used singleton transformations and high-throughput experimentation (HTE) setups with broad application to pharmaceutical chemistry. By illuminating the practical rules that govern NiPC synthesis and administration, this work equips the community with an actionable understanding to enable wide, normalized adoption of simple NiPC methods.

Microorganisms in the human gut influence the efficacy and metabolism of host-targeted small molecule therapeutics, including the frontline Parkinson’s disease drug levodopa (L-dopa). Previous work has identified a mechanism-based inhibitor of gut bacterial decarboxylases that degrade L-dopa, α-fluoromethyltyrosine (AFMT). However, early experiments with AFMT in rodent models suggested undesirable in vivo metabolism by host tyrosine hydroxylase, producing a metabolite likely to worsen Parkinson’s phenotypes and prevent application as an L-dopa co-treatment. Here, we demonstrate oxidation of AFMT in vitro by recombinant human tyrosine hydroxylase. We then develop AFMT analogs that retain activity against bacterial decarboxylases but have reduced susceptibility to host hydroxylation. Suitable arenes for inhibitor design were identified using assays with commercially available noncanonical amino acids, which revealed aryl difluorination as a promising modification. Difluoroaryl AFMT derivatives are less prone to degradation by tyrosine hydroxylase in vitro yet still inhibit L-dopa metabolism by bacterial decarboxylases. This work exemplifies how substrate reactivity can streamline design of mechanism-based enzyme inhibitors, as well as how constraints posed by the host can be incorporated during development of microbiome-targeted therapeutics. The compounds reported here are promising starting points for future studies in animal models and further exploration of gut bacterial effects on L-dopa treatment efficacy.

Alcohols and aryl carboxylic acids are among the most commercially abundant, synthetically versatile, and operationally convenient building blocks in organic chemistry. Despite their widespread availability, the direct formation of C(sp³)-C(sp²) bonds from these functional groups remains a challenge. Recently, our group developed robust protocols to harness alcohols as alkyl radical precursors, but the activation of aryl acids remains relatively unexplored. Herein, we describe the merger of N-heterocyclic carbene (NHC)-mediated deoxygenation and nickel-mediated decarbonylation of aryl acids toward C(sp³)-C(sp²) bond formation. The utility of this method is demonstrated through the synthesis of a diverse range of aryl-alkyl cross-coupled products and the late-stage functionalization of complex molecules, including drugs, natural products, and biomolecules.

Molybdenum-dependent catechol dehydroxylases in gut Actinobacteria catalyze the removal of para-hydroxyl groups from catechols, a central reaction in the microbial metabolism of polyphenol compounds. However, the substrates of most putative catechol dehydroxylases remain unidentified due to the challenges of obtaining these enzymes from standard heterologous expression systems. In this work, we establish Gordonibacter urolithinfaciens as a versatile bacterial host to express active catechol dehydroxylases. Using this system, we rapidly deorphanize eight previously uncharacterized gut bacterial catechol dehydroxylases that selectively dehydroxylate intermediates in the gut bacterial metabolism of plant-derived catechins and lignans. Unexpectedly, we discover multiple instances of distinct catechol dehydroxylases that have evolved to selectively metabolize individual substrate enantiomers, setting the stage for future efforts to elucidate their mechanisms and evolution. Altogether, these findings greatly increase our knowledge of these metalloenzymes, illustrating the power of bacterial genetics to accelerate enzyme discovery and providing a more complete understanding of transformations relevant to the health benefits of phytochemicals.

Arenes get a light boost onto copper: Insertion of palladium into an aryl halide bond is the first step in numerous variants of cross-coupling chemistry used to make carbon-carbon bonds. Copper is an appealing alternative catalyst for such reactions because of its abundance and downstream reactivity profile. However, this preliminary step, termed oxidative addition, is often prohibitively slow for the cheaper metal. Le et al. report a photocatalytic way around this problem. A photoredox catalyst paired with a silane can activate aryl bromides to react with copper, likely via aryl radicals. The copper in this case then catalyzes trifluoromethylation of the arenes. Science , this issue p. 1010

Photocatalysis for organic synthesis has experienced an exponential growth in the past 10 years. However, the variety of experimental procedures that have been reported to perform photon-based catalyst excitation has hampered the establishment of general protocols to convert visible light into chemical energy. To address this issue, we have designed an integrated photoreactor for enhanced photon capture and catalyst excitation. Moreover, the evaluation of this new reactor in eight photocatalytic transformations that are widely employed in medicinal chemistry settings has confirmed significant performance advantages of this optimized design while enabling a standardized protocol.