Braca

Single component flavin-dependent halogenases (FDHs) possesses both flavin reductase and FDH activity in a single enzyme. We recently reported that the single component FDH AetF catalyzes site-selective bromination and iodination of a variety of aromatic substrates and enantioselective bromolactonization and iodoetherification of styrenes bearing pendant carboxylic acid or alcohol substituents. Given this inherent reactivity and selectivity, we explored the utility of AetF as catalyst for alkene and alkyne C-H halogenation. We find that AetF catalyzes halogenation of a range of 1,1-disubstituted styrenes, often with high stereoselectivity. Despite the utility of haloalkenes for cross-coupling and other applications, accessing these compounds in a stereoselective manner typically requires functional group interconversion processes, and selective halogenation of 1,1’-disubstituted olefins remains rare. We also establish that AetF and homologues of this enzyme can halogenate terminal alkynes. Mutagenesis studies and deuterium kinetic isotope effects are used to support a mechanistic proposal involving covalent catalysis for halogenation of unactivated alkynes by AetF homologues. These findings expand the scope of FDH catalysis and continue to show the unique utility of single component FDHs for biocatalysis.

The development of bimolecular homolytic substitution (SH2) catalysis has expanded cross-coupling logic by enabling the selective merger of any primary radical with any secondary or tertiary radical via a radical sorting mechanism. SH2 catalysis can be used to merge common feedstock chemicals—such as alcohols, acids, and halides—in any permutation for the construction of a single C(sp3)–C(sp3) bond. The ability to sort these two distinct radicals across commercially available alkenes in a three-component manner would enable the simultaneous construction of two C(sp3)–C(sp3) bonds, greatly accelerating access to drug-like chemical space. However, the simultaneous in situ formation of electrophilic and primary nucleophilic radicals in the presence of unactivated alkenes is problematic, typically leading to statistical radical recombination, hydrogen atom transfer, disproportionation, and other deleterious pathways. Herein, we report the use of bimolecular homolytic substitution catalysis to sort an electrophilic radical and a nucleophilic radical across an unactivated alkene. This reaction involves the in situ formation of three distinct radical species, which are then differentiated by size and electronics, allowing for regioselective formation of desired dialkylated products. This work accelerates access to pharmaceutically relevant C(sp3)-rich molecules and defines a novel mechanistic paradigm for alkene dialkylation.

Nature Chemical Biology, Published online: 20 November 2023; doi:10.1038/s41589-023-01484-2

Oxygen sensitivity hampers applications of metal-dependent CO2 reductases. Here, Oliveira et al. describe how an allosteric disulfide bond controls the activity of a CO2 reductase, preventing its physiological reduction during transient O2 exposure and allowing aerobic handling of the enzyme.

The state-of-the-art for glycosylation primarily relies on the classical polar reactions of heteroatomic nucleophiles with electrophilic glycosyl oxocarbenium intermediates. While such an ionic glycosylation strategy has worked well to deliver O-glycosides, its utilization in N-glycoside synthesis is often plagued by the subdued reactivity of N-nucleophiles under the acidic reaction conditions required for activating glycosyl donors. Exploring the reactivity of glycosyl radical intermediates could open up new glycosylation pathways. However, despite the recent significant progress in radical-mediated synthesis of C-glycosides, harnessing the reactivity of glycosyl radicals for the generation of canonical O- or N-glycosides remains elusive. Herein, we report the first examples of glycosyl radical-mediated N-glycosylation reaction using readily accessible glycosyl sulfone donors and N-nucleophiles under mild copper-catalyzed photoredox-promoted conditions. The method is efficient, selective, redox-neutral, and broadly applicable, enabling facile access to a variety of complex N-glycosides and nucleosides in a streamlined fashion. Importantly, the present system tolerates the presence of water and offers unique chemoselectivity, allowing selective reaction of NH sites over hydroxyl groups that would otherwise pose challenges in conventional cationic N-glycosylation.

Nature Chemistry, Published online: 16 November 2023; doi:10.1038/s41557-023-01368-x

The inherent rigidity of the azaarene ring structure has made it challenging to achieve remote stereocontrol through asymmetric catalysis on these substrates. Now, through a photoenzymatic process, an ene-reductase system facilitates the production of diverse azaarenes with distant γ-stereocentres, highlighting the potential of biocatalysts for stereoselectivity at remote sites.

This study (1) resolved a longstanding query in the field of gold redox catalysis concerning the reaction between PhICl₂ and [(Ar)Au(PR₃)] by unveiling the mechanism for transmetallation between gold(I) and gold(III) complexes, (2) utilized this insight to develop a predictive conceptual framework for this reaction, and (3) experimentally validated the reliability of the prediction, establishing a foundation for advancements in this field.

Abstract

Gold redox catalysis, often facilitated by hypervalent iodine(III) reagents, offers unique reactivity but its progress is mainly hindered by an incomplete mechanistic understanding. In this study, we investigated the reaction between the gold(I) complexes [(aryl)Au(PR₃)] and the hypervalent iodine(III) reagent PhICl₂, both experimentally and computationally and provided an explanation for the formation of divergent products as the ligands bonded to the gold(I) center change. We tackled this essential question by uncovering an intriguing transmetalation mechanism that takes place between gold(I) and gold(III) complexes. We found that the ease of transmetalation is governed by the nucleophilicity of the gold(I) complex, [(aryl)Au(PR₃)], with greater nucleophilicity leading to a lower activation energy barrier. Remarkably, transmetalation is mainly controlled by a single orbital – the gold d_x ² _−y ² orbital. This orbital also has a profound influence on the reactivity of the oxidative addition step. In this way, the fundamental mechanistic basis of divergent outcomes in reactions of aryl gold(I) complexes with PhICl₂ was established and these observations are reconciled from first principles. The theoretical model developed in this study provides a conceptual framework for anticipating the outcomes of reactions involving [(aryl)Au(PR₃)] with PhICl₂, thereby establishing a solid foundation for further advancements in this field.

Visible light-induced Pd catalysis typically operates through the transfer of a single electron. The resulting hybrid Pd radical species can participate in a range of radical-based transformations otherwise challenging or unknown via conventional 2-electron processes. This Minireview highlights the recent progress in this emerging area.

Abstract

Visible light-induced Pd catalysis has emerged as a promising subfield of photocatalysis. The hybrid nature of Pd radical species has enabled a wide array of radical-based transformations otherwise challenging or unknown via conventional Pd chemistry. In parallel to the ongoing pursuit of alternative, readily available radical precursors, notable discoveries have demonstrated that photoexcitation can alter not only oxidative addition but also other elementary steps. This Minireview highlights the recent progress in this area.

Atroposelective metathesis catalyzed by artificial enzymes in aqueous solution would provide an attractive and sustainable route to drug molecules and other compounds of interest. We demonstrate that this is possible using artificial metalloenzymes harboring a ruthenium cofactor.

Abstract

Atropisomers – separable conformers that arise from restricted single-bond rotation – are frequently encountered in medicinal chemistry. However, preparing such compounds with the desired configuration can be challenging. Herein, we present a biocatalytic strategy for achieving atroposelective synthesis relying on artificial metalloenzymes (ArMs). Based on the biotin-streptavidin technology, we constructed ruthenium-bearing ArMs capable of producing atropisomeric binaphthalene compounds through ring-closing metathesis in aqueous media. Further, we show that atroposelectivity can be fine-tuned by engineering two close-lying amino acid residues within the streptavidin host protein. The resulting ArMs promote product formation with enantiomeric ratios of up to 81 : 19, while small-molecule catalysts for atroposelective metathesis under aqueous reaction conditions are yet unknown. This study represents the first demonstration that stereoselective metathesis can be achieved by an artificial metalloenzyme.

Despite the unique reactivity of vitamin B12 and its derivatives, B12-dependent enzymes remain underutilized in biocatalysis. In this study, we repurpose the B12-dependent transcription factor CarH to enable non-native radical cyclization reactions. An engineered variant of this enzyme, CarH*, catalyzes the formation γ- and δ-lactams via either redox-neutral or reductive ring closure with marked enhancement of reactivity and selectivity relative to the free B12 cofactor. CarH* also catalyzes an unusual spirocyclization via dearomatization of pendant arenes to produce bicyclic 1,3-diene products instead of 1,4-dienes provided by existing methods. These results and associated mechanistic studies highlight the importance of protein scaffolds for controlling the reactivity of B12 and expanding the synthetic utility of B12-dependent enzymes.

Cobalt compounds might enable cheaper and more-complex photocatalysis processes