Braca

Organohalogen compounds are extensively used as building blocks, intermediates, pharmaceuticals, and agrochemicals due to their unique chemical and biological properties. Installing halogen substituents, however, frequently requires functionalized starting materials and multistep functional group interconversion. Several classes of halogenases evolved in nature to enable halogenation of a different classes of substrates; for example, site-selective halogenation of electron rich aromatic compounds is catalyzed by flavin-dependent halogenases (FDHs). Mechanistic studies have shown that these enzymes use FADH2 to reduce O2 to water with concomitant oxidation of X- to HOX (X = Cl, Br, I). This species travels through a tunnel within the enzyme to access the FDH active site. Here, it is believed to interact with an active site lysine proximal to bound substrate, enabling electrophilic halogenation with selectivity imparted via molecular recognition, rather than directing groups or strong electronic activation. The unique selectivity of FDHs led to several early biocatalysis efforts, preparative halogenation was rare, and the hallmark catalyst-controlled selectivity of FDHs did not translate to non-native substrates. FDH engineering was limited to site-directed mutagenesis, which resulted in modest changes in site-selectivity or substrate preference. To address these limitations, we optimized expression conditions for the FDH RebH and its cognate flavin reductase (FRed), RebF. We then showed that RebH could be used for preparative halogenation of non-native substrates with catalyst-controlled selectivity. We reported the first examples in which the stability, substrate scope, and site selectivity of an FDH were improved to synthetically useful levels via directed evolution. X-ray crystal structures of evolved FDHs and reversion mutations showed that random mutations throughout the RebH structure were critical to achieving high levels of activity and selectivity on diverse aromatic substrates, and these data were used in combination with molecular dynamics simulations to develop predictive model for FDH selectivity. Finally, we used family-wide genome mining to identify a diverse set of FDHs with novel substrate scope and complementary regioselectivity on large, three-dimensionally complex compounds. The diversity of our evolved and mined FDHs allowed us to pursue synthetic applications beyond simple aromatic halogenation. For example, we established that FDHs catalyze enantioselective reactions involving desymmetrization, atroposelective halogenation, and halocyclization. These results highlight the ability of FDH active sites to tolerate different substrate topologies. This utility was further expanded by our recent studies on the single component FDH/FRed, AetF. While we were initially drawn to AetF because it does not require a separate FRed, we found that it halogenates substrates that are not halogenated efficiently or at all by other FDHs and provides high enantioselectivity for reactions that could only be achieved using RebH variants after extensive mutagenesis. Perhaps most notably, AetF catalyzes site-selective aromatic iodination and enantioselective iodoetherification. Together, these studies highlight the origins of FDH engineering, the utility and limitations of the enzymes developed to date, and the promise of FDHs for an ever-expanding range of biocatalytic halogenation reactions.

Nature Synthesis, Published online: 01 July 2024; doi:10.1038/s44160-024-00587-5

The use of alkyl halides in radical cross-couplings generally requires silicon reagents as halogen abstractors. Now Me3N–BH3 is reported to facilitate these couplings with both aryl bromides and aryl boronic acids under either nickel or copper catalysis.

A dual bio-/photocatalytic system has been developed for achieving previously elusive diastereo- and enantioselective radical lactonizations. By integrating directed evolution and photoinduced single-electron oxidation, we repurposed engineered ene-reductases to steer non-natural radical C−O formations giving a diverse array of enantioenhanced 5- and 6-membered lactones with vicinal stereocenters, part of which bears a quaternary stereocenter.

Abstract

Repurposing enzymes to catalyze non-natural asymmetric transformations that are difficult to achieve using traditional chemical methods is of significant importance. Although radical C−O bond formation has emerged as a powerful approach for constructing oxygen-containing compounds, controlling the stereochemistry poses a great challenge. Here we present the development of a dual bio-/photo-catalytic system comprising an ene-reductase and an organic dye for achieving stereoselective lactonizations. By integrating directed evolution and photoinduced single electron oxidation, we repurposed engineered ene-reductases to steer non-natural radical C−O formations (one C−O bond for hydrolactonizations and lactonization-alkylations while two C−O bonds for lactonization-oxygenations). This dual catalysis gave a new approach to a diverse array of enantioenhanced 5- and 6-membered lactones with vicinal stereocenters, part of which bears a quaternary stereocenter (up to 99 % enantiomeric excess, up to 12.9 : 1 diastereomeric ratio). Detailed mechanistic studies, including computational simulations, uncovered the synergistic effect of the enzyme and the externally added organophotoredox catalyst Rh6G.

Nature Catalysis, Published online: 26 June 2024; doi:10.1038/s41929-024-01191-8

This Editorial deals with scientific language in research papers, considering the causes — as well as the problems — associated with the use of hyperbolic statements.

Nature Synthesis, Published online: 27 June 2024; doi:10.1038/s44160-024-00584-8

Combining a natural decarboxylase and an artificial metathase, a microbial cell factory is created that enables the synthesis of cycloalkenes from fatty diacids in a whole-cell hybrid biocatalytic cascade process.

Nature Synthesis, Published online: 27 June 2024; doi:10.1038/s44160-024-00575-9

Artificial metalloenzymes are useful catalysts in synthesis, but their use in cells is a challenge. Now, the development of an engineered whole-cell enzymatic cascade, which converts glucose-derived fatty diacids into cycloalkenes, is reported. The cascade process combines a decarboxylase with an artificial metalloenzyme that catalyses an abiotic olefin metathesis reaction.

In this study, we showcase cobalt-catalyzed asymmetric dearomatization of indoles with aryl amides, achieving remarkable enantioinduction and exceptional regioselectivity. This dual catalytic strategy, which integrates photocatalyst and cobalt, represents a pioneering approach in asymmetric C−H bond functionalization. Through detailed experimental investigations and DFT calculations, we present a plausible mechanism to elucidate the reaction pathway.

Abstract

In this study, we unveil a novel method for the asymmetric dearomatization of indoles under cobalt/photoredox catalysis. By strategically activating C−H bonds of amides and subsequent migratory insertion of π-bonds present in indole as reactive partner, we achieve syn-selective tetrahydro-5H-indolo[2,3-c]isoquinolin-5-one derivatives with excellent yields and enantiomeric excesses of up to >99 %. The developed method operates without a metal oxidant, relying solely on oxygen as the oxidant and employing an organic dye as a photocatalyst under irradiation. Control experiments and stoichiometric studies elucidate the reversible nature of the enantiodetermining C−H activation step, albeit not being rate-determining. This study not only expands the horizon of cobalt-catalyzed asymmetric C−H bond functionalization, but also showcases the potential synergy between cobalt and photoredox catalysis in enabling asymmetric synthesis of complex molecules.

We report an efficient protocol for chiral dihydroisoquinolone-fused indolines through a cobaltaphotoredox catalyzed enantioselective C−H activation/dearomatization of indoles. Mechanistic studies indicate the excited photocatalyst was quenched by cobalt(II) species in the presence of Salox ligand. The stoichiometric reactions of cobaltacycle intermediate suggest the irradiation of light also play a critical role in the dearomatization step.

Abstract

Photocatalysis holds a pivotal position in modern organic synthesis, capable of inducing novel reactivities under mild and environmentally friendly reaction conditions. However, the merger of photocatalysis and transition-metal-catalyzed asymmetric C−H activation as an efficient and sustainable method for the construction of chiral molecules remains elusive and challenging. Herein, we develop a cobalt-catalyzed enantioselective C−H activation reaction enabled by visible-light photoredox catalysis, providing a synergistic catalytic strategy for the asymmetric dearomatization of indoles with high levels of enantioselectivity (96 % to >99 % ee). Mechanistic studies indicate that the excited photocatalyst was quenched by divalent cobalt species in the presence of Salox ligand, leading to the formation of catalytically active chiral Co(III) complex. Moreover, stoichiometric reactions of cobaltacycle intermediate with indole suggest that the irradiation of visible light also play a critical role in the dearomatization step.

Nitrogen-containing compounds are valuable synthetic intermediates and targets in nearly every chemical industry. While methods for nitrogen-carbon and nitrogen-heteroatom bond formation have primarily relied on nucleophilic nitrogen atom reactivity, molecules containing nitrogen-halogen bonds allow for reactivity through electrophilic or radical mechanisms at the nitrogen center. Despite the growing synthetic utility of nitrogen-halogen-containing compounds, selective catalytic strategies for their synthesis are largely underexplored. We recently discovered that the vanadium-dependent haloperoxidase (VHPO) class of enzymes are a suitable biocatalyst platform for nitrogen-halogen bond formation. Herein, we show that VHPOs perform selective halogenation of a range of substituted benzamidine hydrochlorides to produce the corresponding N’-halobenzimidamides. This biocatalytic platform is applied to the synthesis of 1,2,4-oxadiazoles from the corresponding N-acylbenzamidines in high yield and with excellent chemoselectivity. Finally, the synthetic applicability of this biotechnology is demonstrated in an extension to nitrogen-nitrogen bond formation and the chemoenzymatic synthesis of the Duchenne muscular dystrophy treatment, ataluren.

Catalytic allylations have emerged as versatile processes for assembling C−C or C−heteroatom bonds. Traditionally, noble transition metals like Pd, Rh, or Ir have been extensively employed for these processes. However, recent sustainable catalytic strategies have shifted towards utilizing base metals as catalysts. Consequently, this review outlines the breakthroughs in cobalt-catalyzed allylic alkylations, emphasizing their noteworthy advancements in the field.

Abstract

The rising demand and financial costs of noble transition metal catalysts have emphasized the need for sustainable catalytic approaches. Over the past few years, base-metal catalysts have emerged as ideal candidates to replace their noble-metal counterparts because of their abundance and easiness of handling. Despite the significant advancements achieved with precious transition metals, earth-abundant cobalt catalysts have emerged as efficient alternatives for allylic substitution reactions. In this review, allylic alkylations at sp³-carbon centers mediated by cobalt will be discussed, with a special focus on the mechanistic features, scope, and limitations.

Nature Synthesis, Published online: 14 June 2024; doi:10.1038/s44160-024-00563-z

Aldehyde-bearing proteins are shown to be suitable substrates for Horner–Wadsworth–Emmons reactions. Applying this process to proteins and glycoproteins enables site-specific bioconjugation with tunable reaction kinetics.

The remarkable efficiency with which enzymes catalyze small molecule reactions has driven their widespread application in organic chemistry. Here, we employ automated fast-flow solid-phase synthesis to access full-length enzymes without restrictions on the number and structure of non-canonical amino acids incorporated. We demonstrate the total syntheses of Fe-dependent Bacillus subtilis myoglobin (BsMb) and sperm whale myoglobin (SwMb), which displayed excellent enantioselectivity and yield in carbene transfer reactions. Absolute control over enantioselectivity in styrene cyclopropanation was achieved using L- and D-BsMb mutants which delivered each enantiomer of cyclopropane product in identical and opposite enantiomeric enrichment. BsMb mutants outfitted with non-canonical amino acids were used to facilitate detailed structure-activity relationship studies, revealing a previously unrecognized hydrogen-bonding interaction as the primary driver of enantioselectivity in styrene cyclopropanation.

A silver(I)-containing i-motif DNA hybrid catalyst enables the catalysis of Diels–Alder reactions with high reactivity and excellent enantioselectivity, in which the catalytic center of copper(II) ion specifically coordinates with one nitrogen atom of adenine and two nearby phosphate-oxygen atoms in the loop region.

Abstract

The inherent chiral structures of DNA serve as attractive scaffolds to construct DNA hybrid catalysts for valuable enantioselective transformations. Duplex and G-quadruplex DNA-based enantioselective catalysis has made great progress, yet novel design strategies of DNA hybrid catalysts are highly demanding and atomistic analysis of active centers is still challenging. DNA i-motif structures could be finely tuned by different cytosine-cytosine base pairs, providing a new platform to design DNA catalysts. Herein, we found that a human telomeric i-motif DNA containing cytosine-silver(I)-cytosine (C-Ag⁺-C) base pairs interacting with Cu(II) ions (i-motif DNA(Ag⁺)/Cu²⁺) could catalyze Diels–Alder reactions with full conversions and up to 95 % enantiomeric excess. As characterized by various physicochemical techniques, the presence of Ag⁺ is proved to replace the protons in hemiprotonated cytosine-cytosine (C : C⁺) base pairs and stabilize the DNA i-motif to allow the acceptance of Cu(II) ions. The i-motif DNA(Ag⁺)/Cu²⁺ catalyst shows about 8-fold rate acceleration compared with DNA and Cu²⁺. Based on DNA mutation experiments, thermodynamic studies and density function theory calculations, the catalytic center of Cu(II) ion is proposed to be located in a specific loop region via binding to one nitrogen-7 atom of an unpaired adenine and two phosphate-oxygen atoms from nearby deoxythymidine monophosphate and deoxyadenosine monophosphate, respectively.

Nature, Published online: 11 June 2024; doi:10.1038/d41586-024-01717-x

The same mRNA technology that quickly brought the world a vaccine for COVID-19 is now showing promise as a bespoke therapy for cancer.

Nature, Published online: 06 June 2024; doi:10.1038/s41586-024-07628-1

Unlocking carbene reactivity by metallaphotoredox α-elimination

Nature, Published online: 31 May 2024; doi:10.1038/d41586-024-01664-7

Tech heavyweights brawl over whether research needs to be published to count as science. Plus, the first recipient of a gene-edited pig liver is ‘doing very well’ and how Viking-age hunters took down the world’s biggest animal.

Four parties hammer out agreement filled with bad news for scientists

Nature Catalysis, Published online: 29 May 2024; doi:10.1038/s41929-024-01176-7

A boronic enzyme

Nature Communications, Published online: 27 May 2024; doi:10.1038/s41467-024-48873-2

Transition-metal catalyzed cross-electrophile coupling (XEC) is a powerful tool for the construction of molecules but XEC between carbon electrophile and chlorosilanes to access organosilicon compounds remains underdeveloped. Here the authors disclose a highly efficient cobalt-catalyzed cross-electrophile alkynylation of a broad range of unactivated chlorosilanes with alkynyl sulfides as a stable and practical alkynyl electrophiles.

Highly stereoselective Michael addition of cyclic ketones to nitroolefins was promoted by a designer artificial enzyme harboring a catalytic pyrrolidine residue through enamine catalysis. Diverse chiral γ-nitroketones were prepared by this efficient biocatalytic strategy for ketone functionalization in a study highlighting the utility of artificial enzymes for new-to-nature reactions.

Abstract

Consistent introduction of novel enzymes is required for developing efficient biocatalysts for challenging biotransformations. Absorbing catalytic modes from organocatalysis may be fruitful for designing new-to-nature enzymes with novel functions. Herein we report a newly designed artificial enzyme harboring a catalytic pyrrolidine residue that catalyzes the asymmetric Michael addition of cyclic ketones to nitroolefins through enamine activation with high efficiency. Diverse chiral γ-nitro cyclic ketones with two stereocenters were efficiently prepared with excellent stereoselectivity (up to 97 % e.e., >20 : 1 d.r.) and good yield (up to 86 %). This work provides an efficient biocatalytic strategy for cyclic ketone functionalization, and highlights the usefulness of artificial enzymes for extending biocatalysis to further non-natural reactions.

Nature Chemistry, Published online: 23 May 2024; doi:10.1038/s41557-024-01535-8

The σ-type cyclopropenium cations (CPCs) are unstable species and currently underdeveloped. Now, an iodine(III)-based cyclopropenyl transfer reagent has been developed, which can generate electrophilic cyclopropenyl-gold(III) species as equivalents of σ-type CPCs. The synthetic potential has been demonstrated by the transfer of σ-type CPCs to terminal alkynes and vinylboronic acids.

A computational modeling approach is applied to rationalize the impact of streptavidin mutations and length of the biotion cofactor on the enantioselective Suzuki-Miyaura synthesis of binaphthyls by means of an Artificial Metalloenzyme built employing the streptavidin-biotin technology. The integrative computational approach includes DFT calculations, protein-ligand dockings and molecular dynamics simulations.

Abstract

An Artificial Metalloenzyme (ArM) built employing the streptavidin-biotin technology has been used for the enantioselective synthesis of binaphthyls by means of asymmetric Suzuki-Miyaura cross-coupling reactions. Despite its success, it remains a challenge to understand how the length of the biotin cofactors or the introduction of mutations to streptavidin leads the preferential synthesis of one atropisomer over the other. In this study, we apply an integrated computational modeling approach, including DFT calculations, protein-ligand dockings and molecular dynamics to rationalize the impact of mutations and length of the biotion cofactor on the enantioselectivities of the biaryl product. The results unravel that the enantiomeric differences found experimentally can be rationalized by the disposition of the first intermediate, coming from the oxidative addition step, and the entrance of the second substrate. The work also showcases the difficulties facing to control the enantioselection when engineering ArM to catalyze enantioselective Suzuki-Miyaura couplings and how the combination of DFT calculations, molecular dockings and MD simulations can be used to rationalize artificial metalloenzymes.