Braca

Nature Synthesis, Published online: 10 July 2024; doi:10.1038/s44160-024-00581-x

Eliminating the substrate-specific constraints in alkene hydroalkylation reactions, where heteroatom-containing substrates are often required to achieve enantioselectivity, remains a challenge. Now a cobalt-hydride catalyst is shown to overcome heteroatom constraints through C–H···π interactions between substrates and catalysts, enabling the efficient construction of chiral tertiary carbon centres at the benzyl position.

Abstract

A copper catalyzed aerobic formal addition of aliphatic C(sp3)−H bonds to alkenes via a phenyl radical mediated intermolecular HAT process is reported herein, in which the phenylhydrazine not only acts as a HAT reagent precursor, but also as a hydrogen atom donor. This reaction affords an alternative method for the direct formal addition of aliphatic C(sp3)−H bonds to alkenes utilizing air as the radical initiator without additional reductants at ambient temperature. A variety of alkanes and electron-deficient alkenes are successfully incorporated, furnishing a series of aliphatic C(sp3)−H formal addition products in 20–93% yield. Preliminary mechanistic studies show that the 2-tetrahydrofuranyl and phenyl radical are formed in this reaction.

A highly efficient biocatalytic route for the atroposelective synthesis of biaryls by dynamic kinetic resolution (DKR) was developed. This DKR approach features a transient aza-acetal bridge-promoted racemization followed by an engineered imine reductase (IRED)-catalyzed stereoselective reduction to generate the axial chirality, providing various biaryls in high yield with excellent enantioselectivity (up to >99 : 1 er).

Abstract

Axially chiral biaryl compounds are ubiquitous scaffolds in natural products, bioactive molecules, chiral ligands and catalysts, but biocatalytic methods for their asymmetric synthesis are limited. Herein, we report a highly efficient biocatalytic route for the atroposelective synthesis of biaryls by dynamic kinetic resolution (DKR). This DKR approach features a transient six-membered aza-acetal-bridge-promoted racemization followed by an imine reductase (IRED)-catalyzed stereoselective reduction to construct the axial chirality under ambient conditions. Directed evolution of an IRED from Streptomyces sp. GF3546 provided a variant (S-IRED-Ss-M11) capable of catalyzing the DKR process to access a variety of biaryl aminoalcohols in high yields and excellent enantioselectivities (up to 98 % yield and >99 : 1 enantiomeric ratio). Molecular dynamics simulation studies on the S-IRED-Ss-M11 variant revealed the origin of its improved activity and atroposelectivity. By exploiting the substrate promiscuity of IREDs and the power of directed evolution, our work further extends the biocatalysts’ toolbox to construct challenging axially chiral molecules.

Nature Chemistry, Published online: 19 July 2024; doi:10.1038/s41557-024-01562-5

Although natural terpenoid cyclases generate polycyclic structures through cationic intermediates, alternative radical cyclization pathways are underexplored. Now an artificial radical cyclase has been prepared by anchoring a biotinylated cobalt Schiff-base complex within a chimeric streptavidin scaffold. Chemogenetic optimization of the catalytic performance affords enantioenriched terpenoids via a metal-catalysed H-atom transfer mechanism.

The onset of Darwinian evolution represents a key step in the transition of chemical systems into living ones. Here, we show the emergence of Darwinian evolution in two systems of self-replicating molecules, where natural selection favors replicator mutants best capable of catalyzing the production of the precursors required for their own replication. Such selection for protometabolic activity was observed in a system where trimer and hexamer replicators compete for common resources, as well as in a system of different hexamer replicator mutants. An out-of-equilibrium replication-destruction regime was implemented in a flow reactor, where replication from continuously supplied dithiol building blocks needs to keep up with “destruction” by outflow. Selection occurred based on the ability of the mutants to activate a cofactor that photocatalytically produces singlet oxygen which, in turn, enhances the rate by which dithiol building blocks are converted into disulfide-based replicator precursors. Selection was based on a functional trait (catalytic activity) opening up Darwinian evolution as a tool for catalyst development. This work functionally integrates self-replication with protometabolism and Darwinian evolution and marks a further advance in the de-novo synthesis of life.

Nature, Published online: 17 July 2024; doi:10.1038/s41586-024-07709-1

Embedding of a new engineered thermostable hydrolase into polymer materials enables the production of biodegradable and home-compostable plastics suitable for industrial packaging applications.

Nature Catalysis, Published online: 11 July 2024; doi:10.1038/s41929-024-01194-5

The precise functionalization of distant aromatic C(sp2)–H bonds remains largely unexplored. Here the authors report a para-selective acylation strategy to target remote aryl C(sp2)–H bonds away from an activated functionality through radical N-heterocyclic carbene organocatalysis.

Nature Synthesis, Published online: 11 July 2024; doi:10.1038/s44160-024-00583-9

A strategy for the cobalt-hydride-catalysed enantioselective hydroalkylation of 1,1-disubstituted styrenes is demonstrated, enabling the efficient construction of chiral tertiary carbon centres at the benzyl position. This method overcomes the requirement for a heteroatom-containing substrate, with enantiocontrol instead achieved through C–H···π interactions between the substrate and catalyst.

Artificial enzymes that operate with pnictogen bonds or σ-hole interactions in general are introduced: Transfer hydrogenation of quinolines accelerates with biotinylated pnictogen-bonding cofactors and their interfacing with streptavidin and mutants, shows saturation behavior with transition-state recognition three orders of magnitude beyond substrate recognition, and the emergence of stereoselectivity.

Abstract

The objective of this study was to create artificial enzymes that capitalize on pnictogen bonding, a σ-hole interaction that is essentially absent in biocatalysis. For this purpose, stibine catalysts were equipped with a biotin derivative and combined with streptavidin mutants to identify an efficient transfer hydrogenation catalyst for the reduction of a fluorogenic quinoline substrate. Increased catalytic activity from wild-type streptavidin to the best mutants coincides with the depth of the σ hole on the Sb(V) center, and the emergence of saturation kinetic behavior. Michaelis–Menten analysis reveals transition-state recognition in the low micromolar range, more than three orders of magnitude stronger than the millimolar substrate recognition. Carboxylates preferred by the best mutants contribute to transition-state recognition by hydrogen-bonded ion pairing and anion-π interactions with the emerging pyridinium product. The emergence of challenging stereoselectivity in aqueous systems further emphasizes compatibility of pnictogen bonding with higher order systems catalysis.

Nature Communications, Published online: 09 July 2024; doi:10.1038/s41467-024-50141-2

Exploring the promiscuity of native enzymes is a promising strategy for expanding their synthetic applications. Here, the authors show that old yellow enzymes (OYEs) can facilitate the Morita-Baylis-Hillman reaction (MBH reaction), leveraging substrate similarities between MBH reaction and reduction, and engineer GkOYE.8 with no reduction activity, but enhanced MBH activity.

Synthesis
DOI: 10.1055/a-2343-1001

Since their discovery in 2011, gold-catalyzed transformations of vinyldiazo compounds have become an important synthetic tool, enabling the identification of new reaction patterns that have greatly expanded the versatility of these reagents. In this short review, we showcase the most relevant advances that have been made in this exciting area of research.1 Introduction2 Gold-Catalyzed Transformations of Vinyldiazo Compounds Involving Metal Carbene Intermediates2.1 Liu’s Seminal Work: Vinylogous Reactivity of Au(I) Vinyl Carbenes2.2 Gold-Catalyzed Reactions of Vinyldiazo Compounds with Alkenes2.3 Gold-Catalyzed Reactions of Vinyldiazo Compounds with Alkynes2.4 Gold-Catalyzed Reactions of Vinyldiazo Compounds with Allenes2.5 Gold-Catalyzed Reactions of Vinyldiazo Reagents with Aromatic Compounds2.6 Gold-Catalyzed Reactions of Vinyldiazo Compounds with Nitriles2.7 Gold-Catalyzed Diazo Cross-Couplings3 Gold-Catalyzed Transformations of Vinyldiazo Compounds That Do Not Involve Initial Dinitrogen Extrusion3.1 Gold-Catalyzed Formal [n+2] Cycloaddition Reactions through the Vinyl Moiety of Vinyldiazo Compounds3.2 Gold-Catalyzed Transformations of Vinyldiazo Compounds Involving Initial Activation of the Non-Diazo Reagent4 Conclusions
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

Methods for introducing subtle modifications at the level of single atoms/bonds (‘skeletal editing’) are highly desirable in organic and medicinal chemistry, owing to their potential for fine-tuning the structure and biological activity of organic molecules. While contemporary methods for skeletal editing of organic molecules largely rely on modification of pre-existing functional groups, opportunities for executing these transformations at ubiquitous yet unreactive aliphatic C(sp3)—H sites are currently unavailable. Here, we report a chemoenzymatic strategy for enabling skeletal editing via ring expansion with high site-selectivity at the level of one or more aliphatic C—H sites in complex molecules. By combining cytochrome P450-catalyzed C—H oxidation with chemical oxidation and subsequent Baeyer-Villiger rearrangement or ketone homologation, a panel of structurally and functionally diverse natural products were edited by inserting a lactone or carbonylmethylene moiety into aliphatic regions of their carbocyclic skeletons. Using engineered P450 catalysts with divergent regioselectivity, a set of different ring-expanded products could be readily obtained from a single parent molecule, highlighting the potential of this approach for skeletal edit scanning and/or library generation. By enabling the targeting of aliphatic C—H sites with tunable site-selectivity, this strategy provides a powerful tool to rapidly access skeletally edited derivatives of natural products and other bioactive molecules that would be hard to attain by purely chemical means. We envision this approach can also enable the device of non-traditional retrosynthetic disconnections for the synthesis of complex molecules.

Nature Communications, Published online: 05 July 2024; doi:10.1038/s41467-024-50082-w

Direct reduction of unactivated alkyl halides for C(sp3)-N couplings under mild conditions presents a significant challenge in organic synthesis. Here the authors introduce an in situ formed pyridyl carbene-ligated copper (I) catalyst that is capable of abstracting halide atom and generating alkyl radicals for general C(sp3)-N couplings under visible light.

Publication date: 8 August 2024

Source: Chem, Volume 10, Issue 8

Author(s): Xiang Zhang, Dongping Chen, Julian Stropp, Ryo Tachibana, Zhi Zou, Daniel Klose, Thomas R. Ward

The enantioselective reduction of dialkyl ketones containing two similar alkyl groups is challenging. Although human carbonic anhydrase II (hCAII) naturally catalyzes the reaction of achiral water and CO₂ to form achiral carbonic acid, the active zinc site in hCAII catalyzes, through a zinc-hydride, highly enantioselective reductions of a wide range of dialkyl ketones. Variants of hCAII react with distinct selectivites.

Abstract

Human carbonic anhydrase II (hCAII) naturally catalyzes the reaction between two achiral molecules—water and carbon dioxide—to yield the achiral product carbonic acid through a zinc hydroxide intermediate. We have previously shown that a zinc hydride, instead of a hydroxide, can be generated in this enzyme to create a catalyst for the reduction of aryl ketones. Dialkyl ketones are more challenging to reduce, and the enantioselective reduction of dialkyl ketones with two alkyl groups that are similar in size and electronic properties, is a particularly challenging transformation to achieve with high activity and selectivity. Here, we show that hCAII, as well as a double mutant of it, catalyzes the enantioselective reduction of dialkyl ketones with high yields and enantioselectivities, even when the two alkyl groups are similar in size. We also show that variants of hCAII catalyze the site-selective reduction of one ketone over the other in an unsymmetrical aliphatic diketone. Computational docking of a dialkyl ketone to variants of hCAII containing the zinc hydride provides insights into the origins of the reactivity of various substrates and the high enantioselectivity of the transformations and show how a confined environment can control the enantioselectivity of an abiological intermediate.

Redox-diverse myoglobins containing four different cofactors with different redox potentials (−198 to +147 mV vs. NHE) were studied as catalysts for alkene cyclopropanation through carbene transfer. Myoglobin with a positive redox potential is highly reactive for electron-deficient alkenes, such as 1-octene. In contrast, myoglobin with a negative redox potential accelerates the formation of a detectable carbene intermediate.

Abstract

Design of metal cofactor ligands is essential for controlling the reactivity of metalloenzymes. We investigated a carbene transfer reaction catalyzed by myoglobins containing iron porphyrin cofactors with one and two trifluoromethyl groups at peripheral sites (FePorCF₃ and FePor(CF₃)₂, respectively), native heme and iron porphycene (FePc). These four myoglobins show a wide range of Fe(II)/Fe(III) redox potentials in the protein of +147 mV, +87 mV, +42 mV and −198 mV vs. NHE, respectively. Myoglobin reconstituted with FePor(CF₃)₂ has a more positive potential, which enhances the reactivity of a carbene intermediate with alkenes, and demonstrates superior cyclopropanation of inert alkenes, such as aliphatic and internal alkenes. In contrast, engineered myoglobin reconstituted with FePc has a more negative redox potential, which accelerates the formation of the intermediate, but has low reactivity for inert alkenes. Mechanistic studies indicate that myoglobin with FePor(CF₃)₂ generates an undetectable active intermediate with a radical character. In contrast, this reaction catalyzed by myoglobin with FePc includes a detectable iron–carbene species with electrophilic character. This finding highlights the importance of redox-focused design of the iron porphyrinoid cofactor in hemoproteins to tune the reactivity of the carbene transfer reaction.

Nature, Published online: 03 July 2024; doi:10.1038/s41586-024-07506-w

This Review considers developments in enzymes, biosynthetic pathways and cellular engineering that enable their use in catalysis for new chemistry and beyond.

We illustrate the oxygen-tolerant and benign nature of active bio-inspired cobaloxime complexes featuring the axial coordination with imidazole or histidine. These complexes provide efficient chemical transformations like amine synthesis. This transformation is complemented by concur-rent evolution of H₂ through synergistic utilization of a photocatalyst and a cobaloxime-based catalyst.

Abstract

Developing a water-soluble, oxygen-tolerant, and acid-stable synthetic H₂ production catalyst is vital for renewable energy infrastructure. To access such an effective catalyst, we strategically incorporated enzyme-inspired, multicomponent outer coordination sphere elements around the cobaloxime (Cl−Co−X) core with suitable axial coordination (X). Our cobaloximes with axial imidazole or L-histidine coordination in photocatalytic HAT including the construction of anilines via a non-canonical cross-coupling approach is found superior compared to commonly used cobaloxime catalysts. The reversible Co(II)/Co(I) process is influenced by the axial N ligand's nature. Imidazole/L-histidine with a higher pKa promptly produces H₂ upon irradiation, leading to the improved reactivity compared to previously employed axial (di)chloride or pyridine analogue.

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.