Braca

Nature, Published online: 19 November 2024; doi:10.1038/d41586-024-03746-y

The largest scholarly search engine is celebrating its 20th birthday, but AI-driven competitors offer advantages.

Nature, Published online: 20 November 2024; doi:10.1038/s41586-024-08327-7

Photocatalytic C–F bond activation in small molecules and polyfluoroalkyl substances

Introducing an arginine (Arg) residue adjacent to the latent bioreactive unnatural amino acid (Uaa) significantly accelerates both SuFEx and PFEx reaction rates between proteins. This offers a general and biocompatible strategy to harness these robust click chemistries for fundamental and applied biological research, applicable in vitro and in vivo.

Abstract

Sulfur fluoride exchange (SuFEx) and phosphorus fluoride exchange (PFEx) click chemistries are advancing research across multiple disciplines. By genetically incorporating latent bioreactive unnatural amino acids (Uaas), these chemistries have been integrated into proteins, enabling precise covalent linkages with biological macromolecules and paving the way for new applications. However, their suboptimal reaction rates in proteins limit effectiveness, and traditional catalytic methods for small molecules are often incompatible with biological systems or in vivo applications. We demonstrated that introducing an arginine adjacent to the latent bioreactive Uaa significantly boosts SuFEx and PFEx reaction rates between proteins. This method is effective across various Uaas, target residues, and protein environments. Notably, it also enables efficient SuFEx reactions in acidic conditions, common in certain cellular compartments and tumor microenvironments, which typically hinder SuFEx reactions. Furthermore, we developed the first covalent cell engager that substantially enhances natural killer cell activation through improved covalent interaction facilitated by arginine. These findings provide mechanistic insights and offer a biocompatible strategy to harness these robust chemistries for advancing biological research and developing new biotherapeutics.

Synthesis of substituted anilines upon nucleophilic addition of secondary amines to cyclohexanone derivatives followed by aromatization of the enamine by employing a combination of Ir-polypyridine complex as a photoredox catalyst and cobaloxime as H2-evolution catalyst was developed recently by Leonori et al. In this work, we replace homogeneous photoredox catalyst by heterogeneous mesoporous graphitic carbon nitride (mpg-CN) that is free of rare elements. Substituted aromatic amine and H2 are formed simultaneously. Combination of X-Ray spectroscopies revealed charge transfer from cobaloxime to mpg-CN in the dark. Illumination of the catalytic system with visible light induces electron transfer from mpg-CN to cobaloxime and formation of persistent Co(II) species. The results of DFT modelling suggest that the studied reaction is strongly endothermic and endergonic. Thus, energy of photons is stored in the reaction products – H2 and the aromatic amine.

Nature, Published online: 11 November 2024; doi:10.1038/d41586-024-03708-4

The code underlying the Nobel-prize-winning tool for modelling protein structures can now be downloaded by academics.

Biocatalysts are prized for their selectivity, tunability, and their compatibility with environmentally-friendly reaction conditions. Introduction of unnatural cofactors opens the door to new reactive enzymatic intermediates, and in turn, the possibility for new biochemical reactions. In the present study, we employed a de novo biosynthesized, non-natural cofactor, cobalt protoporphyrin IX,1 to generate a mono-nuclear cobalt hydride intermediate in the active site of a common P450 scaffold. We show that this cobalt hydride intermediate engages in metal-hydrogen atom transfer (M-HAT) reactivity, a well-studied and highly utilized reactivity pattern in synthetic chemistry,2 but which is not known to operate in nature. Because the required cofactor is fully biosynthesized and incorporated into proteins in vivo, the catalysts are highly amendable to directed evolution. We leveraged the ability to quickly access these new artificial metalloenzymes with a colorimetric screen and evolved new variants for M-HAT-mediated deallylation of phenols. We showed how common silanes have a propensity to hydrolysis that can be overcome with directed evolution by accelerating metal-hydride formation from a bulky, water stable silane. During this evolution, we discovered that variants were catalyzing HAT to the colorimetric probe itself, resulting in a unique reductive dearomatization reaction. This radical process occurs efficiently under aerobic conditions and reactions of this type have not been observed previously. These discoveries demonstrate how the tunability of biocatalytic systems can enable innovations in synthetic chemistry. We anticipate that further engineering and study of M-HAT biocatalysts will prompt new questions about hydrogen atom transfer reactivity and enable the adoption of biocatalysts for numerous synthetically useful transformations.

Transition metal–hydrides have been widely exploited in homogenous catalysis for hydrofunctionalization of unsaturated moieties, including carbonyls, alkenes and alkynes. As a complement to the well-established chemistry of these complexes involving heterolytic metal–hydride bond cleavage, metal–hydride hydrogen atom transfer (MHAT) has attracted increased interest, as it offers a promising strategy for radical hydrofunctionalziation of unactivated alkenes thus enabling late-stage diversification of complex molecules. However, due the weak interactions between the prochiral organic radical species and the enantiopure metal catalyst, achieving asymmetric MHAT remains challenging. Herein, we report our efforts to repurpose cytochrome P450 enzymes to catalyze asymmetric MHAT, a new-to-nature reaction. Directed evolution of the well-studied P450BM3 (CYP102A1) enzyme led to the identification of a triple mutant that catalyzes asymmetric MHAT radical cyclization of unactivated alkenes to afford diverse cyclic compounds, including pyrrolidines, in up to a 97:3 enantiomeric ratio under aerobic whole cell conditions. Mechanistic investigations support an MHAT mechanism proceeding via homolytic cleavage of a fleeting iron(III)hydride species. Directed evolution using CYP119 as hemoprotein scaffold led to the identification of a stereocomplementary MHATase, highlighting the potential of repurposed hemoproteins for MHAT biocatalysis. Our study showcases the potential of integrating abiotic metal–hydride activity into native metalloenzymes to expand the scope of asymmetric radical biocatalysis.

When nature evolves a gene over eons at scale, it produces a diversity of homologous sequences with patterns of conservation and change that contain rich structural, functional, and historical information about the gene. However, natural gene diversity ...

Synlett
DOI: 10.1055/a-2442-1796

Spirocyclobutanes have gained significant attention in medicinal chemistry discovery programs due to their broad spectrum of biological activities and clinical applications. Utilizing ring strain in small molecules to drive organic transformations is one of the most powerful tools in chemical synthesis. Our research group has focused on developing new synthetic strategies enabled by ring strain to construct complex molecules selectively and efficiently. This account summarizes our recent efforts toward the synthesis of a library of functionalized spirocyclobutanes by harnessing the ring strain of bicyclo[1.1.0]butanes. Three spicrocyclization cascades have been developed to incorporate a diverse range of radical precursors into spirocycobutanes.1 Introduction2 Synthesis of Spirocyclobutyl Lactones and -Lactams using Bifunctional Reagents3 Dual Photoredox/Nickel Catalysis for the Synthesis of Spirocyclobutyl Lactams4 Synthesis of Spirocyclobutyl Oxindoles under Photoredox Catalysis5 DFT Studies6 Conclusion
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Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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

Nature Synthesis, Published online: 05 November 2024; doi:10.1038/s44160-024-00671-w

The chemical synthesis of nucleoside analogues with modifications at the 2-position often requires multiple steps and the extensive use of protecting groups. Now, biocatalytic cascades are reported for the synthesis of 2-functionalized sugars and 2′-functionalized nucleosides, using enzymes derived from those of the purine nucleoside salvage pathway.

An innovative concerted electron-fluoride transfer (cEF⁻T) mechanism is revealed for C(sp³)−F activation by Lewis base-boryl radicals (L_BBRs) with the aid of DFT calculations. Orbital interaction analyses have been conducted for rational design of L_BBRs that could selectively activate the resilient C−F bonds in fluoroalkanes, which enables the direct abstraction of a fluorine atom from fluorocarbons and the generation of an alkyl radical, broadening the scope of XAT reactions.

Abstract

Selective C−F bond activation through a radical pathway in the presence of multiple C−H bonds remains a formidable challenge, owing to the extraordinarily strong bond strength of the C−F bond. By the aid of density functional theory calculations, we disclose an innovative concerted electron-fluoride transfer mechanism, harnessing the unique reactivity of Lewis base-boryl radicals to selectively activate the resilient C−F bonds in fluoroalkanes. This enables the direct abstraction of a fluorine atom and subsequent generation of an alkyl radical, thus expanding the boundaries of halogen atom transfer reactions.

Photocatalyzed reversible addition-fragmentation chain transfer (RAFT) polymerizations are achieved using photoactive zinc myoglobin without the need for any additional reducing agents or co-catalysts. Zinc myoglobin shows improved catalytic activity over the free zinc porphyrin cofactor (zinc mesoporphyrin IX) and leads to controlled polymerizations with predictable molecular weights, low dispersities, and retention of chain-end functional groups.

Abstract

Protein photocatalysts provide a modular platform to access new reaction pathways and affect product outcomes, but their use in polymer synthesis is limited because co-catalysts and/or co-reductants are required to complete catalytic cycles. Herein, we report using zinc myoglobin (ZnMb), an inherently photoactive protein, to mediate photoinduced electron/energy transfer (PET) reversible addition-fragmentation chain transfer (RAFT) polymerizations. Using ZnMb as the sole reagent for catalysis, photomediated polymerizations of N,N-dimethylacrylamide in PBS were achieved with predictable molecular weights, dispersity values approaching 1.1, and high chain-end fidelity. We found that initial apparent rate constants of polymerization increased from 4.6×10–5 s⁻¹ for zinc mesoporpyhrin IX (ZnMIX) to 6.5×10–5 s⁻¹ when ZnMIX was incorporated into myoglobin to yield ZnMb, indicating that the protein binding site enhanced catalytic activity. Chain extension reactions comparing ZnMb-mediated RAFT polymerizations to thermally-initiated RAFT polymerizations showed minimal differences in block copolymer molecular weights and dispersities. This work enables studies to elucidate how protein modifications (e.g., secondary structure folding, site-directed mutagenesis, directed evolution) can be used to modulate polymerization outcomes (e.g., selective monomer additions towards sequence control, tacticity control, molar mass distributions).

Nature Communications, Published online: 27 October 2024; doi:10.1038/s41467-024-53584-9

The serotonin transporter (SERT) is a target for antidepressants and psychostimulants. Through a combination of non-canonical amino acid incorporation, protein purification, and spectroscopic fluorescence techniques, this study reports on changes in conformational dynamics of SERT imposed by the binding of ions and ligands.

Nature Chemistry, Published online: 23 October 2024; doi:10.1038/s41557-024-01657-z

About two thirds of western society are extroverts, but the contemplative nature of science means that this is not true of the academic population. Bruce Gibb discusses extraversion and introversion in science and asks whether the movement towards larger projects involving teams of scientists is making it harder for introverts and for disruptive discoveries.

Nature Catalysis, Published online: 17 October 2024; doi:10.1038/s41929-024-01234-0

The replacement of palladium with other metal catalysts in C–C bond-forming reactions is attractive in terms of costs and sustainability. Now an iron-based catalyst is successfully employed in the Suzuki cross-coupling of aryl chlorides with aryl boronic esters activated with tert-butyl lithium.

Nature Chemistry, Published online: 27 September 2024; doi:10.1038/s41557-024-01646-2

Despite widespread use of azides across material science and various areas across chemistry, the underlying biosynthetic pathways for its formation have so far been unknown. Now, a promiscuous ATP-utilizing enzyme, Tri17, capable of synthesizing various azide molecules has been identified. Biochemical, structural and computational analyses support a potential molecular mechanism for azide formation by Tri17.