Braca

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.

Synlett
DOI: 10.1055/a-2408-0043

The metal hydride catalyzed alkene hydroalkylation enables efficient alkyl–alkyl coupling, yielding structurally diverse chiral organic compounds. However, the control of stereochemical selectivity in alkene hydroalkylation still heavily relies on the assistance of substrate Lewis basic functional groups or polar heteroatom functional groups. We have recently developed a cobalt hydride catalytic system and established a paradigm of enantioselective control assisted by C–H···π noncovalent interactions. This approach enables the asymmetric hydroalkylation of 1,1-disubstituted styrenes, thereby circumventing the limitations imposed by substrate heteroatom functional groups.1 Introduction2 Reaction Development3 Synthetic Applications4 Mechanistic Investigation5 Conclusion and Future Outlook
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

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A photocatalyst-free photoinduced radical difluoromethylation approach for the convenient synthesis of difluoromethylated oxindoles from N-arylacrylamides with difluoromethyl phenoxathiinium salt (PT-CF2H+BF4-) was developed, this transformation involves radical difluoromethylation/cyclization cascade process and features photocatalyst-free, mild reaction conditions, broad substrate scope and good functional groups tolerance. With this method, a wide variety of N-arylacrylamides were successfully converted to desired difluoromethylated oxindoles in good to excellent yields.

This integrated computational and experimental study comprehensively examines the viability of competing inner-sphere electron transfer (ISET) and outer-sphere electron transfer (OSET) processes in [Cu(dap)2]+-mediated atom-transfer radical additions (ATRA) of olefins and CF3SO2Cl that can deliver both R–SO2Cl and R–Cl products. Five sterically- and electronically-varied representative alkenes were selected from which to explore and reconcile the range of experimentally observed outcomes. Findings are consistent with photoexcited [Cu(dap)2]+ initiating photoelectron transfer via ISET and the subsequent regeneration of the oxidized catalyst via single-electron transfer in the ground state via ISET to close the catalytic cycle and liberate products. R–SO2Cl/R–Cl product ratios appear to be primarily governed by the relative rates of direct catalyst regeneration {i.e., [Cu(dap)2SO2Cl]•+ + R•} and ligand exchange {i.e., [Cu(dap)2SO2Cl]•+ + Cl– }. Through this work, a more consistent and more complete conceptual framework has been developed to better understand this chemistry and how catalyst regeneration occurs. It is this important ground state process, which closes the catalytic cycle, and ultimately controls the enantioselectivity of ATRA reactions employing chiral copper photocatalysts

Geometrically defined allylic alcohols with SE, SZ, RE and RZ stereoisomers serve as valuable intermediates in synthetic chemistry, attributed to the stereoselective transformations enabled by the alkenyl and hydroxyl functionalities. When an ideal scenario presents itself with four distinct stereoisomers as potential products, the simultaneous control vicinal stereochemistry in a single step would offer a direct pathway to any desired stereoisomer. Here, we unveil a metallaphotoredox migration strategy to access stereodefined allylic alcohols through vinylic C–H activation with aldehydes. This method harnesses a chiral nickel catalyst in concert with a photocatalyst to enable a 1,4-Ni migration by using readily accessible 2-vinyl iodoarenes as starting materials. The efficacy of this methodology is highlighted by the precise construction of all stereoisomers of allylic alcohols bearing analogous substituents and the efficient synthesis of key intermediates en route to Myristinin family. Experimental and computational studies have shed light on pivotal aspects including the synergy of metal catalysis and photocatalysis, the driving forces behind the migration, and the determination of absolute configuration in the C–H addition process.

Nature Synthesis, Published online: 26 September 2024; doi:10.1038/s44160-024-00658-7

Catalytic methods that generate Z-alkenes are rare due to the energetic favourability of the corresponding E-alkenes. Now, a bisphosphine–iron catalyst mediates the multicomponent dialkylation of allenes, using dialkylzinc reagents and alkyl halides, to selectively form functionalized trisubstituted Z-alkenes.

Nature Synthesis, Published online: 26 September 2024; doi:10.1038/s44160-024-00654-x

The synthetic use of highly reactive alkyl radicals typically results in low chemoselectivity due to competing side reactions. Now, a redox-state-tuned copper catalytic method is reported, which enables the enantioconvergent cross-coupling of cyclopropyl radicals and terminal alkynes with high chemo- and stereoselectivity.

Nature Catalysis, Published online: 24 September 2024; doi:10.1038/s41929-024-01215-3

The merger of photocatalysis and transition metal catalysis has broadened the scope of chemical reactivity in organic synthesis. This Review provides an overview of the use of metallaphotoredox catalysis for sp3 C–H functionalizations that occur via single-electron, rather than hydrogen atom transfer.

Nature Chemistry, Published online: 25 September 2024; doi:10.1038/s41557-024-01624-8

Amines are predominant motifs in pharmaceuticals, but complex amines are challenging to generate. Now, enabled by triple Au–H/Au+/Au–H relay catalysis, the synthesis of complex and structurally diverse amines by a direct reductive hydroamination of alkynes with nitroarenes is reported. Catalytic intermediates were isolated to elucidate the mechanism.

Ni-catalyzed asymmetric reductive cross-coupling reactions provide rapid and modular access to enantioenriched building blocks from simple electrophile precursors. Reductive coupling reactions that can diverge through a common organometallic intermediate to two distinct families of enantioenriched products are particularly versatile but underdeveloped. Here, we describe the development of a bis(oxazoline) ligand that enables the desymmetrization of meso-anhydrides. When secondary benzylic electrophiles are employed, doubly stereoselective acyl cross-coupling proceeds to give ketone products with catalyst control over three newly formed stereogenic centers. Alternatively, use of primary alkyl halides in the presence of an additional halogen atom transfer catalyst results in decarbonylative alkylation to give enantioenriched beta-alkyl acids. Analysis of reaction rates for a range of both catalysts and substrates supports the notion that tuning the different electrophile activation steps with the two catalysts is required for enhanced reaction performance. These studies illustrate how reaction design can diverge a common Ni-acyl intermediate to either acyl or decarbonylative coupling products and highlight how dual ligand systems can be used to engage unactivated alkyl halides in Ni-catalyzed asymmetric reductive coupling.

A highly enantioselective cobalt-catalyzed semipinacol rearrangement of symmetric α,α-diarylallylic alcohols is disclosed. A chiral cobalt-salen catalyst generates a highly electrophilic carbocation surrogate following hydrogen atom transfer and radical–polar crossover steps. This methodology provides access to enantioenriched α-aryl ketones through invertive displacement of a cobalt(IV) complex during 1,2-aryl migration. A combination of readily available reagents, silane and N-fluoropyridinium oxidant, are used to confer this type of reactivity. An exploration into the effect of aryl substitution revealed the reaction tolerates para- and meta-halogenated, mildly electron-rich and electron-poor aromatic rings with excellent enantioselectivities and yields. The yield of the rearrangement diminished with highly electron-rich aryl rings whereas very electron-deficient and ortho-substituted arenes led to poor enantiocontrol. A Hammett analysis demonstrated the migratory preference for electron-rich aromatic rings, which is consistent with the intermediacy of a phenonium cation.

Designing sequences for specific protein backbones is a key step in creating new functional proteins. Here, we introduce GeoSeqBuilder, a deep learning framework that integrates protein sequence generation with side chain conformation prediction to produce the complete all-atom structures for designed sequences. GeoSeqBuilder uses spatial geometric features from protein backbones and explicitly includes three-body interactions of neighboring residues. GeoSeqBuilder achieves native residue type recovery rate of 51.6%, comparable to ProteinMPNN and  other leading methods, while accurately predicting side chain conformations. We first used GeoSeqBuilder to design sequences for thioredoxin and a hallucinated three-helical bundle protein. All the 15 tested sequences expressed as soluble monomeric proteins with high thermal stability, and the 2 high-resolution crystal structures solved closely match the designed models. The generated protein sequences exhibit low similarity (minimum 23%) to the original sequences, with significantly altered hydrophobic cores. We further redesigned the hydrophobic core of glutathione peroxidase 4, and 3 of the 5 designs showed improved enzyme activity. Although further testing is needed, the high experimental success rate in our testing demonstrates that GeoSeqBuilder is a powerful tool for designing novel sequences for predefined protein structures with atomic details. GeoSeqBuilder is available at https://github.com/PKUliujl/GeoSeqBuilder

An in vitro enzyme cascade for mevalonate phosphorylation and ATP regeneration was optimized for productivity and productivity-cost-ratio using Bayesian optimization (BO) for the proposal of new experiments with an expected improvement. In four BO rounds, the optimal compound concentrations were found to reach an optimum, while avoiding replicated experiments and being robust to outlying experimental results. Institute and/or researcher Twitter usernames: @Luetz_Lab: @RosenthalKatrin; @ericvonlieres.

Abstract

The optimization of enzyme cascades is a complex and resource-demanding task due to the multitude of parameters and synergistic effects involved. Machine learning can support the identification of optimal reaction conditions, for example, in the case of Bayesian optimization (BO), by proposing new experiments based on Gaussian process regression (GPR) and expected improvement (EI). Here, in this research BO is used to optimize the concentrations of the reaction components of an enzyme cascade. The productivity-cost-ratio is chosen as the optimization objective in order to achieve the highest possible productivity, which was normalized to the costs of the materials used to prevent convergence to ever-increasing enzyme concentrations. To reduce the experimental effort, contrary to common practice in biological experiments, replicates were not used; instead, the algorithm's proposed experiments and inherent uncertainty quantification were relied upon. This approach balances parameter space exploration and exploitation, which is critical for the efficient and effective identification of optimal reaction conditions. At the optimized reaction conditions identified in this study, the productivity-cost ratio is doubled to 38.6 mmol L⁻¹ h⁻¹ €⁻¹ compared to a reference experiment. The parameter optimization required only 52 experiments while being robust to outlying experimental results.

Modular type I polyketide synthases (PKSs) comprise a family of enzymes that synthesize a diverse class of natural products with medicinal applications. The biochemical features of these systems include the extension and processing of polyketide chains in a stepwise, stereospecific manner, organized by a series of modules divided into distinct catalytic domains. Previous work revealed that a primary hurdle for utilizing PKS modules to create diverse macrolactones hinges on the selectivity of the thioesterase (TE) domain. Herein, we generated novel hybrid 12-membered macrolactone/lactam ring systems employing unnatural amide-containing hexaketide intermediates in conjunction with an engineered TE S148C mutant from the pikromycin (Pik) biosynthetic pathway. Specifically, unnatural macrocycle (3) was initially formed in severely attenuated yields compared to the native product generated from the natural hexaketide substrate. A stepwise directed evolution campaign generated Pik TE variants with enhanced selectivity for macrocycle formation over hydrolysis. Over three rounds of evolution, a series of mutant Pik TE proteins were identified, and further combinations of beneficial mutations carried from each round produced a composite variant with six-fold enhanced isolated yield of the hybrid macrocycle compared to the parent TE S148C mutant enzyme. This study offers new insights into the range of amino acid residues, both proximal and distal to the active site, that impart improved selectivity and yield against the unnatural polyketide substrate and overcoming a key PKS pathway gatekeeper.

Nature Communications, Published online: 14 September 2024; doi:10.1038/s41467-024-52249-x

Branched alkenyl sulfides are useful moieties in synthesis and materials. Here, the authors disclose a hydromethylthiolation of alkynes via cobalt hydride catalysis, resulting in Markovnikov regioselectivity, proceeding via electrophilic thiolation.

Nature Chemistry, Published online: 16 September 2024; doi:10.1038/s41557-024-01603-z

Nitrile-containing molecules and their biosynthetic enzymes are uncommon in nature. Now, a nitrile-forming diiron enzyme involved in the biosynthesis of aetokthonotoxin—the ‘eagle-killing’ neurotoxin—has been characterized using biochemical, structural and biophysical methods. High-resolution protein crystal structures together with the identification of catalytically relevant tryptophan-based products provide mechanistic insights into this unusual nitrile-forming reaction.

Nature Chemical Biology, Published online: 11 September 2024; doi:10.1038/s41589-024-01712-3

By enriching productive mutational paths, a Kemp eliminase that speeds up proton abstraction >108-fold was developed in only five evolution rounds. Recombining it with a variant differing by 29 substitutions revealed the underlying fitness landscape.

Nature, Published online: 10 September 2024; doi:10.1038/s41586-024-08004-9

Stereospecific radical coupling with a non-natural photodecarboxylase

Nature Chemistry, Published online: 09 September 2024; doi:10.1038/s41557-024-01633-7

Simultaneous functionalization of reactive and inert remote sites presents a powerful approach to access complex molecules, yet it is hindered by precise remote C(sp3)–H activation. Now, the accurate translocation of functional groups and remote C–H desaturation has been achieved in parallel through combining functional group migration and cobalt-promoted hydrogen atom transfer.

Mining company scientists demand retraction of paper claiming environmental contamination