Enantioconvergent Cu-catalysed N-alkylation of aliphatic amines.

Chiral amines are commonly used in the pharmaceutical and agrochemical industries1. The strong demand for unnatural chiral amines has driven the development of catalytic asymmetric methods1,2. Although the N-alkylation of aliphatic amines with alkyl halides has been widely adopted for over 100 years, catalyst poisoning and unfettered reactivity have been preventing the development of a catalyst-controlled enantioselective version3-5. Here we report the use of chiral tridentate anionic ligands to enable the copper-catalysed chemoselective and enantioconvergent N-alkylation of aliphatic amines with α-carbonyl alkyl chlorides. This method can directly convert feedstock chemicals, including ammonia and pharmaceutically relevant amines, into unnatural chiral α-amino amides under mild and robust conditions. Excellent enantioselectivity and functional-group tolerance were observed. The power of the method is demonstrated in a number of complex settings, including late-stage functionalization and in the expedited synthesis of diverse amine drug molecules. The current method indicates that multidentate anionic ligands are a general solution for overcoming transition-metal-catalyst poisoning.

Copper-Catalyzed Enantioconvergent Radical N-Alkylation of Diverse (Hetero)aromatic Amines.

The 3d transition metal-catalyzed enantioconvergent radical cross-coupling provides a powerful tool for chiral molecule synthesis. In the classic mechanism, the bond formation relies on the interaction between nucleophile-sequestered metal complexes and radicals, limiting the nucleophile scope to sterically uncongested ones. The coupling of sterically congested nucleophiles poses a significant challenge due to difficulties in transmetalation, restricting the reaction generality. Here, we describe a probable outer-sphere nucleophilic attack mechanism that circumvents the challenging transmetalation associated with sterically congested nucleophiles. This strategy enables a general copper-catalyzed enantioconvergent radical N-alkylation of aromatic amines with secondary/tertiary alkyl halides and exhibits catalyst-controlled stereoselectivity. It accommodates diverse aromatic amines, especially bulky secondary and primary ones to deliver value-added chiral amines (>110 examples). It is expected to inspire the coupling of more nucleophiles, particularly challenging sterically congested ones, and accelerate reaction generality.

Na2S2O3 Catalyzed Three-Component Synthesis and Anti-Bacterial Activity of 3-Methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones.

An efficient and green method for synthesizing 3-methyl-4-(hetero) arylmethylene isoxazole-5(4H)-ones was developed using a recyclable and environmental-friendly catalyst, Na2S2O3, and 16 target compounds were successfully synthesized under the obtained optimal reaction condition. Using rifampicin as a positive control, the antibacterial activity of all synthesized compounds was tested by micro dilution method, among them, 3-methyl-4-[(2,4-dimethoxyphenyl) methylene]-isoxazole-5-one (4 m) presented wonderful antimicrobial activity, which may contribute to the development of anti-tuberculosis drugs.

Neurogenic Effects of Inorganic Arsenic and Cdk5 Knockdown in Zebrafish Embryos: A Perspective on Modeling Autism.

The exact mechanisms of the development of autism, a multifactorial neurological disorder, are not clear. The pathophysiology of autism is complex, and investigations at the cellular and molecular levels are ongoing to provide clarity. Mutations in specific genes have been identified as risk factors for autism. The role of heavy metals in the pathogenesis of autism is subject to many studies and remains debatable. Although no exact neuronal phenotypes have been identified linked to autistic symptoms, overproduction and reduction of specific neurons have been implicated. A growing literature on generating genetic and non-genetic models of autism aims to help with understanding mechanistic studies that can explain the complexity of the disorder. Both genetic and non-genetic methods of zebrafish have been used to model autism. For several human autism risk genes, validated zebrafish mutant models have been generated. There is growing evidence indicating a potential link between autism and inorganic arsenic exposure. We have previously shown that inorganic arsenic induces supernumerary spinal motor neurons via Sonic hedgehog (Shh) signaling pathway, and Cdk5 knockdown causes an overproduction of cranial and spinal motor neurons in zebrafish. Here, in this review, we provide a perspective on what these findings of neurogenic phenotypes mean in terms of dysregulated pathways of motor neuron development and their applicability to understanding cellular and molecular underpinnings of autism.

Copper-Catalyzed Enantioselective C(sp3 )-SCF3 Coupling of Carbon-Centered Benzyl Radicals with (Me4 N)SCF3.

In contrast with the well-established C(sp2 )-SCF3 cross-coupling to forge the Ar-SCF3 bond, the corresponding enantioselective coupling of readily available alkyl electrophiles to forge chiral C(sp3 )-SCF3 bond has remained largely unexplored. We herein disclose a copper-catalyzed enantioselective radical C(sp3 )-SCF3 coupling of a range of secondary/tertiary benzyl radicals with the easily available (Me4 N)SCF3 reagent. The key to the success lies in the utilization of chiral phosphino-oxazoline-derived anionic N,N,P-ligands through tuning electronic and steric effects for the simultaneous control of the reaction initiation and enantioselectivity. This strategy can successfully realize two types of asymmetric radical reactions, including enantioconvergent C(sp3 )-SCF3 cross-coupling of racemic benzyl halides and three-component 1,2-carbotrifluoromethylthiolation of arylated alkenes under mild reaction conditions. It therefore provides a highly flexible platform for the rapid assembly of an array of enantioenriched SCF3 -containing molecules of interest in organic synthesis and medicinal chemistry.

Cu(I)-Catalyzed Chemo- and Enantioselective Desymmetrizing C-O Bond Coupling of Acyl Radicals.

Transition-metal-catalyzed enantioselective functionalization of acyl radicals has so far not been realized, probably due to their relatively high reactivity, which renders the chemo- and stereocontrol challenging. Herein, we describe Cu(I)-catalyzed enantioselective desymmetrizing C-O bond coupling of acyl radicals. This reaction is compatible with (hetero)aryl and alkyl aldehydes and, more importantly, displays a very broad scope of challenging alcohol substrates, such as 2,2-disubstituted 1,3-diols, 2-substituted-2-chloro-1,3-diols, 2-substituted 1,2,3-triols, 2-substituted serinols, and meso primary 1,4-diols, providing enantioenriched esters characterized by challenging acyclic tetrasubstituted carbon stereocenters. Partnered by one- or two-step follow-up transformations, this reaction provides a convenient and practical strategy for the rapid preparation of chiral C3 building blocks from readily available alcohols, particularly the industrially relevant glycerol. Mechanistic studies supported the proposed C-O bond coupling of acyl radicals.

Copper-Catalyzed Enantioconvergent Radical C(sp3)-N Cross-Coupling of Activated Racemic Alkyl Halides with (Hetero)aromatic Amines under Ambient Conditions.

The enantioconvergent C(sp3)-N cross-coupling of racemic alkyl halides with (hetero)aromatic amines represents an ideal means to afford enantioenriched N-alkyl (hetero)aromatic amines yet has remained unexplored due to the catalyst poisoning specifically for strong-coordinating heteroaromatic amines. Here, we demonstrate a copper-catalyzed enantioconvergent radical C(sp3)-N cross-coupling of activated racemic alkyl halides with (hetero)aromatic amines under ambient conditions. The key to success is the judicious selection of appropriate multidentate anionic ligands through readily fine-tuning both electronic and steric properties for the formation of a stable and rigid chelating Cu complex. Thus, this kind of ligand could not only enhance the reducing capability of a copper catalyst to provide an enantioconvergent radical pathway but also avoid the coordination with other coordinating heteroatoms, thereby overcoming catalyst poisoning and/or chiral ligand displacement. This protocol covers a wide range of coupling partners (89 examples for activated racemic secondary/tertiary alkyl bromides/chlorides and (hetero)aromatic amines) with high functional group compatibility. When allied with follow-up transformations, it provides a highly flexible platform to access synthetically useful enantioenriched amine building blocks.

PTSA-catalyzed selective synthesis and antibacterial evaluation of 1,2-disubstituted benzimidazoles.

Herein, we developed a convenient and efficient method via protonation of p-toluenesulfonic acid promoted cyclocondensation of o-phenylenediamine and aldehydes for selectively synthesizing 1,2-disubstituted benzimidazoles. This method displayed broad substrate adaptability and afforded the desired products in moderate to excellent yield in short reaction time. The effect of different substituents on the yield was investigated by extending optimum reaction conditions, which was further confirmed by theoretical calculations. It suggested that the surface electrostatic potential of oxygen atom and nitrogen atom on the substrates played important role in the synthesis of 1,2-disubstituted benzimidazoles. Besides, the crystal structure of compound 2t in the orthorhombic space group P2(1)/c was presented. Also, the anti-mycolicibacterium smegmatis (MC2155) activity was evaluated using rifampicin as a positive control. The products (2a, 2b, 2c, 2i, 2j, 2k, 2m) showed good antibacterial activities which were comparable to rifampicin.

Gene expression analyses reveal potential mechanism of inorganic arsenic-induced apoptosis in zebrafish.

Our previous study showed that sodium arsenite (200 mg/L) affected the nervous system and induced motor neuron development via the Sonic hedgehog pathway in zebrafish larvae. To gain more insight into the effects of arsenite on other signaling pathways, including apoptosis, we have performed quantitative polymerase chain reaction array-based gene expression analyses. The 96-well array plates contained primers for 84 genes representing 10 signaling pathways that regulate several biological functions, including apoptosis. We exposed eggs at 5 h postfertilization until the 72 h postfertilization larval stage to 200 mg/L sodium arsenite. In the Janus kinase/signal transducers and activators of transcription, nuclear factor κ-light-chain-enhancer of activated B cells, and Wingless/Int-1 signaling pathways, the expression of only one gene in each pathway was significantly altered. The expression of multiple genes was altered in the p53 and oxidative stress pathways. Sodium arsenite induced excessive apoptosis in the larvae. This compelled us to analyze specific genes in the p53 pathway, including cdkn1a, gadd45aa, and gadd45ba. Our data suggest that the p53 pathway is likely responsible for sodium arsenite-induced apoptosis. In addition, sodium arsenite significantly reduced global DNA methylation in the zebrafish larvae, which may indicate that epigenetic factors could be dysregulated after arsenic exposure. Together, these data elucidate potential mechanisms of arsenic toxicity that could improve understanding of arsenic's effects on human health.

Synthesis of α-Quaternary ß-Lactams via Copper-Catalyzed Enantioconvergent Radical C(sp3 )-C(sp2 ) Cross-Coupling with Organoboronate Esters.

The copper-catalyzed enantioconvergent radical C(sp3 )-C(sp2 ) cross-coupling of tertiary α-bromo-ß-lactams with organoboronate esters could provide the synthetically valuable α-quaternary ß-lactams. The challenge arises mainly from the construction of sterically congested quaternary stereocenters between the tertiary alkyl radicals and chiral copper(II) species. Herein, we describe our success in achieving such transformations through the utilization of a copper/hemilabile N,N,N-ligand catalyst to forge the sterically congested chiral C(sp3 )-C(sp2 ) bond via a single-electron reduction/transmetalation/bond formation catalytic cycle. The synthetic potential of this approach is shown in the straightforward conversion of the corresponding products into many valuable building blocks. We hope that the developed catalytic cycle would open up new vistas for more enantioconvergent cross-coupling reactions.

Copper-Catalyzed Chemo- and Enantioselective Radical 1,2-Carbophosphonylation of Styrenes.

The copper-catalyzed enantioselective radical difunctionalization of alkenes from readily available alkyl halides and organophosphorus reagents possessing a P-H bond provides an appealing approach for the synthesis of α-chiral alkyl phosphorus compounds. The major challenge arises from the easy generation of a P-centered radical from the P-H-type reagent and its facile addition to the terminal side of alkenes, leading to reverse chemoselectivity. We herein disclose a radical 1,2-carbophosphonylation of styrenes in a highly chemo- and enantioselective manner. The key to the success lies in not only the implementation of dialkyl phosphites with a strong bond dissociation energy to promote the desired chemoselectivity but also the utilization of an anionic chiral N,N,N-ligand to forge the chiral C(sp3 )-P bond. The developed Cu/N,N,N-ligand catalyst has enriched our library of single-electron transfer catalysts in the enantioselective radical transformations.

Copper-Catalyzed Enantioconvergent Radical C(sp3 )-N Cross-Coupling: Access to α,α-Disubstituted Amino Acids.

Transition-metal catalyzed enantioconvergent cross-coupling of tertiary alkyl halides with ammonia offers a rapid avenue to chiral unnatural α,α-disubstituted amino acids. However, the construction of chiral C-N bonds between tertiary-carbon electrophiles and nitrogen nucleophiles presented a great challenge owing to steric congestion. We report a copper-catalyzed enantioconvergent radical C-N cross-coupling of alkyl halides with sulfoximines (as ammonia surrogates) under mild conditions by employing a chiral anionic N,N,N-ligand with a long spreading side arm. An array of α,α-disubstituted amino acid derivatives were obtained with good efficiency and enantioselectivity. The synthetic utility of the strategy has been showcased by the elaboration of the coupling products into different chiral α-fully substituted amine building blocks.

Ligand Development for Copper-Catalyzed Enantioconvergent Radical Cross-Coupling of Racemic Alkyl Halides.

The enantioconvergent cross-coupling of racemic alkyl halides represents a powerful tool for the synthesis of enantioenriched molecules. In this regard, the first-row transition metal catalysis provides a suitable mechanism for stereoconvergence by converting racemic alkyl halides to prochiral radical intermediates owing to their good single-electron transfer ability. In contrast to the noble development of chiral nickel catalyst, copper-catalyzed enantioconvergent radical cross-coupling of alkyl halides is less studied. Besides the enantiocontrol issue, the major challenge arises from the weak reducing capability of copper that slows the reaction initiation. Recently, significant efforts have been dedicated to basic research aimed at developing chiral ligands for copper-catalyzed enantioconvergent radical cross-coupling of racemic alkyl halides. This perspective will discuss the advances in this burgeoning area with particular emphasis on the strategic chiral anionic ligand design to tune the reducing capability of copper for the reaction initiation under thermal conditions from our research group.

A Counterion/Ligand-Tuned Chemo- and Enantioselective Copper-Catalyzed Intermolecular Radical 1,2-Carboamination of Alkenes.

The copper-catalyzed enantioselective intermolecular radical 1,2-carboamination of alkenes with readily accessible alkyl halides is an appealing strategy for producing chiral amine scaffolds. The challenge arises from the easily occurring atom transfer radical addition between alkyl halides and alkenes and the issue of enantiocontrol. We herein describe a radical alkene 1,2-carboamination with sulfoximines in a highly chemo- and enantioselective manner. The key to the success of this process is the conceptual design of a counterion/highly sterically demanded ligand coeffect to promote the ligand exchange of copper(I) with sulfoximines and forge chiral C-N bonds between alkyl radicals and the chiral copper(II) complex. The reaction covers alkenes bearing distinct electronic properties, such as aryl-, heteroaryl-, carbonyl-, and aminocarbonyl-substituted ones, and various radical precursors, including alkyl chlorides, bromides, iodides, and the CF3 source. Facile transformations deliver many chiral amine building blocks of interest in organic synthesis and related areas.

Design of Hemilabile N,N,N-Ligands in Copper-Catalyzed Enantioconvergent Radical Cross-Coupling of Benzyl/Propargyl Halides with Alkenylboronate Esters.

The enantioconvergent radical C(sp3)-C(sp2) cross-coupling of alkyl halides with alkenylboronate esters is an appealing tool in the assembly of synthetically valuable enantioenriched alkenes owing to the ready availability, low toxicity, and air/moisture stability of alkenylboronate esters. Here, we report a copper/chiral N,N,N-ligand catalytic system for the enantioconvergent cross-coupling of benzyl/propargyl halides with alkenylboronate esters (>80 examples) with good functional group tolerance. The key to the success is the rational design of hemilabile N,N,N-ligands by mounting steric hindrance at the ortho position of one coordinating quinoline ring. Thus, the newly designed ligand could not only promote the radical cross-coupling process in the tridentate form but also deliver enantiocontrol over highly reactive alkyl radicals in the bidentate form. Facile follow-up transformations highlight its potential utility in the synthesis of various enantioenriched building blocks as well as in the late-stage functionalization for drug discovery.

Galaxy-ML: An accessible, reproducible, and scalable machine learning toolkit for biomedicine.

Supervised machine learning is an essential but difficult to use approach in biomedical data analysis. The Galaxy-ML toolkit (https://galaxyproject.org/community/machine-learning/) makes supervised machine learning more accessible to biomedical scientists by enabling them to perform end-to-end reproducible machine learning analyses at large scale using only a web browser. Galaxy-ML extends Galaxy (https://galaxyproject.org), a biomedical computational workbench used by tens of thousands of scientists across the world, with a suite of tools for all aspects of supervised machine learning.

The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2020 update.

Galaxy (https://galaxyproject.org) is a web-based computational workbench used by tens of thousands of scientists across the world to analyze large biomedical datasets. Since 2005, the Galaxy project has fostered a global community focused on achieving accessible, reproducible, and collaborative research. Together, this community develops the Galaxy software framework, integrates analysis tools and visualizations into the framework, runs public servers that make Galaxy available via a web browser, performs and publishes analyses using Galaxy, leads bioinformatics workshops that introduce and use Galaxy, and develops interactive training materials for Galaxy. Over the last two years, all aspects of the Galaxy project have grown: code contributions, tools integrated, users, and training materials. Key advances in Galaxy's user interface include enhancements for analyzing large dataset collections as well as interactive tools for exploratory data analysis. Extensions to Galaxy's framework include support for federated identity and access management and increased ability to distribute analysis jobs to remote resources. New community resources include large public servers in Europe and Australia, an increasing number of regional and local Galaxy communities, and substantial growth in the Galaxy Training Network.

Enantioselective Hydroxylation of Dihydrosilanes to Si-Chiral Silanols Catalyzed by In Situ Generated Copper(II) Species.

Catalytic enantioselective hydroxylation of prochiral dihydrosilanes with water is expected to be a highly efficient way to access Si-chiral silanols, yet has remained unknown up to date. Herein, we describe a strategy for realizing this reaction: using an alkyl bromide as a single-electron transfer (SET) oxidant for invoking CuII species and chiral multidentate anionic N,N,P-ligands for effective enantiocontrol. The reaction readily provides a broad range of Si-chiral silanols with high enantioselectivity and excellent functional group compatibility. In addition, we manifest the synthetic potential by establishing two synthetic schemes for transforming the obtained products into Si-chiral compounds with high structural diversity. Our preliminary mechanistic studies support a mechanism involving SET for recruiting chiral CuII species as the active catalyst and its subsequent σ-metathesis with dihydrosilanes.

Enantioconvergent Cu-Catalyzed Radical C-N Coupling of Racemic Secondary Alkyl Halides to Access α-Chiral Primary Amines.

α-Chiral alkyl primary amines are virtually universal synthetic precursors for all other α-chiral N-containing compounds ubiquitous in biological, pharmaceutical, and material sciences. The enantioselective amination of common alkyl halides with ammonia is appealing for potential rapid access to α-chiral primary amines, but has hitherto remained rare due to the multifaceted difficulties in using ammonia and the underdeveloped C(sp3)-N coupling. Here we demonstrate sulfoximines as excellent ammonia surrogates for enantioconvergent radical C-N coupling with diverse racemic secondary alkyl halides (>60 examples) by copper catalysis under mild thermal conditions. The reaction efficiently provides highly enantioenriched N-alkyl sulfoximines (up to 99% yield and >99% ee) featuring secondary benzyl, propargyl, α-carbonyl alkyl, and α-cyano alkyl stereocenters. In addition, we have converted the masked α-chiral primary amines thus obtained to various synthetic building blocks, ligands, and drugs possessing α-chiral N-functionalities, such as carbamate, carboxylamide, secondary and tertiary amine, and oxazoline, with commonly seen α-substitution patterns. These results shine light on the potential of enantioconvergent radical cross-coupling as a general chiral carbon-heteroatom formation strategy.

Genetic analysis of 20 patients with hypomyelinating leukodystrophy by trio-based whole-exome sequencing.

Hypomyelinating leukodystrophies (HLDs) are a rare group of disorders characterized by myelin deficit of the brain-based on MRI. Here, we studied 20 patients with unexplained HLD to uncover their genetic etiology through whole-exome sequencing (WES). Trio-based WES was performed for 20 unresolved HLDs families after genetic tests for the PLP1 duplication and a panel of 115 known leukodystrophy-related genes. Variants in both known genes that related to HLDs and promising candidate genes were analyzed. Minigene splicing assay was conducted to confirm the effect of splice region variant. All 20 patients were diagnosed with HLDs clinically based on myelin deficit on MRI and impaired motor ability. Through WES, in 11 of 20 trios, 15 causative variants were detected in seven genes TUBB4A, POLR1C, POLR3A, SOX10, TMEM106B, DEGS1, and TMEM63A. The last three genes have just been discovered. Of 15 variants, six were novel. Using minigene splicing assay, splice variant POLR3A c.1770 + 5 G > C was proved to disrupt the normal splicing of intron 13 and led to a premature stop codon at position 618 (p.(P591Vfs*28)). Our analysis determined the molecular diagnosis of 11 HLDs patients. It emphasizes the heterogenicity of HLDs, the diagnostic power of trio-based WES for HLDs. Comprehensive analysis including a focus on candidate genes helps to discover novel disease-causing genes, determine the diagnosis for the first time, and improve the yield of WES. Moreover, novel mutations identified in TUBB4A, POLR3A, and POLR1C expand the mutation spectrum of these genes.