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.

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.

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.

Identification of miRNA-mRNA network and immune-related gene signatures in IgA nephropathy by integrated bioinformatics analysis.

BACKGROUND: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, and its diagnosis depends mainly on renal biopsy. However, there is no specific treatment for IgAN. Moreover, its causes and underlying molecular events require further exploration. METHODS: The expression profiles of GSE64306 and GSE93798 were downloaded from the Gene Expression Omnibus (GEO) database and used to identify the differential expression of miRNAs and genes, respectively. The StarBase and TransmiR databases were employed to predict target genes and transcription factors of the differentially expressed miRNAs (DE-miRNAs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to predict biological functions. A comprehensive analysis of the miRNA-mRNA regulatory network was constructed, and protein-protein interaction (PPI) networks and hub genes were identified. CIBERSORT was used to examine the immune cells in IgAN, and correlation analyses were performed between the hub genes and infiltrating immune cells. RESULTS: Four downregulated miRNAs and 16 upregulated miRNAs were identified. Forty-five and twelve target genes were identified for the upregulated and downregulated DE-miRNAs, respectively. CDKN1A, CDC23, EGR1, HIF1A, and TRIM28 were the hub genes with the highest degrees of connectivity. CIBERSORT revealed increases in the numbers of activated NK cells, M1 and M2 macrophages, CD4 naive T cells, and regulatory T cells in IgAN. Additionally, HIF1A, CDC23, TRIM28, and CDKN1A in IgAN patients were associated with immune cell infiltration. CONCLUSIONS: A potential miRNA-mRNA regulatory network contributing to IgAN onset and progression was successfully established. The results of the present study may facilitate the diagnosis and treatment of IgAN by targeting established miRNA-mRNA interaction networks. Infiltrating immune cells may play significant roles in IgAN pathogenesis. Future studies on these immune cells may help guide immunotherapy for IgAN patients.

Effect of parathyroid hormone-related protein on intracellular calcium ion and cyclic adenosine monophosphate concentrations in cardiac fibroblasts.

OBJECTIVE: This study aimed to determine the effect of parathyroid hormone-related protein (PTHrP) on proliferation of cardiac fibroblasts (CFs) in primary cultures of neonatal Wistar rats. METHODS: Different PTHrP concentrations were added to CFs of neonatal Wistar rats and the cells were grouped according to the concentrations added. A verapamil (VPL) group and a calcitriol (CAL) group were also established. Changes in cell proliferation and in cyclic adenosine monophosphate and calcium ion levels were identified and recorded. RESULTS: We found that as the concentration of PTHrP increased, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT, a tetrazolium salt) colorimetric absorbance values (A values) decreased. These values in the PTHrP groups were significantly lower than those in the control group. MTT colorimetric A values and 3H-thymidine deoxyribose intake were lower in the VPL group, low-dose CAL group, and the PTHrP 10-7 mol/L group compared with the control group. However, MTT colorimetric A values and 3H-thymidine deoxyribose intake were higher in the high-dose CAL group than in the PTHrP 10-7 mol/L group. As PTHrP concentrations increased, intracellular cyclic adenosine monophosphate concentrations also increased. CONCLUSION: PTHrp, VPL, and low-dose CAL inhibit proliferation of CFs, while high-dose CAL promotes proliferation of CFs.

Photoinduced Copper-Catalyzed Asymmetric Decarboxylative Alkynylation with Terminal Alkynes.

We describe a photoinduced copper-catalyzed asymmetric radical decarboxylative alkynylation of bench-stable N-hydroxyphthalimide(NHP)-type esters of racemic alkyl carboxylic acids with terminal alkynes, which provides a flexible platform for the construction of chiral C(sp3 )-C(sp) bonds. Critical to the success of this process are not only the use of the copper catalyst as a dual photo- and cross-coupling catalyst but also tuning of the NHP-type esters to inhibit the facile homodimerization of the alkyl radical and terminal alkyne, respectively. Owing to the use of stable and easily available NHP-type esters, the reaction features a broader substrate scope compared with reactions using the alkyl halide counterparts, covering (hetero)benzyl-, allyl-, and aminocarbonyl-substituted carboxylic acid derivatives, and (hetero)aryl and alkyl as well as silyl alkynes, thus providing a vital complementary approach to the previously reported method.

Copper-catalyzed enantioselective Sonogashira-type oxidative cross-coupling of unactivated C(sp3)-H bonds with alkynes.

Transition metal-catalyzed enantioselective Sonogashira-type oxidative C(sp3)-C(sp) coupling of unactivated C(sp3)-H bonds with terminal alkynes has remained a prominent challenge. The difficulties mainly stem from the regiocontrol in unactivated C(sp3)-H bond functionalization and the inhibition of readily occurring Glaser homocoupling of terminal alkynes. Here, we report a copper/chiral cinchona alkaloid-based N,N,P-ligand catalyst for asymmetric oxidative cross-coupling of unactivated C(sp3)-H bonds with terminal alkynes in a highly regio-, chemo-, and enantioselective manner. The use of N-fluoroamide as a mild oxidant is essential to site-selectively generate alkyl radical species while efficiently avoiding Glaser homocoupling. This reaction accommodates a range of (hetero)aryl and alkyl alkynes; (hetero)benzylic and propargylic C(sp3)-H bonds are all applicable. This process allows expedient access to chiral alkynyl amides/aldehydes. More importantly, it also provides a versatile tool for the construction of chiral C(sp3)-C(sp), C(sp3)-C(sp2), and C(sp3)-C(sp3) bonds when allied with follow-up transformations.

Effects of Huaiqihuang Granules Adjuvant Therapy in Children with Primary Nephrotic Syndrome.

OBJECTIVE: This study aims to observe the curative effect of Huaiqihuang Granules adjuvant therapy on primary nephrotic syndrome (PNS). METHODS: A total of 112 children with PNS were randomly divided into three groups, and changes in serum inflammatory cytokines, interleukin, lymphocyte subsets and immunoglobulin were observed. RESULTS: Before treatment, IL-18, TNF-α, CD8+ increased, while IL-10, CD4+, NK cells, IgA, IgG and Foxp3+Treg cells decreased. After Huaiqihuang Granules treatment, IL-18, TNF-α, CD8+ decreased, while IL-10, CD4+, NK cells, IgA, IgG and Foxp3+Treg cells increased. CONCLUSION: Functions of cell immunity and humoral immunity in PNS patients before treatment were suppressed and disordered. Huaiqihuang granules can play a role in immunoregulation, with slight side reactions.