α-Chiral nitriles are prevalent structural motifs in natural products, drugs, and pharmaceutically active compounds. In addition, because the cyano group can undergo various diversifying reactions, they are very versatile chiral building blocks for the synthesis of optically active aldehydes, ketones, carboxylic acids, carboxamides, amines, and N-heterocycles such as tetrazolium. Accordingly, the catalytic enantioselective cyanation reaction, as one of the most important C–C bond forming reactions, has been intensely studied in the past three decades. While traditional efforts mainly focus on the addition of the cyanide to highly polarized electrophiles as well as alkene hydrocyanation, intriguing directions in enantioselective cyanations have been opened, including the development of enantioselective alkene cyanofunctionalization, cyanation via C–H bond functionalization, and C–C bond cleavage, as well as the invention of bifunctional cyanating agents to design asymmetric tandem synthesis and to exploit enantioselective cyanide-free cyanation reactions. Additionally, significant advances have also been made in developing unprecedented chiral catalysts to address a long-term challenge, the catalytic enantioselective synthesis of structurally diverse C α-tetrasubstituted or quaternary α-chiral nitriles. This perspective aims to highlight these impressive advances, illustrates their key advantages and future applications, and provides some inspiration for related research.

We report carbonyl-stabilized phosphorus ylides as general and efficient catalysts for the cyanosilylation of ketones. The N,N-diethylacetamide derived phosphorane is identified as an extremely efficient catalyst for the cyanosilylation of dialkyl ketones, alkyl aryl ketones, diaryl ketones, and α,β-unsaturated enones with catalyst loading down to 0.005 mol %, the lowest ever known for ketone cyanosilylation. Aldehydes, aldimines, and ketimines are also viable substrates. By NMR and React IR analysis, as well as electrical conductivity experiments, it is proposed that the phosphorane acts as a Lewis base in order to mediate the reaction via the desilylative nucleophilic activation of TMSCN.

We report that phosphorane can activate (salen)­TiCl2 complex to achieve unprecedented excellent enantioselectivity and a broad substrate scope in the cyanation of nitroolefins. Our cyanating reagent Me2(CH2Cl)­SiCN proves to be more active than TMSCN in this reaction, allowing 11 β-aliphatic nitrolefins and 12 β-CF3 nitroolefins (either β-aryl or aliphatic) to work well to give the corresponding tertiary or quaternary β-nitronitriles with high to excellent enantioselectivity.

BackgroundAutoimmune hepatitis (AIH) is mediated by a cascade of T cell-mediated events directed at liver cells and persistent inflammation within the liver can eventually result in liver cirrhosis. Targeting glutamine metabolism has an impact on T cell activation and differentiation. However, the effect of glutamine metabolism blocking upon AIH remains unknown. We use glutaminase antagonist 6-diazo-5-oxo-L-norleucine (DON) for in vitro assays and its prodrug 2-(2-amino-4-methylpentanamido)-DON (JHU083) for in vivo assays to investigate the potential therapeutic effect and molecular mechanism of glutamine metabolism blocking in an AIH murine model.MethodsAIH mice were treated with JHU083 or vehicle before concanavalin A (ConA) administration, and disease severity was examined. Then activation and differentiation [including Th1/Th17 cells and cytotoxic T lymphocytes (CTL)] of T cells from Vehicle-WT, JHU083-AIH and Vehicle-AIH mice were tested. Furthermore, in vitro T cell activation and differentiation were measured using separated splenocytes stimulated with ConA with or without DON. The activation and differentiation of T cells were tested using flow cytometry, qRT-PCR and ELISA. Phosphorylation level of mammalian target of rapamycin (mTOR) and 70 kDa ribosomal protein S6 kinase (P70S6K) were examined by western blotting.ResultsJHU083 and DON significantly suppressed the activation of T cells and inhibited the differentiation of Th1/Th17 cells and CTL in vivo and in vitro. Besides, we demonstrated that glutamine metabolism blocking inhibited T cells activation and differentiation through decreasing the mRNA expression of amino acid transporter solute carrier family 7 member 5 (SLC7A5) and mitigating the activation of mTOR signaling.ConclusionsWe proved that targeting glutamine metabolism represents a potential new treatment strategy for patients with AIH and other T cell-mediated disease. Mechanistically, we demonstrated that glutamine metabolism blocking inhibits T cells activation and suppresses the differentiation of Th1/Th17 cells and CTL.