A gold(I)-catalyzed cyclization of enynone-nitriles with amines to 2,3-DHPs assisted by La(OTf)3 has been developed. The compatibility with abundant nucleophiles, high functional group tolerance, rapid assembly of molecular complexity, and late-stage functionalization of bioactive substances make this approach attractive for the construction of 2,3-DHPs, which have rarely been synthesized in the literature. The reaction proceeds via cascade cyclization involving gold/Lewis acid cooperative activation of the alkene and the cyano moiety.

The homogeneous catalytic hydrogenation of benzo-fused heteroarenes generally provides partially hydrogenated products wherein the heteroaryl ring is preferentially reduced, such as quinoline hydrogenation, leading to 1,2,3,4-tetrahydroquinoline. Herein, we report a carbocycle-selective hydrogenation of fused N-heteroarenes (quinoline, isoquinoline, quinoxaline, etc.) using the Ru complex of a chiral spiroketal-based diphosphine (SKP) as the catalyst, affording the corresponding 5,6,7,8-tetrahydro products in high chemoselectivities. This catalytic system is also effective for the asymmetric carbocycle hydrogenation of fused heteroarenes bearing a boryl or amino group. Experimental studies provided a strong support for the homogeneous nature of the catalysis, and an inner-sphere mechanism was proposed for the hydrogenation. DFT calculations indicated that the hydrogenation is initiated by eta 4-coordinative activation of quinoline carbocycle to Ru dihydride complex of SKP, followed by metal-to-ligand hydride transfer. Subsequent carbocycle reduction proceeds via consecutive steps of the H2 oxidative addition and C-H reductive elimination.

A novel strategy for site-selective benzylic C-H oxidation has been developed through mediated electrolysis. A bulky maleimide N-oxyl radical (MINO) generated by proton-coupled electrochemical oxidation of N-hydroxymaleimide (NHMI), serves as a hydrogen atom-transfer mediator. Good-to-excellent site selectivity was observed among different substrates, providing a practical approach for site-selective benzylic C-H oxidation. Additionally, the hydrogen-atom transfer mechanism for C-H electrochemical oxidation allows the oxidation to proceed at much lower anode potentials relative to direct electrolysis and with minimal reliance on the substrate's electronic properties. (c) 2024, Dalian Institute of Chemical Physics, Chinese Academy of Sciences. Published by Elsevier B.V. All rights reserved.

It has been established that N-acetyltransferase (murine NAT1 (mNAT1) and human NAT2 (hNAT2)) mediates insulin sensitivity in type 2 diabetes. Here we show that mNAT1 deficiency leads to a decrease in cellular spermidine-a natural polyamine exhibiting health-protective and anti-ageing effects-but understanding of its mechanism is limited. We identify that mNAT1 and hNAT2 modulate a type of post-translational modification involving acetylated spermidine, which we name acetylhypusination, on receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-a key regulator of inflammation and cell death. Spermidine supplementation decreases RIPK1-mediated cell death and diabetic phenotypes induced by NAT1 deficiency in vivo. Furthermore, insulin resistance and diabetic kidney disease mediated by vascular pathology in NAT1-deficient mice can be blocked by inhibiting RIPK1. Finally, we demonstrate a decrease in spermidine and activation of RIPK1 in the vascular tissues of human patients with diabetes. Our study suggests a role for vascular pathology in diabetes onset and progression and identifies the inhibition of RIPK1 kinase as a potential therapeutic approach for the treatment of type 2 diabetes.