Synthesis of [2.2]Paracyclophane-Fused Heterocycles via Palladium-Catalyzed C-H Activation/Annulation of [2.2]Paracyclophanecarboxamides with Arynes.

[2.2]Paracyclophane-fused heterocycles represent an important scaffold. Traditional approaches often suffer from tedious synthetic routes, and the development of catalytic synthesis of them remains in its infancy. Herein, by employing highly strained aryne intermediates as partners, we have developed a concise protocol by palladium-catalyzed C-H activation/annulation from [2.2]paracyclophanecarboxamide substrates. [2.2]Paracyclophane-fused quinolinone products are obtained in good yields (up to 84%). Furthermore, the utility of the process has been shown through the synthesis of [2.2]paracyclophane-fused heterocyclic catalysts.

A low-nuclear Ag4 nanocluster as a customized catalyst for the cyclization of propargylamine with CO2.

The preparation of 2-Oxazolidinones using CO2 offers opportunities for green chemistry, but multi-site activation is difficult for most catalysts. Here, A low-nuclear Ag4 catalytic system is successfully customized, which solves the simultaneous activation of acetylene (-C≡C) and amino (-NH-) and realizes the cyclization of propargylamine with CO2 under mild conditions. As expected, the Turnover Number (TON) and Turnover Frequency (TOF) values of the Ag4 nanocluster (NC) are higher than most of reported catalysts. The Ag4* NC intermediates are isolated and confirmed their structures by Electrospray ionization (ESI) and 1H Nuclear Magnetic Resonance (1H NMR). Additionally, the key role of multiple Ag atoms revealed the feasibility and importance of low-nuclear catalysts at the atomic level, confirming the reaction pathways that are inaccessible to the Ag single-atom catalyst and Ag2 NC. Importantly, the nanocomposite achieves multiple recoveries and gram scale product acquisition. These results provide guidance for the design of more efficient and targeted catalytic materials.

Novel substituted 4-(Arylethynyl)-Pyrrolo[2,3-d]pyrimidines negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGlu5) Treat depressive disorder in mice.

In view of the fact that the G-protein-coupled receptors (GPCRs) sit at the top of the signaling pathways triggering a diverse range of signaling cascades towards a cellular event, GPCRs are regarded as central drug targets. mGlu5, a type of classical GPCRs, is highly expressed in the central nervous system (CNS) and responds to the neurotransmitter glutamate. Researches show that mGlu5 is a potential drug target for the treatment of depression. Up to now, multiple mGlu5 negative allosteric modulators (NAMs) have entered clinical trials, but no small molecule mGlu5 NAM has yet to reach market. Herein, we report the structural optimization and structure-activity relationship studies of a series of novel mGlu5 NAMs. Among them, the novel compound 10b is a high-affinity mGluR5 antagonist, with an IC50 value of 11.5 nM. Besides, we evaluated the anti-depressant effect of compound 10b using the chronic unpredictable mild stress (CUMS)-induced depression model. The data showed that the mice in CUMS group were featured by decreased level of serum 5-HT and increased level of serum CORT, and the expression of synaptic proteins were reduced, including GluA1, GluA2, p-PKA, BDNF and TrkB. However, those factors for identifying sensitivity to depression-like behaviors could be improved by compound 10b treatment. The preliminary toxicology evaluations indicated that compound 10b had a good safety profile in vivo. Collectively, the compound 10b represents a promising lead compound for the treatment of depressive disorder.

Construction of highly enantioenriched spirocyclopentaneoxindoles containing four consecutive stereocenters via thiourea-catalyzed asymmetric Michael-Henry cascade reactions.

The thiourea-catalyzed asymmetric synthesis of highly enantioenriched spirocyclopentaneoxindoles containing chiral amide functional groups using simple 3-substituted oxindoles and nitrovinylacetamide as starting materials was achieved successfully. This protocol features operational simplicity, high atom economy, and high catalytic asymmetry, thus representing a versatile approach to the synthesis of highly enantioenriched spirocyclopentaneoxindoles.

Enantioselective Assembly of Spirolactones through NHC-Catalyzed Remote γ-Carbon Addition of Enals with Isatins.

A chiral N-heterocyclic carbene (NHC)-catalyzed formal [4 + 2] annulation of ß-methyl substituted enals with isatins was developed to construct six-membered spirolactones bearing highly congested quaternary carbon stereocentersin good yields and high enantioselectivities. The strategy realized a challenging remote γ-carbon addition of enals and chiral control of ß-methyl substituted enals in the presence of the NHC catalyst only.