Catalytic Asymmetric Cyclizative Rearrangement of Anilines and Vicinal Diketones to Access 2,2-Disubstituted Indolin-3-ones.

The efficient synthesis of chiral 2,2-disubstituted indolin-3-ones is of great importance due to its significant synthetic and biological applications. However, catalytic enantioselective methods for de novo synthesis of such heterocycles remain scarce. Herein, a novel cyclizative rearrangement of readily available anilines and vicinal diketones for the one-step construction of enantioenriched 2,2-disubstituted indolin-3-ones is presented. The reaction proceeds through a self-sorted [3+2] heteroannulation/regioselective dehydration/1,2-ester shift process. Only chiral phosphoric acid is employed to promote the entire sequence and simplify the manipulation of this protocol. Various common aniline derivatives are successfully applied to asymmetric synthesis as 1,3-binuclephiles for the first time. Remarkably, the observed stereoselectivity is proposed to originate from an amine-directed regio- and enantioselective ortho-Csp2-H addition of the anilines to the ketones. A range of synthetic transformations of the resulting products are demonstrated as well.

Multicomponent Cyclizative 1,2-Rearrangement Enabled Enantioselective Construction of 2,2-Disubstituted Pyrrolinones.

The 1,2-rearrangement reaction is one of the most important approaches to construct carbon-carbon bonds in organic synthesis. However, the development of catalytic asymmetric 1,2-rearrangements is still far from mature and often suffers from problems such as complex substrates, single product structure, and lack of synthetic application. Multicomponent reaction has been recognized as a robust tool for the synthesis of diverse and tunable products from readily available starting material. Conceptionally and practically, the development of multicomponent asymmetric 1,2-rearrangements is highly desirable. In this regard, we report herein a three-component benzilic acid-type rearrangement of 2,3-diketoesters, aromatic amines and aldehydes for the asymmetric construction of synthetically challenging pyrrolinones bearing aza-quaternary stereocenters. To the best of our knowledge, this reaction represents the first example of organocatalyzed multicomponent asymmetric 1,2-rearrangements.

Zinc chloride-catalyzed cyclizative 1,2-rearrangement enables facile access to morpholinones bearing aza-quaternary carbons.

Morpholines and morpholinones are important building blocks in organic synthesis and pharmacophores in medicinal chemistry, however, C3-disubstituted morpholines/morpholinones are extremely difficult to access. Here we show the ZnCl2-catalyzed cyclizative 1,2-rearrangement for the efficient synthesis of morpholinones bearing aza-quaternary stereocenters. A series of structurally diverse C3-disubstituted morpholin-2-ones which are difficultly accessible by existing methods were efficiently constructed from readily available two achiral linear compounds. Notably, mechanistic studies reveal that this reaction proceeds via an unusual sequence of direct formal [4 + 2] heteroannulation regioselectively delivering specific α-iminium/imine hemiacetals followed by a 1,2-esters or amides shift process, which is different from the reported mechanism of the aza-benzilic ester rearrangements.

Asymmetric Construction of α,α-Disubstituted Piperazinones Enabled by Benzilic Amide Rearrangement.

An unprecedent asymmetric catalytic benzilic amide rearrangement for the synthesis of α,α-disubstituted piperazinones is reported. The reaction proceeds via a domino [4+1] imidazolidination/formal 1,2-nitrogen shift/1,2-aryl or alkyl migration sequence, employing readily available vicinal tricarbonyl compounds and 1,2-diamines as starting materials. This approach provides an efficient access to chiral C3-disubsituted piperazin-2-ones with high enantiocontrol, which are exceedingly difficult to access from the existing synthetic methodologies. The observed enantioselectivity was proposed to be controlled by dynamic kinetic resolution in the 1,2-aryl/alkyl migration step. The resulting densely functionalized products are versatile building blocks to bioactive natural products, drug molecules and their analogues.

Synthesis of heterocyclic ring-fused analogs of HMG499 as novel degraders of HMG-CoA reductase that lower cholesterol.

HMG-CoA reductase (HMGCR) is the rate-limiting enzyme in cholesterol de novo biosynthesis and its degradation may bring therapeutic benefits for the treatment of cardiovascular disease (CVD) and nonalcoholic steatohepatitis (NASH). Before, we disclosed compound HMG499 as a potent HMGCR degrader, which could be a promising agent for treating CVD, however its side-effect of promoting cholesterol accumulation in cells should be eliminated before progression. Herein, a series of novel heterocyclic ring-fused analogs of HMG499 were synthesized and investigated for their activities of stimulating HMGCR degradation using a HMGCR (TM1-8)-GFP reporting system. Among them, the most active compound 29 (QH536) showed an EC50 of 0.22 µΜ in promoting HMGCR degradation, which was about 2 times more potent than HMG499 (EC50 = 0.43 µM). Interestingly, 29 was different from HMG499, it had no side-effect of inducing cholesterol accumulation in cells. Mechanistic studies disclosed that 29 could significantly decrease statin-induced accumulation of HMGCR protein via ubiquitination and degradation of HMGCR through ubiquitin-proteasome pathway and inhibit the cholesterol biosynthesis in cells. Therefore, these heterocyclic ring-fused analogs could be used as promising leads for the development of new types of agents against CVD. Furthermore, 29 also lowered cholesterol levels and suppressed TGFß1-induced proliferation of LX-2 hepatic stellate cells in a dose-dependent manner. In particular, 29 not only decreased the NASH associated fibrotic mRNA and protein expression of α-SMA, COL1A1, TIMP1 and TGFß1 but also suppressed cholesterol levels and inflammatory genes of TNF-α, IL-6 an IL-1ß in RAW264.7 macrophage cells, indicating that 29 may bring therapeutic benefit to treat NASH.

Synthesis of plant-derived cholesterol from bisnoralcohol.

Currently, the market demand of the non-animal-derived cholesterol is increasing. A novel synthetic route of producing cholesterol was developed through multiple reactions from plant-sourced and commercially available bisnoralcohol (BA). The key reaction conditions, including solvents, reaction temperatures, bases and reducing agents of the route were investigated and optimized. In this straightforward synthetic pathway of cholesterol, most of the reaction steps possess high conversions with average yields of 94%, and the overall yield is up to 74% (5 steps) from the BA. The epicholesterol and were also synthesized. This promising route offers economical and efficient strategies for potential large-scale production of plant-derived cholesterol.

Network pharmacology-based identification for therapeutic mechanisms of Dangguikushen pill in acne vulgaris.

The Dangguikushen (DGKS) pill is a proprietary traditional Chinese medicine that has shown superior efficacy in the treatment of acne vulgaris for many years. A network pharmacology-based analysis was performed to explore the potential anti-acne compounds, core therapeutic targets, and the main pathways, involved in the DGKS pill bioactivity. The matching results between the predicted targets of the DGKS pill and the well-known targets of acne vulgaris were collected, followed by network establishment using protein-protein interaction (PPI) data. Cytoscape was utilized to analyze the network and screen the core targets. Furthermore, the Database for Annotation, Visualization and Integrated Discovery (DAVID), and ClueGO were used for the enrichment analysis of the Kyoto Encyclopedia of Genes and Genomics (KEGG) pathways and Gene Ontology biological processes (GO-BP). Finally, the "compound-target-pathway" network was constructed. This approach identified 19 active compounds, 46 therapeutic targets, and 12 core therapeutic targets of the DGKS pill. The biological processes were primarily related to reactive oxygen species (ROS) metabolic process, gland morphogenesis, and female gonad development. The DGKS pill was significantly associated with eight pathways including the PI3K-Akt, TNF, NF-kappa B, and p53 signaling pathways. DGKS pill might have a synergistic effect on the inhibition of excessive sebaceous lipogenesis and sebocyte differentiation, and likewise, anti-inflammatory effects via the different signaling pathways (PI3K-Akt, TNF, NF-kappa B, and p53).