Total Syntheses of Phleghenrines A and C.

Herein, we report the total syntheses of phleghenrines A and C from commercially available starting materials in 7 and 8 steps, respectively. Notable steps include an inverse electron-demand Diels-Alder reaction between a masked o-benzoquinone and a N-protected enamine to prepare one key intermediate with a bicyclo[2.2.2]octenone core, a Büchner-Curtius-Schlotterbeck one-carbon insertion to expand the bicyclo[2.2.2]octenone to a bicyclo[3.2.2]nonenone, and Trauner's modified 2-pyridone synthesis to install the 2-pyridone moiety.

Regio-controllable [2+2] benzannulation with two adjacent C(sp3)-H bonds.

Regiocontrol in traditional cycloaddition reactions between unsaturated carbon compounds is often challenging. The increasing focus in modern medicinal chemistry on benzocyclobutene (BCB) scaffolds indicates the need for alternative, more selective routes to diverse rigid carbocycles rich in C(sp3) character. Here, we report a palladium-catalyzed double C-H activation of two adjacent methylene units in carboxylic acids, enabled by bidentate amide-pyridone ligands, to achieve a regio-controllable synthesis of BCBs through a formal [2+2] cycloaddition involving σ bonds only (two C-H bonds and two aryl-halogen bonds). A wide range of cyclic and acyclic aliphatic acids, as well as dihaloheteroarenes, are compatible, generating diversely functionalized BCBs and hetero-BCBs present in drug molecules and bioactive natural products.

Discovery and Biological Characterization of PRMT5:MEP50 Protein-Protein Interaction Inhibitors.

Protein arginine methyltransferase 5 (PRMT5) is a master epigenetic regulator and an extensively validated therapeutic target in multiple cancers. Notably, PRMT5 is the only PRMT that requires an obligate cofactor, methylosome protein 50 (MEP50), to function. We developed compound 17, a novel small-molecule PRMT5:MEP50 protein-protein interaction (PPI) inhibitor, after initial virtual screen hit identification and analogue refinement. Molecular docking indicated that compound 17 targets PRMT5:MEP50 PPI by displacing the MEP50 W54 burial into a hydrophobic pocket of the PRMT5 TIM barrel. In vitro analysis indicates IC50 < 500 nM for prostate and lung cancer cells with selective, specific inhibition of PRMT5:MEP50 substrate methylation and target gene expression, and RNA-seq analysis suggests that compound 17 may dysregulate TGF-ß signaling. Compound 17 provides a proof of concept in targeting PRMT5:MEP50 PPI, as opposed to catalytic targeting, as a novel mechanism of action and supports further preclinical development of inhibitors in this class.

Catalytic Hydroxycyclopropanol Ring-Opening Carbonylative Lactonization to Fused Bicyclic Lactones.

A novel palladium-catalyzed ring opening carbonylative lactonization of readily available hydroxycyclopropanols was developed to efficiently synthesize tetrahydrofuran (THF) or tetrahydropyran (THP)-fused bicyclic γ-lactones, two privileged scaffolds often found in natural products. The reaction features mild reaction conditions, good functional group tolerability, and scalability. Its application was demonstrated in a short total synthesis of (±)-paeonilide. The fused bicyclic γ-lactone products can be easily diversified to other medicinally important scaffolds, which further broadens the application of this new carbonylation method.

Cu-catalyzed hydroxycyclopropanol ring-opening cyclization to tetrahydrofurans and tetrahydropyrans: short total syntheses of hyperiones.

Tetrahydrofurans (THFs) and tetrahydropyrans (THPs) are important core scaffolds frequently found in many molecules of medicinal importance. Herein, we report a novel copper-catalyzed hydroxycyclopropanol ring-opening cyclization methodology to synthesize di- or tri-substituted THFs and THPs. In this reaction, a strained C-C bond was cleaved and a new Csp3-O bond was formed to produce the aforementioned O-heterocycles. The new THF synthesis features a broad substrate scope, scalability, and good functional-group tolerability. It enabled us to complete the shortest enantioselective syntheses of hyperiones A and B (3 and 4 steps, respectively), which is significantly shorter than the previously reported two total syntheses (≥10 steps).

Catalytic Cyclopropanol Ring Opening for Divergent Syntheses of γ-Butyrolactones and δ-Ketoesters Containing All-Carbon Quaternary Centers.

Catalytic ring opening cross coupling reactions of strained cyclopropanols have been useful for the syntheses of various ß-substituted carbonyl products. Among these ring opening cross coupling reactions, the formation of α,ß-unsaturated enone byproducts often competes with the desired cross coupling processes and has been a challenging synthetic problem to be addressed. Herein, we describe our efforts in developing divergent syntheses of a wide range of γ-butyrolactones and δ-ketoesters containing all-carbon quaternary centers via copper-catalyzed cyclopropanol ring opening cross couplings with 2-bromo-2,2-dialkyl esters. Our mechanistic studies reveal that unlike the previously reported cases, the formation of α,ß-unsaturated enone intermediates is actually essential for the γ-butyrolactone synthesis and also contributes to the formation of the δ-ketoester product. The γ-butyrolactone synthesis is proposed to go through an intermolecular radical conjugate addition to the in situ generated α,ß-unsaturated enone followed by an intramolecular radical cyclization to the ester carbonyl double bond. The reactions are effective to build all-carbon quaternary centers and have broad substrate scope.

Identification of mangiferin as a potential Glucokinase activator by structure-based virtual ligand screening.

The natural product mangiferin (compound 7) has been identified as a potential glucokinase activator by structure-based virtual ligand screening. It was proved by enzyme activation experiment and cell-based assays in vitro, with potency in micromolar range. Meanwhile, this compound showed good antihyperglycemic activity in db/db mice without obvious side effects such as excessive hypoglycaemia.

Stereoselective synthesis of α-linked 2-deoxy glycosides enabled by visible-light-mediated reductive deiodination.

2-Deoxy sugars and their derivatives occur abundantly in many pharmaceutically important natural products. However, the construction of specific 2-deoxy-glycosidic bonds remains as a challenge. Herein, we report an efficient way to prepare 2-deoxy-α-glycosides by glycosylation of 2-iodo-glycosyl acetate and subsequent visible-light-mediated tin-free reductive deiodination. We have successfully applied the postglycosylational-deiodination strategy in the synthesis of more than 30 mono-, di-, tri-, tetra- and pentadeoxysaccharides with excellent stereoselectivity and efficiency. This method has also been applied to the synthesis of a 2-deoxy-tetrasaccharide containing four α-linkages.