Catalytic Asymmetric Vinylogous Conjugate Addition of Butenolide to 2-Ester-Substituted Chromones: Access to Chiral Chromanone Lactones via Trapping of a Copper(I) Enolate by Trimethyl Borate.

A copper-catalyzed asymmetric vinylogous conjugate addition of butenolide to 2-ester-substituted chromones is described, and it delivers syn- or anti-chromanone lactones with high stereoselectivities. The enantioselectivity-determining step varied with the use of B(OMe)3 as an additive, resulting in enhanced stereoselectivities, as revealed by density functional theory calculations, which also provided theoretical insight into the origin of the ligand-dependent diastereodivergence.

Concise and Stereodivergent Approach to Chromanone Lactones through Copper-Catalyzed Asymmetric Vinylogous Addition of Siloxyfurans to 2-Ester-Substituted Chromones.

Vicinal oxygen-containing tetra- and tri-substituted stereocenters exist widely in chromanone lactone and tetrahydroxanthone natural products. Their enantioselective construction in a single step remains elusive and poses a formidable challenge for chemical synthesis. Here, we report the first copper(I)-catalyzed asymmetric vinylogous additions of siloxyfurans to 2-ester-substituted chromones, which enable concise and enantioselective assembly of chromanone lactones. Both syn and anti adducts can be accessed with excellent diastereo- and enantioselectivity by judicious choice of the chiral ligands. Our approach allowed for the efficient synthesis of (-)-blennolide B with precise stereochemical control, which provides a formal synthesis of secalonic acid A.

Mitochondrial complex I inhibitors suppress tumor growth through concomitant acidification of the intra- and extracellular environment.

The disruption of the tumor microenvironment (TME) is a promising anti-cancer strategy, but its effective targeting for solid tumors remains unknown. Here, we investigated the anti-cancer activity of the mitochondrial complex I inhibitor intervenolin (ITV), which modulates the TME independent of energy depletion. By modulating lactate metabolism, ITV induced the concomitant acidification of the intra- and extracellular environment, which synergistically suppressed S6K1 activity in cancer cells through protein phosphatase-2A-mediated dephosphorylation via G-protein-coupled receptor(s). Other complex I inhibitors including metformin and rotenone were also found to exert the same effect through an energy depletion-independent manner as ITV. In mouse and patient-derived xenograft models, ITV was found to suppress tumor growth and its mode of action was further confirmed. The TME is usually acidic owing to glycolytic cancer cell metabolism, and this condition is more susceptible to complex I inhibitors. Thus, we have demonstrated a potential treatment strategy for solid tumors.

anti-Selective Catalytic Asymmetric Nitroaldol Reaction of α-Keto Esters: Intriguing Solvent Effect, Flow Reaction, and Synthesis of Active Pharmaceutical Ingredients.

A rare-earth metal/alkali metal bimetallic catalyst proved particularly effective for enantioselectively coupling nitroalkanes and α-keto esters in an anti-selective manner to afford synthetically versatile, densely functionalized, and optically active α-nitro tertiary alcohols. A chiral diamide ligand captured two distinct metal cations, giving rise to a catalytically competent solid-phase heterobimetallic catalyst by simple mixing via self-assembly. The advantage of the solid-phase asymmetric catalyst was realized by successful application to the enantio- and diastereoselective reaction in a continuous-flow platform. The use of closely related solvents in terms of structures and polarity parameters, THF and its methylated congener 2-Me-THF, had an unexpectedly large solvent effect both on the reaction rate and the stereoselectivity. The nitroaldol products share a privileged unit for active pharmaceutical ingredients, as demonstrated by the streamlined enantioselective synthesis of the marketed antifungal agents efinaconazole and albaconazole.

Oxa- and Azacycle Formation via Migrative Cyclization of Sulfonylalkynol and Sulfonylalkynamide with N-Heterocyclic Carbene.

An N-heterocyclic carbene promotes cyclization of sulfonylalkynols and sulfonylalkynamides that accompanies 1,2-migration of the sulfonyl groups. This reaction provides a novel access to oxa- and azacycles possessing a pendent vinyl sulfone functionality, which, in turn, is amenable for further transformations.

Enhanced rate and selectivity by carboxylate salt as a basic cocatalyst in chiral N-heterocyclic carbene-catalyzed asymmetric acylation of secondary alcohols.

The rate and enantioselectivity of chiral NHC-catalyzed asymmetric acylation of alcohols with an adjacent H-bond donor functionality are remarkably enhanced in the presence of a carboxylate cocatalyst. The degree of the enhancement is correlated with the basicity of the carboxylate. With a cocatalyst and a newly developed electron-deficient chiral NHC, kinetic resolution and desymmetrization of cyclic diols and amino alcohols were achieved with extremely high selectivity (up to s = 218 and 99% ee, respectively) at a low catalyst loading (0.5 mol %). This asymmetric acylation is characterized by a unique preference for alcohols over amines, which are not converted into amides under the reaction conditions.

Chemoselective conversion of α-unbranched aldehydes to amides, esters, and carboxylic acids by NHC-catalysis.

Depending on the N-heterocyclic carbene catalyst utilized, α-unbranched aldehydes selectively provided amides, esters, or carboxylic acids through oxidation by NCS. The α-unbranched aldehyde underwent these reactions chemoselectively in the presence of an aromatic or α-branched aldehyde.