Ruthenium-Catalyzed Hydrohydroxyalkylation of Acrylates with Diols and α‑Hydroxycarbonyl Compounds To Form Spiro- and α‑Methylene-γ-butyrolactones

Under the conditions of ruthenium(0)-catalyzed hydrohydroxyalkylation, vicinal diols <b>1a</b>–<b>1l</b> and methyl acrylate <b>2a</b> are converted to the corresponding lactones <b>3a</b>–<b>3l</b> in good to excellent yield. The reactions of methyl acrylate <b>2a</b> with hydrobenzoin <b>1f</b>, benzoin <i>didehydro</i>-<b>1f</b>, and benzil <i>tetradehydro</i>-<b>1f</b> form the same lactone <b>3f</b> product, demonstrating that this process may be deployed in a redox level-independent manner. A variety of substituted acrylic esters <b>2a</b>–<b>2h</b> participate in spirolactone formation, as illustrated in the conversion of <i>N</i>-benzyl-3-hydroxyoxindole <b>1o</b> to cycloadducts <b>4a</b>–<b>4h</b>. Hydrohydroxyalkylation of hydroxyl-substituted methacrylate <b>2i</b> with diols <b>1b</b>, <b>1f</b>, <b>1j</b>, and <b>1l</b> forms α-<i>exo</i>-methylene-γ-butyrolactones <b>5b</b>, <b>5f</b>, <b>5j</b>, and <b>5l</b> in moderate to good yield. A catalytic cycle involving 1,2-dicarbonyl–acrylate oxidative coupling to form oxaruthenacyclic intermediates is postulated. A catalytically competent mononuclear ruthenium­(II) complex was characterized by single-crystal X-ray diffraction. The influence of electronic effects on regioselectivity in reactions of nonsymmetric diols was probed using <i>para</i>-substituted 1-phenyl-1,2-propanediols <b>1g</b>, <b>1m</b>, and <b>1n</b> and density functional theory calculations

Ruthenium-Catalyzed Hydrohydroxyalkylation of Acrylates with Diols and α‑Hydroxycarbonyl Compounds To Form Spiro- and α‑Methylene-γ-butyrolactones

Under the conditions of ruthenium(0)-catalyzed hydrohydroxyalkylation, vicinal diols <b>1a</b>–<b>1l</b> and methyl acrylate <b>2a</b> are converted to the corresponding lactones <b>3a</b>–<b>3l</b> in good to excellent yield. The reactions of methyl acrylate <b>2a</b> with hydrobenzoin <b>1f</b>, benzoin <i>didehydro</i>-<b>1f</b>, and benzil <i>tetradehydro</i>-<b>1f</b> form the same lactone <b>3f</b> product, demonstrating that this process may be deployed in a redox level-independent manner. A variety of substituted acrylic esters <b>2a</b>–<b>2h</b> participate in spirolactone formation, as illustrated in the conversion of <i>N</i>-benzyl-3-hydroxyoxindole <b>1o</b> to cycloadducts <b>4a</b>–<b>4h</b>. Hydrohydroxyalkylation of hydroxyl-substituted methacrylate <b>2i</b> with diols <b>1b</b>, <b>1f</b>, <b>1j</b>, and <b>1l</b> forms α-<i>exo</i>-methylene-γ-butyrolactones <b>5b</b>, <b>5f</b>, <b>5j</b>, and <b>5l</b> in moderate to good yield. A catalytic cycle involving 1,2-dicarbonyl–acrylate oxidative coupling to form oxaruthenacyclic intermediates is postulated. A catalytically competent mononuclear ruthenium­(II) complex was characterized by single-crystal X-ray diffraction. The influence of electronic effects on regioselectivity in reactions of nonsymmetric diols was probed using <i>para</i>-substituted 1-phenyl-1,2-propanediols <b>1g</b>, <b>1m</b>, and <b>1n</b> and density functional theory calculations

Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2

Protein lysine methyltransferases have recently emerged as a new target class for the development of inhibitors that modulate gene transcription or signaling pathways. SET and MYND domain containing protein 2 (SMYD2) is a catalytic SET domain containing methyltransferase reported to monomethylate lysine residues on histone and nonhistone proteins. Although several studies have uncovered an important role of SMYD2 in promoting cancer by protein methylation, the biology of SMYD2 is far from being fully understood. Utilization of highly potent and selective chemical probes for target validation has emerged as a concept which circumvents possible limitations of knockdown experiments and, in particular, could result in an improved exploration of drug targets with a complex underlying biology. Here, we report the development of a potent, selective, and cell-active, substrate-competitive inhibitor of SMYD2, which is the first reported inhibitor suitable for in vivo target validation studies in rodents