Stereoselective syntheses of the 2-Isopropenyl-2,3-dihydrobenzofuran nucleus: potential chiral building blocks for the syntheses of tremetone, hydroxytremetone, and rotenone

The first enantioselective synthesis of the 2-isopropenyl-2,3-dihydrobenzofuran skeleton of tremetone and hydroxytremetone from (E)-4-(2-hydroxyphenyl)-2-methyl-2-butenyl methyl carbonate and (E)-4-(2,6-dihydroxyphenyl)-2-methyl-2-butenyl methyl carbonate, respectively, is described. The key step is a catalytic palladium-mediated reaction in the presence of the chiral Trost ligand.     

N-Capping of primary amines with 2-acyl-benzaldehydes to give isoindolinones

A unique reactivity pattern, first observed in the conversion of the marine natural product pestalone into pestalachloride A, was investigated. It was shown that 2-formyl-arylketones smoothly react with ammonia and primary amines, respectively, under mild conditions to afford 3-substituted isoindolinones in high yield. The reaction represents a new option for the derivatization (N-capping) of primary amines. As the substrates are readily accessible the methodology opens a short and modular access to pharmaceutically relevant substituted isoindolinones.     

Jak1 has a dominant role over Jak3 in signal transduction through γc-containing cytokine receptors

Genetic deficiency of Jak3 leads to abrogation of signal transduction through the common gamma chain (γc) and thus to immunodeficiency suggesting that specific inhibition of Jak3 kinase may result in immunosuppression. Jak1 cooperates with Jak3 in signaling through γc-containing receptors. Unexpectedly, a Jak3-selective inhibitor was less efficient in abolishing STAT5 phosphorylation than pan-Jak inhibitors. We therefore explored the roles of Jak1 and Jak3 kinase functionality in signaling using a reconstituted system. The presence of kinase-inactive Jak1 but not kinase-inactive Jak3 resulted in complete abolishment of STAT5 phosphorylation. Specific inhibition of the "analog-sensitive" mutant AS-Jak1 but not AS-Jak3 by the ATP-competitive analog 1NM-PP1 abrogated IL-2 signaling, corroborating the data with the selective Jak3 inhibitor. Jak1 thus plays a dominant role over Jak3 and these data challenge the notion that selective ATP-competitive Jak3 kinase inhibitors will be effective.     

Enantioselective Nickel-Catalyzed Hydrocyanation of Homostilbenes

We investigated the previously unknown enantioselective Ni-catalyzed hydrocyanation of 1,3-diarylpropenes (homostilbenes). For this purpose, a series of (E)-homostilbenes were prepared by (microwave-assisted) Pd-catalyzed coupling of allylic alcohols with aryl-boronic acids. Employing our established catalyst system formed from Ni(cod)₂ and a TADDOL-derived chiral phosphine-phosphite ligand and using TMSCN as an in situ source of HCN, the hydrocyanation of various homostilbenes was studied. The synthetic usefulness of the methodology was demonstrated in a short synthesis of the new (allo-) colchicine analogue 7-cyano-11-methoxy-colchinol involving an PIDA-mediated oxidative cyclization of the corresponding hydrocyanation product to set up the 7-membered ring. The absolute configuration of 2,4-diphenylbutyronitrile was assigned by comparison of experimental and calculated ECD spectra.