Leucascandrolide A and neopeltolide are structurally homologous marine natural products that elicit potent antiproliferative profiles in mammalian cells and yeast. The scarcity of naturally available material has been a significant barrier to their biochemical and pharmacological evaluation. We developed practical synthetic access to this class of natural products that enabled the determination of their mechanism of action. We demonstrated effective cellular growth inhibition in yeast, which was substantially enhanced by substituting glucose with galactose or glycerol. These results, along with genetic analysis of determinants of drug sensitivity, suggested that leucascandrolide A and neopeltolide may inhibit mitochondrial ATP synthesis. Evaluation of the activity of the four mitochondrial electron transport chain complexes in yeast and mammalian cells revealed cytochrome bc(1) complex as the principal cellular target. This result provided the molecular basis for the potent antiproliferative activity of this class of marine macrolides, thus identifying them as new biochemical tools for investigation of eukaryotic energy metabolism.
Recently, hyperbranched dendritic macromolecules are attracting much attention due to their specific structures and characteristics. These molecules with regular branching have been prepared by a stepwise method, i.e., repetition of reactions and subsequent purification.1•2 Another synthetic method recently developed is polycondensation or polyaddition of a AB" type monomer
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A new method for the catalytic enantioselective Strecker reaction (cyanation) of N-diphenylphosphinoyl ketoimines is described. The asymmetric catalyst is a chiral gadolinium complex prepared from Gd(OiPr)3 and the d-glucose-derived ligand 3 in a 1:2 ratio. The reaction has a broad substrate generality, giving high enantioselectivity from aromatic, ethyl, primary alkyl, and alpha,beta-unsaturated ketoimines. The products could be easily converted to disubstituted alpha-amino acids and their derivatives.
Highly selective tail-to-tail dimerization of methyl methacrylate has been realized by an N-heterocyclic carbene catalyst, giving dimethyl 2,5-dimethyl-2-hexenedioate with an E/Z ratio of 95:5 in 86% isolated yield. The umpolung mechanism is proposed on the basis of interception of the intermediates using ESI-MS analyses and deuterium-labeling experiments.
N-heterocyclic carbenes (NHCs) smoothly catalyze the oxa-Michael addition polymerization of hydroxyl functionalized acrylate monomers at room temperature via a zwitterionic intermediate.
The first catalytic enantioselective Reissert reaction of pyridine derivatives that affords products with excellent regio- and enantioselectivity is described. The key for success is the development of new Lewis acid-Lewis base bifunctional asymmetric catalysts containing an aluminum as a Lewis acid and sulfoxides or phosphine sulfides as a Lewis base. These reactions are useful for the synthesis of a variety of chiral piperidine subunits, and catalytic enantioselective formal synthesis of CP-293,019, a selective D4 receptor antagonist, was achieved. Preliminary mechanistic studies indicated that both sulfoxides and phosphine sulfides can activate TMSCN as a Lewis base. In addition, the sulfoxides with appropriate stereochemistry might stabilize a highly enantioselective bimetallic complex (a presumed active catalyst) through internal coordination to aluminum.
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