Cascade Reaction To Crowded Carbons

Making a quaternary carbon center is tough enough as it is, but that can pale in comparison to making a crowded tertiary center next to it. Caltech’s Brian M. Stoltz, Jan Streuff, and colleagues have adapted a metal-catalyzed reaction to do both those things at once (Nat. Chem., DOI: 10.1038/nchem.518). Stoltz’s team previously developed a palladium-mediated process for making lone quaternary centers. The researchers wondered whether they might be able to intercept an intermediate in that reaction, presumably a palladium enolate, with another reactant. They imagined that the resulting cascade of events might lead to products with additional stereocenters. Inspired by another group’s efforts in enolate chemistry, they found that electron-poor aryl-substituted malononitriles worked. In a cut-and-paste maneuver, the malononitriles replace an ester moiety on the β-ketoester starting material to make optically pure products with adjacent quaternary and tertiary stereocenters. So far, other electrophiles don’t work as well as malononitriles. “You can imagine a list of other things you could trap that enolate with—we’d like to broaden the scope of the electrophile,” Stoltz says.