Angew. Chem. Int. Ed. 51, 1248–1251 (2012)

Domino reactions offer facile access to complex molecular architectures, often with exquisite stereochemical control. Shi et al. provide an elegant example of this approach in a new [2+2+2] cycloaddition reaction combining Michael and Henry reactions to access a cyclohexane product with stereochemically defined substituents at each ring carbon. In particular, the authors used an α-ketoester as a latent reactive enolate with two nitroalkene electrophiles to extend and finally join the carbon chain. The first step of the reaction—formation of a metal enolate—was critical to direct the stereochemistry of the entire sequence. As a result, the authors synthesized a series of rigid chiral ligands intended to similarly induce chirality in the metal complex, identifying a single Cu–diamine complex as providing excellent yields and enantioselectivity. With their catalyst in hand, the authors demonstrated the versatility of the reaction by varying both ketoester and nitroalkene starting materials: divergent ketoesters were well tolerated, as were a range of aromatic nitroalkenes, though aliphatic nitroalkenes were not applicable and a single nitroalkene modified with an ortho-substituted benzaldehyde proved problematic. The reaction proceeds at room temperature and gram scale using only 0.1 mol% catalyst, and so it should provide straightforward entry into a variety of complex synthetic routes.