Synergistic Noncovalent Catalysis Facilitates Base-Free Michael Addition.

ABSTRACT

Carbon-carbon bond-forming processes that involve the deprotonation of a weakly acidic C-H pro-nucleophile using a strong Brønsted base are central to synthetic methodology. Enzymes also catalyze C-C bond formation from weakly C-H acidic substrates; however, they accomplish this at pH 7 using only collections of noncovalent interactions. Here, we show that a simple, bioinspired synthetic cage catalyzes Michael addition reactions using only Coulombic and other weak interactions to activate various pro-nucleophiles and electrophiles. The anion-stabilizing property of the cage promotes spontaneous pro-nucleophile deprotonation, suggesting acidity enhancement equivalent to several pKa units. Using a second noncovalent reagent-commercially available 18-crown-6-facilitates catalytic base-free addition of several challenging Michael partners. The cage's microenvironment also promotes high diastereoselectivity compared to a conventional base-catalyzed reaction.