Synthesis of organocatalysts using non-covalent chemistry; understanding the reactivity of ProNap, an enamine-type organocatalyst that can self assemble with complementary co-catalysts

A promising but relatively unexplored approach to tuning asymmetric catalysts is to design catalysts that can self-assemble with a family of complementary co-catalysts. In order to study the mechanism of self-assembled enamine catalysts that are tagged with a supramolecular receptor, a new series of more soluble complementary co-catalysts have been developed. The formation of hydrogen-bonded supramolecular pre-catalysts was established by NMR and X-ray crystallography. NMR studies have identified an enamine intermediate in the reactions between the supramolecular organocatalyst ProNap and aldehydes in which the co-catalysts are hydrogen-bonded. The formation of imidazolidinones from ketones is a reversible process that is likely to coincide with formation of trace amounts of the productive enamine intermediate. The equilibrium is reached much faster in the presence of the complementary co-catalysts, explaining the faster initial rates and greater productivity when ketones are used in stoichiometric quantities relative to the Michael acceptor in asymmetric Michael reactions. These imidazolidinones are a parasitic dead-end in the reaction of aldehydes, both for the self-assembled Proline derivatives and for simple Proline-derived amides. Catalysts prepared from (S)-pyrrolidine-3-carboxylic acid are immune to this and high-yielding nitro-Michael reaction using aldehydes can be achieved.