Issue Date: July 19, 2010
Lewis Acid-Base Combo Generates A Lactam
Two catalytic cycles, one using a Lewis base and the other a Lewis acid, can work concurrently to combine a hydrazone and an aldehyde to create a substituted γ-lactam ring, report Karl A. Scheidt and colleagues at Northwestern University (Nat. Chem., DOI: 10.1038/nchem.727). These substituted, five-membered rings typically have biological activity and are common in natural products. Scheidt and coworkers took a cue from biological systems that use acids and bases to activate substrates in an enzyme active site and developed a cooperative catalytic system that uses an N-heterocyclic carbene (NHC) as a Lewis base and magnesium di-tert-butoxide as a Lewis acid. The carbene adds to the aldehyde to generate a nucleophilic enediamine. Meanwhile, the magnesium compound complexes with and activates the hydrazone. The enediamine then adds to the hydrazone, and an intramolecular acylation closes the γ-lactam ring, releasing and regenerating the N-heterocyclic carbene. Finally, the magnesium compound dissociates. The system works with a variety of hydrazone and aldehyde substrates with good yields and high diastereo- and enantioselectivity.
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