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Protonation-Assisted Conjugate Addition of Axially Chiral Enolates: Asymmetric Synthesis of Multisubstituted β-Lactams from α-Amino Acids



β-Lactams with contiguous tetra- and trisubstituted carbon centers were prepared in a highly enantioselective manner through 4-exo-trig cyclization of axially chiral enolates generated from readily available α-amino acids. Use of a weak base (metal carbonate) in a protic solvent (EtOH) is the key to the smooth production of β-lactams. Use of the weak base is expected to generate the axially chiral enolates in a very low concentration, which undergo intramolecular conjugate addition without suffering intermolecular side reactions. Highly strained β-lactam enolates thus formed through reversible intramolecular conjugate addition (4-exo-trig cyclization) of axially chiral enolates undergo prompt protonation by EtOH in the reaction media (not during the work-up procedure) to give β-lactams in up to 97 % ee.

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