Exploiting β-Amino Acid Enolates in Direct Catalytic Diastereo- and Enantioselective C−C Bond-Forming Reactions

In contrast to the widespread use of α-amino acid-equivalent enolates for the preparation of non-natural amino acids, the utilization of β-amino-acid counterparts has been limited. This deficit has resulted in a short supply of β^{2, 2}-amino acids bearing two substituents at the α-carbon, especially for peptide synthesis. Herein, racemic 4-substituted isoxazolidin-5-ones were used as precursors of β²-amino acid enolates in the direct catalytic diastereo- and enantioselective C−C bond-forming reactions, constructing two adjacent stereocenters in a highly stereoselective fashion. The obtained adducts were smoothly coupled with α-amino acid-derived α-ketoacids to afford α/β^{2, 2}-hybrid dipeptides suitable for 9-fluorenylmethoxycarbonyl (Fmoc)-based solid-phase peptide synthesis. Moreover, the Mannich adducts obtained from isatin-derived imines were converted to spirocyclic β-lactams, which have recently received increased attention due to their unique biological activities and conformational preferences.