Synthesis of β-lactams and cyclo-β-dipeptides from β-amino acids: experimental observations and theoretical analysis

The cyclization of β-amino acids by means of activating agents is one of the most useful approaches for the construction of β-lactams; however, we found that when PhP(O)Cl2 (in Et3N) is employed as the activating agent, cyclization of the derived ‘active ester’ affords varying amounts of cyclo-β-dipeptides, depending on reactions conditions (solvent, temperature, and concentration), as well as on the substitution pattern in the starting β-amino acid. Theoretical rationalization of the experimental results was achieved by modeling studies of the presumed intermediates, both at semi-empirical (MNDO, AM1, and PM3) and at ab initio (HF/3-21G) levels. In the latter calculations, simulation of solvents was accomplished by means of self-consistent reaction field theory (Onsager’s method).