Synthesis, Separation and Absolute Configuration Determination by ECD Spectroscopy and TDDFT Calculations of 3-Amino-β-lactams and Derived Guanidines

Four isomeric chiral 3-amino-β-lactams 4 with p-fluorophenyl and p-methoxyphenyl substituents at N and C-4 positions, similar to the cholesterol absorption inhibitor ezetimibe, have been prepared as diastereomerically and enantiomerically pure compounds by ester enolate/imine cyclocondensation. The same route afforded analogues with a 1,3-benzodioxole instead of the p-methoxyphenyl group. Moreover, β-lactams 4a,b were converted into benzoylguanidine derivatives. The series of chiral β-lactams and β-lactam guanidines was characterized by electronic circular dichroism (ECD) spectroscopy, and their absolute configurations were assigned based on ECD TDDFT calculations. The calculations also demonstrated that the β-lactam sector and helicity rules cannot be applied to β-lactams appended with aromatic chromophores such as the present ezetimibe analogues.