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

Abstract

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.