Circular Dichroism and Conformational Dynamics of Cephams and Their Carba and Oxa Analogues

The biological activity of bicyclic β‐lactam antibiotics depends strongly on the absolute configuration of the bridgehead carbon atom. Frelek and co‐workers proposed an empirical helicity rule relating the configuration of the bridgehead carbon atom to the sign of the 220 nm band in the electronic circular dichroism (CD) spectrum of β‐lactams. Here we use synthetic organic chemistry, CD spectroscopy, and time‐dependent density functional theory (TDDFT) to investigate the validity of this structure–property relationship for eight model compounds. For conformationally flexible β‐lactams, substantial thermal effects are found which must be included in calculations. To this end, we combine TDDFT calculations of CD with full quantum‐mechanical Born–Oppenheimer molecular dynamics (MD) simulations for the first time. The CD spectra are sampled with ground‐state density functional trajectories of up to 60 ps. The MD simulations show a surprisingly high sensitivity of the CD to the molecular conformation. On the other hand, the relation between CD and thermally averaged structural parameters is much less complex. While the helicity rule does not seem to hold for individual conformers, it is confirmed by the calculations for seven out of eight systems studied if thermally averaged CD spectra and structures are considered. Since thermal effects on CD can be larger than typical inherent inaccuracies of TDDFT, our results emphasize the need for a systematic treatment of conformational dynamics in CD calculations even for moderately flexible systems. Temperature‐dependent CD measurements are very useful for this purpose. Our results also suggest that CD spectroscopy may be used as a sensitive probe of conformational dynamics if combined with electronic structure calculations. Surprising sensitivity to conformational changes is observed in time‐dependent density functional theory (TDDFT) molecular dynamics (MD) simulations of β‐lactam circular dichroism (CD). Nevertheless, a simple helicity rule correctly predicts the CD at 220 nm from the absolute configuration of the bridgehead carbon atom, which is crucial for biological activity. The picture shows the lowest energy conformer of a carbacepham, its experimental CD spectrum, and CD spectra calculated at 0 (TDDFT) and 350 K (TDDFT MD).