Ring-Expanded Bicyclic β-Lactams: A Structure−Chiroptical Properties Relationship Investigation by Experiment and Calculations

Abstract

In the present work, the validity of the helicity rule relating the absolute configuration of the bridgehead carbon atom in bicyclic β-lactams to the sign of the 220 nm band observed in their electronic circular dichroism (ECD) spectra is examined for ring-expanded cephalosporin analogues. To this end, a series of model compounds with a seven-membered ring condensed with the β-lactam unit was synthesized. A key step of their synthesis was either the ring-closing metathesis (RCM) or the free radical cyclization leading to the seven-membered ring with an S, O, or C atom at the 6 position in the bicyclic skeleton. To investigate the scope and limitations of the simple, empirically established helicity rule, a combination of ECD spectroscopy, variable-temperature ECD measurements, X-ray analysis, and time-dependent density functional theory (TD-DFT) calculations was used. A comparison of the experimental ECD spectra with the spectra simulated by TD-DFT calculations gives a reasonable interpretation of the Cotton effects observed in the 240-215 nm spectral range. The results suggest that the helicity rule does not apply to the investigated compounds because of the planarity of their amide chromophore. Thus, these compounds do not constitute an exception to the rule that was established for bi- and polycyclic β-lactams with the nonplanar amide chromophore only.

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

“…However, for small deviations from planarity of the -lactam ring, the helicity rule should not be considered at all. [21,29,30] The comparison between experimental and TDDFT-calculated ECD and absorption spectra is, in all cases, good over the whole wavelength range. It is always recommended in ECD TDDFT calculations to test several different functionals, with special attention towards range-separated functionals such as CAM-B3LYP [33] and ωB97X-D, [34] which generally outperform global hybrids.…”

“…Most importantly, the band allied with the n-π* transition must be identified in the ECD spectrum. [21,25,[27][28][29][30] These findings further demonstrate that a safe ECD absolute configuration determination of -lactams cannot be based exclusively on the sector/helicity rule. The applicability of the sector/helicity rule has been verified for -lactams containing additional aromatic, diene and carbonyl chromophores, [22,25,27,28] and the rule was found to be valid in almost all cases.…”

“…The structures and data for all conformers of 4c are listed in the Supporting Information as an example; the lowest-energy structures for the three compounds are shown in Figure 4. [29] On the other hand, in all DFT minima, the aryl substituent at C-4 is entirely placed in a sector with negative sign contribution; [22][23][24][25] therefore, the sector rule seems to hold in all cases ( Table 2). In particular, the O= C-N-C4 dihedral angle, which is given primary importance in the aforementioned helicity rule, [26] was negative for the most stable conformers of 4a and 5a, and positive for those of 4c (Table 2).…”

Synthesis, cytotoxic, anti-lipoxygenase and anti-acetylcholinesterase capacities of novel derivatives from harmine

“…The mixture was stirred for 48 h at room temperature, then poured into ice-cold water, and extracted with dichloromethane. After removal of solvent, the resulting residue was purified by silica gel column chromatography (EtOAc) to give compound 2 (850 mg, 60%) 36 .…”

The use of carbonyl group anisotropy effect in determination of the relative configuration of carbapenams

“…Therefore, it would be advantageous to have a fast and unequivocal method to verify the configuration at newly formed stereogenic centers. The absolute configuration of the bridgehead carbon atom, C-5 at bicyclic β-lactams, can be established by CD spectroscopy [9][10][11][12][13][14][15][16] whereas the same assignment by NMR spectroscopy is not always as simple since it may be interlinked to the known configuration of the other stereogenic center. The …”