Conformational Flexibility and Absolute Stereochemistry of (3R)‐3‐hydroxy‐4‐aryl‐β‐lactams Investigated by Chiroptical Properties and TD‐DFT Calculations

Abstract

The effect of conformational flexibility on the chiroptical properties of a series of synthetic (3R)-3-hydroxy-4-aryl-β-lactams of known stereochemistry (1-6) was investigated by means of electronic circular dichroism (ECD) measurements and time-dependent density functional theory (TD-DFT) calculations. The application of the β-lactam sector rules allowed a correct stereochemical characterization of these compounds, with the exception of a thienyl-substituted derivative (cis-). TD-DFT calculations yielded accurate predictions of experimental ECD spectra and [α](D) values, allowing us to assign the correct absolute configuration to all the investigated compounds. A detailed analysis of the β-lactam ring equilibrium geometry on optimized conformers identified regular patterns for the arrangement of atoms around the amide chromophore, confirming the validity of the β-lactam sector rules. However, relevant variations in theoretical chiroptical properties were found for compounds bearing a heterocyclic substituent at C4 or a phenyl substituent at C3, whose conformers deviate from these regular geometric patterns. This behavior explains the failure of the β-lactam sector rules in cis-. This study showed the importance of conformational flexibility for the determination of chiroptical properties and highlighted the strengths and weaknesses of the different methods for the stereochemical characterization of chiral molecules in solution.

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

“…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 assignment is further confirmed by the nature of these transitions assigned through Table 3 and Figure 5. A few -lactams with aromatic substituents at N-1 and C-4 similar to our compounds 4 and 5, including some ezetimibe analogues, have been previously investigated by DFT and TDDFT calculations; [25,28] however, no transition or orbital analysis was reported. The two aromatic chromophores define a negative exciton chirality for all low-energy conformers found for -lactams (3S,4R)-4a, (3R,4R)-4c, and (3S,4R)-5a ( Figure 4); therefore, the exciton chirality rule [41] predicts a negative exciton couplet as found experimentally and confirmed by TDDFT calculations.…”

“…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. Most importantly, the band allied with the n-π* transition must be identified in the ECD spectrum.…”

Advantages of electronic circular dichroism detection for the stereochemical analysis and characterization of drugs and natural products by liquid chromatography

“…Consequently, a dedicated class of helicity rules were developed [101,102], which were successfully applied to a series of chiral βlactam derivatives [103,104]. The two different approaches (sector and helicity rules) are both legitimate, and their combination even serves to describe the chiral perturbations in a more accurate fashion [79].…”