Stereochemistry of the Brivaracetam Diastereoisomers

Abstract

The stereochemistry of all four stereoisomers of brivaracetam was determined using vibrational circular dichroism (VCD) spectroscopy. By comparing experimentally obtained VCD spectra and computationally simulated ones, the absolute configurations can be confidently assigned without prior knowledge of their relative stereochemistry. Neither the corrected mean absolute errors analysis of the nuclear magnetic resonance (NMR) data, nor the matching of experimental and calculated infrared spectra allowed the diastereoisomers to be distinguished. VCD spectroscopy itself suffices to establish the absolute configurations of all diastereoisomers. The relative stereochemistry could also be statistically confirmed by matching experimental and computed NMR spectra using the CP3 algorithm. The combination of VCD and NMR is recommended for molecules bearing more than one chiral center, as the relative configurations obtained from NMR serve as an independent check for those established with VCD. Analysis of the calculated VCD spectra reveals that the localized NH2 scissoring mode at around 1600 cm‐1 is characteristic for intramolecular hydrogen bonding, while the orientation of the ethyl group is reflected by the delocalized modes between 1150 and 1050 cm‐1. Chirality 28:215–225, 2016. © 2016 Wiley Periodicals, Inc.

Vibrational Circular Dichroism Absolute Configuration of Natural Products From 2015 to 2019

“…The AC was confidently assigned as (2S,4'R)−239, (2S,4'S)−240, (2R,4'R)−241, and (2R,4'S)−242 ( Figure 66) without prior knowledge of their relative stereochemistry. 111 Both enantiomers of rubrobramide were separated by optical resolution of a sample obtained by total synthesis. The AC of natural (+)-rubrobramide (243) (Figure 67), isolated from the fungis Cladobotryum rubrobrunnescens, was determined as (2S,5R,7S,8S) by VCDEC.…”

Reassignment of the absolute configuration of plakinidone from the sponge consortium Plakortis halichondrioides–Xestospongia deweerdtae using a combination of synthesis and a chiroptical approach

“…Nevertheless, successful attempts exist for the absolute configuration assignment of large and flexible molecules. 17,22,23 In such cases, the use of other methods such as the synthesis of model compounds based on well-established reactions or NMR studies, are helpful for structure elucidation. Herein, the assignment of the C11 center of natural plakinidone derivative 1 was ascertained by enantioselective syntheses of fragment 5 .…”

Model-averaging of ab initio spectra for the absolute configuration assignment via vibrational circular dichroism

“…As an intermediate choice, populations can be derived from standard enthalpies (HP populations), thus neglecting only the entropic corrections. [29][30][31] We have checked the relevance of the choice of the thermal averaging scheme, adopting all 3 weightings EP, HP and GP. Frequency scaling factors λ have been determined optimizing the agreement between the experimental VA spectra and those computed by EP weightings and the single γ value of 4 cm −1 (irrelevant variations have been found for the HP and GP weighting schemes).…”