Absolute configuration assignment of (+)‐fluralaner using vibrational circular dichroism

Abstract

The absolute configurations of the separated enantiomers of fluralaner, a racemic animal health product used to prevent fleas and ticks, have been assigned using vibrational circular dichroism (VCD). The crystallographic structure of the active enantiomer (+)-fluralaner has previously been shown to have the (S) configuration using small molecule crystallography. We sought a faster analytical method to determine the absolute configuration of the separated enantiomers. When comparing the measured IR (infrared) and VCD spectra, it is apparent that the amide carbonyl groups appear in the IR but are nearly absent in the VCD. Computational work to calculate the VCD and IR using in vacuo models, implicit solvation, and explicitly solvated complexes has implicated conformational averaging of the carbonyl VCD intensities.

Chiral Lanthanide Complexes with l- and d-Alanine: An X-ray and Vibrational Circular Dichroism Study

“…In the uncomplexed alanine, the band is split into antisymmetric and symmetric components at 1620 and 1596 cm −1 , respectively. Unlike in the solution [ 72 , 73 , 74 , 75 ], and in line with our previous investigations [ 76 ], and other new findings [ 77 ], the VCD spectra show the presence of quite intense ν(C=O) bands ( Figure 4 ), despite the fact that they are ca. 10 4 times weaker than the IR ones.…”

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

“…thereby confirming that the active (+)-enantiomer has the (S) AC as earlier determined by singlecrystal X-ray diffraction. 120 VCD studies of a commercial sample of (−)-(S)-nicotine (258) (Figure 73), confirmed the presence of 2 main conformers at room temperature. Experimental and calculated results indicated that hyperconjugative interactions play a dominant role in the conformational equilibrium.…”

CF3: an overlooked chromophore in VCD spectra. A review of recent applications in structural determination

“…The polyhalogenated ether 1 (Isourane®) is a widely used anesthetic 33 and the diamide 2 (Fluralaner®) is used in veterinary medicine. 34 Of course, they are not the only CF 3 containing drugs submitted to VCD investigations, 35,36 but, as far as we know, they are the rst and the latest, respectively, to be investigated by this technique. In particular we would like to point out the systematic and complete contribution of Polavarapu and collaborators, who, at the offset of the VCD-DFT approach, established not only the absolute conguration (AC) of isourane, but also that of desurane and 1,2,2,2-tet-rauoroethyl methyl ether by discussing also their relationship with 1-methoxytetrauoropropionic acid, another anesthetic of the same family.…”

“…33 Right: VCD (top) and IR experimental spectra of (AE)-Fluralaner, 2. 34 intense IR doublet between 1100 and 1200 cm À1 in the spectra of molecules 1 and 2, both exhibiting a negative-positive couplet in their VCD spectra due to the antisymmetric and symmetric C-F stretching modes of the CF 3 group (see Table 1). The signed character of VCD in this region gives to this couplet a relevant diagnostic value for the assignment of the absolute conguration at the stereogenic carbon bearing a CF 3 group.…”