VCD configuration of enantiopure/‐enriched tetrasubstituted α‐fluoro cyclohexanones and their use for epoxidation of trans‐olefins

Abstract

The configurations of three enantiopure tetrasubstituted alpha-fluoro cyclohexanones (-)-5Ia, (-)-5IIa and (-)-6a were determined by VCD and proved to be (-)-(2S,5R)-5Ia, (-)-(2R,5R)-5IIa, and (-)-(2R,5R)-6a. The VCD study also identified the conformers populated in CDCl3 solution, including higher-energy gas-phase conformers with equatorial fluorine for 5Ia and 5IIa that are stabilized in CDCl3 solution. Used as catalysts for epoxidation of trans olefins (beta-methylstyrene, stilbene, methyl p-methoxy cinnamate) by oxone, it was found that (-)-5Ia is the most efficient for all trans olefins (providing, respectively, 62%, 90% and 66% ee) but that all three ketones provide high ee% with stilbene (78-90% ee). Moreover, the configurations predicted from the stereo outcome of the epoxidation reaction are identical to those determined by VCD.

Application of chiral technology in a pharmaceutical company. Enantiomeric separation and spectroscopic studies of key asymmetric intermediates using a combination of techniques. Phenylglycidols

“…[37][38][39] More recently, the spectroscopic approach of comparing observed and calculated vibrational circular dichroism (VCD) spectra, electronic circular dichroism (ECD), or optical rotation (OR) values has gained popularity due to the ease of data acquisition and the ability to calculate spectra and values with commercially available software and supercomputers or modern, powerful PCs and Linux clusters. [40][41][42][43][44][45][46][47][48][49] In the case of VCD, besides absolute stereochemistry of molecules containing one or more asymmetric centers, or planes or axes of asymmetry, i.e., atropisomerism, [50][51][52][53] additional information can be obtained, including solution conformation 54,55 and real-time reaction monitoring. 56,57 VCD has been applied specifically to pharmaceuticallyrelevant molecules.…”

Vibrational Circular Dichroism: A Valuable Tool for Conformational Analysis and Absolute Configuration Assignment of Chiral 1‐Aryl‐2,2,2‐Trifluoroethanols

“…[ Previous studies have been devoted to chiral paracyclophanes, employing several techniques including OR, [7] ECD [8,9] and even VCD, [9,10] which were also used to investigate molecules bearing the CF 3 group. [11][12][13][14] The presence of fluorine atoms and aryl groups poses interesting problems in both calculation and spectra interpretation, namely does the OH group preferentially interact with the CF 3 group rather than with the Ar group? Does the solvent play a role on the appearance and stability of molecular conformations?…”

“…From Polavarapu [11] and Freedman [12] we learned that VCD spectra of CF 3 -containing compounds calculated in vacuo and weighed by the thermal average procedure should be corrected, by taking into account the solvent polarity effect. This is why the DFT-calculated dipole moment m of each conformer of 1 and 2 was considered and the previously derived population factors were multiplied by a factor proportional to the calculated m. The corrected population factors are reported in Table 1.…”

Enantiomeric separation and determination of absolute stereochemistry of asymmetric molecules in drug discovery—Building chiral technology toolboxes

“…Besides determining absolute stereochemistry of molecules containing one or more asymmetric centers, or planes or axes of asymmetry, i.e., atropisomerism, [319][320][321][322][323][324] additional information about solution conformation can be obtained. 304,[325][326][327] Also, VCD can be used for real-time reaction monitoring. [328][329][330] VCD has been used to determine the absolute stereochemistry of natural products, 320,331 compounds derived via asymmetric enzymatic catalysis, 332 as well as carboxylic acids 333,334 and alcohols 204 in derivatized form in order to improve calculations by obviating the presence of dimers or rigidifying the molecule of interest, respectively.…”