A rational approach to predict and modulate stereolability of chiral α substituted ketones

Abstract

An effective strategy to assess and modulate the stereolability of chiral alpha substituted ketones (C alpha SKs) is presented. The tendency of C alpha SKs to retain or change their configuration in water is analyzed as a function of thermodynamic proton-release attitude of alpha asymmetric atoms inside the structures by linear Brønsted correlations. A molecular modeling procedure was developed to analyze and suggest chemical modifications of C alpha SKs in view to obtain the desired grade of stereochemical stability. The approach was employed to predict the tendency to enantiomerize in water of two ketones (1 and 2) endowed with inhibitory activity against monoamine oxidases (MAOs) and the results were confirmed by experimental kinetics measurements performed in organic medium. As a demonstration of practical potentialities of the approach, four new structures, conceived as simple chemical modifications of 1 and 2, were designed to improve/reduce the stereostability grade of the starting anti-MAO ketones. The possibility to extend easily the procedure to other classes of C-H acids appears of interest.

Inductive and Mesomeric Effects of the [60]Fulleropyrrolidine Fragment and [60]Fullerene Sphere: A Quantitative Evaluation Based on Theory and Experiments

“…For this purpose, we plotted Δlog(k t ) values related to 10 mono-and 4 disubstituted ketones against the relevant σ p values available in the literature (see Table 3). [21] Linear correlation analysis afforded quite good agreement among the data, with an R 2 coefficient of 0.911, see Equation (5).…”

“…[12] However, the water solubility of pristine [a] Extrapolated to 50°C by a straight line regression (R 2 = 0.983) from four relevant kinetic data at temperatures of 30, 35, 40, 45°C (ref. [11] ).…”

“…In fact, proton abstraction from C α would necessarily lead to a loss of the configuration of this centre, which could be inverted or restored by subsequent reprotonation. Within an established solvent and base catalyst, the rate constant governing this process (i.e., the enantiomerization rate constant of 1, k e ) will be strictly related to the acidity of H α , [5] and therefore, also to the electron-withdrawing properties of C 60 . Thus, measuring k e might also provide a decisive contribution toward achieving our goal.…”

Racemisation in Chemistry and Biology

“…[151] Semiempirical AM1 calculations were used to understandt he racemisation in acetonitrile of two chiralk etones, 62 and 63 ( Figure 20). [152] The aforementioned studies by Servi and co-workers and by Zeng and co-workersc orrelate the rate constants for racemisation of amino acids with experimental rate constants. [71,124] However,these computationalstudies provide correlations strictly within compound classes.…”

Fundamental Developments of Chiral Phase Chromatography in Connection with Enantioselective Synthesis of β‐Amino Acids

“…Important clues of the role of carbonyl functional groups in cellulose esters pointed out that these constitute the main binding chiral sites, which can interact with racemic compounds through hydrogen bonding and dipole‐dipole interactions for chiral discrimination ,. Over the course of the years, a highly refined understanding about the chiral recognition mechanism performed by polysaccharides derivatives has been achieved through detailed studies combining diverse techniques,, such as NMR spectroscopy, solid state NMR, attenuated total reflectance infrared spectroscopy, vibrational circular dichroism, and electrostatic potential surfaces (EPSs) determined via Density Functional Theory (DFT) calculations, among others …”