Studies of enantiomerization of chiral 3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide type compounds

Abstract

An on-column HPLC procedure using a chiral stationary phase (CSP) was developed for the determination of rate constants and free energy barriers of enantiomerization of (+/-)IDRA21. Subsequently, the HPLC method was applied for investigation of two structurally related chiral compounds. The individual enantiomers of the studied compounds were isolated in parallel by preparative HPLC and rate constants and free energy barriers of enantiomerization were determined in different solvents. The on-column enantiomerization data revealed that CSP induces different rate constants for the two enantiomers. The results generated off-line were used to determine the influence of solvents on the racemization of (+) and (-) IDRA21 and to gain further insight into the enantiomerization mechanism of chiral 3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide type compounds.

Enantiomerization of chiral 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide by stopped-flow multidimensional HPLC☆

“…A stopped-flow procedure previously developed was employed to study the on-column enantiomerization of the (S)-and (R)-2 enantiomers [13]. The racemic mixture of (±)(R,S)-2 was chromatographed at low temperature (0 • C) on the OD-R CSP.…”

“…The on-column HPLC stopped-flow procedure previously developed was used to study the enantiomerization of (±)(R,S)-2 [13].…”

“…More recently it was developed a procedure for the determination of rotational barriers of configurationally labile compounds based on single column stopped-flow HPLC (sfHPLC) and stoppedflow GC (sfGC) where, in contrast to dynamic methods, computer simulation is not necessary [13][14][15][16][17][18][19][20][21][22][23][24][25][26]. Unfortunately, by using single column dynamic and stopped-flow methods, enantiomerization Step 1: (±)(R,S)-2 was injected and a quantitatively separation of enantiomers occurred in the first chiral OD-R column at low temperature conditions.…”

“…Previously, we have reported the resolution of IDRA21 enantiomers by chiral chromatography and found that a rapid interconversion (enantiomerization) of the IDRA21 enantiomers occurred in aqueous solution [12]. A procedure for the determination of apparent rate constants and apparent free energy barriers of enantiomerization without the implementation of computer simulation has been developed [13][14][15][16][17][18][19][20][21][22][23][24][25][26]. The HPLC stopped-flow procedure developed was applied to study on-column enantiomerization of several chiral benzothiadiazines and it turned out a relatively low activation barrier of enantiomerization in aqueous solvents [13].…”

A novel software tool for high throughput measurements of interconversion barriers: DCXplorer☆

“…Furthermore no special analytical equipment is necessary. For the evaluation ଝ This paper is part of the Special Issue 'Enantioseparations', dedicated to W. of elution profiles obtained by dynamic chromatography or electrophoresis sophisticated methods have been developed in the past for the relatively fast and precise determination of reaction rate constants [4][5][6][7][8][9][10][11][12][13][14][15][16]. Despite these efforts, there is still a need for improvement in the evaluation process of dynamic elution profiles [17], because using iterative computer simulations, especially for large datasets is computationally expensive and direct calculation with the approximation function [18][19][20] is only possible for the investigation of enantiomerization processes of racemic mixtures.…”