Localized Partitioning of Enantiomers in Solid Samples of Sulfoxides: Importance of Sampling Method in Determination of Enantiopurity

Abstract

Localized partitioning of amorphous enantioenriched aryl benzyl sulfoxides in the solid state can lead to substantial variation in enantiopurities, even for sulfoxides which do not show detectable levels of self-disproportionation of enantiomers (SDE) during chromatography on an achiral stationary phase. The importance of preparation of representative samples of enantioenriched sulfoxides for chiral HPLC to enable reproducible results is clear.

Recommended Tests for the Self-Disproportionation of Enantiomers (SDE) to Ensure Accurate Reporting of the Stereochemical Outcome of Enantioselective Reactions

“…It is worth emphasizing again that the SDE is a ubiquitous phenomenon that is always occurring anytime an enantioenriched sample is subjected to any type of physicochemical treatment, or simply being exposed to conditions conducive to physicochemical transformations, such as sublimation during storage [ 10 , 66 , 79 , 80 ]. There are several parameters to describe or quantify the SDE, e.g., SDE range, SDE yield, maximum theoretical SDE yield, etc.…”

“…Thus, since many small organic compounds, especially fluorine-containing ones, possess sufficiently high volatilities, they are prone to the SDE during processes involving gas-phase transformations. Even during the course of solvent removal under vacuum [ 40 , 44 ] or sample drying, as well as the way in which the compounds are stored [ 10 , 66 , 79 , 80 ], the ee of scalemic samples can be altered. Obviously then, SDEvS/E represents a major concern with regard to the quality and reliability of reported stereochemical outcomes of catalytic enantioselective reactions, as well as for the isolation of natural products and the handling of pharmaceutically active intermediates [ 123 , 124 , 125 ].…”

“…Due to the highly polar nature of the S–O bond, scalemic sulfoxides are prone to the SDEvC, rendering the sulfoxide functionality an SDE-phoric group [ 81 ]. This property is known to lead to mistakes in the evaluation of the sulfoxide enantiopurity if due care is not taken in the work up and purification steps [ 80 , 85 ]. The first warning of apparent difficulties caused by the SDEvC of enantioenriched sulfoxides was reported by Prof. Henri B. Kagan [ 38 ] in 1994.…”

“…Inspired by Kagan’s work, several investigations [ 26 , 71 , 80 , 85 , 102 ] revealed the remarkable persistence and high magnitude of the SDEvC for structurally varied chiral sulfoxides. In particular, SDE via routine, gravity-driven achiral column chromatography of methyl n -pentyl sulfoxide ( 21 , Scheme 5 ) was systematically studied [ 85 ].…”

Flurbiprofen: A Study of the Behavior of the Scalemate by Chromatography, Sublimation, and NMR

“…Although the ∆ee's for flurbiprofen by SDEvS are not large, there are potential dangers posed by the SDEvS during the preparation, handling, and, particularly, the long-term storage of the drug as SDEvS has been observed during the storage of scalemates with sublimed material in the upper reaches of the container [41,71] as well as with localized partitioning within the sample bulk itself [72]. Even rotary evaporation has been reported [73,74] to effect SDEvS.…”