Possible Case of Halogen Bond‐Driven Self‐Disproportionation of Enantiomers (SDE) via Achiral Chromatography

Abstract

The major breakthrough reported in this work is the discovery of likely halogen bond-driven self-disproportionation of enantiomers (SDE). Taking into account that the halogen-bonding interactions can be rationally designed and can match, or even exceed, the strength of the more familiar hydrogen bond, this discovery clearly opens an unexpected new direction of research in the areas of molecular chirality and the SDE phenomenon.

The self-disproportionation of enantiomers (SDE): a menace or an opportunity?

“…Other compounds for which SDE via gravity-driven column chromatography has been observed include the mebroqualones, 60 mandelic acid, 61 and stilbene oxide, 61 thus demonstrating that the SDE can be driven by different intermolecular forces. But due to the innate ability of the amides of chiral amines, 7 – 14 α-amino acid esters, 6b , 9 , 11 and β-amino acid esters 15 as well as sulfoxides 16 – 18 , 28 and trifluoromethyl-containing compounds 4 , 19 – 22 for the formation of homo- and/or heterochiral aggregates by way of strong intermolecular forces resulting in a high magnitude of SDE via chromatography, the term SDE-phoric groups has recently been introduced 7 and applied to these groups (see Section 4.1 SDE-phoric groups and predictability).…”

“…Finally, while dipole–dipole and aromatic π–π interactions, and hydrogen bonds especially, are well recognized as interactions that can give rise to the SDE phenomenon, halogen bond-driven SDE was an unexpected observation, 60 and moreover, a strong magnitude of the SDE phenomenon was found for compounds where halogen bonding was present. Thus, in the examination 60 of a set of eight mebroqualone derivatives by both MPLC and gravity-driven column chromatography, in all six cases subjected to MPLC, enantiopure samples (>99% ee) were obtained with Δee's of up to 81% ee and SDE yields generally high, even for samples of initial ee's as low as 28.4% ee and were as much as 74%. Gravity-driven column chromatography provided enantiopure samples (>99% ee) for three of the six compounds with the remaining three compounds tested still yielding samples of >90% ee, all from initial samples of 61–70% ee.…”

“…Other examples of drugs exhibiting SDE are the mebroqualone-type GABAergic drugs possessing axial chirality 13b , 14 , 60 (see Section 4.2 New directions and novel, unconventional enantiopurification methods), cephalotaxine, 90 precursors to norepinephrine transporter inhibitors, 12 chloromezanone 54 ( 19 ), and benzodiazepine camazepam 54 ( 20 ) in addition to many others. 91 It is worth noting that focused research on the SDE properties of marketed drugs has never been systematically undertaken and all reported examples are the results of accidental or anecdotal observations.…”

The self‐disproportionation of enantiomers (SDE): The effect of scaling down, potential problems versus prospective applications, possible new occurrences, and unrealized opportunities?

“…for a sample of 9 ( R = Et ), again under otherwise near‐identical chromatographic conditions. This case is notable in that the MPLC and gravity‐driven column chromatography results are from the same study . While the SDE is fairly pronounced in both cases (57 and 23%, respectively), though with the MPLC expressing a significantly higher Δee, only for MPLC the early eluted fractions can again provide essentially enantiopure material.…”

“…The compounds represent a diversity of structural types 1 ‐ 8 , as well as all types of chirality represented (central, axial, planar, and helical) with axial chirality being particularly ( 9 ‐ 12 ) prominent and even helical chirality being represented ( 13 ) . Note that the selection displayed here includes that infamous drug now on the comeback trail, thalidomide ( 14 , R = H ) and its fluoro analog 14 ( R = F ) , the fluorinated analog 15 of the drug donepezil, a new, highly promising compound for the treatment of Alzheimer's disease and other Alzheimer‐like maladies, membroqualone ( 9 , R = Me ) , a GABAergic drug possessing potent sedative, hypnotic, and anticonvulsant properties, and also the set of proton pump inhibitors used for the treatment of peptic ulcers, the sulfoxide‐containing prazoles ( 16 ) . Furthermore, although the intermolecular interactions leading to SDE via chromatography tend to be dominated by hydrogen bonding, many types of intermolecular interactions can be involved and combinations thereof, including possible halogen bonding (e.g., 9 ), as well as π–π (e.g., 10 and 13 ) and dipole–dipole interactions (with some compounds having only dipole–dipole interactions, e.g., 17 and 18 ) .…”