Self-disproportionation Of Enantiomers Research Articles

The self-disproportionation of enantiomers (SDE) of α-amino acid derivatives: facets of steric and electronic properties.

α-Amino acids (α-AAs) are in extremely high demand in nearly every sector of the food and health-related chemical industries and continue to be the subject of intense multidisciplinary research. The self-disproportionation of enantiomers (SDE) is an emerging and one of the least studied areas of α-AA or enantiomeric properties, critically important for their production and application. In the present work, we report a detailed study of the SDE via achiral, gravity-driven column chromatography for a set of N-acylated, N-carbonylated, N-fluoroacylated, and N-thioacylated α-amino acid esters. As well as thioacylation, attention was paid to the effect of altering the R group of the ester functionality, the side chain, or that of the acyl group attached to the amide nitrogen, whereby it was found that electron-withdrawing groups in the latter moiety had a pronounced effect on the magnitude and behavior of the resulting SDE phenomenon. Intriguingly, in the case of N-fluoroacylated derivatives, by favoring the formation of dimeric associates and effecting a strong bias toward homochiral associates over heterochiral associates, the SDE magnitude was greatly reduced contrary to intuitive expectations. Energy estimates resulted from DFT calculations.

Access to the enantiopure pyrrolobenzodiazepine (PBD) dilactam nucleus via self-disproportionation of enantiomers

A short synthesis of an enantiopure pyrrolobenzodiazepine (PBD) dilactam featuring early installation of the C2-C3 unsaturation is reported. An enantioselective cooperative catalytic cascade followed by self-disproportionation of enantiomers via sublimation afforded the enantiopure 2,3-dihydro-1H-pyrrole key intermediate, 1. N-Acylation followed by reduction and lactam formation furnished the PBD dilactam.

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

Herein we report on the well-documented, yet not widely known, phenomenon of the self-disproportionation of enantiomers (SDE): the spontaneous fractionation of scalemic material into enantioenriched and -depleted fractions when any physicochemical process is applied. The SDE has implications ranging from the origins of prebiotic homochirality to unconventional enantiopurification methods, though the risks of altering the enantiomeric excess (ee) unintentionally, regrettably, remain greatly unappreciated. While recrystallization is well known as an SDE process, occurrences of the SDE in other processes are much less recognized, e.g. sublimation and even distillation. But the most common process that many workers seem to be completely ignorant of is SDE via chromatography and reports have included all manner of structures, all types of interactions, and all forms of chromatography, including GC. The SDE can be either a blessing - as a means to obtain enantiopure samples from scalemates - or a curse, as unwitting alteration of the ee leads to errors in the reporting of results and/or misinterpretation of the system under study. Thus the ramifications of the SDE are relevant to any area involving chirality - natural products, asymmetric synthesis, etc. Moreover, there is grave concern regarding errors in the literature, in addition to the possible occurrence of valid results which may have been overlooked and thus remain unreported, as well as the potential for the SDE to alter the ee, particularly via chromatography, and the following concepts will be conveyed: (1) the SDE occurs under totally achiral conditions of (a) precipitation, (b) centrifugation, (c) evaporation, (d) distillation, (e) crystallization, (f) sublimation, and (g) achiral chromatography (e.g. column, flash, MPLC, HPLC, SEC, GC, etc.). (2) The SDE cannot be controlled simply by experimental accuracy and ignorance of the SDE unavoidably leads to mistakes in the recorded and reported stereochemical outcome of enantioselective transformations. (3) The magnitude of the SDE (the difference between the extremes of enantioenrichment and -depletion) can be controlled and used to: (a) minimize mistakes in the recorded experimental values and (b) to develop unconventional and preparatively superior methods for enantiopurification. (4) The magnitude of the SDE cannot be predicted but can be expected for compounds possessing SDE-phoric groups or which have a general tendency for strong hydrogen or halogen bonds or dipole-dipole or aromatic π-π interactions. (5) An SDE test and the rigorous reporting and description of applied physicochemical processes should become part of standard experimental practice to prevent the erroneous reporting of the stereochemical outcome of enantioselective catalytic reactions and the chirooptical properties of scalemates. New directions in the study of the SDE, including halogen bonding-based interactions and novel, unconventional enantiopurification methods such as pseudo-SDE (chiral selector-assisted SDE resolution of racemates), are also reported.

Chiral sulfoxides: advances in asymmetric synthesis and problems with the accurate determination of the stereochemical outcome.

Chiral sulfoxides are in extremely high demand in nearly every sector of the chemical industry concerned with the design and development of new synthetic reagents, drugs, and functional materials. The primary objective of this review is to update readers on the latest developments from the past five years (2011-2016) in the preparation of optically active sulfoxides. Methodologies covered include catalytic asymmetric sulfoxidation using either chemical, enzymatic, or hybrid biocatalytic means; kinetic resolution involving oxidation to sulfones, reduction to sulfides, modification of side chains, and imidation to sulfoximines; as well as various other methods including nucleophilic displacement at the sulfur atom for the desymmetrization of achiral sulfoxides, enantioselective recognition and separation based on either metal-organic frameworks (MOF's) or host-guest chemistry, and the Horner-Wadsworth-Emmons reaction. A second goal of this work concerns a critical discussion of the problem of the accurate determination of the stereochemical outcome of a reaction due to the self-disproportionation of enantiomers (SDE) phenomenon, particularly as it relates to chiral sulfoxides. The SDE is a little-appreciated phenomenon that can readily and spontaneously occur for scalemic samples when subjected to practically any physicochemical process. It has now been unequivocally demonstrated that ignorance in the SDE phenomenon inevitably leads to erroneous interpretation of the stereochemical outcome of catalytic enantioselective reactions, in particular, for the synthesis of chiral sulfoxides. It is hoped that this two-pronged approach to covering the chemistry of chiral sulfoxides will be appealing, engaging, and motivating for current research-active authors to respond to in their future publications in this exciting area of current research.

A fast, new method to enhance the enantiomeric purity of non-racemic mixtures: self-disproportionation of enantiomers in the gas antisolvent fractionation of chlorine-substituted mandelic acid derivatives

Gas antisolvent precipitation is a particle formation technique, when typically pressurized carbon dioxide is added to an organic solution resulting in immediate and high oversaturation and precipitation of fine particles. Provided that a reasonable share of the originally dissolved material remains dissolved in the carbon dioxide – organic mixed solvent, these components can be extracted during the washing phase. This method is called gas antisolvent fractionation. Gas antisolvent fractionation has been applied for the first time to enantiomeric enrichment of non-racemic mixtures, and demonstrated on the example of chlorinated mandelic acid derivatives. Due to self-disproportionation of enantiomers, the precipitated solid and the extracted fractions have different enantiomeric excesses if gas antisolvent fractionation is carried out on a non-racemic mixture. However, there is a limit in the enantiomeric excess (ee) that can be achieved correlating strongly with the atmospheric melting eutectic behavior of the compounds. Thus, if initial enantiomeric mixtures have a higher than eutectic ee, a >99% ee can be reached in the crystalline product. The strong correlation between the high-pressure experiments and the atmospheric melting eutectic behavior suggest that despite the very large oversaturation during the antisolvent precipitation, the composition of the products (i.e., the crystalline and the extracted phases) is thermodynamically determined. Technological advantages such as short operational time, or the possibility of controlling the crystal morphology suggest that the development of an efficient technique of enantiomeric purification is possible based on gas antisolvent fractionation.

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

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.

A question of policy: should tests for the self-disproportionation of enantiomers (SDE) be mandatory for reports involving scalemates?

The self-disproportionation of enantiomers (SDE) is a phenomenon that can lead to the perturbation of the enantiomeric excess (ee) in fractions obtained from a scalemic sample that has been subjected to a physical process. While fractional crystallization is widely appreciated as a means to effect enantiopurification, processes that are potentially able to give rise to the SDE phenomenon, notably chromatography, are greatly underappreciated in this regard. In this exposition we question if sufficient care is being taken by workers to avoid the erroneous reporting of stereochemical outcomes in asymmetric synthesis, natural products work, and other chiral-based areas of study due to ignorance of the SDE phenomenon and recommend the incorporation of SDE tests via sublimation and achiral chromatography as outlined herein to check for the occurrence of the SDE phenomenon in the applied methodology and routine experimental work.

Asymmetric Michael addition reaction organocatalyzed by stereoisomeric pyrrolidine sulfinamides under neat conditions. A brief study of self-disproportionation of enantiomers

This paper describes the synthesis of all four possible stereoisomers of the pyrrolidine sulfinamides derived from (S)-proline or (R)-proline and either enantiomer of t-butylsulfinamide. These bifunctional derivatives were examined as organocatalysts in the asymmetric Michael addition reaction, finding that the pyrrolidine stereocenter, rather than the stereogenic sulfur, is responsible for the observed stereocontrol in the asymmetric reaction. This result is in accordance with previous reports in the literature (aldol reactions: W. Wan, J. Hao, and coworkers, RSC Adv.2014, 4, 26563–26568; J. A. Ellman et al., Tetrahedron2011, 67, 4412–4416). Consequently, no evidence for double stereoinduction is found. The desired Michael adducts were obtained with good yields, high diastereoselectivities, and moderate to good enantioselectivities. Some tests designed to examine the potential manifestation of self-disproportionation of enantiomers (SDE) were carried out by means of chromatographic purification and subsequent evaluation of the enantiopurity of the corresponding Michael adducts.

Self‐disproportionation of Enantiomers (SDE) of Chiral Nonracemic Amides via Achiral Chromatography

AbstractThis article is based on a review of literature devoted to the phenomenon of SDE via achiral chromatography since the appearance of the seminal work of Professor Emanuel Gil‐Av. The discussed examples of chromatographic studies are related to amides derived from chiral amines and α‐ and β‐amino acids. We discuss the observed SDE magnitude as a function of a compound's structure, and composition of eluent and stationary phases, providing some mechanistic considerations. Particular emphasis is given to the aspect of SDE via achiral chromatography as an emerging unconventional enantiomeric purification technique.

Self-Disproportionation of Enantiomers (SDE) via achiral gravity-driven column chromatography of N-fluoroacyl-1-phenylethylamines

The study of the self-disproportionation of enantiomers (SDE) via gravity-driven achiral column chromatography of a series of N-fluoroacetylated amides derived from 1-phenylethylamine is described. The chromatographic experiments performed with N-fluoroacetylated amides confirmed, that the process of molecular association in solution leading to the SDE manifestation, is sensitive to the fluorine content and type of solvent used. Thus, the two opposite eluting profiles for the same compound were observed in two different eluents. Moreover, the amides bearing perfluoroalkyl groups showed opposite eluting order as compared to the established profile for fluorine-free N-acetyl-1-phenylethylamine.

Self-disproportionation of enantiomers via achiral gravity-driven column chromatography: A case study of N-acyl-α-phenylethylamines

Herein we report a study of the self-disproportionation of enantiomers (SDE) via gravity-driven achiral column chromatography of a series of amides derived from 1-phenylethylamine. We demonstrated that structural and electronic factors of the substituents play an important role in the observed magnitude of the SDE. For the first time, the SDE phenomenon of amides with that of thioamides was compared. We demonstrate that, in sharp contrast to amides, the substitution of the sulphur atom for the oxygen in the acyl group, strongly reduced the observed magnitude of the SDE. These results clearly indicate the importance of the hydrogen bonding for the formation of homo/hetero-chiral association responsible for manifestation of the SDE phenomenon.

Chiral additive induced self-disproportionation of enantiomers under MPLC conditions: preparation of enantiomerically pure samples of 1-(aryl)ethylamines from racemates

Mixtures of enantiomerically pure (S)-N-formyl-1-phenylethyamine and various racemic N-formyl-1-arylethylamine derivatives, when submitted to achiral medium pressure liquid chromatography, afforded elution profiles in which the enantiomers of N-formyl-1-arylethylamines standout as separate peaks and can be isolated. In all of the investigated N-formyl-1-arylethylamine substrates, the virtually enantiomerically pure (S)-enantiomer eluted as a less polar fraction and subsequently, the (R)-enriched enantiomer mixtures were eluted in the more polar fractions.

Remarkable magnitude of the self-disproportionation of enantiomers (SDE) via achiral chromatography: application to the practical-scale enantiopurification of β-amino acid esters

We report the best performance yet for the self-disproportionation of enantiomers (SDE) via achiral chromatography as typically used in laboratories for the isolated yield of the excess enantiomer using N-acetyl β-amino acid ethyl esters. The results are the most convincing ever demonstration of the capability of the SDE for practical-scale enantiopurification as comparable, or even superior for some systems, to that of recrystallization. For example, from a sample of 94.4% ee, a yield of 71% of enantiopure material was isolated in a single chromatographic run. Moreover, the lack of an esoteric structural entity, e.g. strongly polarizing groups, such as, for instance CF3, highlights the fact that the phenomenon is not dependent on the presence of such and thus the process is relevant to any usual-type structure. In contrast to recrystallization, the procedure is predictable, general, and dependable, boding well for its widespread application in routine laboratory settings.

Enantiomeric Enrichments via the Self‐Disproportionation of Enantiomers (SDE) by Achiral, Gravity‐Driven Column Chromatography: a Case Study Using N‐(1‐Phenylethyl)acetamide for Optimizing the Enantiomerically Pure Yield and Magnitude of the SDE

AbstractThis work explores the self‐disproportionation of enantiomers (SDE) via achiral, gravity‐driven column chromatography as typically used in laboratory settings for the purpose of enantiomeric enrichment using N‐(1‐phenylethyl)acetamide (PEA) as a case study. The major finding of this work is the very large magnitude of the SDE for PEA across a variety of conditions and broad range of starting ee values, thereby facilitating a simple, reliable, and predictable means of obtaining enantiomerically pure samples. For example, starting with a sample of PEA of ee as low as 28%, a single column run yielded an enantiomerically pure sample (>99.9% ee) from the first fractions and a significantly enantiomerically depleted sample (<17% ee) from the final fractions. An assessment of SDE via achiral, gravity‐driven column chromatography was also rendered with regard to the differing objectives that workers might target – a large magnitude of the SDE, obtaining an optimum sample of desired ee, or preparative‐scale separation of the excess enantiomer. Overall, it can be considered that the SDE phenomenon via achiral, gravity‐driven column chromatography – readily applicable in the usual laboratory settings – is a simple and convenient method for enantiomeric enrichment with a high degree of proficiency. Advantages of SDE via achiral, gravity‐driven column chromatography over conventional fractional recrystallization for the enantiomeric enrichment of amides/amines, and applicable also to many other classes of compounds as well, are discussed.

A comprehensive examination of the self-disproportionation of enantiomers (SDE) of chiral amides via achiral, laboratory-routine, gravity-driven column chromatography

The behavior of a series of chiral amides during column chromatography using an achiral stationary phase revealed that a self-disproportionation of enantiomers (SDE) was always observed regardless of amide structure or chromatographic conditions.

Self-disproportionation of enantiomers of thalidomide and its fluorinated analogue via gravity-driven achiral chromatography: mechanistic rationale and implications.

We report on the self-disproportionation of enantiomers (SDE) of non-racemic thalidomide (1) and 3'-fluorothalidomide (2) under the conditions of gravity-driven achiral silica-gel chromatography. The presence of a fluorine atom on the chiral center dramatically alters the structure and polarity of 1 and 2, resulting in the opposite SDE profile on silica-gel.

The self-disproportionation of the enantiomers (SDE) of methyl n-pentyl sulfoxide via achiral, gravity-driven column chromatography: a case study.

This work explores the self-disproportionation of enantiomers (SDE) of chiral sulfoxides via achiral, gravity-driven column chromatography using methyl n-pentyl sulfoxide as a case study. A major finding of this work is the remarkable persistence and high magnitude of the SDE for the analyte. Thus, it is the first case where SDE is observed even in the presence of MeOH in the mobile phase. The study demonstrated the practical preparation, in line with theory, of enantiomerically pure (>99.9% ee) samples of methyl n-pentyl sulfoxide starting from a sample of only modest ee (<35%). Remarkably, it was found that the order of elution was inverted, i.e. enantiomerically depleted fractions preceded later eluting enantiomerically enriched ones, when the stationary phase was changed from silica gel to aluminum oxide. To the best of our knowledge, this is the first occurrence of inverted SDE behavior due solely to a change in the stationary phase. Aberrant SDE behavior was observed in that the ee did not always fall continuously during the progression of the chromatography, and this was attributed to the complexity of the system at hand which cannot be described in simple terms such as the formation only of homo- and heterochiral dimers based on a single interaction. The results nevertheless suggest that all compounds with a chiral sulfoxide moiety in their structure are likely to exhibit the SDE phenomenon and thus this work constitutes the first example of SDE predictability. Moreover, it could well be that optical purification based on the SDE phenomenon is a simple, convenient, and inexpensive method for the optical purification of this class of compounds with a high degree of proficiency.

ChemInform Abstract: Chiral Initiator‐Induces Self‐Disproportionation of Enantiomers via Achiral Chromatography: Application to Enantiomer Separation of Racemate.

Abstract We report here the theoretical design and proof of principle of the first example of a conceptually new approach for the preparation of enantiomerically pure compounds from the racemates by chiral initiator-induced Self-Disproportionation of Enantiomers (SDE) via achiral chromatography.

Chiral initiator-induces self-disproportionation of enantiomers via achiral chromatography: application to enantiomer separation of racemate

Abstract We report here the theoretical design and proof of principle of the first example of a conceptually new approach for the preparation of enantiomerically pure compounds from the racemates by chiral initiator-induced Self-Disproportionation of Enantiomers (SDE) via achiral chromatography.

Optical Purifications via Self‐Disproportionation of Enantiomers by Achiral Chromatography: Case Study of a Series of α‐CF3‐containing Secondary Alcohols

This work demonstrates that self-disproportionation of enantiomers via achiral chromatography can be recommended as inexpensive and general method for optical purification of enantiomerically enriched compounds. In particular, the advantage of this approach over conventional recrystallization is that it can be used for both crystalline as well as liquid compounds.