Patrick Piras

Atropisomerism and Axial Chirality in Heteroaromatic Compounds

Abstract The chapter “Atropisomerism and axial chirality in heteroaromatic compounds” provides a summary of the present knowledge of this important topic. The structure of the chapter is: first a detailed description of the methods used to study atropisomerism, from X-ray diffraction to theoretical calculations (14 items), then the application to different compounds according to the nature of the central bond. Rotation about a C–C bond (5–5, 5–6 and 6–6 rings), rotation about a C–N bond (azoles, oxo- and thioxo-five-membered rings, azines), rotation about an N–N bond (5–5, 5–6 and 6–6 rings), rotation about ortho-ortho’-linked compounds, rotation about N-metal bonds, multiple rotations, to end with axial chiral synthesis. In conclusion, a phenomenon that was discovered in 1922 for diphenic acids and that was extended to heterocycles in 1931 by Adams shows eighty years later to be very active, being expected to grow in importance because it is related to asymmetric synthesis, to materials and to biological properties.

Reviewing mobile phases used on Chiralcel OD through an application of data mining tools to CHIRBASE database.

During the past decade, thousands of compounds have been resolved on Chiralcel OD (a cellulose-based chiral stationary phase) under diverse eluting conditions. Many researches have documented the effects of mobile phase on enantioselectivity for a given family of samples but today no comprehensive study aimed at identifying the associations between the structural features present on solute and appropriate mobile phase conditions has yet been proposed. In this review of mobile phases used on Chiralcel OD, we try to go far beyond a simple enumeration of eluting conditions and an effort is made to explore the utility of data mining tools for assessing the knowledge contained in CHIRBASE database. We have extracted from CHIRBASE the chemical features of 2363 chiral compounds separated on Chiralcel OD and their corresponding mobile phases. This data set was submitted to data mining programs for molecular pattern recognition and mobile phase predictions for new cases. Some substructural characteristics of solutes were related to the efficient use of some specific mobile phases. For example, the application of CH3CN/salt buffer at pH 6-7 was found convenient for reversed-phase separation of compounds bearing a tertiary amine functional group. Furthermore, a cluster analysis allowed the arrangement of the mobile phases according to similarity found in molecular patterns of solutes. A decision tree, which may lead to a more rational choice of the mobile phase under reversed-phase conditions, is also proposed.

Part III: Supercritical Fluid Chromatographic Separations

The enantioseparation of 123 clinically used racemic drugs by supercritical fluid chromatography (SFC) on commercial chiral stationary phases (CSPs) available in 2006 is reviewed. The CSPs were briefly described in Part I of this work. The mobile phase compositions, with organic modifier and additives, are listed. The data was extracted and compiled from the ChirBase database (Marseille, France). All the drugs included are listed according to the thirteen therapeutic classes of the Anatomical Therapeutic Chemical (ATC) classification. It is evident that the nature of the SF mobile phase precludes the use of several classes of CSPs such as the crown ethers, ligand‐exchange or protein‐based CSPs. The polysaccharide based CSPs were responsible for two third of the enantiomer separation listed.

Toward structure-based predictive tools for the selection of chiral stationary phases for the chromatographic separation of enantiomers.

ChirBase, a database for the chromatographic separation of enantiomers containing more than 200,000 records compiled from the literature, was used to develop quantitative structure activity models for the prediction of which chiral stationary phase will work for the separation of a given molecule. Constructuion of QSAR models for the enantioseparation of nineteen chiral stationary phases was attempted using only analyte structural information, leading to the producton of self-consistent models in four cases. These models were tested by predicting which in-house racemic compounds would and would not be resolved on the different columns. Some degree of success was observed, but the sparseness of data within ChirBase, which contains enantioseparations for only a subset of molecules on a subset of columns under a variety of conditions may limit the creation of effective models. Augmented data sets gleaned from automated chromatographic method development systems deployed in academic and industrial research laboratories or the use of models that take other factors such as solvent composition, temperature, etc. into account could potentially be useful for the development of more robust models.

Enantiomers of dimethyl [(2E)-1,3-diphenylprop-2-en-1-yl]propanedioate resulting from allylic alkylation reaction: elution order on major high-performance liquid chromatography chiral columns.

Asymmetric allylic alkylation leading to dimethyl [(2E)-1,3-diphenylprop-2-en-1-yl]propanedioate 1 is a privileged reaction which has been considered in more than 800 references from 1985 to early 2012. This paper thus begins with a thorough review of the literature with a particular focus on the way the ees and absolute configuration of the prevailing enantiomer were claimed and reported by the authors. In a large majority of articles chiral chromatography is used for ees determination. Unfortunately, in too many cases the data, the column or the eluent are not provided. In a significant proportion (5%) the column name is ambiguous. Furthermore, several discrepancies are detected in the assigned order of elution when chiral chromatography data are provided. We therefore decided to firmly establish the chromatographic behavior of the enantiomers of 1, which were obtained from the corresponding racemate by semi-preparative chiral chromatography and their absolute configuration assigned by ECD and VCD spectroscopies. ORD curves show that optical rotation is very weak at 350 nm with indication of inversion of the sign at lower wavelengths. It results in a low sensitivity for on line JASCO polarimeter detector. Chiroptical detection was nicely performed by on line JASCO CD detector set at 254 nm: (-)-(S)-1 shows a (+)-CD(254 nm) sign. Pure enantiomers of authenticated absolute configuration allowed a safe assignment of the order of elution during HPLC or SFC on major chiral stationary phases. Quite interestingly for practical application, the order of elution is reversed on Chiralpak AD-H and IA on going from hexane/EtOH to hexane/2-PrOH in HPLC or on going from CO(2)/EtOH (or MeOH) to CO(2)/2-PrOH in SFC.

Some Aspects of Chiral Separations in Planar Chromatography Compared with HPLC

The paper reviews the latest achievements in chiral separation by planar chromatography (PC) since 2001. The emphasis is on cellulose derivatives and, especially, microcrystalline cellulose triacetate (MCTA). A comparison is made with HPLC data retrieved from Chirbase. It is shown that TLC has some interesting features compared with HPLC. Some enantiomer separations have been successfully achieved by TLC whereas no data are available for HPLC. For tribenzoyl cellulose derivatives general trends for resolution by both TLC and HPLC are discussed. The last part of the paper discusses reasons for the scarcity of publications on chiral separations by either PC or overpressured layer chromatography (OPLC). The possibilities of PC for chiral separations are rather unexploited.

Mining Chromatographic Enantioseparation Data Using Matched Molecular Pair Analysis

We apply matched molecular pair (MMP) analysis to data from ChirBase, which contains literature reports of chromatographic enantioseparations. For the 19 chiral stationary phases we examined, we were able to identify 289 sets of pairs where there is a statistically significant and consistent difference in enantioseparation due to a small chemical change. In many cases these changes highlight enantioselectivity differences between pairs or small families of closely related molecules that have for many years been used to probe the mechanisms of chromatographic chiral recognition; for example, the comparison of N-H vs. N-Me analytes to determine the criticality of an N-H hydrogen bond in chiral molecular recognition. In other cases, statistically significant MMPs surfaced by the analysis are less familiar or somewhat puzzling, sparking a need to generate and test hypotheses to more fully understand. Consequently, mining of appropriate datasets using MMP analysis provides an important new approach for studying and understanding the process of chromatographic enantioseparation.

Chiral separation of some 4a-methyl-1,2,3,4,4a,9a-hexahydro-fluoren-9-one derivatives as a probe for difference in solvation by 2-propanol of carbamate moiety in chiralcel OD-H, chiralpak AD, and chiralpak AS chiral stationary phases

Chromatographic resolution of 12 derivatives in the 4a-methyl-2,3,4,4a-tetrahydro-1H-fluorene and 4a-methyl-1,2,3,4,4a,9a-hexahydrofluoren-9-one series differing by the framework around position 9 and substitution in position 6, are reported on Chiralcel OD, Chiralpak AD, and Chiralpak AS under two elution conditions and according to the two classes of enantiomers. Results from principal component analysis (PCA) as well as hierarchical clustering show a clustering of the actual compounds depending on properties around position 9, the effect of the substituent in position 6 (methyl, chloro or fluoro) not being strong enough to intermesh the data. Carbamate phases show very different properties when they are used in the separation of a series of ketones C and α-chloroketones D, which differ in basicity and the steric requirement around the carbonyl. Analysis of the effect of 2-PrOH content in hexane on the retention is consistent with a large difference in solvation of the carbamate moiety by 2-PrOH, in the order Chiralcel OD > Chiralpak AD > Chiralpak AS. 4a-Methyl-2,3,4,4a-tetrahydro-1H-fluorene derivatives, which lack hydrogen bonding sites, are not discriminated on these CSPs and show identical k′ responses to 2-PrOH content changes on the three CSPs. Chirality 10:770–777, 1998.

Atropisomerism in a 10-Membered Ring with Multiple Chirality Axes: (3Z,9Z)-1,2,5,8-Dithiadiazecine-6,7(5H,8H)-dione Series

For the first time, chirality in (3 Z,9 Z)-1,2,5,8-dithiadiazecine-6,7(5 H,8 H)-dione series was recognized. Enantiomers of the 4,9-dimethyl-5,8-diphenyl analogue were isolated at room temperature, and their thermal stability was determined. X-ray crystallography confirmed the occurrence of a pair of enantiomers in the crystal. Absolute configurations were assigned by comparing experimental and calculated vibrational/electronic circular dichroism spectra of isolated enantiomers. A distorted tesseract (four-dimensional hypercube) was used to visualize the calculated enantiomerization process, which requires the rotation around four chirality axes. Conformers of higher energy as well as several concurrent pathways of similar energies were revealed.

Chirbase : A Database Utilizing a Molecular Recognition Approach for Selection of a Chiral Chromatographic System

The direct resolution of enantiomers by high-performance liquid chromatography using chiral stationary phases is today one of the most powerful techniques employed in pharmaceutical, agrochemical, asymmetric synthesis and related fields. The CHIRBASE database was initially developed in 1988 on Chembase®. It now contains more than 30,000 separations of 10,000 compounds and has been proved to be a very efficient tool An interesting way of extending the current system is by the implementation of CHIRBASE into REACCS™ and ISIS™/Host systems (minicomputer or UNIX workstation). ISIS adds facilities in the searching procedures and provides a large range of chemical descriptors which can be used in similarity searching, and in structure activity studies. The database technique which is being developed links 3D searching techniques and molecular modeling.