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

The purpose of this review is to highlight the necessity of conducting tests to gauge the magnitude of the self-disproportionation of enantiomers (SDE) phenomenon to ensure the veracity of reported enantiomeric excess (ee) values for scalemic samples obtained from enantioselective reactions, natural products isolation, etc. The SDE always occurs to some degree whenever any scalemic sample is subjected to physicochemical processes concomitant with the fractionation of the sample, thus leading to erroneous reporting of the true ee of the sample if due care is not taken to either preclude the effects of the SDE by measurement of the ee prior to the application of physicochemical processes, suppressing the SDE, or evaluating all obtained fractions of the sample. Or even avoiding fractionation altogether if possible. There is a clear necessity to conduct tests to assess the magnitude of the SDE for the processes applied to samples and the updated and improved recommendations described herein cover chromatography and processes involving gas-phase transformations such as evaporation or sublimation

Potentially Mistaking Enantiomers for Different Compounds Due to the Self-Induced Diastereomeric Anisochronism (SIDA) Phenomenon

The NMR phenomenon of self-induced diastereomeric anisochronism (SIDA) was observed with an alcohol and an ester. The alcohol exhibited large concentration-dependent chemical shifts (δ’s), which initially led us to erroneously consider whether two enantiomers were in fact atropisomers. This highlights a potential complication for the analysis of chiral compounds due to SIDA, namely the misidentification of enantiomers. A heterochiral association preference for the alcohol in CDCl3 was determined by the intermolecular nuclear Overhauser effect (NOE) and diffusion measurements, the same preference as found in the solid state. The ester revealed more subtle effects, but concentration-dependent δ’s, observation of intermolecular NOE’s, as well as distinct signals for the two enantiomers in a scalemic sample all indicated the formation of associates. Intermolecular NOE and diffusion measurements indicated that homochiral association is slightly preferred over heterochiral association in CDCl3, thus masking association for enantiopure and racemic samples of equal concentration. As observed with the alcohol, heterochiral association was preferred for the ester in the solid state. The potential problems that SIDA can cause are highlighted and constitute a warning: Due care should be taken with respect to conditions, particularly the concentration, when measuring NMR spectra of chiral compounds. Scalemic samples of both the alcohol and the ester were found to exhibit the self-disproportionation of enantiomers (SDE) phenomenon by preparative TLC, the first report of SDE by preparative TLC

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

2-(2-Fluoro-4-biphenyl) propionic acid (flurbiprofen), from the phenylalkanoic acid family of nonsteroidal anti-inflammatory drugs (NSAID’s), is currently on the pharmaceutical market as a racemate. This racemic compound was tested for its propensity to undergo the self-disproportionation of enantiomers (SDE) phenomenon by various forms of chromatography (SDEvC), such as routine gravity-driven column chromatography, medium-pressure liquid chromatography (MPLC), preparative thin-layer chromatography (PTLC), and size-exclusion chromatography (SEC), as well as by sublimation (SDEvS). Furthermore, examination by nuclear magnetic resonance (NMR) in various solvents found that flurbiprofen exhibited the phenomenon of self-induced diastereomeric anisochronism (SIDA). By measurement of the diffusion coefficient (D), the longitudinal relaxation time (T1), and the transverse relaxation time (T2) using NMR, as well as by electrospray ionization-mass spectrometry (ESI-MS) examinations, the preferred intermolecular association was found to be solvent dependent, e.g., heterochiral association was preferred in toluene, while homochiral association was preferred in more polar solvents. This study also attempted, unsuccessfully, to correlate the NMR measurements of flurbiprofen with chromatographic outcomes for the rationalization and prediction of chromatographic results based on NMR measurements. Because the intermolecular hydrogen bonding of the acid groups in flurbiprofen overwhelmingly predominates over other intermolecular interactions, flurbiprofen seemed to represent a good test case for this idea. The behavior of scalemic samples of flurbiprofen is important, as, although it is currently dispensed as a racemate, clinical applications of the R enantiomer have been investigated. SDEvC and SDEvS both have ramifications for the preparation, handling, and storage of enantioenriched flurbiprofen, and this concern applies to other chiral drugs as well.The authors gratefully acknowledge financial support from the Ministry of Science and Higher Education, Poland (grant no. 668, A.W.; grant no. 659, M.K.; and SMGR.RN.20.264, A.K.) and IKERBASQUE, the Basque Foundation for Science, Spain (V.A.S.)

Synthesis and structural investigation of the cyclochiral boron resorcinarenes obtained from L-amino acids and phenylboronic acid

Wzorek A, Mattay J, Iwanek W. Synthesis and structural investigation of the cyclochiral boron resorcinarenes obtained from L-amino acids and phenylboronic acid. Tetrahedron Asymmetry. 2012;23(3-4):271-277.A diastereoselective synthesis and structural investigation of novel boron derivatives of resorcinarenes from L-amino acids and phenylboronic acid is described. (C) 2012 Elsevier Ltd. All rights reserved

Diastereoselective synthesis of boron-derivatives of resorcinarenes from amino alcohols and triethylborane

Wzorek A, Mattay J, Iwanek W. Diastereoselective synthesis of boron-derivatives of resorcinarenes from amino alcohols and triethylborane. Tetrahedron Asymmetrie. 2007;18(7):815-820.A diastereoselective synthesis of novel boron derivatives of resorcinarenes from chiral amino alcohols and triethylborane is described. (c) 2007 Elsevier Ltd. All rights reserved

Synthesis and Structure of Tetratosyl Bora Derivatives of Resorcinarenes From L-Proline and L-Prolinol

Gawdzik B, Wzorek A, Mattay J, Iwanek W. Synthesis and Structure of Tetratosyl Bora Derivatives of Resorcinarenes From L-Proline and L-Prolinol. Organic Preparations and Procedures International. 2009;41(3):217-227

Can an Intermediate Rate of Nitrogen Inversion Affect Drug Efficacy?

Nitrogen-inversion rates and diffusion coefficients were measured using 1H NMR for 14 drug-like molecules. The slow nitrogen-inversion rates interconverting the enantiomers of these molecules lay within a postulated intermediate range in terms of their ability to bind to proteins bounded by diffusion constraints, potentially affecting the availability, hence efficacy, of these compounds if they were utilized as drugs. The postulated intermediate range is based on a capture-volume concept, whereby the nitrogen inversion during the time a ligand takes to pass through a volume surrounding the protein binding site, as calculated by the diffusion rate, determines if it will influence ligand binding to the protein. In the systems examined here, the measured nitrogen-inversion rates and the times required to traverse the capture volume differed by a few orders of magnitude. Potentially more consequential are intermediate nitrogen-inversion rates in epimeric cases—since the energies of the interconverting species are unequal, a heavy bias against the eutomer might occur. The implications of an intermediate nitrogen-inversion rate are significant for in silico drug design, drug efficacy, molecular modeling of drug–protein binding, pharmacokinetics, drug enantiomer evaluation, etc. Due consideration of the process should thus be taken into account for drug development directions and in vitro evaluation

Diastereoselective α‑Alkylation of Metallo Enamines Generated from N–C Axially Chiral Mebroqualone Derivatives

The reactions of various alkyl halides with the metallo enamines generated from racemic and optically pure N–C axially chiral mebroqualone derivatives were found to proceed with a synthetically attractive stereochemical outcome (up to 99% yield and up to dr = 26:1) allowing preparation of a structurally new type of pharmaceutically interesting compounds possessing elements of axial and central chirality