Enantiomeric impurities in chiral catalysts, auxiliaries, and synthons used in enantioselective syntheses. Part 5

Abstract

The enantiomeric excess of chiral starting materials is one of the important factors determining the enantiopurity of products in asymmetric synthesis. Fifty‐one commercially available chiral reagents used as building blocks, catalysts, and auxiliaries in various enantioselective syntheses were assayed for their enantiomeric purity. The test results were classified within five impurities level (ie, <0.01%, 0.01%‐0.1%, 0.1%‐1%, 1%‐10%, >10%). Previously from 1998 to 2013, several reports have been published on the enantiomeric composition of more than 300 chiral reagents. This series of papers is necessitated by the fact that new reagents are forthcoming and that the enantiomeric purity of the same reagent can vary from batch to batch and/or from supplier to supplier. This report presents chiral liquid chromatography (LC) and gas chromatography (GC) methods to separate enantiomers of chiral compounds and evaluate their enantiomeric purities. The accurate and efficient LC analysis was done using newly introduced superficially porous particle (SPP 2.7 μm) based chiral stationary phases (TeicoShell, VancoShell, LarihcShell‐P, and NicoShell).

Total synthesis of haploscleridamine, villagorgin A and an approach towards lissoclin C

“…Since we had access to both racemic and nonracemic, HPLC analysis was used to assess when racemization occurred (for details see ESI †). [44][45][46] It was quickly apparent that it was at a very early stage in the synthesis, at the reduction of the methyl ester to the corresponding aldehyde using DIBAL-H.…”

Recent advances in the field of chiral crystallization

“…Asymmetric synthesis requires chiral catalysts, auxiliaries or synthons, and complex reaction conditions. [3][4][5][6][7][8] Even then, a high enantiomeric excess product is not necessarily obtained. However, if the product is formed from a prochiral material in a reversible reaction, then the reversibility of that reaction creates an easy pathway to deracemization, as shown in Figure 6.…”

“…These are then crystallized, and deracemization is utilized instead of asymmetric synthesis. Asymmetric synthesis requires chiral catalysts, auxiliaries or synthons, and complex reaction conditions 3–8 . Even then, a high enantiomeric excess product is not necessarily obtained.…”

“…Further, in 2019, 13 of 24 small molecule drugs approved by the FDA contained residues or derivatives of amino acids 2 . Synthesis of enantiomerically pure drugs usually results in chiral impurities even with the use of asymmetric synthesis or enzymatic synthesis 3–8 . There are four basic methods for obtaining single enantiomers, namely, chiral separations, asymmetric synthesis, biological production or intervention (either by an organism or an enzyme from an organism), and chiral crystallization 3 .…”

Symmetrization of Peaks in Chiral Chromatography with an Area-Invariant Resolution Enhancement Method

“…Most enantiomeric separations produce tailing peaks, but fronting or “Eiffel-tower” shapes also are possible in some rare cases. , In well-optimized instruments, peak asymmetry can still originate from tubing, frits, detector geometry, and the packed bed structure . An asymmetric peak is problematic for the following reasons: (i) it is challenging to accurately integrate it for area extraction in an enantiomeric purity analysis; (ii) in cases of disproportionate enantiomeric ratios, the low-concentration enantiomer’s peak often appears on the trailing edge of the higher-concentration enantiomer’s peak − (in limited cases inverted chirality columns approach can be used); and (iii) the presence of noise further obscures the weak trailing edge of the signal.…”