Determination of Enantiomeric Excess in the High Enantiopurity Limit Using Chiral Tagging Rotational Spectroscopy

Abstract

Chiral tag rotational spectroscopy can be used for quantitative determination of the ratio of the two enantiomers of a chiral molecule. The strategy for chiral tag rotational spectroscopy is to convert the enantiomers of the analyte into diastereomers through non-covalent attachment of a small, chiral tag molecule. The analyte enantiomer ratio, which is used to determine the enantiomeric excess (EE), is determined by comparing the transition intensities of rotational transitions for the homochiral and heterochiral complexes when both a racemic and enantiopure tag sample is used. A calibration curve for EE determination of 3-methylcyclohexanone tagged with 3-butyn-2-ol will be presented. The role that intensity fluctuations in back-to-back measurements of the rotational spectra of the chiral tag complexes play in determining the EE measurement accuracy will be described. In applications to pharmaceutical chemistry the main need is the ability make quantitative EE determinations in the high enantiopurity limit of the analyte. This requirement poses challenges for chiral tag rotational spectroscopy from both the measurement sensitivity and the availability of high enantiopurity tag samples. Two analysis methods for high EE measurements will be discussed. In one case, the enantioimpurity detection limit is decreased by the co-adding of multiple rotational transitions of the homochiral and heterochiral tag complex. The second strategy uses a lower enantioimpurity tag to speed the EE determination of high enantioimpurity samples. In this case, the ability to accurately determine the tag EE is crucial and the functional dependence of EE measurement precision in chiral tag rotational spectroscopy provides the limit on measurement accuracy that can be achieved.

Conformational Landscape, Chirality Recognition and Chiral Analyses: Rotational Spectroscopy of Tetrahydro‐2‐Furoic Acid⋅⋅⋅Propylene Oxide Conformers

“…The standard deviations of the experimental ee values obtained decrease as the ee values increases. A similar decreasing trend of the standard deviations has been reported by Pate and co‐workers [41,42] …”

“…Here we selected transition pairs of the most abundant homo‐/heterochiral diastereomers, i. e. homochiral I (v_c) and heterochiral I (v_d). The ee tag of PO value was taken to be 99.8 % as previously reported [41,42] . The results are demonstrated in Figure 5 in the form of histograms and the transitions and their intensities used in the analyses are summarized in Table S9, Supporting Information.…”

“…The ee tag of PO value was taken to be 99.8 % as previously reported. [41,42] The results are demonstrated in Figure 5 in the form of histograms and the transitions and their intensities used in the analyses are summarized in Table S9, Supporting Information. The vertical axis represents the number of transition pairs and the horizontal axis is the ee of sample.…”

“…A similar decreasing trend of the standard deviations has been reported by Pate and coworkers. [41,42] There are several distinctive advantages of chiral-tag CP-FTMW spectroscopy in comparison to some other commonly used chiral analysis tools, such as the NMR chiral shift agent approach: [43,44] 1) It does not require a sample analyte of known ee as a reference. One can use any suitable tag sample with known ee.…”