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Mosher ester analysis for the determination of absolute configuration of stereogenic (chiral) carbinol carbons

Abstract

This protocol details the most commonly used nuclear magnetic resonance (NMR)-based method for deducing the configuration of otherwise unknown stereogenic, secondary carbinol (alcohol) centers (R1R2CHOH (or the analogous amines where OH is replaced by NH2)). This 'Mosher ester analysis' relies on the fact that the protons in diastereomeric α-methoxy-α-trifluoromethylphenylacetic acid (MTPA) esters (i.e., those derived from conjugation of the carbinol under interrogation with MTPA) display different arrays of chemical shifts (δs) in their 1H NMR spectra. The protocol consists of the following: (i) preparation of each of the diastereomeric S- and R-MTPA esters and (ii) comparative (ΔδSR) analysis of the 1H NMR spectral data of these two esters. By analyzing the sign of the difference in chemical shifts for a number of analogous pairs of protons (the set of ΔδSR values) in the diastereomeric esters (or amides), the absolute configuration of the original carbinol (or amino) stereocenter can be reliably deduced. A typical Mosher ester analysis requires approximately 4–6 h of active effort over a 1- to 2-d period.

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Figure 1
Figure 2: Commonly encountered representations of the conformations (rotational isomers) used for the analysis of each of the diastereomeric MTPA esters 4S and 4R.
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Hoye, T., Jeffrey, C. & Shao, F. Mosher ester analysis for the determination of absolute configuration of stereogenic (chiral) carbinol carbons. Nat Protoc 2, 2451–2458 (2007). https://doi.org/10.1038/nprot.2007.354

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