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

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 their¹H NMR spectra. The protocol consists of the following: (i) preparation of each of the diastereomeric S- and R-MTPA esters and (ii) comparative (∆δ^SR) analysis of the¹H 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 ∆δ^SR 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.