MTPA vs MPA in the Determination of the Absolute Configuration of Chiral Alcohols by ¹H NMR

Abstract

Molecular mechanics, semiempirical (AM1), and aromatic shielding effect calculations and DNMR experiments show that MTPA esters are constituted by three main conformers in close populations due to restricted rotation around the Cα−CO and Cα−Ph bonds. The small predominance of one conformer and the simultaneous operation of aromatic shielding and deshielding effects on the alcohol part, due to the orientation of the Ph ring, explains the small ΔδRS values observed. A graphical description of the aromatic magnetic field distribution in the conformers of MTPA and MPA esters and its use to correlate the average chemical shifts with the absolute stereochemistry is presented. Comparison of MTPA with MPA (two conformers) as reagents for determination by NMR of absolute stereochemistry indicates that MTPA esters are intrinsically limited by the greater complexity of their conformational composition, yield very small ΔδRS values, and are consequently less reliable for configurations assignment of chiral alcohols than MPA or other arylmethoxyacetic acid reagents such as (R)- and (S)-α-methoxy-α-(9-anthryl)acetic acids.