An NMR strategy for determination of configuration of remote stereogenic centers: 3-methylcarboxylic acids

A method has been developed for determining the absolute configuration of carboxylic acids bearing a methyl substituent at C(3). A series of 1-arylethylamide derivatives of such acids was prepared in which both the amine- and acid-derived portions were of known configuration. Diagnostic chemical shift differences (Δδ's) were identified for various proton resonances in each pair of diastereomeric amides and a new method was established based on the observed trends. A conformational model (supported by computational calculations) consistent with the observed differential shielding effects is offered. This approach represents a general strategy that can be adapted to other substructures.