MTPA (Mosher) Amides of Cyclic Secondary Amines: Conformational Aspects and a Useful Method for Assignment of Amine Configuration

Abstract

Mosher's MTPA (methoxy(trifluoromethyl)phenylacetyl) technology is a well-known tool used to determine the absolute configuration of chiral alcohols and primary amines. The technique now has been extended to include secondary amines. A number of MTPA amide derivatives have been prepared from cyclic amines. Both piperidines and pyrrolidines have been studied. A detailed discussion of the conformational issues associated with both amide bond rotation and ring flipping is presented. The observed 1H NMR chemical shifts are correlated into a model that allows unambiguous determination of absolute configuration of cyclic secondary amines. While the presence of amide rotamers must be accounted for in the analysis, this is a relatively straightforward process that follows from detailed evaluation of coupling constant data and is often aided by COSY. The exceptionally large Δδ values observed for these MTPA amides make this a valuable and reliable method for assigning amine configuration.