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Abstract: A general protocol for the design of successful chiral derivatizing agents (CDAs) for the NMR assignment of absolute configuration is described. The design of the most efficient arylalkoxyacetic acid reagent for the assignment of chiral thiols is taken as example. The importance of theoretical calculations in the discovery of the conformational preference of modelled arylmethoxyacetic acid (AMAA) thioesters is stressed, as well as NMR experiments to confirm the conformations predicted for the different CDAs and to select for synthesis the most adequate for that substrate. The modification of the aryl moiety of the AMAA system has shown not to provide especially good CDAs while the introduction of a sterically hindered tert-BuO group results in a more appropriate conformation leading to 2-naphtyl-tert-butoxyacetic acid (2-NTBA) as the most efficient CDA for thiols. [Copyright &y& Elsevier]