Stepwise Approach toward First Generation Nonenzymatic Hydrolases

The synthesis and reactivity study of a first generation serine protease mimic is described. Central in the design stands the possibility of stabilization of the transition state by an amino triol such as 8t. En route to 8t, a series of amino alcohols (4-8) was obtained, the reactivity of which was studied toward esterification by acetylimidazole (AcIm) and by p-nitro-2,2,2-trifluoroacetanilide (PNTFA). Interesting reactivity differences were observed between the cis- and the trans-series, especially between 7c and 7t (AcIm), and between 8c and 8t (PNTFA). In both cases the results are explained by invoking extra stabilization of the tetrahedral oxyanion.