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Abstract:
This work describes the development of a novel enantioselective activation mode for carboxylic acids via self-assembly organocatalysis. In the first part, the heterodimerization between sterically congested chiral phosphoric acid catalysts and carboxylic acids is presented. Upon association, an exceptionally synergistic effect is observed: the acidity of the catalyst is enhanced and the nucleophilicity of the carboxylic acid is increased. Explorations on this catalytic system allowed to unlock the first enantioselective ring openings of aziridines and epoxides to 1,2-diols, 1,2-aminoalcohols and 1,2-thioalcohols in Brønsted acid catalysis. An unusual reaction mechanism was harnessed, in which the phosphoric acid primarily establishes an interaction with the nucleophile rather than with the electrophile. This apparent change of polarity of the catalytic cycle allowed to effectively override the instability of the acid organocatalyst towards an alkylative deactivation in the presence of highly reactive electrophiles. Thorough mechanistic investigations, including theoretical analysis on the heterodimeric species and kinetic studies on the catalytic cycle were conducted in order to allow the detailed codification of this new reaction mode.
