One catalyst for both enantiomers: uncovering the inversion of enantioselectivity in cinchona-mediated desymmetrization of glutaric meso-anhydrides

A puzzling inversion of enantioselectivity dependent on catalyst loading was observed during the quinine-mediated desymmetrization of glutaric meso-anhydrides. This study presents the improvement of the catalytic path by the inclusion of carboxylic acid additives up to synthetically useful levels. The novel protocol utilizing 0.1 equiv of alkaloid and xanthene-9-carboxylic acid at room temperature (rt) was found comparable to the protocol requiring 1.1 equiv of alkaloid at −30 °C. Thus, by altering the protocol the same catalyst produces the opposite enantiomer. This occurrence was rationalized by an extensive computational study of the interactions governing the molecular complexes formed by quinine, methanol, 3-methylglutaric anhydride, and the acetic acid. It was found that in a quinine catalyzed reaction the alcohol and the anhydride were directly hydrogen bonded to the catalyst. On the other hand, in the reaction with additive the acid intercalates between the alcohol and quinine. Due to this insertion the alcohol approaches the anhydride from the opposite face, in agreement with the observed inversion of enantioselectivity