Here we describe our studies on solvent-dependent enantiodivergent Mannich-type reactions utilizing conformationally flexible guanidine/bisthiourea organocatalyst (S,S)-1. Our mechanistic investigations revealed that the stereo-determining steps in both the (R)- and (S)-selective Mannich-type reactions are governed by the cooperative effect of guanidine and thiourea in the inherently monomeric structure of (S,S)-1. Based on the mechanistic similarity between the (R)- and (S)-selective Mannich-type reactions, we discovered that (S,S)-1-catalyzed reactions show unique reversibility in mixed solvent systems. We highlight the development of sequential enantiodivergent organocatalysis using (S,S)-1, which allows enantio-switching with single-flask operation and high in situ tunability.
