The Integral Role of Conjugate Acids in Brønsted Base-Catalyzed Regiodivergent Synthesis

Catalyst-controlled diversity-oriented synthesis (CatDOS) is an important research area for expanding molecular complexities and achieving high atomic economics. Many regiodivergent syntheses have been achieved through metal catalysis, covalent organocatalysis, and non-covalent organocatalysis by controlling the molecular recognition function of the catalysts. However, the development of regiodivergent CatDOS through Brønsted base organocatalysis was relatively less developed than others so far. Numerous studies about Brønsted base organocatalysis have demonstrated the powerful molecular recognition abilities of their cationic conjugate acids mainly in controlling the stereoselectivity instead of the regioselectivity. This concept review aims to conceptualize a new perspective to consider the potential role of the cationic conjugate acid of Brønsted bases for regiodivergent CatDOS. Recent representative examples are selected to demonstrate the potential of cationic conjugate acids in site-selectivity control in single bond and multiple bonds formation reactions. The summarized results show that even the conjugate acid of common tertiary amines, protic ammonium ions, could affect the regioselectivity in the early- or late-stage step during multiple bonds formation after initial deprotonation. The results also suggested that the properties and ion-pairing interactions of conjugate acid could be more important than the basicity of the base in controlling regioselectivity. Perspectives and hypotheses for explaining the mechanism of regioselectivity are also included in this review.