Cooperative Noncovalent Interactions Controlling Amine-Catalyzed Aldol Reaction Pathways Catalyzed by the Bifunctional Amino Quaternary Phosphonium Ion

Members of a new class of bifunctional amino quaternary
phosphonium
salts have been synthesized and utilized as catalysts in aldol condensation
reactions, as demonstrated herein. These secondary amines feature
a phosphonium ion connected by a carbon chain, enabling the quaternary
phosphonium ion to engage in distinct cooperative noncovalent interactions.
These interactions work in tandem to stabilize different transition
state complexes, exclusively controlling competing amine-catalyzed
aldol pathways via the Mannich mechanism. Comprehensive mechanistic
investigations were conducted through theoretical calculations. This
study uncovers a proximity-driven catalytic mechanism in which the
distance between the N and the P+ of the bifunctional catalyst
emerges as a critical factor determining catalytic efficacy. The method
has been demonstrated through its application to the total synthesis
of several bioactive natural products.