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

J Org Chem. 2024 Oct 18;89(20):14851-14863. doi: 10.1021/acs.joc.4c01635. Epub 2024 Sep 29.

Abstract

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.