Chiral phosphoric acid catalyzed intermolecular [4 + 2] cycloaddition for the synthesis of chiral azomethine imines: mechanism and stereochemical model

Abstract

Azomethine imines are an outstanding class of 1,3-dipolar species that are important synthetic building blocks for di-nitrogenated heterocycles. Despite their significance, the current synthesis methods for chiral azomethine imines rely on kinetic resolution and remain underdeveloped. Here, we report a computational study of chiral phosphoric acid (CPA) catalyzed intermolecular [4 + 2] cycloaddition between methyl diazoacetate and dienes. Our calculations revealed that a diene bearing an electron-donating group facilitates this [4 + 2] cycloaddition and a narrow chiral pocket of CPA is advantageous for achieving excellent enantioselectivity. The fine-tuned interactions between substrates and the substituents on the sidearms of CPA catalysts are indispensable for achieving excellent enantioselectivity. Through comprehensive mechanistic insights, we have designed a synthetic route for chiral azomethine imines, which holds great potential in organic and medicinal chemistry.