Synthetic Application and Structural Elucidation of Axially Chiral Dicarboxylic Acid: Asymmetric Mannich-type Reaction with Diazoacetate, (Diazomethyl)phosphonate, and (Diazomethyl)sulfone

Abstract

The past decade has witnessed the burgeoning research fields of chiral Brønsted acid catalysis. However, carboxylic acids, arguably the most general acids in organic chemistry, have rarely been used as chiral Brønsted acid catalysts. In this context, we developed axially chiral dicarboxylic acid and evaluated its catalytic activity in asymmetric Mannich-type reaction of aromatic aldehyde-derived N-Boc imines and tert-butyl diazoacetate. To demonstrate the remarkable generality of this catalytic system, tert-butyl diazoacetate was replaced with its phosphorus and sulfur analogues, (diazomethyl)phosphonate and (diazomethyl)sulfone, by which synthetically valuable chiral β-amino phosphonates and β-amino sulfones could be obtained with high enantioselectivities under identical reaction conditions. X-ray crystallographic analysis of axially chiral dicarboxylic acid complexed with a pyridine derivative revealed its unique internal hydrogen bonding, a property that serves as a basis for its distinctive acidity and chiral scaffold.