Direct Asymmetric α-C Conjugate Addition of Aminomethylphosphonate Enabled by Carbonyl/Iminium Double Organoactivation

As important bioisosteres of α-amino acids, chiral α-aminophosphonic acids exhibit broad bioactivities and are widely employed in pharmaceuticals. Direct asymmetric α-C conjugate addition of aminomethylphosphonate to α,β-unsaturated ketones is an intriguing strategy to make bioactive chiral phosphonic 1-pyrrolines. However, this transformation remains challenging due to the low α-C–H acidity of the aminomethylphosphonate, significant steric hindrance from the phosphonate moiety and interference by side reactions. In this work, we report the direct enantioselective α-C conjugate addition of NH₂-unprotected aminomethylphosphonate to α,β-unsaturated ketones, by applying an organo-organo double activation strategy that employs pyridoxal to activate aminomethylphosphonates into reactive carbanions, while concurrently using pyrrolidine to convert α,β-unsaturated ketones into active iminium species. Various chiral phosphonic 1-pyrrolines are synthesized in high yields with excellent diastereo- and enantioselectivity (up to 99% yield, > 20:1 dr, 99% ee). Furthermore, the methodology can be extended to a one-pot sequential synthesis of structurally diverse quaternary α-aminophosphonate derivatives.