Chiral Brønsted Acid-Catalyzed Direct Mannich Reactions via Electrophilic Activation

TLDR

The stereochemical pathway was elucidated by synthesizing Boc-(S)-phenylglycine methylester, demonstrating the reaction’s enantioselective course. Phosphoric acid derivatives of general structure 1, especially 1d with 3,3′‑bisaryl substituents, act as highly effective Brønsted acid catalysts for the direct Mannich addition of acetyl acetone to N‑Boc‑protected arylimines, enabling mild synthesis of β‑aminoketones and diverse phenylglycine derivatives with excellent enantioselectivity.

Abstract

It was found that the phosphoric acid derivatives of general structure 1 serve as highly effective catalysts for the direct addition of acetyl acetone to N-Boc-protected arylimines. The beneficial effects of the 3,3'-bisaryl substituents of the catalysts on the enantioselectivity are greatly appreciated, and thus 1d functions as an excellent catalyst. The Brønsted acid-catalyzed direct Mannich reactions presented herein provide an attractive way to construct beta-aminoketones under extremely mild conditions. The stereochemical course of this reaction was established through the synthesis of Boc-(S)-phenylglycine methylester. The transformation thus demonstrated is applicable to a useful method for the synthesis of various phenylglycine derivatives.