Rh2(Ph3COO)3(OAc)/Chiral Phosphoric Acid Cocatalyzed N-Alkyl Imines-Involved Multicomponent Reactions Yielding N-(Anthrancen-9-ylmethyl) Isoserines as Drug Intermediates

N-(Anthrancen-9-ylmethyl) isoserines are useful drug intermediates but short for efficient synthesis. We herein report the synthesis of N-(anthrancen-9-ylmethyl) isoserines via a Rh-2(Ph3COO)(3)(OAc) and chiral phosphoric acid (CPA) synergistically catalyzed multicomponent reaction (MCR) of N-alkyl imines, alcohols, and diazoesters. The method representing the first example of N-alkyl imines-involved MCR is featured by high atom-economy, high diastereo-and enantioselectivities, and broad substrate scope. DFT calculations on the mechanism of the MCR reveals that the hydrophobic interactions and pi-pi stackings between N-(anthrancen-9-ylmethyl) imines and Rh-2(Ph3COO)(3)(OAc)/CPA cocatalyst is essential to the reactivity and stereocontrol. The synthetic applications of the MCR products include the semisynthesis of paclitaxel, its alkyne-tagged derivative, and beta-lactam as an anticancer agent overcoming paclitaxel-resistance. We expect this work to shed light on the development of new N-alkyl imines-involved reactions and on the synthesis of drugs with isoserines as intermediates.

Automated summary

This study reports a method for synthesizing N-(anthrancen-9-ylmethyl) isoserines using a catalyst and chiral phosphoric acid in a multicomponent reaction. The method is efficient, selective, and applicable to a wide range of substrates, making it suitable for synthesizing drug intermediates.