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

Abstract

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 Rh2(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 π-π stackings between N-(anthrancen-9-ylmethyl) imines and Rh2(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 β-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.