A Sustainable Catalytic Enantioselective Synthesis of Norstatine Derivatives

Norstaine derivatives are of important value in pharmaceutic science. However, their catalytic asymmetric synthesis is rare. We developed a sustainalbe method via chiral phosphoric acid (CPA)-[Rh(OAc)2]2 co-catalyzed multi-component reactions (MCR) of diazoacetates with alcohol/water and imines. The method allows us to synthesize a library of 45 norstatines with excellent enanotioselectivites and broad substrate scope which includes anti-α-aryl-norstatines 11-1, anti-α-alkyl-norstatines 11-2, syn-α-hydro-norstatines 11-3 and syn-α-aryl-norstatines 11-4. The sustainablity of the method lies in the reliable scalability, improved safety, and reusable [Rh(OAc)2]2 catalyst. The synthetic value of norstatine derivatives was demonstrated by preparing oxazolinone 14, ezetimibe analogue 15, and taxol C-13 chain 16. Mechanistic study reveals the synergenetic catalysis of CPA and [Rh(OAc)2]2 is essential to maintain chemo- and enanatioselectivity. Control experiments support the mechanism where the reactions go through the trapping of hyper-reactive oxonium ylides with imines. Shortly, we report herein the sustainable catalytic enantioselective synthesis of both syn- and anti-norstatines derivatives. We believe the method might shed the light on the sustainable syntheis of norstatine derivative-based drug candiates.