Multicomponent coupling and macrocyclization enabled by Rh(III)-catalyzed dual C–H activation: Macrocyclic oxime inhibitor of influenza H1N1

Abstract

•Rh(III)-catalyzed dual C–H multicomponent coupling and macrocyclization •Biomimetic modularization strategy promotes rapid discovery of lead compounds •Dual C–H macrocyclization is compatible with various reaction coupling •Access to novel macrocyclic oxime inhibitor of influenza H1N1 Herein, we describe a practical streamlined two-component dual C–H activation macrocyclization strategy entailing an in situ-generated directing group. The reaction mode is based on Rh(III)-catalyzed three-component coupling involving cascade C(sp3)–H/C(sp2)–H bond dual activation. The process is facilitated by readily obtainable amidation reagents, namely, aryl-substituted 1,4,2-dioxazol-5-ones, which can be transformed into amide directing groups via a rhodium-nitrene intermediate. DFT calculations revealed that the C–N versus C–C bond formation chemoselectivity was highly controllable. The synthetic utility of this multicomponent reaction is highlighted by the late-stage C–H functionalization of various complex natural macrocyclic compounds, triterpenoids, biologically active molecules, and drugs. Moreover, the developed method enables the expedient and diversified synthesis of complex macrolactams, and phenotypic screening indicated several unique oxime-containing macrolactams accessed via this strategy showing potent anti-Flu (H1N1) activity with no overt cytotoxic effects. Herein, we describe a practical streamlined two-component dual C–H activation macrocyclization strategy entailing an in situ-generated directing group. The reaction mode is based on Rh(III)-catalyzed three-component coupling involving cascade C(sp3)–H/C(sp2)–H bond dual activation. The process is facilitated by readily obtainable amidation reagents, namely, aryl-substituted 1,4,2-dioxazol-5-ones, which can be transformed into amide directing groups via a rhodium-nitrene intermediate. DFT calculations revealed that the C–N versus C–C bond formation chemoselectivity was highly controllable. The synthetic utility of this multicomponent reaction is highlighted by the late-stage C–H functionalization of various complex natural macrocyclic compounds, triterpenoids, biologically active molecules, and drugs. Moreover, the developed method enables the expedient and diversified synthesis of complex macrolactams, and phenotypic screening indicated several unique oxime-containing macrolactams accessed via this strategy showing potent anti-Flu (H1N1) activity with no overt cytotoxic effects.