Diverse C–H Activation in Asymmetric Multicomponent Coupling: Unlocking Anti-Parkinson Pseudo-Natural Macrocycles

The development of the multicomponent coupling of diverse C–H bonds to rapidly construct complex molecules has been highly appealing in the chemistry community. However, making such asymmetric processes is highly challenging due to the inherent difficulty in the activity and selectivity. Here, we describe a Rh(III)-catalyzed asymmetric multicomponent coupling involving diversified C(sp3)–H and C(sp2)–H activation. The asymmetric process is facilitated by a combined ex situ and in situ amide formed directing group-assisted chiral Rh(III) catalyst strategy. This strategy is distinctive for its capacity to expeditiously convert a variety of aliphatic C–H bonds of oximes, N-heterocycles, and C–H of aromatic compounds with maleimides in a highly chemo-selective and diversified chiral controllable manner. Moreover, the synthetic utility of this asymmetric multicomponent coupling is exemplified by the efficient and enantioselective synthesis of pseudo-natural macrocyclic oxime (S)-YWB0337. This compound demonstrated promising efficacy in the clearance of α-synuclein aggregates associated with Parkinson’s disease (PD).