Temperature-Controlled Divergent Asymmetric Synthesis Of Indole-Based Medium-Sized Heterocycles

Medium-sized rings(MSRs)are ubiquitous in numerous natural products,especially molecules featuring an indole-based MSR,always exhibit significant biological activities.Literature studies have shown that the synthesis of MSRs compounds have problems such as cross-loop interaction,susceptibility to intermolecular reactions,and stereoselectivity cannot be well controlled.Therefore,it is urgent to develop simple,efficient,green-friendly synthesis methods to build this core skeleton.Vinylethylene carbonates(VECs)are important synthetic,and since Yoshida first used it to participate in palladium-catalyzed decarboxylation in 1987,VECs have been widely used in a variety of catalytic systems and have shown unique advantages in constructing various chiral center ring skeletons.However,among the reported catalytic reactions,few can achieve different cyclization reactions at the same time,and the chirality can not be well controlled.Therefore,in this paper,we report a temperature-controlled catalytic strategy for the divergent synthesis of different types of MSRs starting from the same substrate set.Firstly,VECs were decarboxylated to form π-allyl palladium intermediate by using transition metal palladium and planar chiral bisphosphine ligand as catalysis.Then,π-allyl palladium intermediate carried out [5 + 4] cyclization reaction with indole azadiene substrate,affording an indole-based aza-nine-membered ring with high yields(up to 99%)and excellent enantioselectivities(up to >99:1 er).Subsequently,by increasing the reaction temperature,spiro seven-membered ring indole products with excellent enantioselectivities(up to 99:1 er)were obtained,and the structure of these products could be further diversified by various conversions.In addition,we further investigated the reaction mechanism through controlled experiments and DFT calculations,which is more helpful to understand the observed regional and enantioselectivities of palladium-catalyzed [5 + n] cyclization.