An enantioselective four-component reaction via assembling two reaction intermediates

Abstract Reaction intermediate is a key molecular entity that has been used in explaining how the starting materials converts into the final products in the reaction, and it is always unstable, high-reactive, and short-lived. Extensive efforts have been devoted in identifying and characterizing such species via advanced physico-chemical analytical techniques. As an appealing alternative, trapping experiment with additional chemicals represents an efficient and powerful tool in this field. More importantly, this trapping strategy opens an opportunity to discovering new multicomponent reactions, and theoretically, novel multicomponent reactions with a ‘higher order’ variant could be developed via assembling two reaction intermediates. Herein, we report a highly diastereoselective and enantioselective four-component reactions (containing alcohols, diazoesters, enamines/indoles and aldehydes) that involve the coupling of in situ generated two intermediates (iminium and enol). These four-component reactions proceed under mild reaction conditions and show high functional group tolerance as well as broad substrate scope, affording the desired four-component coupling products (> 100 examples) with high efficiency. Notably, present four-component reaction is well compatible with a number of classic MCRs. A plausible mechanism with cross interception of the two active intermediates is also proposed based on a set of experimental and computational analyses. We hope that this strategy provides a new avenue for the development of novel higher-order MCRs in future research.