Cobalt-catalyzed alkyne silylamidation unlocks <i>Z</i> -selective unnatural dehydropeptides synthesis

Due to their unique conformational properties and activities, dehydropeptides play a pivotal role in the fields of biological and medicinal chemistry. Yet, the synthesis of unnatural dehydropeptides still suffers from cumbersome steps and less generality, in particular, with rather limited structural diversity. Herein, a modular cobalt-catalyzed 1,2-silylamidation of non-conjugated alkynes with dioxazolones and silylzinc pivalates is disclosed, thus affording structurally diverse non-canonical sila-dehydropeptides with complete control of regio- and stereoselectivity. Notably, the reaction enables efficient peptide ligation between peptide-containing dioxazolones and peptide-containing alkynes in a <i>Z</i>/<i>E</i>-stereoselective and diastereoretentive manner. Moreover, broad substrate scope, outstanding functional group compatibility, as well as facile late-stage diversifications of pharmaceutically active molecules substantiate the synthetic value of this method.