Unnatural Cyclopeptide\nSynthesis via Cu-Catalyzed\n1,3-Dipolar Cycloaddition of Azomethine Ylides

Cyclic peptides are valued synthetic targets in organic\nand medicinal\nchemistry. Herein, we report an efficient strategy for the synthesis\nof unnatural cyclic peptides via the Cu-catalyzed 1,3-dipolar cycloaddition\nof azomethylene ylides. Linear precursors of different lengths and\nbearing diverse amino acids (26 examples) are shown to be compatible\nwith this method, affording good yields and complete <i>endo</i>-diastereoselectivities. Density functional theory (DFT) calculations\nsupport a stepwise mechanism in which Cu plays a key role in the preorganization\nof the reactants.