Enantioselective Synthesis of Medium-Sized Rings via a General Palladium-Catalyzed (6 + <i>n</i> ) Annulation Platform

The catalytic construction of medium-sized rings, particularly in an enantioselective manner, remains a significant challenge due to inherent entropic penalties and stereocontrol issues, yet it is an area of great interest. Herein, we disclose the development of a general (6 + <i>n</i>) annulation strategy leveraging 2-(4<i>H</i>-benzo[<i>d</i>][1,3]oxazin-4-yl)acrylates as versatile precursors for the efficient assembly of medium-sized rings. Through palladium-catalyzed formal (6 + 5) and (6 + 3) cycloadditions with vinylethylene carbonates (VECs) or trimethylenemethanes (TMMs), we have successfully achieved the regioselective construction of 11- and 9-membered heterocycles, respectively. Of particular note, the enantioselective (6 + 3) annulation, facilitated by rational chiral ligand design, afforded enantioenriched 9-membered heterocycles (up to 75% yield and 93% ee). Featuring readily available starting materials, structural modularity, and mild reaction conditions, this methodology represents a robust platform for accessing synthetically valuable medium-sized ring systems, including their enantioselective variants, thereby addressing a long-standing limitation in organic synthesis.