Lewis Acid-Catalyzed Enantioselective (4 + 3)/Thia-(3 + 2) Cycloadditions of Bicyclobutanes and Enaminothiones: Catalyst-Directed Divergent Synthesis of Bridged Sulfur Heterocycles

Despite significant advancements in the synthesis of sulfur heterocycles and bridged bicyclo[n.1.1]-bioisosteres, the straightforward construction of sulfur-containing bridged bicyclic molecules, particularly in the enantiopure form, continues to pose a considerable challenge in exploring new chemical spaces for drug discovery. We herein report regiodivergent catalyst-controlled Lewis acid-catalyzed cycloaddition reactions between bicyclobutanes (BCBs) and enaminothiones. Using a zinc catalyst, the first thia-(3 + 2) cycloaddition of BCBs was achieved with good regioselectivity and broad functional group tolerance. In contrast, reactions using a scandium Lewis acid catalyst produced valuable thiabicyclo[4.1.1]octanes (thia-BCOs) in good yield through (4 + 3) cycloaddition reactions with the same starting materials. Notably, an unprecedented Lewis acid-catalyzed asymmetric (4 + 3) cycloaddition reaction involving BCBs was explored, thereby expanding the chemical space of enantiopure BCO scaffolds. Experimental investigations coupled with density functional theory calculations provide valuable insights into the reaction pathway and elucidate the origins of enantioselectivity in the current (4 + 3) cycloaddition reaction.