Catalytic 1,2-Radical Acyloxy Migration: A Strategy to Access Novel Chemical Space and Reaction Profiles

ConspectusRadical migration represents a powerful strategy for reaction discovery and development in organic synthesis, offering access to unprecedented functional molecules and chemical space. In this Account, we describe our contributions to the field, particularly focusing on 1,2-radical acyloxy migration (RAM), a process involving the transposition of a radical and an acyloxy group. We highlight its application in carbohydrate modification and allyl carboxylate trifunctionalization, demonstrating how this reactivity enables the streamlined synthesis of novel glycomimetics and facilitates selective 1,2,3-trifunctionalization of allyl carboxylates. These advances establish 1,2-RAM as a versatile platform for catalytic radical transformations, unlocking new opportunities in reaction development and functional molecule design.Our approach leverages excited-state palladium and ground-state nickel catalysis to modify carbohydrates, specifically at the C2 position. This strategy enables C2-deoxy-hydrogenation, deuteration, iodination, alkenylation, allylation, ketonylation, and arylation reactions, providing direct access to unprecedented glycomimetics. These transformations streamline the synthesis of structurally diverse glycomimetics, facilitating the discovery and development of carbohydrate-based functional molecules. Furthermore, the mild reaction conditions and high functional group tolerance of these catalytic systems make them particularly attractive for late-stage functionalization, broadening their applicability in complex molecule synthesis.Beyond carbohydrates, we have extended 1,2-RAM reactivity to achieve unprecedented 1,2,3-trifunctionalization of allyl carboxylates. By employing excited-state phosphine catalysis, we demonstrate a 1,3-carbobromination reaction accompanied by an acyloxy shift. This proof-of-concept study lays the foundation for developing a broader range of 1,2,3-trifunctionalization reactions, effectively transforming allyl carboxylates into substituted isopropyl carboxylate donors. This advancement expands the synthetic utility of allyl carboxylates, enabling the rapid construction of structurally diverse molecular scaffolds.In summary, the 1,2-RAM reactivity opens a new avenue for reaction discovery and development, granting access to new functional molecules and chemical space. The mild conditions, broad functional group compatibility, and unique reactivity of this approach make it a valuable tool for chemical synthesis. We anticipate that merging 1,2-RAM with other catalytic platforms will further advance bond disconnection strategies, provide access to new functional molecules, and expand the frontiers of chemical synthesis.