Enantioselective Synthesis of Six-Membered Lactams via Intramolecular Aza-Heck Reactions

• Gavin Hansen, Chemistry, University of Delaware

• Laura Alonso, Chemistry, University of Delaware

Nitrogen heterocycles are ubiquitous in natural products, making methods for their efficient and stereoselective synthesis highly desirable. Recently, reactions involving electrophilic nitrogen have garnered significant attention due to their unique reactivity, enabling mild syntheses of complex structures that would otherwise require lengthy linear sequences. Prior research by the Don Watson group pioneered this area by enabling the formation of five-membered lactams via intramolecular Aza-Heck chemistry. However, the enantioselective synthesis of larger lactams has remained largely inaccessible using this approach. Building on an initial racemic six membered hit, this study seeks to expand the scope of enantioenriched products available through intramolecular Aza-Heck lactamization. Making use of the University of Delaware HTE center and its extensive library of chiral ligands, a wide range of conditions was screened to enable enantioselective lactamization. Additionally, a variety of substrates bearing diverse structural and electronic characteristics were synthesized and evaluated under the optimized conditions to elucidate trends in reactivity and enantioselectivity. These insights aim to develop powerful tools for the mild and stereoselective formation of nitrogen heterocycles.