Enantioselective ring-closing aminomethylamination of aminodienes enabled by modified Trost ligands

Optically active N-heterocycles are important building blocks in organic synthesis and medicinal chemistry. However, an enantioselective synthetic protocol with excellent compatibility across the normal-sized, medium-sized, and macro-sized rings remains largely rare. We herein report a Pd-catalyzed highly enantioselective ringclosing aminomethylamination of aminodienes with aminals via CN bond metathesis, which provides rapid access to enantiomer- enriched 5- to 16- membered b- aminoallylated N-heterocycles (up to 98% ee) under mild conditions with the use of modified Trost ligands. In addition, the enantioselective synthesis of chiral tetrahydroisoquinolines (THIQs) has also been realized by this method. The unity of this method has been demonstrated by the formal synthesis of the natural product (+)-(8S,13R)-cyclocelabenzine. Mechanistically, the reaction goes through a challenging and less known stereoselective migratory insertion of alkene into an alkyl-Pd species. We also conducted a detailed analysis of the stereochemical outcome of the reaction, which provided an intriguing view of enantioselection.

Automated summary

Optically active N-heterocycles are important in organic synthesis and medicinal chemistry. However, enantioselective synthetic protocols for different ring sizes are rare. This study reports a Pd-catalyzed enantioselective ring-closing aminomethylamination of aminodienes with aminals, producing enantiomer-enriched N-heterocycles with high ee values. The method also enables the synthesis of chiral tetrahydroisoquinolines and has potential for the formal synthesis of natural products.