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

Abstract

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 ring-closing aminomethylamination of aminodienes with aminals via C–N bond metathesis, which provides rapid access to enantiomer-enriched 5- to 16-membered β-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. • Enantioselective migratory insertion of alkene to alkyl-palladium intermediates • Highly efficient synthesis of enantioenriched 5- to 16-membered N -heterocycles • Access to C-4 enantioenriched THIQs with excellent functional-group tolerance • First example of asymmetric C–N bond metathesis reaction Not only are N -heterocycles privileged structural motifs in natural alkaloids, but they are also widely utilized as key intermediates for the synthesis of pharmaceutical molecules and drug candidates. Efficient synthetic approaches toward optically active N -heterocycles, especially ones general for the construction of versatile ring systems, are of paramount importance. The enantioselective domino Heck cyclization/cross-coupling reactions are a powerful approach to functionalized chiral heterocyclic compounds. However, the use of sp 3 C-hybridized alkyl electrophiles in such sequential transformations remains largely elusive. Herein, with modified Trost-type ligands, we report an efficient Pd-catalyzed asymmetric ring-closing reaction that gives access to enantiomer-enriched 5- to 16-membered N -heterocycles. A Pd-catalyzed highly enantioselective ring-closing aminomethylamination of aminodienes with aminals via C–N bond metathesis has been established; it provides rapid and unique access to a wide range of optically active N -heterocycles bearing 5- to 16-membered rings in good to excellent enantioselectivities (up to 98% ee) under mild conditions with the use of modified Trost ligands. Mechanistically, the reaction goes through a challenging and less known stereoselective migratory insertion of alkene into an alkyl-Pd species. This success represents the first time that the Trost ligand has been used to induce asymmetry in Heck reactions.