Transition Metal-Catalyzed Diastereo-, Enantio-, and Z/E-Selective Allylation and Alkylation of Azatrienes for the Preparation of Chiral Amine Derivatives

Abstract

The stereoselective synthesis and derivatization of chiral allylic amines have attracted extensive attention in synthetic chemistry, not only because this motif is prevalent in pharmacologically active compounds but also due to its importance as a structural element in chiral ligands and functional molecules. Chiral allylic amines bearing two contiguous stereogenic centers represent particularly valuable building blocks, but are challenging to prepare, as their synthesis requires precise control over multiple stereochemical features.To address these challenges, this dissertation describes the development of transition-metal hydride–catalyzed reductive coupling reactions of azatrienes that enable highly stereoselective construction of chiral allylic amine derivatives. Using copper hydride catalysis, enantio- and diastereoselective syntheses of chiral allylic amino alcohols were achieved with broad functional group tolerance and high levels of efficiency and selectivity. Subsequently, cobalt- and nickel-hydride catalytic systems were investigated for the synthesis of chiral allylic amines via reductive coupling with alkyl electrophiles, demonstrating the feasibility of extending azatriene reactivity to radical-based catalytic system, while also revealing challenges associated with achieving effective stereocontrol. In addition, density functional theory (DFT) calculations were performed to gain mechanistic insight into the copper-catalyzed processes for both ketone and imine couplings with different copper-based catalysts. The computed energy profiles suggest that azatriene hydrocupration is followed by a stereocontrolled C–C bond-forming event, providing a mechanistic rationale for the experimentally observed regio- and stereochemical outcomes.