Atropisomeric lactam chemistry: catalytic enantioselective synthesis, application to asymmetric enolate chemistry and synthesis of key intermediates for NET inhibitors

Abstract In the presence of ( R )-SEGPHOS-Pd(OAc) 2 catalyst, the intramolecular N -arylation of ortho - tert -butyl-NH-anilides possessing an iodophenyl group proceeded in a highly enantioselective manner (89–98% ee) to give optically active atropisomeric lactams having an N–C chiral axis. MPLC purification of the enantio-enriched lactam products using an achiral silica gel column led to a further increase in the enantiomeric purity (>99% ee). The reaction of the lithium enolate prepared from the optically active atropisomeric lactam with various alkyl halides gave α-substituted and α,α-disubstituted lactam products with high diastereoselectivity. α-Alkylated lactam derivatives were efficiently converted to key intermediates for the synthesis of an NET inhibitor.