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

摘要

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 alpha-substituted and alpha,alpha-disubstituted lactam products with high diastereoselectivity. alpha-Alkylated lactam derivatives were efficiently converted to key intermediates for the synthesis of an NET inhibitor.