Chemistry of Atropisomeric Quinazolinones Possessing a Carbon-Nitrogen Chiral Axis

Recently, atropisomers owing to the rotational restriction around an N-C single bond (N-C axially chiral compounds) have received much attention in the field of synthetic organic chemistry. In particular, the catalytic enantioselective synthesis of various N-C axially chiral compounds and their application to asymmetric reactions have been reported by many groups. Bioactive compounds possessing an N-C axially chiral structure have also been known. The typical example of such bioactive N-C axially chiral compounds is quinazolin-4-one derivatives bearing an ortho-substituted phenyl group at 3-position. However, the catalytic asymmetric synthesis of N-C axially chiral quinazlolin-4-one derivatives has never been reported. We succeeded in the enantioselective synthesis of 3-(2-bromophenyl)quinazolin-4-one derivatives (GABA agonist, mebroqualone derivatives) through chiral Pd-catalyzed reductive asymmetric desymmetrization with 3-(2,6-dibromophenyl)quinazolin-4-ones. Furthermore, it was found that the reaction of various alkyl halides with the enolate prepared from quinazolinone products proceeds in a highly diastereoselective manner by the asymmetric induction due to the N-C axial chirality. The self-disproportionation of enantiomers (SDE) and crystal structure (chirality-dependent halogen bond) in mebroqualone derivatives, the preparation of N-C axially chiral quinazolinones bearing an ortho-fluorophenyl group, and the creation of isotopic atropisomers based on N-C axially chiral quinazolinone scaffold are also described.