Chiral Pd-Catalyzed Enantioselective Syntheses of Various N–C Axially Chiral Compounds and Their Synthetic Applications

ConspectusBiaryl atropisomers are key structural components in chiral ligands, chiral functional materials, natural products, and bioactive compounds, and their asymmetric syntheses have been reported by many groups. In contrast, although the scientific community has long been aware of atropisomers due to rotational restriction around N–C bonds, they have attracted scant attention and have remained an unexplored research area. In particular, their catalytic asymmetric synthesis and the synthetic applications were unknown until recently. This Account describes studies conducted by our group on the catalytic enantioselective syntheses of N–C axially chiral compounds and their applications in asymmetric reactions.In the presence of a chiral Pd catalyst, the reactions of achiral secondary ortho-tert-butylanilides with 4-iodonitrobenzene proceeded in a highly enantioselective manner (up to 96% ee), affording N–C axially chiral N-arylated ortho-tert-butylanilides in good yields. The application of the present chiral Pd-catalyzed N-arylation reaction to an intramolecular version gave N–C axially chiral lactams with high optical purity (up to 98% ee). These reactions were the first highly enantioselective syntheses of N–C axially chiral compounds with a chiral catalyst. Since the publication of these reactions, N–C axially chiral compounds have been widely accepted as new target molecules for catalytic asymmetric reactions. Furthermore, chiral-Pd-catalyzed intramolecular N-arylations were applied to the enantioselective syntheses of N–C axially chiral quinoline-4-one and phenanthridin-6-one derivatives. We also succeeded in the enantioselective syntheses of various N–C axially chiral compounds using other chiral Pd-catalyzed reactions. That is, optically active N–C axially chiral N-(2-tert-butylphenyl)indoles, 3-(2-bromophenyl)quinazolin-4-ones, and N-(2-tert-butylphenyl)sulfonamides were obtained through chiral Pd-catalyzed 5-endo-hydroaminocyclization, monohydrodebromination (reductive asymmetric desymmetrization), and Tsuji-Trost N-allylation, respectively. The study of the catalytic asymmetric synthesis of axially chiral indoles has contributed to the development of not only N–C axially chiral chemistry but also the chemistry of axially chiral indoles. Subsequently, the catalytic asymmetric syntheses of various indole derivatives bearing a C–C chiral axis as well as an N–C chiral axis have been reported by many groups. Moreover, axially chiral quinazlolin-4-one derivatives, which were obtained through chiral Pd-catalyzed asymmetric desymmetrization, are pharmaceutically attractive compounds; for example, 2-methyl-3-(2-bromophenyl)quinazolin-4-one product is a mebroqualone possessing GABA agonist activity.Most of the N–C axially chiral products have satisfactory rotational stability for synthetic applications, and their synthetic utility was also demonstrated through application to chiral enolate chemistry. That is, the reaction of various alkyl halides with the enolate prepared from the optically active anilide, lactam, and quinazolinone products proceeded with high diastereoselectivity by asymmetric induction due to the N–C axial chirality.At the present time, N–C axially chiral chemistry has become a popular research area, especially in synthetic organic chemistry, and original papers on the catalytic asymmetric syntheses of various N–C axially chiral compounds and their synthetic applications have been published.