Development of Chiral Pyridine-Dihydroisoquinoline (PyDHIQ) Ligands and Application to Palladium-Catalyzed Asymmetric Conjugate Additions

Abstract

Transition metal-catalyzed asymmetric conjugate additions have been widely applied to the construction of tertiary or quaternary stereocenters. Especially, palladium catalysis in the reaction could provide operationally practical transformations using air- and moisture-stable catalytic systems using arylboronic acids. Moreover, quaternary stereocenters could be generated in the palladium catalytic system with high enantioselectivity by use of chiral bidentate (N,N)-ligands such as PyOx or BOx ligand scaffolds. Nevertheless, the substrates in the palladium-catalyzed conjugate addition are still limited. Heterocyclic acceptors or heterocyclic nucleophiles were underdeveloped despite their numerous bioactivities. We anticipated that the development of well-designed chiral ligands could address these challenges remained in the field, and chiral dihydroisoquinoline scaffolds were chosen for the potential ligand candidates in the palladium-catalyzed conjugate addition. This thesis describes the development of chiral pyridine-dihydroisoquinoline (PyDHIQ) ligands and their application to palladium-catalyzed asymmetric conjugate addition. Chapter 2 explores the design and synthesis of chiral PyDHIQ ligands. Initial developments of palladium-catalyzed asymmetric conjugate addition using synthesized PyDHIQ ligands were also described. In chapter 3, the substrates were successfully expanded to 2-substituted chromones in aqueous media, affording tetrasubstituted stereocenters at the C2 position of chromanones. Notably, this is the first example of asymmetric conjugate addition to 2-substituted chromanones. In chapter 4, the developed catalytic system was applied to β-substituted α,β-unsaturated δ-lactams, providing chiral β-quaternary δ-lactams. This methodology was successfully applied to the first asymmetric formal synthesis of (-)-picenadol. In addition, it was found that there are attractive noncovalent interactions between N-Cbz-δ-lactams and PyDHIQ ligands in an enantioselectivity-determining step by DFT calculations and NCI plot analysis.