Harnessing Weak Interactions and Reactive Intermediates in Palladium-Catalyzed Asymmetric C–C Bond Formation

Abstract

Palladium-catalyzed asymmetric C–C bond formation represents a cornerstone of modern synthetic chemistry for the construction of structurally complex molecules. This thesis explores two complementary aspects of this strategy: ligand design and the control of reactive intermediates. In Chapter 2, the mechanistic role of pyridine–dihydroisoquinoline （PyDHIQ） ligands in Pd- catalyzed asymmetric arylation reactions is investigated through density functional theory （DFT） calculations and noncovalent interaction （NCI） analysis. The studies reveal that β-substituted chromones and β-substituted δ- lactams operate in distinct kinetic regimes, resulting in fundamentally different ligand requirements. For chromone substrates, the 2,6-dimethylbenzyl （DMB） substituent suppresses catalyst deactivation and sustains productive turnover, whereas lactam substrates are governed by a conventional rate-limiting step. Extension of the PyDHIQ platform to the asymmetric 1,2-arylation of N-Cbz hydrazones further demonstrates the importance of ortho- substituted aromatic motifs for stereochemical control, establishing substrate-dependent aromatic-substituent effects as a key determinant of reactivity and enantioselectivity. In Chapter 3, a silyl ether-tethered asymmetric intramolecular Diels–Alder reaction proceeding through a catalytically generated chiral palladium enolate is developed. Incorporation of a Si–O linkage provides a removable tether that enables access to synthetically versatile oxygenated polycyclic frameworks. Mechanistic studies revealed that catalyst turnover requires a nucleophilic additive, leading to the identification of a previously unrecognized turnover pathway involving outer-sphere substitution at an η³-allyl–Pd intermediate. This work constitutes the first example of a silicon-tethered intramolecular Diels–Alder reaction mediated by a chiral Pd enolate and demonstrates, for the first time, nucleophile-promoted turnover of a palladium enolate, thereby expanding the synthetic utility of Pd-enolate catalysis in asymmetric bond construction. PhD/CH 20182100 Huijeong Ryu （류희정）, Harnessing Weak Interactions and Reactive Intermediates in Palladium-Catalyzed Asymmetric C–C Bond Formation （약한 상호작용과 반응성 중간체를 활용한 팔라듐 촉매 비대칭 탄소–탄소 결합 형성에 대한 연구）, Department of Chemistry, College of Natural Sciences, 2026, 162p, Prof. Sukwon Hong