New routes to planar chiral ligands and their use in asymmetric catalysis : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Chemistry at Massey University, Manawatū, New Zealand

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Massey University
This thesis contains 8 chapters detailing 3 optimised methods to synthesise [2.2]paracyclophane derivatives and our studies in the C-H activation field, namely selective remote β-C-H activation of cyclic amines, and enantioselective γ-C(sp³)-H functionalisation of cyclic amines, as well as a future direction. As the main focus of this thesis is on the development of novel planar chiral [2.2]paracyclophane derivatives, Chapter 1 starts with a brief description of [2.2]paracyclophane chemistry. A short introduction about the synthesis of key enantioenriched [2.2]paracyclophane derivatives is given. Finally, a short introduction of the recent applications of [2.2]paracyclophane-based ligands in asymmetric catalysis is also mentioned. Chapter 2 describes the synthesis of (RSp,SRP)-4-tert-butyl[2.2]paracyclophane phosphine oxide (SPO) and attempts to synthesise its asymmetric variant. Further, its synthetic utility is investigated, mainly in Suzuki-Miyaura cross-coupling, Buchwald-Hartwig amination, and Au(I)-catalysed cyclisation reactions. Additionally, a general route to the P-stereogenic [2.2]paracyclophane-derived phosphines via the reduction of tertiary phosphine oxides is reported. Chapter 3 mainly outlines attempts for β-C(sp³)-H activation of cyclic amine to target the shortest route of epibatidine moiety. A stepwise approach is mentioned. Firstly, a range of heteroatom-substituted secondary phosphine oxides (HASPOs) is evaluated to access (chiral) indolines via intramolecular C(sp³)-H activation. Next, an intramolecular C(sp³)-H activation of 7-azanorbornane, a core skeleton of epibatidine, is investigated. The third approach is mainly targeted for the directing-group-assisted intermolecular C(sp³)-H activation of 7-azanorbornane. Lastly, enantioselective γ-C(sp³)-H activation of N-cyclohexylpicolinamide using various chiral Brønsted acids, again targeting the epibatidine moiety by the late-stage cyclisation, is described. In a search for suitable planar chiral Brønsted acid, an optimised single-step protocol for the synthesis of [2.2]paracyclophanes carboxylic acid derivatives is reported in Chapter 4. This protocol proceeds via C(sp²)-H activation of chiral oxazolines and their coupling with bromo[2.2]paracyclophanes. Chapters 5 & 6 are related to pyridine sulfinates. Chapter 5 describes an attempted regioselective C-H functionalisation of aromatic acids via desulfitative coupling with pyridine-2-sulfinate. A detailed study with catalytic Pd(OAc)₂ and pre-formed palladacycle is mentioned. The effect of catalytic Pd(OAc)₂ on homo-coupling of pyridine-2-sulfinates is also investigated. The potential of sulfinates as nucleophilic coupling partners is investigated in Chapter 6. A novel methodology to synthesise pyridyl[2.2]paracyclophanes is described. The method involves desulfitative cross-coupling reactions between pyridine sulfinates and bromo[2.2]paracyclophanes. One of the interesting results of the desulfitative coupling with the unreactive (±)-4-bromo-5-amino[2.2]paracyclophane is also mentioned. Chapter 7 explains the future scope of the research work mentioned in this thesis. Finally, Chapter 8 describes the experimental procedures and characterisation of the synthesised compounds mentioned in Chapters 2 to 6.
Asymmetric synthesis, Chirality