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Item 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(Massey University, 2021) Mungalpara, MaulikThis 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.Item The synthesis and chemistry of [2.2]paracyclophane amino acid derivatives : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Chemistry at Massey University, Manawatū, New Zealand(Massey University, 2020) Etheridge, LeonieDue to the ever-growing requirement for chiral compounds, new conditions for stereoselective synthesis are in constant development. Asymmetric organocatalysis is well-studied, with peptide catalysts popular due to their modular and highlyfunctionalisable nature. One such example of their utility is in the Michael reaction, a well-studied carbon-carbon bond forming reaction. [2.2]Paracyclophane is an aromatic industrial precursor compound with remarkable structural and electronic properties. Its conformational bulk and rigidity make it an attractive target for integration into sterically-hindered unnatural amino acids for incorporation into peptides that may be effective organocatalysts. An updated route to 4-amino-13-[2.2]paracyclophane-carboxylic acid (Pca) was developed and optimised. The synthetic route comprises four steps with an overall yield of 50%. This compares with previous routes which had yields between 7 and 48% for 6 - 7 steps. Peptide coupling conditions for the poorly-reactive Pca were developed with some success; including devising a route for direct synthesis of a glycine residue on Pca’s aniline. Four new Pca-containing peptides were described. The above work sets the stage for development of interesting new planar chiral peptide compounds with diverse chemistry. Three Pca-containing peptides were studied as asymmetric organocatalysts in Michael addition between trans-β-nitrostyrene and hexanal and were compared to proline, a known catalyst for this reaction. These tests were performed to probe the relationship between relative conformation between the carboxylic acid and amine moieties of the catalyst, and the catalyst’s stereoselectivity. The Pca-containing catalysts showed an interesting trend to reversal of the prevailing syn product configuration.Item A study of new planar chiral monophosphine ligands based on [2.2]paracyclophane and their use in catalysis : Chemistry, Institute of Fundamental Sciences, Massey University : Masters thesis under the supervision of Dr. Gareth J. Rowlands(Massey University, 2011) Wang, Jingjing; Wang, JingjingThe Suzuki-Miyaura coupling reaction is one of the most powerful methods for the construction of biaryls. The biaryl motif has great importance in pharmaceutical, agrichemical and material science industries, and is often axially chiral. The outcome of a Suzuki-Miyaura coupling reaction can be influenced by many factors, but the ligand plays the most vital role. A large number of ligands have been developed, including many chiral ligands for asymmetric reactions. While ligand design has focused on molecules containing either central or axial chirality, little has been focused on planar chiral ligands. In this project, three new ligands based on the [2.2]paracyclophane backbone have been designed, pseudo-ortho substituted monophosphines (L1 and L2), secondary phosphine oxide and arylindolyl phosphine ligands (L3 and L4). Unfortunately, similar analogues of L1 and L2 were reported before our results, and a synthesis route to the secondary phosphine oxide ligands was not achieved. The use of L1 in gold mediated cyclisation was investigated, which concluded that L1 was not suitable for this kind of reaction. However, arylindolyl phosphine ligands were prepared successfully, and produced promising preliminary results in achiral Suzuki-Miyaura coupling reactions. Interesting X-ray crystallography structure of brominated indole is discussed.