Saudi Cultural Missions Theses & Dissertations
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Item Restricted Iridium-Catalysed Hydrosilylation of Carbonyl Derivatives: Design and Applications(University of Oxford, 2028-06-15) Almehmadi, Yaseen A; Dixon, Darren JChapter 1: the tertiary amide is a ubiquitous functional group and plays an irreplaceable role in medicinal chemistry. Its robust nature has meant – in the past – that selective manipulation of this motif remained elusive. The reductive activation through hydrosilylation of tertiary amides – using Vaska’s complex (IrCl(CO)(PPh3)2) – has emerged as a powerful strategy for the chemoselective transformation of amides into reactive enamines and iminium ions. Furthermore, these synthetically valuable species can be accessed in the presence of traditionally more reactive functional groups. This approach to amide reductive activation via hydrosilylation has been exploited in a range of downstream C–C bond forming processes, and has seen significant applications in total synthesis, enabling streamlined routes for the synthesis of complex natural product architectures. This chapter covers the development of this synthetic strategy, from initial hydrosilylation studies, to its flourishing use in the reductive functionalization of amide-containing molecules, both simple and complex. Chapter 2: a new reductive strategy for the stereo- and regioselective synthesis of functionalized isoquinuclidines has been developed. Pivoting on the chemoselective iridium (I) catalyzed reductive activation of β,γ-unsaturated δ-lactams, the efficiently produced reactive dienamine intermediates readily undergo [4+2] cycloaddition reactions with a wide range of dienophiles, resulting in the formation of bridged bicyclic amine products. This new synthetic approach was extended to aliphatic starting materials, resulting in the efficient formation of cyclohexenamine products, and readily applied as the key step in the shortest (5-step) total synthesis of vinca alkaloid catharanthine to date, proceeding via its elusive biosynthetic precursor, dehydrosecodine. Chapter 3: three-dimensional nitrogen-rich bridged ring systems are of great interest in drug discovery owing to their distinctive physicochemical and structural properties. However, synthetic approaches towards N–N bond containing bridged heterocycles are often inefficient and/or require tedious synthetic strategies. Herein, we delineate an iridium-catalyzed reductive approach to such architectures from C,N,N-cyclic hydrazide substrates using IrCl(CO)[P(OPh)3]2 and tetramethyldisiloxane (TMDS) which provided efficient first time access to the unstabilized and highly reactive C,N,N-cyclic azomethine imine dipoles. These were stable and isolable in their dimeric form, but, upon dissociation in solution, reacted with a broad range of dipolarophiles in [3+2] cycloaddition reactions with high yields and good diastereoselectivities, enabling the direct synthesis of nitrogen-rich sp3 pyrazoline polycyclic ring systems. Density functional theory (DFT) calculations were performed to elucidate the origin of diastereoselectivity of the cycloaddition reaction, and principal moment of inertia (PMI) analysis was conducted to enable visualization of the topological information of the dipolar cycloadducts. Chapter 4: The synthesis of sterically hindered alpha- or beta-tertiary ethers has long been constrained by the limitations of traditional SN2 and related SN1 approaches owing to poor reactivity arising from steric hindrance or competitive elimination / rearrangement pathways. Herein, we describe a general solution to the hindered ether synthesis problem via an iridium catalyzed reductive deoxygenation of readily prepared ester starting materials. Employing the IrCl(CO)(P[OCH(CF3)2]3)2 complex at 1 mol% and 4 equivalents of tetramethyldisiloxane (TMDS) as the terminal reductant, this alternative synthetic approach to hindered and non-hindered alkyl, aryl and benzyl ethers features mild reaction conditions in a single vessel using low catalyst loadings and with readily available starting materials to access both acyclic and cyclic product ethers in good to excellent yield. Control experiments demonstrated that the IrCl(CO)(P[OCH(CF3)2]3)2/TMDS catalyst system could not only rapidly hydrosilylate esters to mixed silyl/alkyl hemiacetal intermediates but also catalyze reduction of acetals directly to ether functionality, revealing the necessary Lewis acidic and hydridic properties required for this deoxygenative transformation.16 0Item Restricted Clicking Towards Sustainability: Synthesis of Poly(isoxazole)s from Biomass via Nitrile Oxide/Yne Polymerisation(Saudi Digital Library, 2023-11-01) Alhathir, Abdulrahman Saad; Clark, AndrewClick chemistry has been a reliable, selective, and simple synthetic method for incorporating heteroatoms in polymer chemistry and material science. Poly(isoxazole)s can be prepared by the polycycloaddition of two clickable monomers, such as nitrile oxides and dialkynes. In addition, the potential of further modifying poly(isoxazole) structures through ring-opening is a promising area of research. However, the synthesis of poly(isoxazole)s from sustainably sourced materials, such as vegetable oils and lignins, has not been well studied. To address this, novel isoxazole-containing model compounds of poly(isoxazole)s derived from renewable stearic acids (C17H35CO2H) and vanillin-based substrates with various chemical structures were initially synthesised using nitrile oxide click chemistry. The reductive cleavage of the N-O bonds in the rings of isoxazole compounds was studied and successfully achieved using several reducing reagents, including Mo(CO)6 and Raney-Ni, for post-polymerisation modification. Subsequently, novel stearic acid- and vanillin-based poly(isoxazole)s were prepared through the click polycycloaddition between dipolarophilic dialkyne monomers and in situ generated aromatic nitrile oxides using step-growth polymerisations. The polymerisation was conducted under copper-mediated and base-mediated conditions. The highest molecular weight polymers were obtained under free-catalyst polymerisation conditions by employing environmentally-friendly solvents such as ethanol and THF. Finally, the post-polymerisation modification of the prepared stearic acid- and vanillin-based poly(isoxazole)s using Raney-Ni conditions resulted in partial success in achieving the intended cleavage reactions and the formation of desired poly(-enaminoketone)s. Overall, this thesis contributes to the understanding of poly(isoxazole) synthesis from renewable sources. The findings highlight the potential of sustainably sourced materials for polymer synthesis and the importance of optimising reaction conditions for desired polymer properties.29 0