Foster, RW; (2015) Sustainable approaches to novel heterocyclic scaffolds for medicinal chemistry. Doctoral thesis , UCL (University College London).

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Abstract

This thesis investigates new methods for the environmentally sustainable synthesis of heterocyclic scaffolds for application in medicinal chemistry. Chapter I introduces general principles of sustainability in synthetic organic chemistry. This includes the characterization and application of sustainable solvents and the use of biomass feedstocks in synthesis. Chapter II explores the synthesis of substituted isoindolinones via a ruthenium-catalyzed alkyne cyclotrimerization. The introduction details the synthesis and medicinal application of isoindolinones and describes previous research involving alkyne cyclotrimerizations. Following this, the development of a regioselective alkyne cyclotrimerization reaction in a sustainable solvent is reported. The optimized alkyne cyclotrimerization conditions are then used to synthesize a selection of isoindolinone products. Chapter III describes the application of a kinetically-controlled furan-Diels–Alder reaction to the synthesis of heterocyclic scaffolds, including the endo-cantharimide. The study and application of furan-Diels–Alder reactions are introduced. Following this, the Diels–Alder reaction of a 3-alkoxyfuran under sustainable reaction conditions is explored experimentally and applied to the diastereoselective synthesis of endo-cantharimides. The potential application of endo-cantharimides in medicinal chemistry is discussed with the aid of biological testing and the Diels–Alder reactions of 3-alkoxyfurans is probed with the aid of computational calculations. Chapter IV concerns the cyclization of reducing sugars to prepare chiral tetrahydrofurans. The role of tetrahydrofurans in medicinal chemistry, the synthesis of tetrahydrofurans from sugar derivatives and the application of hydrazones in synthetic chemistry are introduced. Following this the development of a hydrazone-mediated cyclization of L-arabinose under sustainable reaction conditions is reported. The optimized conditions are applied to prepare tetrahydrofurans from other sugars. The manipulation of the tetrahydrofuran products is also explored. Chapter V draws some general conclusions from the thesis and describes potential future directions for the research. Chapter VI contains the details of experimental procedures and compound characterization for the results discussed in Chapters II–IV.

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