Multi Internal Nucleophile Ring Expansion Reactions

This thesis describes a novel method for the cyclisation of linear precursors possessing multiple internal nucleophiles, via multi internal nucleophile ring expansion (multi-INRE) cascade reactions to yield novel heterocyclic-macrocyclic lactones. Section 2.1 describes the design of proposed novel linear multi-INRE precursor A and associated synthetic strategies. Section 2.2 presents the multistep synthesis route to linear multi-INRE precursor A which, after considerable optimisation, was achieved on a threegram scale with an overall yield of 50%. Section 2.3 details the first reported multi-INRE reaction, with the synthesis of heterocyclic-macrocyclic lactone B. Section 2.3 also comments on the atroposelectivity of the multi-INRE reaction A → B with a kinetic model proposed to explain the selectivity. Section 3.3 details the synthesis and subsequent cyclisation of two aliphatic linear precursors (C) via multi-INRE reactions. In this section, two novel aliphatic linear precursors possessing two internal amine nucleophiles (C) and their respective multi-INRE heterocyclic macrocyclic lactone products (D) are synthesised. Section 3.4 details the screening of multi-INRE reaction A → B, culminating in the discovery of conditions that enable a yield of 73% for the initial multi-INRE. Finally, chapter four details the design of three other potential linear precursors containing two internal nucleophiles and describes the progress made towards the synthesis of each (E, F and G).