Synthesis of medium-sized rings via nucleophile-induced cascade expansion

This thesis details the development of a novel method for the synthesis of medium-sized lactones and lactams via a cascade process referred to in this thesis as ‘Nucleophile-Induced Cyclisation Expansion’ (NICE). In this approach, linear precursors are designed to contain an internal nucleophilic catalyst, to ensure the NICE proceeds via a cyclic transition state containing a 5 to 7 membered ring (i.e. I → II → III). This approach avoids the high-dilution conditions typically required to synthesise medium-sized rings by end-to-end cyclisation. The majority of the challenges associated with synthesising medium-sized rings by NICE centre on the synthesis of the linear precursor. In this thesis two different retrosynthetic approaches to synthesising linear precursors are detailed, referred to as the EI + N and E + IN approaches as summarised in Figure 1.
Section 7.2 details the synthesis of linear precursors composed of an aliphatic amine as the internal nucleophile and a primary amine as the terminal nucleophile to synthesise novel medium-sized lactams. An EI + N retrosynthetic approach was used to synthesise the linear precursors as shown in Figure 1, where a molecule composed of an electrophilic carbonyl group and aliphatic amine as the internal nucleophile (EI), is reacted with a molecule composed of the terminal nucleophile (N).
Section 7.3 also focuses on an EI + N retrosynthetic approach, but by using bromopropan-1-ol an alternative N-building block. The subsequent linear precursors synthesised contains an alcohol group as the terminal nucleophile. Therefore, upon NICE lactones are synthesised analogous to the lactams shown in Section 7.2.
Section 7.4 focuses on the synthesis of linear precursors by the alterative E + IN retrosynthetic approach as shown in Figure 1. A range of different E-building blocks were synthesised composed of an electrophilic carbonyl group. Different commercially available amino alcohols were used as the IN-building blocks to introduce an internal and the terminal nucleophile into the linear precursor. Upon deprotection and NICE the different linear precursors were ring expanded into a range of structurally diverse medium-sized lactones.