Nucleophile Inducing Cyclisation/ring Expansion reactions (NICE) for synthesis of medium-sized rings and macrocycles Illya Zalessky and William P Unsworth University of York, Heslington, UK My PhD has been focused on developing novel ring enlargement methods for the synthesis of functionalised macrocycles (12+ membered rings) and medium-sized rings (8–11 membered rings). These large ring systems are usually difficult to make, with one of the key challenges is the effective control of the intra- and intermolecular reactions during end-to-end cyclisation (Box A). To get around these unwanted intermolecular side reactions, various approaches have been discovered and developed. These include high dilution reactions (e.g. 0.0005 M or lower) and pseudo-highdilution approaches. The internal nucleophile ring expansion (INRE, boxes B and C) is a novel approach developed in the Unsworth group as a method to access medium-sized rings from linear precursors via a cyclisation/ring expansion cascade series of reactions. During my PhD studies, I have worked on using S- and Se-containing starting materials (as the internal nucleophile, highlighted green in box D) in INRE for the first time. EDC-HCl and HOBt were used to activate carboxylic acids (the electrophilic component, highlighted in pink in box D) to afford various medium-sized ring products in high yields with a high functional group tolerance. Along with testing different internal nucleophiles, I tested various terminal nucleophiles (highlighted in blue in box D). Attention then turned to incorporating additional heteroatoms on the linker to enable a more extended ring expansion cascade and obtain macrocyclic frameworks (n >1, highlighted orange in box D). I have managed to synthesise linear precursors with two, three and four different heteroatoms as nucleophiles, which yielded the desired macrocycles at a standard concentration. The biggest achievement in my PhD research has been the development of method to vary the electrophilic component. Previously, only carboxylic acid was used as the electrophile, but I have managed to discover seven new electrophilic components and increase the diversity of medium-sized rings. This work in discovering new electrophile, terminal and internal nucleophiles, resulted in developing a quick and easy method for synthesis related to a medium-sized ring with various functionalities under mild conditions at a standard dilution of 0.1–0.05 M.
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