Synthesis and functionalisation of highly substituted oxetanes : molecular scaffolds for drug discovery

• Main Author: Davis, Owen Alexander
• Other Authors: Bull, James
• Published: Imperial College London 2016
• Subjects: 540
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.754662

This thesis details new approaches to the synthesis and functionalisation of highly substituted, diversely functionalised oxetanes (Scheme 1). These types of 2-substituted oxetanes constitute desirable 3-dimensional motifs for medicinal chemistry, which exhibit desirable physicochemical properties as fragment molecules and could be core scaffolds to be grown along multiple vectors. The first section presents an introduction to the methods of oxetane synthesis, drug discovery, the recent incorporation of oxetanes into drug discovery and other uses of oxetanes. Section 3 describes investigations into the derivatisation of the C=C double bond of novel 2-methyleneoxetanes. Section 4 then outlines the successful development of a rapid, efficient and functional group tolerant 2-step synthesis of 2,2-substituted oxetanes via a Rh(II)-catalysed O–H insertion and a C–C bond forming cyclisation utilising anion stabilising groups to stabilise the intermediate carbanion. This methodology initially employed diazo malonate derivatives and alcohols bearing leaving groups (b-halohydrins) to access di, tri and tetrasubstituted oxetanes with a diverse range of functional groups. This was then expanded to incorporate a wider range of functionalised diazo compounds, including combinations of ester, amide, sulfone, phosphonate, nitrile and (hetero)aromatic substituents as anion stabilising groups (Section 5). These highly substituted oxetanes contained handles which underwent derivatisation to access diversely functionalised molecules. Finally, incorporation of the ketone moiety into this methodology led to a C–O bond forming cyclisation, forming 1,4-dioxenes (Section 6). In order to achieve high yields, a Ru(II)-catalysed O–H insertion was developed. Initial investigations into the derivatisation of these unusual partially saturated heterocycles were conducted to access functionalised 3-dimensional scaffolds potentially of interest in medicinal chemistry.