Fragment based drug discovery is a well established approach used in the development of drug and lead-like compounds. Our aim was to design and synthesise a variety of novel 3D fragments that access new chemical space, and incorporate the oxetane motif. Oxetanes are currently receiving enormous attention as important motifs for drug discovery due to their desirable physicochemical properties. 2-Sulfonyl oxetanes were designed as non-planar fragments with desirable drug-like properties which could be further derivatised into more lead-like compounds. Currently there is a sparcity of synthetic methods for oxetane preparation.This presentation will describe a novel strategy to synthesise oxetanes involving an intramolecular carbon-carbon bond formation. Four novel oxetane fragments were accessed on over 1 g scale. The fragments were then successfully functionalised via organometallic intermediates at the intact oxetane and aromatic rings into larger lead-like compounds. Studies into the stability of these compounds to conditions of varying pH will also be presented.The second part of this presentation will discuss the synthesis of 2-sulfinyl oxetanes and functionalisation via sulfoxide magnesium exchange. This strategy will allow functionalisation of the intact oxetane ring, and provide a valuable divergent approach to novel oxetane structures.

2-(aryl-sulfonyl)oxetanes as designer 3D fragments for fragment screening: Synthesis and strategies for functionalization

248th National Meeting (2014)

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