PhD Development of novel bicyclopentanes (BCP) bioisosteres from bench stable [1.1.1]-propellane precursors

Loughborough University

Bicyclo-[1.1.1]-pentanes (BCPs) are an exciting class of strained, sp3 rich carbon. While their initial use was in the materials sector, recent impact has been in medicinal chemistry, drug development and the agrochemical sector. Their appeal is due to a unique 3-D structure, a direct consequence of its high sp3 carbon content, and has led to its use as a bioisosteres for the tert-butyl group, internal alkynes and significantly, mono- and disubstituted arenes.Their synthesis is accomplished using hetero- or homolytic cleavage and relies on the inherent strain in the central carbon-carbon bond of [1.1.1]-propellane. However, the practical isolation and storage of [1.1.1]-propellane is very problematic it is isolated as a solution in ethereal solvents, it must be cryogenically stored, and should be used before its rapid degradation.In this project we will pioneer a stable crystalline alternatives of [1.1.1]-propellane. Functionalization will be explored using several nucleophiles, providing orthogonal 1,3-disubstituted-[1.1.1]-bicyclopentane (BCP) precursors amenable to subsequent cross-coupling reactions (e.g., transition metal and photoredox mediated). This methodology will provide a superior synthetic approach to 1,3-disubstituted BCPs, with far less waste, as well as delivering stable crystalline BCP precursors.