Functionalisation of Propellanes and Bicycloalkanes using Multicomponent Reactions

"Project MultiProp aims to advance the field of synthetic organic chemistry by exploring the use of small-ring propellanes in multicomponent reactions (MCRs). Radical ring-opening reactions of these propellanes lead to bicyclo[n.1.1]alkanes (BCAs), which are sp3 rich ""cage"" hydrocarbons that are of high interest in drug design. Specific examples include bicyclo[1.1.1]pentanes (BCPs), which have demonstrated to be bioisosteres of para-substituted benzene rings, alkynes, and tert-butyl groups; and bicyclo[3.1.1]heptanes (BCHeps), which have proved to be potential meta-arene analogues. Molecules incorporating these rigid scaffolds typically exhibit enhanced pharmacological properties compared to their parent structures, such as improved solubility and reduced metabolic susceptibility, while preserving their three-dimensional configuration.Despite the utility of BCAs in medicinal chemistry, their synthesis using multi-component reactions is underdeveloped. This proposal aims to address this gap by developing novel methodologies for the application of propellanes in diverse multicomponent chemical processes, thereby streamlining access to functionalised BCAs. The project comprises three Work Packages:WP1: Developing new multicomponent protocols for the C–H functionalisation of organic molecules using propellanes as substrates, and the C–H functionalisation of bicycloalkanes.WP2: Applying Norrish type I and II photochemical reactions to propellanes, and related 1,5-hydrogen atom transfer / functionalisation reactions, for the synthesis of functionalised BCAs.WP3: Developing N-heterocyclic carbene-promoted MCRs using alcohols and propellanes as substrates, where NHC-activated alcohols serve as radical precursors for the synthesis of highly substituted BCPs and BCHeps.MultiProp thus seeks to expand the chemical space of propellane-derived molecules, opening new avenues for their applications in synthetic organic chemistry, medicinal chemistry, and materials science."