Azabicyclo[1.1.0]butane in the strain-release-driven synthesis of functionalised azetidines

Despite the favourable properties that azetidine rings can engender drug-compounds with, methods for the modular synthesis of azetidine-based structures are significantly underexplored. This thesis outlines the development of several novel strategies that facilitate the assembly of functionalised azetidines and azetidine-containing spirocycles. Key to achieving these new modes of reactivity was the ability to harness the inherent strain energy of azabicyclo[1.1.0]butyl lithium (ABB-Li), which provides a strong thermodynamic driving force to access unexplored regions of chemical space. The essential criteria for these targeted protocols were that they must be operationally simple, tolerant of a broad range of functional groups, modular and must generate products with the potential for further elaboration. In this context, a unique approach toward the synthesis of azetidine-containing spirocycles was established through the development of an electrophile-induced spirocyclisation-desilylation reaction. This was achieved via the single step synthesis of ABB-ketone precursors bearing silyl-protected alcohols which could be effectively transformed into a library of new spiro azetidines, with a range of substituents and ring sizes. Building on this success, a novel strain-release-driven Friedel-Crafts spirocyclisation reaction of azabicyclo[1.1.0]butane-tethered (hetero)aryls was subsequently investigated. This reaction was discovered to proceed through an unexpected interrupted Friedel-Crafts mechanism, generating a highly complex azabicyclo[2.1.1]hexane scaffold. This dearomatised intermediate, formed exclusively as a single diastereomer, could be subsequently converted to the Friedel-Crafts product upon electrophilic activation of the tertiary amine, or trapped as a Diels-Alder adduct in one-pot. Finally, the successful realisation of a four-component [1,2]-Brook rearrangement/strain-release-driven anion relay sequence and its application to the modular synthesis of acyl azetidines is described. The rapidity of the reaction, as confirmed by in situ infra-red spectroscopy, leveraged the strain-release ring-opening of azabicyclo[1.1.0]butane to drive the equilibrium of the Brook rearrangement. These newly developed procedures demonstrate the potential of utilising strain-release as a synthetic strategy for the rapid assembly of sp3-rich heterocycles. The wider application of these reactivity regimes will open new vistas to access nitrogen-containing drug-like cores that can be easily diversified through the judicious choice of starting materials and further elaborated via the orthogonal manipulation of multiple functional handles.