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

Abstract

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.

Date of Award	24 Jan 2023
Original language	English
Awarding Institution	University of Bristol
Supervisor	Adam Noble (Supervisor) & Varinder K Aggarwal (Supervisor)