Azabicycloalkanes: Synthesis and Applications

Small ring azabicyclic amines are predicted to possess unique molecular properties, but lack of synthetic access has to date prevented their thorough evaluation and deployment in high value functional molecules, including drugs.

Much recent attention has focused on small-ring carbocyclic frameworks such as bicyclo[1.1.1]pentanes (BCPs), but analogous azabicyclic compounds are poorly described in the literature, which is surprising given the ubiquity of amines in bioactive organic molecules.

A literature screen reveals that azabicyclo[2.2.1]heptanes are equivalent to BCPs in frequency of occurrence, but their [3.1.1] isomers and smaller azabicyclo[2.1.1]hexane relatives are much rarer.

Azabicyclo[1.1.1]pentanes are essentially unknown, despite one isomer being an attractive bioisostere of the pyridine ring system.

This proposal aims to address this ‘void’ in the bioisostere portfolio by introducing ‘small-ring azabicyloalkanes’ (ABAs) as novel motifs of great potential in drug discovery.

As well as representing new bioisosteres for biologically-relevant heterocycles (not limited to pyridines, but also piperidines, pyrrolidines, etc.), ABAs offer new opportunities for drug design in their own right due to the impact of the bicyclic scaffold on amine hybridization.

This project will deliver general access to small ring ABAs using a wide variety of novel chemical approaches, explore their functionalization, and demonstrate their application. It will use rational theoretical design to tailor ABA properties and develop structural models.

Ultimately, this proposal will access a new domain of chemical space with broad application in organic and medicinal chemistry.