Building bridges from flatland: synthetic approaches and applications of 2-aza- and 2-oxa-bicyclo[2.1.1]hexanes

Abstract

The 2-azabicyclo[2.1.1]hexane (2-aza-BCH) and 2-oxabicyclo[2.1.1]hexane (2-oxa-BCH) motifs are bridged, saturated heterocycles with vast utility in medicinal chemistry. Over the past decades, chemists have explored numerous routes for their preparation allowing access to a variety of substitution patterns and a number of applications in the pharmaceutical sciences. Whilst 2-azabicyclo[2.1.1]hexane is a useful mimic of pyrrolidines, it can also serve as a rigid proline replacement and has found applications in peptidomimetic chemistry as well as drug molecules in a number of therapeutic areas. 2-oxabicyclo[2.1.1]hexane, an isosteric replacement of ortho- or meta- substituted phenyl rings or a useful, robust, metabolically stable, solubility-improving motif in its own right has also been of interest to the synthetic community. This review acts as a roadmap of the synthetic routes to access these heterocycles, allowing for comparisions of these two exciting classes of saturated heterocycles whilst hopefully inspiring new directions in the field.