Strained spiro heterocycles as potential bioisosteres: an update on the synthesis of heteroatom-containing spiro[2.3]hexanes and spiro[3.3]heptanes

The interest of medicinal chemists in strained spiro heterocycles has continuously risen, given their potential as non-classical three-dimensional bioisosteres, as it has been shown that their inherent structural characteristics can impose beneficial physicochemical properties on lead compounds (e.g., metabolic stability, lipophilicity). In particular, strained spiro heterocycles containing at least one four-membered ring are in demand, as the inclusion of a small ring results in a more rigid and denser molecular space, whereas the inclusion of a heteroatom allows for placement of an exit vector orthogonal to the neighbouring carbon-centered exit vectors. The continuous development of new strained spiro heterocycles, their site-specific functionalisation, and their application as bioisostere is thus imperative. This review provides an overview of progress since 2014 with a particular focus on heteroatom-containing spiro[2.3]hexanes and spiro[3.3]heptanes.