In 2009, Lovering et al. demonstrated how the degree of carbon bond saturation in a molecule, as measured by a simple metric, the fraction of sp -carbon atoms (Fsp 3 ), tends to increase as compounds progress from the drug discovery phase, through the clinical phases of development, and ultimately to the marketed drug. Fsp 3 has since become a widely used 1D molecular property descriptor for assessing a compound's drug-likeness. Lovering et al. also used this metric as a measure of molecular complexity, which they correlated with an improved chance of successful progression along the drug discovery and development pathway. The origins of these correlations are manifold: a drug with a high degree of three-dimensional character typically enables better shape complementarity with the three-dimensional active site of its biological target, ensuring better alignment of recognition motifs (for example, H-bond acceptors and donors) with residues lining the target active site; this in turn not only leads to increased potency but also increased selectivity, and a concomitant improved safety profile arising from a reduction in off-target engagement. Important physicochemical properties are also affected by the degree of saturation and three-dimensionality of a compound, in particular solubility and melting point, both of which are key parameters controlling oral bioavailability and drug absorption. Lovering showed a positive correlation between Fsp 3 and solubility, and a negative correlation with melting point. As a consequence of their attractive drug-likeness parameters, there has been a drive to populate compound screening libraries with a greater proportion of sp 3 -rich scaffolds. Providing such scaffolds possess favorable physicochemical properties and safety profiles, it follows that they should provide better starting points for drug discovery programs and in so doing, help to reduce the high rates of attrition that blight the drug development process. Conformationally well-defined, three-dimensional scaffolds are particularly attractive starting points for compound library assembly; a lower entropic penalty upon binding, combined with an ability to orient key recognition motifs in the pharmacophore along well-defined exit vectors to interact optimally with a target, can lead to a more favorable free energy of binding and increased potency compared with conformationally more flexible analogues. Reduced conformational flexibility has also been associated with improved oral bioavailability. Conformational rigidity in sp -rich systems can be achieved in various ways, for example, through bridged systems and ring fusion in polycycles, 8c and of interest to us, through spiro systems. Spirocyclic molecules are widespread amongst bioactive natural products, and have received growing interest as scaffolds for drug discovery. The presence of a spiranic center within the core of a molecular scaffold, that is, not at its periphery, necessarily introduces a high degree of three-dimensionality, typically significant conformational rigidity and a limited number of low-energy conformations. Functionality embedded within the constituent rings then introduces exit vectors and a means to predictably orient recognition motifs into well-defined regions of three-dimensional space, which is attractive for structure-based drug design. 8a,14 Moreover, there are examples in which the incorporation of a spirocycle imparts favorable physicochemical properties, 15 and an improved pharmacokinetics profile compared with non-spirocyclic analogues. A number of groups have reported diversity libraries of spiro(hetero)cyclic compounds 16 and bis-spirocyclic frameworks. Müller and co-workers used a cheminformatics approach to classify systematically the structures and chemical space interrogated by spirocycles of known biological activity. This study highlighted the capacity for this type of scaffold to access a significant volume of biologically relevant chemical space, reinforcing the attraction of deploying spirocycles for drug discovery.