The availability of high-quality, structurally-diverse small molecule libraries is crucial to the discovery and development of new drugs and chemical probes. Much recent attention has been focused upon the developments of libraries of screening compounds and fragments with high degrees of sp character, to complement the more sp 2 -rich nature of many commercial screening libraries. This latter facet is undoubtedly driven at least in part by the widespread use of synthetic methods (e.g. amide formation, Suzuki coupling) which can rapidly generate large libraries from widely-available starting materials, but which often lead to 'hit' molecules which have poor properties for subsequent development into lead compounds. In some cases this is identified as a potential contributory factor to the high attrition rates of new small molecule drugs. A variety of complementary approaches to the synthesis of diverse sp 3 -rich compound libraries has been taken. "Bottom-up" diversity-oriented synthetic approaches employ structurally and/or stereochemically-diverse building blocks to generate sp 3rich libraries. Alternatively, inspiration has been sought from natural products, which are inherently biologically-relevant as well as structurally distinct from synthetic compounds. Generation of compound libraries based on sub-structures of biologically-validated natural products ('pseudo-natural products') has proven highly productive in the discovery of new bioactive compound classes; alternatively, remodelling of natural product scaffolds themselves can generate distinct but related scaffold architectures with distinct activity. We have focused attention on a complementary approach, wherein complexity-generating cycloaddition reactions have been used to rapidly generate highly-functionalised polycylic scaffolds which can be further diversified by subsequent addition/modification, ring addition, ring expansion or ring cleavage. This approach facilitates the rapid assembly of diverse scaffold libraries that are entirely synthetic but distantly related to natural products: the biological relevance of these compounds has been demonstrated in, for example, the creation of fragment libraries providing crystallographic hits against distinct protein classes and the identification of molecules active against the Hedgehog signaling pathway and as antiparasitic agents. At the heart of this approach is the need for highly efficient complexity-generating reactions. Dearomatisation reactions can be efficient ways to rapidly increase molecular complexity, creating sp 3 -rich 3D skeleta from simple sp 2 -rich building blocks. We have recently developed an oxidative dearomatisation reaction that generates spirotricyclic diamines in a single step from readily-available (hydroxyphenyl)propyl ureas. The resulting products contain rich functionality which we believed would be ideal for exploitation in a top-down approach to the generation of diverse scaffolds (Figure ). Herein we describe the successful realisation of this approach, and the generation of a small screening library based upon the scaffolds generated. The biological relevance of these scaffolds is demonstrated through phenotypic screening in a cell painting assay: distinct phenotypic effects are observed for compounds based on scaffolds which are structurally distinct but synthetically closely-related.