Spirocycles frequently occur in natural products and experience increasing interest in drug discovery, given their richness in sp centers and distinct three-dimensionality. We have systematically explored chemical space populated with currently available bioactive spirocycles. Compounds containing spiro systems were classified and their scaffolds and spirocyclic ring combinations analyzed. Nearly 47 000 compounds were identified that contained spirocycles in different structural contexts and were active against roughly 200 targets, among which several pharmaceutically relevant members of the G protein-coupled receptor (GPCR) family were identified. Spirocycles and corresponding compounds displayed notable scaffold diversity but contained only limited numbers of combinations of differently sized rings. These observations indicate that there should be significant potential to further expand spirocyclic chemical space for drug discovery, exploiting the privileged substructure concept. Inspired by those findings, we embarked on the design and chemical synthesis of three distinct novel spirocyclic scaffolds that qualify for downstream library synthesis, thus exploring principally new chemical space with high potential for pharmaceutical research.

High-throughput screening (HTS) represents a major cornerstone of drug discovery. The availability of an innovative, relevant and high-quality compound collection to be screened often dictates the final fate of a drug discovery campaign. Given that the chemical space to be sampled in research programs is practically infinite and sparsely populated, significant efforts and resources need to be invested in the generation and maintenance of a competitive compound collection. The European Lead Factory (ELF) project is addressing this challenge by leveraging the diverse experience and know-how of academic groups and small and medium enterprises (SMEs) engaged in synthetic and/or medicinal chemistry. Here, we describe the novelty, diversity, structural complexity, physicochemical characteristics and overall attractiveness of this first batch of ELF compounds for HTS purposes.

Two conformationally restricted threedimensional aminoketone scaffolds have been synthesized in only three steps, using a continuous flow photochemistry approach, which is also amenable to scale-up. In addition, several approaches to further derivatize these scaffolds for the synthesis of low molecular weight compound libraries have been detailed.

A synthesis of the bicyclo[2.1.1]hexane substructure of solanoeclepin A (1), the most active natural hatching agent of potato cyst nematodes, was approached via an intramolecular [2 + 2] photocycloaddition. Aldehyde 12 containing the dioxenone chromophore served as a useful starting material, allowing the synthesis of a variety of photocycloaddition substrates via Grignard addition or via a Nozaki-Hiyama-Kishi reaction. Photolysis of the unsubstituted alkene 14 led to the expected crossed cycloadduct bicyclo[2.1.1]hexane 15 according to the so-called rule of five. However, several functionalized alkenes 18, 20, and 31 exhibited a complete reversal of cycloaddition regioselectivity, providing straight cycloadducts bicyclo[2.2.0]hexanes 21-26 and 4, respectively. Their structures were proved by a combination of extensive NMR measurements, X-ray analyses, and subsequent retro-aldol reactions. The latter de Mayo process allowed the formation of spiro-[3.5]nonane 35 and spiro[3.4]octane 36 as well as the cyclobutanes 37 and 38. Finally, the cyclization of the more rigid lactone precursor 28 occurred in high yield in the desired fashion with complete regio- and stereoselectivity to give 3 containing the core bicyclo[2.1.1]hexane skeleton of the natural product.

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