Scheme 2.1 Key enyne cycloisomerization step in Nicolaou’s total synthesis of platensimycin.

      Source: Adapted from Nicolaou et al. [15].

In contrast, a comparatively small number of spirocycle containing drugs have been investigated in the last decades, and spirocyclic molecules are still under‐represented in marketed drugs [2]. Selected examples of spirocycle containing drugs are shown in Table 2.1, including spironolactone 3 which has been known for over 50 years [20]. It seems fair to state that historically drug design strategies in medicinal chemistry have been heavily inspired (or biased?) by the advances in synthetic chemical methods toward new molecular scaffolds. This raises the question of chemical diversity and unconscious bias toward traditional/ubiquitous building blocks and reliable reactions/protocols for assembling increasingly complex molecules. As a compelling example, the phenyl ring and its related (hetero)aromatic analogues are over‐represented and virtually all best‐selling, over‐the‐counter drugs contain at least one such unit in their core scaffold or as a substituent. It is not particularly surprising as a plethora of synthetic methods for aromatic functionalization have been conceptually and experimentally well established for decades [21]. Such methods include, for example, a wide range of additions and substitutions, cross‐couplings, and aromatization strategies. While this is obviously a significant advantage for the rapid access to a wide range of analogues from a core structure, this bias is an important factor slowing down the discovery of new bioactive scaffolds. Historically, spirocycles have been considered difficult motifs to synthesize, mainly due to the presence of a quaternary carbon center. While chirality is often found in evolutionary optimized, complex natural product‐derived drugs (e.g. Griseofulvin 5, Ivermectin 8), early examples of synthetic spirocyclic drugs (e.g. fluspirilene 13) are achiral. The introduction of stereogenic centers allows higher structural complexity and diversity across the three dimensions, and it has been suggested to be advantageous for the discovery of ligands targeting biological receptors, such as an enzyme active site or a protein–protein interaction (PPI) interface [22]. Equally important is the control of their configuration for achieving optimal interaction with the chiral target receptor. It is well illustrated by the contrasted potencies and/or pharmacologies of various stereoisomers of a wide range of chiral drugs [23, 24], including the infamous thalidomide [25]. Controlling the stereochemical outcome, hence chirality of spirocycles, has been a major focus of synthetic organic chemists in the last decade, and this is reflected by the exponentially growing number of articles in organic chemistry journals reporting the syntheses of increasingly complex spirocyclic systems. Overall, spirocycles have gained increasing popularity in modern drug discovery, and the recent development of robust synthetic methodologies have made them an integral part of the medicinal chemists’ arsenal of pharmacophores for the development of small synthetic molecules targeting therapeutically important biological pathways. This brief chapter captures several important literature examples that illustrate some key applications of spirocycles for the development of bioactive molecules of relevance to the pharmaceutical sector. The breadth of synthetic methods available for the preparation of a wide range of spirocycles will be discussed in the subsequent chapters.

2.2 General Features

The sp³‐rich character of spirocycles and resulting extended range of exit vectors spanning across all three spatial dimensions represent an exciting opportunity for expanding molecular complexity while maintaining structural rigidity. These two parameters are also of prime importance for optimizing the thermodynamic fingerprint of chemical probes and drugs, and achieve optimal potency and selectivity profiles. At the same time, structural novelty opens valuable avenues for exploring new chemical spaces and IP protection of novel bioactive scaffolds. Spirocycles give access to more rigid scaffolds and better‐defined directionality of exit vectors, particularly for spirocycles containing small rings (e.g. cyclobutanes, oxetanes, azetidines, and thietanes, Figures 2.2 and 2.3), which are conformationally highly restricted. Studies by Lovering showed a positive correlation between the simple indicator of saturation Fsp³ = (number of sp³ hybridized carbons/total carbon count) and the number of stereogenic centers as compounds progress through clinical trials, suggesting an enrichment in these features along clinical development [26]. Another direct consequence of their sp³ richness is their higher density of exit vectors (D _ev, Figure 2.2) compared with sp²‐rich systems. D _ev can be a useful primary indicator to rapidly estimate the three‐dimensionality of a scaffold and its potential for molecular complexity and diversity generation through synthesis. We use this indicator