Spirocyclic Scaffolds in Medicinal Chemistry

Abstract

Spirocyclic scaffolds are incorporated in various approved drugs and drug candidates. The increasing interest in less planar bioactive compounds has given rise to the development of synthetic methodologies for the preparation of spirocyclic scaffolds. In this Perspective, we summarize the diverse synthetic routes to obtain spirocyclic systems. The impact of spirocycles on potency and selectivity, including the aspect of stereochemistry, is discussed. Furthermore, we examine the changes in physicochemical properties as well as in in vitro and in vivo ADME using selected studies that compare spirocyclic compounds to their nonspirocyclic counterparts. In conclusion, the value of spirocyclic scaffolds in medicinal chemistry is discussed.

Photocatalytic Hydroaminoalkylation of Styrenes with Unprotected Primary Alkylamines

“… 41 Of the ∼43 000 known small-molecule THQs featuring alkylation α to nitrogen at C(2), only a third are α,α-dialkylated (almost exclusively α,α-dimethyl), and only ∼1% are spirocyclic at C(2). 42 Given the explosion of interest in spirocycles in medicinal chemistry over the past two decades, 43 the rarity of spirocyclic THQs is somewhat surprising. Thus, a modular strategy to access C(2)-(di)alkylated (including spirocyclic) THQs that is relatively insensitive to the electronics of the benzenoid component could greatly expand the accessible chemical space in this area.…”

New Methods for the Synthesis of Spirocyclic Cephalosporin Analogues

“…Although the focus of this work has been the fusion of antioxidants, such as coumarins and flavonoids, with the cephalosporin core, we anticipate that spiro-cyclisation could be achieved with a range of other interesting catechol species, such as dopamine, apomorphine, catechin and caffeic acid. Given the recent rise in interest in the synthesis of spirocyclic motifs in medicinal chemistry [ 52 ], we anticipate that this new approach to spirocyclisation might be implemented across other target structures.…”

Modern Synthetic Strategies with Organoselenium Reagents: A Focus on Vinyl Selenones

“…In the past decade, the development of new methods for the synthesis of spirocycles became a hot topic in organic synthesis. The conformational rigidity, the three-dimensional nature with substituents in well-defined spatial disposition, the improved physicochemical and pharmacokinetic properties and the relative structural novelty make spirocycles attractive leads in drug discovery programs [ 24 , 25 ]. In fact, compared to flat aromatic compounds, they seem to have more chances to maximize specific interactions with biomolecules.…”