A short scalable route to bis-morpholine spiroacetals and oxazepane analogues: useful 3D-scaffolds for compound library assembly

sp3-Rich molecular scaffolds incorporating nitrogen heterocycles represent important starting points for the assembly of compound screening libraries and drug discovery. Herein, we report a four-step synthesis of a conformationally well-defined sp3-rich scaffold, incorporating two morpholine rings embedded within a spiroacetal framework. The synthesis involves the intermediacy of a 2-chloromethyl-substituted morpholine, accessed from readily available starting materials, namely aminoalcohols and epichlorohydrin. Base-mediated dehydrochlorination affords an exocyclic enol ether, from which the second morpholine ring is constructed in two steps. Scaffold synthesis is high-yielding and can be performed on large scale. The methodology allows ready substitution of one –or both– of the morpholine rings for 1,4-oxazepanes and the generation of 6,7- and 7,7-spiroacetal analogues, which are virtually unexplored in drug discovery. Substituted 6,6-systems can also be prepared, and in some instances, undergo acid-mediated anomerization to deliver the scaffolds in high diastereoselectivity. The two amine functionalities embedded in the 6,6- and 6,7-spiroacetal scaffolds were sequentially functionalized, allowing the generation of a diverse physical compound library. These library compounds occupy a similar chemical space to small-molecule drugs that have been approved for clinical application by the Food and Drug Administration yet are structurally dissimilar, and may therefore act upon novel targets, representing attractive starting materials for drug discovery.