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

04 November 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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.

Keywords

spiroacetal
morpholine
compound library
oxazepane
spirocycle
KNIME
library enumeration
enol ether

Supplementary materials

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Supporting Information
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Synthesis of the Stolz cross-coupling precursors, significance of solvent choice for hydrogenolysis of carbamate 9, optimization of the synthesis of 6,7-spiroacetal 20, synthesis of 7,6-spiroacetal 24 and attempted synthesis of larger ring systems, synthesis of spiroacetals 59 and 60, general experimental details, experimental procedures and complete compound char-acterization data, 1H- and 13C-NMR data for all compounds, X-ray crystallographic data for spiroacetals 8 and 24, library enumeration including KNIME workflows, library analysis and selection of diversity subset for physical library synthesis.
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Supporting Information
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Scanned copies of NMR spectra.
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