Bicyclic 1,4-Dioxepanes for Drug Discovery: Multigram Synthesis, Physicochemical, and Structural Characterization

Fused and spirocyclic 1,4-dioxepanes bearing a saturated heterocyclic amine ring are proposed as promising molecular frameworks for early drug discovery. The key step of their synthesis included double alkylation of an appropriate saturated N-heterocyclic 1,2-diol with α,α′-dichloroisobutylene. Further chemical modification of the terminal exocyclic double bond in the resulting bicyclic intermediates provided access to a series of valuable building blocks bearing common functional groups as the synthetic handles. The developed protocols demonstrated high efficiency at multigram scale. The potential of the synthesized bicyclic compounds for isosteric replacements was evaluated by physicochemical and conformational profiling, that is, pK_a and LogP measurements, virtual library enumeration, and exit vector analysis based on X-ray diffraction data.