Bicyclic 1,4-Dioxepanes – Novel Advanced Building Blocks for Drug Discovery

A series of fused and spirocyclic 1,4-dioxepanes bearing a saturated heterocyclic amine ring were synthesized. The key step of the synthesis included double alkylation of an appropriate saturated N-heterocyclic 1,2-diol with alpha,alpha'-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 (amine, carboxylic acid, alcohol, etc.) The developed protocols demonstrated high efficiency, versatility, and applicability, offering a synthetic platform for accessing novel 1,4-dioxepane-containing frameworks with potential utility in chemical and pharmaceutical research. Additional evidence for that was obtained by physicochemical profiling of the synthesized bicyclic compounds (i.e., pKa and LogP measurements), which evaluated their potential for isosteric replacements.