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

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Fused and spirocyclic 1,4-dioxepanes are underexplored scaffolds in medicinal chemistry.
• Incorporating saturated heterocyclic amine rings offers unique structural and physicochemical properties.

Purpose of the Study:

• To develop efficient synthetic routes to novel fused and spirocyclic 1,4-dioxepanes.
• To explore the potential of these compounds as building blocks for early drug discovery.
• To evaluate their suitability for isosteric replacement strategies.

Main Methods:

• Double alkylation of N-heterocyclic 1,2-diols with α,α'-dichloroisobutylene.
• Chemical modification of exocyclic double bonds in bicyclic intermediates.
• Physicochemical profiling (pK_a, LogP) and conformational analysis (X-ray diffraction, virtual libraries).

Main Results:

• High-efficiency, multigram-scale synthesis of target dioxepanes achieved.
• Versatile building blocks with common functional groups were generated.
• Physicochemical and conformational data support their potential for isosteric replacement.

Conclusions:

• The developed synthetic protocols are efficient and scalable.
• The synthesized dioxepanes represent valuable scaffolds for drug discovery programs.
• These compounds offer promising opportunities for isosteric modifications in lead optimization.