Skeletal Editing Approach to Bridge-Functionalized Bicyclo[1.1.1]pentanes from Azabicyclo[2.1.1]hexanes

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Azabicyclo[2.1.1]hexanes (aza-BCHs) and bicyclo[1.1.1]pentanes (BCPs) are valuable 3D scaffolds in drug design.
• Replacing flat aromatic groups with these sp³-rich cores enhances metabolic stability.
• Efficient methods for interconverting these scaffolds are needed for drug development.

Purpose of the Study:

• To develop a novel synthetic strategy for scaffold hopping between aza-BCH and BCP cores.
• To enable efficient access to bridge-functionalized BCPs via a nitrogen-deleting skeletal edit.
• To facilitate exploration of 3D chemical space for pharmaceutical applications.

Main Methods:

• Utilizing photochemical [2+2] cycloadditions to synthesize multifunctional aza-BCH frameworks.
• Implementing a deamination step to convert aza-BCHs into BCPs.
• Employing a modular sequence for skeletal editing.

Main Results:

• A new method for scaffold hopping between aza-BCH and BCP structures was established.
• The strategy allows for the synthesis of bridge-functionalized BCPs, a challenging target.
• The modular sequence provides access to diverse privileged bridged bicycles.

Conclusions:

• The described method offers a direct route for skeletal editing between aza-BCH and BCP systems.
• This approach expands synthetic accessibility to valuable 3D molecular frameworks for drug discovery.
• The strategy facilitates the interpolation of chemical space between these important bioisosteres.