Photocatalytic Deoxygenative Hydroalkylation Enables Modular Access to CF3-Substituted Oxetanes

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Photocatalysis

Background:

• Trifluoromethyl (CF3)-substituted oxetanes are valuable tert-butyl bioisosteres in drug discovery.
• The synthesis of CF3-substituted oxetanes is currently challenging, limiting their application.

Purpose of the Study:

• To develop an efficient and modular synthesis for CF3-substituted oxetanes.
• To expand access to these important bioisosteric motifs for medicinal chemistry applications.

Main Methods:

• Visible-light photocatalytic hydroalkylation of α-CF3 oxetane benzoates with unactivated alkenes.
• Formate-mediated reductive generation of α-CF3 oxetanyl radicals.
• Mild reaction conditions with broad substrate scope and functional group tolerance.

Main Results:

• Successful synthesis of diverse CF3-substituted oxetanes from simple starting materials.
• Demonstration of a modular protocol for accessing these underexplored motifs.
• Facilitation of the incorporation of CF3-substituted oxetanes into medicinally relevant molecules.

Conclusions:

• The reported method provides a new, efficient route to CF3-substituted oxetanes.
• This protocol enhances the accessibility of valuable bioisosteres for drug development.
• The study expands the synthetic toolbox for medicinal chemists seeking novel drug candidates.