Strain-Release-Driven Modular Synthesis of Oxetane-Based Amide Bioisosteres: Concise, Robust and Scalable Approach

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Amide bioisosterism is a key strategy in drug development for optimizing drug properties and creating novel chemical entities.
• Oxetane-amines present unique opportunities as bioisosteres but are underexplored due to synthetic challenges.
• Existing synthetic methods for oxetane derivatives are often complex and not widely applicable.

Purpose of the Study:

• To develop a practical, modular, robust, and scalable synthetic method for oxetane-containing amide bioisosteres.
• To facilitate the synthesis of previously inaccessible or difficult-to-produce oxetane derivatives.
• To demonstrate the utility of the new method in medicinal chemistry, exemplified by addressing a known metabolic issue in ketoconazole.

Main Methods:

• A two-step synthesis utilizing commercially available oxetan-3-one.
• Formation of amine-benzotriazole intermediates via reaction with oxetan-3-one's reactive keto group.
• Mild reaction of intermediates with organometallic reagents to yield amino-oxetanes.

Main Results:

• Successful construction of oxetane-containing amide bioisosteres through a straightforward procedure.
• Good to high yields of various amino-oxetanes obtained using diverse aliphatic and aromatic organometallic reagents.
• Demonstrated simplification of synthesizing complex oxetane derivatives.
• Successfully addressed a metabolic liability in ketoconazole using the developed method.

Conclusions:

• The reported two-step method provides a facile and broadly applicable route to oxetane-containing amide bioisosteres.
• This approach significantly enhances the accessibility of novel oxetane derivatives for drug discovery programs.
• The method offers a valuable tool for medicinal chemists to overcome synthetic hurdles and improve drug candidates.