Modular Access to Functionalized Oxetanes as Benzoyl Bioisosteres

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Agrochemical Research

Background:

• Bioisosterism is key for optimizing drug properties.
• 3-Aryl oxetanes are important benzoyl bioisosteres but synthetically challenging.
• Limited use in pharmaceuticals and agrochemicals due to synthetic difficulties.

Purpose of the Study:

• To develop a modular synthetic strategy for functionalized 3-aryl oxetanes.
• To enable easier access to oxetane analogues for drug discovery and agrochemical applications.
• To overcome the synthetic challenges associated with 3-aryl oxetanes.

Main Methods:

• A novel modular synthesis using oxetanyl trichloroacetimidates.
• Strategy inspired by Schmidt glycosylation, utilizing aryl halides and nucleophiles.
• Application in late-stage functionalization and analogue synthesis.

Main Results:

• Developed an operationally simple protocol for diverse functionalized oxetanes.
• Demonstrated broad applicability through late-stage functionalization of complex molecules.
• Enabled rapid synthesis of oxetane analogues of known bioactive compounds and marketed drugs.

Conclusions:

• The new strategy provides facile access to valuable 3-aryl oxetanes.
• This approach facilitates the exploration of oxetanes in drug discovery and agrochemicals.
• Mechanistic insights suggest the oxetane oxygen stabilizes key carbocation intermediates.