Synthesis of 1-Substituted Bicyclo[2.1.1]hexan-2-ones via a Sequential SmI₂-Mediated Pinacol Coupling and...

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• Bicyclic ketones are important scaffolds in organic synthesis.
• Developing efficient synthetic routes to complex molecules is crucial for drug discovery.
• Samarium diiodide (SmI2) is a versatile reagent for reductive coupling reactions.

Purpose of the Study:

• To develop a novel two-step synthetic procedure for 1-substituted bicyclo[2.1.1]hexan-5-ones.
• To demonstrate the utility of these bicyclic ketones in the synthesis of sp3-rich drug analogs.
• To synthesize an analog of nitazoxanide, an antiparasitic and antiviral drug.

Main Methods:

• A SmI2-mediated transannular pinacol coupling reaction was used.
• An acid-catalyzed pinacol rearrangement followed the coupling reaction.
• Cyclobutanedione derivatives served as starting materials.

Main Results:

• A diverse range of 1-substituted bicyclo[2.1.1]hexan-5-ones were successfully prepared.
• The synthesized bicyclic ketones were utilized in further synthetic transformations.
• An sp3-rich analog of nitazoxanide was synthesized, showcasing the method's applicability.

Conclusions:

• The developed two-step procedure provides an efficient route to valuable bicyclic ketone intermediates.
• These intermediates are useful for constructing sp3-rich molecular architectures relevant to medicinal chemistry.
• The synthesis of a nitazoxanide analog highlights the potential of this methodology in drug development.