Intramolecular, Interrupted Homo-Nazarov Cascade Biscyclizations to Angular (Hetero)Aryl-Fused Polycycles

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Catalysis

Background:

• Accessing complex polycyclic structures is crucial in medicinal chemistry and natural product synthesis.
• Existing methods for constructing angular fused polycycles often require multiple steps and harsh conditions.
• The development of efficient cascade reactions is highly desirable for streamlining synthetic routes.

Purpose of the Study:

• To report a novel tin tetrachloride (SnCl4)-catalyzed intramolecular, interrupted homo-Nazarov cascade biscyclization.
• To develop a scalable and modular synthetic route for cyclopropyl homo-Nazarov cyclization precursors.
• To demonstrate the utility of the developed method through the total synthesis of a natural product.

Main Methods:

• Tin tetrachloride (SnCl4) catalyzed intramolecular, interrupted homo-Nazarov cascade biscyclization.
• Decarboxylation of enolizable products to yield angular fused polycycles.
• Modular synthesis of cyclopropyl homo-Nazarov cyclization precursors.
• Eight-step total synthesis of (±)-1-oxoferruginol.

Main Results:

• The cascade biscyclization provides access to angular (hetero)aryl-fused polycycles.
• Subsequent decarboxylation yielded angular products in up to 71% yield over two steps, with trans-diastereomers predominating.
• The synthetic route allows for the construction of various fused polycyclic systems, including 6,6,6-, 6,6,5-, 6,5,6-, 6,6,5,6-, and 6,6,6,5-fused structures.
• The method was successfully applied to an 8-step total synthesis of the antibacterial abietane diterpenoid (±)-1-oxoferruginol.

Conclusions:

• A novel and efficient SnCl4-catalyzed cascade biscyclization strategy has been established for the synthesis of angular polycycles.
• The developed method offers a scalable and modular approach to diverse fused polycyclic frameworks.
• The successful total synthesis of (±)-1-oxoferruginol highlights the practical utility and robustness of this synthetic methodology.