Breaking through the synthetic barriers to medium-sized ring formation opens new frontiers in pharmaceutical chemistry
If you've ever caught the faint scent of jasmine on a night breeze or caught a rather less pleasant whiff in a public restroom, you've encountered an indole. This unique chemical compound, often described as smelling floral at extreme dilution and fecal at higher concentrations, is far more than a curiosity for the senses. It is a versatile organic framework found in everything from the perfumes on your shelf to the neurotransmitters in your brain6 .
Indole consists of a benzene ring fused to a pyrrole ring, containing nitrogen.
Found in neurotransmitters, perfumes, and many pharmaceutical compounds.
The drive to create indole-annulated compounds isn't just for academic exercise. Many of the most powerful bioactive natural products and pharmaceuticals are built on these complex skeletons2 .
Used to treat migraine headaches by constricting blood vessels.
A life-saving drug used to control postpartum bleeding.
A potent anti-cancer agent derived from the Madagascar periwinkle plant3 .
For years, chemists have faced a "Goldilocks" problem in ring synthesis:
Synthetic accessibility of different ring sizes
The direct synthesis of medium-sized rings—specifically seven- to nine-membered ones—has remained a formidable challenge due to:
A comprehensive 2025 review by Nemoto and colleagues categorizes the modern approaches for building 3,4-fused tricyclic indoles into two main philosophies2 .
This approach, known as Category I, uses a pre-formed indole molecule as the starting canvas. Chemists then perform a series of reactions to draw the new, third ring directly onto this framework2 .
Category II is a more daring, "all-in" approach. Instead of starting with an indole, chemists begin with a simpler linear chain and simultaneously construct both the pyrrole ring of the indole and the new fused ring system2 .
A 2021 experiment provides a clever solution to the medium-ring problem through selective ring-opening5 .
Instead of forcing linear chain closure, researchers started with a spiroindoline—a molecule containing the desired eight-membered ring in a strained configuration—then induced selective ring-opening to form the desired indole-annulated eight-membered lactam5 .
Spiroindoline synthesized from β-carboline via dearomative Heck reaction5 .
Spiroindoline dissolved in DCE with catalytic methanesulfonic acid5 .
Acid protonates alkene, triggering C–C bond fragmentation5 .
Methanol traps the cationic intermediate5 .
Yields indole-annulated eight-membered lactam5 .
The researchers successfully synthesized a wide range of eight-membered lactams, demonstrating broad applicability5 .
| Entry | Acid | Solvent | Temperature | Time (h) | Yield (%) |
|---|---|---|---|---|---|
| 1 | HOAc | DCE | 60 °C | 12 | 0 |
| 2 | TFA | DCE | 60 °C | 2 | 68 |
| 3 | HCl | DCE | 60 °C | 2 | 80 |
| 4 | MsOH | DCE | Room Temp. | 2 | 89 |
| 5 | MsOH | DCM | Room Temp. | 2 | 81 |
| 6 | MsOH | Toluene | Room Temp. | 2 | 58 |
The synthesis of complex indole-annulated structures relies on a specialized toolkit of reagents and catalysts.
| Reagent / Catalyst | Function in Annulation | Example from Research |
|---|---|---|
| Chiral Iridium Catalyst | Enables asymmetric synthesis, creating single mirror-image forms of a molecule (enantiomers). | Used in dearomative cyclizations to build seven- to nine-membered rings with high enantioselectivity1 . |
| Brønsted Acids (e.g., MsOH, CPA) | Promotes reactions by protonating substrates, activating them for ring-opening or cyclization. | MsOH catalyzed the protonation-induced ring-opening of spiroindolines5 . Chiral Phosphoric Acids (CPAs) control stereochemistry in Friedel-Crafts reactions4 . |
| Transition Metal Catalysts (e.g., Rh(III), Zn(II)) | Facilitates key bond-forming steps like C-H activation and cyclization via unique reaction pathways. | Rh(III) catalysts enabled domino C-H activation/annulation with 1,6-enynes2 . Zn(II) halides catalyzed tandem cyclopropane ring-opening/Conia-ene reactions. |
| Spiroindoline Precursors | Acts as a strained, high-energy intermediate that can be rearranged into the target medium-sized ring. | Served as the key starting material for the acid-induced ring-expansion to eight-membered lactams5 . |
| 4-Alkynyl Indoles | Provides a reactive alkyne handle on the indole core, allowing for intramolecular cyclization. | Used as substrates in Zn-catalyzed and radical-based annulation reactions to form the new fused ring2 . |
The successful development of methods to access indole-annulated medium-sized rings is more than a technical achievement; it is a gateway to discovery. By making these complex structures readily available for the first time, chemists can now systematically explore a vast new chemical space.
This enables the creation of diverse compound libraries for high-throughput screening against a range of diseases. The ongoing refinement of asymmetric catalysis ensures that these new potential drugs can be synthesized as single, pure enantiomers, a critical requirement for pharmaceutical development1 4 .
From the foundational Fischer indole synthesis to the modern, elegant strategies of ring expansion and tandem cyclizations, the quest to add a "charm" of a third ring to indole has fundamentally expanded the horizons of organic chemistry. This progress promises to accelerate the discovery of the next generation of life-saving therapeutics, proving that sometimes, the most powerful solutions come in ring-shaped packages.