Macrocyclization via remote meta-selective C-H olefination using a practical indolyl template

Area of Science:

• Organic Chemistry
• Catalysis
• Medicinal Chemistry

Background:

• Macrocyclic compound synthesis via C-H activation is challenging.
• Developing efficient and versatile macrocyclization strategies is crucial.

Purpose of the Study:

• To develop a novel palladium-catalyzed macrocyclization strategy.
• To demonstrate the synthesis of diverse macrocyclic compounds including macrolides, coumarins, and the antitumor drug belinostat.
• To explore the use of copper acetate and molecular oxygen as oxidants.

Main Methods:

• Palladium-catalyzed remote meta-C-H olefination using an indolyl template.
• Intramolecular and intermolecular C-H olefination reactions.
• In situ monitoring using Fourier-transform infrared spectroscopy and ESI-MS.

Main Results:

• An efficient macrocyclization strategy via Pd-catalyzed meta-C-H olefination was developed.
• The method successfully synthesized macrolides and coumarins.
• Intermolecular olefination yielded the antitumor drug belinostat from simple precursors.
• Copper acetate and O2 replaced silver salts as oxidants.
• A cyclopalladated intermediate was detected for the first time.

Conclusions:

• The developed strategy offers an efficient route to diverse macrocyclic compounds.
• This method provides a practical approach for synthesizing complex molecules, including pharmaceuticals.
• The use of copper and oxygen as oxidants presents a greener alternative.