Sonogashira Cross‐Coupling Reaction in Natural Product Synthesis
Ghulam Shabir, Aamer Saeed, Ayesha Mariyam, Rikza Noor, Sehar Saeed, Tahreem Mushtaq, Fatima Akraam, Muhammad Abdullah, Sumra Razzaq, Mouazama MobeenABSTRACT
The Sonogashira cross‐coupling reaction, developed in 1975, has become a vital method for carbon–carbon bond formation in synthetic organic chemistry, particularly between terminal alkynes and aryl or vinyl halides. This palladium‐mediated transformation, often aided by copper (I) iodide, is widely used in the construction of natural products and biologically active molecules under mild conditions. This review provides a critical overview of the mechanism, catalyst development, and synthetic scope of the Sonogashira reaction, with particular emphasis on copper‐free protocols, reduced palladium loadings, catalytic efficiency, and improved reaction performance. Notable applications include the synthesis of Calothrixin B, glycoporphyrins, estrone analogues, synthesis of asparenydiol, and complex alkaloids such as aspergilline A. Additionally, alternative strategies such as sila‐Sonogashira coupling, oxidative ring formation, and the construction of frameworks such as pyrazoles, enediyne‐based compounds, and polysaccharide derivatives are discussed in terms of their synthetic utility and efficiency. Recent advances in copper‐free, low‐palladium, solvent‐free, and other more sustainable Sonogashira methodologies are also highlighted, together with comparative consideration of catalyst systems, reaction conditions, and synthetic performance. These developments underscore the Sonogashira reaction's adaptability, synthetic utility, and continuing importance in modern organic and medicinal chemistry.