Strategies for Modification of Tryptophan Residues: Recent Advances and Future Perspectives in Photo‐/ Electrochemical‐Induction, and Metal Catalysis

Abstract Tryptophan (Trp) is an essential amino acid distinguished by its unique indole ring, making it an ideal target for chemical modification. Recent advancements in modification strategies, including photo‐/electrochemical‐induced, and metal‐catalyzed techniques, have significantly enhanced the efficiency and selectivity of Trp modifications, expanding its applications across drug development, materials science, and environmental monitoring. Photochemical‐induced modifications, which utilize light energy to drive reactions under mild conditions, offer a green and efficient method for Trp transformation. This approach often improves Trp's optical properties, such as fluorescence, thereby enhancing its utility in bioimaging and sensor applications. Light‐driven modifications also allow the introduction of functional groups, yielding bioactive derivatives with potential therapeutic benefits. Electrochemical‐induced modifications, which leverage electric energy to precisely regulate oxidation and reduction processes, enable selective Trp modifications through fine‐tuning of applied potential. This method supports the targeted addition of functional groups like hydroxyl or amino groups, essential for synthesizing Trp derivatives aimed at modulating protein activity and developing new therapeutic agents. Both photo‐ and electrochemical methods generate radical intermediates via single‐electron transfer (SET), aligning well with Trp's redox‐active nature. These methods also offer mild and controllable conditions that address chemo‐ and regioselectivity challenges inherent in traditional bioconjugation strategies. The promising advantages of photo‐ and electrochemical redox catalysis underscore the appeal of novel Trp‐based bioconjugation methods. In addition, metal‐catalyzed transformations using transition metals such as palladium or copper allow for complex modifications, including C−H activation and cross‐coupling reactions, which enable site‐selective alterations within the Trp molecule. These metal‐catalyzed modifications yield derivatives with enhanced chemical, optical, or biological properties, suitable for applications in optoelectronics, biosensors, and medicinal chemistry. Collectively, these advancements in Trp modification elevate its utility across diverse scientific disciplines, providing a versatile platform for creating novel compounds with superior chemical, biological, and optical characteristics. This review aims to comprehensively summarize the latest advancements in Trp modification, with an emphasis on their transformative impact across various fields.