Invisible architects: traceless directing group strategy towards late-stage functionalization and synthesis of drug derivatives

Abstract

Site-selective C–H bond functionalization, such as C–C or C–X (X = heteroatom) bonds, remains a challenging task. Traditionally, directing groups are used to achieve high selectivity for such processes; however, many of them require additional steps for removal, thereby reducing the overall efficiency and atom economy of the process. Traceless directing groups (TDGs) offer a smart solution, which can be attached temporarily, guide the reaction, and then detached without affecting other parts of the molecule. This approach minimizes waste and streamlines the synthetic process. In this review, we have highlighted the role of carboxylic acid derivatives, nitrogen-based groups, and related functionalities as TDGs, along with insights from mechanistic studies and their applications in drug synthesis and bioactive pharmaceuticals. Herein, we document the synthesis of over 35 complex molecules reported between 2017 and 2025. In addition, we also summarize the synthesis of several value-added products, providing a more comprehensive perspective on the potential of TDG chemistry and its applications.