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, but many of them required additional steps for removal, reducing overall efficiency and atom economy of the process. Traceless directing groups (TDG) offer a smart solution that 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 traceless directing groups, along with insights from mechanistic studies and their applications in drug synthesis, and bio-active pharmaceuticals. Herein, we have documented >35 complex molecules accomplished during 2017 to 2025. In addition, we have also summarized the synthesis of several value-added products, thereby offering a more comprehensive perspective on the potential of TDG chemistry and its application.