Development and Applications of Water-Compatible Reactions: A Journey to Be Continued

Conspectus The pursuit of novel and eco-friendly methods in organic synthesis is gaining prominence, with a strong emphasis on green transformations using renewable and sustainable resources. Among these environmentally conscious approaches, water-compatible reactions stand out for their many advantages. Water, as a solvent, offers unmatched abundance, cost-efficiency, and environmental compatibility compared to organic solvents. Its use eliminates the need for complex protection and deprotection steps for reactive functional groups in multistep synthesis and enables the use of water-soluble substrates like proteins and carbohydrates. Water-compatible reactions also provide opportunities to combine with enzymes, resulting in chemoenzymatic transformations that can increase efficiency. Additionally, these reactions facilitate site-specific modification and the bioconjugation of biomolecules, leading to bioconjugate therapeutics. Over nearly three decades, our research group has been dedicated to developing innovative water-compatible methodologies and concepts. This Account provides a comprehensive overview of our contributions since 1994. Our central strategy revolves around integrating green chemistry principles into our methods, focusing on (i) developing reactions that can operate under mild conditions, including room temperature, atmospheric pressure, and physiological pH; (ii) designing atom-economical reactions that minimize waste production; (iii) replacing toxic and flammable organic solvents with eco-friendly alternatives like water and ethanol; and (iv) reducing reliance on metals or halogenated compounds in specific reactions. In this Account, we detail our achievements in developing efficient methodologies in aqueous media, highlighting their scope, limitations, asymmetric control, and applications for synthesizing complex molecules and functionalizing peptides and proteins. Mechanistic investigations underlying these developments are also discussed when applicable. Furthermore, we offer insights into the reasoning behind our work and address future opportunities and challenges in this area of research. We hope that this Account will inspire continued interest and foster new breakthroughs. By exploring innovative and broadly applicable strategies that expand the water-compatible synthetic toolbox, we aim to pave the way for the truly green and sustainable synthesis of complex molecules and pharmaceuticals.