Olefin isomerization-Michael addition cascade in aqueous micelles: a new piperazine-based antifungal chemotype

Abstract

Advancing sustainability and catalysis in synthetic organic processes has emerged as a central theme, driven by pressing environmental challenges associated with the manufacture of fine chemicals, pharmaceuticals, agrochemicals, and functional materials. At the core of this shift is the growing use of alternative reaction media, particularly water, and the adoption of energy-efficient processes, owing to their inherent advantages and superior environmental performance. In this context, we report a water-assisted olefin isomerization-Michael addition cascade reaction of functionalized β,γ-unsaturated olefins with amines in aqueous SDS micelles (2% w/w). The reaction proceeds at room temperature without the need for additional catalysts, additives, or activators, and demonstrates a broad substrate scope with excellent yields and functional group tolerance. Process scalability, recyclability of the aqueous micelles, 100% atom economy, and a low E factor further underscore the sustainability and efficiency of this methodology. Mechanistic studies establish that water plays a central role in enabling the amine-assisted olefin isomerization (β,γ → α,β) followed by Michael addition, likely through stabilization of reactive intermediates via water-mediated hydrogen-bonding networking. The resulting nitrile-containing piperazine derivatives were evaluated for antifungal activity. Compounds 3g and 3h demonstrated promising antifungal activity, showing molecular synergy with fluconazole and inducing ROS-mediated fungal growth inhibition, an important mechanistic strategy for combating fungal infections. Furthermore, these compounds demonstrated efficacy against a rapidly growing, drug-resistant clinical strain of Candida auris, a pathogen ranked as a critical priority by the WHO. Overall, our findings reaffirm the growing importance of sustainable chemistry in shaping the future of drug discovery and development.