Shackles Off: A Kilo Scale Synthesis of Rawal’s Diene

Despite superior reactivity compared to Danishefsky's diene, Rawal's diene suffered from low commercial availability, limited scalability, and obscure stability issues. Herein, we present an optimized, scalable synthetic protocol that achieves yields suitable for the diene’s semi-industrial production, with adjustments to reagent concentrations, reaction conditions, and isolation procedures to enhance the efficiency of the synthetic protocol. Complementing synthetic advancements, this work explores the diene's physicochemical stability under diverse storage conditions. Rigorous quality control methodologies exploiting NMR and IR spectroscopy facilitate precise monitoring of purity and degradation pathways, establishing robust analytical standards. Additionally, the work demonstrates the utility of Rawal's diene in multigram syntheses of 2-alkyl-2,3-dihydro-4H-pyran-4-ones, showcasing its applicability for medicinal chemistry purposes. The findings disclosed in the paper establish a foundation for the broader adoption and commercialization of Rawal's diene, enabling its integration into academic and industrial workflows.