eSpiro: A Scalable and Sustainable Electrosynthetic Route to Spiroketals via Anodic Oxidation of Malonic Acids

Abstract

Spiroketals are important structural motifs found in natural products, pharmaceuticals, and agrochemicals. However, their synthesis often requires hazardous reagents and harsh conditions, limiting their accessibility. Here, we present eSpiro, a novel electrosynthetic method for the efficient and sustainable synthesis of spiroketals via anodic oxidation of malonic acids. This approach offers a metal- and mercury-freealternative to conventional acid-catalysed or transition metal-mediated cyclisations. The reaction proceeds through a sequential Hofer-Moest decarboxylation, followed by Brønsted acid-mediated cyclisation, achieving high yields with broad functional group tolerance. We further explore the reaction scope and demonstrate its scalability, achieving up to 98% yield in batch. Additionally, we investigate a flow electrolysis setup, highlighting key challenges such as substrate stability, in-line solvent system switch and gas evolution, while demonstrating preliminary success in integrating electrochemical oxidation with downstream acid-catalysed cyclisation. This work provides a practical and eco-friendly route to spiroketals, with potential for industrial applications in organic synthesis.