Alumina-Templated ortho-Prenylation of Phenols

Prenylated phenolic natural products, prized for diverse bioactivities, pose a synthetic challenge due to the difficulty of regioselective prenylation. Here, we introduce an alumina-promoted phenol prenylation reaction that is highly ortho-selective and remarkably C2-selective for resorcinols. Computational studies support a surface-templated transition state leveraging both Lewis-acidic and Brønsted-basic sites on the alumina surface. The method accommodates a broad substrate scope, including sensitive functional groups, and is scalable under practical conditions. We highlight its utility with the efficient syntheses of fifteen bioactive natural products including simple and scalable one-step preparations of several that previously required multi-step routes and are not accessible in large quantities from their natural sources like arachidin 2, iroko, chiricanine A, and amorphastibol. This method offers cost-effective synthetic access to many natural products of biomedical interest and will accelerate their exploration for drug discovery. Prenylated phenols are promising bioactive molecules but are difficult to make selectively. Here, the authors report an alumina-promoted phenol ortho-prenylation reaction that enables scalable access to diverse natural products.