Multigram Synthesis of 2-Oxaadamantane and 5-Substituted Derivatives

The 2-oxaadamantane cage is a promising building block in drug discovery. However, its synthesis is often hindered by complex and low-yielding methods. We report a scalable and cost-effective synthesis of 2-oxaadamantane, a valuable adamantane analogue that addresses the challenges associated with adamantane’s lipophilicity and solubility. Our approach utilizes inexpensive reagents and mild reaction conditions in a four-step process, providing a readily accessible route to this key intermediate. We further demonstrate methods for the synthesis of 5-substituted 2-oxaadamantanes and provide an improved synthesis of a diketone precursor suitable for the preparation of 1-substituted derivatives. This work significantly enhances the availability of these valuable adamantane building blocks for medicinal chemistry applications.