Biocatalytic Access to Natural Mosquito Repellent p ‐Menthane‐3,8‐diol via Direct Asymmetric Prins Cyclohydration

ABSTRACT Vector‐borne diseases pose a rising global health challenge, necessitating the development of safe and effective pest protection agents. Here, we report a highly selective biocatalytic direct Prins cyclohydration for the synthesis of (1 R )‐ cis ‐ p ‐menthane‐3,8‐diol (PMD), a natural insect repellent with high efficacy. By strategically engineering squalene‐hopene cyclases (SHCs), we achieved >96% diastereomeric excess, surpassing previous synthetic methods. Structural and mechanistic analyses suggest direct Prins cyclohydration and a precisely positioned water molecule within the enzyme's active pocket adjacent to the final carbocation that drives hydration and catalytic efficiency. Fine‐tuning the biocatalytic setup enabled preparative scale production, without losing much product selectivity. Moreover, we demonstrate access to the other naturally occurring PMD isomers from ( R )‐ and ( S )‐citronellal, as well as a one‐pot cascade starting from E / Z ‐citral. This study paves the way for highly selective access to stereodefined terpene‐derived repellents and establishes engineered squalene‐hopene cyclases as a tool for direct asymmetric Prins cyclohydration.