Biocatalytic stereocontrolled head-to-tail cyclizations as a tool for streamlined hybrid synthesis of terpenes

Abstract The stereocontrolled cationic cyclization cascade is a vital step in the modular biogenesis of terpenes, as it defines the carbon skeleton's three-dimensional structure in one atom-economical step. While nature has adopted this strategy for eons, state-of-the-art synthetic routes to asymmetrically access cyclic terpenes still rely predominantly on sequential multi-step scaffold remodelling of a few abundant precursors. Herein, we bridge this long-standing methodological gap and demonstrate the target-oriented synthesis ability of the squalene-hopene cyclase. Our mechanistic insights show that the biocatalytic head-to-tail cyclization is highly customizable by mechanism-guided enzyme engineering and substrate-focused setup engineering. As a result, we demonstrate two- or three-step hybrid synthetic routes of pheromones, fragrances, and drug candidates by merging a stereocontrolled cyclization with interdisciplinary synthetic and catalytic methods. This biomimetic strategy significantly reduces the synthesis effort to terpenes and provides rapid access to thousands of head-to-tail-fused scaffolds.