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

11 May 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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. Herein, we bridge this long-standing methodological gap by unlocking 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.


cation-olefin cyclization
squalene-hopene cyclase
new to-nature conditions
hybrid synthesis

Supplementary materials

Supplementary information for the main text
This file contains Supporting figures, tables, NMR data, chromatograms, mass spectra, chemical syntheses, preparative scale biotransformations, computational data and general methods.


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.