Asymmetric Cation-Olefin Monocyclization by Engineered Squalene–Hopene Cyclases

Michael Eichenberger, Sean Hüppi, David Patsch, Natalie Aeberli, Raphael Berweger, Sandro Dossenbach, Eric Eichhorn, Felix Flachsmann, Lucas Hortencio, More Authors

Research output: Contribution to journalArticleScientificpeer-review

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Abstract

Squalene–hopene cyclases (SHCs) have great potential for the industrial synthesis of enantiopure cyclic terpenoids. A limitation of SHC catalysis has been the enzymes’ strict (S)-enantioselectivity at the stereocenter formed after the first cyclization step. To gain enantio-complementary access to valuable monocyclic terpenoids, an SHC-wild-type library including 18 novel homologs was set up. A previously not described SHC (AciSHC) was found to synthesize small amounts of monocyclic (R)-γ-dihydroionone from (E/Z)-geranylacetone. Using enzyme and process optimization, the conversion to the desired product was increased to 79 %. Notably, analyzed AciSHC variants could finely differentiate between the geometric geranylacetone isomers: While the (Z)-isomer yielded the desired monocyclic (R)-γ-dihydroionone (>99 % ee), the (E)-isomer was converted to the (S,S)-bicyclic ether (>95 % ee). Applying the knowledge gained from the observed stereodivergent and enantioselective transformations to an additional SHC-substrate pair, access to the complementary (S)-γ-dihydroionone (>99.9 % ee) could be obtained.

Original languageEnglish
Pages (from-to)26080-26086
Number of pages7
JournalAngewandte Chemie - International Edition
Volume60
Issue number50
DOIs
Publication statusPublished - 2021

Keywords

  • chemoenzymatic synthesis
  • cyclization
  • protein engineering
  • squalene–hopene cyclases
  • substrate engineering

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