Asymmetric Cation‐Olefin Monocyclization by Engineered Squalene–Hopene Cyclases

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. The intrinsic capability of squalene–hopene cyclases to convert (E)‐ or (Z)‐substrates enantiospecifically to (S)‐ or (R)‐configurated monocyclic terpenoids was put into action by a combination of enzyme evolution and substrate engineering for the synthesis of (S)‐ and (R)‐γ‐dihydroionone with >99 % ee.