TY - JOUR
T1 - Asymmetric Cation-Olefin Monocyclization by Engineered Squalene–Hopene Cyclases
AU - Eichenberger, Michael
AU - Hüppi, Sean
AU - Patsch, David
AU - Aeberli, Natalie
AU - Berweger, Raphael
AU - Dossenbach, Sandro
AU - Eichhorn, Eric
AU - Flachsmann, Felix
AU - Hortencio, Lucas
AU - More Authors, null
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - chemoenzymatic synthesis
KW - cyclization
KW - protein engineering
KW - squalene–hopene cyclases
KW - substrate engineering
UR - http://www.scopus.com/inward/record.url?scp=85115019464&partnerID=8YFLogxK
U2 - 10.1002/anie.202108037
DO - 10.1002/anie.202108037
M3 - Article
AN - SCOPUS:85115019464
SN - 1433-7851
VL - 60
SP - 26080
EP - 26086
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 50
ER -