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Squalene-hopene cyclases (SHCs) have great potential for the industrial synthesis of enantiopure cyclic terpenoids. A limitation of SHC catalysis so far, however, 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 such as ( R )- and ( S )-γ-dihydroionone, an SHC wild-type library including 18 novel homologs was set up. A previously not described SHC from Acidothermus cellulolyticus ( Aci SHC) was found to synthesize small amounts of the desired monocyclic ( R )-γ-dihydroionone from ( E/Z )-geranylacetone. Using enzyme and process optimization, the conversion to the desired product was increased by two orders of magnitude to 79%. Notably, analyzed Aci SHC 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 through substrate engineering.

Vetiver oil, produced on a multiton‐scale from the roots of vetiver grass, is one of the finest and most popular perfumery materials, appearing in over a third of all fragrances. It is a complex mixture of hundreds of molecules and the specific odorant, responsible for its characteristic suave and sweet transparent, woody‐ambery smell, has remained a mystery until today. Herein, we prove by an eleven‐step chemical synthesis, employing a novel asymmetric organocatalytic Mukaiyama–Michael addition, that (+)‐2‐epi‐ziza‐6(13)en‐3‐one is the active smelling principle of vetiver oil. Its olfactory evaluation reveals a remarkable odor threshold of 29 picograms per liter air, responsible for the special sensuous aura it lends to perfumes and the quasi‐pheromone‐like effect it has on perfumers and consumers alike., Despite the advance of modern analytic techniques, the smelling principle of vetiver oil is still unknown owing to its extremely complex matrix of over 150 compounds. A concise stereoselective total synthesis proves (+)‐2‐epi‐ziza‐6(13)en‐3‐one to be the key to the quasi‐pheromone‐like aura of vetiver that magically resembles the effect of Iso E Super.