Biocatalytic Directed Cationic Cyclization Cascades toward Fragrance Ingredients

Key words

squalene–hopene cyclase - directed cyclization - cascade reaction - molecular anchoring - monocyclization - fragrances

Significance

The Hauer group and a collaborative effort between the groups of Buller and ­Bornscheuer and Givaudan independently report the development of engineered squalene–hopene cyclases (SHCs) for stereoselective, cationic cyclization cascades toward natural products and, in particular, fragrance ingredients. The Hauer group describes a biocatalytic monocyclization of neryl acetone by using an engineered SHC from Alicyclobacillus acidocaldarius (AacSHC) to give (R)-γ-dihydroionone in excellent yield and enantioselectivity. Buller and collaborators report a complimentary stereodivergent approach from either neryl or geranyl acetone by using variants based on a previously unidentified SHC from Acidothermus cellulolyticus (AciSHC).

Comment

Cationic cyclization cascades serve as powerful tools for the rapid assembly of complex carbon skeletons in a highly efficient manner. However, stereoselective methods to interrupt the cascade at a desired intermediate to preferentially ­access monocyclic products are challenging and underdeveloped. The Hauer group devised a strategy to overcome this limitation by engineering the active site of an SHC. Specific addition of stabilizing hydrogen-bonding interactions for substrate anchoring favors deprotonation over the usual bicycle formation. Buller and collaborators demonstrated that the stereoselectivity of the cyclization is governed by the double-bond geometry of the starting material, due to identical prefolding of the chair.

Publication History

Article published online:
17 September 2021