Expanding the Cation Cage: Squalene-Hopene Cyclase-Mediated Enantioselective Semipinacol Rearrangement

Abstract

Squalene-hopene cyclases (SHCs) are the biocatalytic pendant to asymmetric Brønsted-acid catalysis and thus comprise enormous synthetic potential. Nevertheless, their substrate scope is currently limited to terpenes. Herein, we present how to tailor the SHC’s cation cage for an enantioselective semipinacol rearrangement of bicyclic allylic alcohols to produce valuable oxa-carbon spirocyclic compounds. Exploiting the subtle divergence of SHC active sites combined with structure-guided semirational engineering, we designed a biocatalyst with a high catalytic performance of ∼4500 TTN and excellent enantioselectivity of 99.5% enantiomeric excess (ee). In silico studies suggest that a broadened active site is pivotal for catalysis. This intricate cationic rearrangement is easily scalable, employing lyophilized cell powder in water. Furthermore, our substrate scope studies demonstrate the acceptance of diverse ring-sized substrates but also reveal that the naturally confined active site limits the function as a general “semipinacolase.” This study showcases the ability to harness the SHC’s cation cage to tap into the broader field of asymmetric Brønsted-acid catalysis.