Remote Biocatalytic Stereoselective Synthesis of Axially and Centrally Chiral Alkylidene Cyclopentanols

Axially chiral alkylidene cycloalkanes are important scaffolds found in various bioactive molecules, yet their synthetic methods remain underdeveloped. In particular, the construction of alkylidene cycloalkanes bearing both axial and central chiralities poses a significant challenge. In this work, we present an efficient and green strategy for synthesizing axially chiral alkylidene cyclopentanones and cyclopentanols through a remotely controlled kinetic resolution (KR) approach. Directed evolution of an alcohol dehydrogenase (TbSADH) from Thermoethanolicus brockii yielded a variant (TbSADH-I86A/W110R/Y267L) capable of catalyzing the stereoselective reduction, affording a diverse range of axially and centrally chiral alkylidene cyclopentanols with high enantio- and diastereoselectivity, as well as excellent selectivity factors (ee up to 99%, dr up to >99:1, and s up to >100). Additionally, we demonstrated the stereodivergent synthesis of alcohols featuring both axial and central chirality via chemoenzymatic methods. To elucidate the molecular recognition mechanisms, molecular docking studies were conducted, revealing that the altered active pocket geometry of the mutant enzyme enhances both activity and enantioselectivity. This methodology not only provides a novel biocatalytic platform for accessing nonatropisomeric axially chiral structures with dual chirality elements but also underscores the potential of enzymatic strategies as powerful tools for remote stereocontrol in synthetic organic chemistry.