Biocatalytic Activation of Sulfur Heteroaromatics Facilitates Dearomatizing Cross-Couplings to Set Stereogenic Centers or Axes

The enantioselective manipulation of abundant flat (hetero)aromatic building blocks through either dearomatization, to establish new stereocenters, or cross-coupling, to construct a stereogenic axis, is an attractive means to generate three-dimensional molecular architectures. By merging the selectivity of engineered biocatalysts with the versatility of chemical synthesis, we establish a new platform for the metal-free enantioselective manipulation of sulfur-containing heteroaromatics, allowing either point or axial chirality to be set. The key to this approach is our ability to leverage the prochirality of sulfur heteroarenes; biocatalytic oxidation of benzothiophenes "switches on" reactivity and establishes a sulfur stereocenter that directs the stereochemical course of subsequent cross-couplings with non-prefunctionalized partners. Exploiting a previously unexplored mechanism, either point-to-point or point-to-axial chirality transfer from sulfur selectively delivers two different sets of chiral molecules. Enzyme evolution is used to convert a wild-type oxygenase into an efficient and selective engineered <i>S</i>-oxygenase capable of furnishing enantiopure benzothiophene <i>S</i>-oxides─little-known sulfoxides whose configurational stability we map out. Our integrated chemoenzymatic approach provides a blueprint for unlocking the potential of sulfur chirality, lying dormant in important heterocycles, to direct transformations that deliver diverse enantioenriched products.