1,2‐ or 1,3‐Hydride Shifts: What Controls Guaiane Biosynthesis?

A systematic computational study addressing the entire chemical space of guaianes in conjunction with an analysis of all known compounds shows that 1,3‐hydride shifts are rare events in guaiane biosynthesis. As demonstrated here, 1,3‐hydride shifts towards guaianes can only be realized for two stereochemically well defined out of numerous possible stereoisomeric skeletons. One example is given by the mechanism of guaia‐4(15)‐en‐11‐ol synthase from California poplar, an enzyme that yields guaianes with unusual stereochemical properties. The general results from DFT calculations were experimentally verified through isotopic‐labeling experiments with guaia‐4(15)‐en‐11‐ol synthase.