Phytophenol Dimerization Reaction: From Basic Rules to Diastereoselectivity and Beyond.

Phytophenol dimerization, which is a radical-mediated coupling reaction, plays a critical role in many fields, including lignin biosynthesis. To understand the reaction, 2,2-diphenyl-1-picrylhydrazyl radical was used to initiate a series of phytophenol dimerization reactions in methanol. The products were identified using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-ESI-Q-TOF-MS/MS) analysis in situ. The identified products mainly included biphenols, magnolol, honokiol, gingerol 6,6'-dimers, 3,6-dimethoxylcatechol β,β' dimer, euphorbetin, bis-eugenol, dehydrodiisoeugenol, trans-ε -viniferin, (+) pinoresinol, and (-) pinoresinol. Structure-function relationship analysis allowed four basic rules to be defined: meta -excluded, C-C bonding domination, ortho -diOH co-activation, and exocyclic C=C involvement. The exocyclic C=C involvement, however, required conjugation with the phenolic core and the para -site of the -OH group, to yield a furan-fused dimer with two chiral centers. Computational chemistry indicated that the entire process was completed via a radical coupling reaction and an intramolecular conjugate addition reaction. Similar results were also found for the horseradish peroxidase (HRP)-catalyzed coniferyl alcohol dimerization, which produced (+) and (-) pinoresinols (but no (-) epipinoresinol), suggesting that the HRP-catalyzed process was essentially an exocyclic C=C-involved phytophenol dimerization reaction. The reaction was highly diastereoselective. This was attributed to the intramolecular reaction, which prohibited Re -attack. The four basic rules and diastereoselectivity can explain and even predict the main products in various chemical and biological events, especially oxidase-catalyzed lignin cyclization.