Chapter 14: Pericyclases in Natural Product Biosynthesis

Characterization of the role and extent of pericyclic reactions in natural product biosynthetic pathways has dramatically increased over the past decade. By definition, pericyclic transformations involve the concerted conversion of a substrate to product without any detectable intermediates. Examples of four major types: electrocyclizations (e.g. 7-dehydrocholesterol to pre-vitamin D₃), cycloadditions (e.g. Diels–Alder [4+2]-cyclizations in conversion of trienes to decalins), sigmatropic shifts (e.g. Cope rearrangements), and Alder-ene reactions have been validated to occur in biologic systems. Diels–Alderases have been found to catalyze intramolecular decalin formations and spiro-tetronate/spiro-tetramate cyclizations, as well as intermolecular cyclizations. Pericyclase-catalyzed heteroatom cyclizations include pyridine ring formation in thiazole-containing nonribosomal thiazolopeptide antibiotics. In the biosynthetic route to the vinca anticancer alkaloids vinblastine and vincristine, a metabolic precursor stemmadenine has been shown to undergo variants of enzyme-catalyzed [4+2]-cyclizations to give catharanthine and tabersonine frameworks.