Chapter 6: Isoprenoids/Terpenes

This largest class of natural products, with >75 000 known structures, arises from a pair of five-carbon isopentenyl diphosphate isomers, one acting as a π-electron double bond carbon nucleophile, the other as an allylic cation electrophile in C–C bond alkylations. Isoprene/terpene chain growth thus occurs five carbons at a time in head-to-tail couplings by prenyl transferase enzymes. At both the C15 or C20 chain length stages, enzymes can carry out related head-to-head chain couplings to generate the C30 hexaene squalene or the C40 nonaene phytoene. Squalene is the precursor to cyclase-mediated conversion to tetracyclic sterol frameworks and pentacyclic plant systems, such as amyrin and cycloartenol. The C10 (geranyl-PP = monoterpene), C15 (farnesyl-PP = sesquiterpene), and C20 (geranylgeranyl = diterpene) head-to-tail coupled metabolites can undergo many variations of internal carbocation-mediated cyclizations to generate a large array of mono- to tetracyclic olefins and alcohols. The predominant animal sterol is the C27 membrane lipid cholesterol, available from the initial C30 biosynthetic tetracyclic lanosterol by oxygenative removal of three C–CH₃ groups. This phase of sterol metabolism marks a shift from carbocation-based reactions, to radical chemistry by oxygenases, as nine O₂ molecules are consumed. In further conversion of cholesterol to the female sex hormone estradiol, another eight O₂ molecules are consumed, for a total of 17 O₂ being reductively split in the metabolic traverse from lanosterol to cholesterol. Meroterpenoid assembly involves the intersection of isoprene biosynthetic machinery with polyketide- or indole-processing enzymes.