Chapter 10: Alkaloids II: Indole Terpenes

Tryptophan (Trp) is the starting metabolite for a large family of indole alkaloids that are coupled to isoprene side chains, often highly elaborated, which arise from indole C₃-carbanion chemistry on C₁ of the allylic carbocation derived for Δ²-prenyl diphosphate cosubstrates. Roquefortines, for example, fit into this category. As does the anticholinesterase metabolite physostigmine. Trp-Xaa diketopiperazines formed by two-module NRPS assembly lines are also common substrates for complexity-generating prenylations (gliotoxin, fumitremorgin, spirotryprostatin, notoamide). While the C₃ carbon of indole in tryptamine is the most nucleophilic, natural product enzymes can deliver prenyl groups to indole C₂–C₇ as well as to N₁. Epoxidations by oxygenases on prenyl side chains lead to multicyclic product frameworks, as in the conversion of farnesyl indole to the fused pentacyclic scaffolds of sespenine and xiamycin D. The conversion of tripartite strictosidine (pyrroloindole-secologanin-acetal-glycoside) to the vinca alkaloid anticancer agents vinblastine and vincristine is among the most complex biosynthetic pathways, whose biosynthetic logic and enzymatic machinery have been deciphered in the past decade. Glycosidase action unravels both an enolate and an aldehyde in the strictosidine aglycone, and this dual reactivity potential is guided to stemmadenine, then catharanthine, and tabersonine. Tabersonine is modified in seven enzymatic steps to vindoline and then coupled to catharanthine to give vinblastine, which is a double oxidation away from vincristine.