Hapalindole metabolites are a diverse group of indole alkaloids defined by their polycyclic ring system, various stereoisomers, unique functional groups and promising biological activities. These metabolites are formed by a class of enzymes known as the Stig Cyclases that catalyze three steps: 1) a Cope Rearrangement, 2) 6-exo-trig cyclization, and 3) terminal electrophilic aromatic substitution (EAS) from a common indole C-3 geranylated (3-GC) intermediate. They further undergo late-stage C-H functionalization reactions (e.g. halogenation, oxidation, prenylation), generating the diversity observed in this class of metabolites. Here, we disclose a previously unseen shunt metabolite (11-DMAC) resulting from the enzymatic Cope Rearrangement at carbon 11 with dimethylallyl pyrophosphate (DMAPP). This was discovered while we were working toward a one pot biocatalytic synthesis of 12-epi-ambiguine H derivatives. The isolation of 11-DMAC further strengthens the Cope Rearrangement hypothesis for the formation of hapalindole metabolites. We also present an effort toward the total synthesis of a C-2 derivative via a synthetic Cope Rearrangement. Furthermore, derivatization of the starting material resulted in new 11-DMAC metabolites, revealing a broad substrate scope with potential pharmacological activity. Efficient biosynthesis or total synthesis of these derivatized shunt metabolites can provide many potential synthons towards total synthesis efforts of a diverse range of indole alkaloids.

Isolation and structural diversification of novel metabolite for further insight into rare biocatalytic cope rearrangement and synthesis of indole alkaloid natural products

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