Four analogs of geranylgeranyl diphosphate (GGPP) with shifted double bonds were synthesised and enzymatically converted with 14 diterpene synthases of previously reported function, including two newly characterised homologs of the benditerpe-2,6,15-triene synthase Bnd4 and the venezuelaene synthase VenA. In successful cases the products were isolated and structurally characterised by NMR spectroscopy, revealing the formation of various diterpenoids with skeletons that have not been reported from natural sources. Isotopic labelling experiments in conjunction with DFT calculations were performed to give insights into hydride migrations in the biosynthesis of the non-natural diterpenes benditerpe-2,7(19),15-triene and venezuelaxenene and their natural counterparts from GGPP.
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