Chemoenzymatic\nFormation of Oxa-Terpenoids by Sesqui-\nand Diterpene Synthase-Mediated Biotransformations with 9‑Oxy-FPP\nEther Derivatives

Farnesyl pyrophosphate derivatives bearing an additional\noxygen\natom at position 5 proved to be very suitable for expanding the substrate\npromiscuity of sesquiterpene synthases (STSs) and the formation of\nnew oxygenated terpenoids. Insertion of an oxygen atom in position\n9, however, caused larger restraints that led to restricted acceptance\nby STSs. In order to reduce some of the proposed restrictions, two\nFPP-ether derivatives with altered substitution pattern around the\nterminal olefinic double bond were designed. These showed improved\npromiscuity toward different STSs. Four new cyclized terpenoids with\nan embedded ether group were isolated and characterized. In the case\nof two cyclic enol ethers, also the corresponding “hydrolysis”\nproducts, linear hydroxyaldehydes, were isolated. Interestingly, all\ncyclization products originate from an initial 1 → 12 cyclization\nunprecedented when native farnesyl pyrophosphate serves as a substrate.\nWe found that the most suitable FPP derivative with an additional\noxygen at position 9 does not carry any methyl group on the terminal\nalkene, which likely reduces steric congestion when the preferred\nconformation for cyclization is adopted in the active site.