Chemoenzymatic Synthesis of Structurally Diverse Terpenoids from Farnesyl Pyrophosphates Modified at the Central Alkene Unit

Sesquiterpene synthases (STSs) enable cationic cascade reactions with farnesyl pyrophosphate (FPP) resulting in an immense variety of oligocyclic sesquiterpenes. Their substrate promiscuity allows access to new sesquiterpene carbon skeletons. We explored the ability of eight STSs to process three distinct synthetic FPP derivatives modified at the central isoprenyl unit. These include the incorporation of a keto group at C7 ("keto"-FPP), the relocation of the olefinic double bond into the methyl group ("iso"-FPP), and the shift of the double bond toward the aliphatic terminus of the FPP backbone and loss of the methyl group at C7 ("nor-iso" FPP). We report the enzymatic production of 18 new terpenoids, including a large variety of new oxaterpenoids. One of these is known as a late stage intermediate in the total synthesis of the sex pheromone periplanone B, which is secreted by females of the American cockroach <i>Periplaneta americana</i> to attract mates. Thus, a formal chemoenzymatic synthesis of this pheromone is disclosed.