Enzymatic Formation of an Unnatural Hexacyclic C₃₅ Polyprenoid by Bacterial Squalene Cyclase

A C₃₅ polyprene in which a farnesyl C₁₅ unit is connected in a head-to-head fashion to a geranylgeranyl C₂₀ unit was enzymatically converted to an unnatural hexacyclic polyprenoid by squalene:hopene cyclase from Alicyclobacillus acidocaldarius. This is the first demonstration of the remarkable ability of the squalene cyclizing enzyme to perform construction of unnatural hexacyclic skeleton. The cyclization of the C₃₅ polyprene was initiated by a proton attack on the terminal double bond of the C₁₅ unit and proceeded without rearrangement of carbon and hydrogen. The substrate should be folded in chair−chair−chair−chair−boat−boat conformation to achieve the stereochemistry of the cyclization product.