Cyclization of farnesyl diphosphate to pentalenene. Orthogonal stereochemistry in an enzyme-catalyzed SE′ reaction

Abstract

Pentalenene synthase catalyzes the cyclization of farnesyl diphosphate (1) to the sesquiterpene hydrocarbon pentalenene (4). Separate incubations of (4S,8S)-[4,8-3H2, 4,8-14C2]farnesyl diphosphate (1a) and (4R,8R)-[4,8-3H2, 4,814C2]farnesyl diphosphate (1b) with pentalenene synthase isolated from Streptomyces UC5319 and analysis of the derived labeled pentalenenes, 4a and 4b, respectively, by chemical degradation established that H-8si of FPP was lost upon cyclization to pentalenene. Consideration of the plausible conformations of the enzymatic cyclization intermediates indicates that the electrophilic allylic addition-elimination (SE′) reaction in which the C-4,5 bond of pentalenene is formed involves an orthogonal relationship between the C—C bond being formed and the C—H bond that is ultimately broken.