Terpenoid biosynthesis and the stereochemistry of enzyme-catalysed allylic addition—elimination reactions

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Abstract
Allylic addition—elimination reactions are widely used in the enzyme-catalysed formation of terpenoid metabolites. It has earlier been shown that the isoprenoid chain elongation reaction catalysed by farnesyl pyrophosphate synthase involving successive condensations of dimethylallyl pyrophosphate (DMAPP) and geranyl pyrophosphate (GPP) with isopentenyl pyrophosphate (IPP) corresponds to such an S E' reaction with net syn stereochemistry for the sequential electrophilic addition and proton elimination steps. Studies of the enzymic cyclization of farnesyl pyrophosphate (FPP) to pentalenene have now established the stereochemical course of two additional biological S E' reactions. Incubation of both (9R)-and (9S)-[9- 3 H, 4,8- 14 ] FPP with pentalenene synthase and analysis of the resulting labelled pentalenene has revealed that H-9 re of FPP becomes H-8 of pentalenene, while H-9 si undergoes net intramolecular transfer to the adjacent carbon, becoming H-l re (lH-loc) of pentalenene, as confirmed by subsequent experiments with [10- 2 H, 11- 13 C]FPP. These results correspond to net anti-stereochemistry in the intramolecular allylic addition—elimination reaction. The stereochemical course of a second S E < reaction has now been examined by analogous incubations of (4 S , 8 S )-[4,8- 3 H, 4,8- 14 C ]FPP and (4 R ,8R)-[4,8- 3 H, 4,8- 14 C ]FPP with pentalenene synthase. Determ ination of the distribution of label in the derived pentalenenes showed stereospecific loss of the original H-8 si proton. Analysis of the plausible conformation of the presumed reaction intermediates revealed that the stereochemical course of the latter reaction cannot properly be described as either syn or anti, since cyclization and subsequent double bond formation require significant internal motions to allow proper overlap of the scissile C—H bond with the developing carbocation.

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