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Aristolochene synthase-catalyzed cyclization of 2-fluorofarnesyl-diphosphate to 2-fluorogermacrene A

Miller, David James, Yu, Fanglei and Allemann, Rudolf Konrad 2007. Aristolochene synthase-catalyzed cyclization of 2-fluorofarnesyl-diphosphate to 2-fluorogermacrene A. Chembiochem 8 (15) , pp. 1819-1825. 10.1002/cbic.200700219

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Abstract

The mechanism of the conversion of (E,E)-farnesyl diphosphate (FPP, 1 a) to aristolochene (6) catalyzed by aristolochene synthase from Penicillium roqueforti has been proposed to proceed through the neutral intermediate germacrene A (4 a). However, much of the experimental evidence is also in agreement with a mechanism in which germacrene A is not an intermediate in the predominant mechanism that leads to the formation of aristolochene, but rather an off-pathway product that is formed in a side reaction. Hence, to elucidate the mechanism of FPP cyclisation the substrate analogue 2-fluoroFPP (1 b) was synthesized, and upon incubation with aristolochene synthase was converted to a single pentane extractable product according to GC-MS analysis. On the basis of NMR analyses this product was identified as 2-fluorogermacrene A (4 b). Variable temperature 1H NMR spectroscopy indicated the existence of two conformers of 4 b that were in slow exchange at −60 °C, while at 90 °C the two isomers gave rise to averaged NMR signals. In the major isomer (∼75 %) the methyl groups on C3 and C7 were most likely in the down–down orientation as had been observed for other (E,E)-germacranes. This work suggests that after an initial concerted cyclisation of FPP to germacryl cation deprotonation leads to the formation of germacrene A, and provides compelling evidence that germacrene A is indeed an on-pathway product of catalysis by aristolochene synthase.

Item Type: Article
Status: Published
Schools: Chemistry
Cardiff Catalysis Institute (CCI)
Subjects: Q Science > QD Chemistry
Uncontrolled Keywords: enzyme catalysis ; fluorine;natural products ; structure–activity relationships ; terpenoids
Publisher: WileyBlackwell
ISSN: 1439-4227
Last Modified: 04 Jun 2017 02:49
URI: http://orca.cf.ac.uk/id/eprint/12494

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