Pentalenene biosynthesis and the enzymatic cyclization of farnesyl pyrophosphate.  Anti stereochemistry in a biological SE' reaction

Cane, David E.; Abell, C.; Lattman, Rene.; Kane, Charles T.; Hubbard, Brian; Harrison, Paul

doi:10.1021/ja00220a081

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“…Feeding of 30 c resulted in [ 2 H 15 ]‐ 23 (Figure S2D in the Supporting Information), with retention of all 15 deuterium atoms. This result corroborates the previous finding that the conversion of cation 18 via 19 into 20 (Scheme ) proceeds without proton exchange with the medium, in full agreement with the known mechanism of the pentalenene synthase 24. 25 Feeding experiments with the isotopologues 30 d – h confirmed the results obtained with 30 a – c (see the Supporting Information).…”

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confidence: 90%

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The Stereochemical Course and Mechanism of the IspH Reaction

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Section: Methodssupporting

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“…Specific removal of the 9‐ pro ‐ S hydrogen atom yields α‐humulene ( 19 ). The abstracted proton is reintroduced at C‐10 without significant exchange with the medium 24. Concomittant cyclization to 20 , a 1,2‐H − shift to 21 , cyclization to 22 , and deprotonation yields 23 .…”

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confidence: 99%

The Stereochemical Course and Mechanism of the IspH Reaction

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“…The most likely explanation is that the stereochemistry of deprotonation is determined by the relative positioning of the substrate and the relevant enzymic base. Intriguingly, this final deprotonation occurs immediately adjacent to the sites of deprotonation and reprotonation involved in the formation and further cyclization of the presumed humulene intermediate (5,10). While the three C-H bonds in question, H-8si of FPP (HA of 7), H-9si of FPP, and H-Ire of pentalenene are not parallel to each other, they do extend in the same general direction in the various intermediates (5,10 CHEM.…”

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confidence: 96%

“…A total of 67 fractions (250 drops perfraction) was collected and a 10-pL aliquot of every other fraction was counted for radioactivity. Fractions 29-33 were combined and lyophilized at (5)(6)(7)(8)(9)(10) x Tom. Two 5-rnL portions of 1.0 M ammonium hydroxide were added and the resulting solution was lyophilized each time to near dryness.…”

Section: ~-[4-~~]-3-~eth~1-3-buten-l-yl Diphosphate (2a) (13)mentioning

confidence: 99%

“…Elestrophilic attack on the si face of the C-10, 11 double bond is followed by removal the H-9si proton. The proton that is removed does not undergo exchange with the medium, but is redonated to the re face of the C-9,10 double bond of the intermediate humulene, leading to formation of the protoilludyl cation 6 (5,10). Following a 1,2-hydride shift, the resultant cation 7 attacks the remaining double bond, leading, after loss of one of the original H-8 protons of FPP, to formation of pentalenene (4).…”

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

Cane¹,

Weiner²

1994

Can. J. Chem.

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Can. J. Chem. 72, 118 (1994). Pentalenene synthase catalyzes the cyclization of farnesyl diphosphate (1) to the sesquiterpene hydrocarbon pentalenene (4). Separate incubations of ( 4~, 8~) - [ 4 , 8 -~~~, 4,8-14~2]farnesyl diphosphate (la) and ( 4~, 8~) - [ 4 , 8 -~~~, 4,814~2]farnesyl diphosphate (lb) with pentalenene synthase isolated from Streptotnyces UC53 19 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 additionelimination (SF,) 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. (SE,). au cours de laquelle se forme la liaison C-4.5 du pentalknkne, implique une relation orthogonale entre la liaison C-C qui se forme et la liaison C-H qui sera finalement briste.[Traduit par la rCdaction]The formation of c a r b o n~a r b o n bonds by the electrophilic attack of carbenium ions on double bonds is one of the most important reactions in the biosynthesis of hundreds of isoprenoid metabolites, including linear polyprenols (dolichols, ubiquinones), cyclic terpenes (mono-, sesqui-, and diterpenes), and steroids and other triterpenes (cholesterol, a-amyrin) (I). Although this process has considerable precedent in solution phase chemistry and much is known about the physical organic chemistry of carbenium ions themselves, the enzymatic reactions remain poorly understood, both with respect to the means by which such reactive species are manipulated and stabilized by protein catalysts and the manner in which enzymes exercise regiochemical and stereochemical control over such reactions (2).One particularly important subclass of these electrophilic reactions involves the quenching of positive charge resulting from the initial addition to the double bond by the removal of one of the original allylic protons. This allylic addition%limi-nation formally corresponds to an SE process. Cornforth and Popjak have shown that the key chain elongation step of polyprenol biosynthesis, typified by the farnesyl diphosphate (FPP, 1) synthase reaction, involves a pair of net syn allylic additionelimination reactions (3). (Scheme I). By contrast, the closely analogous prototropic rearrangement of isopentenyl diphosphate (IPP, 2) to dimethylallyl diphosphate (DMAPP, 3) has been shown to occur with net anti stereochemistry (4). In more recent studies of the cyclization of farnesyl diphosphate (I) to the sesquiterpene hydrocarbon pentalenene (4), we have shown that theinitial SEl reaction takes place with net anti stereochemistry (5) (Scheme 2). Overton has described model experiments 'Dedicated with great affection and warm admiration to Professor Ian D. Spenser.2~u t h o r to whom correspondence may be addressed.in which an intramolecular SF reaction was shown to proceed...

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Der stereochemische Verlauf und Mechanismus der IspH‐Reaktion

et al. 2012

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Pentalenene biosynthesis and the enzymatic cyclization of farnesyl pyrophosphate. Anti stereochemistry in a biological SE' reaction

Cited by 21 publications

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The Stereochemical Course and Mechanism of the IspH Reaction

The Stereochemical Course and Mechanism of the IspH Reaction

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

Der stereochemische Verlauf und Mechanismus der IspH‐Reaktion

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Pentalenene biosynthesis and the enzymatic cyclization of farnesyl pyrophosphate. Anti stereochemistry in a biological SE' reaction

Cited by 21 publications

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The Stereochemical Course and Mechanism of the IspH Reaction

The Stereochemical Course and Mechanism of the IspH Reaction

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

Der stereochemische Verlauf und Mechanismus der IspH‐Reaktion

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