Trichodienes

Propose a mechanism for the biosynthesis of the sesquiterpene trichodiene from famesyl diphosphate. The process involves cyclization to give an intermediate secondary carbocation, followed by several carbocation rearrangements. 

A descriptor for an enzyme active site that permits binding of a family of related compounds (e.g., mimics of the reaction intermediate) that can be derived from the initial binding and conformational changes in the substrate. This concept arose from the observation that a number of monoterpene cyclases were incapable of discriminating between enantiomers of the reaction intermediate, even though the enzyme catalyzes the synthesis of an enantiomerically pure product from an achiral substrate. An example is trichodiene synthase which catalyzes the cyclization of farnesyl diphosphate to trichodiene. 

A term used to describe inhibition induced by a second inhibitor. A particular inhibitor (F) may be a weak inhibitor for a certain enzyme however, in the presence of a second inhibitor (F), inhibition is greatly enhanced. An example of such a system is the inhibitory effect of inorganic pyrophosphate on trichodiene synthase by certain aza analogues Both enantiomers of serine are weak inhibitors of y-glutamyl transpeptidase (L-serine has a Ki value of 10.7 mM), but in the presence of borate ion, they are potent inhibitors ... 

Gallo, A. (2004). Isolation and characterisation of a trichodiene synthase homologous gene in Trichoderma harzianum. Physiol. Mol. Plant Pathol. 65,11-29. 

Straus, N. A., and Wong, B. (1998). Stachybotrys chartarum trichodiene synthase (TR15) gene, complete cds. GenBank accession no. AF053926, direct submission, 17. March 1998.. ... 

Transferase, amino, alanine Call Tiss Trichodiene, 15-hydroxy Pi 0.2 Trideca-5-10-12-trien-2-one, (E)-6-12-dim-ethyl-9-iso-propyl Lf ... 

Zook, M., K. Johnson, T. Hohn, and R. Hammerschmidt. Structural characterization of 15-hydroxytrychodiene, a ses-quiterpenoid produced by tansformed tobacco cell suspension cultures expressing a trichodiene synthase gene from Fusarium sporotrichoid.es. Phytochemistry 1996 43(6) 1235-1237. Eklund, A.M., I. Eorsblom, ]. E. Berg, C. Damberg, and I. Wahlberg. Tobacco chemistry. Four new cyclized cembranoids from tobacco. Acta Chem Scand Ser A 1998 52(10) 1254-1262. 

The direct coupling of the tin enolate (175 Scheme 25) with (30) gives complex (176) in good yield (87%). Fortuitously, the bond formation gives approximately a 5 1 mixture in favor of the diastereomer required for trichothecene synthesis. Further elaboration of the major isomer leads to (i)-trichodiene (167), representing an eight step diastereoselective total synthesis of the natural product from p-methyl-anisole, which compares very favorably with previous methods.32-36... 

A quantum chemical investigation of the biosynthesis of farnesyl pyrophosphate through the condensation of isopentenyl pyrophosphate and dimethylallyl pyrophosphate suggests that the mechanism is concerted, although the transition state has carbocationic character.164 Quantum chemical calculations were performed on the cyclization of the farnesyl cation to the sesquiterpene pentalenene.165 Two distinct pathways with similar activation barriers were identified, each differing from previous proposed mechanisms, and each involving unusual carbocationic intermediates. Mechanisms previously proposed for enzyme-catalysed formation of the sesquiterpene trichodiene involve carbocation intermediates with a 1,4-hydride transfer as the key step, e.g. (89) -> (90) - (91).166 Quantum chemical calculations, however, show a... 

The following application of the synthetic equivalent 110 was carried out. Complex 107 was utilized for the total syntheses of trichothecene (122), trichodiene and trichodermol, applying the reaction of cationic complex 107 with a /f-kcto ester or tin enolate [28]. The tin enolate of cyclopentanone 119 reacted with the complex 107 with high diastereoselectivity to give the diene complex 120 in high yield. After... 

Crystal structure determinations of trichodiene synthases were reported, including structures of ternary complexes incorporating inorganic pyrophosphate and an aza analogue of the bisabolyl carbocation intermediate.220,221 The conformation and orientation of the carbocation analogue lead to the conclusion that carbocation intermediates... 

CANE, D. E., XUE, Q., FITZSIMONS, B. C., Trichodiene synthase, probing the role of the highly conserved aspartate-rich region by site-directed mutagenesis, Biochem., 1996 35,12369-12376. 

RYNKIEWICZ, M. J., CANE, D. E CHRISTIANSON, D. W., Structure of trichodiene synthase from Fusarium sporotrichioides provides mechanistic inferences on the terpene cyclization cascade, Proc. Natl. Acad. Sci. USA, 2001, 98, 13543-13548. 

A cell-free extract obtained from T. roseum has been shown to convert trans,trans-farnesyl pyrophosphate into trichodiene (87), the bicyclic hydrocarbon precursor of the trichothecane sesquiterpenoids.42 Related studies in this area have also been reported.43,44 Chemical and spectroscopic evidence has been reported which is consistent with the structure assigned to vetisporin (88), a new antibiotic isolated from Verticimonosporium diffractum.45... 

Myrothecium verrucaria and M. roridum,383 but neither [l,8-14C2]-(l jR,6i S)-a-bisabolol nor its (l S)-isomer was incorporated into the verrucarol skeleton,384 thus indicating that bisabolene derivatives are probably not intermediates in the formation of the trichothecane skeleton. The recent report of the occurrence of trichodiol (118) and of (119) has led to speculation385 that direct cyclization of 2-cis-6-trans-farnesol might be involved in the formation of the trichothecane skeleton the conversion of an intermediate such as trichodiene (120) into (118) should involve... 

Two cyclizations produce the trichodiene ring skeleton and a secondary carbocation. 

A hydride shift, two methyl shifts, and loss of -H+ yield trichodiene. 

An elegant diastereocontrolled synthesis of the sesquiteipene trichodiene (201) relies on a smooth regio- and stereo-selective Diels-Alder reaction of 2-[(phenylthio)methyl]-1,3-butadiene (197) with the a-methylenelactone (198), giving the para adduct (199) in 89% yield (Scheme 47). ... 

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