Of trichodiene

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... 

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. 

The stereoselective synthesis of (+)-trichodiene was accomplished by K.E. Harding and co-workers. The synthesis of this natural product posed a challenge, since it contains two adjacent quaternary stereocenters. For this reason, they chose a stereospecific electrocyclic reaction, the Nazarov cyclization, as the key ring-forming step to control the stereochemistry. The cyclization precursor was prepared by the Friedel-Crafts acylation of 1,4-dimethyl-1-cyclohexene with the appropriate acid chloride using SnCU as the catalyst. The Nazarov cyclization was not efficient under protic acid catalysis (e.g., TFA), but in the presence of excess boron trifluoride etherate high yield of the cyclized products was obtained. It is important to note that the mildness of the reaction conditions accounts for the fact that both of the products had an intact stereocenter at C2. Under harsher conditions, the formation of the C2-C3 enone was also observed. 

Additions to Cyclohexenones and Related Systems - Irradiation of 3-methylcyclohexenone in methanol solution in the presence of the ester (42) results in the synthesis of adduct (43) in moderate yields. This product was used as the starting material for an approach to the synthesis of trichodiene. The enone (44) undergoes photochemical reaction with 2,3-dimethylbut-2-ene in benzene or acetonitrile solution and using 350 nm light.The four products were identified as (45), (46), (47) and (48). The formation of the oxetane (45) follows the conventional route and the cycloadduct (48) arises via the biradical... 

Cane et a/.92 have re-examined the biosynthesis of trichodiene (127) by incubation of trans,trans[ -3U2,12,13-14C]farnesyl pyrophosphate (156) [3H/14C atom ratio 2 2] with a cell-free extract of Trichothecium roseum. A crystalline derivative of the trans-diol derived from the endocyclic double bond of labelled trichodiene had a... 

The [1,1 5.6] rearrangement is employed in the stereoselective C-5 to C-6 bond formation of trichodiene, the biosynthetic progenitor of triehothecenes such as sambucinol and neosporol552. As the vinyl ether double bond of allyl vinyl ether 1 cannot be controlled, the rearrangement affords a 1 1 mixture of aldehydes Z553-754. However, it has been demonstrat-ed 555 -557 that the selectivity for the chair transition state is 85% for the vinyl ethers 1. 

Conjugated dienes are also reduced, usually via 1,4-addition to give an alkene. When the diene unit in 463 was treated with sodium metal in ammonia, a 65% yield of 464 was obtained, as part of Meyer s synthesis of (-)-trichodiene." As expected, a mixture of 1,4-reduction (to give 464) and 1,2-reduction (to give 465) was observed (in a ratio of 85 15), which is common with this type of reduction. Note that the nonconjugated exomethylene group in 450 was not reduced under these conditions. 

Previous results on helicobasidin (51) have suggested that y-bisabolene (54) is not a precursor. A similar conclusion has been reached for trichodermol (52) and trichothecin (53). Hanson and co-workers showed that tritium from [2- H,2- C]geranyl pyrophosphate (4 n = 1) is incorporated into all three bicyclic sesquiterpenoids. The suggested explanation is that the tritium atom is transferred by a 1,4-shift as shown in Scheme 6. The involvement of trichodiene (50) was confirmed by Machida and Nozoe. They also isolated deshydroxy-trichodermol and trichodiol A (55), which may be a precursor of the tricyclic system (see arrows). Bisabolene derivatives, as expected, were not incorporated. ... 

Scheme 2. Biosynthesis of trichodiene (49) and trichothecolone (101) from mevalonic acid lactone (105), labelled atom <...

Much effort, using mainly Fusarium spp., has been devoted to the identification of the oxygenation, cyclisation and esterification steps which take place after the formation of trichodiene. Fermentations carried out on a large scale, or in the presence of enzyme inhibitors, such as ancymidol (225) or xanthotoxin (219), or with mutant strains (223), have yielded metabolic products [(47), (52), (53), (59) Table 8] which are proven intermediates. They are derived from trichodiene by plausible pathways involving allylic hydroxylation at positions 2a and 11a, fol-... 

Hesketh AR (1992) Metabolic Studies on the Transformation of Trichodiene to Trichothecene Mycotoxins. Mycotoxin Res 8 52... 

Nozoe S, Machida Y (1970) Structure of Trichodiene. Tetrahedron Lett 2671... 

Desjardins AE, Plattner RD, Beremand MN (1987) Ancymidol Blocks Trichothecene Biosynthesis and Leads to Accumulation of Trichodiene in Fusarium sporotrichioides and Gibberella pulicaris. Appl Environ Microbiol 53 1860... 

Desjardins AE, Hohn TM, McCormick SP (1992) Effect of Gene Dismption of Trichodiene Synthase on the Virulence of Gibberella pulicaris. Mol Plant-Microbe Interact 5 214... 

Wagner-Meerwein rearrangements are prevalent in the biosynthesis of terpenoids and steroids [21], An example can be represented by the concerted rearrangements (1,3-hydride and 1,2-methyl shift) that lead to the biosynthesis of trichodiene, an intermediate of the terpenes verrucarin A and roridin A (Section 3.2.24) (Figure 1.18). 

Takahashi-Ando N, Ochiai N, Tokai T, Ohsato S, Nishiuchi T, Yoshida M, Fujimura M, Kimura M (2008) A screening system for inhibitors of trichothecene biosynthesis hydroxylation of trichodiene as a target. Biotechnol Lett 30 1055-1059... 

A similar result was observed during the s)mthesis of trichodiene (Eq. 57).264... 

The Nazarov cyclization was the key step in a synthesis of ( )-trichodiene (35) by Harding and co-workers. One significant challenge in the preparation of this natural product is the presence of two adjacent quaternary stereocenters, and Harding and co-workers selected the Nazarov cyclization to tackle this problem. Although the reaction was not efficient under protic acid catalysis, the presence of an excess of boron trifluoride etherate enabled the production of 34a/b in good yield, whereby double bond migration had occurred. These specific reaction conditions were key to the success of this transformation, since under milder conditions or shorter reaction times, the expected a,p-unsaturated ketone was observed. 

The nearly complete catalytic intolerance for glutamyl and alanyl substitutions in the DDxxD motif of limonene synthase is novel and unlike the much less pronounced effects of comparable substitutions in the sesquiterpene cyclase trichodiene synthase [97, 98]. However, pre-steady state kinetic analysis of trichodiene synthase [101] and several other sesquiterpene synthases [102] has recently shown that product release is rate limiting in these cases, and thus can mask the kinetic influence of the aspartate mutations on earlier steps in the catalytic cycle. In the instance of monoterpene cyclase catalysis, product release is not the slow step since comparison of k at values with GPP and LPP as substrate clearly reveals the initial ionization-isomerization to be rate limiting. Thus, perturbations that influence the first ionization step will be fully reflected in overall rate suppression for limonene synthase. This kinetic sensitivity at the initial steps of the reaction cycle does not, however, explain the near complete intolerance of limonene synthase to aspartate substitution in the DDxxD motif and it is thus tempting to speculate a more specific, but presently unidentified, influence on the requisite isomerization of GPP. 

Consistent with the participation of arginine residues in diphosphate orientation and ionization by monoterpene and sesquiterpene synthases [91,117] is the substitution of a highly conserved RxR motif by RxC in y-humulene synthase (residues 306-308). Perhaps this substitution in y-humulene synthase perturbs diphosphate binding in much the same way as was suggested for the central arginine mutation in the DRRYR motif of trichodiene synthase which resulted in multiproduct formation [117]. 

Harding and Clement s synthesis of trichodiene uses the predictable stereochemical course of the 4tt-electrocycliza-tion to control relative stereochemistry at two adjacent allcarbon atom quaternary centers. Harding and Clement s strategy is conceptually related to Whitesell and Minton s ikarugamycin synthesis that was discussed in the context of Scheme 19.1. 

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