Trichodiene synthesis

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. 

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... 

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). ... 

The first chemical synthesis of an optically active trichodiene, (-)-trichodiene involved a Claisen-lreland rearrangement as the key step to connect the vicinal quaternary centers. J.C. Gilbert and co-workers found that the rearrangement occurred with complete facial selectivity and excellent diastereoselectivity to afford an advanced intermediate that was directly converted to (-)-trichodiene. 

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... 

Full details of the neat synthesis of the ketone (126) and its methylenation to give trichodiene (127) have been published.82 Unfortunately, sixteen attempts with different reagents to carry out a similar methylenation of the diastereoisomeric ketone (128) to give bazzanene (129) failed. A number of new and very interesting trichothecane sesquiterpenoids have been isolated from Myrothecium verrucaria. These include trichodermadienediol A (130), trichoverrol A (131), and trichoverrin A (132) together with their B counterparts which are epimeric at C-7. 83 The trichoverrins are clearly biosynthetic intermediates of the more toxic macrocyclic... 

Modification of enzymes involved in the synthesis from universal precursors of other secondary metabolites has also been demonstrated. The sesquiterpene synthases are a large family of enzymes that act by a common mechanism and catalyze the cyclization of famesyl diphosphate, each to form a distinct sesquiterpene. The active site of the synthase that produces trichodiene, the... 

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. 

In 1986, Kraus [129], Gilbert [130] and VanMiddlesworth [131] all reported application of the Ireland-Claisen rearrangement in syntheses of the trichothecenes trichodiene and bazzanene. In each case the diastereoselectivity of the rearrangement was minimal as a result of a lack of stereoselectivity in the enolization of the ester. The Kraus synthesis is illustrative (Scheme 4.136). Treatment of the cyclo-... 

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. 

Methodology of this type has also been applied to the synthesis of the related compounds trichodiene and trichodermol, and also to the alkaloid limaspermine. The following protocol is representative of carbanion addition to cationic tricarbonyl(Ti -cyclohexadienyl)iron complexes. 

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. 

P-Silyl divinyl ketones (Nazarov reagents) in the presence of BF3 OEt2 cyclize to give cyclopentenones, generally with retention of the silyl group. BF3-OEt2 is used for the key step in the synthesis of the sesquiterpene trichodiene, which has adjacent quaternary centers, by catalyzing the cyclization of the dienone to the tricyclic ketone (eq 13). Trifluoroacetic acid and trifluo-roacetic anhydride do not catalyze this cyclization. 

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