Trichothecenes synthesis

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... 

As mentioned in the Introduction, the group 3 biomimetic approach (see Scheme 1) has been the most popular route to the trichothecene skeleton. Two different moieties have served as the electrophilic site for biomimetic cyclization. When the cyclization proceeds via an allylic carbonium ion (127) (Path A, Scheme 9), the desired trisubstituted olefin (126) is obtained directly. On the other hand, the Michael acceptor (128) (PathB) yields, upon cyclization, a ketone (129) which must then be transformed into the olefin (126), a process which shows good but not complete regioselectivity. Hence, Path A, which can also be entered from the enone (128), is the superior route. Further analysis of Scheme 9 reveals that the primary stereochemical challenge of the biomimetic approach is to control the relative stereochemistry at the two quaternary centers C-5 and C-6. Within the context of trichothecene synthesis, a number of useful protocols have been devised for this purpose and include photocyclization (99), selective ring contraction (134), Diels-Alder cycloaddition (117,125) conjugate addition (27,120), and interconversion of dienyl iron complexes (114). 

Within this series of compounds there has been some disagreement as to the stereochemical outcome of epoxide formation via sulfonium ylides. While Anderson implied that the anti-QpoxidQ (185) was formed from ketone (184), Goldsmith has presented strong evidence that this reaction actually yields the 5j -stereoisomer (188), the wrong stereoisomer for trichothecene synthesis. This latter result is consistent with earlier studies in the trichothecene field (33, 51). 

Group 2 includes some 80 sesquiterpene trichothecenes, which are particularly associated with fungi belonging to the group Fusarium. Fusarium species are widely known both as plant pathogens and contaminants of stored foods snch as maize. Trichothecenes are strong inhibitors of protein synthesis in mammalian cells. There have been many incidents of poisoning of farm animals cansed by contamination of their food by these componnds. 

Cundliffe, E., Cannon, M., and Davies, J. (1974). Mechanism of inhibition of eukaryotic protein synthesis b trichothecene fungal toxins. Proc. Natl. Acad. Sci. USA 71, 30-34. 

Azcona-Olivera, J. I. et al. Induction of cytokine mRNAs in mice after oral exposure to the trichothecene vomitoxin (deoxynivalenol) Relationship to toxin distribution and protein synthesis inhibition. Toxicol. Appl. Pharmacol. 133, 109, 1995. 

Trichothecene mycotoxin Toxin produced by fungal molds it inhibits protein synthesis, impairs DNA synthesis, and interferes with cell membrane structure and function. 

Trichothecene mycotoxins are produced by a number of fungal molds of the Fusarium, Myrotecium, Trichoderma, and Stachybotrys genera. They inhibit protein synthesis, impair DNA synthesis, and interfere with cell membrane structures and functions. The potential routes of exposure are inhalation, ingestion, and skin absorption. A terrorist may take advantage of any of these routes. 

More recently, acetylene is reported to give under irradiation a photoadduct 48 with enone 47 by a-attack [46], After deacetoxylation and ionic rearrangement, a simple approach to the synthesis of optically active trichothecene seems possible [46 a] using the rearranged cyclopenteno bicyclic compound 48 (Scheme 22). 

M. Fetizon, D. D. Khac, and N. D. Tho, An approach to the synthesis of optically active trichothecenes from tri-O-acetyl-D-glucal, Tetrahedron Lett., 26 (1986) 1777-1780. 

Proctor RH Fusarium toxins Trichothecenes and Fumonisins in Cary JW, Linz JE, Bhatnagar D (eds) Microbial Foodbome Diseases Mechanism of pathogenesis and toxin synthesis. Lancaster, Technomic Publishing 2000, pp 363—381. 

Trichothecenes are potent inhibitors of protein synthesis due to binding to the 60S ribosomal unit and this is believed to be the main mechanism of toxicity. However, recent experimental data suggest that activation of the mitogen-activated protein kinases (MAPKs) through the ribosomal stress response could be another mechanism that operates via apoptotic and proinflammatory processes. 

Trichothecenes inhibit synthesis of protein, RNA and DNA as well as mitochondrial and electron transport chain function stimulate lipid peroxidation alter cell membrane function induce apoptosis modulate immune responses activate mitogen-activated protein kinases (MAPKs) and induce gene expression of numerous chemokines and cytokines and alter neurotransmitter levels. 

Trichothecenes can be divided into two groups based on their site of action on protein synthesis. Trichothecenes with hydroxyl and acetyl substitutions at both C-3 and C-4, such as T-2 toxin, DAS, verrucarin A, preferentially inhibit initiation while DON, trichodermin, crotocin, and verucarol inhibit elongation and/or termination (McLaughlin et al, 1977). Trichothecenes inhibit both DNA and RNA synthesis... 

Some biological effects may be mediated by reaction of the epoxy groups of trichothecenes with sulfhydryl groups on enzymes and binding of certain trichothecenes to membrane components. T-2 toxin rapidly affected glucose, nucleotide and amino acid transporters as well as calcium/ potassium channel activities in vitro indicating alteration of cell membrane functions independent of protein synthesis inhibition (Brunner and Morris, 1988). In pigs, DAS was... 

Experimentally, the macrocyclic trichothecenes satra-toxin G, isosatratoxin F, and roridin A have been shown to cause nasal and pulmonary toxicity when administered intranasally or intratracheally to mice. Intranasal exposure of satratoxin G and roridin A induced apoptosis of olfactory sensory neurons resulting in atrophy of the olfactory epithelium and olfactory nerve layer of the olfactory bulb in the frontal brain (Islam et al, 2006, 2007). Alveolar-type II cells and alveolar macrophages were injured following intratracheal instillation of isosatratoxin F or Stachybotrys spores with marked changes in surfactant synthesis and secretion (Rand et al, 2002). 

A mechanistically related and mild fragmentation is that of 2-trimethylsilylethyl esters (Tmse esters). The Tmse residue is a selectively cleavable carboxy-protecting group (see Volume 6, Chapter 3.2) Examples are known for the synthesis, via these esters, of peptides, macrolides such as curvularin and macrocyclic trichothecenes like verrucinol (Scheme 54). °... 

Several woikers have observed differences in the stereoselectivity of the reactions of (1) and (2) with ketones related to the trichothecene family of natural products (Scheme 4). Reaction of ketone (12) with (1) stereoselectively led to epoxide (13), whereas ylide (2) gave (14) instead. Very high dia-stereoselection was obtained in the late stages of a synthesis of (+)-phyllanthocin treatment of ketone... 

The defined geometry of these steps has permitted the synthesis of some cycloheptane acids related to terpenoid natural products. The key reaction was the rearrangement of a suitably substituted bicy-clo[4.2.0]octane. Thus the photoaddition of ethylene to 3-methylcyclohexenone gave the ketone (42), which was converted to the alcohol (43). On treatment with HgO and HBF4 this gave the unstable hydroxy aldehyde (44), which was readily oxidized to the dicarboxylic acid (45 Scheme 17).- Ring expansion methodology was also used in an approach to the synthesis of the trichothecenes (see Scheme 18).32... 

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