Verrucarinic derivatives

The successful synthesis of optically active 7 then led to the first synthesis of verrucarin A (8), a macrotrilactone with significant cytostatic activity. The synthesis involved esterification of the primary alcohol of verrucarol (the tricyclic fragment) with the acetate of 7 (DCC, 4-pyrrolinopyridine) and then with a protected derivative of (E, Z)-muconic acid. After deprotection (Bu4NF), lactonization was effected by the Mitsunobu procedure (7,405-406). 

IVIchoverroids. T. are open chain ester derivatives of verrucarol (see scirpenols) and some are biogenetic precursors of the macrocyclic tric(h)othecenes ( bac-charinoids, roridins, verrucarins) they are isolated from cultures of Myrothecium verrucaria, M. roridum, and Fusarium graminearum. The T., of which more than 20 are now known, exhibit weak or no cytotoxic properties and weak antifungal activities. Trichoverri-tone also has antibacterial activity. 

Breitenstein W, Tamm Ch (1977) Verrucarins and Roridins, Part 34. Verrucarin K, the First Natural Trichothecene Derivative Lacking the 12,13-Epoxy Group. Helv Chim Acta 60 1522... 

There exist just a few total syntheses of macrocyclic trichothecenes. However, all of these deal with the synthesis of verrucarol (454), a hydrolysis product of the naturally occurring verrucarin A (380). Venucarol (454) represents the sesquiterpenoid moiety of most macrocyclic trichothecene derivatives. To date, there are several syntheses of this moiety. In 1998, the most recent total synthesis was published by Tadano et al. (327). 

For the second building block for verrucarin A (380), a derivative of verrucarinic acid (465) was synthesized in enantiomerically pure form from diester 461. Cleavage with pig liver esterase led to monoester 462, which was reduced to the alcohol with borane dimethylsulfide complex and protected with TBSCl to obtain the molecule 463. a-Hydroxylation with molybdenum oxide generated alcohol 464, and final protection and saponification afforded compound 465 (Scheme 8.16). 

Having verrucarol (454), the derivative of verrucarinic acid (465), and the half ester of ( ,Z)-muconic acid (456) all on hand, the total synthesis of verrucarin A (380) could be completed in a further five steps. Thus, verrucarol (454) was esterified first with compound 465 and second with compound 460. Then, molecule 467 was desilylated, macrolactonized under Yamaguchi conditions, and finally deprotected to achieve the natural product verrucarin A (380) (Scheme 8.17). 

There are a large number of different trichothecenes and ideally their analysis requires confirmation using GC-MS and analysis of the macrocyclic trichothecenes, which includes the verrucarins, ror-idins, and satratoxins, requires considerable experience and a specialized laboratory. However, well-established methods are available for individual trichothecenes of particular importance, such as T-2 toxin, diacetoxyscirpenol, deoxynivalenol, and neosolaniol. The large niunber of Fusarium trichothecenes are acylated derivatives of a much smaller niunber of parent alcohols, such as T-2 tetraol, scirpentriol, deoxynivalenol, and nivalenol, so another approach to their analysis is to hydrolyze the possibly complex mixture of trichothecenes to the parent alcohols and analyze these as their trimethylsilyl ethers. However, when this is done, there is often a poor correlation between total trichothecene content and observed toxicity, reflecting the large differences in the toxicity of different acyl derivatives even of the same parent alcohol. 

Most synthetic work directed toward the macrocyclic trichothecenes has focused on the verrucarins, particularly verrucarin A (37) and verrucarin J (40). For verrucarin A there now exist two total syntheses 106, 133), starting from verrucarol (82), as well as innumerable reports on the synthesis of verrucarinic acid derivatives, a principal component of the macrocyclic ribbon (see Scheme 32). 

Reaction of the verrucarinic acid derivative (247) with verrucarol (82), mediated by DCC and 4-N,N-dimethylaminopyridine (DMAP), yielded the monoester (250) by exclusive acylation at C-15. A similar esterification procedure attached the muconic acid (249) to C-4. Following desilylation the seco acid (251) was cyclized (52%) and deacetylated to yield verrucarin A (37). When alternative conditions for the esterification of acid (249) were employed, partial isomerization of the , Z-isomer (251) to an E,E-isomer was observed. However, lactonization of this mixture produced only the natural E,Z-macrocyclic (37) as the E,E-isomer failed to cyclize. Such reactivity differences have been observed with other trichothecanoid macrocycles (22, 148), although, as shall be seen, E,E-macrocycles can be prepared if so desired 115, 121). 

As part of the recent surge in methodology related to control of acyclic stereochemistry, numerous reports have appeared on the synthesis of racemic and chiral verrucarinic acid derivatives. These are summarized in Scheme 32. In most instances, the eventual synthesis of verrucarin A is not the primary concern of these efforts. 

In addition to the route discussed in Scheme 31, Tamm and co-workers have developed two other syntheses of chiral verrucarinic acid derivatives (67). One of their newer routes (259->254) closely mimics Still s original work in the area (see Scheme 30) by utilizing a chiral epoxidation to establish the desired absolute stereochemistry. Their second alternative involves an enantioselective hydroboration (260 261) which proceeded with only mediocre optical induction. 

Breitenstein, W., and Ch. Tamm Verrucarin K, the first natural trichothecane derivative lacking the 12,13-epoxy group. Helv. Chim. Acta 60, 1522 (1977). 

Trost, B. M., and P. G. McDougal Synthesis of optically active verrucarinic acid derivatives. Tetrahedron Letters 23, 5497 (1982). 

Butyrolactones can be obtained from carbonyls and the /8-lithiopropionate (58), derived from /3-bromopropionic acid by sequential treatment with n-butyl-lithium and lithium naphthalenide. Although yields are generally less than 50%, the method could find use as a simple route to spirolactones. The spirolac-tone (59), a potential precursor of the trichothecane antibiotic verrucarin A, has been obtained by a Diels-Alder reaction using a-methylenesuccinic anhydride as ene component followed by borohydride reduction to the lactone. Spirolactone... 

The macrocyclic ester derivatives of trichothecene alcohols (Figs. 7 and 8) possess remarkable biological properties. Verrucarin A (32) was the first member of this group whose structure was established by the extensive use of chemical and spectroscopic methods (Gutzwiller and Tamm, 1965a Tamm and Gutzwiller, 1962). The structure was then confirmed by an X-ray analysis... 

The first naturally occurring trichothecene derivative without the 12,13-epoxy group has recently been isolated from a strain of M. verrucaria (Breitenstein and Tamm, 1977). The structure of this compound, named verrucarin K (46), is shown in Fig. 8. 

The intermediacy of trichodiol (67) in the biosynthetic scheme has not yet been established conclusively. As stated by Machida and Nozoe (1972b), trichodiol (67) might be a metabolite of 12,13-epoxytrichothec-9-ene (5). In this connection, the recent isolation of verrucarin K (46) (Breitenstein and Tamm, 1977) is noteworthy. As stated earlier, this compound is the first naturally occurring trichothecene derivative lacking the 12,13-epoxy group. In view of this isolation, an alternative pathway may be postulated consisting of the direct cyclization of an intermediate of type 69 to the trichotheca-9,12-diene system 70 (Fig. 13). 

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