Structure strobilurins

Only in 1986, it could finally be demonstrated that mucidin is identical to strobilm-in A. In the meantime, more than 15 strobilurins and oudemansins became known, some with more complex structures. Strobilurin and oude-... 

Strobilurin A, Strobilurin and Myxothiazole new inhibitors of the bci segment of the respiratory chain with an ( )-/l-methoxyacrylate system as common structural elements , FEBS Lett., 1981,132, 329-333. 

Nuclear magnetic resonance (NMR) spectroscopy, with X-ray analysis, forms the basis for the determination of the structures of most of the compounds discussed in this chapter. H and 13C NMR played a key role in the revision of the structure of the antifungal metabolite strobilurin D 2, which was shown to contain a benzodioxepin moiety rather than epoxide <1999T10101>. 9-Methoxystrobilurin K was also shown to contain a 1,4-benzodioxepin <1997TL7465>. 

Many fungicides are being isolated from a variety of natural sources. Some of them may be useful as such. More often, variations on their structure are made to enhance activity reduce toxicity to the crop plant increase their stability to hydrolysis, light, enzymes and to make their chemical syntheses commercially attractive. Strobilurin (11.60) is such a case. It was isolated from a wood-rotting mushroom. This lead has resulted in a whole new class of fungicides, the (3-methoxyacrylates.269 A related compound is found in another mushroom. 

The fungicides are very versatile in the contol of fungi that have become resistant to the demethylase inhibitor (DMI) fungicides described later. They have surprisingly low mammalian toxicity, but as with many other respiratory poisons, they show some toxicity to fish and other aquatic organisms. They may also be toxic to earthworms. In fungi they inhibit spore germination. The structures show the natural products strobilurin B and azoxystrobin, which has been marketed since 1996. 

Natural products with a ew-dimethyl benzodioxepin ring have been detected, for example, the antifungal natural product strobilurin (31) <90JAN661>, and several benzodioxepin derivatives, i.e., compounds (32) and (33), with a similar structural feature have been synthesized in the total synthesis of (-I-)-paraherquamide B <90TL6325, 96JA557>. 

During the evolutionary process of lead-structure optimization, probably well over 50 000 strobilurin analogues were synthesized by competing industrial fungicide discovery research groups worldwide. Several compound types, and even specific compounds, were made independently at almost the same time. 

Several aspects of strobilurin fungicides, including the natural lead-structures, have already been summarized [2-9]. The elegant path that led to the discovery... 

From the BASF group, a first review concentrated on the discovery of BAS 490 F (kresoxim-methyl), on pharmacophore variations and on structure-activity relationships at the mitochondrial target level [7]. Another paper was focused more on biokinetic features, and their affect on final biological properties [8j. In 1999 a general review summarized the historical evolution from natural products to commercial strobilurins up to trifloxystrobin, and the international R D competition, including some dramatic patent races [9j. Additionally, strobilurins have been reviewed in Russian, Chinese and Indian journals [10-13]. 

An important Rosetta Stone came from the discovery that strobilurin A, oudemansin A and myxothiazol A not only share a common structural feature, namely... 

At this point, mention should also be made of two other active strobilurins with interesting structures ... 

Fig. 13.2.7. Target-level activity of a series of strobilurin oximino esters as a function of the lipophilicity of the substituents X. p/50 is the negative logarithm of the /50 value from the yeast mitochondria test. Each point represents a variant of the general structure shown.

A rough summary of the structure-activity experiences with strobilurins is visualized in Fig. 13.2.8. It illustrates the complex intercorrelation network between... 

---