Toxins of Amanita Phalloides

Among the homodetic, polycyclic, biologically-active tryptophan peptides, the toxins of the Amanita phalloides represent a special case [see reference 427) and 349) for a review]. In fact, the poisonous components of this deathcap, the phallotoxins and amatoxins (Fig. 9), both contain a cycloheptapeptide structure with an additional intramolecular covalent bond connecting the p-sulfur atom of a L-cysteine residue with the carbon atom in position 2 of the indole ring of a L-tryptophan residue. In the amatoxins the thioether bridge is oxidized to the sulfoxide (Fig. 9). 

Total synthesis of these toxins presented peptide chemistry with several problems, in particular formation of the sulfur bridge. The latter was explored with model compounds 430, 431). It was found 428) that the coupling reaction between the sulfur of N-acetyl-L-cysteine and the 2-position of the indole nucleus of N-acyl-L-trypto-phan was reproducible and profitable if glacial acetic acid was used as a solvent. The formation of the intermediate S-chloride from the cysteine derivative and N-chlorosuccinimide at room temperature was followed colorimetrically, and the tryptophan component added at the moment of maximum extinction. 

The main representative of the phallotoxins, phalloidin, also contains, like all members of this group, a y-hydroxy-leucine residue. It has been found extremely difficult to introduce this amino acid residue as a component of a peptide chain, because of its tendency to form a y-lactone ring. When the norvaline analog (norphalloin Fig. 10) was proved to be even more toxic than the natural toxins 113), the first synthesis of a phallotoxin had been achieved. Later on, a number of synthetic analogs of norphalloin were synthesized in order to obtain information on structure-activity relationships 115, 166, 427). 

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