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In order to explore the route for the preparation of cyclodepsipeptide by cyclization through an ester bond formation, two analogs of AM-toxin II, cyclotetradepsipeptide, were synthesized. As a preliminary experiment, synthesis of [L-Phe3, L-Ser(Bzl)4]-AM-toxin II, containing L-Phe and L-Ser(Bzl) in place of L-App (2-amino-5-phenyl-pentanoic acid) and delta Ala (alpha, beta-dehydroalanine), respectively, was attempted. Cyclization of H-L-Hmb-L-Phe-L-Ser(Bzl)-L-Ala-OH in CH2Cl2 at 10 mM concentration using water-soluble carbodiimide (EDC) and 4-dimethylaminopyridine (DMAP) successfully gave a cyclic monomer in 16% yield. Cyclization of H-L-Hmb-L-App-L-Ser(Bzl)-L-Ala-OH under the same conditions also afforded a cyclic monomer, [L-Ser(Bzl)4]AM-toxin II, in 19% yield. Analytical parameters of these cyclic monomers obtained were identical to those of the authentic samples obtained by cyclization through a peptide bond formation.

A cyclic tetradepsipeptide with a sequence corresponding to AM-toxin III (a phytotoxic peptide) was synthesized by a conventional method in order to confirm the proposed structure. This was mediated through a deamination reaction of precursor cyclotetradepsipeptide containing a D-2, 3-diaminopropionic acid residue by the Hofmann degradation method. The synthetic peptide and natural AM-toxin III were identical in regard to t.l.c., crystal form, mass spectrum and biological activity in causing necrosis on apple leaves. Two analogs, [l-O-methyl-L-tyrosine]-AM-toxin and [l-L-tyrosine]-AM-toxin showed extremely weak activity; the relationship between the bulkiness of an aromatic side chain at position 1 of AM-toxin III and its biological activity is discussed.

The vitroxins, toxic cyclic heptapeptides from Amanita virosa fungi, contain a 3,4-dihydroxy-L-proline, an imino acid scarcely accessible in greater amounts. Therefore in the syntheses of the analogs described this imino acid was replaced by 4-cis-hydroxy-L-proline, a component of the analogously toxic phallotoxins. The following syntheses are described: 1a = cyclo (L-alanyl-D-threonyl-D-seryl-L-4-cis-hydroxy-L-prolyl-L-alanyl-2- methylthio-L-tryptophyl-L-leucyl), 1b = 1a but with 2-methylsulfonyl-L-tryptophan in position 6, 2a = cyclic (L-valyl-D-threonyl-D-seryl-4-cis-hydroxy-L-prolyl-L-alanyl-2- methylthio-L-tryptophyl-hydroxyl-L-leucyl), and 2b = 2a, but with 2-methylsulfonyl-L-tryptophan in position 6. In a test for binding strength to rabbit muscle F-actin 2b and 2a exhibited about 40% of that of demethylphalloin. Analogs 1a and 2b have not been tested.

In order to investigate the influence of the side-chain length at position 3 of AM-toxin I (cyclic tetradepsipeptide) on necrotic activity for apple leaf, two analogs of AM-toxin I, [L-2-amino-4-(p-methoxyphenyl)butanoic acid]-AM-toxin I and [L-2-amino-6-(p-methoxyphenyl)hexanoic acid]-AM-toxin I, were synthesized by the conventional method. Spectra of 1H-n.m.r., u.v. and CD of the analogs were similar to those of natural or synthetic AM-toxin I. The toxic activities of the analogs for apple leaf, however, were weak, indicating that the exact side-chain length at position 3 must be one of the important factors for the induction of the activity. The interaction between AM-toxin I and a possible receptor on apple leaf is discussed.