SYNTHESES OF FURTHER ANALOGUES OF NORPHALLOIN. GLY¹‐, L‐VAL¹‐ AND D‐ABU₂‐ NORPHALLOIN AND (β‐TRIDEUTERO)‐ALA₅‐ NORPHALLOIN*

Abstract

The norphalloin analogues with glycine and L‐valine instead of L‐alanine in position 1, (II and III), with D‐α‐aminobutyric acid instead of D‐threonine in position 2 (IV), and with β‐trideutero‐L‐alanine instead of L‐alanine in position 5 (β‐D3‐I), have been synthesized according to Chart I, mainly using the mixed anhydride method. For the final cyclization step to III the p‐nitrophenylester method was employed. Analogue IV showed toxicity in the white mouse with doses <5 mg per kg body weight, whereas II and III were nontoxic. The deuterated norphalloin analogue proved by p.m.r. measurement that in fact the methyl group of alanyl residue no.5 is located above the indole nucleus, as suggested in a former publication (4).

Synthesis of the Death-Cap Mushroom Toxin α-Amanitin

“…The first challenge is the most formidable as l -Trp must be selectively oxidized at positions 6 and 3 to afford a 6-hydroxy-trypta­thionine cross-link (Figure , bottom panel, left), which must undergo sulfoxidation in a later step. Routes to a tryptathionine cross-link have involved the reaction of tryptophan with a cysteine–sulfenyl chloride or iodide, either with orthogonally protected monomers or in the context of a peptide macrocycle in the case of phalloidin derivatives. − A trypta­thionine cross-link may also be introduced in peptides containing Cys/Trp by treatment with Hg/HOAc . Yet none of these methods has been applied to amanitins, nor toward trypta­thionylation with 6-hydroxy- l -tryptophan.…”

Synthesis and Reactivity of 4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole. A Novel One-pot Synthesis of N-Substituted Indole-2-thiols

“…2-[(E)-2-Chloro-5-nitrobenzylidene]-4-[2-chloro-5-nitrophenyl]-1,3-dithiole (18). A mixture of compound 3 (0.5 g, 2.07 mmol) and K 2 CO 3 (0.86 g, 6.21 mmol) in MeCN (20 mL) was stirred and refluxed for 6 h. After it was cooled to room temperature, the mixture was poured into water (200 mL) and refluxed for an additional 1 h. The precipitate was filtered and thoroughly washed with water to yield 0.42 g (95%) of 18 as an orange powder, mp 220-223 °C.…”

“…1 H NMR (300 MHz, CDCl 3 ): δ 6.92 (s, 1H), 7.36 (s, 1H), 7.79 (d, 1H), 7.89 (d, 1H), 8.02 (dd, 1H), 8.24 (d, 1H), 8.27 (dd, 1H), 8.34 (d, 1H). MS (EI + mode): m/z 426 (M + , 100%), 390 (18), 298 (8), 264 (13), 199 (58), 164 (19), 155 (43), 132 (28), 123 (19). HRMS (EI + mode): m/z calcd for M + 425.9303, found 425.9305.…”

“…Org example, been demonstrated as useful intermediates in the synthesis of 2,2′-dithiobisindole tyrosine kinase inhibitors. 7,14, 15 Wieland et al [16][17][18][19] carried out notable synthetic work on phalloidin as well as natural and nonnatural analogues of the phallotoxins. Phalloidine is a cyclic heptapeptide fungal toxin produced by Amanita Phalloides (the Death Cap mushroom) comprised of a 2-thioindole fragment as a cross-linker.…”

“…Several natural products having specific biological activity contain the indole-2-thiol fragment. For example, cruciferous sulfur-containing phytoalexins, such as brassilexin, sinalexin, and cyclobrassinin occurring in plants, have a broad antimicrobial activity, playing crucial roles in their resistance to pathogen invasion. ,,, Indole-2-thiol derivatives have, for example, been demonstrated as useful intermediates in the synthesis of 2,2‘-dithiobisindole tyrosine kinase inhibitors. ,, Wieland et al − carried out notable synthetic work on phalloidin as well as natural and nonnatural analogues of the phallotoxins. Phalloidine is a cyclic heptapeptide fungal toxin produced by Amanita Phalloides (the Death Cap mushroom) comprised of a 2-thioindole fragment as a cross-linker.…”