Synthetic Studies on Quinoxaline Antibiotics. II. Synthesis of Triostin A

Abstract

Triostin A, a cyclic octadepsipeptide, was synthesized with Z–d-Ser[Boc–Ala–MeCys(Bzl)–MeVal]–OH and Z–d-Ser[H–Ala–MeCy(Bzl)–MeVal]–OTce as key intermediates. The synthetic antibiotic was compared with natural triostin A in terms of chromatographic behaviors, NMR spectra, and antimicrobial activity to establish their identity. The NMR data on S,S′-dibenzyldihydrotriostin A showed that this intermediate lacking the disulfide linkage also existed as two conformers in chloroform. This observation excludes the possibility that the conformer equilibrium known to occur with triostin A is a consequence of the reversed chirality of the disulfide bond.

Synthesis of Cyclopeptidic Analogues of Triostin A with Quinoxalines or Nucleobases as Chromophores

“…The linear octapeptide 5 (Figure 3) was generated by SPPS and required a protecting group strategy that takes into account the permanent protection of the positions of later disulfide formation and quinoxaline or nucleobase attachment as well as N‐terminal Fmoc protection for setting up the peptide chain. Subsequent cyclization reactions were easily performed in solution and the disulfide‐bridged cyclopeptide that was obtained was modified at a later stage with quinoxaline or various nucleobases 26…”

“…The acetamidomethyl (Acm) protecting group allows iodine‐mediated deprotection and formation of the disulfide bond in a single step. Selective intramolecular oxidation to disulfide 6 was performed under high dilution in 80% aqueous acetic acid (Scheme ) 26,31. The alternative on‐resin cyclization in a solution of iodine and DMF turned out to be less efficient than the reaction in solution.…”

Application of multicomponent reactions in the total synthesis of natural peptides

“…35 The vital precursor for U3CR reaction, the isonitrile 27 was prepared in several steps from the conversation of compound 26, which was in turn obtained in 91% yield from compound 25. The synthesis of another precursor, the component-acylated serine 31, was commenced with D-Ser derivative 28 36,37 and N-Boc-N-Me-L-Val 29 38 as the starting materials. Compound 28 was reacted with compound 29 in the presence of EDCI and DMAP in CH 2 Cl 2 to give compound 30 in 65% yield.…”

Syntheses of Triostin A Antibiotic and Nucleobase‐Functionalized Analogs as New DNA Binders

“…We coupled amino acids Z--Ser-OTce (10) and Fmoc--Ser-OTce (11) with N-Boc-N-Me-Val-OH to yield the esters 12 and 13, respectively. [16] We deprotected these depsipeptides using 4  HCl in dioxane and then coupled them with N-Me-Boc--Cys(Acm)-OH. [22,23] We obtained tridepsipeptides 14 and 15, respectively, by activation with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI·HCl) and 1-hydroxy-7-azabenzotriazole (HOAt).…”

“…Two solution-phase syntheses of triostin A by Olsen et al and Shin et al are known to date, both following a strategy of linking the tetrapeptides followed by macrocyclization and oxidation or vice versa. [15,16] A differentiation of the amino groups for functionalization was not required in these triostin A syntheses as triostin A is symmetrical. In addition, an elegant solid-phase protocol was recently provided.…”