Total Synthesis and Structural Revision of Cyclotetrapeptide Asperterrestide A

Abstract

The structural revision of cyclotetrapeptide asperterrestide A has been achieved based on total synthesis and molecular modeling. For these studies, (2R,3S)-MePhe­(3-OH) and (2S,3S)-MePhe­(3-OH) suitably protected for peptide synthesis were prepared via a stereoselective reduction of a ketone precursor derived from L- or d-serine, using L-selectride or DIBAL-H. The synthesis of the proposed structure of asperterrestide A (1a) was accomplished by solution-phase synthesis of a linear precursor followed by macrolactamization. The NMR spectra of our synthetic 1a were not identical to those reported for the natural compound. Molecular modeling studies suggested that the correct structure 1b was the one in which the stereochemistry at the α-positions of the Ala and MePhe­(3-OH) residues is the opposite to that of the proposed structure. This was confirmed by the total synthesis of 1b and its subsequent structural characterization.

Natural Cyclopeptides as Anticancer Agents in the Last 20 Years

“…Moreover, the growth of the influenza virus strains H1N1 and H3N2 could also be inhibited by asperterrestide A [310]. Just like other cyclic tetrapeptide natural products, synthesis of the compound remains challenging [311].…”

Solid-Phase Total Synthesis of Dehydrotryptophan-Bearing Cyclic Peptides Tunicyclin B, Sclerotide A, CDA3a, and CDA4a using a Protected β-Hydroxytryptophan Building Block

“…The resulting mixture was stirred for 17.5 h at room before the mixture was acidified with 1 M HCl (pH ca. 84 A solution of anthranilic acid (2.0 g, 14.6 mmol, 1.0 equiv) in a mixture dioxane (40 mL) and 10 % Na2CO3 (aq) (30 mL) at room temperature was treated with a solution of FmocOSuc (5.2 g, 15.3 mmol, 1.05 equiv) in dioxane (20 mL). A white precipitate began to form upon the final addition of the FmocOSuc.…”

“…Fmoc-Ant-OH was coupled using a procedure described by Masuda et al 84 A solution of Fmoc-Ant-OH (2.32) (3.0 equiv), HOBt (4.5 equiv.) and DIC (3.0 equiv) in DMF (2.0 mL) was added to the peptide.…”

Cyclic peptides bearing thed‐Phe‐2‐Abz turn motif: Structural characterization and antimicrobial potential

“…[14][15][16] 2-Aminobenzoic acid (2-Abz) is a nonprotein β-amino acid found in peptide secondary metabolites such as the antiviral and cytotoxic peptide asperterrestide A, isolated from the fermentation broth of the marine-derived fungus Aspergillus terreus SCSGAF0162. 17,18 Both 2-Abz and its sulfonic acid homologue (orthanilic acid) have been extensively studied and implemented within synthetic turn motifs. [19][20][21][22][23][24][25] Our previous studies showed that the D-Phe-2-Abz turn motif 21 appeared sufficient to nucleate β-hairpin formation in a short hydrophobic peptide devoid of cyclic constraints.…”

“…2‐Aminobenzoic acid (2‐Abz) is a nonprotein β‐amino acid found in peptide secondary metabolites such as the antiviral and cytotoxic peptide asperterrestide A, isolated from the fermentation broth of the marine‐derived fungus Aspergillus terreus SCSGAF0162 17,18 . Both 2‐Abz and its sulfonic acid homologue (orthanilic acid) have been extensively studied and implemented within synthetic turn motifs 19–25 .…”