Total Synthesis and Structural Revision of Cyclotetrapeptide Asperterrestide A

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 alpha-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.