Total synthesis-driven structure determination of viridamide A

Abstract The originally reported structure of viridamide A was determined to be incorrect based on total synthesis, and the reassignment of NMR spectra suggested a new proposed structure of viridamide A. While the newly proposed structure was successfully synthesized, its 1H NMR spectrum exhibited discrepancies with respect to that of the natural product, particularly in the chemical shifts of the δ-protons of the Pro residue and N-Me moieties. These discrepancies suggested a possible misassignment of amino acid configurations around the C-terminus. Hence, we synthesized 2 diastereomers by replacing the Val or the Pro residue with a corresponding D-amino acid. The 1H NMR spectrum of the D-Val analog closely matched that of the natural product. Finally, both diastereomers possessing (R)- or (S)-methoxymethine group at the C39 position were synthesized. The NMR spectra of diastereomers were compared with that of the natural product, confirming that the absolute configuration at the C39 position was R.