Short Synthesis of (+)-Actinobolin: Simple Entry to Complex Small-Molecule Inhibitors of Protein Synthesis

Abstract

We report a concise synthesis of the naturally occurring protein synthesis inhibitor (+)-actinobolin (1). The densely functionalized and stereochemically complex molecular structure of 1 was assembled from (-)-quinic acid, L-threonine, and L-alanine as the principal components. Our route is based around a convergent strategy that features conjugate addition of an α-amino radical in the key fragment-coupling step. The dramatically simplified synthesis of (+)-actinobolin proceeding in 9 steps with 18 % overall yield has practical implications for analog preparation, as demonstrated herein.

Keywords: Antibiotics; Natural Products; Organic Synthesis; Radical Chemistry; Ribosome Inhibitors.