Synthesis of Molleureas A-C: 2-(2-Aminoethyl)benzoic Acid-Derived Oligomeric Natural Products from Didemnum Molle

The molle family of secondary metabolites, isolated from the marine tunicate Didemnum molle, are unusual oligomeric amide compounds derived from 2-(2-aminoethyl)benzoic acid (ortho-carboxyphenethylamine) and phenethylamine units that can also include urea, amine, and carbamate functionalities. The total synthesis of molleamine A, mollecarbamate A, and molleureas A-C is described. The disubstituted urea formation required for the molleureas is achieved by the reaction of primary amines with carbamoylimidazole reagents. The carbamoylimidazole reagents, which act as isocyanate equivalents, are readily prepared from primary amines and carbonyldiimidazole (CDI). The N-Boc-substituted 2-(2-aminoethyl)benzoic acid fragment was synthesized from the acid-catalyzed cyclization of methylphenethylcarbamate to give dihydroisoquinolone, followed by acid-promoted ring cleavage and Boc protection. The unsymmetrical compound molleurea A was synthesized using both a stepwise method and a one-pot method through a two-directional, nonsymmetric chain synthesis. In the latter case, the phenethylamine-derived carbamoylimidazole reagent undergoes reaction with both the primary amine and carboxylic acid functional groups of 2-(2-aminoethyl)benzoic acid, giving urea and amide functional groups, respectively.