Activation of a terminal carboxylic acid by an internal oxazole: a novel synthesis of macrocyclodepsipeptide

A new concept for the construction of macrocyclodepsipeptides from simple and readily available starting materials has been developed. The sequence consists of (a) a three-component reaction of an aldehyde, an amino alc., and a dipeptide isocyanate and (b) a domino process involving an activation of the terminal carboxylic acid function by a built-in aminooxazole followed by a macrocyclization under acidic conditions. The synthesis is atom-economic since only a mol. of water and "MeO" is lost in the entire sequence. The overall process is also ecol. benign since LiOH and TFA are the only reagents used, while water and low-mol. wt. alc. (MeOH) are the only side products formed. [on SciFinder (R)]