Synthesis of Cyclopeptide Alkaloids by Cyclooligomerization of Dipeptidyl Oxazolines

Cyclodehydration of Cbz-valylthreonine methyl esters with Burgess reagent provides access to cis- and trans-oxazoline segments for cyclooligomerization reactions. The ratio of 12-, 18-, 24-, and larger-ring macrocycles obtained in this process is kinetically controlled and dependent on the relative stereochemistry of the backbone α-carbons. A network of bifurcated hydrogen bonds rigidifies the peptidyl oxazoline strand and positions the valine side chains in either pseudoaxial or pseudoequatorial orientations. In the former case, transannular strain prevents the formation of 12-membered cyclopeptide alkaloids. Several X-ray structures illustrate the conformational preferences in this family of marine natural product analogs.