Cyclo-?oligomerization has been widely utilized as a powerful tool, for efficient synthesis of various macrocyclic peptides, with the potential to create a plethora of dimer, trimer, and tetramer macrocycles for applications in medicine, drug design, and catalysis. Petides containing �-turn inducing constraint elements like: oxazolines, oxazoles, thiazolines, thiazoles and imidazoles are ideal precursors for cyclooligomerization reactions to form peptide macrocycles, because of the imidate linkage fused into their five membered rings with a rigid transoid conformation leading to an extended structure with the mutually reactive terminal groups far apart to react intramolecularlyWe now report that cbz-?dipeptidoyl benzotriazolides can be cyclized in a cyclo-?oligomerization fashion to access different peptide macrocycles. Since the cyclooligomerization cascade is kinetically controlled, at higher concentration of the substrate, relative preferred ring size of the macrocycles is determined by the relative configurations of the cyclization precursors and the �-turn introducer. Increased substrate concentration with higher Pd/C load allows for the spontaneous formation of larger peptide macrocycles. During formation of intramollecular 7-membered rings, the ground-state E geometry of the peptide bond prevents the peptides from attaining the ring-like conformation conducive to intramolecular cyclization. However, larger ring sized product of cyclooligomerization do not pose this problem because they can accommodate cis peptide bonds easier.

Cyclo-oligomerization of dipeptidoyl benzotriazolides into peptide macrocycles

248th National Meeting (2014)

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