Cyclic and polycyclic peptides have emerged as valuable pharmaceutical templates due to their resistance to chemical or enzymatic hydrolysis and high selectivity. Especially bicyclic peptides found in nature exhibit a macrocyclic structure that is further constrained by an intramolecular linkage connecting two side chains of the peptide. Celogentin C is one of such bicyclic peptides which possess potent antimitotic activty1. The celogentin family peptides are characterized by a central tryptophan residue, cross-linked from the C2-position of the indole ring to the N1-position of the imidazole ring of a histidine residue. Further, the β-carbon of leucine is crosslinked to the C6-position of the tryptophan indole to form the second ring. Due to these unusual cross links between the side chains of leucine-tryptophan-histidine, the chemical synthesis of the celogentin family of peptides is very tedious, labour intensive and low yielding2-3. The main challenge in the synthesis of celogentin C is the formation of the two key cross-links between tryptophan-histidine and tryptophan-leucine. We report efforts toward synthesis of celogentin C on solid support, including oxidative coupling, Larock indole synthesis, Suzuki coupling and silylation reactions on solid phase.
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1 Christina Leung, T. W.; Williams, D. H.; C J Barna, J.; Foti, S.; B.Oelrichs, P., Structural studies on the peptide moroidin from laportea moroides. Tetrahedron 1986, 42 (12), 3333-3348.
2 Suzuki, H.; Morita, H.; Iwasaki, S.; Kobayashi, J. i., New antimitotic bicyclic peptides, celogentins D–H, and J, from the seeds of Celosia argentea. Tetrahedron 2003, 59 (28), 5307-531
3 Ma, B.; Banerjee, B.; Litvinov, D. N.; He, L.; Castle, S. L., Total Synthesis of the Antimitotic Bicyclic Peptide Celogentin C. Journal of the American Chemical Society 2010, 132 (3), 1159-1171.