Total Synthesis of Reniochalistatin E

Reniochalistatin E (1) is one of the five related cyclic peptides isolated from the marine sponge Reniochalina stalagmitis. The discovery of these compounds resulted from a screening program directed toward the identification of proline-rich bioactive compounds. Reniochalistatin E is the only member of the family to possess a tryptophan amino acid residue. Given the cytotoxicity observed for 1, efforts were directed toward developing a synthetic route to 1. The first total synthesis of 1 has been accomplished in a 15-step route in an overall 5.0% yield. The synthetic sample of reniochalistatin E was shown to have similar activity toward HeLa and RPMI-8226 cell lines compared to the natural sample, with IC₅₀ values of 16.9 vs 17.3 μM and 4.5 vs 4.9 μM, respectively. Interestingly, both of the fully deprotected octapeptides constructed toward the synthesis of reniochalistatin E were shown to have cytotoxicity. The route provides a means to probe the structure-activity relationship of 1 and further biological investigations.