First isolated from the fermentation broth of <i>Apiospora montagnei</i> Sacc. TC 1093, the natural products TMC-95 A–D are of great interest because of their biological activity against the 20S proteasome. This distinctive activity makes them promising candidates as agents for the treatment of cancer. However, constructing such complex molecular structures requires many synthetic steps, which hinders their potential medical use. These active compounds feature a peptide-based structure composed of tyrosine, asparagine, a highly oxidized tryptophan, (<i>Z</i>)-1-propenylamine, and 3-methyl-2-oxopentanoic units. A particularly unusual bond is found in these natural products: a biaryl connection between the tryptophan and tyrosine residues and, as a result of this strange C–C linkage, axial chirality is observed around this bond. Our primary interest in this project is to develop chemical conditions to form this important biaryl linkage via oxidative coupling of suitable tripeptide-based building blocks. Such an oxidative coupling can make the synthetic production of TMC-95 significantly easier, by starting with the inexpensive and widely available natural amino acid units. With an easier synthetic route, TMC-95-based compounds could become viable anti-tumor drug candidates.

Development of a biaryl oxidative coupling-based route to the anti-tumor natural products TMC-95

256th National Meeting (2018)

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