A total synthesis of the cytotoxic marine natural product haouamine A is proposed. This important alkaloid contains an unprecedented 3-aza-[7]-paracyclophane ring system fused to a tricyclic core unit. The significant decrease in activity of haouamine B, which differs only by an additional phenolic hydroxyl group, demonstrates that small changes in the structure of these compounds can have dramatic effects in their activity. Novel methodology is proposed for the synthesis of this core unit based on an ortho- lithiation/alkylation sequence of benzoic acids, followed by an intramolecular extension of Myers' decarboxylative Heck-type reaction. This method can be extended to a variety of other ring systems for the synthesis of other important biologically active compounds. Overall, the highly flexible, modular synthesis that is proposed will enable the preparation of haouamine A and a variety of fragments and analogs to facilitate the biological study of haouamine A. Completion of this research may ultimately provide compounds with improved therapeutic profiles for the treatment of cancer. ? ?
| Dineen, Thomas A; Zajac, Matthew A; Myers, Andrew G (2006) Efficient transamidation of primary carboxamides by in situ activation with N,N-dialkylformamide dimethyl acetals. J Am Chem Soc 128:16406-9 |
