Synthesis of dimeric and tetrameric macrolactams with cytotoxic activity

Cyclization of amino acid 14, in turn prepared from 4,4-dimethylcyclohex-2- en-1-one by standard chemistry, yielded the dimeric and tetrameric macrolac tams 15 and 16, respectively, representing the first examples of "taxoid-li ke" compounds with heterocyclic B rings. Compounds 15 and 16 exhibited mode rate antiproliferative activity in an in vitro cytotoxicity assay. Conseque ntly, an orthogonally diprotected, dimeric macrolactam 19 was synthesized a nd, after selective deprotection of the hydroxy group, was coupled with the docetaxel side chain to give the final compound 2, showing three-dimension al shape similarity to paclitaxel. Contrary to our expectations, 2 proved t o be as active as the parent compound 15. The structure of 15 has been conf irmed by X-ray crystallographic analysis and is also reported.