Phenanthropiperidine alkaloids: Methodology development, synthesis and biological evaluation.

摘要

The phenanthropiperidines are remarkably potent anti-proliferative alkaloids. Only one member of this class has been tested in the clinic, but the trials were terminated shortly thereafter due to adverse neurological side-effects. This work is directed towards the development of safe phenanthropiperidines for the treatment of cancer. It focuses on synthetic methodologies that facilitate their preparation and biological studies to better understand their neurological effects.The preparation of cyclic enaminones in high enantiomeric purity is made possible through a one-flask, two-step protocol that uses mild Boc-deprotection conditions to suppress racemization. This reaction enables the preparation of monocyclic and bicyclic, six- and seven-membered enaminones, some of which can be used as precursors to phenanthropiperidine alkaloids.Elaboration of the enaminone scaffold was made possible with a direct palladium(II)-catalyzed arylation using aryltrifluoroborates as coupling partners. Combined with the enaminone methodology this approach gives rapid access to enantiomerically pure 3-arylpiperidines. The utility of these scaffolds were demonstrated in the synthesis of two natural products: (+)-ipalbidine and (+)-antofine.A short and high-yielding synthetic route has also been devised to provide tylocrebrine, the only phenanthropiperidine to enter clinical trials. We report the first enantioselective synthesis of tylocrebrine which uses a novel aryl-alkene oxidative coupling reaction that surmounts the historical challenge of obtaining a single phenanthrene regioisomer. A small collection of tylocrebrine analogs were prepared and studied along with tylocrebrine to elucidate the cause of tylocrebrine's neurological side-effects. Although the causes remain elusive, tylocrebrine and several of its analogs were found to bind to key biogenic amine receptors, disclosing another potential risk factor for their therapeutic use. The phenanthrene substitution pattern, however, had an marked influence on binding and could be used to minimize these off-target interactions.