Synthetic and mechanistic studies on the azabicyclo[7.3.1]enediyne core and naphtho[2,3-h]quinoline portions of dynemicin A

Article abstract of DOI:10.1021/ja970435v

The synthesis of the 13-keto-10-azabicyclo[7.3.1]enediyne core structure of dynemicin A has been achieved by two routes, Schemes 4 and 6. The chemistry of the 13-keto core structure is dominated by the unusually facile bridgehead enolization. Comparison of the rates of cycloaromatization of a variety of enediynes revealed that substantial rate differences occurred even though the distance between the bonding acetylenes was virtually identical. A non-radical cycloaromatization pathway, initiated by thiol addition to the enediyne system, was discovered, and the simple core amine 26 exhibits modest in vitro and in vivo antitumor activity. Finally, two methods for the synthesis of the naphtho[2,3-h]quinoline portion of dynemicin A are described, and both these compounds also exhibit antitumor activity.