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

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.