Molecular design and chemical synthesis of potent enediynes. 1. Dynemicin model systems equipped with N-tethered triggering devices

Abstract

In this article the molecular design and chemical synthesis of a series of enediynes (12-19, Chart I) related to the dynemicin A structure and carrying N-tethered triggering devices are described. The design envisioned the [(arylsulfonyl) ethoxy]carbonyl group attached at the nitrogen atom as a triggering device for the Bergman cycloaromatization reaction because of its ability to undergo β-elimination under basic conditions, liberating the labile free amine intermediate. A number of tethering groups on the aromatic ring were also installed in these systems for future incorporation of other desirable moieties such as delivery systems and solubility enhancers. The chemical synthesis of the designed systems proceeded from the corresponding quinoline intermediates 46, 49, and 52 (Scheme VII) through acetylide additions to quinoline (intermolecular) and carbonyl (intramolecular) functionalities as the key steps. Bergman cycloaromatization experiments under basic and acidic conditions demonstrated the abilities of these compounds to generate benzenoid diradicals. A number of potent DNA-cleaving compounds and cytotoxic agents emerged from these studies.