The first total synthesis of N1999-A2: absolute stereochemistry and stereochemical implications into DNA cleavage.

Abstract

Enediyne antitumor antibiotics have attracted immense attention among chemists and biologists alike because of their unique chemical structures, potent antitumor activities, and fascinating biological modes of action. As a novel addition to this family, the nonprotein and extremely strained nine-membered enediyne antibiotic N1999-A2 strongly inhibits the growth of various tumor cell lines and bacteria, and cleaves DNA in a base-specific manner. The attractive features of this molecule lie not only within the chemical structure being analogous to the neocarzinostatin chromophore, itself a potent anticancer agent, but also in that it can invoke remarkably strong biological activities even without a stabilizing apoprotein carrier and a glycoside functionality that can accelerate the rate of DNA cleavage. In this regard, N1999-A2 serves as a leading enediyne-based antitumor agent with minimal functionality that is able to act on DNA selectively. We therefore focused on this unique, unstable, and stereochemically unknown compound and undertook the formidable challenge of devising an efficient strategy that would be flexible enough to ultimately construct a series of related highly strained systems.