Direct modification of the complex natural product, Calicheamicin. Calicheamicin g1 I is a member of a class of enediyne antibiotics with potent anti-tumor activity. Calicheamicin's intriguing structure contains a linear trisulfide, as well as potentially reactive functional groups such as its enediyne, an a,b-unsaturated ketone, and a thioester (Figure ). Clinically, calicheamicin is conjugated to antibodies that target the drug to diseased tissue. The conjugation chemistry requires selective manipulation of the trisulfide domain of calicheamicin, so we thought that our newly discovered metathesis chemistry might be adaptable to the modification of this important anti-tumor medicine. We also regarded calicheamicin as a good testing ground for the selectivity and scope of our trisulfide metathesis chemistry. In particular, its complex structure would be an advance in substrate scope far beyond the substrates tested in Figure . Furthermore, our working hypothesis of the mechanism of the trisulfide metathesis in Figure does not invoke thiolate or thiyl radical intermediates-species that would otherwise cleave calicheamicin's sensitive trisulfide and provoke Bergman cyclization of the enediyne. In this way, attempting the trisulfide metathesis on calicheamicin would also provide potential mechanistic insight and corroboration of our mechanistic hypothesis.