Synthetic studies related to reductively activated antitumor antibiotics

Abstract

Exploration of synthetic approaches to two classes of antitumour antibiotics, believed to function through DNA alkylation after bioreductive activation analogous to that established for mitomycin C, is described. Transformation of mitomycin-related pyrrolo[1,2-a]indoles into the bicyclic hydroxylamine hemiketal ring system found in antitumour antibiotic FR-900482 via a bromination-methanolysis sequence followed by oxidative ring expansion with N-benzenesulfonyl oxaziridines (Davis' reagent) is presented. Attempts at improving the two-step transformation using Davis' reagent to effect both steps are observed to yield anomalous addition products. Mechanistic studies suggest that this addition reaction proceeds via a zwitterionic intermediate. The possibility that such an intermediate is also involved in oxygen atom transfer reactions of Davis' reagent is discussed.

A synthetic route to prekinamycin, a biosynthetic precursor to the kinamycins which were proposed to incorporate an N-cyanobenzo[b]carbazole ring system, is described. A preparation of what was expected to be O-acetyl-O-methyl prekinamycin (190), in an unambiguous manner, in 21% overall yield from o-anisidine is presented. Careful comparison of the spectroscopic characteristics of 190 with those of the kinamycins is shown to prove that the kinamycins are derivatives of diazofluorene and not of N-cyanocarbazole as previously believed. The significance of this structural revision in the context of the biosynthesis and possible mode of action of the kinamycins is discussed.

Finally, a synthetic route to the carbon skeleton present in the revised structure of prekinamycin but lacking the substituents present in the D-ring of the natural product, is presented as well as a route to an aromatic acid (283) which is a logical precursor to prekinamycin via this synthetic strategy.