The study of oxyanion-promoted cycloaromatizations

Tefsit Bekele, Purdue University

Abstract

Upon suitable activation, the enediyne natural products like neocarzinostain chromophore undergo cycloaromitization to generate diradicals that damage DNA strands with high potency. The mechanism of the C2–C6 (Schmittel) cyclization of benzannulated enyne-allenes, substrates similar to those intermediates found in the cyclization of enediyne natural products, was investigated using a kinetic isotope effect analysis. The first order kinetics of cycoaromatization were studied by 1H NMR and verified an ene reaction mechanism instead of a diradical mechanism that was assumed previously. Non-benzannulated enyne-allenes have also been synthesized for the study of accelerated Myers cyclization. Those that have bulky substituents at the alkyne terminus did not undergo cycloaromatization after enolization. When the bulky substituents were replaced with a less sterically demanding group, a moderately slow C2–C7 (Myers) cyclization was observed. A simple ten-membered enediyneone prodrug was synthesized using an intramolecular Nozaki-Hiyama-Kishi cyclization as the key step. Reaction with thiolate nucleophiles led to rapid cycloaromatization via the C2–C7 (Myers) cyclization. Trapping experiments using 1,4-cyclohexadiene support the intermediacy of an aromatic diradical in the cycloaromatization. Reaction of the prodrug with thiol nucleophiles in aqueous buffer did not promote DNA cleavage, as judged by agarose gel electrophoresis of supercoiled ΦX174 plasmid DNA. An improved prodrug that could bind DNA better through intercalation was synthesized by conjugating the enediynone prodrug to ethidium bromide. DNA cleavage assay using ΦX174 plasmid DNA has shown that the newly improved prodrug did not have any DNA cleaving properties in vitro.

Degree

Ph.D.

Advisors

Lipton, Purdue University.

Subject Area

Organic chemistry

COinS