The study of alkoxide-promoted enyne-allene cyclizations

Steven Richard Brunette, Purdue University

Abstract

The enediyne antitumor antibiotics are profoundly effective against a number of cancer cell lines, manifesting their bioactivity through timely cycloaromatization of an unsaturated carbocyclic core to afford an aryl diradical. With facile cyclization of these natural products intimately related to the constraints imparted on the pharmacophore by the complex molecular structure of these systems, the design of simple systems which retain the potent bioactivity of the natural products proves to be a challenge. A novel, enolization triggering mechanism for the facile generation of cycloaromatization-labile enyne-allenes was studied. Two separate systems were investigated, a cyclic ten-membered unsaturated ketone and a benzannulated enyne-allene. Both were found to rapidly and efficiently undergo cyclization when triggered by enolization. Ten-membered unsaturated cyclic ketones were generated in situ and shown to spontaneously cycloaromatize at room temperature to afford ethoxy substituted naphthols. Benzannulated enyne-allenolates were synthesized and shown to undergo facile cyclization to afford both formal Diels-Alder and ene reaction products, with a substantial rate acceleration over that of non-ionic analogues. The cyclization regiochemistry of these systems differed from that exhibited by the ten-membered cyclic ketones to afford substituted indanone and fluorenone products rather than naphthol derivatives. Although the exact mechanism of cyclization for both of these systems was not able to be strictly proven, no experimental evidence is inconsistent with a radical pathway.

Degree

Ph.D.

Advisors

Lipton, Purdue University.

Subject Area

Organic chemistry|Oncology|Pathology|Pharmacology|Pharmacology

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