Synthesis of an α,3-Dehydrotoluene Biradical Precursor with DNA Cleaving Activity and Studies Directed Toward the Total Synthesis of Tetracycline

Citation

Parrish, Cynthia Ann (1999) Synthesis of an α,3-Dehydrotoluene Biradical Precursor with DNA Cleaving Activity and Studies Directed Toward the Total Synthesis of Tetracycline. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/3m0y-w259. https://resolver.caltech.edu/CaltechTHESIS:09122016-085802807

Abstract

The synthesis and characterization of a model of the enediyne antibiotics is described. The prepared conjugate consists of an α,3-dehydrotoluene biradical precursor tethered to an N-methylpyrrolecarboxamide minor groove binding element. The conjugate is shown to bind and cleave DNA with sequence selectivity. The binding domain is shown to localize the allene-ene-yne effector domain for sequence-selective DNA cleavage at micromolar concentrations of substrate. The time course of DNA cleavage parallels the rate of cyclization of the bioconjugate in organic solvent to form an α,3-dehydrotoluene biradical. These results indicate that the (Z)-allene-ene-yne functional group is a viable effector domain for the cleavage of DNA upon mild thermal activation.

Synthetic studies directed toward a concise and versatile synthesis of the antibiotic tetracycline are described. A strategy based on an isobenzofuran Diels-Alder cycloaddition to assemble the two halves of tetracycline is presented. The synthesis of the phthalide lefthand half is shown in five steps with 56% overall yield from commercially available starting materials. Several isobenzofuran Diels-Alder reactions are described that model the proposed condensation of the two halves of tetracycline. Specifically, a thermal DielsAlder reaction is successfully demonstrated with an enone dienophile containing an a-ester functional group. The synthesis of 6-dimethylaminomethyl-2,2-dimethyl-1,3-dioxin-4-one as a protected and fully functionalized right-hand half of the A ring of tetracycline is described. Strategies are discussed that aim to utilize this substrate in the synthesis of the right-hand half of tetracycline. A novel and potentially rapid route involving intermediate 2,4- or 2,5-cyclohexadienones from the oxidation of phenol precursors is briefly examined.

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