Synthesis of an α,3-Dehydrotoluene Biradical Precursor with DNA Cleaving Activity and Studies Directed Toward the Total Synthesis of Tetracycline
<p>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...
| Summary: | <p>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.</p>
<p>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.</p> |
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