Issue Date: August 27, 2007
Tetracycline synthesis improves
In 2005, Andrew G. Myers and colleagues at Harvard University reported an enantioselective semisynthetic route to tetracyclines that yielded an unprecedented series of structurally diverse analogs of this broad-spectrum class of antibiotics. In an ongoing effort to develop a fully synthetic route to tetracyclines, Myers and graduate student Jason D. Brubaker now report a completely different pathway to a key precursor in the synthesis (Org. Lett., DOI: 10.1021/ol071377d). The precursor (shown) contains the A and B rings of the four-ring tetracycline molecule. Important steps in the new route, which proceeds in nine steps with 21% overall yield on a multigram scale, include enantioselective addition of divinylzinc to a heterocyclic starting material and an endo-selective intramolecular Diels-Alder cycloaddition. "We believe that this innovation will fuel the discovery of large numbers of new candidate antibiotics and may provide the basis for novel tetracyclines to be synthesized on a scale sufficient for their clinical development," they write.
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