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Enantioselective Synthesis of Pactamycin, a Complex Antitumor Antibiotic

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Science  12 Apr 2013:
Vol. 340, Issue 6129, pp. 180-182
DOI: 10.1126/science.1234756

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Preparing Pactamycin

Microbially derived organic compounds often have remarkably intricate structures that confer striking bioactivity, but such complexity may become an impediment to drug development. Pactamycin is one such case—a potent antibiotic used to probe ribosome structure and function that in its native form is too cytotoxic for therapeutic application. Malinowski et al. (p. 180; see the Perspective by Codelli and Reisman) present a 15-step laboratory-scale synthesis of this molecule that offers prospects for the generation of structural analogs that could facilitate further exploratory medicinal research.

Abstract

Medicinal application of many complex natural products is precluded by the impracticality of their chemical synthesis. Pactamycin, the most structurally intricate aminocyclopentitol antibiotic, displays potent antiproliferative properties across multiple phylogenetic domains, but it is highly cytotoxic. A limited number of analogs produced by genetic engineering technologies show reduced cytotoxicity against mammalian cells, renewing promise for therapeutic applications. For decades, an efficient synthesis of pactamycin amenable to analog derivatizations has eluded researchers. Here, we present a short asymmetric total synthesis of pactamycin. An enantioselective Mannich reaction and symmetry-breaking reduction sequence was designed to enable assembly of the entire carbon core skeleton in under five steps and control critical three-dimensional (stereochemical) functional group relationships. This modular route totals 15 steps and is immediately amenable for structural analog synthesis.

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