Plans are presented to complete a total synthesis of spongistatin 1 (altohrytin A), a potent antifungal and cytotoxic agent of marine origin. Because of its potent bioactivity, spongistatin is a promising drug candidate, but it would be virtually impossible to obtain sufficient quantities from natural sources. The goal of this project is to develop a synthesis that is sufficiently practical that it can be used to prepare approximately five grams of the material, which would be sufficient for a phase I clinical trial. Plans are also presented to complete a total synthesis of the 14- membered macrolide antibiotic lankamycin. Although an efficient and convenient synthetic route to the aglycone seco-acid has been developed in previous work, the macrolactonization reaction has not yet been achieved. In fact, this common transformation is often a limiting step in macrolide total synthesis. The goal of the coming project period is to apply modern methods of computer modelling, NMR conformational analysis, and synthesis to identify a suitable substrate for the macrolactonization.
| Heathcock, Clayton H; McLaughlin, Mark; Medina, Jesus et al. (2003) Multigram synthesis of the C29-C51 subunit and completion of the total synthesis of altohyrtin C (spongistatin 2). J Am Chem Soc 125:12844-9 |
| Hubbs, Jed L; Heathcock, Clayton H (2003) A second-generation synthesis of the C1-C28 portion of the altohyrtins (spongistatins). J Am Chem Soc 125:12836-43 |
| Wallace, G A; Scott, R W; Heathcock, C H (2000) Synthesis of the C29-C44 portion of spongistatin 1 (altohyrtin A). J Org Chem 65:4145-52 |
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