News and Publications

Studies in Organic Synthesis and Bioorganic Chemistry

Although its role has changed with time, organic synthesis remains the heart of organic chemistry because it is the expression of chemical reactivity.

We are interested generally in novel organic chemical reactivity, and a broad goal of our research is to approximate the efficiency with which Nature creates architecturally complex, biologically active products. Currently, our studies in organic synthesis include WS9885B (compound 1 in Fig. 1), a microtubule-stabilizing natural product with an intimidating structure; FR901483, a novel fungal metabolite with potent immunosuppressive activity; and hispidospermidin, a cell growth inhibitor with an interesting cagelike architecture. Recently, we described a concise solution to the chemical problem posed by fumagillin, a highly oxygenated and densely functionalized natural product that inhibits the proliferation of endothelial cells (angiogenesis).

When we commit to an architecturally novel natural product as an objective for our research, we speculate about the origin of such a structure in Nature, and we often devise strategies that are predicated on proposed biogenetic pathways. Although the biosynthesis of WS9885B is not yet known, the complex architecture of this substance could conceivably arise from a structural type that is much less complex in a relative sense. We are examining the hypothesis that WS9885B could form by spontaneous intramolecular reorganization of a polyunsaturated structure of type 2 through the reaction cascade shown in Figure 1. Future objectives of this research are to determine if the strained and reactive bridgehead alkene of WS9885B causes covalent modification of microtubules or other cellular components and to establish if the marked cytotoxicity of this natural product stems solely from its capacity to stabilize microtubules.

Publications

Vanderwal, C.D., Vosburg, D.A., Weiler, S., Sorensen, E.J. Postulated biogenesis of WS9885B and progress toward an enantioselective synthesis. Org. Lett. 1:645, 1999.

Vosburg, D.A., Weiler, S., Sorensen, E.J. A concise synthesis of fumagillol. Angew. Chem. Int. Ed. 38:971, 1999.