News and Publications
The Skaggs Institute for Chemical Biology
Scientific Report 1998-1999
Studies in Organic Synthesis and Bioorganic Chemistry
E.J. Sorensen, G. Adam, H. Seike, J. Tamiya, C. Vanderwal, D. Vosburg, G.
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
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.
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.