News and Publications

Synthesis of Natural Products and Bioorganic Chemistry

E.J. Sorensen, G. Adam, E. Alexanian, E. Anderson,K. Pekari, J. Rohde, H. Seike, W. Shipe, L. Stark, J. Tamiya, C. Vanderwal, D. Vosburg

ORGANIC SYNTHESIS

We are interested in organic chemical reactivity, complex molecular architectures, and biologically active natural products. Our achievements include the total synthesis of the angiogenesis inhibitor fumagillin, the immunosuppressant FR901483, the cell growth inhibitor hispidospermidin, and the microtubule-stabilizing natural product FR182877 (Fig. 1).

In designing a synthesis for a novel natural product, we often think about how the structure might have been created naturally, and we study the chemical feasibility of structural transformations that may have counterparts in the biogenesis of the product. Our efforts to approximate the efficiency with which architecturally complex, biologically active products are created naturally are reflected in our recent syntheses of FR901483, hispidospermidin, and FR182877.

Our proposal for the biogenesis of FR182877 was predicated on the following question: Can the complex molecular framework of compound 1 in Figure 2 form by intramolecular reorganization of a much simpler polyunsaturated structure such as compound 2? Our successful synthesis of FR182877 provided a chemical rationalization of its molecular structure and was the first report of a double transannular Diels-Alder reaction. Our convergent approach to the guanacastepene family of natural products exploits a stereoelectronically controlled fragmentation of a strained 4-membered ring (Fig. 3).

BIOORGANIC CHEMISTRY

Our continued interest in the natural product fumagillin led us to develop a library of fumagillin-like probes for use in activity-based proteomics experiments. In collaboration with B. Cravatt, Department of Cell Biology, we are using chemical synthesis to create novel biotinylated affinity agents that react with the active members of particular families of biochemically important proteins. We are especially interested in activity-based probes for protein profiling that are based on the structures of bioactive, electrophilic natural products. We used these probes to visualize enzyme activities in complex tissue proteomes, including proteins present in low amounts and proteins that are bonafide markers of diseases such as cancer. We anticipate that these reactivity-based methods will accelerate both the assignment of protein function and the identification of disease-associated protein targets.

We are also collaborating with the staff members of 4 laboratories at TSRI to study the RNA-binding and nuclear transport functions of the Rev protein of HIV type 1. Chemical syntheses of natural products that inhibit Rev will enable us to characterize this important protein and perhaps develop new HIV type 1 Rev inhibitors.

PUBLICATIONS

Adam, G.C., Sorensen, E.J., Cravatt, B.F. Proteomic profiling of mechanistically distinct enzyme classes using a common chemotype. Nat. Biotechnol. 20:805, 2002.

Shipe, W.D., Sorensen, E.J. A convergent synthesis of the tricyclic architecture of the guanacastepenes featuring a selective ring fragmentation. Org. Lett. 4:2063, 2002.

Vanderwal, C.D., Vosburg, D.A., Sorensen, E.J. Intramolecular allenolate acylations in studies toward a synthesis of FR182877. Org. Lett. 3:4307, 2001.

Vosburg, D.A., Vanderwal, C.D., Sorensen, E.J. A synthesis of (+)-FR182877, featuring tandem transannular Diels-Alder reactions inspired by a postulated biogenesis. J. Am. Chem. Soc. 124:4552, 2002.