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Studies in Organic Synthesis and Bioorganic Chemistry

With its power to create new molecules, the science of organic synthesis is uniquely poised to take advantage of insights gained from studies of the relationship between the constitution and reactivity of organic molecules. An important function of contemporary organic synthesis, and a major mission of the research in our group, is the establishment of concise and innovative pathways for the chemical synthesis of novel, biologically active, naturally occurring substances. Although our interests in this area are varied, natural products that combine challenging molecular architecture with promising biological properties are particularly attractive to us.

Our studies on the synthesis of natural products include FR901483, a novel fungal metabolite with potent immunosuppressive activity; hispidospermidin, a cell growth inhibitor with an interesting cagelike structure; eleutherobin, a scarce marine-derived secondary metabolite with potential anticancer activity; and fumagillin, a novel fungal metabolite that inhibits angiogenesis (Fig. 1). In each case, an effort is made to develop strategies that are of a more general interest to organic chemistry.

We also seek ways in which concepts of organic chemistry can be applied to the design and synthesis of small molecules capable of inhibiting the action of biologically important enzymes. In collaboration with B. Cravatt, Department of Cell Biology, we recently synthesized a collection of anilides derived from fatty acids and showed that these substances inhibit fatty acid amide hydrolase, an enzyme that regulates levels of neuromodulatory fatty acid amides in vivo and may be involved in the regulation of the sleep cycle in mammals. An important goal of this work is to uncover the chemical mechanism by which this enzyme catalyzes the hydrolysis of its endogenous fatty acid amide substrates.