This project will continue work to develop new organometallic methodology to prepare C-C bonds in a stereoselective fashion, and applications of this methodology. In particular, the preparation of (2-alkenyl-3-pentene-1,5-diyl)iron complexes and their transformation into vinylcyclopropanes and divinylcyclopropanes will be targeted. The divinylcyclopropanes are likely to undergo rearrangement to cycloheptadienes. These reactions will be applied to the synthesis of beta-aminocyclopropanecarboxylic acids and frondosin A, an inhibitor of the binding of interleukin-8 to its receptor.
With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Professor William A. Donaldson of the Department of Chemistry at Marquette University. Professor Donaldson's research efforts revolve around the development of organometallic methodology for the formation of cyclopropanes and cycloheptadienes, structural motifs present in a variety of biologically relevant molecules. Successful development of the methodology will have an impact on synthesis in the pharmaceutical and agricultural industries.
Intellectual merits. The long-range research goal of this project was to develop new chemical reactions and sequences of chemical reactions for the construction of carbon-carbon bonds. In particular, these reactions were designed to control the 3-dimensional shape of molecules. During this grant period we further developed a sequence of reactions for the preparation of molecules containing rings of seven carbon atoms. This sequence utilizes the ability of an iron atom to stabilize positive charge on a carbon atom such that the cationic compounds can be prepared and stored for extended periods of time. In order to demonstrate the utility of these reactions, during this grant period we applied this methodology to a four-step route for the preparation of the carbon skeleton (1) of frondosin A. Frondosin A is present in the organic extracts of the marine sponge Euryspongia sp. These extracts exhibit HIV inhibitory activity. In addition, we utilized this methodology to prepare isolated from the marine sponge Euryspongia sp, inhibits the binding of interlukin-8 to its receptor. An addition compound prepared by this methodology, 1-hydroxymethyl-4-(4’-hydroxypheny)cycloheptane (2), was tested for its ability to bind to the two forms of the human estrogen receptor (ERa and ERb). This in vitro testing identified the above compound to be the most potent and selective ERb agonist known to date (ERb agonist IC50 = 5.4 ± 0.3 nM; ERb antagonist IC50 = 137 nM). Given that ERb agonists have been proposed for treating breast cancer (in combination with ERa agonists) and for treating depression and anxiety, it could be useful for any of these diseases. Broader impacts. This grant aided in the development of human resources through support to one postdoctoral research fellow, three Ph.D. candidates and two M.S. candidates. To date, two of the three Ph.D. candidates and both of the M.S. candidates have completed their studies and received their respective degrees. These former students are now employed in the chemical industry or have continued on for further advanced study. The remaining Ph.D. candidate will complete the requirements for his degree in May 2014 and has accepted a postdoctoral research associate position in an academic laboratory. While reduction in the initial support from NSF did not allow for stipend support to undergraduate students, none-the-less three undergraduates participated in research supported by this grant and chemicals which they used were purchased with NSF funds.
