Cyclopentanone derived natural products remain important targets for total synthesis and method development in order to prepare materials for bioassay and structure-function studies. Since much of the molecular complexity of natural products may not be important for biological activity, the development of new synthetic methods that provide easy access to highly functionalized compounds will be important in defining the limiting structures necessary to support the sought after biological action. In this light, the unique ability of transition metals to allow organic chemists to form carbon-carbon bonds under neutral conditions at ambient temperatures from highly functionalized substrates should make organotransition metal chemistry a powerful synthetic tool for structure-function studies. Synthetic methods based on organotransition metal chemistry are proposed for the synthesis of 5-alkylidene cyclopentenones, a general family of organic molecules possessing biological activity with some specific members showing significant antitumor activity (clavulones, chlorovulones, and punaglandins). Preliminary efforts will focus on developing a newly discovered route to 5-alkylidene cyclopentenediones by the reaction of terminal alkynes with cationic maleoylcobalt complexes. Alkylidene cyclopentenediones will be used as precursors to 5-alkylidene-4-hydroxycyclopentenones by selective 1,2-addition of carbon nucleophiles to one of the ketone groups; however, alkylidene cyclopentenediones themselves show significant in vitro antitumor activity (IC50 activity in the 5-20 microgram / mL range was found for two simple alkylidene cyclopentenediones submitted for testing to Bristol Myers) and structure function studies will be pursued for these simple, but reactive molecules. Beyond developing this new route to 5-alkylidene cyclopentenediones, novel synthetic methods utilizing stoichiometric and catalytic transition metal species such as 3-alkylidene metallacyclobutanones and acrylyl metal complexes will be probed in a search for highly convergent new methods of cyclopentenone and alkylidene cyclopentenone synthesis.
NIH ExPorter
NIH ExPorter