Total Synthesis of Highly Oxygenated Icetexane Diterpenoids

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DESCRIPTION (provided by applicant): The development of new strategies and methods for the total synthesis of biologically active natural products and medicinally important compounds are important for the study of general medicine. By building complex molecules, we gain access to significant quantities of natural products with biological activity for further testing. In addition, we gain the ability to access analogs of these compounds in an attempt to improve bioactivity. The focus of the research is the development and utilization of a new cycloisomerization reaction or the synthesis of seven-membered rings and its application to the total synthesis of a biologically important family of natural products. Specifically, this project focuses on A) the use of gallium salts, which are cheaper and less toxic than other commonly used cycloisomerization metal catalysts, to activate alkynes in the isomerization of indene intermediates to form seven-membered rings as well as, B) the utilization of this methodology in the total synthesis of natural products with biological activity. This methodology can be applied to the total synthesis of the icetexane natural products, isolated from various members belonging to the Salvia genus. The members of this family have been shown to exhibit interesting biological activities. For example, komaroviquinone, isolated from Dracocephalum komarovi, shows trypanocidal activity against the infectious form of Trypanosoma cruzi, the causative agent for Chagas' disease. Another important bioactivity displayed by komaroviquinone is inhibition of the chemokine receptor CCR5, which plays a vital role in HIV infection. Inhibition of CCR5 could lead to a general method for curbing infection. Icetexone, anastomosine, and dihydroanastomosine are three compounds in this family that have yet to be synthesized. They differ from other members in the family through the inclusion of an additional 5- membered lactone ring. The bioactivity of these compounds has not been fully studied; however, preliminary accounts suggest that the C5 epimer of icetexone displays trypanocidal activity comparable to that found in komaroviquinone. The study of methodology and total synthesis benefits public health by allowing for the synthesis of molecules that can lead to more effective treatments for common diseases, such as Chagas' disease. These studies can also lead to the synthesis of analogs of molecules that may improve on current treatments of disease.