The principal objective of the proposed research is to develop an economical and chemically novel total synthesis of forskolin and related compounds of biomedical interest. Forskolin is the major (0.1% dry wt.) bioactive constituent of the INdian medicinal plant Coleus forskohlii, and displays antihypertensive and bronchospasmolytic activity, prevents platelet aggregation, lowers intraocular pressure, and promotes sensory nerve regeneration. These effects stem from the compounds ability to stimulate adenylate cyclase via a mechanism not fully understood. Forskolin-like compounds therefore have clinical potential in the treatment of glaucoma, cardiovascular disease, and asthma. The plan for the construction of the carbocyclic framework of the target does not employ the usual Diels-Alder methodology, but relies on an internal Michael addition-aldol condensation strategy involving the little studied 3-hydroxy-2(5H)-furanone system. Also featured in the scheme is a plan for a stereospecific synthesis of the pyranone ring of the target via a geometrically constrained hydroxyolefin cyclization. The nature of the interaction of forskolin with adenylate cyclase has not been elucidated at this time; compounds generated in this study will be suitable for radio, fluorescent, and photoaffinity labelling which may aid in the understanding of this interaction. In addition, the analogs produced will be available for biological evaluation so that the clinical potential of forskolin-like compounds may be more fully defined.
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