TOTAL SYNTHESIS OF FORSKOLIN

拟议研究的主要目标是制定一项 经济和化学上新颖的毛喉素及其相关化合物的全合成 具有生物医学意义的化合物。 毛喉素是主要的（0.1%干重）。印第安人的生物活性成分 药用植物毛喉鞘蕊花，并显示抗高血压和 支气管痉挛活性，防止血小板聚集，降低 眼内压，并促进感觉神经再生。 这些 这些作用源于化合物刺激腺苷酸环化酶的能力， 一种尚未完全理解的机制。 因此，毛喉素样化合物具有 在治疗青光眼，心血管疾病， 和哮喘。 目标的碳环框架的构建计划 不采用通常的Diels-Alder方法，而是依赖于 内部迈克尔加成-羟醛缩合策略涉及的小 研究了3-羟基-2（5 H）-呋喃酮体系。 计划的另一个特色是 通过以下途径立体定向合成目标吡喃酮环的计划： 几何约束的羟基烯烃环化。 毛喉素与腺苷酸环化酶的相互作用的性质还没有 目前已阐明;本研究中产生的化合物将 适用于放射性、荧光和光亲和标记， 对这种互动的理解。 此外，类似物 生产的产品将可用于生物学评价， 毛喉素样化合物的潜力可以更充分地确定。

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.