TANDEM EPOXIDE-OLEFIN CYCLIZATION-PINACOL REARRANGEMENT

本提案概述了环氧化物-烯烃环化-蒎烯重排串联的发展。在路易斯酸的作用下，该反应将含有三甲基硅氧基、烯基和环氧取代基的单环烷烃转化为顺式双环烷烃。各种环烷烃环尺寸、烯基取代基和环氧化物将加入到反应底物中，并将注意到这些变量对反应的设施、立体选择性和区域选择性的影响。例如，在环氧化物的末端加入阳离子稳定功能应该会导致环化模式从外端切换到内端。将探讨的反应的另一种变化是使用乙烯基硅烷作为烯基取代基。这将导致在反应产物中存在碳硅键，它可以被氧化成醇。总的来说，这些研究将提供一种有效的方法，可预测地产生各种高取代的双环产品。由于这些产物中的一些可能具有生物活性或可能是产生具有生物学意义的化合物的中间体，因此该过程无疑将在医学研究中得到广泛应用。环氧烷-烯烃环化-蒎醇重排的实用性在一个从未在实验室合成过的天然产物修饰的二萜类克鲁烯D的全合成中得到了证明。

This proposal outlines the development of a tandem epoxide-olefin cyclization-pinacol rearrangement. This reaction will convert monocyclic alkanes bearing trimethylsilyloxy, alkenyl, and epoxy substituents into cis-bicyclic alkanones by the action of a Lewis acid. A variety of cycloalkane ring sizes, alkenyl substituents, and epoxides will be incorporated into the reaction substrates, and the effects that each of these variables has on the facility, stereoselectivity, and regioselectivity of the reaction will be noted. For example, incorporating cation-stabilizing functionality at the terminus of the epoxide should cause the mode of cyclization to switch from exo to endo. Another variation of the reaction that will be explored is the use of a vinylsilane as the alkenyl substituent. This would result in the presence of a carbon-silicon bond in the reaction product, which can be oxidized to an alcohol. Collectively, these studies will provide an effective method of predictably generating a wide variety of highly substituted bicyclic products. As several of these products are likely to either have biological activity or be intermediates leading to biologically significant compounds, this process will doubtless find wide application in medicinal research. The utility of the tandem epoxide-olefin cyclization- pinacol rearrangement is demonstrated in a proposed total synthesis of the modified labdane diterpenoid cluytene D, a natural product which has never been synthesized in the laboratory.